Pyridazines as SARM1 inhibitors

Abstract

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

Description

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

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

[0003] Sterile Alpha and Toll / Interleukin receptor-1 (TIR) motif-containing 1 (SARM1) has been identified as a central executor of the injury-induced axonal death pathway known as Wallerian degeneration (O'Neill, L.A. & Bowie, A.G., Nat. Rev. Immunol., 2007, 7, 353-364; Osterloh, J.M. et al., Science, 2012, 337, 481-484; Gerdts, J. et al., J. Neurosci. 33, 2013, 13569-13580). Mechanistic studies have revealed that activation of SARM1 via axonal injury or forced dimerization of the SARM1-TIR domain promotes rapid depletion of nicotinamide adenine dinucleotide (NAD+), leading to axonal degeneration (Gerdts, J. et al., Science, 2015, 348, 453-457). Genetic knockout of SARM1 allows for the preservation of axons for 14 days or more after nerve transection (Osterloh, J.M. et al., Science, 2012, 337, 481-484; Gerdts, J. et al., J. Neurosci., 2013, 33, 13569-13580) and improves functional outcomes after traumatic brain injury in mice (Henninger, N. et al., Brain 139, 2016, 1094-1105). In addition to the role of SARM1 in direct axonal injury, SARM1 has been observed to be necessary for axonal degeneration in conditions such as chemotherapy-induced peripheral neuropathy. Deletion of SARM1 blocks chemotherapy-induced peripheral neuropathy, both inhibiting axonal degeneration and increased pain sensitivity that develops after chemotherapy with vincristine treatment (Geisler et al., Brain, 2016, 139, 3092-3108).

[0004] WO 2021 / 142006 A1 and WO 2022 / 046606 A1 disclose certain compounds and methods useful for inhibiting SARM1 and / or treating and / or preventing axonal degeneration.

[0005] There are currently no approved drugs for the treatment and / or prevention of axonal degeneration. The need for potent SARM1 inhibitors with improved metabolic profile for the treatment and prevention of pathological conditions involving axonal degeneration has not been met.

[0006] The present invention provides novel SARM1 inhibitors for the treatment and prevention of pathological conditions involving axonal degeneration. Furthermore, the present invention provides novel SARM1 inhibitors with improved potency and subject to reduced metabolic clearance.

[0007] Accordingly, the present invention provides a compound of Formula III:

[0008]

[0009] wherein

[0010] X is N and Y is CH, or X is CH and Y is N;

[0011] R 5 is selected from hydrogen, halogen, -NH2, -OC 1-3 alkyl and C 1-3 alkyl optionally substituted with 1-3 halogen atoms, -OH or -OCH3, C

[0012] when R 5 is hydrogen, then ring A is selected from: and

[0013] when R 5 is selected from halogen, -NH2, -OC 1-3 alkyl and C 1-3 alkyl optionally substituted with 1-3 halogen atoms, -OH or -OCH3, C

[0014] R 1 and R 2 together with the atoms to which they are attached form a 5- to 6- membered saturated heterocyclic ring, wherein one of the carbon atoms is optionally replaced with a heteroatom selected from oxygen and nitrogen, and wherein one of the carbon atoms is optionally substituted with cyano, -OR d or C 1-3 alkyl.​​​​​​1-3 alkyl is optionally substituted with -NH2or -OR d substituted;

[0015] R 3 is selected from hydrogen and C 1-4 alkyl;

[0016] R 4 is selected from phenyl optionally substituted with 1 to 3 R b heteroatoms selected from oxygen, nitrogen, and sulfur and optionally substituted with 1 to 3 R b heteroatoms selected from oxygen, nitrogen, and sulfur and optionally substituted with 1 to 3 R b 9- to 10-membered fully or partially aromatic bicyclic heteroaryl;

[0017] each R a is independently selected from hydrogen, halogen, cyano, and C d alkyl optionally substituted with halogen, -OR 1-4 , -NH2, or cyano; and

[0018] each R b is independently selected from halogen, cyano, C 1-4 alkyl, -NH2, -OH, monohalomethyl, dihalomethyl, trihalomethyl, and -OC 1-4 alkyl; and

[0019] R c is selected from halogen, cyano, -OC e alkyl optionally substituted with R 1-3 , -OR d , -NH2, or cyano; and 1-4 alkyl; and

[0020] R d is selected from hydrogen, C 1-4 alkyl, and -CH2OP(O)(OH)2;

[0021] R e is selected from

[0022] or a pharmaceutically acceptable salt thereof.

[0023] In one embodiment of the application, X is N and Y is CH.

[0024] In another embodiment, R 5 is hydrogen, and ring A is selected from: substituted with -CH2OP(O)(OH)2at one nitrogen atom optionally substituted at a nitrogen atom with -CH2OP(O)(OH)2 optionally substituted at a nitrogen atom with -CH2OP(O)(OH)2

[0025] In another embodiment, R 5 is selected from halogen, -NH2, -OC 1-3 alkyl and C 1-3 alkyl, and ring A is selected from: optionally substituted at a nitrogen atom with -CH2OP(O)(OH)2 optionally substituted at a nitrogen atom with -CH2OP(O)(OH)2 optionally substituted at a nitrogen atom with -CH2OP(O)(OH)2 optionally substituted at a nitrogen atom with -CH2OP(O)(OH)2

[0026] In another embodiment, R 5 is selected from -CH3, -CH2OH, -NH2, -CH2F and -OCH3.

[0027] In one embodiment, the compound is of Formula IIIa:

[0028]

[0029] wherein B is selected from O, NH, C-R 6 , wherein R 6 is selected from hydrogen, cyano, -OC 1-3 alkyl, or C d substituted with -NH2or -OR 1-3 alkyl, R 7 and R 8 are independently selected from hydrogen and -OH, and n is 0 or 1. In another embodiment, the compound is of Formula IIIa(i):

[0030]

[0031] wherein n is 0 or 1.

[0032] In another embodiment, the compound is selected from one of Formulae IIIa(ii) to IIIa(xii):

[0033]

[0034] In another embodiment, R 3 is hydrogen.

[0035] In one embodiment, ring A is selected from those optionally substituted with -CH2OP(O)(OH)2 at a nitrogen atom. The nitrogen atom may be optionally replaced by -CH2OP(O)(OH)2. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2. And each R a It is independently selected from hydrogen, cyano, -CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CN, -OCH3, -F and -Cl.

[0036] In another embodiment, ring A is optionally substituted with -CH2OP(O)(OH)2 at a nitrogen atom. And R c Selected from cyano, -CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CN, -OCH3, -F, -Cl,

[0037] In another implementation, R 4 Selected from 1 to 3 Rs b Substituted phenyl groups and heteroatoms containing 1 to 3 selected oxygen, nitrogen, and sulfur atoms, optionally surrounded by 1 to 3 R atoms. b Substituted 5- to 6-membered heteroaryl. In one embodiment, R 4 To be arbitrarily selected by 1 to 3 R b Substituted phenyl. In another embodiment, R 4 It contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and is optionally surrounded by 1 to 3 R atoms. b Substituted 5- to 6-membered heteroaryl groups. In another embodiment, R 4 To be arbitrarily selected by 1 to 3 R b Substituted pyridine. In one embodiment, R 4 Selected from:

[0038] In one implementation, R 4 By 1 to 3 R b Replace, and each R b Independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, and fluoromethyl. In another embodiment, R 4 Selected from:

[0039]

[0040]

[0041] The present invention further provides a compound of formula IV:

[0042]

[0043] in

[0044] X is N and Y is CH, or X is CH and Y is N;

[0045] R 5 Selected from hydrogen and -CH3, optionally substituted with -OH, -NH2, or 1-3 halogen atoms, wherein:

[0046] When R 5 C is optionally substituted with -OH, -NH2 or 1-3 halogen atoms. 1-3 When alkyl, ring A is selected from those optionally substituted with -CH2OP(O)(OH)2 at a nitrogen atom. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2.

[0047] When R 5 When it is hydrogen, then ring A comes from: a nitrogen atom optionally substituted with -CH2OP(O)(OH)2.

[0048] R 1 R 2 and R 3 Each is independently selected from hydrogen and C. 1-4 Alkyl, wherein R 2 and R 3 Together with the atoms they are attached to, they can optionally form 3- to 6-membered saturated carbon rings;

[0049] R 4 Selected from 1 to 3 Rs b The substituted phenyl group contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and is optionally surrounded by 1 to 3 R atoms. b The substituted 5- to 6-membered heteroaryl group contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and is optionally surrounded by 1 to 3 R atoms. b Substituted 9- to 10-membered fully or partially aromatic bicyclic heteroaryl groups;

[0050] R a Selected from hydrogen, halogen, cyano and C 1-4 alkyl;

[0051] Each R bindependently selected from halogen, cyano, -OH, -NH2, C 1-4 alkyl, monohalomethyl, dihalomethyl, trihalomethyl, and -OC 1-4 alkyl;

[0052] R c selected from -OR d or R e substituted -OC 1-3 alkyl, and -OR d or 1-3 halogen atoms; and 1-4 alkyl; and

[0053] R d selected from H, -CH3, -CF3, -CHF2, and -CH2OP(O)(OH)2; and

[0054] R e selected from

[0055] or a pharmaceutically acceptable salt thereof.

[0056] In one embodiment of the application, X is N and Y is CH.

[0057] In another embodiment, R 5 is C 1-3 alkyl optionally substituted with -OH, -NH2, or 1-3 halogen atoms, and ring A is selected from: optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2 In one embodiment, R 5 is selected from -CH3, CH2OH, CH2F, and ring A is selected from: optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2

[0058] In another embodiment, R 5 is hydrogen, and ring A is

[0059] In another embodiment, R 1 , R 2 , and R 3 are all hydrogen.

[0060] In one embodiment, ring A is selected from:

[0057] optionally substituted at one nitrogen atom with -CH2OP(O)(OH)2 and R a is selected from hydrogen, cyano, and -CH3.

[0061] In one embodiment, ring A is and R c is selected from -OCH3, -CH2OCH3, -CH2CH2OCH3, -OCH2CH2OH, -OCH2CH2OCH3, -OCH2CH2OCHF2, -CH2CH2OCH2OP(O)(OH)2,

[0062] In another embodiment, R 4 is selected from phenyl optionally substituted with 1 to 3 R b substituted with 1 to 3 R b In one embodiment, R 4 is phenyl optionally substituted with 1 to 3 R b In another embodiment, R 4 is a 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1 to 3 R b In another embodiment, R 4 is pyridine optionally substituted with 1 to 3 R b In one embodiment, R 4 is selected from:

[0063] In one embodiment, R 4 is substituted with 1 to 3 R b and each R b is independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl, and fluoromethyl. In another embodiment, R 4 is selected from:

[0064]

[0065] The present application also provides a compound of Formula I:

[0066]

[0067] wherein

[0068] X is N and Y is CH, or X is CH and Y is N;

[0069] ring A is selected from ring A is selected from

[0070] R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen and C 1-4 alkyl, wherein R 1 and R 2 together with the atoms to which they are attached can optionally form a 5- to 6- membered saturated heterocyclic ring, wherein one of the carbon atoms is optionally replaced by a heteroatom selected from the group consisting of oxygen and nitrogen, or wherein R 2 and R 3 together with the atoms to which they are attached can optionally form a 3- to 6- membered saturated carbocyclic ring;

[0071] R 4 is selected from the group consisting of phenyl optionally substituted with 1 to 3 R b and 5- to 6- membered heteroaryl containing 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 R b ;

[0072] R a is selected from the group consisting of hydrogen, halogen, cyano and C 1-4 alkyl optionally substituted with halogen, -OH, -NH2or cyano;

[0073] each R b is independently selected from the group consisting of halogen, cyano, C 1-4 alkyl, trihalomethyl and -OC 1-4 alkyl,

[0074] or a pharmaceutically acceptable salt thereof.

[0075] In one embodiment of the present application, X is N and Y is CH. In a separate embodiment, X is CH and Y is N.

[0076] In one embodiment of the present application, R 1 is hydrogen. In another embodiment, R 2 is hydrogen. In another embodiment, R 3 is hydrogen. In one embodiment, R 1 , R 2 and R 3 are hydrogen. In another embodiment, R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen and C 1-4 alkyl, wherein R 1 and R 2 together with the atoms to which they are attached can optionally form a 5- to 6- membered saturated heterocyclic ring, wherein one of the carbon atoms is optionally replaced by a heteroatom selected from the group consisting of oxygen and nitrogen, or wherein R 2 and R 3together with the atom to which they are attached can optionally form a 3- to 6- membered saturated carbocyclic ring.

[0077] In another embodiment, the compound is of Formula II:

[0078]

[0079] wherein X, Y, ring A, and R 4 as defined above and Z is selected from CH2, O, NH, or a bond. In one embodiment, Z is CH2. In another embodiment, Z is O. In an alternative embodiment, Z is NH. In another embodiment, Z is a bond. In another embodiment, the compound is selected from Formula Ila and Formula lib:

[0080]

[0081] wherein X, Y, ring A, Z, and R 4 as defined above.

[0082] In another embodiment of the application, R a is selected from hydrogen, cyano, and C 1-4 alkyl. In one embodiment, R a is hydrogen. In one embodiment, R a is methyl. In another embodiment, R a is cyano.

[0083] In one embodiment of the application, ring A is selected from

[0084] In one embodiment of the application, each R b is selected from halogen and cyano. In another embodiment, each R b is halogen. In yet another embodiment, each R b is selected from fluorine, chlorine, and bromine.

[0085] In another embodiment of the application, R 4 is selected from

[0086] In another embodiment, R 4 is selected from

[0087] In one embodiment of the application, the compound is selected from

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105] or a pharmaceutically acceptable salt thereof.

[0106] The present application provides a pharmaceutical composition 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.

[0107] The present application provides a method of treating or preventing a disease associated with axonal degeneration in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0108] The present application also provides a method of treating or preventing a disease associated with SARM1 activation in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound according to any of the above embodiments, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0109] The present application also provides a method of treating or preventing a disease selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy, and chemotherapy-induced peripheral neuropathy in a patient comprising administering to a patient in need of such treatment an effective amount of a compound of any one of the above embodiments, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.

[0110] The present application provides a compound of any one of the above embodiments, or a pharmaceutically acceptable salt thereof, for use in therapy.

[0111] Further, the present application provides a compound of 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.

[0112] Further, the present application provides a compound of 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.

[0113] The present application provides the use of a compound of 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.

[0114] Further, the present application provides the use of a compound of 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.

[0115] As used herein, the term "alkyl," used alone or as part of a larger moiety, refers to a saturated, straight-chain or branched hydrocarbon group containing one or more carbon atoms.

[0116] As used herein, the term "bicyclic heteroaryl" refers to a chemical group in which two rings, at least one of which is a heterocyclic or heteroaromatic ring, are joined together.

[0117] As used herein, the term "carbocyclic" refers to a cyclic saturated group containing only carbon atoms.

[0118] As used herein, the term "heteroaryl" refers to a cyclic aromatic group containing one or more heteroatoms.

[0119] 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.

[0120] As used herein, the term "heterocycle" refers to a cyclic saturated group containing carbon atoms and one or more heteroatoms.

[0121] As used herein, the term "patient" refers to a human.

[0122] As used herein, the term "prevent" refers to preventing the onset of a disease or avoiding complications resulting therefrom after its onset.

[0123] As used herein, the term "treat" includes slowing, halting, or reversing the progression or severity of an existing symptom or disorder.

[0124] As used herein, the term "effective amount" refers to an amount or dose of a compound of the present application, or a pharmaceutically acceptable salt thereof, administered to a patient, either singly or in multiple doses, that provides a desired effect in the patient under diagnosis or treatment.

[0125] The compounds of the present application are preferably formulated into pharmaceutical compositions for administration by any route that makes the compound bioavailable, including oral and transdermal routes. Most preferably, such compositions are for oral administration. Such pharmaceutical compositions and methods for their preparation are well known in the art (see, e.g., Remington: The Science and Practice of Pharmacy, A. Adejare, Editor, 23rd Edition, Elsevier Academic Press, 2020).

[0126] Several compounds of the present application contain a 5-membered nitrogen heteroaromatic ring that can exist in several tautomeric forms. For 1,2,4-triazole rings, there are three possible tautomeric forms:

[0127]

[0128] For pyrazole and imidazole rings, there are two possible tautomeric forms:

[0129]

[0130] These tautomeric forms are intended to be encompassed by the present disclosure and claims. When substituted at one nitrogen atom with -CH2OP(O)(OH)2, the aforementioned 5-membered nitrogen heteroaromatic rings can be in any of the following forms:

[0131]

[0132] It is understood that the present application contemplates all individual enantiomers and diastereomers, as well as mixtures of enantiomers and / or diastereomers, including racemates of the formulas, substituents, fragments, and compounds described herein.

[0133] The compounds of the application, or pharmaceutically acceptable salts thereof, can be prepared according to the following Preparations and Examples by methods well known and appreciated in the art. Suitable reaction conditions for the steps of these Preparations and Examples are well known in the art, and appropriate substitutions of solvents and co-reagents are within the skill of the art. Likewise, those skilled in the art will appreciate that synthetic intermediates can be isolated and / or purified by various well-known techniques as needed or desired, and often various intermediates will be used directly in subsequent synthetic steps with little or no purification. By way of illustration, compounds of the Preparations and Examples can be isolated, for example, by purification on silica gel, by filtration, or by crystallization directly. Further, those skilled in the art will appreciate that in some cases, the order in which moieties are introduced is not important. The particular sequence of steps needed to produce the compounds of the application depends on the particular compound being synthesized, the starting compound, and the relative liability of the substituted moieties, and is well understood by the skilled chemist. Unless otherwise indicated, all substituents are as previously defined, and all reagents are well known and appreciated in the art.

[0134] Certain abbreviations are defined below: "ACN" means acetonitrile; "AcOH" means acetic acid; "Aib" means 2-aminoisobutyric acid; "n-BuLi" means n-butyllithium; "t-BuOH" means tert-butanol; "t-BuOK" means potassium tert-butoxide; "t-BuONa" means sodium tert-butoxide; "Boc2O" means di-tert-butyl dicarbonate; "DABCO" means 1,4-diazabicyclo[2.2.2]octane; "DAST" means (diethylamino)sulfur trifluoride; "DBU" means 1,8-diazabicyclo[5.4.0]undec-7-ene; "DCM" means dichloromethane; "DIPEA" or "DIEA" means N,N-diisopropylethylamine; "DMA" means dimethylacetamide; "DMAc" means dimethylacetamide; "DMF" means dimethylformamide; "DMAP" means 4-dimethylaminopyridine; "DMSO" means dimethyl sulfoxide; "DPPA" means diphenyl phosphoryl azide; "ee" means enantiomeric excess; "Et3N" or "TEA" means triethylamine; "EtOAc" means ethyl acetate; "EtOH" means ethanol; "Et3SiH" means triethylsilane; "HATU" means (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; "HFIP" means hexafluoroisopropanol; "HPLC" means high performance liquid chromatography; "hr." or "hrs." means hour(s)."hour(s)" means one or more hours; "IPA" means isopropyl alcohol; "KOAc" means potassium acetate; "LDA" means lithium diisopropylamide; "LiHMDS" means lithium bis(trimethylsilyl)amide; "MeI" means methyl iodide; "MeOH" means methanol; "NaBH3CN" means sodium cyanoborohydride; "NaHMDS" means sodium bis(trimethylsilyl)amide solution; "NBS" means N-bromosuccinimide; "NCS" means N-chlorosuccinimide; "NIS" means N-iodosuccinimide; "min" means minute or minutes; "Pd(dppf)Cl2" means (1,1'bis(diphenylphosphino) ferrocene)dichloropalladium-dichloromethane; "Pd(PPh3)4" means tetrakis(triphenylphosphine)palladium(0); "Pd2(dba)3" means tris(dibenzylideneacetone)dipalladium(0); "Pd(t-Bu3P)2" means bis(tri-tert-butylphosphine)palladium(0); "Pd(OAc)2" means palladium(II) acetate; "PMB-Cl" means 4-methoxybenzyl chloride; "Prep-HPLC" means preparative HPLC; "SEM-Cl" means 2-(trimethylsilyl)ethoxymethyl chloride; "SFC" means supercritical fluid chromatography; "TBAF" means tetra-n-butylammonium fluoride; "TBDPS" means tert-butyldiphenylsilyl; "TBHP" means tert-butyl hydroperoxide; "TBTU" means 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate; "TFA" means trifluoroacetic acid; "THF" means tetrahydrofuran; and "T3P" means propanephosphonic acid anhydride; "XPhos" means dicyclohexyl[2',4',6'-tris(propan-2-yl)[1,1'-biphenyl]-2-yl]phosphine.

[0135] Scheme 1

[0136] In the following schemes, R z is alkyl, such as methyl, or hydrogen; Ar is aryl or heteroaryl; and X is N or C.

[0137]

[0138] Scheme 1, step A depicts formation of compound (2) from compound (1) using propiononitrile as the reagent in a solvent such as THF using a base such as LiHMDS. Step B shows cyclization of compound (2) using EtOH and hydrazine hydrate solution and a base such as Na2C03 in a solvent such as AcOH to give compound (3). Step C shows addition of (4-methoxybenzyl)hydrazine hydrochloride to compound (3) using an acid such as AcOH in a solvent such as EtOH to give compound (4). Step D depicts amide coupling of compound (4) with an aryl propionic acid in a solvent such as DMA using a coupling reagent such as HATU and a base such as DIPEA to give compound (5). One skilled in the art will recognize that many other amide coupling reagents, bases, and solvents can be used to perform this coupling. Step E depicts acidic deprotection of compound (5) with an acid such as TFA in a solvent such as DCM to give compound (6).

[0139] Scheme 2

[0140]

[0141] Scheme 2, step A depicts formation of compound (9) from compound (8) by addition of hydrazine hydrate solution in a solvent such as EtOH. Step B shows addition of methyl carbamimidothioate sulfate, hydrazine hydrate solution to compound (9) using a base such as NaOH to form compound (10). Step C shows intramolecular cyclization of compound (10) to compound (11) by use of a base such as NaOH. Step D depicts coupling of compound (11) with bromopentanoic acid in a solvent such as DMA using a coupling reagent such as TBTU and a base such as DIPEA to give compound (12). One skilled in the art will recognize that many other amide coupling reagents, bases, and solvents can be used to perform this coupling. Step E shows a two-step reaction in which compound (12) is subjected to acyl migration followed by intramolecular cyclization under favorable 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 give compound (13) with the nitrogen in the triazole protected by SEM. Step F shows reaction of compound (13) with an aryl bromide compound such as l-(bromomethyl)-4-fluorobenzene using a base such as LiHMDS and a solvent such as THF to form compound (14). Step G depicts acidic deprotection of compound (14) with an acid such as TFA in a solvent such as DCM to give compound (15).

[0142] Scheme 3

[0143]

[0144] Scheme 3, step A depicts the conversion of compound (16) to compound (17) via a Curtius rearrangement using DPPA and a base such as Et3N in a solvent such as t-butanol. Step B shows a Suzuki coupling between compound (17) and methylboronic acid using a catalyst such as Pd(dppf)Cl2and a base such as potassium carbonate in a solvent system such as dioxane and water to give compound (18). Those skilled in the art will recognize that there are many catalyst, ligand, base, and solvent combinations that can be used to perform such a coupling. Step C shows the conversion of compound (18) to compound (19) using a catalyst system comprising Ph3P and Pd(OAc)2, Et3SiH as a reducing agent, and Et3N as a base. Step D depicts the deprotection of compound (19) using an acid such as HC1 in a solvent system such as dioxane and DCM to give compound (20). Step E shows the bromination of compound (20) using CuBr2and a reagent such as tert-butyl nitrite in a solvent such as ACN to form compound (21). Step F shows the coupling of compound (21) with tert-butyl N-(lH-pyrazol-4-yl)carbamate using a catalyst system such as CuI and N,N'-dimethyl-l,2-cyclohexanediamine and a base such as K3PO4to form compound (22). Step G shows the acidic deprotection of compound (22) with an acid such as HC1 in a solvent such as DCM and dioxane to give compound (23). Step H shows the amide coupling of compound (23) with an arylpropionic acid using a coupling reagent 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 reagents, bases, and solvents can be used to perform this coupling.

[0145] Scheme 4

[0146]

[0147] Scheme 4, step A depicts the formation of a Weinreb amide from compound (25) using N, O-dimethylhydroxylamine hydrochloride in a solvent (such as THF) containing a base (such as LiHMDS) to give compound (26). Step B shows the addition of EtOAc to compound (26) using a base (such as LDA) in a solvent (such as THF) to give compound (27). Step C shows the addition of trichloroacetonitrile to compound (27) using a base (such as sodium acetate trihydrate) in a solvent (such as EtOH) to give compound (28). Step D depicts the cyclization of compound (28) with (4-methoxybenzyl)hydrazine hydrochloride using a base (such as Et3N) in a solvent (such as EtOH) to give compound (29). Step E shows the basic hydrolysis of compound (29) using NaOH in a solvent system (such as THF, EtOH, and water) to give compound (30). Step F shows the amide coupling of compound (30) with ammonium chloride using a coupling reagent (such as HATU) and a base (such as DIPEA) in a solvent (such as DMF) to give compound (31). Those skilled in the art will recognize that many other amide coupling reagents, bases, and solvents can be used to perform this coupling. Step G shows the amide coupling of compound (31) with an arylpropionic acid using a coupling reagent (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 reagents, bases, and solvents can be used to perform this coupling. Step H depicts the acidic deprotection of compound (32) with an acid (such as TFA) in a solvent (such as DCM) to give compound (33). Step I shows the dehydration of compound (33) using the Burgess reagent (methyl N-(triethylammonium sulfonyl)carbamate) and a solvent (such as DMF) to give compound (34).

[0148] Scheme 5

[0149]

[0150] Scheme 5, step A depicts the conversion of compound (35) to compound (36) by the addition of an aryl bromide compound such as 4-(bromomethyl)-l-chloro-2-fluorobenzene to compound (35) using a strong base such as NaHMDS and a solvent such as THF. Step B shows the deprotection of compound (36) using HF.Et3N in a solvent such as THF to give compound (37). Step C depicts the oxidation of compound (37) using the Dess-Martin reagent in a solvent such as DCM to give compound (38). Step D shows the reduction of compound (38) using NaBH3CN and amine coupling with an amine such as 3-(5-methylpyridazin-4-yl)-lH-l,2,4-triazol-5-amine in AcOH and MeOH as solvents to give compound (39). Step E depicts the conversion of compound (39) to compound (40) using H2O2 and a base such as LiOH.H2O in a solvent such as THF. Step F shows the intramolecular cyclization of compound (40) to compound (41) by using a coupling reagent such as T3P, a base such as DIPEA in a solvent such as DMA. Alternatively, step G is the intramolecular cyclization of compound (39) to compound (42) by using a base such as LiOH.H2O in a solvent system such as H2O2, water and THF.

[0151] Scheme 6

[0152]

[0153] Scheme 6, step A depicts the reaction of compound (42a) with hydrazine hydrate and an acid (such as AcOH), followed by the reaction of the intermediate with sodium nitrite to give compound (42b). Step B shows the reaction of compound (42b) with tributyl(prop-1-yn-1-yl)stannane in a solvent (such as toluene) to form compound (42c). Step C depicts the protection of compound (42d) with SEM-Cl using a base (such as NaH) in a solvent (such as DMF) to give compound (43). Step D shows the protection of compound (42e) with Boc20 using a base (such as DMAP) in a solvent (such as DCM) to form compound (42f). Step E depicts the reaction of compound (42f) with an aryl bromide compound using a base (such as LDA) in a solvent (such as THF) to give compound (42g). Step F shows the acidic deprotection of compound (42g) with an acid (such as HC1) in a solvent (such as dioxane) to form compound (42h). Step G depicts the Stille coupling of compound (43) with compound (42c) in a catalyst system (such as Pd(PPh3)4and CuI) in a solvent (such as DMF) to give compound (44). Step H shows the coupling of compound (44) with compound (42h) in a catalyst system (such as CuI and N,N'-dimethyl-1,2-cyclohexanediamine) and a base (such as K3PO4) to form compound (45). Step I shows the acidic deprotection of compound (45) with an acid (such as TFA) in a solvent (such as DCM) to give compound (46).

[0154] Scheme 7

[0155]

[0156] Scheme 7, step A depicts the conversion of compound (47) to compound (48) using a strong base (such as LDA) in a solvent (such as THF) by the addition of 6-fluoro-nicotinaldehyde. Step B shows the reduction of compound (48) to compound (49) using Pd / C in the presence of H2gas in a solvent (such as EtOH). Step C depicts 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 reagent (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 recognize that many other amide coupling reagents, bases, and solvents can be used to perform this coupling. Step D shows the conversion of compound (50) to compound (51) by a two-step reaction involving acyl transfer followed by intramolecular cyclization using a base (such as t-BuOK) in a solvent (such as DMF).

[0157] Scheme 8

[0158] In the following scheme, when n = 1, R 6 is H, OTBDPS or OH; when n = 0, R 6 is H; Ar is aryl; Z is CH, N or C-R c .

[0159]

[0160] Scheme 8, step A depicts the protection of compound (52) with SEM-Cl using a base such as NaH in a solvent such as ACN to give compound (53). Step B shows an amide coupling of compound (53) with an acid chloride (54) using a base such as TEA or pyridine in a solvent such as ACN, DCM to form compound (55). Step C depicts the conversion of compound (55) to compound (58) by using a base such as t-BuOK or K2CO3 in a solvent such as ACN.

[0161] Alternatively, compound (58) can be prepared by the reaction as shown in step D, which shows the protection of 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 the oxidation of compound (57) using a reagent such as RuCl3.H2O and NaClO in a solvent such as EtOAc to form compound (58).

[0162] Step F shows the reaction of compound (58) with an aryl bromide compound using a base such as LiHMDS or LDA in a solvent such as THF to give compound (59). Optionally, R 6Step G depicts a Stille coupling of compound (59) with stannous pyridazine compound in a solvent such as dioxane, in a catalyst system such as Pd(tBu3P)2 and CsF or Pd(PPh3)4 to form compound (60). Alternatively, compound (59) can be coupled with bis(pinacolato)diboron in a solvent such as dioxane using a catalyst such as Pd(dppf)Cl2 and a base such as KOAc. The boronate intermediate is then coupled with a pyridazine compound in a solvent such as dioxane, in a catalyst system such as Pd(dppf)Cl2 and a base such as K2CO3 to give compound (60). Step H shows acidic deprotection of compound (60) with an acid such as TFA or a mixture of TFA and triflic acid in a solvent such as DCM to give compound (61). Step I depicts reaction of compound (61) with di-tert-butyl (chloromethyl)phosphonate using a base such as Cs2CO3 or CsF in a solvent such as DMF to form isomeric compounds (62) and (63). Step J shows acidic deprotection of compounds (62) and (63) with an acid such as TFA or AcOH in a solvent such as DCM or H2O to give compounds (64) and (65).

[0163] Scheme 9

[0164]

[0165] Step A of Scheme 9 depicts coupling of compound (66) with (67) using a base such as K2CO3 in a solvent such as ACN to give compound (68). Step B shows dechlorination of compound (68) in a solvent such as EtOH, in a catalyst system such as Pd(OAc)2, PPh3 and Et3SiH and a base such as TEA to form compound (69). Step C depicts saponification of compound (69) using a base such as LiOH in a solvent such as THF and H2O to give compound (70). Step D shows reaction of compound (70) with DPPA using a base such as DiPEA in a solvent such as t-BuOH and dioxane to form compound (71). Step E depicts acidic deprotection of compound (71) using an acid such as HFIP to give compound (72). Step F shows amide coupling of compound (72) with (73) using a coupling reagent such as POCl3 in a solvent such as pyridine to form compound (74). Step G depicts cyclization of compound (74) using a base such as K2CO3 in a solvent such as ACN to produce compound (75).

[0166] Scheme 10

[0167] In the following scheme, R a is H or CI.

[0168]

[0169] Scheme 10, step A depicts a chlorination reaction of compound (76) using sulfuryl chloride in a solvent such as DCM to give compound (77). Step B shows a transformation of compound (77) to ester (78) using a base such as NaOH in a solvent such as MeOH. Step C depicts a bromination of compound (78) using bromine in an acid such as AcOH to form compound (79). Step D shows a coupling of compound (79) with (80) using a base such as K3PO4 in a solvent such as DMF in a catalyst system such as CuI and N,N'-dimethyl-1,2-cyclohexanediamine to give compound (81). Step E depicts a bromination of compound (81) using NBS in a solvent such as DCM to form compound (82). Step F shows a protection reaction of compound (82) with SEM-Cl using a base such as NaH in a solvent such as THF to give compound (83). Step G depicts a Stille coupling of compound (83) with a pyridazine stannane compound in a solvent such as dioxane in a catalyst system such as Pd(tBu3P)2 and CsF to form compound (84). Step H shows a saponification of compound (84) using a base such as LiOH in a solvent such as THF and H2O to give compound (85). Step I depicts an amide coupling of compound (85) with NH4CI using a coupling reagent such as HATU and a base such as DIPEA in a solvent such as DMF to form compound (86). Step J shows a transformation of the amide of compound (86) to a nitrile using SOCl2 in a solvent such as DMF to give compound (87). Step K depicts an acidic deprotection of compound (87) with an acid such as TFA in a solvent such as DCM to produce compound (88).

[0170] Scheme 11

[0171]

[0172] Scheme 11, step A shows reacting compound (89) with hydrazine in a solvent such as EtOH to give compound (90). Step B depicts intermolecular cyclization of compounds (90) and (91) using a base such as K2CO3 in a solvent such as EtOH to form compound (92). Step C shows dechlorination of the pyrazidine of compound (92) using Pd / C and H2gas in a solvent such as MeOH to give compound (93). Step D depicts Sandmeyer reaction of compound (93) using tert-butylnitrite and CuCl2in a solvent such as ACN to form compound (94). Step E shows saponification of compound (94) using a base such as LiOH in a solvent such as THF and H2O to give compound (95). Step F depicts bromination of compound (95) using bromine and a base such as NaOH in a solvent such as H2O to form compound (96). Step G shows coupling reaction of compounds (96) and (97) using a base such as K3PO4in a solvent such as DMF in a catalyst system such as CuI and N,N'-dimethyl-1,2-cyclohexanediamine to give compound (98).

[0173] Scheme 12

[0174]

[0175] Scheme 12, step A depicts the protection of compound (99) with SEM-Cl using a base such as NaH in a solvent such as THF to afford compound (100). Step B shows the hydrogenation of compound (100) using Pd / C and H2gas in a solvent such as MeOH to form compound (101). Step C depicts the coupling of compound (101) with (102) using a base such as pyridine in a solvent such as DCM followed by coupling using a base such as K2CO3in a solvent such as MeOH to afford compound (103). Step D shows the cyclization of compound (103) using a base such as K2CO3in a solvent such as ACN to afford compound (104). Step E shows the reaction of compound (104) with an aryl bromide using a base such as LiHMDS in a solvent such as THF to afford compound (105). Step F depicts the acidic deprotection of compound (105) with an acid such as TFA in a solvent such as DCM to form compound (106). Step G shows the iodination of compound (106) using NIS in a solvent such as ACN to afford compound (107). Step H depicts the reaction of compound (107) using Na2SO3in a solvent mixture such as EtOH, H2O, and ACN to form compound (108). Step I shows the Stille coupling of compound (108) with a pyridazine compound (109) in a solvent such as DMF in a catalyst system such as Pd2(dba)3and XPhos to produce compound (110).

[0176] Scheme 13

[0177]

[0178] Scheme 13, step A depicts reacting compound (111) with an aryl bromide compound using a base such as LiHMDS in a solvent such as THF to give compound (112). Step B shows acidic deprotection of compound (112) with an acid such as HC1 in a solvent such as dioxane to form compound (113). Step C depicts cyclization of compound (114) with an aryl amine compound in a solvent such as toluene to give compound (115). Step D shows reacting compound (115) with an aryl bromide compound using a base such as LDA in a solvent such as THF to give compound (116). Step E depicts conversion of the carboxylic acid of compound (116) to an amide using Boc20, NH4HCO3, a base such as pyridine in a solvent such as ACN to form compound (117). Step F shows conversion of the amide of compound (117) to a nitrile using POCl3in a solvent such as DMF to give compound (118). Step G depicts acidic deprotection of compound (118) with an acid such as triflic acid in a solvent such as TFA to form compound (113). Step H shows coupling of compound (119) with (113) using a base such as K3PO4in 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 depicts reduction of the aldehyde of compound (120) using a reducing agent such as NaBH4in a solvent such as MeOH to form compound (121). Step J shows acidic deprotection of compound (121) with an acid such as TFA in a solvent such as DCM to yield compound (122).

[0179] Preparation 1

[0180] 2-methyl-3-(5-methylpyridazin-4-yl)-3-oxopropanenitrile

[0181]

[0182] To a mixture of propanenitrile (500 mg, 9 mmol) in THF (10 mL) was added slowly LiHMDS (1.6 M in THF, 5.6 mL, 9 mmol) at -60 °C. The reaction mixture was stirred for 1 h and then a solution of ethyl 5-methylpyridazine-4-carboxylate (747 mg, 4.5 mmol) in THF (5 mL) was added slowly at -60 °C and stirred for 2 h. The reaction mixture was concentrated in vacuo to give the title compound (788 mg, crude). ES / MS m / z 176 (M+H).

[0183] The compounds in Table 1 were prepared in essentially the same manner as found in Preparation 1.

[0184] Table 1

[0185]

[0186] Preparation 2a

[0187] 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole

[0188]

[0189] 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 by ice water and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water (10 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product as a yellow oil (9.50 g, crude). ES / MS (m / z): 233 (M+H).

[0190] Preparation 2b

[0191] 4-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-2-carboxaldehyde

[0192]

[0193] To a solution of crude 4-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH- imidazole (9.50 g, 40.8 mmol) in THF (30 mL) was added n-butyllithium (3.92 g, 61.2 mmol) at -78 °C. The mixture was stirred at -78 °C for 30 min, then DMF (14.9 g, 204 mmol) was added at the same temperature. The reaction mixture was stirred at -78 °C for 2 h, then quenched by saturated ammonium chloride (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (30 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (0-20%) to give the title compound as a yellow oil (6.20 g, 53% over two steps). ES / MS (m / z): 233 (M-28+H).

[0194] Preparation 2c

[0195] 3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)methanol

[0196]

[0197] To a solution of ethyl 3-chloro-lH-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 a crude product which was purified by silica gel flash chromatography eluting with EtOAc in petroleum ether (0-50%) to give the title compound as a colorless oil (1.3 g, 98%). ES / MS (m / z): 305 (M+H).

[0198] Preparation 2e

[0199] (3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)methanol

[0200]

[0201] To a solution of 3-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-5- carboxylic acid ethyl ester (1.3 g, 4.3 mmol) in THF (15 mL) was added LiAlH4(3.2 mL, 6.4 mmol, 2 M 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 in vacuo to give the title compound as a colorless oil (1.05 g, 93%). ES / MS (m / z): 263 (M+H).

[0202] Preparation 2j

[0203] 3-(4-chloro-3-fluorobenzyl)-2-oxopyrrolidine-l-carboxylic acid tert-butyl ester

[0204]

[0205] To a solution of tert-butyl 2-oxopyrrolidine-l-carboxylate (3 g, 16.2 mmol) in THF (15 mL) at -78 °C was added LiHMDS (21.1 mL, 1 M in THF, 21.1 mmol) dropwise. The reaction mixture was stirred at -78 °C for 1 h, then a solution of 4- (bromomethyl)-l-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 another 2 h, then quenched by saturated NH4Cl (50 mL). The mixture was extracted with EtOAc (80 mL x 3). The combined organic layers were washed with water (50 mL), saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash 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).

[0206] The compounds in Table lc were prepared in essentially the same manner as found in the preparation of 2j.

[0207] Table lc

[0208]

[0209]

[0210] Preparation 2aa

[0211] 3-(4-chloro-3-fluorobenzyl)pyrrolidin-2-one

[0212]

[0213] 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 HC1 (4 M in dioxane, 10 mL). The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo to give the title compound as a white solid (750 mg, 92%). ES / MS (m / z): 228 (M+H).

[0214] The compounds in Table 1d were prepared in essentially the same manner as found in Preparation 2aa.

[0215] Table 1d

[0216]

[0217]

[0218] Preparation 2aq

[0219] 1 -(3-bromo- 1 -(4-methoxybenzyl)- 1 H- 1,2,4-triazol-5-yl)-5-hydroxy-3-(3,4,5- trifluorobenzyl)piperidin-2-one

[0220]

[0221] To a mixture of 1 -(3-bromo- 1 -(4-methoxybenzyl)- 1 H- 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 in water, 10.6 mmol). The reaction mixture was stirred at 25 °C for 4 hours. The mixture was diluted with water (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with saturated aqueous NaCI (10 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash 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).

[0222] Preparation 2au

[0223] 1 -Bromo-4-fluoro-2-(fluoromethyl)benzene

[0224]

[0225] 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 h and then warmed to ambient temperature. The reaction was quenched by 1 N NaHC03(30 mL). The mixture was extracted with DCM (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-3%) to give the title compound as a colourless oil (2.86 g, 91.3%). 1 H NMR (CDC13) 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).

[0226] The compounds in Table 1f were prepared in essentially the same manner as found in the preparation of 2au.

[0227] Table 1f

[0228]

[0229] Preparation 2aw

[0230] 4-Fluoro-2-(fluoromethyl)benzaldehyde

[0231]

[0232] To a solution of 1-bromo-4-fluoro-2-(fluoromethyl)benzene (1.00 g, 4.830 mmol) in THF (10 mL) was added n-BuLi (2.125 mL, 2.5 M in hexanes, 5.313 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 30 min and DMF (529.7 mg, 7.246 mmol) was added, stirring was continued for 4 h. The reaction was quenched by saturated NH4CI (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with saturated aqueous NaCI (10 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-3%) to give the title compound as a colourless crystals (240 mg, 29.2%). 1H NMR (CDCI3): δ 10.04 (s, 1 H), 7.92-7.88 (m, 1 H), 7.46 (dd, J = 1.4 Hz & 9.6 Hz, 1 H), 7.25-7.20 (m, 1 H), 5.91 (d, J = 34.4 Hz, 2 H).

[0233] Preparation 2ax

[0234] 1 -(Bromomethyl)-4-fluoro-2-(fluoromethyl)benzene

[0235]

[0236] To a solution of 4-fluoro-2-(fluoromethyl)benzaldehyde (400 mg, 2.28 mmol) in MeOH (4 mL) was added NaBH4(173 mg, 4.56 mmol) at ambient temperature. After stirring at 25 °C for 1 h, the reaction mixture was quenched with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product.

[0237] To a solution of the crude material (385 mg, 2.43 mmol) in DCM (2 mL) was added PBr3(1.36 g, 5.01 mmol) at 0 °C. After stirring at 0 °C for 1 h, the reaction mixture was quenched by saturated NaHC03(5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a brownish oil (290 mg, 52% over two steps). 1 H NMR (CDCI3): δ 10.04 (s, 1 H), 7.92-7.88 (m, 1 H), 7.46 (dd, J = 1.4 Hz & 9.6 Hz, 1 H), 7.25-7.20 (m, 1 H), 5.91 (d, J = 34.4 Hz, 2 H).

[0238] The compounds in Table 1g were prepared in essentially the same manner as found in Preparation 2ax.

[0239] Table 1g

[0240]

[0241]

[0242] Preparation 2bg

[0243] 3-hydroxy-2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0244]

[0245] To a solution of 3-hydroxy-2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidine-1-carboxylic acid tert-butyl ester (1.50 g, 3.85 mmol) in THF (30 mL) at -78 °C under nitrogen was added NaHMDS (918 mg, 5.01 mmol) dropwise. The reaction mixture was stirred at -78 °C for 1 h. To the mixture was added 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (1.01 g, 3.85 mmol) in THF (10 mL) dropwise at -78 °C. After stirring at -78 °C for 30 min, 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 in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-20%) to give the title compound (500 mg, 18.9%) as a white solid. ES / MS (m / z): 290 (M+H).

[0246] Preparation 2bh

[0247] 2-(difluoromethyl)-4-fluoro-1-methylbenzene

[0248]

[0249] To a solution of 5-fluoro-2-methylbenzaldehyde (6.00 g, 43.4 mmol) in DCM (20 mL) at 0 °C was added DAST (35.0 g, 217 mmol). The mixture was allowed to warm and stirred at ambient temperature for 16 h. The reaction mixture was quenched with ice water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting with petroleum ether (100%) to give the title compound (5.00 g, 72%) as a colorless oil. ES / MS (m / z): 161 (M+H).

[0250] The compounds in Table 1h were prepared in essentially analogous fashion to that found in the preparation of 2bh.

[0251] Table 1h

[0252]

[0253] Preparation 2bo

[0254] 6-(difluoromethyl)nicotinic acid methyl ester

[0255]

[0256] To a mixture of 5-bromo-2-(difluoromethyl)pyridine (2.00 g, 9.7 mmol) in DMF (10 mL) was added Et3N (2.94 g, 29.1 mmol), MeOH (995 μί, 24.6 mmol) and Pd(OAc)2(216 mg, 0.97 mmol). The reaction mixture was stirred at 75 °C under a CO atmosphere for 24 h and then cooled to ambient temperature. The reaction mixture was poured into water (30 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (1%) to give the title compound as a colourless oil (1.5 g, 82%). ES / MS (m / z): 188 (M+H).

[0257] The compounds in Table 1i were prepared in essentially analogous fashion to that found in the preparation of 2bo.

[0258] Table 1i

[0259]

[0260]

[0261] Preparation 2bt

[0262] (6-(difluoromethyl)pyridin-3-yl)methanol

[0263]

[0264] To a solution of 6-(difluoromethyl)nicotinic acid methyl ester (500 mg, 2.7 mmol) in THF (6 mL) at ambient temperature was added a solution of 1 M LiAlH4in THF (3.24 mL, 3.24 mmol) and then stirred at 25 °C for 1 h. The reaction mixture was poured onto ice water (20 mL) and extracted with EtOAc (40 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow oil (170 mg, 40%). ES / MS (m / z): 160 (M+H).

[0265] The compounds in Table 1j are prepared in a manner essentially analogous to that found in Preparation 2bt.

[0266] Table 1j

[0267]

[0268] Preparation 2bv

[0269] 5-(Bromomethyl)-2-(difluoromethyl)pyridine

[0270]

[0271] 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, and then stirred at 25 °C for 2 h. The reaction mixture was poured onto ice water (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with petroleum ether (100%) to give the title compound as a colorless oil (70 mg, 30%). ES / MS (m / z): 224 (M+H).

[0272] The compounds in Table 1k are prepared in a manner essentially analogous to that found in Preparation 2bv.

[0273] Table 1k

[0274]

[0275] Preparation 3

[0276] 4-Methyl-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-amine

[0277]

[0278] 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% aqueous solution) (563 mg, 9.0 mol). The mixture was stirred at 80 °C for 16 h. Then to the reaction mixture was added saturated aqueous Na2CO3 solution to adjust the pH to 8-9, and then the organic solvent was removed in vacuo. Water (20 mL) was added, and the mixture was stirred for 1 h. The resulting solid was filtered, and the filter cake was washed with water (10 mL x 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).

[0279] The compounds in Table 2 were prepared in essentially the same manner as found in Preparation 3.

[0280] Table 2

[0281]

[0282] Preparation 4a

[0283] Chloro-2-fluoro-4-iodo-5-methoxybenzene

[0284]

[0285] To a solution of 2-chloro-l-fluoro-4-methoxybenzene (5.00 g, 31.1 mmol) in chloroform (300 mL) at 20 °C was added silver(I) 2,2,2-trifluoroacetate (24.8 g, 112 mmol) and iodine (16.6 g, 65.4 mmol). After stirring at 20 °C for 2 h, the reaction mixture was filtered through a pad of celite. The filtrate was diluted with DCM (100 mL), washed with sodium sulfite solution (100 mL x 2) and saturated aqueous NaCl (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-1%) to give the title compound (8.00 g, 86.7%) as a colorless oil. 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).

[0286] Preparation 4b

[0287] 1-Chloro-2-fluoro-5-methoxy-4-methylbenzene

[0288]

[0289] 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-trioxatriphosphaadamantane in THF (9.49 g, 75.6 mmol), potassium carbonate (3.73 g, 27.0 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (988 mg, 1.35 mmol) at ambient temperature. The reaction mixture was stirred at 85 °C for 2 h under nitrogen. 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 in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-1%) to give the title compound as a colourless 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).

[0290] Preparation 4c

[0291] 1-(Bromomethyl)-4-chloro-5-fluoro-2-methoxybenzene

[0292]

[0293] 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 for 16 h under nitrogen. After cooling to ambient temperature, the reaction mixture was quenched with water (15 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with sodium thiosulfate (20 mL x 2), saturated aqueous NaCl (30 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-1%) to give the title compound as a white solid (900 mg, 71%). 1H NMR (DMSO-d6) δ 7.54 (d, J = 12.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 4.59 (s, 2H), 3.87 (s, 3H).

[0294] The compounds in Table 2a were prepared in essentially the same manner as found in Preparation 4c.

[0295] Table 2a

[0296]

[0297] Preparation 4i

[0298] 5-chloropentanoic acid tert-butyl ester

[0299]

[0300] To a solution of tert-butyl alcohol (17 g, 0.23 mol) in pyridine (20 mL) at 0 °C was added 4-dimethylaminopyridine (39 mg, 0.32 mmol) and 5-chloropentanoyl chloride (10 g, 65 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 3 hours. The mixture was poured into sodium bicarbonate solution (150 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with 1 N HCI (200 mL), saturated aqueous NaCl (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title crude compound as a yellow oil (13.0 g, 73%). 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).

[0301] Preparation 4j

[0302] 5-chloro-2-(4-chloro-5-fluoro-2-methoxybenzyl)pentanoic acid tert-butyl ester

[0303]

[0304] To a solution of LDA (3.87 mL, 2M in THF, 7.74 mmol) in THF (10 mL) at 0 °C under nitrogen was added a solution of tert-butyl 5-chloropentanoate (1.42 g, 5.16 mmol) in THF (4 mL). The reaction mixture was stirred at 0 °C for 1 h. 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 h. The reaction mixture was quenched with ammonium chloride solution (15 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc / petroleum ether (0-5%) to give the title compound as a yellow oil (770 mg, 28.3%). 1 H NMR (CDCI3) δ 6.92 (d, J = 9.4 Hz, 1 H), 6.81 (d, J = 6.1 Hz, 1 H), 3.81 (s, 3 H), 3.53 (t, J = 6.4 Hz, 2 H), 2.76-2.73 (m, 2 H), 2.63-2.58 (m, 1 H), 1.87-1.75 (m, 2 H), 1.71-1.58 (m, 2 H), 1.35 (s, 9 H).

[0305] The compounds in Table 2b were prepared in essentially the same manner as found in Preparation 4j.

[0306] Table 2b

[0307]

[0308]

[0309] Preparation 4l

[0310] 5-chloro-2-(4-chloro-5-fluoro-2-methoxybenzyl)pentanoic acid

[0311]

[0312] 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) at 20 °C was added TFA (6 mL). After stirring for 2 h, the reaction mixture was concentrated in vacuo. The residue was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a brown oil (660 mg, crude), which was used in the next step. ES / MS (m / z): 309 (M-H).

[0313] The compounds in Table 2c were prepared in essentially the same manner as found in Preparation 4l.

[0314] Table 2c

[0315]

[0316] Preparation 4n

[0317] 1-(2,4-Dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid methyl ester

[0318]

[0319] To a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid (3.0 g, 10.74 mmol) in MeOH (40 mL) at 0 °C was added SOCl2(2.56 g, 21.48 mmol) and stirred at 70 °C for 16 h. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo to give the title compound as a colorless oil (2.9 g, 80%). ES / MS (m / z): 293 (M+H).

[0320] Preparation 4o

[0321] 1-(2,4-Dimethoxybenzyl)-4-(hydroxymethyl)pyrrolidin-2-one

[0322]

[0323] 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 NaBH4(1.419 g, 37.50 mmol) at ambient temperature. The reaction mixture was stirred at 50 °C for 4 h under nitrogen. After cooling to ambient temperature, the reaction mixture was quenched with water (100 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting 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).

[0324] Preparation 4p

[0325] 2-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1h-imidazole

[0326]

[0327] 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 x 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 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).

[0328] Preparation 4q

[0329] 1-((2-(trimethylsilyl)ethoxy)methyl)-1h-imidazole-2-amine

[0330]

[0331] A suspension of 2-nitro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazole (20.0 g, 82.3 mmol) and palladium (10% on carbon, 2.0 g, 10% w / w) in MeOH (300 mL) was stirred under a balloon of hydrogen at 25 °C for 16 h. The mixture was filtered through a pad of celite. The filtrate was concentrated to give the title compound as a black oil. (16.8 g, 97%). ES / MS (m / z): 214 (M+H).

[0332] Preparation 4r

[0333] 5-chloro-N-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)pentanamide

[0334]

[0335] To a solution of l-((2-(trimethylsilyl)ethoxy)methyl)-lH-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 in vacuo. The residue was dissolved in MeOH (200 mL) and K2CO3(43.09 g, 311.8 mmol) was added. After stirring at 25 °C for 4 h, the reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound as a yellow oil (22.0 g, 84%). ES / MS (m / z): 332 (M+H).

[0336] Preparation 4s

[0337] l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)piperidin-2-one

[0338]

[0339] To a solution of 5-chloro-N-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-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 in vacuo. The residue was purified by silica gel flash 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).

[0340] Preparation 4t

[0341] 3-(3,4-Difluorobenzyl)-l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2- yl)piperidin-2-one

[0342]

[0343] To a mixture of l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)piperidin-2- one (5.0 g, 16.75 mmol) in THF (60 mL) was added LiHMDS (67.0 mL, 1M in THF, 67.01 mmol) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 2 h, and then a solution of 4-(bromomethyl)-l,2-difluorobenzene (2.428 g, 11.73 mmol) in THF (20 mL) was added slowly. After stirring at -78 °C for 1 h, the reaction mixture was quenched by ammonium chloride (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash 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).

[0344] Preparation 4u

[0345] 3-(3,4-Difluorobenzyl)-l-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2- yl)piperidin-2-one

[0346]

[0347] To a mixture of 3-(3,4-difluorobenzyl)-l-(l-((2-(trimethylsilyl)ethoxy)methyl)- lH-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 by saturated aqueous NaHC03(30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (2.60 g, 98%) as a yellow solid. ES / MS (m / z): 292 (M+H).

[0348] Preparation 4v

[0349] 3-(3,4-difluorobenzyl)-l-(4,5-diiodo-lH-imidazol-2-yl)piperidin-2-one

[0350]

[0351] To a mixture of 3-(3,4-difluorobenzyl)-l-(lH-imidazol-2-yl)piperidin-2-one (2.20 g, 7.175 mmol) in ACN (30 mL) was slowly added l-iodopyrrolidine-2,5-dione (2.26 g, 10.04 mmol) in ACN (20 mL) at 25 °C. After stirring at 25 °C for 2 h, the reaction was quenched by water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was concentrated in vacuo to give the crude product as a brown oil. (3.50 g, 65%). ES / MS (m / z): 544 (M+H).

[0352] The compounds in Table 2d were prepared in a manner essentially analogous to that found in the preparation of 4v.

[0353] Table 2d

[0354]

[0355]

[0356] Preparation 4x

[0357] 3-(3,4-difluorobenzyl)-l-(4-iodo-lH-imidazol-2-yl)piperidin-2-one

[0358]

[0359] A mixture of 3-(3,4-difluorobenzyl)-l-(4,5-diiodo-lH-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 x 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-15%) to give the title compound as a yellow oil (1.40 g, 67%). ES / MS (m / z): 418 (M+H).

[0360] The compounds in Table 2e were prepared in a manner essentially analogous to that found in the preparation of 4x.

[0361] Table 2e

[0362]

[0363] Preparation 4z

[0364] 1-(3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5-yl)piperidine

[0365]

[0366] To a solution of 3,5-dibromo-4H-l,2,4-triazole (150.0 g, 661.2 mmol) in THF (1.5 L) was added DIPEA (147 mL, 846.3 mmol) dropwise at 0 °C. The mixture was stirred at 0 °C for 5 min, then SEM-Cl (150 mL, 846.3 mmol) was added at 10 °C. The mixture was allowed to warm and stirred at ambient temperature for 2 h. Pipedine (340 mL, 3.438 mol) was added to the above solution at ambient temperature. The resulting mixture was heated to 70 °C and stirred for 16 h. The reaction mixture was poured into ice water (1.5 L) and extracted with EtOAc (1.5 L x 3). The combined organic phases were washed with 1 N HC1, saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel flash 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).

[0367] The compounds in Table 2f are prepared in a manner essentially analogous to that found in Preparation 4z.

[0368] Table 2f

[0369]

[0370]

[0371] Preparation 4ac

[0372] 1-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one

[0373]

[0374] 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) at 0 °C was added sodium hypochlorite (392.9 mL, 7.5 wt%, 477.4 mmol). The mixture was stirred at 0 °C for 5 min. To the mixture was added a suspension of ruthenium(III) chloride trihydrate (7.921 g, 35.13 mmol) in EtOAc (100 mL) at 10 °C. After warming and stirring at ambient temperature for 16 h, the mixture was filtered to remove solids. The filtrate was extracted with EtOAc (1 L x 3). The combined organic phases were washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-30%) to give the title compound as a light yellow oil (95 g, 75%). ES / MS (m / z): 375 (M+H).

[0375] The compounds in Table 2g are prepared in a manner essentially analogous to that found in Preparation 4ac.

[0376] Table 2g

[0377]

[0378]

[0379] Preparation 4af

[0380] 3,5-dibromo-1-(4-methoxybenzyl)-1H-1,2,4-triazole

[0381]

[0382] To a suspension of 3,5-dibromo-lH-l,2,4-triazole (1.00 g, 4.41 mmol) in DMF (10 mL) was added cesium carbonate (2.87 g, 8.82 mmol) at ambient temperature. To the mixture was added l-chloromethyl-4-methoxy-benzene (1.04 g, 6.61 mmol) and stirred at ambient temperature for 16 h, diluted with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography eluting 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).

[0383] Preparation 4ag

[0384] 3,5-dibromo-4-methyl-lH-pyrazole

[0385]

[0386] To a solution of 3,4,5-tribromo-lH-pyrazole (5 g, 16.55 mmol) in THF (25 mL) was added n-BuLi (2.5 M in THF, 14.6 mL, 36.45 mmol) dropwise at -78 °C. The mixture was stirred at -78 °C for 30 min, and then a solution of Mel (2.35 g, 16.55 mmol) in THF (25 mL) was added at the same temperature. After stirring at -78 °C for another 1 h, the reaction mixture was quenched by saturated aqueous NH4Cl and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography and preparative HPLC to give the title compound as a white solid (1.52 g, 38.6%). ES / MS (m / z): 239 (M+H).

[0387] Preparation 4ah

[0388] 3,5-dibromo-4-methyl-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole

[0389]

[0390] To a suspension of 3,5-dibromo-4-methyl-lH-pyrazole (1.52 g, 6.39 mmol) in THF (15 mL) was added NaH (60% in oil, 307 mg, 7.67 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 30 min, and then SEM-Cl (1.06 g, 6.39 mmol) was added 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 x 2). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-5%) to give the title compound as a light brown solid (2.08 g, 32.5%). ES / MS (m / z): 369 (M+H).

[0391] Preparation 4ai

[0392] 1,2,4,5-tetrazine

[0393]

[0394] Formamidine acetate (60.0 g, 576.3 mmol) was cooled with an ice water bath at 0 °C, and then hydrazine hydrate (94.72 mL, 1.556 mol) was added dropwise. The reaction mixture was stirred at 25 °C for 1 h, and then cooled to 0 °C again. Water (20 mL) was added to the reaction mixture and stirred at 0 °C for another 1 h. The precipitate was collected by filtration, dissolved in acetic acid (200 mL) and cooled to 0 °C. Sodium nitrite (19.88 g, 288.2 mmol) was added to the reaction mixture in small portions at 0 °C. After stirring at 0 °C for 1 h, the reaction was quenched with water (300 mL) and extracted with DCM (300 mL x 4). The organic layer was washed with saturated aqueous NaHC03until it was neutralized, dried over MgS04, filtered and concentrated in vacuo at 25 °C to give the title compound as a red solid (7.41 g, 12.7%). 1 HNMR (CDC13) δ 10.41 (s, 2H).

[0395] Preparation 4aj

[0396] 4-methyl-5-(tributylstannyl)pyridazine

[0397]

[0398] To a stirred 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 in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with saturated sodium carbonate solution (30 mL) and saturated aqueous NaCl (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a solid (528 mg, 71.2%): ES / MS (m / z): 275 (M+H).

[0399] Preparation 4ak

[0400] (5-(trimethylstannyl)pyridazin-4-yl)methanol

[0401]

[0402] To a stirred 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 in vacuo. The residue was dissolved in EtOAc (50 mL) and washed with saturated sodium carbonate solution (30 mL) and saturated aqueous NaCl (30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a solid (528 mg, 71.2%): ES / MS (m / z): 275 (M+H).

[0403] Preparation 4al

[0404] 4-(Methoxymethyl)-5-(trimethylstannyl)pyridazine

[0405]

[0406] To a suspension of (5-(trimethylstannyl)pyridazin-4-yl)methanol (200 mg, 682 μmol) in THF (5 mL) at 0 °C was added NaH (40.9 mg, 60% in oil, 1.02 mmol). The mixture was stirred at 0 °C for 10 min, then MeI (96.7 mg, 682 μmol) was added at the same temperature. After stirring at 0 °C for 6 h, the mixture was quenched by water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a brown oil. (120 mg, 46%): ES / MS (m / z): 289.0 (M+H).

[0407] Preparation 4am

[0408] (2-Amino-4-chlorophenyl)methanol

[0409]

[0410] To a solution of 1M BH3 in THF (39.6 mL, 39.6 mmol) was added 2-amino-4- chlorobenzoic acid (2.00 g, 11.7 mmol) portionwise and then stirred at 25 °C for 3 days. The mixture was quenched with MeOH (200 mL) then concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (1:1) to give the title compound as a white solid (1.40 g, 71%). ES / MS (m / z): 158 (M+H).

[0411] The compounds in Table 2h were prepared in a manner essentially analogous to that found in the preparation of 4am.

[0412] Table 2h

[0413]

[0414] Preparation 4ao

[0415] (5-Chloro-2-(hydroxymethyl)phenyl)carbamic acid tert-butyl ester

[0416]

[0417] 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 and then stirred at 50 °C under N2for 2 days. The mixture was concentrated in vacuo to give the title compound as a yellow oil (10.01 g, 99+%). ES / MS (m / z): 184 (M+H-Boc). 1 HNMR (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).

[0418] Preparation 4ap

[0419] (2-(Bromomethyl)-5-chlorophenyl)carbamic acid tert-butyl ester

[0420]

[0421] To a solution of tert-butyl (5-chloro-2-(hydroxymethyl)phenyl)carbamate (5.00 g, 19.4 mmol) in THF (50 mL) was added triphenylphosphine (7.63 g, 29.1 mmol) and NBS (5.18 g, 29.1 mmol) portionwise. After stirring at 25 °C for 2 h, the reaction mixture was added to water (200 mL) and extracted with EtOAc (200 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (9:1) to give the title compound as a yellow solid (5.9 g, 76%). ES / MS (m / z): 264 (M+H-t-Bu).

[0422] The compounds in Table 2i were prepared in essentially the same manner as found in Preparation 4aq.

[0423] Table 2i

[0424]

[0425] Preparation 5

[0426] 5-methylpyridazine-4-carbohydrazide

[0427]

[0428] To a solution of 5-methylpyridazine-4-carboxylic acid ethyl ester (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, then concentrated in vacuo to give the title compound as a yellow solid (6 g, crude). ES / MS m / z 153 (M+H).

[0429] Preparation 6

[0430] 2-(5-methylpyridazine-4-carbonyl)hydrazine-1-carboxamide

[0431]

[0432] To a solution of crude 5-methylpyridazine-4-carbohydrazide (6 g, 39.21 mmol) in water (20 mL) was added carbamimidoylthiomethyl sulfate (8.18 g, 58.82 mmol) and NaOH (1.17 g, 29.39 mmol), and then the mixture was stirred at ambient temperature for 16 h. The resulting precipitate was filtered and dried in vacuo to give the title compound as a yellow solid (4 g, 52.6%). ES / MS (m / z): 195 (M+H).

[0433] Preparation 7

[0434] 3-(5-methylpyridazine-4-yl)-1H-1,2,4-triazol-5-amine

[0435]

[0436] To a solution of 2-(5-methylpyridazine-4-carbonyl)hydrazine-1-carboxamide (4 g, 20.51 mmol) in water (20 mL) 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 in vacuo to give the title compound as a white solid (3.1 g, 85%). ES / MS m / z 177 (M+H).

[0437] Preparation 8

[0438] 1-(4-methoxybenzyl)-3-(5-methylpyridazine-4-yl)-1H-pyrazol-5-amine

[0439]

[0440] To a stirred mixture of crude 3-(5-methylpyridazin-4-yl)-3-oxopropanenitrile (10.3 g, 64 mmol) in EtOH (120 mL) was added AcOH (11.7 g, 192 mmol) slowly, followed by (4-methoxybenzyl)hydrazine hydrochloride (18 g, 96 mmol), and then the reaction mixture was 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 as a brown solid (11 g, 58.5%). ES / MS m / z 296 (M+H).

[0441] Preparation 8a

[0442] 4-methoxypyridazine

[0443]

[0444] To a solution of 4-bromopyridazine hydrobromide (4.50 g, 18.8 mmol) in MeOH (100 mL) at 0 °C was added sodium methoxide (16.9 g, 93.8 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred for 4 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel flash 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).

[0445] Preparation 8b

[0446] 4-bromo-5-methoxypyridazine

[0447]

[0448] 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), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting 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).

[0449] Preparation 8c

[0450] 4-methoxy-5-(trimethylstannyl)pyridazine

[0451]

[0452] To a solution of 4-bromo-5-methoxypyridazine (250 mg, 1.26 mmol) in 1,4-dioxane (5 mL) at ambient temperature was added bis-(triphenylphosphine)-palladium chloride (88.3 mg, 126 μmol) and 1,1,1,2,2,2-hexamethyldistannane (824 mg, 2.52 mmol). 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 x 3). The combined organic layers were washed with saturated aqueous NaCl (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a brown oil (250 mg, 20.4%). ES / MS (m / z): 275 (M+H).

[0453] Preparation 8d

[0454] 3-chloro-5-hydrazinylpyridazine

[0455]

[0456] To a solution of 3,5-dichloropyridazine (10.0 g, 67.1 mmol) in EtOH (150 mL) at 80 °C was added hydrazine hydrate (4.30 g, 134 mmol) dropwise. The mixture was stirred at 80 °C for 1 hour. After cooling to ambient temperature, the mixture was concentrated in vacuo to give the crude title compound as a yellow solid (9.0 g, 78%). ES / MS (m / z): 145 (M+H).

[0457] Preparation 8e

[0458] 5-amino-1-(6-chloropyridazin-4-yl)-1h-pyrazole-4-carboxylic acid ethyl ester

[0459]

[0460] A mixture of 3-chloro-5-hydrazinylpyridazine (9.00 g, 62.3 mmol), (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 in vacuo. The residue was dissolved in EtOAc (100 mL) and water (100 mL) was added and separated. The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with water and saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by flash chromatography on silica gel eluting with EtOAc / 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).

[0461] Preparation 8f

[0462] 5-amino-1-(pyridazin-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0463]

[0464] A mixture of 5-amino-1-(6-chloropyridazin-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (10.0 g, 37.4 mmol) and Pd / C (1.0 g, 10% w / w) in MeOH (500 mL) was stirred under a balloon of hydrogen at 50 °C for 3 h. After cooling to ambient temperature, the mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo. The residue was triturated with EtOAc (50 mL) to give the title compound as a yellow solid (6.0 g, 55%). ES / MS (m / z): 234 (M+H).

[0465] The compounds in Table 2h were prepared in essentially the same manner as found in the preparation of 8f.

[0466] Table 2h

[0467]

[0468] Preparation 8h

[0469] 5-amino-1-(pyridazin-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0470]

[0471] A mixture of tert-butyl nitrite (0.79 g, 7.7 mmol) and CuCl2(1.2 g, 12 mmol) in ACN (20 mL) was stirred at 65 °C for 10 min. Ethyl 5-amino-1-(pyridazin-4-yl)-1H-pyrazole-4-carboxylate (1.5 g, 5.1 mmol) was added to the mixture. After stirring at 65 °C for 2 h, the reaction was allowed to cool to ambient temperature, quenched with ammonium hydroxide (100 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash 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).

[0472] Preparation 8i

[0473] 5-Chloro-1-(pyridazin-4-yl)-1H-pyrazole-4-carboxylic acid

[0474]

[0475] 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 h, the reaction mixture was adjusted to pH 4 with HCl (2 M) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a yellow solid (1 g, 90%). ES / MS (m / z): 225 (M+H).

[0476] The compounds in Table 2i were prepared in a manner essentially analogous to that found in the preparation of 8i.

[0477] Table 2i

[0478]

[0479] Preparation 8k

[0480] 4-(4-Bromo-5-chloro-1H-pyrazol-1-yl)pyridazine

[0481]

[0482] To a solution of 5-chloro-l-(pyridazin-4-yl)-lH-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 x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel flash chromatography eluting with EtOAc / pet. ether (0-30%) to give the title compound as a yellow solid (120 mg, 32%). ES / MS (m / z): 259 (M+H).

[0483] The compounds in Table 2j were prepared in a manner essentially analogous to that found in the preparation of 8k.

[0484] Table 2j

[0485]

[0486] Preparation 8m

[0487] 2-(6-chloropyridazin-4-yl)-2H-l,2,3-triazole-4-carboxylic acid methyl ester

[0488]

[0489] To a solution of 2H-l,2,3-triazole-4-carboxylic acid methyl ester (2.0 g, 15.7 mmol) in dry ACN (150 mL) was added 3,5-dichloropyridazine (2.34 g, 15.7 mmol) and K2CO3(6.52 g, 47.2 mmol) at ambient temperature. The mixture was stirred at 90 °C for 16 h. After cooling to ambient temperature, the mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. The residue was purified by silica gel flash chromatography eluting with EtOAc / pet. ether (0-50%) to give the title compound as an off-white solid (1.49 g, 40%). ES / MS (m / z): 240 (M+H).

[0490] Preparation 8n

[0491] 2-(pyridazin-4-yl)-2H-l,2,3-triazole-4-carboxylic acid methyl ester

[0492]

[0493] To a solution of methyl 2-(6-chloropyridazin-4-yl)-2H-l,2,3-triazole-4-carboxylate (1.44 g, 6 mmol) in EtOH (150 mL) was added Et3SiH (1.4 g, 12 mmol), TEA (1.22 g, 12 mmol), PPh3 (157 mg, 0.6 mmol) and Pd(OAc)2 (135 mg, 0.6 mmol) at ambient temperature. After purging and degassing with N2 three times, the mixture was stirred at 60 °C under nitrogen for 2 h. After cooling to ambient temperature, the solution was concentrated in vacuo to give a residue. The residue was purified by silica gel flash column chromatography eluting with EtOAc / petroleum ether (0-50%) to give the title compound as an off-white solid (1.2 g, 98%). ES / MS (m / z): 206 (M+H).

[0494] Preparation 8o

[0495] 2-(Pyridazin-4-yl)-2H-l,2,3-triazole-4-carboxylic acid

[0496]

[0497] To a suspension of methyl 2-(pyridazin-4-yl)-2H-l,2,3-triazole-4-carboxylate (1.1 g, 5.36 mmol) in THF / water (120 mL, 5 / 1) was added LiOH H2O (901 mg, 21.5 mmol) at ambient temperature. After stirring at ambient temperature for 2 h, the reaction mixture was adjusted to pH = 3 with 1 N HC1. The precipitated solid was filtered and dried in vacuo overnight to give the title compound as an off-white solid (700 mg, 70%). ES / MS (m / z): 192 (M+H).

[0498] Preparation 8p

[0499] (2-(Pyridazin-4-yl)-2H-l,2,3-triazol-4-yl)carbamic acid tert-butyl ester

[0500]

[0501] To a solution of 2-(pyridazin-4-yl)-2H-l,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 in vacuo 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).

[0502] Preparation 8q

[0503] 2-(Pyridazin-4-yl)-2H-l,2,3-triazole-4-amine

[0504]

[0505] A solution of tert-butyl (2-(pyridazin-4-yl)-2H-l,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 h. The solvent was removed to give crude material which was washed with MeOH to give the title compound as a brown solid. ES / MS (m / z): 163 (M+H).

[0506] Preparation 8r

[0507] 4-Bromopyridazine

[0508]

[0509] To a suspension of cuprous bromide (42.99 g, 299.7 mmol) in ACN (200 mL) was added tert-butylnitrite (47.39 g, 459.5 mmol) at ambient temperature. The reaction was stirred at 65 °C for 0.5 h, and then pyridazine-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 allowed to cool to ambient temperature, quenched by the addition of ammonium hydroxide (100 mL), and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash 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).

[0510] Preparation 8s

[0511] 4-(4-bromo-lH-pyrazol-l-yl)pyridazine

[0512]

[0513] To a solution of 4-bromo-lH-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 allowed to cool to ambient temperature, quenched by the addition of water (100 mL), and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography 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).

[0514] The compounds in Table 2k were prepared in a manner essentially analogous to that found in the preparation of 8s.

[0515] Table 2k

[0516]

[0517] Preparation 8u

[0518] 4-bromo-l-(pyridazin-4-yl)-lH-pyrazole-5-carbaldehyde

[0519]

[0520] To a mixture of 4-(4-bromo-lH-pyrazol-l-yl)pyridazine (1.00 g, 4.01 mmol) in THF (100 mL) was added LDA (645 mg, 6.02 mmol) dropwise at -70 °C under nitrogen. The reaction was stirred at -70 °C for 1 h, then DMF (2.93 g, 40.1 mmol) was added dropwise to the mixture. After stirring for 3 h, the reaction was quenched slowly with water (50 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with saturated aqueous NaCl (100 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow solid (1.00 g, 37.5%). ES / MS (m / z): 253 (M+H).

[0521] Preparation 8v

[0522] (4-bromo-l-(pyridazin-4-yl)-lH-pyrazol-5-yl)methanol

[0523]

[0524] To a solution of 4-bromo-l-(pyridazin-4-yl)-lH-pyrazole-5-carbaldehyde (1.00 g, 1.50 mmol) in MeOH (20 mL) was added NaBH4(171 mg, 4.51 mmol) at 20 °C. The reaction was stirred at 20 °C for 2 h. The reaction mixture was concentrated in vacuo to give the crude material. The crude material was purified by silica gel flash 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).

[0525] Preparation 8w

[0526] 4-(4-bromo-5-(((tert-butyldimethylsilyl)oxy)methyl)-lH-pyrazol-l-yl)pyridazine

[0527]

[0528] To a solution of (4-bromo-l-(pyridazin-4-yl)-lH-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 by water (20 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with saturated aqueous NaCl (50 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-20%) to give the title compound (320 mg, 73.3%) as a white solid. ES / MS (m / z): 369 (M+H).

[0529] Preparation 8x

[0530] (E)-3-bromo-l-(pyridazin-4-yl)-lH-pyrazole-5-carbaldehyde oxime

[0531]

[0532] To a mixture of 4-(3-bromo-lH-pyrazol-l-yl)pyridazine (760 mg, 3.32 mmol) in THF (20 mL) was added LDA (2.0 M in THF, 4.97 mmol) dropwise at -78 °C under nitrogen. The mixture was stirred at -78 °C for 1 h, and then DMF (485 mg, 6.63 mmol) was added. After stirring at -78 °C for 4 h, the reaction mixture was quenched by saturated aqueous NH4CI (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCI (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude product.

[0533] To a suspension of the crude material (900 mg, 35% purity, 1.24 mmol) and sodium carbonate (528 mg, 4.98 mmol) in EtOH (10 mL) was added hydroxylamine hydrochloride (259 mg, 3.73 mmol) at ambient temperature. The mixture was stirred at 60 °C for 2 h, and then filtered to remove inorganic salts. The filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and washed with water (20 mL). The organic layer was washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography eluting with MeOH / DCM (0-3%) to give the title compound as a light brown solid (290 mg, 80.9%). ES / MS (m / z): 268 (M+H).

[0534] Preparation 8y

[0535] 3-bromo-1-(pyridazin-4-yl)-1H-pyrazole-5-carbonitrile

[0536]

[0537] 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 for 0.5 h, and then oxalyl chloride (639 mg, 5.03 mmol) was added at 0 °C. After stirring at ambient temperature for 16 h, the mixture was quenched with water (10 mL) and extracted with DCM (10 mL x 2). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash 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).

[0538] Preparation 8z

[0539] (Z)-2-((dimethylamino)methylene)-3-oxobutanoic acid ethyl ester

[0540]

[0541] 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 in vacuo 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).

[0542] Preparation 8aa

[0543] 1 -(6-chloropyridazin-4-yl)-5-methyl- 1 H-pyrazole-4-carboxylic acid ethyl ester

[0544]

[0545] To a solution of (Z)-ethyl 2-((dimethylamino)methylene)-3-oxobutanoate (9.00 g, 48.6 mmol) in MeOH (30 mL) was added 3-chloro-5-hydrazinylpyridazine (7.00 g, 48.6 mmol) at ambient temperature. 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).

[0546] Preparation 8ab

[0547] 3-(4-chloro-3,5-difluorobenzyl)- 1 -(4-chloro-3 -(pyridazin-4-yl)- 1 -((2- (trimethylsilyl)ethoxy)methyl)- 1 H-pyrazol-5-yl)pyrrolidin-2-one

[0548]

[0549] To a solution of 3-(4-chloro-3,5-difluorobenzyl)-l-(3-(pyridazin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-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. To the mixture was added EtOAc (20 mL), followed by washing with water (20 mL) and saturated aqueous NaCl (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-100%) to give the title compound as a yellow oil (350 mg, 84%). ES / MS (m / z): 554 (M+H).

[0550] The compounds in Table 21 were prepared in essentially analogous fashion to that found in Preparation 8ab.

[0551] Table 21

[0552]

[0553] Preparation 8ad

[0554] 1-(3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5-yl)-3-(4- fluoro-2-(fluoromethyl)benzyl)piperidin-2-one

[0555]

[0556] To a solution of l-(3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5- yl)piperidin-2-one (736 mg, 1.94 mmol) in THF (10 mL) was added LiHMDS (3.88 mL, 1.0 M in THF, 3.88 mmol) dropwise at -78 °C under nitrogen. After stirring at -78 °C for 1 h, l-(bromomethyl)-4-fluoro-2-(fluoromethyl)benzene (412 mg, 1.75 mmol) was added, followed by stirring at -78 °C for 2 h. The reaction mixture was quenched by saturated ammonium chloride (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with saturated aqueous NaCl (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography 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).

[0557] The compounds in Table 2m are prepared in a manner essentially analogous to that found in Preparation 8ad.

[0558] Table 2m

[0559]

[0560]

[0561]

[0562]

[0563]

[0564] Preparation 8bd

[0565] 3-(4-Fluoro-2-(fluoromethyl)benzyl)-l-(3-(pyridazin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5-yl)piperidin-2-one

[0566]

[0567] A mixture of l-(3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-l,2,4- triazol-5-yl)-3-(4-fluoro-2-(fluoromethyl)benzyl)piperidin-2-one (20 mg, 38 pmol), 4- (tributylstannyl)pyridazine (14 mg, 38 pmol), CsF (18 mg, 0.12 mmol), and bis[tris(tert- butyl)phosphine]palladium (2.0 mg, 3.8 pmol) in 1,4-dioxane (1 mL) was degassed and purged with nitrogen at ambient temperature (x 3), 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 solution (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution (5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash 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).

[0568] The compounds in Table 2n are prepared in a manner essentially analogous to that found in Preparation 8bd.

[0569] Table 2n

[0570]

[0571]

[0572]

[0573]

[0574]

[0575]

[0576]

[0577] Preparation 9

[0578] N-methoxy-N,5-dimethyl-pyridazine-4-carboxamide

[0579]

[0580] A mixture of 5-methylpyridazine-4-carboxylic acid ethyl ester (1.2 g, 7.23 mmol), N,0-dimethylhydroxylamine hydrochloride (1.42 g, 14.46 mmol) in THF (20 mL) was stirred at -70 °C for 5 min. LiHMDS (1 M in THF, 50.6 mL, 50.6 mmol) was added slowly 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 in vacuo. The crude product was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (3:97) to give the title compound as a yellow oil (0.94 g, 71.2 %). ES / MS m / z 182 (M+H).

[0581] Preparation 10

[0582] 3-(5-methylpyridazin-4-yl)-3-oxo-propionic acid ethyl ester

[0583]

[0584] To a mixture of EtOAc (1.37 g, 15.6 mmol) in THF (20 mL) was added slowly LDA solution (1 M in THF, 15.6 mL) at -70 °C and stirred for 1.5 h. N-methoxy-N,5-dimethyl-pyridazine-4-carboxamide (0.94 g, 5.2 mmol) in THF (8 mL) was added slowly and stirred at -70 °C for 2.0 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 in vacuo. The crude product was purified by silica gel column chromatography eluted with EtOAc / petroleum ether (1 : 1) to give the title compound as a yellow oil (0.53 g, 49.1%). ES / MS m / z 209 (M+H).

[0585] Preparation 11

[0586] (Z)-3-amino-4,4,4-trichloro-2-(5-methylpyridazine-4-carbonyl)but-2-enoic acid ethyl ester

[0587]

[0588] To a mixture of 3-(5-methylpyridazine-4-yl)-3-oxo-propionic acid ethyl ester (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 h. The reaction mixture was concentrated in vacuo to give the title compound as a yellow oil (1.08 g, crude). ES / MS m / z 352 (M+H).

[0589] Preparation 12

[0590] 5-amino-1-(4-methoxybenzyl)-3-(5-methylpyridazine-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester

[0591]

[0592] To a mixture of (Z)-3-amino-4,4,4-trichloro-2-(5-methylpyridazine-4-carbonyl)but-2-enoic acid ethyl ester (1.08 g, crude) in EtOH (10 mL) was added Et3N (0.77 g, 7.6 mmol) and (4-methoxybenzyl)hydrazine hydrochloride (0.58 g, 3.05 mmol), and then the mixture was stirred at 65 °C for 2 h. The reaction mixture was then concentrated in vacuo. The crude was purified by silica gel column chromatography, eluted with EtOAc / petroleum ether (3:97) to give the title compound as a yellow-brown oil (0.54 g, 58.1 %). ES / MS m / z 368 (M+H).

[0593] Preparation 13

[0594] 5-amino-1-(4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)-1H-pyrazole-4-carboxylic acid

[0595]

[0596] To a mixture of 5-amino-1-(4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (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 h, then the reaction mixture was concentrated in vacuo. 1M aqueous HC1 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, then dried in vacuo to give the title compound as a yellow solid (350 mg, 70.1 %). ES / MS m / z 340 (M+H).

[0597] Preparation 14

[0598] 5-amino-1-(4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)-1H-pyrazole-4-carboxylic acid amide

[0599]

[0600] A mixture of 5-amino-l-(4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)-lH- 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 h. 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 in vacuo to give the title compound as a brown oil (400 mg, crude). ES / MS m / z 339 (M+H).

[0601] Preparation 15

[0602] 1-(4-methoxybenzyl)-4-methyl-3-(5-methylpyridazin-4-yl)-lH-pyrazol-5-amine

[0603]

[0604] 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. To the reaction mixture was slowly added saturated aqueous Na2CO3solution to adjust the pH to 8-9 and extracted with EtOAc (80 mL x 2). The combined organic layers were dried and concentrated in vacuo to give crude material (1.8 g), which was purified by reverse phase chromatography (ACN = 2-30% in 10 mM NH4HCO3) to give the title compound as a brown solid (800 mg, 58%). ES / MS m / z 310 (M+H).

[0605] Preparation 16

[0606] 3-(6-chloro-5-fluoropyridin-3-yl)-N-(l-(4-methoxybenzyl)-4-methyl-3-(5- methylpyridazin-4-yl)-lH-pyrazol-5-yl)propanamide

[0607]

[0608] A mixture of 1 -(4-methoxybenzyl)-4-methyl-3-(5-methylpyridazin-4-yl)- 1 H-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) which was then extracted with EtOAc (80 mL x 2). The combined organic layers were dried and concentrated in vacuo. The crude material was purified by reverse phase chromatography (ACN in 10 mM NH4HCO3= 2-60%) to give the title compound as a light yellow solid (360 mg, 46%). ES / MS m / z 495 (M+H).

[0609] The compounds in Table 3 were prepared in essentially the same manner as found in Preparation 16.

[0610] Table 3

[0611]

[0612] Preparation 18

[0613] 5-(3-(6-Fluoropyridin-3-yl)propanamido)-3-(5-methylpyridazin-4-yl)-1 H-pyrazole-4- carboxamide

[0614]

[0615] A mixture of 5-(3-(6-fluoropyridin-3-yl)propanamido)-1 -(4-methoxybenzyl)-3-(5- methylpyridazin-4-yl)-1 H-pyrazole-4-carboxamide (1 10 mg, 0.3 mmol) and TFA (2 mL) in DCM (1 mL) was stirred at ambient temperature for 12 h. The reaction mixture was concentrated in vacuo. To the residue was added sodium bicarbonate solution to adjust the pH to about 8. The slurry was filtered and the filter cake was washed with ice water (20 mL), dried in vacuo to give the title compound as a brown solid (70 mg, crude). ES / MS m / z 370 (M+H).

[0616] Preparation 18a

[0617] 2,2,2-Trichloro-1 -(4-chloro-1 H-pyrrol-2-yl)ethan-1 -one

[0618]

[0619] To a solution of 2,2,2-trichloro-l-(lH-pyrrol-2-yl)ethan-l-one (20.00 g, 94.14 mmol) in DCM (40 mL) was added sulfuryl dichloride (15.25 g, 113.0 mmol) at 0 °C. The reaction mixture was stirred at 20 °C for 20 h under nitrogen atmosphere. 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 x 3). The combined organic layers were washed with water (10 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting 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).

[0620] Preparation 18b

[0621] 4-Chloro-lH-pyrrole-2-carboxylic acid methyl ester

[0622]

[0623] To a solution of 2,2,2-trichloro-l-(4-chloro-lH-pyrrol-2-yl)ethan-l-one (12.10 g, 44.11 mmol) in MeOH (20 mL) was added sodium hydroxide (5.293 g, 132.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude material. The crude material was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-20%) to give the title compound as a white solid (4.96 g, 63%). ES / MS (m / z): 160 (M+H).

[0624] Preparation 18c

[0625] 5-Bromo-4-chloro-lH-pyrrole-2-carboxylic acid methyl ester

[0626]

[0627] To a solution of methyl 4-chloro-lH-pyrrole-2-carboxylate (1.5 g, 8.1 mmol) in AcOH (10 mL) was added Br2(1.4 g, 8.9 mmol) dropwise at ambient temperature. The reaction mixture was stirred at 60 °C for 15 min. After cooling to ambient temperature, the reaction mixture was concentrated to give crude material. The crude material was dissolved in water (10 mL), adjusted to pH > 7 with saturated sodium bicarbonate and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting 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).

[0628] Preparation 18d

[0629] Methyl 4-chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-l-yl)-lH-pyrrole-2- carboxylate

[0630]

[0631] To a mixture of 3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one (500 mg, 1.80 mmol) and methyl 5-bromo-4-chloro-lH-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-l,2-cyclohexanediamine (513 mg, 3.60 mmol) at 20 °C. The reaction was stirred at 60 °C for 14 h under nitrogen in a sealed tube. After cooling to ambient temperature, the reaction was quenched by the addition of water (20 mL) and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-20%) to give the title compound as a colourless oil (500 mg, 67.8%). ES / MS (m / z): 387 (M+H).

[0632] The compounds in Table 3a were prepared in essentially analogous fashion to that found in the preparation of 18d.

[0633] Table 3a

[0634]

[0635] Preparation 18f

[0636] 3-bromo-4-chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylic acid

[0637]

[0638] 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 (300 mg, 0.51 mmol) in DCM (10 mL) was added a solution of NBS (100 mg, 0.56 mmol) in DCM (10 mL) dropwise 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 x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-20%) to give the title compound (200 mg, 61.2%) as a white solid. ES / MS (m / z): 605 (M+H).

[0639] The compounds in Table 3b were prepared in essentially analogous fashion to that found in Preparation 18f.

[0640] Table 3b

[0641]

[0642]

[0643] Preparation 18i

[0644] 3-bromo-4-chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylic acid

[0645]

[0646] 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 pmol) in THF (10 mL) was added NaH (15.5 mg, 644 pmol) at 0 °C under nitrogen. The reaction was stirred at 20 °C for 5 min. SEM-Cl (107 mg, 644 pmol) was added to the mixture. After stirring at 20 °C for 5 h, the reaction was quenched by the addition of water (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-20%) to give the title compound (200 mg, 76.8%) as a white solid. ES / MS (m / z): 617 (M+Na).

[0647] The compounds in Table 3c were prepared in essentially analogous fashion to that found in Preparation 18i.

[0648] Table 3c

[0649]

[0650]

[0651] Preparation 18k

[0652] 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)

[0653] 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 methyl ester (Compound 2)

[0654]

[0655] 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) at ambient temperature under nitrogen 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). 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 x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash 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).

[0656] The compounds in Table 3d were prepared in essentially the same manner as found in the preparation of 18k.

[0657] Table 3d

[0658]

[0659] Preparation 18m

[0660] 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)

[0661] 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)

[0662]

[0663] 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-carboxylic acid methyl ester (90 mg, 71 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 methyl ester (90 mg, 71 μmol) in THF (6 mL) and water (2 mL) was added lithium hydroxide (17 mg, 0.71 mmol) at ambient temperature. The reaction was stirred at 60 °C for 3 h. After cooling to ambient temperature, the reaction was quenched with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound 1 (80 mg, 93%) ES / MS (m / z): 547 (M+H) and the title compound 2 (80 mg, 88%) ES / MS (m / z): 581 (M+H) as yellow solids.

[0664] The compounds in Table 3e were prepared in a manner essentially analogous to that found in the preparation of 18m.

[0665] Table 3e

[0666]

[0667] Preparation 18o

[0668] 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 methyl ester (Compound 1)

[0669] 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 methyl ester (Compound 2)

[0670]

[0671] To a solution of 5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1-yl)-3-(pyridazin-4- yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carboxylic acid (70 mg, 58 pmol) 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 pmol) in DMF (5 mL) at 20 °C was added DIEA (21 mg, 0.16 mmol), HATU (31 mg, 81 pmol) and ammonium chloride (5.8 mg, 0.11 mmol). 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 x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-50%) to give the title compound 1 (70 mg, 96%) ES / MS (m / z): 546 (M+H) and the title compound 2 (70 mg, 98%) ES / MS (m / z): 580 (M+H) as yellow solids.

[0672] The compounds in Table 3f were prepared in essentially analogous fashion to that found in Preparation 18o.

[0673] Table 3f

[0674]

[0675]

[0676] Preparation 18r

[0677] 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)

[0678] 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)

[0679]

[0680] To a mixture of 5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-l-yl)-3-(pyridazin-4- yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrole-2-carboxamide (60 mg, 45 μmol) and 4-chloro-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-l-yl)-3-(pyridazin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrrole-2-carboxamide (60 mg, 52 μmol) in DMF (6 mL) was added SOCl2(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 solution (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution (10 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-50%) to give the title compound 1 (20 mg, 80%) as a yellow solid; ES / MS (m / z): 528 (M+H) and the title compound 2 (20 mg, 83%) as a yellow solid; ES / MS (m / z): 562 (M+H).

[0681] The compounds in Table 3g were prepared in a manner essentially analogous to that found in Preparation 18r.

[0682] Table 3g

[0683]

[0684] Preparation 18v

[0685] 1-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrole-2-carboxaldehyde

[0686]

[0687] To a solution of 1H-pyrrole-2-carbaldehyde (1.00 g, 10.5 mmol) in DMF (15 mL) was added NaH in oil (631 mg, 60 wt%, 15.8 mmol) at 0 °C. After stirring for 2 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 x 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (1:9) to give the title compound as a yellow oil (1.80 g, 49%). ES / MS (m / z): 226 (M+H).

[0688] Preparation 18w

[0689] 4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrole-2-carbaldehyde

[0690]

[0691] 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 in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (1:4) to give a mixture of two isomers of the title compound as a yellow oil (1.50 g, 23%). The crude was used directly in the next step. ES / MS (m / z): 260 (M+H).

[0692] Preparation 18x

[0693] (E)-3-(4-Chloro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)acrylic acid ethyl ester

[0694]

[0695] To a solution of 4-chloro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrrole-2- carboxaldehyde (1.40 g, 5.39 mmol) in DCM (20 mL) was added ethyl 2- (triphenyl-l5-phosphaneylidene)acetate (4.69 g, 13.5 mmol). After stirring at 25 °C for 12 h, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / pet. ether (1 :10) to give the title compound as a yellow oil (0.47 g, 25%). ES / MS: (m / z) = 330 (M+H).

[0696] Preparation 18y

[0697] N-(2-bromo-5-fluoropyridin-3-yl)neopentanamide

[0698]

[0699] 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) dropwise. After stirring at 25 °C for 5 h, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / pet. ether (95:5) to give the title compound as a yellow oil (10.0 g, 99%). ES / MS (m / z): 275 (M+H).

[0700] The compounds in Table 3h were prepared in a manner essentially analogous to that found in Preparation 18y.

[0701] Table 3h

[0702]

[0703] Preparation 18aa

[0704] (E)-3-(5-fluoro-3-neopentanamidopyridin-2-yl)acrylic acid ethyl ester

[0705]

[0706] To a mixture of N-(2-bromo-5-fluoropyridin-3-yl)neopentanamide (4.35 g, 15.8 mmol) in DMF (25 mL) was added 1,4-diazabicyclo[2.2.2]octane (0.35 g, 3.1 mmol), ethyl acrylate (3.16 g, 31.6 mmol), K2CO3(4.36 g, 31.5 mmol), and Pd(OAc)2(0.71 g, 3.2 mmol) under nitrogen. After stirring at 120 °C for 3 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 x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM (100%) to give the title compound as a yellow solid (857.0 mg, 15%). ES / MS (m / z): 295 (M+H).

[0707] The compounds in Table 3i were prepared in a manner essentially analogous to that found in Preparation 18aa.

[0708] Table 3i

[0709]

[0710] Preparation 18ad

[0711] 3-(5-Fluoro-3-neopentanamidopyridin-2-yl)propanoic acid ethyl ester

[0712]

[0713] To a mixture of (E)-3-(5-fluoro-3-neopentanamidopyridin-2-yl)propenoic acid ethyl ester (857 mg, 2.91 mmol) and nickel(II) chloride hexahydrate (692 mg, 2.91 mmol) in MeOH (10 mL) was added NaBH4(165 mg, 14.37 mmol) portionwise 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 x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a yellow solid (830 mg, 85%). ES / MS (m / z): 297 (M+H).

[0714] The compounds in Table 3j were prepared in a manner essentially analogous to that found in Preparation 18ad.

[0715] Table 3j

[0716]

[0717] Preparation 18ag

[0718] 3-(5-fluoro-3-neopentanamidopyridin-2-yl)propanoic acid

[0719]

[0720] To a solution of ethyl 3-(5-fluoro-3-neopentanamidopyridin-2-yl)propanoate (830 mg, 2.8 mmol) in THF (6.4 mL) and H2O (1.6 mL) was added a solution of lithium hydroxide monohydrate (235 mg, 5.6 mmol) in H2O (1.5 mL). After stirring at 25 °C for 4 h, 1 M HC1 (6 mL) was added, followed by concentration in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (95:5) to give the title compound as a yellow oil (608 mg, 76%). ES / MS (m / z): 269 (M+H).

[0721] The compounds in Table 3k were prepared in a manner essentially analogous to that found in Preparation 18ag.

[0722] Table 3k

[0723]

[0724]

[0725] Preparation 18al

[0726] 3-(5-fluoro-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-3-yl)propanoic acid ethyl ester

[0727]

[0728] 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 in vacuo to give the title compound as an orange solid (1.10 g, 95%). ES / MS (m / z): 228 (M+H-84).

[0729] The compounds in Table 3l were prepared in a manner essentially analogous to that found in Preparation 18al.

[0730] Table 31

[0731]

[0732] Preparation 18an

[0733] 3-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanoic acid ethyl ester

[0734]

[0735] To a solution of 3-(5-fluoro-6-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridin-3- yl)propanoic acid ethyl ester (1.10 g, 3.79 mmol) in DCM (10 mL) was added TFA (10 mL). After stirring at ambient temperature for 2 h under nitrogen, the reaction mixture was concentrated in vacuo. To the residue was added water (20 mL), basified to pH = 8 with saturated NaHC03solution, and extracted with DCM (20 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound as an orange oil (800 mg, 91%). ES / MS (m / z): 228 (M+H).

[0736] Preparation 18ao

[0737] 3-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanoic acid ethyl ester

[0738]

[0739] To a solution of 3-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanoic acid ethyl ester (700 mg, 3.08 mmol) in DCM (10 mL) was added Mn02(1.93 g, 22.2 mmol). After stirring at 40 °C for 2 h under nitrogen, the reaction mixture was diluted with DCM (30 mL) and filtered. The filtrate was concentrated in vacuo to give the title compound as an orange liquid (650 mg, 94%). ES / MS (m / z): 254 (M+H).

[0740] Preparation 18ap

[0741] 3-(5-fluoro-6-(hydroxymethyl)pyridin-3-yl)propanoic acid ethyl ester

[0742]

[0743] 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 for 10 min under nitrogen, the reaction mixture was stirred at ambient temperature for 2 h under nitrogen. The reaction was quenched with H2O (20 mL) and extracted with DCM (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (500 mg, 92%) as an orange liquid. ES / MS (m / z): 248 (M+H).

[0744] Preparation 18aq

[0745] 2-((2-chlorothiazol-5-yl)methyl)propanedioic acid diethyl ester

[0746]

[0747] To a mixture of 2-chloro-5-(chloromethyl)thiazole (4.00 g, 23.8 mmol) and propanedioic acid diethyl ester (38.13 g, 238 mmol) in t-BuOH (120 mL) was added t-BuONa (7.66 mL, 71.41 mmol) portionwise at 0 °C under nitrogen. After stirring at 0 °C for 2 h under nitrogen, the reaction mixture was quenched with H2O (40 mL) and extracted with DCM (100 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (92:8) to give the title compound (31.0 g, crude) as a yellow oil. ES / MS (m / z): 292 (M+H).

[0748] Preparation 18ar

[0749] 2-((2-chlorothiazol-5-yl)methyl)propanedioic acid diethyl ester

[0750]

[0751] To a solution of 2-((2-chlorothiazol-5-yl)methyl)propanedioic acid diethyl ester (31.0 g, crude) in THF (100 mL) was added a solution of lithium hydroxide monohydrate (13.0 g, 0.31 mol) and H2O (25 mL). After stirring at 20 °C for 9 h, the reaction mixture was concentrated in vacuo to remove the organic solvent. Water (40 mL) was added to the residue and washed with petroleum ether (120 mL x 3). The aqueous solution was used directly in the next step without further purification. ES / MS (m / z): 236 (M+H).

[0752] Preparation 18as

[0753] 3-(2-chlorothiazol-5-yl)propanoic acid

[0754]

[0755] A solution of 2-((2-chlorothiazol-5-yl)methyl)malonic acid was acidified with sulfuric acid (4 M) to pH = 2-3, followed by stirring at 100 °C for 16 h. The reaction mixture was allowed to cool to ambient temperature and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (1:3) to give the title compound as a white solid (1.3 g, 28.6%, over 3 steps). ES / MS (m / z): 192 (M+H).

[0756] Preparation 18at

[0757] 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0758]

[0759] 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, and then stirred at 0 °C for 2 h. The mixture was quenched with cold water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a colorless oil (1 g, 63%). ES / MS (m / z): 299 (M+H-58).

[0760] Preparation 18au

[0761] 3,5-dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde

[0762]

[0763] To a solution of 3,4,5-tribromo-lH-pyrazole (90.0 g, 295 mmol) in THF (2 L) was added dropwise a solution of n-BuLi in THF (236 mL, 590 mmol) at -60 °C. After stirring at -60 °C for 1 h, DMF (114 mL, 1.48 mol) was added dropwise to the reaction mixture. The mixture was stirred at -60 °C for another 1 h and at ambient temperature for 3 h. To the mixture was added dropwise SEM-Cl (78.4 mL, 443 mmol) at ambient temperature and the resulting mixture was stirred for 16 h. The reaction mixture was poured into NaHC03solution (1.5 L) and extracted with EtOAc (1.5 L x 3). The combined organic phase was washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0 to 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).

[0764] Preparation 18av

[0765] 3,5-Dibromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-4-yl)methanol

[0766]

[0767] To a solution of 3,5-dibromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-4- carbaldehyde (10 g, 26 mmol) in MeOH (100 mL) was added NaBH4(2 g, 52 mmol) portionwise at -5 °C and then stirred at -5 °C for 2 h. The mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (7 g, 70%) as a white solid. ES / MS (m / z): 409 (M+Na).

[0768] Preparation 18aw

[0769] 3,5-Dibromo-4-(methoxymethyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole

[0770]

[0771] To a solution of (3,5-dibromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-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, and then Mel (7.37 g, 27.3 mmol) was added. After stirring at 0 °C for 2 h, the mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (1:1) to give the title compound (2.1 g, 95%) as a yellow solid. ES / MS (m / z): 401 (M+H).

[0772] Preparation 18ax

[0773] 3,5-dibromo-4-fluoro-lH-pyrazole

[0774]

[0775] To a solution of 4-fluoro-lH-pyrazole (25 g, 290 mmol) in EtOH / H2O (1:1.5) (400 mL) was added NaOAc (167 g, 2034 mmol) and Br2(186 g, 1163 mmol) at 0 °C. The mixture was allowed to warm up and stirred at ambient temperature for 12 h. The mixture was combined, extracted with EtOAc (200 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude material was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (15%) to give the title compound (18 g, 26%) as a colorless oil. ES / MS (m / z): 245 (M+H).

[0776] Preparation 18ay

[0777] 3,5-dibromo-4-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole

[0778]

[0779] 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) portion wise at 0 °C. After stirring for 1 h, SEM-Cl (15 g, 89 mmol) was added drop wise at 0 °C and then stirred at ambient temperature for 2 h. The mixture was quenched with water (400 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with EtOAc / pet. ether (10%) to give the title compound as a yellow oil (19 g, 67%). 1 H 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).

[0780] Preparation 18az

[0781] 3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-amine

[0782]

[0783] To a solution of 3-bromo-1H-pyrazol-5-amine (10 g, 62.11 mmol) in dry ACN (20 mL) cooled at 0 °C was added NaH (60%, 3.7 g, 93.17 mmol) slowly. The mixture was stirred at 0 °C for 30 min and then SEM-Cl (11.3 g, 68.32 mmol) was added slowly. After stirring at ambient temperature for 2 h, the mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH / DCM (12%) to give the title compound as a yellow oil (7 g, 39%). ES / MS (m / z): 292 (M+H).

[0784] Preparation 18ba

[0785] 5-Bromo-N-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pentanamide

[0786]

[0787] To a mixture of 3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-amine (7 g, 24.05 mmol) and Et3N (12.1 g, 120.27 mmol) in ACN (50 mL) was added 5-bromopentanoyl chloride (9.8 g, 48.11 mmol) dropwise. After stirring at ambient temperature for 12 h, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH / DCM (5%) to give the title compound as a yellow oil (8 g, 73%). ES / MS (m / z): 456 (M+H).

[0788] Preparation 18bb

[0789] 1-(3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)piperidin-2-one

[0790]

[0791] To a solution of 5-bromo-N-(3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-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 in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH / DCM (5%) to give the title compound as a colorless oil (3.5 g, 54%). ES / MS (m / z): 374 (M+H).

[0792] Preparation 18bc

[0793] N-(3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)-3-(4-chloro-3- fluorophenyl)acrylamide

[0794]

[0795] To a solution of 3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-amine (5 g, 17.2 mmol) in DMA (30 mL) was added HATU (13 g, 34.4 mmol), 3-(4-chloro-3-fluorophenyl)propanoic acid (4.2 g, 20.6 mmol) and DIPEA (6.6 g, 51.5 mmol). After stirring at 120 °C for 12 h, the reaction mixture was allowed to cool, water (100 mL) was added, followed by extraction with EtOAc (100 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (25%) to give the title compound as a yellow oil (5.2 g, 64%). ES / MS m / z: 476 and 478 (M+H).

[0796] The compounds in Table 3m were prepared in a manner essentially analogous to that found in the preparation of 18bc.

[0797] Table 3m

[0798]

[0799] Preparation 18be

[0800] 4-bromo-N-(3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5- yl)butanamide

[0801]

[0802] To a solution of 3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-amine (85.00 g, 292.1 mmol) in DCM (800 mL) was added pyridine (69.23 g, 876.3 mmol) and 4-bromobutyryl 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 x 2). The organic layers were combined, washed with saturated aqueous NaCl (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude title compound as a yellow oil (150.00 g, 99+%). The crude product was used directly in the next step. ES / MS (m / z): 440 (M+H).

[0803] Preparation 18bf

[0804] 1 -(3-bromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-5-yl)pyrrolidin-2-one

[0805]

[0806] To a solution of 4-bromo-N-(3-bromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H- pyrazol-5-yl)butanamide (150.00 g, 340.1 mmol) in ACN (800 mL) was added potassium 2-methylpropan-2-olate (114.55 g, 1023.7 mmol) at 0 °C and then stirred at 25 °C for 2 h. The mixture was filtered and the filtrate was concentrated in vacuo to give crude material. The crude material was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (13%) to give the title compound as a yellow oil (46.00 g, 37%). ES / MS (m / z): 360 (M+H).

[0807] Preparation 18bg

[0808] 1 -(3-bromo-4-fluoro-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-5-yl)pyrrolidin-2- one

[0809]

[0810] To a solution of 1 -(3-bromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-5-yl)pyrrolidin- 2-one (50.60 g, 139.8 mmol) in ACN (600 mL) was added (1 -chloromethyl-4-fluoro-1,4- diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (111.82 g, 349.5 mmol) and then stirred at 80 °C for 1.5 h. The mixture was filtered and the filtrate was concentrated in vacuo to give crude material. The crude was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (15%) to give the title compound as a yellow oil (18.00 g, 34%). ES / MS (m / z): 378 (M+H).

[0811] Preparation 19

[0812] N-(3,6-dichloropyridazin-4-yl)carbamic acid tert-butyl ester

[0813]

[0814] To a mixture of 3,6-dichloropyridazine-4-carboxylic acid (4 g, 20.76 mmol) in 1,4-dioxane (100 mL) was added Et3N (2.11 g, 20.8 mmol), DPPA (5.77 g, 20.76 mmol) and tert-butanol (26.6 mL) and the mixture was stirred at 110 °C for 3 h. The mixture was concentrated in vacuo. The residue was purified via silica gel flash chromatography eluting with EtOAc / petroleum ether (15:85) to give the title compound as a white solid (4.31 g, 85%). ES / MS m / z 264.1 (M+H).

[0815] Preparation 20

[0816] N-(6-chloro-3-methyl-pyridazin-4-yl)carbamic acid tert-butyl ester

[0817]

[0818] To a mixture of N-(3,6-dichloropyridazin-4-yl)carbamic acid tert-butyl ester (0.4 g, 1.52 mmol) in 1,4-dioxane:water (4:1) (15 mL) was added methylboronic acid (0.45 g, 7.58 mmol), Pd(dppf)Cl2(0.2 g, 0.3 mmol) and K2CO3(0.6 g, 4.55 mmol) and then stirred at 80 °C under N2atmosphere for 12 h. The mixture was concentrated in vacuo. The crude was purified via silica gel flash chromatography eluting with EtOAc / petroleum ether (20:80) to give the title compound as a yellow solid (0.25 g, 67%). ES / MS m / z 244.1 (M+H).

[0819] Preparation 21

[0820] N-(3-methylpyridazin-4-yl)carbamic acid tert-butyl ester

[0821]

[0822] To a mixture of N-(6-chloro-3-methyl-pyridazin-4-yl)carbamic acid tert-butyl ester (5.1 g, 21 mmol) in EtOH (100 mL) was added Ph3P (0.5 g, 2.1 mmol), Pd(OAc)2(0.47 g, 2.1 mmol), Et3N (4.2 g, 42 mmol) and Et3SiH (7.3 g, 63 mmol). The mixture was stirred at 80 °C under N2atmosphere for 5 h. The reaction mixture was concentrated in vacuo. The residue was purified via silica gel flash chromatography eluting with EtOAc / petroleum ether (80:20) to give the title compound as a yellow solid (3.9 g, 89%). ES / MS m / z 210.1 (M+H).

[0823] Preparation 22

[0824] 3-methylpyridazin-4-amine

[0825]

[0826] To a mixture of N-(3-methylpyridazin-4-yl)carbamic acid tert-butyl ester (0.5 g, 2.40 mmol) in DCM (3 mL) at 0 °C was added HC1 in 1,4-dioxane (4 M, 3 mL) and then stirred at ambient temperature for 12 h. The mixture was concentrated in vacuo to give the crude title compound as a yellow solid (0.27 g, 99+%). ES / MS m / z 110.0 (M+H).

[0827] Preparation 23

[0828] 4-bromo-3-methylpyridazine

[0829]

[0830] To a mixture of 3-methylpyridazin-4-amine (0.2 g, 1.8 mmol) and CuBr2(1.63 g, 7.34 mmol) in ACN (10 mL) was added tert-butyl nitrite (0.38 g, 3.7 mmol) and then stirred at 65 °C for 30 min. The reaction mixture was concentrated in vacuo. Ammonia (15 wt%, 50 mL) was added to the reaction, which was then extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give the crude title compound as a brown oil (0.1 g, 32%). ES / MS m / z 173.1 (M+H).

[0831] Preparation 23a

[0832] Trimethyl(3-((tetrahydro-2H-pyran-2-yl)oxy)prop-1-yn-1-yl)stannane

[0833]

[0834] To a solution of 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (5.5 g, 39 mmol) in dry THF (80 mL) was slowly added n-BuLi in THF (23.4 mL, 2.5 molar, 58.5 mmol) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 0.5 h and then slowly added trimethyltin chloride (8.6 g, 43 mmol). After stirring at -78 °C for 4 h under nitrogen, the mixture was quenched with saturated NH4Cl solution (100 mL) and then extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow oil (9.3 g, 70%). 1 H NMR (DMSO-d6): δ

[0835] 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).

[0836] Preparation 23b

[0837] 4-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-5-(trimethylstannyl)pyridazine

[0838]

[0839] 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 and then cooled to ambient temperature, quenched by water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH / DCM (0-15%) to give the title compound as a yellow oil (7.6 g, 59%). ES / MS (m / z): 359 (M+H).

[0840] Preparation 24

[0841] N-[1-(3-methylpyridazin-4-yl)pyrazol-4-yl]carbamic acid tert-butyl ester

[0842]

[0843] To a mixture of N-(1 H-pyrazol-4-yl)carbamic acid tert-butyl ester (0.2 g, 1 mmol) in DMF (10 mL) was added 4-bromo-3-methylpyridazine (0.38 g, 2 mmol), K3PO4(0.7 g, 3.3 mmol), CuI (0.2 g, 1 mmol) and N,N'-dimethyl-1,2-cyclohexanediamine (0.16 g, 1 mmol) and then stirred at 90 °C under N2atmosphere for 2 h. The mixture was quenched with H2O (20 mL) and extracted with EtOAc (50 mL x 3). The combined EtOAc layers were concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting 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).

[0844] Preparation 25

[0845] 1-(3-methylpyridazin-4-yl)pyrazol-4-amine

[0846]

[0847] To a mixture of N-[1-(3-methylpyridazin-4-yl)pyrazol-4-yl]carbamic acid tert-butyl ester (50 mg, 0.18 mmol) in DCM (2 mL) was added HC1 in 1,4-dioxane (4 mol / L, 2 mL). The mixture was stirred at ambient temperature for 2 h then concentrated in vacuo to give the title compound (50 mg, 99+%) as a yellow oil. ES / MS m / z 176.2 (M+H).

[0848] Preparation 26

[0849] 1-(5-amino-3-(5-methylpyridazin-4-yl)-1 H-1,2,4-triazol-1 -yl)-5-bromopentan-1 -one

[0850]

[0851] To a mixture of 3-(5-methylpyridazin-4-yl)-lH-l,2,4-triazol-5-amine (3.1 g, 17.61 mmol) and 5-bromopentanoic acid (3.5 g, 19.38 mmol) in DMA (20 mL) was added DIPEA (5.7 g, 44.03 mmol) slowly at 0 °C, and then TBTU (8.5 g, 26.42 mmol) was added. The mixture was stirred at 10 °C for 4 h, then water (50 mL) was added. The resulting precipitate was filtered, and the filter cake was dried in vacuum to give the title compound as a white solid (5 g, 85%). ES / MS m / z 341.1 (M+H).

[0852] Preparation 27

[0853] 1-(3-(5-methylpyridazin-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5-yl)piperidin-2-one

[0854]

[0855] To a solution of l-(5-amino-3-(5-methylpyridazin-4-yl)-lH-l,2,4-triazol-l-yl)-5- bromopentan-l-one (5 g, 14.79 mmol) in DMF (20 mL) was added NaH (1.18 g, 29.59 mmol) slowly at 0 °C, and then stirred at 0 °C for 4 h. SEM-Cl (2.8 mL, 16.27 mmol) was added slowly at 0 °C, then stirred for 1 h. The mixture was added to water (100 mL), then extracted with EtOAc (200 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, concentrated in vacuum, and purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (20:80) to give the title compound as a brown oil (2.6 g, 45%). ES / MS m / z 389.2 (M+H).

[0856] Preparation 28

[0857] 3-(4-fluorobenzyl)-l-(3-(5-methylpyridazin-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5-yl)piperidin-2-one

[0858]

[0859] 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 dry THF (10 mL) at -78 °C was added a solution of LiHMDS (1 M in THF, 1.3 mL, 1.3 mmol). After stirring for 30 min, a solution of 1-(bromomethyl)-4-fluorobenzene (189 mg, 1.0 mmol) in dry THF (5 mL) was added to the reaction mixture and stirred at -78 °C for 1.5 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (50 mL x 2). The combined organic layers were dried and concentrated in vacuo, 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).

[0860] Preparation 30a

[0861] ((5-(3-(3,4-difluorobenzyl)-2-oxopiperidin-1-yl)-3-(pyridazin-4-yl)-1H-1,2,4-triazol-1- yl)methyl)di-tert-butylphosphonate (isomer 1)

[0862]

[0863] 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)phosphonate (1.383 g, 5.346 mmol) and cesium fluoride (2.030 g, 13.37 mmol) in dry DMF (40 mL) was stirred at ambient temperature for 16 h. The mixture was treated with water (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified on a reverse-phase column chromatography with a gradient of ACN / H2O (0-60%). The appropriate fractions were combined, concentrated in vacuo and extracted with EtOAc. The organic layer was concentrated in vacuo to give the title compound as a yellow solid (1.0 g, 60%). ES / MS (m / z): 593 (M+H).

[0864] The compounds in Table 4a were prepared in essentially the same manner as found in Preparation 30a.

[0865] Table 4a

[0866]

[0867]

[0868] Preparation 31

[0869] (R)-4-benzyl-3-((R)-5-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-3- fluorobenzyl)pentanoyl)oxazolidin-2-one

[0870]

[0871] A solution of (R)-4-benzyl-3-(5-((tert-butyldimethylsilyl)oxy)pentanoyl)oxazolidin- 2-one (CAS Registry Number 1353545-65-9, prepared as in Li et al. Tetrahedron (2012), 68(3), 846-850) (3 g, 7.67 mmol) in dry THF (30 mL) was cooled to -78 °C under N2and then a solution of NaHMDS in THF (2 M, 4.2 mL, 8.44 mmol) was added dropwise while keeping the temperature below -65 °C. After stirring the mixture for 2 h, a solution of 4-(bromomethyl)-1-chloro-2-fluorobenzene (4.3 g, 19.18 mmol) in dry THF (10 mL) was added. The mixture was stirred overnight while the temperature was slowly allowed to rise to ambient temperature. The reaction mixture was cooled to -78 °C, quenched with saturated NaHCO3(100 mL), and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH / DCM (5-10%) to give the title compound as a yellow oil (3.0 g, 60%). ES / MS m / z 534 (M+H).

[0872] The compounds in Table 5 were prepared in essentially analogous fashion to that found in Preparation 31.

[0873] Table 5

[0874]

[0875]

[0876] Preparation 35

[0877] (R)-4-benzyl-3-((R)-2-(4-chloro-3-fluorobenzyl)-5-hydroxypentanoyl)oxazolidin-2- one

[0878]

[0879] 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 dry THF (10 mL) was added dropwise HF.Et3N (3 g, 9.38 mmol) and then stirred at ambient temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 50-60% EtOAc / petroleum ether to give the title compound as a white oil (0.65 g, 83%). ES / MS m / z 420 (M+H).

[0880] The compounds in Table 6 were prepared in essentially analogous fashion to that found in Preparation 35.

[0881] Table 6

[0882]

[0883]

[0884] Preparation 39

[0885] (R)-5-((R)-4-benzyl-2-oxooxazolidin-3-yl)-4-(4-chloro-3-fluorobenzyl)-5- oxopentanal

[0886]

[0887] 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) and then stirred at ambient temperature for 1 hour. The reaction mixture was quenched with saturated aqueous NaS2O3 (30 mL) and saturated aqueous NaHCO3 (30 mL) and then extracted with EtOAc (100 mL x 5). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 20-40% EtOAc / petroleum ether to give the title compound as a white oil (1.2 g, 65%). ES / MS m / z 418 (M+H).

[0888] The compounds in Table 7 were prepared in essentially analogous fashion to that found in Preparation 39.

[0889] Table 7

[0890]

[0891]

[0892] Preparation 43

[0893] (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

[0894]

[0895] 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 h. NaBH3CN (302 mg, 4.8 mmol) was then added. The mixture was stirred at ambient temperature for 12 h and then concentrated in vacuo. Water (10 mL) was added and extracted with EtOAc (50 mL x 2). The combined organics were dried over anhydrous sodium sulfate, concentrated in vacuo and purified via silica gel flash chromatography eluting with EtOAc / petroleum ether (1 :5) to give the title compound as a yellow oil (500 mg, 43%). ES / MS m / z 697 (M+H).

[0896] The compounds in Table 8 were prepared in essentially the same manner as found in Preparation 43.

[0897] Table 8

[0898]

[0899]

[0900] Preparation 45

[0901] (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

[0902]

[0903] A mixture of 3-(5-methylpyridazin-4-yl)-lH-l,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 h. NaBH3CN (214 mg, 3.4 mmol) was added. The mixture was stirred at ambient temperature for 12 h and then concentrated in vacuo. Water (5 mL) was added to the residue, which was extracted with EtOAc (30 mL x 2). The combined organic layers were dried, concentrated in vacuo 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 as a yellow oil (60 mg, 6%). ES / MS m / z 579 (M+H)+.

[0904] The compounds in Table 8a were prepared in essentially analogous fashion to that found in Preparation 45.

[0905] Table 8a

[0906]

[0907] Preparation 48a

[0908] (R)-4-benzyl-3-((S)-2-((6-chloro-5-fluoropyridin-3-yl)methyl)-5-((3-(5- methylpyridazin-4-yl)-lH-pyrazol-5-yl)amino)pentanoyl)oxazolidin-2-one

[0909]

[0910] To a solution of (R)-4-benzyl-3-((S)-2-((6-chloro-5-fluoropyridin-3-yl)methyl)-5-((l- (4-methoxybenzyl)-3-(5-methylpyridazin-4-yl)-lH-pyrazol-5-yl)amino)pentanoyl)oxazolidin- 2-one (1.35 g, 1.94 mmol) in DCM (10 mL) at 0 °C was added TFA (8 mL). After stirring at ambient temperature for 6 h, the reaction mixture was concentrated in vacuo. To the residue was added water (5 mL) and saturated NaHC03(15 mL). The resulting precipitate was filtered and purified by preparative HPLC to give the title compound as a white solid (120 mg, 11%). ES / MS (m / z): 578 (M+H).

[0911] Preparation 49

[0912] (S)-2-(4-chloro-3-fluorobenzyl)-5-((3-(5-methylpyridazin-4-yl)-lH-l,2,4-triazol-5- yl)amino)pentanoic acid

[0913]

[0914] A mixture of (R)-4-benzyl-3-((S)-2-(4-chloro-3-fluorobenzyl)-5-((3-(5- methylpyridazin-4-yl)-lH-l,2,4-triazol-5-yl)amino)pentanoyl)oxazolidin-2-one (60 mg, 0.1 mmol) and H2O2(20 mg, 0.6 mmol) in THF / water (4 / 1, 3 mL) was stirred at ambient temperature for 10 min, and then LiOH.H2O (13 mg, 0.3 mmol) was added. The mixture was stirred at ambient temperature for 16 h, and then quenched with aqueous Na2SO3(10 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, concentrated in vacuo, 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).

[0915] The compounds in Table 9 were prepared in a manner essentially analogous to that found in Preparation 49.

[0916] Table 9

[0917]

[0918] Preparation 49c

[0919] 3-oxomorpholine-4-carboxylic acid tert-butyl ester

[0920]

[0921] To a solution of morpholine-3-one (1 g, 10 mmol) in DCM (20 mL) was added Boc2O (4.3 g, 20 mmol) and DMAP (0.24 g, 2 mmol), and then stirred at ambient temperature for 1 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel flash chromatography eluting with MeOH / DCM (2:98) to give the title compound (1.8 g, 90%) as a red solid. MS (m / z): 224 (M+Na) + .

[0922] The compounds in Table 9a were prepared in a manner essentially analogous to that found in Preparation 49c.

[0923] Table 9a

[0924]

[0925] Preparation 50

[0926] 2-(4-chlorobenzyl)-3-oxomorpholine-4-carboxylic acid tert-butyl ester

[0927]

[0928] To a mixture of 2-(4-chlorobenzyl)-3-oxomorpholine-4-carboxylic acid tert-butyl ester (0.3 g, 0.9 mmol) in 1,4-dioxane (5 mL) was stirred at ambient temperature for 2 hours, and then concentrated in vacuo to give the title compound (0.2 g, 96%) as a yellow solid. ES / MS m / z 226.1 (M+H).

[0929] The compounds in Table 9b were prepared in essentially analogous fashion to that found in the preparation of 50.

[0930] Table 9b

[0931]

[0932] Preparation 51

[0933] 2-(4-chlorobenzyl)-3-oxomorpholine-4-carboxylic acid tert-butyl ester

[0934]

[0935] To a mixture of 2-(4-chlorobenzyl)-3-oxomorpholine-4-carboxylic acid tert-butyl ester (0.3 g, 0.9 mmol) in 1,4-dioxane (5 mL) was stirred at ambient temperature for 2 hours, and then concentrated in vacuo to give the title compound (0.2 g, 96%) as a yellow solid. ES / MS m / z 226.1 (M+H).

[0936] Preparation 51a

[0937] 1 -benzyl-4-(hydroxymethyl)pyrrolidin-2-one

[0938]

[0939] To a solution of 1 -benzyl-5-oxopyrrolidine-3-carboxylic acid methyl ester (5.00 g, 21.45 mmol) in MeOH (20 mL) was added NaBH4(1.80 g, 75 mmol) at 0 °C, and then stirred at 25 °C for 12 h under nitrogen. The reaction mixture was quenched with H2O (100 mL) at 0 °C and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting 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).

[0940] Preparation 51b

[0941] 1 -benzyl-4-(hydroxymethyl)pyrrolidin-2-one

[0942]

[0943] To a solution of 1 -benzyl-5-oxopyrrolidine-3-carboxylic acid methyl ester (5.00 g, 21.45 mmol) in MeOH (20 mL) was added NaBH4(1.80 g, 75 mmol) at 0 °C, and then stirred at 25 °C for 12 h under nitrogen. The reaction mixture was quenched with H2O (100 mL) at 0 °C and extracted with EtOAc (40 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography eluting 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).

[0944] The compounds in Table 9b were prepared in a manner essentially analogous to that found in Preparation 51b.

[0945] Table 9b

[0946]

[0947] Preparation 51d

[0948] 1 -Benzyl-3-(4-chloro-3, 5-difluorobenzyl)-4-(methoxymethyl)pyrrolidin-2-one

[0949]

[0950] To a solution of 1 -benzyl-4-(methoxymethyl)pyrrolidin-2-one (3.00 g, 13.5 mmol) in dry THF (10 mL) was added 1 M LiHMDS in THF (17 mL, 17 mmol) dropwise at -78 °C under nitrogen. After stirring at -78 °C for 30 min, a solution of 5-(bromomethyl)-2-chloro-1,3-difluorobenzene (3.27 g, 13.5 mmol) in THF (6 mL) was added dropwise and then stirred at -78 °C for 30 min. The reaction mixture was quenched with water (50 mL) and extracted with DCM (15 mL x 5). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (1 :1 ) to give the title compound as a yellow oil (1.9 g, 37%). MS (m / z): 380 (M+H).

[0951] Preparation 51e

[0952] 3-(4-Chloro-3, 5-difluorobenzyl)-4-(methoxymethyl)pyrrolidin-2-one

[0953]

[0954] To a mixture of 1 -benzyl-3-(4-chloro-3, 5-difluorobenzyl)-4-(methoxymethyl)pyrrolidin-2-one (1.90 g, 5.00 mmol) in CH3NO2 (8 mL) was added KBr (595 mg, 5.00 mmol) and potassium peroxomonosulfate (4.61 g, 7.50 mmol) and then stirred at 80 °C for 96 h. The mixture was allowed to cool to ambient temperature, added to water (30 mL) and extracted with EtOAc (40 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (1 :1 ) to give the title compound as a white solid (900 mg, 62%). ES / MS (m / z): 290 (M+H).

[0955] Preparation 51f

[0956] 1 -(2,4-Dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylic acid

[0957]

[0958] To a solution of 2-methylenebutanedioic acid (4.0 g, 31 mmol) in toluene (40 mL) was added (2,4-dimethoxyphenyl)methanamine (5.7 g, 34 mmol) and then stirred at 110 °C for 16 h. The reaction mixture was allowed to cool and concentrated in vacuo. The residue was dissolved in LiOH solution (1 M, 70 mL) and extracted with EtOAc (50 mL x 3). The aqueous solution was acidified to pH = 4 by adding dilute HC1 solution and extracted with EtOAc (80 mL x 3). The organic phases were combined, washed with saturated aqueous NaCl, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a yellow oil (8.0 g, 89%). ES / MS (m / z): 280 (M+H).

[0959] Preparation 51g

[0960] 1-(2,4-dimethoxybenzyl)-5-oxo-4-(3,4,5-trifluorobenzyl)pyrrolidine-3-carboxylic acid

[0961]

[0962] 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 in THF (18 mL, 36 mmol) at -78 °C under nitrogen. After stirring for 45 min, 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 and then stirred at -78 °C for 2 h. The mixture was added to water (40 mL). The pH was adjusted to 6 with 1 M HC1, followed by extraction with EtOAc (70 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with DCM / MeOH (20:1) to give the title compound as a yellow oil (3.0 g, 47%). ES / MS (m / z): 424 (M+H).

[0963] Preparation 51h

[0964] 1-(2,4-dimethoxybenzyl)-5-oxo-4-(3,4,5-trifluorobenzyl)pyrrolidine-3-carboxylic acid amide

[0965]

[0966] To a solution of l-(2,4-dimethoxybenzyl)-5-oxo-4-(3,4,5-trifluorobenzyl)pyrrolidine-3- carboxylic acid (3.5 g, 8.3 mmol) in ACN (30 mL) was added di-tert-butyl dicarbonate (5.4 g, 25 mmol), ammonium bicarbonate (3.3 g, 41 mmol) and pyridine (1.3 mL, 17 mmol), and then stirred at 25 °C for 2 h. Water (60 mL) was added, and then extracted with EtOAc (80 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (30: 1) to give the title compound (2.5 g, 68%) as a yellow solid. ES / MS (m / z): 423 (M+H).

[0967] The compounds in Table 9c were prepared in a manner essentially analogous to that found in Preparation 51h.

[0968] Table 9c

[0969]

[0970] Preparation 51j

[0971] 1-(2,4-dimethoxybenzyl)-5-oxo-4-(3,4,5-trifluorobenzyl)pyrrolidine-3-carbonitrile

[0972]

[0973] To a solution of l-(2,4-dimethoxybenzyl)-5-oxo-4-(3,4,5-trifluorobenzyl)pyrrolidine-3- carboxylic acid (3.5 g, 8.3 mmol) in ACN (30 mL) was added di-tert-butyl dicarbonate (5.4 g, 25 mmol), ammonium bicarbonate (3.3 g, 41 mmol) and pyridine (1.3 mL, 17 mmol), and then stirred at 25 °C for 2 h. Water (60 mL) was added, and then extracted with EtOAc (80 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (30: 1) to give the title compound (2.5 g, 68%) as a yellow solid. ES / MS (m / z): 423 (M+H).

[0974] Preparation 51l

[0975] 5-oxo-4-(3,4,5-trifluorobenzyl)pyrrolidine-3-carbonitrile

[0976]

[0977] To a solution of l-(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 trifluoromethanesulfonic acid (2.3 g, 15 mmol) and then stirred at 25 °C for 16 h. The reaction mixture was concentrated in vacuo. To the mixture was added saturated aqueous NaHC03solution (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 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 as a white solid (1.2 g, 75%). ES / MS (m / z): 255 (M+H).

[0978] The compounds in Table 9d were prepared in a manner essentially analogous to that found in Preparation 51 1.

[0979] Table 9d

[0980]

[0981] Preparation 51m

[0982] (2-bromo-5-methylphenyl)carbamic acid tert-butyl ester

[0983]

[0984] To a solution of 2-bromo-5-methylaniline (3.00 g, 16.1 mmol) in THF (50 mL) was added 2M NaHMDS in THF (16.1 mL, 32.2 mmol) dropwise at -78 °C. After stirring at -78 °C for 0.5 h, Boc20 (3.52 g, 16.1 mmol) in THF (10 mL) was added dropwise at -78 °C. After stirring at 25 °C for 3 h, the reaction mixture was poured into saturated aqueous NaCl solution (200 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (1 : 1) to give the title compound as a yellow oil (4.3 g, 91.7%). ES / MS (m / z): 232.1 (M+H-56).

[0985] Preparation 51n

[0986] (E)-3-(2-((tert-butoxycarbonyl)amino)-4-methylphenyl)acrylic acid ethyl ester

[0987]

[0988] To a mixture of tert-butyl (2-bromo-5-methylphenyl)carbamate (1.24 g, 4.33 mmol) in 1,4-dioxane (10.8 mL) was added ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (1.18 g, 5.20 mmol), sodium carbonate (1.38 g, 13.0 mmol), PdCl2(dppf) (317.0 mg, 0.43 mmol) and water (1.2 mL). After stirring at 90 °C for 16 h under nitrogen, the reaction mixture was allowed to cool and filtered in vacuo. The mixture was added to water (200 mL) and extracted with EtOAc (200 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (95:5) to give the title compound as a white solid (1.183 g, 77%). ES / MS (m / z): 250 (M+H-tBu).

[0989] Preparation 51o

[0990] 5-bromo-3-fluoro-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyridine

[0991]

[0992] 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 for 2 h under nitrogen, the reaction mixture was allowed to cool, diluted with EtOAc (30 mL), washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as an orange oil (1.49 g, 96%). ES / MS (m / z): 206 and 208 (M+H-84).

[0993] Preparation 52

[0994] 4-methyl-5-(trimethylstannyl)pyridazine

[0995]

[0996] A mixture of 4-bromo-5-methylpyridazine (1 g, 5.81 mmol), hexamethylditin (2.5 g, 7.56 mmol) and Pd(PPh3)4(335 mg, 0.29 mmol) in 1,4-dioxane (12 mL) was stirred at 95 °C under N2for 4 h, and then filtered through celite. The filtrate was concentrated, and the residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (25-35%) to give the title compound as a black solid (490 mg, 33%). ES / MS (ES) m / z 259 (M+H).

[0997] Preparation 52a

[0998] 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-5-methylpyridazine

[0999]

[1000] 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 N2atmosphere for 5 h. The mixture was quenched with saturated aqueous KF solution (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 0-5% MeOH in DCM to give the title compound as a yellow oil (130 mg, 91%). ES / MS m / z 369.1 (M+H).

[1001] Preparation 53

[1002] 2-(4-chlorobenzyl)-4-(3-(5-methylpyridazin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)morpholine-3-one

[1003]

[1004] To a mixture of 2-(4-chlorobenzyl)morpholin-3-one (100 mg, 0.44 mmol) in 1,4-dioxane (2 mL) was added 4-(5-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-5- methylpyridazine (245 mg, 0.67 mmol), N,N'-dimethyl-1,2-cyclohexanediamine (63 mg, 0.44 mmol), K3PO4 (94 mg, 0.44 mmol) and Cul (84 mg, 0.44 mmol). The mixture was stirred at 90 °C under nitrogen for 5 hours. The mixture was then concentrated in vacuo. The residue was purified by preparative HPLC (C18, ACN = 65-95% in 13 mL TFA, 17 min, rt = 8.9 min) to give the title compound as a white solid (35 mg, 15%). ES / MS m / z 514.2 (M+H).

[1005] Preparation 53a

[1006] 5-chloropentanoic acid benzyl ester

[1007]

[1008] To a solution of 5-chloropentanoic acid (10.0 g, 73.2 mmol) in ACN (60 mL) was added (bromomethyl)benzene (13.8 g, 80.5 mmol) and potassium carbonate (12.1 g, 87.9 mmol) at ambient temperature. The reaction mixture was stirred at 80 °C for 16 hours. After cooling to ambient temperature, the solvent was removed in vacuo and the residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-15%) to give the title compound as a colourless oil (9.10 g, 41%). 1 H 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).

[1009] Preparation 54

[1010] 5-chloro-2-((6-fluoropyridin-3-yl)(hydroxy)methyl)pentanoic acid benzyl ester

[1011]

[1012] To a solution of LDA (12 mmol) in THF (24 mL) at -78 °C was added 5-chlorobenzyl valerate (2.9 g, 13 mmol) (prepared as described in Hoffman, M, et al. Chem. Med. Chem., 2018, 13(23), 2546-2557) and stirred at -78 °C for 1 h. A solution of 6-fluoroisonicotinaldehyde (1 g, 8 mmol) in THF (5 mL) was added at -78 °C. The reaction was stirred for another 3 h at -78 °C. The reaction was quenched by NH4CI (50 mL) and extracted with EtOAc (25 mL x 3). The combined organic layers were washed with saturated aqueous NaCI, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 0-20% EtOAc / petroleum ether to give the title compound as a light yellow oil (2.5 g, 86%). ES / MS m / z 352 (M+H).

[1013] The compounds in Table 9e were prepared in essentially the same manner as found in Preparation 54.

[1014] Table 9e

[1015]

[1016] Preparation 55

[1017] (Z)-5-chloro-2-((6-fluoropyridin-3-yl)methylene)pentanoic acid benzyl ester

[1018]

[1019] A solution of 5-chloro-2-((6-fluoropyridin-3-yl)(hydroxy)methyl)pentanoic acid benzyl ester (1.5 g, 4.26 mmol) and TFA (2.2 g, 11 mmol) in DCM (25 mL) was stirred at ambient temperature under nitrogen overnight. DBU (3 g, 19 mmol) was added dropwise while keeping below 30 °C and then stirred for 1 h. The mixture was concentrated in vacuo and the residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0 to 20%) to give the title compound as a light yellow oil (0.9 g, 64%). ES / MS m / z = 334 (M+H).

[1020] The compounds in Table 9f were prepared in essentially the same manner as found in Preparation 55.

[1021] Table 9f

[1022]

[1023] Preparation 56

[1024] 5-chloro-2-((6-fluoropyridin-3-yl)methyl)pentanoic acid

[1025]

[1026] To a solution of (Z)-benzyl 5-chloro-2-((6-fluoropyridin-3-yl)methylidene)pentanoate (0.9 g, 2.7 mmol) in EtOH (30 mL) at ambient temperature was added 10% Pd / C (200 mg) followed by stirring under an atmosphere of H2at ambient temperature for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo to give the crude title compound as a colorless oil (650 mg, crude). ES / MS m / z = 246 (M+H);1H NMR (CDCI3) 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).

[1027] The compounds in Table 9g are prepared in a manner essentially analogous to that found in Preparation 56.

[1028] Table 9g

[1029]

[1030] Preparation 57

[1031] 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

[1032]

[1033] 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), DMAP (15 mg, 0.12 mmol) followed by stirring at ambient temperature for 1 h, then 3-(5-methylpyridazin-4-yl)-lH-l,2,4-triazol-5-amine (233 mg, 1.32 mmol) was added, 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 EtOAc / pet. (1:1) and filtered to give the title compound as a white solid (384 mg, 75%). ES / MS m / z 403 (M+H).

[1034] The compounds in Table 9ah were prepared in a manner essentially analogous to that found in Preparation 57.

[1035] Table 9ha

[1036]

[1037] Preparation 57a-a

[1038] 5-chloro-2-((6-fluoropyridin-3-yl)methyl)-N-(2-(pyridazin-4-yl)-2H-l,2,3-triazol-4- yl)pentanamide

[1039]

[1040] To a solution of 5-chloro-2-((6-fluoropyridin-3-yl)methyl)pentanoic acid (260 mg, 1.06 mmol) in pyridine (6 mL) at 0 °C was added 2-(pyridazin-4-yl)-2H-l,2,3-triazol-4-amine (257 mg, 1.59 mmol) and phosphorous oxychloride (325 mg, 2.12 mmol). The reaction mixture was stirred at 0 °C for 1 h. The solvent was removed in vacuo, the residue was diluted with water (3 mL) and extracted with EtOAc (3 mL x 3). The combined organic layers were washed with water (3 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / pet. (0-100%) to give the title compound as a yellow solid (150 mg, 35%). ES / MS (m / z): 390 (M+H).

[1041] The compounds in Table 9d were prepared in a manner essentially analogous to that found in Preparation 57a-a.

[1042] Table 9d

[1043]

[1044] Preparation 58

[1045] 3-(4-chloro-3-fluorophenyl)-N-(3-(5-methylpyridazin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)propanamide

[1046]

[1047] To a solution of N-(3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)-3- (4-chloro-3-fluorophenyl)propanamide (1 g, 2 mmol) in DMF (10 mL) was added 4- methyl-5-(trimethylstannyl)pyridazine (0.65 g, 2.5 mmol), CuI (40 mg, 0.2 mmol) and Pd(PPh3)4(0.5 g, 0.4 mmol) under nitrogen. After stirring at 100 °C for 12 h, the reaction mixture was allowed to cool to ambient temperature, quenched by the addition of saturated KF solution (30 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude product was purified by silica gel flash chromatography eluting with MeOH / CH2Cl2(7%) to give the title compound as a red oil (0.95 g, 92%). ES / MS (m / z): 490 (M+Na).

[1048] Preparation 58a

[1049] N-(3-(5-(bromomethyl)pyridazin-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5- yl)-3-(4-chloro-3-fluorophenyl)propanamide

[1050]

[1051] 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 in vacuo. The residue was purified by silica gel column chromatography eluting with MeOH / DCM (10%) to give the title compound as colorless oil (0.65 g, 70%). ES / MS (m / z): 568 (M+H).

[1052] Preparation 58b

[1053] 3-(4-chloro-3-fluorophenyl)-N-(3-(5-(fluoromethyl)pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)propanamide

[1054]

[1055] 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 2.5M n-BuLi in THF (0.68 mL, 1.8 mmol) at -78 °C under nitrogen. After stirring at -78 °C for 1 h, N-fluorobenzenesulfonimide (0.43 g, 1.4 mmol) was added and then stirred at -78 °C for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether (25%) to give the title compound as colorless oil (60 mg, 10%). ES / MS (m / z): 508 (M+H).

[1056] Preparation 5ba

[1057] 5-bromo-N-(4-methoxybenzyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3- amine

[1058]

[1059] To a solution of 3,5-dibromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-l,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 allowed to cool, poured into water (300 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH / DCM (5%) to give the title compound as a brown oil (13 g, 71%). ES / MS m / z: 413 (M+H)

[1060] Preparation 58c

[1061] N-(5-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-3-yl)-3-(4- chloro-3,5-difluorophenyl)-N-(4-methoxybenzyl)propanamide

[1062]

[1063] To a solution of 5-bromo-N-(4-methoxybenzyl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-l,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 H2O (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 7% MeOH / DCM to give the title compound as a yellow solid (1.1 g, 49%). ES / MS (m / z): 615 / 617 (M+H).

[1064] Preparation 58d

[1065] 5-((tert-butoxycarbonyl)amino)-2-(4-chloro-3-fluorobenzyl)pentanoic acid

[1066]

[1067] To a solution of 3-(4-chloro-3-fluorobenzyl)-2-oxopiperidine-1 -carboxylic acid tert-butyl ester (1.2 g, 3.5 mmol) in THF (20 mL) at 0 °C was added LiOH (0.22 g, 5.3 mmol) in H2O (5 mL). After stirring at ambient temperature for 2 h, the reaction mixture was quenched dropwise with 1 N HCI (6 mL, 6 mmol) at 0 °C and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with saturated aqueous NaCI (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a colorless oil (1.2 g, 95%). ES / MS (m / z): 382 (M+Na).

[1068] The compounds in Table 9e were prepared in a manner essentially analogous to that found in Preparation 58c.

[1069] Table 9e

[1070]

[1071]

[1072] Preparation 58h

[1073] 5-amino-2-(4-chloro-3-fluorobenzyl)pentanoic acid hydrochloride

[1074]

[1075] 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 4M HCI in 1,4-dioxane (5 mL, 20 mmol). After stirring at ambient temperature for 2 h, the reaction mixture was concentrated in vacuo to give the title compound as a colorless oil (1.2 g, 99+%). ES / MS (m / z): 260 (M+H).

[1076] The compounds in Table 9f were prepared in a manner essentially analogous to that found in Preparation 58g.

[1077] Table 9f

[1078]

[1079] Preparation 58l

[1080] 5-((3-bromo-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-1,2,4-triazol-5-yl)amino)-2-(4- chloro-3-fluorobenzyl)pentanoic acid

[1081]

[1082] 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 in vacuo. The mixture was added to water (25 mL), diluted with HC1 (15 mL, 15 mmol) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with MeOH / DCM (1:9) to give the title compound as a brown oil (0.38 g, 37%). ES / MS (m / z): 535 / 537 (M+H).

[1083] The compounds in Table 9g are prepared in a manner essentially analogous to that found in Preparation 58k.

[1084] Table 9g

[1085]

[1086]

[1087] Preparation 58p

[1088] 1-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-3-(4-chloro-3- fluorobenzyl)piperidin-2-one

[1089]

[1090] To a solution of 5-((3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-l,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 x 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with MeOH / DCM (0-7%) to give the title compound as a brown oil (120 mg, 25%). ES / MS (m / z): 517 (M+H).

[1091] The compounds in Table 9h were prepared in a manner essentially analogous to that found in Preparation 58p.

[1092] Table 9h

[1093]

[1094] Preparation 58s

[1095] 1-(3-bromo-4-fluoro-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)-3-(4- chloro-3,5-difluorobenzyl)pyrrolidin-2-one

[1096]

[1097] To a solution of 1-(3-bromo-4-fluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- pyrazol-5-yl)piperidin-2-one (17.00 g, 45.1 mmol) in THF (200 mL) was added 1M LiHMDS in THF (45.1 mL, 45.1 mmol) at -78 °C under nitrogen. After stirring at -78 °C for 1 h, 5-(bromomethyl)-2-chloro-1,3-difluorobenzene (10.82 g, 45.1 mmol) was added and then stirred at -78 °C under nitrogen for 3 h. The mixture was quenched with saturated NH4Cl solution (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic layers were washed with saturated aqueous NaCl solution (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel flash chromatography eluting with 15% EtOAc / petroleum ether to give the title compound as a yellow oil (14.80 g, 61%). ES / MS (m / z): 538 (M+H)

[1098] The compounds in Table 9i were prepared in a manner essentially analogous to that found in Preparation 58s.

[1099] Table 9i

[1100]

[1101]

[1102] Preparation 58z

[1103] 1-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(3,4,5- trifluorobenzyl)piperidin-2-one

[1104]

[1105] 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 dry THF (40 mL) was added dropwise a 2M solution of LDA in THF (6.4 mL, 12.87 mmol) while keeping the temperature below -65 °C under nitrogen. The mixture was stirred at -78 °C for 1 h and then 5-(bromomethyl)-1,2,3- trifluorobenzene (1.91 g, 8.58 mmol) in dry THF (15 mL) was added slowly. The mixture was allowed to warm up to ambient temperature and stirred for 2 h. The mixture was cooled to -78 °C and quenched with saturated NH4Cl solution (100 mL). The aqueous solution was extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (5-15%) to give the title compound as a yellow oil (2 g, 45%). ES / MS (m / z): 518 (M+H).

[1106] The compounds in Table 9j are prepared in a manner essentially analogous to that found in Preparation 58z.

[1107] Table 9j

[1108]

[1109] Preparation 59

[1110] (E)-2-(7-chlorochroman-4-ylidene)acetic acid ethyl ester

[1111]

[1112] 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) portionwise at 0 °C. After stirring at 0 °C for 30 min, a solution of 7-chlorochroman-4-one (10.00 g, 54.76 mmol) in THF (15 mL) was added dropwise and then stirred at 0 °C for 1 h and then at ambient temperature for a further 16 h. The mixture was added to water (50 mL) and extracted with EtOAc (30 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (9:1) to give the title compound as a white solid (6.0 g, 43.4%). ES / MS (m / z): 253 (M+H).

[1113] Preparation 59a

[1114] 2-(7-chlorochroman-4-yl)acetic acid ethyl ester

[1115]

[1116] To a solution of (E)-2-(7-chlorochroman-4-ylidene)acetic acid ethyl ester (5.00 g, 19.79 mmol) in THF (50 mL) was added Pd / C (1.0 g, 10 wt%, 0.94 mmol) at ambient temperature. After stirring under H2atmosphere at ambient temperature for 16 h, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography on a C18 column (water: ACN = 4:6) to give the title compound as a white solid (3.13 g, 62.0%). ES / MS (m / z): 255 (M+H).

[1117] Preparation 59b

[1118] 2-(7-chlorochroman-4-yl)acetic acid

[1119]

[1120] To a solution of 2-(7-chlorochroman-4-yl)acetic acid ethyl ester (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 h. The reaction mixture was concentrated in vacuo. The mixture was added to water (10 mL) and adjusted to pH = 3-4 with 1 N aqueous HC1 solution. The resulting precipitate was filtered, and the filter cake was dried in vacuo to give the title compound as a white solid (650 mg, 52.0%). ES / MS (m / z): 227 (M+H).

[1121] Preparation 59c

[1122] N-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-2-(7- chlorochroman-4-yl)acetamide

[1123]

[1124] To a mixture of 2-(7-chlorochroman-4-yl)acetic acid (1.30 g, 5.74 mmol), 3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-amine (1.51 g, 5.16 mmol) and pyridine (1.86 mL, 22.9 mmol) in DCM (15 mL) was added POCl3(1.14 g, 7.46 mmol) dropwise at 0 °C. The mixture was warmed to 20 °C and stirred for 3 h. The reaction mixture was quenched with water (30 mL) and extracted with DCM (100 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting 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).

[1125] Preparation 59d

[1126] 4-methoxybutanamide

[1127]

[1128] To a solution of 4-methoxybutanoic acid (2.00 g, 16.9 mmol) in ACN (150 mL) was added NH4HCO3(1.74 g, 22.0 mmol), pyridine (1.60 g, 20.3 mmol) and di-tert-butyl dicarbonate (4.43 g, 20.3 mmol). After stirring at 25 °C for 16 h, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous phase was extracted with EtOAc (50 mL x 2). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (1.98 g, 99.8%) as a white solid. 1 H NMR: (DMSO-d6) δ 7.27 (s, 1H), 6.73 (s, 1H), 3.28 (t, J = 6.4 Hz, 2H), 3.21 (s, 3H), 2.07 (t, J = 8 Hz, 2H), 1.72-1.65 (m, 2H).

[1129] The compounds in Table 9k are prepared in a manner essentially analogous to that found in the preparation of 59d.

[1130] Table 9k

[1131]

[1132] Preparation 59f

[1133] 4-methoxybutyronitrile

[1134]

[1135] To a solution of 4-methoxybutyramide (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 h, the reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The aqueous phase was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound as a colorless oil (538 mg, 47.9%). 1 H NMR: (DMSO-d6) δ 3.47 (t, J = 6 Hz, 2H), 3.34 (s, 3H), 2.50 (t, J = 7.2 Hz, 2H), 1.90-1.84 (m, 2H).

[1136] The compounds in Table 9l were prepared in a manner essentially analogous to that found in Preparation 59f.

[1137] Table 9l

[1138]

[1139] Preparation 59h

[1140] (S)-2-((cyanomethoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester

[1141]

[1142] To a solution of (S)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (5.00 g, 23.0 mmol) in ACN (100 mL) was added NaH (2.3 g, 57.5 mmol) at 0 °C and then stirred for 1 h. To the mixture was added 2-bromoacetonitrile (6.90 g, 57.5 mmol) at -20 °C and then stirred at -20 °C for 12 h. The mixture was quenched with MeOH (20 mL) and concentrated in vacuo to give the crude product. The crude material was purified by silica gel flash chromatography eluting with MeOH / DCM (0-5%) to give the title compound as a yellow oil (5.00 g, 67%). ES / MS (m / z): 201 (M+H-tBu).

[1143] The compounds in Table 9m were prepared in a manner essentially analogous to that found in Preparation 59h.

[1144] Table 9m

[1145]

[1146]

[1147] Preparation 59n

[1148] (S)-2-((l-cyano-2-oxo-2-(pyridazin-4-yl)ethoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester

[1149]

[1150] To a solution of methyl pyridazine-4-carboxylate (2.77 g, 20.0 mmol) in THF (100 mL) at -78 °C under nitrogen was added 1 M LiHMDS in THF (18.5 mL, 18.5 mmol). After stirring for 1 h, a solution of (S)-2-((cyanomethoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (5.00 g, 79 wt%, 15.4 mmol) in THF (20 mL) was added and then stirred at -78 °C for 5 h. The reaction mixture was allowed to warm to ambient temperature and concentrated in vacuo to give the title compound as a brown solid (11.00 g, crude). ES / MS (m / z): 363 (M+H).

[1151] The compounds in Table 9n were prepared in essentially analogous fashion to that found in the preparation of 59n.

[1152] Table 9n

[1153]

[1154]

[1155] Preparation 59w

[1156] (S)-2-(((5-amino-l-(4-methoxybenzyl)-3-(pyridazin-4-yl)-lH-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylic acid tert-butyl ester

[1157]

[1158] To a solution of (2S)-2-((1-cyano-2-oxo-2-(pyridazin-4-yl)ethoxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (11.00 g) in EtOH (200 mL), (4-methoxybenzyl)hydrazine hydrochloride (8.933 g, 47.35 mmol) and AcOH (2.7 mL, 47.35 mmol) were added. After stirring at 80 °C for 12 hours, the mixture was concentrated under vacuum. The residue was purified by reversed-phase chromatography (C18, 2-40% ACN in 10 mmol NH4HCO3) to give the title compound (3.60 g, 46%) as a yellow solid. ES / MS (m / z): 497 (M+H).

[1159] The compounds in Table 9o were prepared in a manner substantially similar to that described in Preparation 59w.

[1160] Table 9o

[1161]

[1162]

[1163] Preparation 59aa

[1164] (S)-2-(((5-bromo-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylic acid tert-butyl ester

[1165]

[1166] 1.15 g (11.1 mmol) of tert-butyl nitrite was added to a mixture of copper(II) bromide (1.62 g, 7.25 mmol) in ACN (10 mL). After stirring at 65 °C for 15 min, a solution of (S)-2-(((5-amino-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (2.40 g, 4.83 mmol) in ACN (5 mL) was added, and the mixture was then stirred at 65 °C for 30 min. The mixture was quenched with water (100 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with a saturated aqueous solution of NaCl (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give the crude product. The crude material was purified by rapid silica gel 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).

[1167] The compounds in Table 9q are prepared in a manner substantially similar to that found in Preparation 59ae.

[1168] Table 9p

[1169]

[1170]

[1171] Preparation 59ae

[1172] 2-(((5-amino-3-(pyridazin-4-yl)-lH-pyrazol-4-yl)oxy)methyl)morpholine-4- carboxylic acid tert-butyl ester

[1173]

[1174] To a solution of tert-butyl 2-((l-cyano-2-oxo-2-(pyridazin-4-yl)ethoxy)methyl)morpholine- 4-carboxylate (2.5 g, 7 mmol) in EtOH (10 mL) was added N2H4.H2O (1 g, 21 mmol) and AcOH (1.3 g, 21 mmol). After stirring at 80 °C for 12 h, the reaction mixture was concentrated in vacuo. The residue was purified by reverse phase column chromatography (C18, 40% ACN in 10 mmol NH4HCO3) to give the title compound as a yellow solid (1 g, 38%). ES / MS (m / z): 377 (M+H).

[1175] The compounds in Table 9q are prepared in a manner substantially similar to that found in Preparation 59ae.

[1176] Table 9q

[1177]

[1178] Preparation 59al

[1179] 4-(4-bromo-5-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)-lH-pyrazol-l-yl)pyridazine

[1180]

[1181] To a solution of (4-bromo-l-(pyridazin-4-yl)-lH-pyrazol-5-yl)methanol (300 mg, 1.18 mmol) in ACN (10 mL) was added 3,4-dihydro-2H-pyran (989 mg, 11.8 mmol) and pyridine 4-methylbenzenesulfonate (29.6 mg, 118 μmol). After stirring at 75 °C for 5 h, it was cooled to ambient temperature, water (20 mL) was added and extracted with EtOAc (50 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting 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).

[1182] Preparation 59am

[1183] 4-(4-bromo-5-(methoxymethyl)-lH-pyrazol-l-yl)pyridazine

[1184]

[1185] To a solution of (4-bromo-l-(pyridazin-4-yl)-lH-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 Mel (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 x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (6: 1) to give the title compound (340 mg, 77%) as a white solid. ES / MS (m / z): 269 / 271 (M+H).

[1186] Preparation 59an

[1187] 3-bromo-5-(pyridazin-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-4- carbaldehyde

[1188]

[1189] To a solution of 3,5-dibromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole-4- carboxaldehyde (3.7 g, 9 mmol) in dry DMF (200 mL) was added 4-(tributylstannyl)pyridazine (3.574 g, 9 mmol), Cul (0.092 g, 0.45 mmol) and Pd(PPh3)4(0.895 g, 0.72 mmol) and then stirred at 100 °C under nitrogen for 2 h. The reaction mixture was allowed to cool to ambient temperature then an aqueous KF solution (300 mL) was added. After stirring at ambient temperature for 2 h, the mixture was filtered through celite, washing with EtOAc (400 mL). The filtrate was collected and extracted with EtOAc (300 mL x 2). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (1 : 1) to give the title compound as a yellow solid (2.5 g, 67%). ES / MS (m / z): 383 / 385 (M+H).

[1190] The compounds in Table 9r were prepared in a manner essentially analogous to that found in the preparation of 59an.

[1191] Table 9r

[1192]

[1193]

[1194] Preparation 59au

[1195] (5-amino-l-(4-methoxybenzyl)-3-(pyridazin-4-yl)-lH-pyrazol-4-yl)methanol

[1196]

[1197] To a solution of 5-amino-l-(4-methoxybenzyl)-3-(pyridazin-4-yl)-lH-pyrazole-4- carboxylic acid ethyl ester (1.5 g, 4.24 mmol) in THF (15 mL) was added 1 M LiAIH4 in THF (4.7 mL, 4.7 mmol) at -5 °C and then stirred at ambient temperature under N2atmosphere for 11 min. To the mixture was added saturated aqueous NH4CI (40 mL) and extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with saturated aqueous NaCI, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH / DCM (7:93) to give the title compound as a yellow solid (475 mg, 29%). ES / MS (m / z): 312 (M+H).

[1198] Preparation 60

[1199] 3-bromo-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-l-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazole-4-carbaldehyde

[1200]

[1201] 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-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazole-4-carbaldehyde (553 mg, 1.44 mmol), Pd(OAc)2(11 mg, 0.06 mmol) and Cs2CO3(854 mg, 2.62 mol). After stirring at 100 °C for 1 h under nitrogen atmosphere, the reaction mixture was allowed to cool to ambient temperature and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-10%) to give the title compound as a yellow oil (0.33 g, 47%). ES / MS (m / z): 554 (M+Na).

[1202] The compounds in Table 9s were prepared in a manner essentially analogous to that found in the preparation of 60.

[1203] Table 9s

[1204]

[1205] Preparation 60g1 -(3-bromo-4-(hydroxymethyl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H- pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one

[1206]

[1207] To a solution of 3-bromo-5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1 - yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-pyrazole-4-carbaldehyde (7.9 g, 14.8 mmol) in THF (100 mL) was added NaBH4(1.12 g, 29.7 mmol) at ambient temperature. After stirring at ambient temperature for 30 min, the reaction mixture was poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with saturated aqueous NaCI, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (EtOAc / petroleum ether (0-40%)) to give the title compound as a yellow oil (7.2 g, 86%). ES / MS (m / z): 558 (M+Na).

[1208] The compounds in Table 9t were prepared in a manner essentially analogous to that found in the preparation of 60g.

[1209] Table 9t

[1210]

[1211]

[1212] Preparation 60k

[1213] 1 -(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H- pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one

[1214]

[1215] 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) at ambient temperature was added Pd2(dba)3 (428 mg, 468 μmol), 4-(tributylstannyl)pyridazine (1.73 g, 4.68 mmol) and 2-(dicyclohexylphosphanyl)-2',4',6'-tris(isopropyl)biphenyl (446 mg, 936 μmol). After stirring at 100 °C under nitrogen for 16 h, the reaction mixture was allowed to cool to ambient temperature, poured into water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-80%) to give the title compound as a brown solid (1.7 g, 63%). ES / MS (m / z): 534 (M+H).

[1216] The compounds in Table 9u are prepared in a manner essentially analogous to that found in the preparation of 60k.

[1217] Table 9u

[1218]

[1219] Preparation 60p

[1220] 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

[1221]

[1222] 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 dry 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), Cul (1.11 g, 5.2 mmol) and K3PO4(16.652 g, 74 mmol) and then stirred at 100 °C under nitrogen for 4 hours. The mixture was allowed to cool to ambient temperature and filtered under vacuum. The filtrate was added to water (200 mL) and extracted with EtOAc (200 mL x 3). The organic layers were combined, washed with saturated aqueous NaCI, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (1 :1 ) to give the title compound as a yellow oil (866 mg, 32%). ES / MS (m / z): 521 (M+H).

[1223] The compounds in Table 9v were prepared in a manner essentially analogous to that found in Preparation 60p.

[1224] Table 9v

[1225]

[1226]

[1227] Preparation 60x

[1228] 2-fluoro-4-((1 -(4-(hydroxymethyl)-5-(pyridazin-4-yl)-1 -((2- (trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-3-yl)-2-oxopyrrolidin-3-yl)methyl)benzonitrile

[1229]

[1230] To a solution of 2-fluoro-4-((1 -(4-formyl-5-(pyridazin-4-yl)-1 -((2- (trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-3-yl)-2-oxopyrrolidin-3-yl)methyl)benzonitrile (970 mg, 1.9 mmol) in THF (10 mL) was added NaBH4(106 mg, 2.8 mmol) in portions and then stirred at ambient temperature for 1 hour. The mixture was added to water (100 mL) and extracted with EtOAc (100 mL x 3). The organic layers were combined, washed with saturated aqueous NaCI, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a white solid (932 mg, 95%). ES / MS (m / z): 523 (M+H).

[1231] The compounds in Table 9w were prepared in a manner essentially analogous to that found in Preparation 60x.

[1232] Table 9w

[1233]

[1234] Preparation 60z

[1235] 5-(3-(2-(difluoromethyl)-4-fluorobenzyl)-2-oxopyrrolidin-1-yl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde

[1236]

[1237] To a solution of 3-bromo-5-(3-(2-(difluoromethyl)-4-fluorobenzyl)-2-oxopyrrolidin-1-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde (300 mg, 95.78 wt%, 526 µmol) in 1,4-dioxane (2 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (217 mg, 1.05 mmol), PdCl2(dppf) (38.5 mg, 52.6 µmol), potassium carbonate (182 mg, 1.31 mmol) and water (0.5 mL), and then stirred at 100 °C under nitrogen for 2 hours. The reaction mixture was allowed to cool to ambient temperature, added to water (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with DCM / MeOH (10:1) to give the title compound (250 mg, 65.9%) as a yellow oil. ES / MS (m / z): 546 (M+H).

[1238] The compounds in Table 9x were prepared in a manner essentially analogous to that found in the preparation of 60z.

[1239] Table 9x

[1240]

[1241]

[1242] Preparation 60ac

[1243] 3-(2-(difluoromethyl)-4-fluorobenzyl)-1-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)pyrrolidin-2-one

[1244]

[1245] 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 NaBH4 (26.2 mg, 693 µmol) at 0 °C, and then stirred 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 x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash column chromatography DCM / MeOH (10:1) to give the title compound (500 mg, 76.3%) as brown oil. ES / MS (m / z): 548 (M+H).

[1246] The compounds in Table 9y were prepared in a manner essentially analogous to that found in the preparation of 60ac.

[1247] Table 9y

[1248]

[1249]

[1250] Preparation 60af

[1251] 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

[1252]

[1253] 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 Cul (51 mg, 0.27 mmol) under nitrogen. After stirring at 100 °C for 12 h, the reaction mixture was allowed to cool to ambient temperature, quenched with saturated aqueous KF solution (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product. The crude was purified by silica gel flash chromatography eluting with EtOAc / pet. ether (75-85%) to give the title compound as a brown oil (750 mg, 44%). ES / MS (m / z): 632 (M+H).

[1254] The compounds in Table 9z are prepared in a manner essentially analogous to that found in the preparation of 60af.

[1255] Table 9z

[1256]

[1257]

[1258]

[1259]

[1260]

[1261]

[1262]

[1263] Preparation 61

[1264] 2-(4-chlorobenzyl)-4-(5-(5-methylpyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)morpholine-3-one

[1265]

[1266] Add 4-(3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-5-methylpyridazine (245 mg, 0.67 mmol), K3PO4 (94 mg, 0.44 mmol), and N to a solution of 2-(4-chlorobenzyl)morpholin-3-one (100 mg, 0.44 mmol) in 1,4-dioxane (2 mL) (2 mL). 1 N 2 -Dimethylcyclohexane-1,2-diamine (63 mg, 0.44 mmol) and CuI (84 mg, 0.44 mmol) were added, and the mixture was stirred at 90 °C under nitrogen for 5 h. The mixture was cooled to ambient temperature and concentrated under vacuum. The residue was purified by preparative HPLC (C18, ACN = 65-95% in 13 mmol TFA, over 17 min, rt = 8.9 min) to give the title compound (35 mg, 15%) as a white solid. ES / MS (m / z): 514 (M+H).

[1267] The compounds in Table 9aa are prepared in a manner substantially similar to that described in Preparation 61.

[1268] Table 9aa

[1269]

[1270]

[1271]

[1272] Preparation 61m

[1273] 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidine-2-one

[1274]

[1275] To a mixture of l-(3-bromo-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-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(l,3,2-dioxaborolane) (757 mg, 2.98 mmol) in 1,4-dioxane (15 mL) was added KOAc (389 mg, 3.98 mmol) and Pd(dppf)Cl2(146 mg, 0.2 mmol) in portions under nitrogen. After stirring at 100 °C for 2 h under nitrogen, the reaction mixture was allowed to cool to ambient temperature, added to water (20 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20: 1) to give the title compound as an orange oil (400 mg, 43%). ES / MS (m / z): 470 (M+H-82).

[1276] The compounds in Table 9ab were prepared in a manner essentially analogous to that found in Preparation 61m.

[1277] Table 9ab

[1278]

[1279] Preparation 61o

[1280] 1-(3-(5-aminopyridazin-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)-3- (3,4,5-trifluorobenzyl)pyrrolidin-2-one

[1281]

[1282] To a solution of 5-bromopyridazin-4-amine (258 mg, 1.49 mmol) in 1,4-dioxane (8 mL) and H2O (1 mL) was added K2CO3 (618 mg, 4.47 mmol), Pd(dppf)Cl2 (109 mg, 0.15 mmol) and 1-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one (700 mg, 1.49 mmol) portion-wise under nitrogen atmosphere. After stirring at 100 °C for 2 h, the reaction mixture was allowed to cool to ambient temperature, added to water (10 mL) and extracted with EtOAc (15 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / MeOH (20:1) to give the title compound (280 mg, 36%) as a white solid. ES / MS (m / z): 519 (M+H).

[1283] The compounds in Table 9ac were prepared in a manner essentially analogous to that found in Preparation 61o.

[1284] Table 9ac

[1285]

[1286] Preparation 61q

[1287] 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

[1288]

[1289] 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 x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (50-60%) to give the title compound (1.3 g, 92%) as a brown oil. ES / MS (m / z): 598 (M+H).

[1290] The compounds in Table 9ad are prepared in a manner essentially analogous to that found in Preparation 61q.

[1291] Table 9ad

[1292]

[1293] Preparation 61t

[1294] (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

[1295]

[1296] 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), PdCl2(dppf) (159 mg, 0.2 mmol) and water (5 mL). After stirring at 100 °C for 12 h under nitrogen, the reaction mixture was allowed to cool to ambient temperature, added to water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (30-40%) to give the title compound as a brown oil (600 mg, 45%). ES / MS (m / z): 590 (M+H).

[1297] The compounds in Table 9ae are prepared in a manner essentially analogous to that found in Preparation 61t.

[1298] Table 9ae

[1299]

[1300] Preparation 61x

[1301] 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

[1302]

[1303] 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 1 N HC1 (30 mL, 30 mmol). After stirring at 60 °C for 5 h, the reaction mixture was allowed to cool to ambient temperature, added to water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound as a brown oil (600 mg, 50%) which was used in the next step without further purification. ES / MS (m / z): 562 (M+H).

[1304] The compounds in Table 9af were prepared in a manner essentially analogous to that found in Preparation 61x.

[1305] Table 9af

[1306]

[1307] Preparation 61z

[1308] 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

[1309]

[1310] 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 x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (420 mg, 98%) as a brown oil which was used in the next step without further purification. ES / MS (m / z): 577 (M+H).

[1311] The compounds in Table 9ag were prepared in a manner essentially analogous to that found in Preparation 61z.

[1312] Table 9ag

[1313]

[1314] Preparation 61ab

[1315] 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

[1316]

[1317] 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 chloride (73.2 mg, 0.58 mmol) at 0 °C. After stirring at 0 °C for 15 min and at 25 °C for another 3 h, the reaction mixture was quenched with water (60 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (300 mg, 82%) as a brown oil which was used in the next step without further purification. ES / MS (m / z): 559 (M+H).

[1318] Preparation 61ac

[1319] 1 -(4-(2-ethoxyethyl)-3-(pyridin-4-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)- 1 H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one

[1320]

[1321] To a solution of (E)-1 -(4-(2-ethoxyvinyl)-3-(pyridin-4-yl)-1 -((2- (trimethylsilyl)ethoxy)methyl)-1 H-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 H2atmosphere for 2 h, the reaction mixture was filtered and concentrated in vacuo to give the title compound (420 mg, 98%) as a brown oil which was used in the next step without further purification. ES / MS (m / z): 577 (M+H).

[1322] Preparation 61ad

[1323] 2-(5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-1 -yl)-3-(pyridin-4-yl)-1 H- pyrazol-4-yl)acetaldehyde

[1324]

[1325] To a solution of (E)-1 -(4-(2-ethoxyvinyl)-5-(pyridin-4-yl)-1 -((2- (trimethylsilyl)ethoxy)methyl)-1 H-pyrazol-3-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin- 2-one (945 mg, 1.65 mmol) in DCM (10 mL) was added TFA (8 mL, 110 mmol) dropwise. After stirring at 25 °C for 12 h, the mixture was concentrated in vacuo. The residue was added to water (30 mL), adjusted to pH 7 with saturated aqueous NaHC03solution, and then extracted with DCM (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (206 mg, 30%) as a white solid. ES / MS (m / z): 415 (M+H).

[1326] Preparation 61ae

[1327] 3-((6-fluoropyridin-3-yl)methyl)-l-(3-(5-methylpyridazin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5-yl)piperidin-2-one

[1328]

[1329] To a solution of 3-((6-fluoropyridin-3-yl)methyl)-l-(3-(5-methylpyridazin-4-yl)- lH-l,2,4-triazol-5-yl)piperidin-2-one (500 mg, 1.36 mmol) in DMF (20 mL) was added t-BuOK (168 mg, 1.5 mmol) at ambient temperature. After stirring at ambient temperature for 15 min, SEM-Cl (250 mg, 1.5 mmol) was added and then stirred at ambient temperature overnight. The reaction mixture was quenched with water (60 mL) and extracted with DCM (25 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with 1% TEA / EtOAc to give the title compound as a brown oil (450 mg, 66%). ES / MS (m / z): 498 (M+H)

[1330] The compounds in Table 9ai were prepared in a manner essentially analogous to that found in Preparation 61ae.

[1331] Table 9ai

[1332]

[1333] Preparation 61ag

[1334] 3-((6-fluoropyridin-3-yl)methyl)-l-(3-(5-methylpyridazin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5-yl)piperidin-2-one (Isomer 1

[1335] 3-((6-fluoropyridin-3-yl)methyl)-l-(3-(5-methylpyridazin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5-yl)piperidin-2-one (Isomer 2)

[1336]

[1337] Racemic 3-((6-fluoropyridin-3-yl)methyl)-l-(3-(5-methylpyridazin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5-yl)piperidin-2-one (450 mg) was separated via SFC (column: IG 20*250 mm, 10 um (Daicel), mobile phase: CO2 / MeOH [0.2% NH3 (7 mol / L in MeOH)] = 45 / 55) to give isomer 1 (140 mg, ee = 100%) and isomer 2 (95 mg, ee = 100%) as light brown oil.

[1338] The compounds in Table 9aj were prepared in a manner essentially analogous to that found in Preparation 61ag.

[1339] Table 9aj

[1340]

[1341]

[1342]

[1343] Preparation 62

[1344] (S)-5-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-3-fluorobenzyl)pentanoic acid

[1345]

[1346] 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 H2O2 (957 mg, 28.14 mmol) at 0 °C. After stirring for 10 min, a solution of LiOH.H2O (844 mg, 14.07 mmol) in H2O (5 mL) was added to the reaction mixture, and then stirred for 20 min. The reaction mixture was poured into NH4Cl solution (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic phase was washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound (1.4 g, 80%) as yellow oil. ES / MS (m / z): 375 (M+H).

[1347] Preparation 62aa

[1348] (S)-5-((tert-butyldimethylsilyl)oxy)-2-(4-chloro-3-fluorobenzyl)-N-(1-(5- methylpyridazin-4-yl)-1H-pyrazol-4-yl)pentanamide

[1349]

[1350] 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, water (50 mL) was added to the reaction mixture and extracted with EtOAc (50 x 3 mL). The combined organic phases were washed with saturated aqueous NaCl, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH / DCM (7%) to give the title compound as a yellow oil (1.1 g, 62%). ES / MS (m / z): 532 and 534 (M+H).

[1351] Preparation 62ab

[1352] (S)-2-(4-chloro-3-fluorobenzyl)-5-hydroxy-N-(1-(5-methylpyridazin-4-yl)-1H- pyrazol-4-yl)pentanamide

[1353]

[1354] 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 dry THF (20 mL) was added Et3N.3HF (1.7 g, 10.6 mmol) dropwise at 0 °C. After stirring at room temperature for 1 h, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with EtOAc / petroleum ether (0-50%) to give the title compound as a yellow oil (0.55 g, 64%). ES / MS (m / z): 418 and 420 (M+H).

[1355] Preparation 62a

[1356] 3-((6-chloropyridin-3-yl)methyl)-l-(3-(5-methylpyridazin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5-yl)piperidin-2-one

[1357]

[1358] To a solution of l-(3-(5-methylpyridazin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5-yl)piperidin-2-one (500 mg, 1.3 mmol) in dry THF (10 mL) was added 1M LiHMDS (1.7 mL, 1.7 mmol) at -78 °C and then stirred for 30 min. To the reaction mixture was added a solution of 5-(bromomethyl)-2-chloropyridine (268 mg, 1.3 mmol) in dry THF (5 mL) and then stirred at -78 °C for 1.5 h. The reaction mixture was quenched with water (20 mL) and extracted with DCM (50 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by 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).

[1359] The compounds in Table 9ak are prepared in a manner essentially analogous to that found in Preparation 62a.

[1360] Table 9ak

[1361]

[1362] Preparation 62d

[1363] (S)-3-((6-chloropyridin-3-yl)methyl)-l-(3-(5-methylpyridazin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5-yl)piperidin-2-one (Isomer 2)

[1364]

[1365] SFC (AD 20*250mm, 10pm, C02 / MeOH [0.2% NH3 (in MeOH 7M)] = 40 / 60) was performed on the racemate 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) to give isomer 1 and isomer 2 (240 mg, 45%) as white solids. The isomer was expected to be isomer 2 by comparison with authentic sample.

[1366] Preparation 62e

[1367] (S)-((5-(3-((6-chloropyridin-3-yl)methyl)-2-oxopiperidin-1-yl)-3-(5-methylpyridazin-4- yl)-1H-pyrazol-1-yl)methyl)phosphonic acid di-tert-butyl ester (isomer 1) and (S)-((3-(3- ((6-chloropyridin-3-yl)methyl)-2-oxopiperidin-1-yl)-5-(5-methylpyridazin-4-yl)-1H-pyrazol- 1-yl)methyl)phosphonic acid di-tert-butyl ester (isomer 2)

[1368]

[1369] To a solution of (S)-3-((6-chloropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1H- pyrazol-5-yl)piperidin-2-one (800 mg, 2.1 mmol, ee = 100%) in dry DMF (80 mL) was added Cs2CO3 (1.7 g, 5.3 mmol) and di-tert-butyl(chloromethyl)phosphonate (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 x 2). The combined organic layers were washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse-phase column chromatography eluting with ACN / NH4HCO3 solution (0-60%) to give 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).

[1370] Preparation 62f

[1371] ((5-(3-(4-chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-4-fluoro-3-(pyridazin-4-yl)- 1H-pyrazol-1-yl)methyl)phosphonic acid di-tert-butyl ester (isomer 1) and ((3-(3-(4-chloro-3,5- difluorobenzyl)-2-oxopyrrolidin-1-yl)-4-fluoro-5-(pyridazin-4-yl)-1H-pyrazol-1-yl)methyl)phosphonic acid di-tert-butyl ester (isomer 2)

[1372]

[1373] To a solution of (isomer 1) 3-(4-chloro-3,5-difluorobenzyl)-1-(4-fluoro-5-(pyridazin-4-yl)- 1H-pyrazol-3-yl)pyrrolidin-2-one (0.21 g, 0.5 mmol) in DMF (7 mL) was added Cs2CO3(0.84 g, 2.6 mmol), NaI (0.08 g, 0.5 mmol) and di-tert-butyl(chloromethyl)phosphonate (0.53 g, 2 mmol). After stirring at 35 °C for one week, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a mixture of the title compounds as yellow oil (0.46 g, 99+%). ES / MS (m / z): 630 (M+H).

[1374] Preparation 62f

[1375] N-(4-(hydroxymethyl)-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5- trifluorophenyl)propanamide

[1376]

[1377] To a solution of 3-(3,4,5-trifluorophenyl)propanoic acid (374 mg, 1.83 mmol) in DMAc (8 mL) was added DIPEA (789 mg, 1.06 mL, 6.10 mmol) and 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 min. 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, and then stirred at 20 °C for 3 h. To the reaction mixture was added ice water (30 mL) and extracted with DCM (20 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting 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).

[1378] Preparation 62h

[1379] 4-(2-(((Di-tert-butoxylphosphoryl)oxy)methoxy)ethyl)-3-(pyridazin-4-yl)-5-(3-(3,4,5- trifluorophenyl)propanamido)-1H-pyrazole-1-carboxylic acid tert-butyl ester

[1380]

[1381] 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 directly in the next step without further purification. ES / MS (m / z): 492 (M+H).

[1382] Preparation 62i

[1383] 4-(2-(((Di-tert-butoxylphosphoryl)oxy)methoxy)ethyl)-3-(pyridazin-4-yl)-5-(3-(3,4,5- trifluorophenyl)propanamido)-1H-pyrazole-1-carboxylic acid tert-butyl ester

[1384]

[1385] 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 Cs2CO3 (2.5 g, 7.67 mmol) and di-tert-butyl (chloromethyl)phosphonate (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 x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse phase chromatography eluting with ACN / water (12.5 mM NH4HCO3) (60-65%) to give the title compound as a yellow solid (500 mg, 16.7%). ES / MS (m / z): 714 (M+H).

[1386] Preparation 62j

[1387] (2-(5-(pyridazin-4-yl)-3-(3-(3,4,5-trifluorophenyl)propanamido)-1H-pyrazol-4- yl)ethoxy)dimethylphosphonate

[1388]

[1389] 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 H2O (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 H2O (2 mL) and dried in vacuo to give the title compound as a white solid (71.7 mg, 20.4%). ES / MS (m / z): 502 (M+H).

[1390] Preparation 62k

[1391] tert-Butyl 2-(((3-(pyridazin-4-yl)-5-(3-(3,4,5-trifluorophenyl)propanamido)-1H-pyrazol-4- yl)oxy)methyl)morpholine-4-carboxylate

[1392]

[1393] To a solution of tert-butyl 2-(((5-amino-3-(pyridazin-4-yl)-lH-pyrazol-4- yl)oxy)methyl)morpholine-4-carboxylate (0.5 g, 1.3 mmol) in DMA (10 mL) was 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 x 3). The organic layers were combined and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH / DCM (10%) to give the title compound as a yellow oil (0.7 g, 93%). ES / MS (m / z): 563 (M+H).

[1394] The compounds in Table 9am were prepared in a manner essentially analogous to that found in Preparation 62k.

[1395] Table 9am

[1396]

[1397]

[1398] Preparation 62s

[1399] N-(4-(Morpholin-2-ylmethoxy)-3-(pyridazin-4-yl)-lH-pyrazol-5-yl)-3-(3,4,5- trifluorophenyl)acrylamide

[1400]

[1401] To a solution of tert-butyl 2-(((3-(pyridazin-4-yl)-5-(3-(3,4,5-trifluorophenyl)propanamido)-lH-pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylate (0.7 g, 1.2 mmol) in DCM (5 mL) was added 4M HC1 in 1,4-dioxane (5 mL, 20 mmol). After stirring at ambient temperature for 1 h, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a brown solid (0.17, 30%). ES / MS (m / z): 463 (M+H).

[1402] Preparation 62t

[1403] 2-(((1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-5-(3-(3,4,5-trifluorophenyl)propanamido)-1H- pyrazol-4-yl)oxy)methyl)morpholine-4-carboxylic acid tert-butyl ester

[1404]

[1405] To a solution of 2-(((5-amino-1-(4-methoxybenzyl)-3-(pyridazin-4-yl)-1H-pyrazol-4- yl)oxy)methyl)morpholine-4-carboxylic acid tert-butyl ester (1.50 g, 3.02 mmol) in DMA (20 mL) was added 3-(3,4,5-trifluorophenyl)propanoic acid (802 mg, 3.93 mmol), N- ethyl-N-isopropylpropan-2-amine (1.95 g, 15.1 mmol) and 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 in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH / DCM (5%) to give the title compound as a brown solid (2.20 g, 93%). ES / MS (m / z): 683 (M+H).

[1406] The compounds in Table 9an were prepared in a manner essentially analogous to that found in Preparation 62t.

[1407] Table 9an

[1408]

[1409] Preparation 62w

[1410] N-(1-(4-methoxybenzyl)-4-(morpholin-2-ylmethoxy)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3- (3,4,5-trifluorophenyl)propanamide

[1411]

[1412] 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 4 M HC1 in 1,4-dioxane (5 mL, 20 mmol). After stirring at 25 °C for 5 h, the mixture was quenched with 7 M NH3 in MeOH (10 mL, 70 mmol) and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH / DCM (12%) to give the title compound as a yellow solid (1.20 g, 48%). ES / MS m / z: 583 (M+H).

[1413] Preparation 62x

[1414] 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

[1415]

[1416] 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 K2CO3 (356 mg, 2.57 mmol) and iodomethane-d3 (149 mg, 1.03 mmol). After stirring at 25 °C for 12 h, the mixture was filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH / DCM (7%) to give the title compound as a yellow solid (250 mg, 47%). ES / MS (ES): m / z = 600 (M+H).

[1417] Preparation 63p

[1418] 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)

[1419]

[1420] SFC (Column: IH 25*250mm, 10um (Daicel) Mobile phase: CO2 / MeOH [0.5% NH3 (in MeOH 7M) = 90 / 10) was performed on racemic 3-(2-(difluoromethyl)-4-fluorobenzyl)-1-(3-(pyridazin-4-yl)-1-((2- (trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one to give isomer 1 and isomer 2 as light brown oil. ES / MS (m / z): 533 (M+H).

[1421]

[1422]

[1423] Example 1

[1424] 3-(6-fluoropyridin-3-yl)-N-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)propanamide

[1425]

[1426] 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 h. The mixture was added to water (50 mL) which was extracted with EtOAc (50 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, concentrated in vacuo 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).

[1427] The compounds in Table 10 were prepared using the appropriate starting materials and reagents in essentially the same procedures as Example 1.

[1428] Table 10

[1429]

[1430] Example 8

[1431] 3-(6-chloropyridin-3-yl)-N-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-yl)acrylamide

[1432]

[1433] A mixture of 3-(5-methylpyridazin-4-yl)-lH-l,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 off and the filtrate was dried over anhydrous sodium sulfate, concentrated in vacuo, slurry in MeOH and filtered to give the title compound as a white solid (364 mg, 63%). ES / MS m / z 344 (M+H).

[1434] The compounds in Table 11 were prepared using essentially the same procedure as Example 8, using the appropriate starting materials and reagents.

[1435] Table 11

[1436]

[1437]

[1438]

[1439]

[1440] Example 14

[1441] 3-(6-chloro-5-fluoropyridin-3-yl)-N-(4-methyl-3-(5-methylpyridazin-4-yl)-lH-pyrazol-5- yl)propanamide

[1442]

[1443] 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 in vacuo to give a crude residue (600 mg). Water (3 mL) and saturated NaHC03(20 mL) were added and the mixture was extracted with EtOAc (80 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue (450 mg) was purified by preparative HPLC (C18, ACN / 10 mM NH4HC03= 32-62%, over 9 min, rt = 8.5 min) to give the title compound as a white solid (208 mg, 76%). ES / MS m / z 375 (M+H).

[1444] Example 15

[1445] N-(4-cyano-3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)-3-(6-fluoropyridin-3- yl)acrylamide

[1446]

[1447] 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 N-triethylammonium sulfonyl (methyl carbamate) (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 NH4HC03= 20-50%, over 9 min, rt = 7.4 min) to give the title compound as a white solid (26 mg, 39.4%). ES / MS m / z 352 (M+H).

[1448] Example 16

[1449] 3-(4-chloro-3-fluorophenyl)-N-(1-(3-methylpyridazin-4-yl)-1H-pyrazol-4-yl)acrylamide

[1450]

[1451] 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) in 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%, 9 min) to give the product as a white solid (21.8 mg, 21%). ES / MS m / z 360 (M+H).

[1452] Example 17

[1453] 3-(4-Fluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin-2-one

[1454]

[1455] 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 in vacuo. Water (3 mL) and saturated NaHCO3(10 mL) was added to the residue which was extracted with EtOAc (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, concentrated in vacuo and purified by preparative HPLC (C18, ACN / 10 mM NH4HCO3 = 20-50%, 9 min, rt = 7.4 min) to give the title compound as a white solid (11 mg, 50%). ES / MS m / z 367 (M+H).

[1456] The compounds in Table 12 were prepared essentially the same as described for Example 17 using the appropriate starting materials and reagents.

[1457] Table 12

[1458]

[1459] Example 19

[1460] 3-((6-Fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5- yl)piperidin-2-one

[1461]

[1462] 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 and then stirred for 2 hours at ambient temperature. The reaction mixture was quenched with water (60 mL) and the pH was adjusted to 6 to 7 with 1 N HC1. The solids were collected by filtration and dried in vacuum to give the crude material. The crude material was slurry in IPA and filtered to give the title compound as a white solid (73 mg, 53%). ES / MS m / z 368 (M+H).

[1463] The compounds in Table 12a were prepared essentially the same as described for Example 19 using the appropriate starting materials and reagents.

[1464] Table 12a

[1465]

[1466] Example 20

[1467] (S)-3-(4-chloro-3-fluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5- yl)piperidin-2-one

[1468]

[1469] 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 hours. The reaction mixture was purified by preparative HPLC (C18, ACN / 10 Mm NH4HCO3 = 42-72%, within 9 min, rt = 8.9 min) to give the title compound as a white solid (6 mg, 42%). ES / MS m / z 401 (M+H).

[1470] Example 21

[1471] 2-(4-chlorobenzyl)-4-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)morpholin-3-one

[1472]

[1473] To a mixture of 2-(4-chlorobenzyl)-4-(3-(5-methylpyridazin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazol-5-yl)morpholin-3-one (70 mg, 0.13 mmol) in DCM (3 mL) was added TFA (1 mL) at 0 °C, then it was stirred at ambient temperature for 3 h. The mixture was concentrated in vacuo. To the residue was added saturated aqueous NaHC03solution at 0 °C, and the resulting solid was filtered to give the title compound as a white solid (35 mg, 67%). ES / MS m / z 384 (M+H).

[1474] The compounds in Table 12b were prepared in essentially the same manner as found in Example 21.

[1475] Table 12b

[1476]

[1477]

[1478] Example 22

[1479] (S)-3-(4-chloro-3-fluorobenzyl)-l-(3-(5-methylpyridazin-4-yl)-lH-pyrazol-5- yl)piperidin-2-one

[1480]

[1481] A mixture of (R)-4-benzyl-3-((S)-2-(4-chloro-3-fluorobenzyl)-5-((3-(5- methylpyridazin-4-yl)-lH-pyrazol-5-yl)amino)pentanoyl)oxazolidin-2-one (150 mg, 0.26 mmol) and H2O2(53 mg, 1.56 mmol) in THF / H2O (4 / 1, 5 mL) was stirred at ambient temperature for 10 min. LiOH.H2O (33 mg, 0.78 mmol) was added and then stirred at ambient temperature for 16 h. The reaction mixture was quenched with aqueous Na2SO3solution (20 mL) and extracted with EtOAc (30 mL x 2). The combined organics were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue was purified by preparative HPLC (C18, ACN / 10 mM NH4HCO3= 48-78%, over 9 min, rt = 8.9 min) to give the title compound as a white solid (37.5 mg, 36%). The material was further purified by SFC [(Instrument: SFC-150 (Waters); Column: AS20*250 mm, 10 um (Daicel); Column temperature: 35 °C; Mobile phase: CO2 / MeOH [0.2% NH3(in MeOH 7M]= 60 / 40; Flow rate: 100 g / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 10.17 min)] and combined with the former batch (12.5 mg) to give the title isomer P3 (rt = 8.901 min) as a white solid (24 mg, 48%). ES / MS m / z 400 (M+H).

[1482] The compounds in Table 13 were prepared in essentially the same manner as found in Example 22.

[1483] Table 13

[1484]

[1485]

[1486] Example 25

[1487] 3-(4-Chloro-3-fluorobenzyl)-3-hydroxy-l-(2-(pyridazin-4-yl)-2H-l,2,3-triazol-4- yl)piperidin-2-one

[1488]

[1489] 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% by weight) in THF (2.5 mL) at -78 °C under nitrogen was added NaHMDS (16 mg, 0.087 mmol) dropwise. The reaction mixture was stirred at -78 °C for 1 h. 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 min, the reaction was quenched by the addition of water (50 mL) and extracted with EtOAc (100 mL x 2). The combined organic layers were washed with saturated aqueous NaCl (50 mL x 2), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel flash chromatography (EtOAc / petroleum ether = 0-20%) to give the title compound (8.7 mg, 32%) as a white solid. ES / MS (m / z): 403 (M+H).

[1490] The compounds in Table 13a were prepared in essentially the same manner as found in Example 63n.

[1491] Table 13a

[1492]

[1493]

[1494] Example 26

[1495] 3-(4-Fluoro-2-(fluoromethyl)benzyl)-1-(3-(pyridazin-4-yl)-1H-1,2,4-triazol-5-yl)piperidin- 2-one

[1496]

[1497] 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 pmol) in DCM (1 mL) was added TFA (31 mg, 0.27 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo. The residue was dissolved in THF (2 mL) and purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10um, mobile phase: A: water (0.2% formic acid) B: ACN; gradient B%: 30%-70% over 15.0 min). The 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).

[1498] The compounds in Table 14 were prepared in essentially the same manner as found in Example 26.

[1499] Table 14

[1500]

[1501]

[1502]

[1503]

[1504]

[1505]

[1506] Example 62

[1507] 3-(4-Chloro-2-hydroxybenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5- yl)piperidin-2-one

[1508]

[1509] To a solution of 3-(4-chloro-2-methoxybenzyl)-l-(3-(5-methylpyridazin-4-yl)- 1-((2-(trimethylsilyl)ethoxy)methyl)-lH-l,2,4-triazol-5-yl)piperidin-2-one (100 mg, 184 μmol) in DCM (3 mL) at 0 °C was added boron tribromide (385 μL, 552 μmol). 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 x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting with MeOH / DCM (0-10%) to give the title compound (6.1 mg, 7.9%) as a white solid. ES / MS (m / z): 399 (M+H).

[1510] The compounds in Table 15 were prepared in a manner essentially analogous to that found in Example 62.

[1511] Table 15

[1512]

[1513]

[1514] Example 68

[1515] 1-(5-chloro-l-(pyridazin-4-yl)-lH-pyrazol-4-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin- 2-one

[1516]

[1517] To a mixture of 4-(4-bromo-5-chloro-lH-pyrazol-l-yl)pyridazine (120 mg, 430 μmol) and 3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one (98.6 mg, 430 μmol) in DMF (10 mL) at ambient temperature under nitrogen was added tripotassium phosphate (274 mg, 1.29 mmol), N 1 ,N 2- dimethylcyclohexane-1,2-diamine (122 mg, 860 pmol) and Cul (81.9 mg, 430 pmol). 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 x 3). The combined organic layers were washed with saturated aqueous NaCl (10 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel flash chromatography eluting 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).

[1518] The compounds in Table 16 were prepared in essentially the same manner as found in Example 68.

[1519] Table 16

[1520]

[1521] Example 72

[1522] 3-((6-fluoropyridin-3-yl)methyl)-1 -(2-(pyridazin-4-yl)-2H-1,2,3-triazol-4- yl)piperidin-2-one

[1523]

[1524] 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 pmol) 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 h. After cooling to ambient temperature, the reaction mixture was filtered and concentrated in vacuo. The crude material was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10um, mobile phase: A: water (10 mmol / L ammonium bicarbonate and 0.05% ammonium hydroxide) B: ACN; B%: 30%-70% over 15.0 min) to give a pure product solution which was lyophilized to give the title compound as a white solid (119 mg, 93%). ES / MS (m / z): 354 (M+H).

[1525] The compounds in Table 17 were prepared in essentially the same manner as found in Example 72.

[1526] Table 17

[1527]

[1528] Example 75

[1529] 5-hydroxy-1-(3-(pyridazin-4-yl)-1H-1,2,4-triazol-5-yl)-3-(3,4,5-trifluorobenzyl)piperidin- 2-one

[1530]

[1531] 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 triflic 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 in vacuo and the residue was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10um, mobile phase: A: water (10 mmol / L ammonium bicarbonate and 0.05% ammonium hydroxide) B: acetonitrile; B%: 30%-70% over 15.0 min). The appropriate fractions were combined, concentrated in vacuo and lyophilized to give the title compound as a white solid (3.7 mg, 3.3%). ES / MS (m / z): 405 (M+H).

[1532] Example 76

[1533] 3-(3,4-difluorobenzyl)-1-(4-(pyridazin-4-yl)-1H-imidazol-2-yl)piperidin-2-one

[1534]

[1535] To a mixture of 3-(3,4-difluorobenzyl)-l-(4-iodo-lH-imidazol-2-yl)piperidin-2-one (80 mg, 0.17 mmol) and 4-(tributylstannyl)pyridazine (81 mg, 0.21 mmol) in dry DMF (5 mL) was added Xphos (17 mg, 35 μmol) and Pd2(dba)3(16 mg, 17 μmol) at ambient temperature. The mixture was stirred at 80 °C under nitrogen for 1 h. After cooling to ambient temperature, the reaction mixture was quenched with water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with saturated aqueous NaCl (5 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel flash 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).

[1536] The compounds in Table 18 were prepared in essentially the same manner as found in Example 76.

[1537] Table 18

[1538]

[1539] Example 79

[1540] 5-(2-oxo-3-(3,4,5-trifluorobenzyl)pyrrolidin-l-yl)-3-(pyridazin-4-yl)-lH-pyrrole-2- carbonitrile

[1541]

[1542] 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 pmol) in DCM (3 mL) at 20 °C was added TFA (1 mL, 0.01 mol) dropwise. After stirring at 20 °C for 2 h, the reaction mixture was concentrated in vacuo to give crude material. The crude material was quenched with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution (10 mL x 2), dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10um, mobile phase: A: water (0.2% formic acid) B: ACN; B%: 30%-70% over 15.0 min). The appropriate fractions were combined and concentrated in vacuo to give the title compound (2.8 mg, 19%) as a grey solid ES / MS (m / z): 398 (M+H).

[1543] The compounds in Table 19 were prepared in a manner essentially analogous to that found in Example 79.

[1544] Table 19

[1545]

[1546]

[1547] Example 87

[1548] (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)

[1549]

[1550] A solution of 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 h. The solvent was removed by nitrogen gas. The residue was triturated with ACN (10 mL) and water (1 mL), filtered, and dried in vacuo to give the title compound (520 mg, 60%) as a yellow solid ES / MS (m / z): 481 (M+H).

[1551] The compounds in Table 20 were prepared in a manner substantially similar to that described in Example 87.

[1552] Table 20

[1553]

[1554]

[1555] Example 92

[1556] (5-(3-(4-chloro-3-fluorobenzyl)-2-oxoperidin-1-yl)-3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-1-yl)methyl dihydrophosphate (isomer 2), ammonium salt

[1557]

[1558] TFA (1 mL) was added to a solution of ((5-(3-(4-chloro-3-fluorobenzyl)-2-oxopiperidin-1-yl)-3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-1-yl)methyl) phosphate di-tert-butyl ester (isomer 2) (300 mg, 0.482 mmol) in DCM (5 mL). The reaction mixture was stirred at ambient temperature for 2 hours. The solvent was removed by evaporation and the residue was purified by preparative HPLC (0.1% NH4HCO3, 50% ACN increased to 80% within 8 min, stopped at 16 min, flow rate: 30 mL / min, Rt: 8 min). The appropriate eluates were combined, evaporated, and lyophilized to give the title compound (240 mg, 94%) as a white solid: ES / MS (m / z): 511 (M+H-NH3).

[1559] The compounds in Table 21 were prepared in a manner substantially similar to that described in Example 92.

[1560] Table 21

[1561]

[1562] Example 94

[1563] 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)

[1564]

[1565] Purification of 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 performed by Daicel ChiralPak IG (250*25 mm, 10 um), mobile phase A: CO2, B: (MEOH:ACN = 1:1), eluted with 55% of B, flow rate: 100 mL / min. The eluent of the first peak was collected and lyophilized to give Isomer 1 (16.9 mg, 16.9%, ee: 100.0%). ES / MS (m / z): 435 (M+H). The eluent of the second peak was collected and lyophilized to give Isomer 2 (20.6 mg, 20.6%, ee: 100.0%). ES / MS (m / z): 435 (M+H).

[1566] The compounds in Table 22 were prepared in a manner essentially analogous to that found in Example 94.

[1567] Table 22

[1568]

[1569]

[1570]

[1571]

[1572]

[1573]

[1574]

[1575]

[1576]

[1577] Example 154

[1578] 1-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one

[1579]

[1580] To a solution of l-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-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 in vacuo. The residue was basified to pH 8 by the addition of saturated aqueous NaHC03solution at 0 °C. The aqueous solution was decanted. The remaining 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).

[1581] The compounds in Table 23 were prepared in a manner essentially similar to that found in Example 154.

[1582] The compounds in Table 23 were prepared in a manner essentially similar to that found in Example 154.

[1583] Table 23

[1584]

[1585]

[1586] Example 159

[1587] 2-Fluoro-4-((l-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-lH-pyrazol-5-yl)-2- oxopyrrolidin-3-yl)methyl)benzonitrile

[1588]

[1589] 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 and then stirred at ambient temperature for 5 hours. The reaction mixture was concentrated in vacuo. The residue was added to water (20 mL), adjusted to Ph 7 with saturated aqueous NaHC03solution, then extracted with DCM (30 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude was purified by preparative HPLC (column: Welch Xtimate 21.2*250mm C18, 10um, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: ACN; B%: 30%-70% over 15.0 min) to give the title compound as a white solid (101 mg, 66%). ES / MS (m / z): 393 (M+H).

[1590] The compounds in Table 24 were prepared in a manner essentially analogous to that found in Example 159.

[1591] Table 24

[1592]

[1593]

[1594] Example 164

[1595] 3-(2-(Diifluoromethyl)-4-fluorobenzyl)-1-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-1H- pyrazol-5-yl)pyrrolidin-2-one

[1596]

[1597] 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 h, and then concentrated to dryness in vacuo. The crude was purified by preparative HPLC (gradient: 20-50% ACN / water (10 mmol NH4HCO3) in 8 min, stop at 15 min; retention time: 12-13 min; flow rate: 30 mL / min; column: BOSTON pHlex ODS 10um 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].

[1598] The compounds in Table 24 were prepared in a manner essentially analogous to that found in Example 164.

[1599] Table 24

[1600]

[1601] Example 167

[1602] 1-(3-(5-(hydroxymethyl)pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)piperidin- 2-one

[1603]

[1604] 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) at 0 °C was added TFA (2 mL), which was then stirred at ambient temperature for 4 h. The reaction mixture was concentrated to dryness in vacuo. To the residue was added saturated aqueous NaHCO3solution (15 mL) at 0 °C. The precipitate was filtered, washed with water (30 mL) and cold MeOH (0.5 mL) to give the title compound (258 mg, 52%) as a white solid. MS (m / z): 418 (M+H).

[1605] The compounds in Table 25 were prepared in a manner essentially analogous to that found in Example 167.

[1606] Table 25

[1607]

[1608]

[1609]

[1610] Example 187

[1611] 3-(4-chloro-3,5-difluorobenzyl)-4-(hydroxymethyl)-1-(3-(5-methylpyridazin-4-yl)- 1H-pyrazol-5-yl)pyrrolidin-2-one

[1612]

[1613] 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 dry DCM (5 mL) at -78 °C under nitrogen was added dropwise boron tribromide in DCM (0.1 mL, 17 wt%, 1.34 μmol) and then stirred at 25 °C for 16 h. The mixture was quenched with saturated aqueous NaHC03solution (5 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with saturated aqueous NaCl solution (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (mobile phase: A: water (10 mM NH4HC03); B: ACN; 15%-35% B in 8 min, stop at 15 min) to give the title compound (65 mg, 56%) as a white solid. ES / MS (m / z): 434 (M+H).

[1614] The compounds in Table 25a were prepared in essentially the same manner as found in Example 187.

[1615] Table 25a

[1616]

[1617] Example 188a

[1618] 1-(3-(5-amino pyridazin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin- 2-one

[1619]

[1620] To a stirred solution of l-(3-(5-amino pyridazin-4-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-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 for 2 h under nitrogen, the mixture was concentrated in vacuo. To the residue was added NaHC03solution (5 mL) and extracted with DCM (5 mL x 3). The combined DCM was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with MeOH (2 mL) and filtered to give the title compound as a white solid (100 mg, 60%). ES / MS (m / z): 389 (M+H).

[1621] The compounds in Table 25b were prepared in a manner essentially analogous to that found in Example 188a.

[1622] Table 25b

[1623]

[1624] Example 189

[1625] 2-(5-(3-(4-chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-l-yl)-3-(pyridazin-4-yl)-lH- pyrazol-4-yl)acetonitrile

[1626]

[1627] To a solution of 2-(5-(3-(4-chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-l-yl)-3-(pyridazin-4- yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-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 in vacuo. The residue was added to water (80 mL), adjusted to pH 7-8 with saturated NaHC03solution, and extracted with EtOAc (80 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (Boston pHlex ODS 21.2 x 250 mm, 10 μm, A: water (10 mM NH4HC03), B: CAN 20-50% B, 10 min, stop at 15 min) to give the title compound as a white solid (120 mg, 71.4%). ES / MS (m / z): 429 (M+H).

[1628] The compounds in Table 25c were prepared in a manner essentially analogous to that found in Example 189.

[1629] Table 25c

[1630]

[1631] Example 189c

[1632] 3-(4-chloro-3-fluorobenzyl)-l-(l-(5-methylpyridazin-4-yl)-lH-pyrazol-4-yl)piperidin- 2-one

[1633]

[1634] To a mixture of 2-(4-chloro-3-fluorobenzyl)-5-hydroxy-N-(l-(5-methylpyridazin-4- yl)-lH-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 allowed to cool to ambient temperature and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (110 mg, 24%). ES / MS (m / z): 400 [M+H].

[1635] Example 189d

[1636] 1-(5-(methoxymethyl)-l-(pyridazin-4-yl)-lH-pyrazol-4-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one

[1637]

[1638] To a solution of 4-(4-bromo-5-(methoxymethyl)-lH-pyrazol-l-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 K3PO4 (64 mg, 0.30 mmol), Pd(OAc)2 (2 mg, 0.01 mmol), and X-Phos (5 mg, 0.01 mmol) under N2. The mixture was heated to 90 °C for 2 h. The mixture was allowed to cool to ambient temperature and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (15 mg, 48%). ES / MS (m / z): 460 [M+H]. 1 ,N 2-Dimethylcyclohexane-1,2-diamine (29 mg, 0.20 mmol) and CuI (29 mg, 0.15 mmol) were added, and the mixture was stirred at 90 °C under a N2 atmosphere for 5 hours. The mixture was cooled to ambient temperature and concentrated under vacuum. The residue was purified by preparative HPLC (C18, ACN / 13 mmol TFA = 65-95%, within 17 min, rt = 8.9 min) to give the title compound (13 mg, 31%) as a white solid. ES / MS (m / z): 418 (M+H).

[1639] Example 190

[1640] 3-((6-(difluoromethyl)pyridin-3-yl)methyl)-1-(4-fluoro-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)pyrrolidine-2-one (isomer 1) and 3-((6-(difluoromethyl)pyridin-3-yl)methyl)-1-(4-fluoro-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)pyrrolidine-2-one (isomer 2)

[1641]

[1642] Purification of racemic 3-((6-(difluoromethyl)pyridin-3-yl)methyl)-1-(4-fluoro-3-(pyridazin-4-yl)-1H-pyrazol-5-yl)pyrrolidone-2-one (100 mg): SFC, OX (4.6*100 mm, 5 μm), mobile phase A: CO2, B: (EtOH [1% NH3 (7 M in MeOH)]), eluted with 45% B, flow rate: 100 mL / min. The eluent from the first peak was collected and lyophilized to give isomer 1 (ee: 100.0%). ES / MS (m / z): 389 (M+H). The eluent from the second peak was collected and lyophilized to give isomer 2 (ee: 100.0%). ES / MS (m / z): 389 (M+H).

[1643] The compounds in Table 26 were prepared in a manner substantially similar to that described in Example 190.

[1644] Table 26

[1645]

[1646]

[1647]

[1648]

[1649]

[1650]

[1651]

[1652]

[1653]

[1654]

[1655]

[1656]

[1657]

[1658]

[1659]

[1660]

[1661] Example 287

[1662] 1 -(3-(5-(fluoromethyl)pyridazin-4-yl)- 1 H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one

[1663]

[1664] To a solution of 1 -(3-(5-(hydroxymethyl)pyridazin-4-yl)- 1 H-pyrazol-5-yl)-3-(3,4,5- trifluorobenzyl)pyrrolidin-2-one (100 mg, 248 μmol) in DCM (2 mL) at 0 °C was added DAST (160 μL, 1.24 mmol) and then stirred at 0 °C for 10 min under nitrogen atmosphere. The reaction was quenched with H2O (3 mL) at ambient temperature and extracted with DCM (5 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (gradient: 25-55% ACN / water (10 mM NH4HCO3) in 10 min, stop at 15 min; retention time: 11-14 min; flow rate: 30 mL / min; column: Boston Phlex ODS 21.2*250 mm, 10 um) to give the title compound as a white solid (3.2 mg, 3.2%). ES / MS (m / z): 406 (M+H).

[1665] Example 291

[1666] 1-(4-(2-hydroxyethyl)-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-3-(3,4,5-trifluorobenzyl)pyrrolidin-2-one

[1667]

[1668] 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 slowly NaBH4(38 mg, 1 mmol). After stirring at 25 °C for 1 h, the reaction mixture was concentrated in vacuo. The residue was added to water (30 mL) and extracted with EtOAc (50 mL x 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude was purified by preparative HPLC (column: Welch Xtimate 21.2 x 250 mm C18, 10 um, mobile phase: A: water (10 mmol / L ammonium bicarbonate) B: ACN; B%: 30%-70% over 15.0 min) to give the title compound (123 mg, 20%) as a white solid. ES / MS (m / z): 417 (M+H).

[1669] Example 292

[1670] 3-hydroxy-1-(5-(methoxymethyl)-1-(pyridazin-4-yl)-1H-pyrazol-4-yl)-3-(3,4,5- trifluorobenzyl)pyrrolidin-2-one

[1671]

[1672] 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) at -75 °C was added a solution of LiHMDS in THF (0.16 mL, 0.16 mmol). After stirring at -75 °C for 1 h, a solution of (1R)-(-)-(10-camphorsulfonyl)oxaziridine (37 mg, 0.16 mmol) in THF (1 mL) was added to the reaction mixture at -75 °C and then stirred at -75 °C for 3 h under nitrogen. The mixture was added to water (20 mL) and extracted with EtOAc (30 mL x 2). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (gradient: 25-55% ACN / water (10 mM NH4HCO3) in 8.0 min, stop at 24 min, RT = 10.3 min) to give the title compound as a yellow solid (5 mg, 10%). ES / MS (m / z): 434 (M+H).

[1673] Example 293

[1674] 3-((6-Fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1H-1,2,4-triazol-5- yl)piperidin-2-one (Isomer 1)

[1675]

[1676] To a solution of 3-((6-fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1- ((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)piperidin-2-one (Isomer 1) (140 mg, 0.28 mmol) in DCM (1 mL) was added TFA (1 mL). After stirring at ambient temperature for 8 h, the reaction mixture was concentrated in vacuo. The residue was added to saturated NaHCO3solution (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC (ACN / 10 mM NH4HCO3 = 30-70%) to give the title compound as a white solid (67 mg, 64%, ee = 99%). ES / MS (m / z): 368 (M+H).

[1677] The compounds in Table 30 were prepared in essentially the same manner as found in Example 293.

[1678] Table 30

[1679]

[1680]

[1681]

[1682] Example 305

[1683] (S)-3-((6-chloro-5-fluoropyridin-3-yl)methyl)-1-(3-(5-methylpyridazin-4-yl)-1H- pyrazol-5-yl)piperidin-2-one

[1684]

[1685] 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 H2O2 (42 mg, 1.25 mmol) at 0 °C. After stirring for 10 min, the reaction mixture was added to a solution of LiOH.H2O (26 mg, 0.62 mmol) in H2O (2 mL) and stirred for 20 min. The reaction mixture was quenched with saturated aqueous NH4Cl solution and extracted with EtOAc (50 mL x 3). The organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was slurry in MeOH (10 mL) and the solid was filtered and dried in vacuo to give the title compound (45 mg, 54%) as a white solid. ES / MS (m / z): 401 (M+H).

[1686] The compounds in Table 31 were prepared in a manner essentially analogous to that found in Example 305.

[1687] Table 31

[1688]

[1689] Example 307

[1690] (S)-3-(4-fluorobenzyl)-1-(3-(5-methylpyridazin-4-yl)-1H-pyrazol-5-yl)piperidin-2-one

[1691]

[1692] ​To a solution of (R)-4-benzyl-3-((S)-2-(4-fluorobenzyl)-5-((3-(5-methylpyridazin-4- yl)-lH-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 in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (20 mg, 23%). ES / MS (m / z): 366 [M+H].

[1693] Example 308

[1694] (S)-(5-(3-((6-chloropyridin-3-yl)methyl)-2-oxopiperidin-l-yl)-3-(5-methylpyridazin-4-yl)- lH-pyrazol-l-yl)methyl dihydrogen phosphate

[1695]

[1696] To a suspension of (S)-((5-(3-((6-chloropyridin-3-yl)methyl)-2-oxopiperidin-l-yl)-3-(5- methylpyridazin-4-yl)-lH-pyrazol-l-yl)methyl) di-tert-butylphosphonate (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 in vacuo. The residue was purified by reverse phase column chromatography eluting with ACN / NH4HCO3 solution (0-40%) to give the title compound as a white solid (95 mg, 58%). ES / MS (m / z): 493 (M+H).

[1697] The compounds in Table 32 were prepared in a manner essentially analogous to that found in Example 308.

[1698] Table 32

[1699]

[1700] Example 310

[1701] (5-(3-(4-chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-4-fluoro-3-(pyridazin-4-yl)- 1H-pyrazol-1-yl)methyl)phosphonic acid di-tert-butyl ester (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)phosphonic acid di-tert-butyl ester (Isomer 1-S2)

[1702]

[1703] To a suspension of Isomer 1-((5-(3-(4-chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-4- fluoro-3-(pyridazin-4-yl)-1H-pyrazol-1-yl)methyl)phosphonic acid di-tert-butyl ester and ((3-(3-(4-chloro-3,5-difluorobenzyl)-2-oxopyrrolidin-1-yl)-4-fluoro-5-(pyridazin-4-yl)- 1H-pyrazol-1-yl)methyl)phosphonic acid di-tert-butyl ester (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 in vacuo. The residue was purified by reverse phase column chromatography eluting with ACN / NH4HCO3 solution (0-40%) to give Isomer 1-S1 as a white solid (95 mg, 25%) and Isomer 1-S2 as a white solid (42 mg, 11%). ES / MS (m / z): 518 (M+H).

[1704] The compounds in Table 33 were prepared in a manner essentially analogous to that found in Example 310.

[1705] Table 33

[1706]

[1707]

[1708] Example 313

[1709] (2-(5-(pyridazin-4-yl)-3-(3-(3,4,5-trifluorophenyl)propanamido)-1H-pyrazol-4-yl)ethoxy) methylphosphonic acid disodium salt

[1710]

[1711] To a solution of (2-(5-(pyridazin-4-yl)-3-(3-(3,4,5-trifluorophenyl)propanamido)-lH- pyrazol-4-yl)ethoxy)methyl dihydrogen phosphate (71.7 mg, 0.14 mmol) in ACN (1 mL) at 25 °C was added NaOH (11.2 mg, 0.28 mmol) in water (1 mL) and then stirred at 25 °C for 5 h. The reaction mixture was lyophilized to give the title compound as a white solid (67.1 mg, 86%). ES / MS (m / z): 502 (M+H).

[1712] Example 314

[1713] 3-(4-Chloro-3,5-difluorophenyl)-N-(4-(morpholin-2-ylmethoxy)-3-(pyridazin-4-yl)-lH- pyrazol-5-yl)propanamide

[1714]

[1715] To a solution of tert-butyl 2-(((3-(3-(4-chloro-3,5-difluorophenyl)propanamido)-5- (pyridazin-4-yl)-lH-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 in vacuo. The residue was purified by preparative HPLC (C18, ACN / 10 mmol NH4HCO3) to give the title compound as a white solid (0.15, 30%). ES / MS (m / z): 479 (M+H).

[1716] The compounds in Table 34 were prepared in essentially the same manner as found in Example 314.

[1717] Table 34

[1718]

[1719] Example 316

[1720] N-(4-((4-Methylmorpholin-2-yl)methoxy)-3-(pyridazin-4-yl)-lH-pyrazol-5-yl)-3-(3,4,5- trifluorophenyl)acrylamide

[1721]

[1722] To a solution of N-(4-(morpholin-2-ylmethoxy)-3-(pyridazin-4-yl)-lH-pyrazol-5- yl)-3-(3,4,5-trifluorophenyl)acrylamide (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 h, the reaction mixture was concentrated in vacuo. 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).

[1723] Example 317

[1724] 3-(4-Chloro-3-fluorophenyl)-N-(4-(2-hydroxyethoxy)-5-(pyridazin-4-yl)-lH-pyrazol-3- yl)acrylamide

[1725]

[1726] To a solution of 3-(4-chloro-3-fluorophenyl)-N-(4-(2-methoxyethoxy)-5-(pyridazin-4- yl)-lH-pyrazol-3-yl)propionamide (0.3 g, 0.7 mmol) in DCM (10 mL) was added 1 M 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 in vacuo. The crude material was purified by reverse phase chromatography eluting with C18, 35% ACN / 10 mM NH4HCO3 to give the title compound (95 mg, 32%) as a white solid. ES / MS (m / z): 406 (M+H).

[1727] Example 318

[1728] N-(4-((4-(Methyl-d3)morpholin-2-yl)methoxy)-3-(pyridazin-4-yl)-lH-pyrazol-5-yl)-3- (3,4,5-trifluorophenyl)acrylamide

[1729]

[1730] To a solution of N-(l-(4-methoxybenzyl)-4-((4-(methyl-d3)morpholin-2-yl)methoxy)-3- (pyridazin-4-yl)-lH-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 trifluoromethanesulfonic acid (0.20 mL, 2.3 mmol). After stirring at 25 °C for 3 h, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound as a white solid (0.12 g, 60%). ES / MS (m / z): 480 (M+H).

[1731] The compounds in Table 35 were prepared in a manner essentially analogous to that found in Example 318.

[1732] Table 35

[1733]

[1734]

[1735] Example 321

[1736] N-(4-(Methoxymethyl)-5-(pyridazin-4-yl)-lH-pyrazol-3-yl)-3-(3,4,5-trifluorophenyl)acrylamide

[1737]

[1738] To a solution of N-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-lH-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 h, the reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC (water:ACN = 20:1) to give the title compound as a white solid (20 mg, 25%). ES / MS (m / z): 392 (M+H).

[1739] Example 322

[1740] 3-(4-Chloro-lH-pyrrol-2-yl)-N-(5-(5-methylpyridazin-4-yl)-lH-pyrazol-3-yl)propanamide

[1741]

[1742] To a solution of N-(4-(2-hydroxyethyl)-5-(pyridazin-4-yl)-lH-pyrazol-3-yl)-3- (3,4,5-trifluorophenyl)propanamide (500 mg, 1.28 mmol) in ACN (10 mL) was added Cul (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 added slowly. After stirring at 50 °C for 1 h under nitrogen, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (gradient: 30-60% ACN / water (0.01% TFA) over 8 min, stop at 14 min; retention time: 8.5 min; flow rate: 30 mL / min; column: BOSTON pHlex ODS 10 um 21.2 x 250 mm 120 A) to give the title compound as a white solid (12 mg, 2.1%). ES / MS (m / z): 255 (M+H).

[1743] Example 323

[1744] N-(4-(2-(difluoromethoxy)ethyl)-5-(pyridazin-4-yl)-lH-pyrazol-3-yl)-3-(3,4,5- trifluorophenyl)acrylamide

[1745]

[1746] To a solution of N-(4-(2-hydroxyethyl)-5-(pyridazin-4-yl)-lH-pyrazol-3-yl)-3- (3,4,5-trifluorophenyl)propanamide (500 mg, 1.28 mmol) in ACN (10 mL) was added Cul (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 added slowly. After stirring at 50 °C for 1 h under nitrogen, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with saturated aqueous NaCl (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (gradient: 30-60% ACN / water (0.01% TFA) over 8 min, stop at 14 min; retention time: 8.5 min; flow rate: 30 mL / min; column: BOSTON pHlex ODS 10 um 21.2 x 250 mm 120 A) to give the title compound as a white solid (12 mg, 2.1%). ES / MS (m / z): 255 (M+H).

[1747] Example 324

[1748] N-(4-(hydroxymethyl)-3-(pyridazin-4-yl)-lH-pyrazol-5-yl)-3-(3,4,5- trifluorophenyl)propanamide

[1749]

[1750] To a solution of N-(4-(hydroxymethyl)-l-(4-methoxybenzyl)-3-(pyridazin-4-yl)-lH- pyrazol-5-yl)-3-(3,4,5-trifluorophenyl)propanamide (180 mg, 0.36 mmol) in DCM (1 mL) at 0 °C was added TFA (1 mL, 0.01 mol) and then stirred at 20 °C for 16 h. The reaction mixture was concentrated in vacuo. 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).

[1751] ARM-SAM-TIR SARM1 IC 50 Assay

[1752] An assay for ARM-SAM-TIR NADase activity is described herein, and this assay is used to measure the efficacy of compounds of the invention to block SARM1 -mediated cleavage of NAD+. The assay is optimized in such a way that the efficacy of the compounds of the invention to inhibit SARM1 activity is characterized and IC50 values are calculated for each compound. The assay utilizes full-length SARM1, which encompasses the ARM, SAM, and TIR domains. As shown herein, expression of this fragment, without the auto-inhibitory N-terminal domain, results in a constitutively active enzyme that cleaves NAD+.

[1753] Preparation of ARM-SAM-TIR lysate (STL)

[1754] NRK1-HEK293T cells were plated at 20 x 106cells per plate on 150 cm 2 plates. The next day, cells were transfected with 15 pg of ARM-SAM-TIR expression plasmid (SEQ ID NO: 1, as disclosed in WO 2019 / 236879, pages 77-81; paragraph

[0310] ).

[1755] Cultures were supplemented with 1 mM NR at the time of transfection to minimize toxicity of ARM-SAM-TIR overexpression. 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 cold PBS (0.01 M Phosphate Buffered Salts NaCl 0.138 M; KCl 0.0027 M; pH 7.4). The cells were resuspended in lysis buffer with protease inhibitors (Complete EDTA-free, Roche) and passed through a French press (Thermo Fisher) at 10,000 psi. The lysate was clarified by centrifugation at 20,000 rpm (Beckman Optima TLX Ultracentrifuge, Thermo Fisher) for 1 h at 4 °C. The supernatant was collected and stored at -80 °C until use. TMCell lysates were prepared in PBS with protease inhibitor cocktail, Roche product #11873580001), and by sonication (Branson Sonifer 450, output = 3, 20 episodes of stroke). The lysates were centrifuged (12,000 x g for 10 min at 4°C) to remove cell debris, and the supernatant (containing ARM-SAM-TIR proteins) was stored at -80°C for later use in the in vitro ARM-SAM-TIR NADase assay (see below). Protein concentration was determined by the Bicinchoninic (BCA) method and used for standardization of lysate concentration.

[1756] ARM-SAM-TIR IC50determination for compounds of Formula I.

[1757] The enzymatic assay was performed in 384-well polypropylene plates in Dulbecco’s PBS buffer with a final assay volume of 20 μΐ^. ARM-SAM-TIR lysate at a final concentration of 5 μg / mL was pre-incubated with the respective compound at a final assay concentration of 1% DMSO for 2 h at ambient temperature. The reaction was initiated by the addition of 5 μΜ final assay concentration of NAD+as substrate. After 2 h incubation at room temperature, the reaction was stopped with 40 μΐ^ of a 7.5% trichloroacetic acid in acetonitrile stop solution. The concentration of NAD+and ADPR was analyzed by the RapidFire high-throughput mass spectrometry system (Agilent Technologies, Santa Clara, CA) using an API4000 triple quadrupole mass spectrometer (AB Sciex Framingham, MA).

[1758] Results are presented in Tables 36A and 36B below. Compounds with activity designated as “A” provide IC 50 < 50 nM; compounds with activity designated as “B” provide IC 50 51-100 nM; compounds with activity designated as “C” provide IC 50 101-500 nM; compounds with activity designated as “D” provide IC50 501-1000 nM; compounds with activity designated as “E” provide IC 50 > 1000 nM.

[1759] Table 36A: HSARM1 IC 50 determination (Part A)

[1760] Example Number IC 50 (nM) 1 C 2 C 3 A 4 B 5 B 6 B 7 E 8 B 9 B 10 D 11 A 12 A 13 A 14 C 15 E 16 D 17 B 18 B 19 C 20 A 21 B 22 A 23 B 24 A

[1761] Table 36B: HSARM1 IC 50 Assay (Part B)

[1762]

[1763]

[1764]

[1765]

[1766] The symbol "-" means data was not collected.

[1767] The results shown in Tables 36A and 36B above demonstrate that the exemplified compounds have hSARM1 inhibitory activity.

[1768] List of Embodiments

[1769] 1. A compound of the formula

[1770]

[1771] wherein

[1772] X is N and Y is CH, or X is CH and Y is N;

[1773] R 5 is selected from hydrogen, halogen, -NH2, -OC 1-3 alkyl and C 1-3 alkyl, wherein

[1774] when R 5 is hydrogen, then ring A is selected from: and

[1775] when R 5 is selected from halogen, -NH2, -OC 1-3 alkyl and C 1-3 alkyl, optionally substituted with 1-3 halogen atoms, -OH or -OCH3, then ring A is selected from: ​​​A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2. The nitrogen atom may be optionally replaced by -CH2OP(O)(OH)2. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2.

[1776] R 1 and R 2 Together with the atoms they are attached to, they form 5- to 6-membered saturated heterocycles, wherein one of the carbon atoms is optionally replaced by a heteroatom selected from oxygen and nitrogen, and wherein one of the carbon atoms is optionally replaced by a cyano group, -OR d Or C 1-3 Alkyl substitution, C 1-3 Alkyl groups are optionally prefixed with -NH2 or -OR d replace;

[1777] R 3 Selected from hydrogen and C 1-4 alkyl;

[1778] R 4 Selected from 1 to 3 Rs b The substituted phenyl group contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and is optionally surrounded by 1 to 3 R atoms. b Substituted 5- to 6-membered heteroaryl groups, and containing 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, optionally surrounded by 1 to 3 R groups. b Substituted 9- to 10-membered fully or partially aromatic bicyclic heteroaryl groups;

[1779] Each R a Independently selected from hydrogen, halogen, cyano, and optionally halogenated, -OR d C-substituted with -NH2 or cyano 1-4 alkyl;

[1780] Each R b Independently selected from halogen, cyano, C 1-4 Alkyl groups, -NH2, -OH, monohalomethyl, dihalomethyl, trihalomethyl, and -OC 1-4 Alkyl; and

[1781] R c Selected from halogens, cyano groups, and optional ground cover R e Replacement -OC 1-3 Alkyl groups and optionally halogenated, -OR d C-substituted with -NH2 or cyano 1-4 Alkyl; and

[1782] R d Selected from hydrogen, C 1-4alkyl and -CH2OP(O)(OH)2;

[1783] R e selected from

[1784] or a pharmaceutically acceptable salt thereof.

[1785] 2. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein X is N and Y is CH.

[1786] 3. The compound according to Embodiment 1 or Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen and ring A is selected from:

[1787] 4. The compound according to Embodiment 1 or Embodiment 2, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from halogen, -NH2, -OC 1-3 alkyl and C 1-3 alkyl optionally substituted with 1-3 halogen atoms, -OH or -OCH3, and ring A is selected from:

[1788] 5. The compound according to Embodiment 4, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from -CH3, -CH2OH, -NH2, -CH2F and -OCH3.

[1789] 6. The compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, which is:

[1790]

[1791] wherein B is selected from O, NH, C-R 6 , wherein R 6 ​​​​​​selected from hydrogen, cyano, -OC 1-3 alkyl or optionally substituted C d alkyl or optionally substituted C 1-3 alkyl;

[1792] R 7 and R 8 are independently selected from hydrogen and -OH, and

[1793] n is 0 or 1, or a pharmaceutically acceptable salt thereof.

[1794] 7. The compound according to Embodiment 6, or a pharmaceutically acceptable salt thereof, which is:

[1795]

[1796] wherein n is 0 or 1, or a pharmaceutically acceptable salt thereof.

[1797] 8. The compound according to Embodiment 6 or 7, or a pharmaceutically acceptable salt thereof, which is selected from:

[1798] or a pharmaceutically acceptable salt thereof.

[1799] 9. The compound according to any one of Embodiments 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.

[1800] 10. The compound according to any one of Embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from: and each R a is independently selected from hydrogen, cyano, -CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CN, -OCH3, -F, and -Cl.

[1801] 11. The compound according to any one of Embodiments 1 to 3 and 5 to 10, or a pharmaceutically acceptable salt thereof, wherein ring A is: and R c ​​selected from cyano, -CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CN, -OCH3, -F, -Cl,

[1802] 12. The compound according to any one of embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from optionally substituted phenyl and 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 R b b

[1803] 13. The compound according to embodiment 12, or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally substituted phenyl. b

[1804] 14. The compound according to embodiment 12, or a pharmaceutically acceptable salt thereof, wherein R 4 is 5- to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted with 1 to 3 R b

[1805] 15. The compound according to embodiment 14, or a pharmaceutically acceptable salt thereof, wherein R 4 is optionally substituted pyridine. b

[1806] 16. The compound according to embodiment 12, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:

[1807] 17. The compound according to any one of embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 4 is substituted with 1 to 3 R b and each R b is independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl and fluoromethyl.

[1808] 18. The compound according to embodiment 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:

[1809]

[1810] 19. A compound of the formula

[1811] ​​​​​

[1812] in

[1813] X is N and Y is CH, or X is CH and Y is N;

[1814] R 5 Selected from hydrogen and -CH3, optionally substituted with -OH, -NH2, or 1-3 halogen atoms, wherein

[1815] When R 5 C is optionally substituted with -OH, -NH2 or 1-3 halogen atoms. 1-3 When alkyl, ring A is selected from those optionally substituted with -CH2OP(O)(OH)2 at a nitrogen atom. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2. and

[1816] When R 5 When it is hydrogen, then ring A comes from: a nitrogen atom optionally substituted with -CH2OP(O)(OH)2.

[1817] R 1 R 2 and R 3 Each is independently selected from hydrogen and C. 1-4 Alkyl, wherein R 2 and R 3 Together with the atoms they are attached to, they can optionally form 3- to 6-membered saturated carbon rings;

[1818] R 4 Selected from 1 to 3 Rs b The substituted phenyl group contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and is optionally surrounded by 1 to 3 R atoms. b The substituted 5- to 6-membered heteroaryl group contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and is optionally surrounded by 1 to 3 R atoms. b Substituted 9- to 10-membered fully or partially aromatic bicyclic heteroaryl groups;

[1819] R a Selected from hydrogen, halogen, cyano and C 1-4 alkyl;

[1820] Each R b Independently selected from halogens, cyano groups, -OH, -NH2, C 1-4 Alkyl, monohalomethyl, dihalomethyl, trihalomethyl and -OC 1-4 alkyl;

[1821] R c Selected from optional land - ORd or R e substituted -OC 1-3 alkyl, and -OR d or 1-3 halo atoms; and 1-4 alkyl; and

[1822] R d is selected from H, -CH3, -CF3, -CHF2, and -CH2OP(O)(OH)2; and

[1823] R e is selected from

[1824] or a pharmaceutically acceptable salt thereof.

[1825] 20. The compound according to Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein X is N and Y is CH.

[1826] 21. The compound according to Embodiment 19 or Embodiment 20, or a pharmaceutically acceptable salt thereof, wherein R 5 is C 1-3 alkyl optionally substituted with -OH, -NH2, or 1-3 halo atoms, and ring A is selected from:

[1827] 22. The compound according to Embodiment 21, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from -CH3, CH2OH, CH2F, and ring A is selected from:

[1828] 23. The compound according to Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen, and ring A is:

[1829] 24. The compound according to any one of Embodiments 19-23, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 3 are all hydrogen.

[1830] ​​25. The compound or pharmaceutically acceptable salt thereof of any one of embodiments 19-22 and 24, wherein ring A is selected from: and R a is selected from hydrogen, cyano, and -CH3.

[1831] 26. The compound or pharmaceutically acceptable salt thereof of any one of embodiments 19, 23, and 24, wherein ring A is: and R c is selected from -OCH3, -CH2OCH3, -CH2CH2OCH3, -OCH2CH2OH, -OCH2CH2OCH3, -OCH2CH2OCHF2, -CH2CH2OCH2OP(O)(OH)2,

[1832] 27. The compound or pharmaceutically acceptable salt thereof of any one of embodiments 19-26, wherein R 4 is selected from phenyl optionally substituted with 1-3 R b and 5- to 6-membered heteroaryl containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R b .

[1833] 28. The compound or pharmaceutically acceptable salt thereof of embodiment 27, wherein R 4 is phenyl optionally substituted with 1-3 R b .

[1834] 29. The compound or pharmaceutically acceptable salt thereof of embodiment 27, wherein R 4 is 5- to 6-membered heteroaryl containing 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1-3 R b .

[1835] 30. The compound or pharmaceutically acceptable salt thereof of embodiment 29, wherein R 4 is pyridine optionally substituted with 1-3 R b .

[1836] 31. The compound or pharmaceutically acceptable salt thereof of embodiment 27, wherein R 4 is selected from:

[1837] 32. The compound or pharmaceutically acceptable salt thereof of any one of embodiments 20-31, wherein R 4substituted by one to three R b substituted by one to three R b are each independently selected from the group consisting of fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl and fluoromethyl.

[1838] 33. The compound according to Embodiment 19, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:

[1839]

[1840]

[1841] 34. A compound of the formula:

[1842]

[1843] wherein

[1844] X is N and Y is CH, or X is CH and Y is N;

[1845] Ring A is selected from

[1846] R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen and C 1-4 alkyl, wherein R 1 and R 2 together with the atoms to which they are attached can optionally form a 5- to 6- membered saturated heterocyclic ring wherein one of the carbon atoms is optionally replaced by a heteroatom selected from oxygen and nitrogen, or wherein R 2 and R 3 together with the atoms to which they are attached can optionally form a 3- to 6- membered saturated carbocyclic ring;

[1847] R 4 is selected from phenyl optionally substituted by one to three R b and 5- to 6- membered heteroaryl containing one to three heteroatoms selected from oxygen, nitrogen and sulfur and optionally substituted by one to three R b ;

[1848] R a is selected from hydrogen, halogen, cyano and C 1-4 alkyl optionally substituted by halogen, -OH, -NH2or cyano;

[1849] each R b is independently selected from halogen, cyano, C 1-4 alkyl, trihalomethyl and -OC 1-4 alkyl, or a pharmaceutically acceptable salt thereof.

[1850] 35. The compound according to Embodiment 34, or a pharmaceutically acceptable salt thereof, wherein X is N and Y is CH.

[1851] 36. The compound according to Embodiment 34, or a pharmaceutically acceptable salt thereof, wherein X is CH and Y is N.

[1852] 37. The compound according to any one of Embodiments 34 to 36, or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , and R 3 are hydrogen.

[1853] 38. The compound according to any one of Embodiments 34 to 36, or a pharmaceutically acceptable salt thereof, which is:

[1854]

[1855] wherein Z is selected from CH2, O, NH, or a bond, or a pharmaceutically acceptable salt thereof.

[1856] 39. The compound according to Embodiment 38, or a pharmaceutically acceptable salt thereof, which is selected from:

[1857]

[1858] or a pharmaceutically acceptable salt thereof.

[1859] 40. The compound according to any one of Embodiments 34 to 39, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from:

[1860] 41. The compound according to any one of Embodiments 34 to 39, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from: and R a is methyl.

[1861] 42. The compound according to any one of Embodiments 34 to 39, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from: and R a is cyano.

[1862] 43. The compound according to any one of Embodiments 34 to 42, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from:

[1863] 44. The compound according to Embodiment 43, or a pharmaceutically acceptable salt thereof, wherein R b is halogen.

[1864] 45. The compound or pharmaceutically acceptable salt thereof of any one of embodiments 34-44, wherein R 4 selected from:

[1865] 46. The compound or pharmaceutically acceptable salt thereof of embodiment 34, selected from:

[1866]

[1867]

[1868] or a pharmaceutically acceptable salt thereof.

[1869] 47. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt thereof of any one of embodiments 1-46, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

[1870] 48. A method of treating or preventing a disease associated with axonal degeneration in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof of any one of embodiments 1-46, or a pharmaceutical composition of embodiment 47.

[1871] 49. A method of treating or preventing a disease associated with SARM1 activation in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt thereof of any one of embodiments 1-46, or a pharmaceutical composition of embodiment 47.

[1872] 50. A method of treating or preventing a disease selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), diabetic neuropathy, and chemotherapy-induced peripheral neuropathy in a patient, comprising administering to a patient in need of such treatment an effective amount of a compound or pharmaceutically acceptable salt the...

Claims

1. A compound of the following formula in X is N and Y is CH, or X is CH and Y is N; R 5 Selected from hydrogen, halogens, -NH2, -OC 1-3 Alkyl groups and C atoms optionally substituted with 1-3 halogen atoms, -OH, or -OCH3 1-3 Alkyl, wherein When R 5 When it is hydrogen, ring A is selected from those that are optionally substituted with -CH2OP(O)(OH)2 at a nitrogen atom. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2. The nitrogen atom may be optionally replaced by -CH2OP(O)(OH)2. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2. and When R 5 Selected from halogens, -NH2, -OC 1-3 Alkyl groups and C atoms optionally substituted with 1-3 halogen atoms, -OH, or -OCH3 1-3 When alkyl, ring A is selected from those optionally substituted with -CH2OP(O)(OH)2 at a nitrogen atom. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2. The nitrogen atom may be optionally replaced by -CH2OP(O)(OH)2. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2. R 1 and R 2 Together with the atoms they are attached to, they form 5- to 6-membered saturated heterocycles, wherein one of the carbon atoms is optionally replaced by a heteroatom selected from oxygen and nitrogen, and wherein one of the carbon atoms is optionally replaced by a cyano group, -OR d Or C 1-3 Alkyl substitution, C 1-3 Alkyl groups are optionally prefixed with -NH2 or -OR d replace; R 3 Selected from hydrogen and C 1-4 alkyl; R 4 Selected from 1 to 3 Rs b The substituted phenyl group contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and is optionally surrounded by 1 to 3 R atoms. b Substituted 5- to 6-membered heteroaryl groups, and containing 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, optionally surrounded by 1 to 3 R groups. b Substituted 9- to 10-membered fully or partially aromatic bicyclic heteroaryl groups; Each R a Independently selected from hydrogen, halogen, cyano, and optionally halogenated, -OR d C-substituted with -NH2 or cyano 1-4 alkyl; Each R b Independently selected from halogen, cyano, C 1-4 Alkyl groups, -NH2, -OH, monohalomethyl, dihalomethyl, trihalomethyl, and -OC 1-4 Alkyl; and R c Selected from halogens, cyano groups, and optional ground cover R e Replacement -OC 1-3 Alkyl groups and optionally halogenated, -OR d C-substituted with -NH2 or cyano 1-4 Alkyl; and R d Selected from hydrogen, C 1-4 Alkyl groups and -CH2OP(O)(OH)2; R e Selected from Or its pharmaceutically acceptable salt.

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

3. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R 5 The atom is hydrogen and ring A is selected from those that are optionally substituted with -CH2OP(O)(OH)2 at one nitrogen atom. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2. The nitrogen atom may be optionally replaced by -CH2OP(O)(OH)2. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2.

4. The compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from halogens, -NH2, -OC 1-3 Alkyl groups and C atoms optionally substituted with 1-3 halogen atoms, -OH, or -OCH3 1-3 Alkyl group, and ring A is selected from those optionally substituted with -CH2OP(O)(OH)2 at a nitrogen atom. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2. The nitrogen atom may be optionally replaced by -CH2OP(O)(OH)2. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2.

5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from -CH3, -CH2OH, -NH2, -CH2F and -OCH3.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, is: B is selected from O, NH, and CR. 6 , where R 6 Selected from hydrogen, cyano, -OC 1-3 Alkyl groups or optionally -NH2 or -OR d Replacement C 1-3 alkyl; R 7 and R 8 Independently selected from hydrogen and -OH, and n is 0 or 1, or a pharmaceutically acceptable salt thereof.

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

8. The compound according to claim 6 or 7, or a pharmaceutically acceptable salt thereof, selected from: Or its pharmaceutically acceptable salt.

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

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

11. The compound according to any one of claims 1 to 3 and 5 to 10, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted with -CH2OP(O)(OH)2 at a nitrogen atom. And R c Selected from cyano, -CH3, -CH2OH, -CH2CH2OH, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH3, -CH2CN, -OCH3, -F, -Cl, 12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from 1 to 3 Rs b Substituted phenyl groups and heteroatoms containing 1 to 3 selected oxygen, nitrogen, and sulfur atoms, optionally surrounded by 1 to 3 R atoms. b Substituted 5- to 6-membered heteroaryl groups.

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 4 To be arbitrarily selected by 1 to 3 R b Substituted phenyl groups.

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

15. The compound of claim 14 or a pharmaceutically acceptable salt thereof, wherein R 4 To be arbitrarily selected by 1 to 3 R b Substituted pyridine.

16. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from:

17. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 4 By 1 to 3 R b Replace, and each R b It is independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl and fluoromethyl.

18. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from:

19. A compound of the following formula in X is N and Y is CH, or X is CH and Y is N; R 5 Selected from hydrogen and -CH3, optionally substituted with -OH, -NH2, or 1-3 halogen atoms, wherein When R 5 C is optionally substituted with -OH, -NH2 or 1-3 halogen atoms. 1-3 When alkyl, ring A is selected from those optionally substituted with -CH2OP(O)(OH)2 at a nitrogen atom. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2. and When R 5 When it is hydrogen, then ring A comes from: the option of replacing a nitrogen atom with -CH2OP(O)(OH)2. R 1 R 2 and R 3 Each is independently selected from hydrogen and C. 1-4 Alkyl, wherein R 2 and R 3 Together with the atoms they are attached to, they can optionally form 3- to 6-membered saturated carbon rings; R 4 Selected from 1 to 3 Rs b The substituted phenyl group contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and is optionally surrounded by 1 to 3 R atoms. b The substituted 5- to 6-membered heteroaryl group contains 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and is optionally surrounded by 1 to 3 R atoms. b Substituted 9- to 10-membered fully or partially aromatic bicyclic heteroaryl groups; R a Selected from hydrogen, halogen, cyano and C 1-4 alkyl; Each R b Independently selected from halogens, cyano groups, -OH, -NH2, C 1-4 Alkyl, monohalomethyl, dihalomethyl, trihalomethyl and -OC 1-4 alkyl; R c Selected from optional land - OR d or R e Replacement -OC 1-3 Alkyl, and -OR d Or -C substituted with 1-3 halogen atoms 1-4 Alkyl; and R d Selected from H, -CH3, -CF3, -CHF2 and -CH2OP(O)(OH)2; and R e Selected from Or its pharmaceutically acceptable salt.

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

21. The compound of claim 19 or claim 20, or a pharmaceutically acceptable salt thereof, wherein R 5 C is optionally substituted with -OH, -NH2 or 1-3 halogen atoms. 1-3 Alkyl group, and ring A is selected from those optionally substituted with -CH2OP(O)(OH)2 at a nitrogen atom. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2.

22. The compound of claim 21 or a pharmaceutically acceptable salt thereof, wherein R 5 The atom is selected from -CH3, CH2OH, CH2F, and ring A is selected from: atom A optionally substituted with -CH2OP(O)(OH)2 at a nitrogen atom. A nitrogen atom may be optionally substituted with -CH2OP(O)(OH)2.

23. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R 5 It is hydrogen, and ring A is: optionally substituted with -CH2OP(O)(OH)2 at a nitrogen atom.

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

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

26. The compound according to any one of claims 19, 23, and 24, or a pharmaceutically acceptable salt thereof, wherein ring A is optionally substituted with -CH2OP(O)(OH) at a nitrogen atom. And R c Selected from -OCH3, -CH2OCH3, -CH2CH2OCH3, -OCH2CH2OH, -OCH2CH2OCH3, -OCH2CH2OCHF2, -CH2CH2OCH2OP(O)(OH)2, 27. The compound according to any one of claims 19 to 26, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from 1 to 3 Rs b Substituted phenyl groups and heteroatoms containing 1 to 3 selected oxygen, nitrogen, and sulfur atoms, optionally surrounded by 1 to 3 R atoms. b Substituted 5- to 6-membered heteroaryl groups.

28. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein R 4 To be arbitrarily selected by 1 to 3 R b Substituted phenyl groups.

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

30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein R 4 To be arbitrarily selected by 1 to 3 R b Substituted pyridine.

31. The compound of claim 27 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from:

32. The compound according to any one of claims 20 to 31, or a pharmaceutically acceptable salt thereof, wherein R 4 By 1 to 3 R b Replace, and each R b It is independently selected from fluorine, chlorine, cyano, trifluoromethyl, difluoromethyl and fluoromethyl.

33. The compound of claim 19 or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from:

34. A compound of the following formula in X is N and Y is CH, or X is CH and Y is N; Ring A is selected from R 1 R 2 and R 3 Each is independently selected from hydrogen and C. 1-4 Alkyl, wherein R 1 and R 2 Together with the atoms to which they are attached, they can optionally form 5- to 6-membered saturated heterocycles in which one of the carbon atoms is optionally replaced by a heteroatom selected from oxygen and nitrogen, or in which R 2 and R 3 Together with the atoms they are attached to, they can optionally form 3- to 6-membered saturated carbon rings; R 4 Selected from 1 to 3 Rs b Substituted phenyl groups and heteroatoms containing 1 to 3 selected oxygen, nitrogen, and sulfur atoms, optionally surrounded by 1 to 3 R atoms. b Substituted 5- to 6-membered heteroaryl groups; R a C selected from hydrogen, halogen, cyano, and optionally substituted with halogen, -OH, -NH2, or cyano. 1-4 alkyl; Each R b Independently selected from halogen, cyano, C 1-4 Alkyl, trihalomethyl and -OC 1-4 alkyl.

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

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

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

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

39. The compound of claim 38 or a pharmaceutically acceptable salt thereof, selected from: Or its pharmaceutically acceptable salt.

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

41. The compound according to any one of claims 34 to 39, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from: And R a It is a methyl group.

42. The compound according to any one of claims 34 to 39, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from: And R a It is a cyano group.

43. The compound according to any one of claims 34 to 42, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from:

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

45. The compound according to any one of claims 34 to 44, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from:

46. ​​The compound of claim 34 or a pharmaceutically acceptable salt thereof, selected from: Or its pharmaceutically acceptable salt.

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

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

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

51. A compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, used in a therapeutic manner.

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

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

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