Compounds, compositions, and mezhods of treating disorders associated with protein misfolding

Abstract

The present disclosure provides compounds of formulae (I) and (II) useful for treating or lessening the severity of diseases or conditions, including those associated with alpha-synuclein protein.

Description

[0001] COMPOUNDS, COMPOSITIONS AND METHODS OF TREATING DISORDERS Background

[0001] α-Synuclein (α-syn) is a 140 amino acid protein encoded by the SNCA gene, and is one of the most abundantly expressed proteins in the nervous system (1% of total cytosolic protein). It is intrinsically disordered in aqueous solutions, but forms α-helical structures on binding to negatively charged lipids. It is predominantly neuronal and localises to presynaptic terminals under physiological conditions. Physiological functions are only partially understood, protein is thought to be involved in membrane interactions, (particularly mitochondrial), and to play a role in regulating dopamine levels. Aggregated forms of α-syn (“Lewy bodies” & “Lewy neurites”) are a hallmark of Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB) and multiple system atrophy (MSA). There is a strong body of pre- clinical data demonstrating that it is smaller, soluble aggregated forms of α-syn, termed “oligomers”, which are a key driver of neurotoxicity. These oligomeric forms of α-synuclein have been shown to have wide-ranging neurotoxicity and underlie the onset and progression of Parkinson’s Disease (PD). These oligomers bind to membranes, receptors and organelles, disrupt metabolic and neuronal functional pathways and ultimately cause neuronal death. Summary

[0002] The present disclosure includes a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are defined herein.

[0003] Additionally, the present disclosure includes methods of preparing a compound of Formula (I) or Formula (II) and methods of using a compound of Formula (I) or Formula (II). Detailed Description Definitions

[0004] The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle" "cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0005] The term "haloaliphatic" refers to an aliphatic group that is substituted with one or more halogen atoms.

[0006] The term "alkyl" refers to a straight or branched alkyl group. Exemplary alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.

[0007] The term "haloalkyl" refers to a straight or branched alkyl group that is substituted with one or more halogen atoms.

[0008] The term "halogen" means F, Cl, Br, or I.

[0009] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term "aryl", as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0010] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, e.g., "heteroaralkyl", or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. 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. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin- 3(4Η)-one. A heteroaryl group may be mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0011] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4- dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in TV-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical", are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0012] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0013] As described herein, compounds of the present disclosure may contain “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0014] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; —(CH2)0-4R∘; —(CH2)0-4OR∘; —O(CH2)0-4R∘, —O—(CH2)0-4C(O)OR∘; —(CH2)0-4CH(OR∘)2; —(CH2)0-4SR∘; —(CH2)0-4Ph, which may be substituted with R∘; —(CH2)0-4O(CH2)0-1Ph which may be substituted with R∘; —CH═CHPh, which may be substituted with R∘; —(CH2)0-4O(CH2)0-1-pyridyl which may be substituted with R∘; —NO2; —CN; —N3; —(CH2)0-4N(R∘)2; —(CH2)0-4N(R∘)C(O)R∘; —N(R∘)C(S)R∘; —(CH2)0-4N(R∘)C(O)NR∘2; —N(R∘)C(S)NR∘2; —(CH2)0-4N(R∘)C(O)OR∘; — N(R∘)N(R∘)C(O)R∘; —N(R∘)N(R∘)C(O)NR∘2; —N(R∘)N(R∘)C(O)OR∘; —(CH2)0-4C(O)R∘; — C(S)R∘; —(CH2)0-4C(O)OR∘; —(CH2)0-4C(O)SR∘; —(CH2)0-4C(O)OSiR∘3; —(CH2)0-4OC(O)R∘; —OC(O)(CH2)0-4SR∘, SC(S)SR∘; —(CH2)0-4SC(O)R∘; —(CH2)0-4C(O)NR∘2; — C(S)NR∘2; —C(S)SR∘; —SC(S)SR∘, —(CH2)0-4OC(O)NR∘2; —C(O)N(OR∘)R∘; — C(O)C(O)R∘; —C(O)CH2C(O)R∘; —C(NOR∘)R∘; —(CH2)0-4SSR∘; —(CH2)0-4S(O)2R∘; — (CH2)0-4S(O)2OR∘; —(CH2)0-4OS(O)2R∘; —S(O)2NR∘2; —(CH2)0-4S(O)R∘; — N(R∘)S(O)2NR∘2; —N(R∘)S(O)2R∘; —N(OR∘)R∘; —C(NH)NR∘2; —P(O)2R∘; —P(O)R∘2; — OP(O)R∘2; —OP(O)(OR∘)2; SiR∘3; —(C1-4 straight or branched alkylene)O—N(R∘)2; or — (C1-4 straight or branched alkylene)C(O)O—N(R∘)2, wherein each R∘may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, —CH2Ph, —O(CH2)0-1Ph, — CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R∘, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0015] Suitable monovalent substituents on R∘(or the ring formed by taking two independent occurrences of R∘together with their intervening atoms), are independently halogen, — (CH2)0-2R●, -(haloR●), —(CH2)0-2OH, —(CH2)0-2OR●, —(CH2)0-2CH(OR●)2; —O(haloR●), — CN, —N3, —(CH2)0-2C(O)R●, —(CH2)0-2C(O)OH, —(CH2)0-2C(O)OR●, —(CH2)0-2SR●, — (CH2)0-2SH, —(CH2)0-2NH2, —(CH2)0-2NHR●, —(CH2)0-2NR●2, —NO2, —SiR●3, —OSiR●3, —C(O)SR●, —(C1-4straight or branched alkylene)C(O)OR●, or —SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R∘include ═O and ═S.

[0016] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O, ═S, ═NNR*2, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)2R*, ═NR*, ═NOR*, —O(C(R*2))2-3O—, or —S(C(R*2))2-3S—, wherein each independent occurrence of R* is selected from hydrogen, C1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR*2)2-3O—, wherein each independent occurrence of R* is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0017] Suitable substituents on the aliphatic group of R* include halogen, —R●, -(haloR●), —OH, —OR●, —O(haloR●), —CN, —C(O)OH, —C(O)OR●, —NH2, —NHR●, —NR●2, or —NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0018] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R†, —NR†2, —C(O)R†, —C(O)OR†, —C(O)C(O)R†, —C(O)CH2C(O)R†, — S(O)2R†, —S(O)2NR†2, —C(S)NR†2, —C(NH)NR†2, or —N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0019] Suitable substituents on the aliphatic group of R†are independently halogen, —R●, - (haloR●), —OH, —OR●, —O(haloR●), —CN, —C(O)OH, —C(O)OR●, —NH2, —NHR●, — NR●2, or —NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4 aliphatic, —CH2Ph, —O(CH2)0- 1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0020] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0021] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N(C1-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

[0022] Combinations of substituents and variables envisioned by this disclosure are only those that result in the formation of stable compounds. The term "stable", as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).

[0023] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0024] The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0025] As used herein, a "therapeutically effective amount" means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat, diagnose, prevent, and / or delay the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of a provided compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, inhibits, prevents, delays onset of, reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder, and / or condition. I

[0026] As used herein, the terms "treatment," "treat," and "treating" refer to partially or completely alleviating, inhibiting, delaying onset of, preventing, ameliorating and / or relieving a disorder or condition, or one or more symptoms of the disorder or condition, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In some embodiments, the term "treating" includes preventing or halting the progression of a disease or disorder. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence. Thus, in some embodiments, the term "treating" includes preventing relapse or recurrence of a disease or disorder.

[0027] The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

[0028] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non- toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound(s) with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the compounds disclosed herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0029] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitorily active metabolite or residue thereof.

[0030] The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that total daily usage of compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. Specific effective dose level for any particular patient or organism will depend upon a variety of factors including disorder being treated and severity of the disorder; activity of specific compound employed; specific composition employed; age, body weight, general health, sex and diet of the patient; time of administration, route of administration, and rate of excretion of a specific compound employed; duration of treatment; drugs used in combination or coincidental with a specific compound employed, and like factors well known in the medical arts. Compounds

[0031] The present disclosure includes a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof wherein R1is hydrogen or optionally substituted C1-C3 alkyl; R2is -S-L2-R2aor -O-L2-R2a; L2is a bond or optionally substituted C1-C3alkylene; R2ais selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, wherein R2ais substituted with n instances of R2b; each R2bis independently selected from the group consisting of halogen, -OH, -ORc, - NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, - C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6 alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of R2bare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; R3is selected from the group consisting of optionally substituted C1-C6alkyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 5-10 membered heteroaryl, wherein R3is substituted with m instances of R3a; each R3ais independently selected from the group consisting of halogen, -OH, -ORc, - NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, - C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of R3aare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; R4is selected from the group consisting of hydrogen, halogen, -CN, -OH, -ORc, -(CH2)1-3Rc, optionally substituted C2-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, wherein R4is substituted with p instances of R4a; each R4ais independently selected from the group consisting of halogen, -OH, -ORc, - NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, - C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of R4aare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; each Rcis independently selected from the group consisting of optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of Rcare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; n is 0, 1, 2, 3, 4, or 5; and m is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, 4, or 5.

[0032] The present disclosure includes A compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof wherein R1is hydrogen or optionally substituted C1-C3 alkyl; R2is -S-L2-R2aor -O-L2-R2a; L2is a bond or optionally substituted C1-C3 alkylene; R2ais selected from the group consisting of C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, wherein R2ais substituted with n instances of R2b; each R2bis independently selected from the group consisting of halogen, -OH, -ORc, - NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, - C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, or two instances of R2bare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; R3is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 5-10 membered heteroaryl, wherein R3is substituted with m instances of R3a; each R3ais independently selected from the group consisting of halogen, -OH, -ORc, - NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, - C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of R3aare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; R4is selected from the group consisting of hydrogen, halogen, -CN, -OH, -ORc, -(CH2)1-3Rc, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, wherein R4is substituted with p instances of R4a; each R4ais independently selected from the group consisting of halogen, -OH, -ORc, - NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, - C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of R4aare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; each Rcis independently selected from the group consisting of optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of Rcare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; n is 0, 1, 2, 3, 4, or 5; and m is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, 4, or 5.

[0033] In some embodiments, the compound is of formula (I-a) or formula (II-a) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, R4, and m are defined herein.

[0034] In some embodiments, the compound is of formula (I-b) or formula (II-b) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, R4, and m are defined herein.

[0035] In some embodiments, the compound is of formula (I-a) or formula (II-c) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, R4, and m are defined herein. R1

[0036] In some embodiments, R1is hydrogen or optionally substituted C1-C3alkyl. In some embodiments, R1is hydrogen. In some embodiments, R1is optionally substituted C1-C3 alkyl. In some embodiments, R1is hydrogen or optionally substituted methyl. In some embodiments, R1is optionally substituted methyl. In some embodiments, R1is methyl. In some embodiments, R1is optionally substituted ethyl. In some embodiments, R1is optionally substituted n-propyl. In some embodiments, R1is optionally substituted iso-propyl. R2

[0037] In some embodiments, R2is -S-L2-R2aor -O-L2-R2a. In some embodiments, R2is -S- L2-R2a. In some embodiments, R2is -O-L2-R2a.

[0038] In some embodiments, R2is selected from the group consisting of . L2

[0039] In some embodiments, L2is a bond or optionally substituted C1-C3 alkylene. In some embodiments, L2is a bond. In some embodiments, L2is optionally substituted C1-C3alkylene. In some embodiments, L2is a bond or optionally substituted C1alkylene. In some embodiments, L2is optionally substituted C1 alkylene. In some embodiments, L2is optionally substituted C2alkylene. In some embodiments, L2is optionally substituted C3alkylene. In some embodiments, L2is -CH2-. R2a

[0040] In some embodiments, R2ais selected from the group consisting of C1-C6 alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, wherein R2ais substituted with n instances of R2b. In some embodiments, R2ais selected from the group consisting of optionally substituted C1-C3alkyl, optionally substituted C2-C3alkenyl, optionally substituted C2-C4alkynyl, optionally substituted 3-6 membered carbocyclyl, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl, wherein R2ais substituted with n instances of R2b. In some embodiments, R2ais optionally substituted C1-C3alkyl, wherein R2ais substituted with n instances of R2b. In some embodiments, Rais selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, and optionally n-propyl. In some embodiments, R2ais optionally substituted C2-C3alkenyl, wherein R2ais substituted with n instances of R2b. In some embodiments, R2ais optionally substituted allyl. In some embodiments, R2ais optionally substituted C2-C4 alkynyl, wherein R2ais substituted with n instances of R2b. In some embodiments, R2ais optionally substituted propargyl. In some embodiments, R2ais optionally substituted optionally substituted 3-6 membered carbocyclyl, wherein R2ais substituted with n instances of R2b. In some embodiments, R2ais optionally substituted cyclopropyl or optionally substituted cyclopropyl. R2b

[0041] In some embodiments, each R2bis independently selected from the group consisting of halogen, -OH, -ORc, -NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, - C(O)NHRc, -C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, or two instances of R2bare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl. In some embodiments, each R2bis independently selected from the group consisting of halogen, -OH, -ORc, -NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, - C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl.

[0042] In some embodiments, each R2bis independently selected from the group consisting of halogen, -OH, and optionally substituted C1-C6 alkyl. In some embodiments, each R2bis independently selected from the group consisting of halogen, -OH, and optionally substituted C1-C3alkyl. In some embodiments, each R2bis independently selected from the group consisting of fluoro, chloro, -OH, and optionally substituted methyl. R3

[0043] In some embodiments, R3is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted 3-7 membered carbocyclyl, , optionally substituted 3-10 membered heterocyclyl, optionally substited phenyl, optionally substituted naphthyl, optionaly subsubstituted 5-10 membered heteroaryl, wherein R3is substituted with m instances of R3a. In some embodiments, R3is an optionally substituted phenyl or optionally substituted 6-membered heteroaryl. In some embodiments, R3is an optionally substituted phenyl or optionally substituted pyridinyl. In some embodiments, R3is optionally substituted 3-7 membered carbocyclyl. In some embodiments, R3is optionally substituted 3-7 membered heterocyclyl. In some embodiments, R3is an optionally substituted phenyl. R3a

[0044] In some embodiments, each R3ais independently selected from the group consisting of halogen, -OH, -ORc, -NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, - C(O)NHRc, -C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6 alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of R3aare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl. In some embodiments, each R3ais independently selected from the group consisting of halogen, -OH, -ORc, -NH2, -CN, -NO2, - C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, -C(O)N(Rc)2, -S(O)2Rc, -(CH2)1- 3Rc, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl. In some embodiments, R3ais halogen. In some embodiments, R3ais chloro or fluoro. In some embodiments R3ais -OMe. In some embodiments, R3ais optionally substituted C1-C6 alkyl. In some embodiments, R3ais optionally substituted methyl. In some embodiments, R3ais -(CH2)1-3Rc. In some embodiments, R3ais -S(O)2Rc. In some embodiments, R3ais -C(O)N(Rc)2. In some embodiments, wherein R3ais -CN. R4

[0045] In some embodiments, R4is selected from the group consisting of hydrogen, halogen, -CN, -OH, -ORc, -(CH2)1-3Rc, optionally substituted C1-C6alkyl, optionally substituted C3-C6carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, wherein R4is substituted with p instances of R4a. In some embodiments, R4is selected from the group consisting of hydrogen, halogen, -CN, -OH, -ORc, -(CH2)1-3Rc, optionally substituted C2-C6 alkyl, optionally substituted C3-C6 carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, wherein R4is substituted with p instances of R4a.

[0046] In some embodiments, R4is optionally substituted C1-C4 alkyl. In some embodiments, R4is optionally substituted methyl. In some embodiments, R4is optionally substituted C2-C4 alkyl. In some embodiments, R4is optionally substituted ethyl, optionally substituted iso- propyl, optionally substituted tert-butyl, and optionally substituted sec-butyl.

[0047] In some embodiments, R4is optionally substituted 3-7 membered heterocyclyl. In some embodiments, R4is optionally substituted 5-7 membered heterocyclyl. In some embodiments, R4is selected from the group consisting of optionally substituted tetrahydrofuranyl, optionally substituted tetrahydropyranyl, optionally substituted piperidinyl, optionally substituted morpholinyl, and optionally substituted oxazepanyl.

[0048] In some embodiments, R4is optionally substituted phenyl. In some embodiments, R4is optionally substituted 5-6 membered heteroaryl. In some embodiments, R4is selected from the group consisting of optionally substituted imidazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, and optionally substituted pyrazinyl. In some embodiments, R4is selected from the group consisting of

[0049] In some embodiments, R4is selected from the group consisting of hydrogen, methyl,

[0002] . R4a

[0050] In some embodiments, each R4ais independently selected from the group consisting of halogen, -OH, -ORc, -NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, - C(O)NHRc, -C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6 alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of R4aare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl. each R4ais independently selected from the group consisting of halogen, -OH, -ORc, -NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, - C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, -C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl. In some embodiments, R4ais selected from the group consisting of halogen, optionally substituted C1-C6 alkyl, optionally substituted 3-7 membered carbocyclyl, and -C(O)ORc. In some embodiments, R4ais selected from the group consisting of halogen, optionally substituted C1-C3alkyl, optionally substituted 3-4 membered carbocyclyl, and - C(O)ORc. In some embodiments, R4ais selected from the group consisting of fluoro, optionally substituted methyl, optionally substituted ethyl, optionally substituted iso-propyl, optionally substituted cyclopropyl, and -Boc.

[0051] The present disclosure includes a compound from Table 1 or a pharmaceutically acceptable salt thereof Table 1

[0003] Alternative Embodiments

[0052] In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In other embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound.

[0053] Unless otherwise specified, the stereochemistry of the compounds of Table 1 and the synthetic intermediates of the Exemplification has been arbitrarily assigned for clarity. Additionally, the present disclosure contemplates tautomers, rotamers, and confirmational isomers of the compounds as drawn herein.

[0054] The present disclosure includes the racemate of any compound disclosed herein. Pharmaceutical Compositions

[0055] In some embodiments, the present disclosure provides a composition comprising a compound of Formula (I) and Formula (II) and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the amount of compound in compositions contemplated herein is such that is effective to measurably treat a disease or disorder in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this disclosure is such that is effective to measurably treat a disease or disorder in a biological sample or in a patient. In certain embodiments, a composition contemplated by this disclosure is formulated for administration to a patient in need of such composition. In some embodiments, a composition contemplated by this disclosure is formulated for oral administration to a patient.

[0056] In some embodiments, compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some preferred embodiments, compositions are administered orally, intraperitoneally or intravenously. In some embodiments, sterile injectable forms of the compositions comprising one or more compounds of Formula (I) and Formula (II) may be aqueous or oleaginous suspension. In some embodiments, suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. In some embodiments, sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. In some embodiments, among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In some embodiments, additional examples include, but are not limited to, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0057] The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0058] Pharmaceutically acceptable compositions comprising one or more compounds of Formula (I) and Formula (II) may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In some embodiments, carriers used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. In some embodiments, useful diluents include lactose and dried cornstarch. In some embodiments, when aqueous suspensions are required for oral use, an active ingredient is combined with emulsifying and suspending agents. In some embodiments, certain sweetening, flavoring or coloring agents may also be added.

[0059] Alternatively, pharmaceutically acceptable compositions comprising a compound of Formula (I) and Formula (II) may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0060] Pharmaceutically acceptable compositions comprising a compound of Formula (I) and Formula (II) may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. In some embodiments, pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

[0061] Pharmaceutically acceptable compositions comprising a compound of Formula (I) and Formula (II) may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0062] In some embodiments, an amount of a compound of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0063] The presently disclosed compounds can be formulated into pharmaceutical compositions along with a pharmaceutically acceptable carrier or excipient. According to this aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I) or Formula (II) in association with a pharmaceutically acceptable excipient, diluent or carrier.

[0064] The formulations of Compounds of Formula (I) or Formula (II) include those suitable for the administration routes detailed herein. They may conveniently be presented in unit dosage form and can be formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. Techniques and formulations generally and suitable for use herein are found in Remington’s Pharmaceutical Sciences (16thedition, Osol, A. Ed. (1980); Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingredient with the excipient or carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid excipients or carriers or finely divided solid excipients or carriers or both, and then, if necessary, shaping the product.

[0065] A typical formulation is prepared by mixing a compound of Formula (I) or Formula (II), and a carrier, diluent or excipient. Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which the compound of Formula (I) or Formula (II), is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non- toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e. , a compound of Formula (I) or Formula (II), or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[0066] The formulations may be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of Formula (I) or Formula (II), or stabilized form of the Compound of Formula (I) or Formula (II), (e.g., complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of Formula (I) or Formula (II) is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.

[0067] The pharmaceutical composition (or formulation) for application may be packaged in a variety of ways depending upon the method used for administering the drug. Generally, an article for distribution includes a container having deposited therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, and the like. The container may also include a tamper-proof assemblage to prevent indiscreet access to the contents of the package. In addition, the container has deposited thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[0068] Pharmaceutical formulations may be prepared for various routes and types of administration. For example, a compound of Formula (I) or Formula (II) having the desired degree of purity may optionally be mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington’s Pharmaceutical Sciences (1980) 16thedition, Osol, A. Ed.), in the form of a lyophilized formulation, milled powder, or an aqueous solution.

[0069] Formulation may be conducted by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable excipients or carriers, i.e. , excipients or carriers that are non-toxic to recipients at the dosages and concentrations employed. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about 8. Formulation in an acetate buffer at pH 5 is a suitable embodiment.

[0070] The compounds of Formula (I) or Formula (II) can be sterile. In particular, formulations to be used for in vivo administration should be sterile. Such sterilization is readily accomplished by filtration through sterile filtration membranes.

[0071] The compound of Formula (I) or Formula (II) ordinarily can be stored as a solid composition, a lyophilized formulation or as an aqueous solution.

[0072] The pharmaceutical compositions comprising a compound of Formula (I) or Formula (II) can be formulated, dosed and administered in a fashion, i.e., amounts, concentrations, schedules, course, vehicles and route of administration, consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The “therapeutically effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to prevent, ameliorate, or treat the coagulation factor mediated disorder. In some embodiments, the amount is below the amount that is toxic to the host or renders the host more susceptible to bleeding.

[0073] Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3- pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). The active pharmaceutical ingredients may also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington’s Pharmaceutical Sciences 16thedition, Osol, A. Ed. (1980).

[0074] Sustained-release preparations of Formula (I) or Formula (II) compounds may be prepared. Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of Formula (I) or Formula (II), which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2- hydroxyethyl- methacrylate), or poly(vi nyl alcohol)), polylactides, copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid- glycolic acid copolymers such as the LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3- hydroxybutyric acid.

[0075] Formulations of a compound of Formula (I) or Formula (II) suitable for oral administration may be prepared as discrete units such as pills, capsules, cachets or tablets each containing a predetermined amount of a compound of Formula (I) or Formula (II).

[0076] Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.

[0077] Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs may be prepared for oral use. Formulations of compounds of Formula (I) or Formula (II) intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

[0078] For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w / w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil- in-water cream base.

[0079] If desired, the aqueous phase of the cream base may include a polyhydric alcohol, i.e. , an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400), and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.

[0080] The oily phase of the emulsions may be constituted from known ingredients in a known manner. While the phase may comprise solely an emulsifier, it may also comprise a mixture of at least one emulsifier and a fat or oil, or both a fat and an oil. A hydrophilic emulsifier included together with a lipophilic emulsifier may act as a stabilizer. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

[0081] Aqueous suspensions of Formula (I) or Formula (II) compounds contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

[0082] The pharmaceutical compositions of compounds of Formula (I) or Formula (II), may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such 1 ,3-butanediol. The sterile injectable preparation may also be prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

[0083] The amount of active ingredient that may be combined with the excipient or carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of excipient or carrier material which may vary from about 5 to about 95% of the total compositions (weightweight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 pg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL / hr can occur.

[0084] Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

[0085] Formulations suitable for topical administration to the eye also include eye drops in which the active ingredient is dissolved or suspended in a suitable excipient or carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of about 0.5 to 20% w / w, for example about 0.5 to 10% w / w, for example about 1.5% w / w.

[0086] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

[0087] Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.

[0088] Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1 , 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of disorders as described below.

[0089] Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such excipients or carriers as are known in the art to be appropriate.

[0090] The formulations may be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient or carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

[0091] The subject matter further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary excipient or carrier therefore. Veterinary excipients or carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered parenterally, orally or by any other desired route.

[0092] In particular embodiments the pharmaceutical composition comprising the presently disclosed compounds further comprise a chemotherapeutic agent. In some of these embodiments, the chemotherapeutic agent is an immunotherapeutic agent. Kits

[0093] Further provided are kits for carrying out the methods detailed herein, which kits comprise one or more compounds described herein or a pharmaceutical composition comprising a compound described herein. The kits may employ any of the compounds disclosed herein. In one variation, the kit employs a compound described herein or a pharmaceutically acceptable salt thereof. The kits may be used for any one or more of the uses described herein, and, accordingly, may contain instructions for use in the treatment of a disorder such as cancer. In some embodiments, the kit contains instructions for use in the treatment of a cancer.

[0094] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any compound described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. One or more components of a kit may be sterile and / or may be contained within sterile packaging.

[0095] The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub-unit doses. For example, kits may be provided that contain sufficient dosages of a compound as disclosed herein (e.g., a therapeutically effective amount) and / or a second pharmaceutically active compound useful for a disorder (e.g., cancer) to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. Kits may also include multiple unit doses of the compounds and instructions for use and may be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0096] The kits may optionally include a set of instructions, generally written instructions, although electronic storage media (e.g., magnetic diskette or optical disk) containing instructions are also acceptable, relating to the use of component(s) of the methods of the present disclosure. The instructions included with the kit generally include information as to the components and their administration to a subject. Methods of Using Compounds of the Present Disclosure

[0097] In some embodiments, the present disclosure provides a method for treating or lessening the severity of a disease or condition associated with alpha-synuclein protein. In some embodiments, a method is used for treating, lessening the severity of, or preventing alpha-synucleinopathies. In some embodiments, the present disclosure provides a method for treating or lessening the severity of a disease or condition associated with alpha-synuclein protein comprises the step of administering to said patient a composition according to the present disclosure. In some embodiments, the present disclosure provides a method for treating or lessening the severity of a disease or condition associated with alpha-synuclein protein comprises the steps of selecting a composition according to the present disclosure and administering to said patient a composition according to the present disclosure.

[0098] The term “disease or condition associated with alpha-synuclein”, as used herein means any disease or other deleterious condition in which alpha-synuclein or alpha-synuclein protein misfolding is known to play a role. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which alpha synuclein or alpha-synuclein protein misfolding is known to play a role. Accordingly, another embodiment of the present disclosure relates to preventing or preventing the severity of one or more diseases in which alpha-synuclein or alpha-synuclein protein misfolding is known to play a role. In some embodiments, a disease or condition associated with alpha-synuclein is a neurodegenerative disease.

[0099] The term “dementia with Lewy Bodies”, as used herein means any disease or other deleterious condition in which dementia occurs with along with the deposition, aggregation, or accumulation of Lewy bodies in the brain. Accordingly, another embodiment of the present disclosure relates to treating or lessening the severity of one or more diseases in which dementia with Lewy bodies is known to play a role. Accordingly, another embodiment of the present disclosure relates to preventing or preventing the severity of one or more diseases in which dementia with Lewy bodies or dementia with Lewy body protein misfolding is known to play a role. In some embodiments, a disease or condition associated with dementia with Lewy bodies is a neurodegenerative disease. In some embodiments, a disease or condition associated with dementia does not occur with Lewy bodies.

[0100] In some embodiments, administration of a compound of the present disclosure results in treating of the prevention of protein misfolding. In some embodiments, administration of a compound of the present disclosure results in prevention of alpha-synuclein protein misfolding. In some embodiments, the present disclosure results in treating or preventing a disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates.

[0101] In some embodiments, preventing protein misfolding is defined as a 10-100% reduction in misfolding of protein misfolding. In some embodiments, preventing protein misfolding is defined as a 20-100% reduction in protein misfolding. In some embodiments, preventing protein misfolding is defined as a 30-100% reduction in protein misfolding. In some embodiments, preventing protein misfolding is defined as a 40-100% reduction in protein misfolding. In some embodiments, preventing protein misfolding is defined as a 50- 100% reduction in protein misfolding. In some embodiments, preventing protein misfolding is defined as a 60-100% reduction in protein misfolding. In some embodiments preventing protein misfolding is defined as a 70-100% reduction in protein misfolding. In some embodiments, preventing protein misfolding is defined as a 80-100% reduction in protein misfolding. In some embodiments, preventing protein misfolding is defined as a 90-100% reduction in protein misfolding. In some embodiments, preventing protein misfolding is defined as a 100% reduction in protein misfolding.

[0102] In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 10-100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 20-100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 30- 100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 40-100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 50-100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 60-100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto- fibrils, fibrils, or aggregates is defined as a 70-100% reduction in protein oligomers, proto- fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 80-100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 90-100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates. In some embodiments, preventing formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates is defined as a 100% reduction in protein oligomers, proto-fibrils, fibrils, or aggregates.

[0103] In some embodiments, compounds and compositions, according to a method of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of protein misfolding. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, severity of the infection, particular agent, its mode of administration, and the like. Compounds of the present disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.

[0104] In some embodiments, compounds and compositions, according to a method of the present disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of formation, deposition, accumulation, or persistence of protein oligomers, proto-fibrils, fibrils, or aggregates. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, severity of the infection, particular agent, its mode of administration, and the like. Compounds of the present disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage.

[0105] In some embodiments, the compounds of the present disclosure act as an antibody. In some embodiments, a compound of the present disclosure bind to at least a portion the alpha- synuclein and prevent at least a portion of alpha-synuclein from aggregating. In some embodiments, a compound of the present disclosure act as an antibody. In some embodiments, a compound of the present disclosure bind to at least a portion the alpha- synuclein and prevent at least a portion of alpha-synuclein from binding to a cell receptor. In some embodiments, a compound of the present disclosure bind to at least a portion of misfolded alpha-synuclein and prevent at least a portion of misfolded alpha-synuclein from aggregating. In some embodiments, a compound of the present disclosure bind to at least a portion of misfolded alpha-synuclein and prevent at least a portion of misfolded alpha- synuclein from binding to cell receptors.

[0106] In some embodiments, a compound of the present disclosure and one or more additional therapeutic agents may be formulated into a single dosage form.

[0107] In some embodiments, a compound of the present disclosure inhibits or reduces the severity of alpha-synuclein induced cytotoxicity. In some embodiments, cytotoxicity is reduced or inhibited in human neurons and glial cells. In some embodiments, a compound of the present disclosure inhibits or reduces the severity of cell-to-cell transmission of oligomeric alpha-synuclein. In some embodiments, cell-to-cell transmission is reduced or inhibited between neurons and glial cells. In some embodiments, a compound of the present disclosure inhibits or reduces the production of caspase. In some embodiments, caspase production is reduced or inhibited in neurons and glial cells.

[0108] In some embodiments, a compound or pharmaceutical composition of the present disclosure is used to treat one or more diseases or conditions associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates is selected from a group consisting of Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic and familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden-Spatz disease, pure autonomic failure, neurodegeneration in combination with brain iron accumulation type-1, a broadly neurodegenerative disease, synucleinopathy, pure autonomic nerve failure, dementia, tauopathy, argyrophilic grain disease, Pick’s disease, Down syndrome, chronic leukemia, lymphoma, schizophrenia, psychosis, or Creutzfeldt- Jakob’s disease.

[0109] In some embodiments, the compound is administered to the subject at a dose of between about 0.001 pg / kg and about 1 ,000 mg / kg, including but not limited to about 0.001 pg / kg, about 0.01 pg / kg, about 0.05 pg / kg, about 0.1 pg / kg, about 0.5 pg / kg, about 1 pg / kg, about 10 pg / kg, about 25 pg / kg, about 50 pg / kg, about 100 pg / kg, about 250 pg / kg, about 500 pg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 25 mg / kg, about 50 mg / kg, about 100 mg / kg, and about 200 mg / kg. Exemplification

[0110] The compounds of the present disclosure may be synthesized by analogy with methods known to the person skilled in the art, and by analogy with the synthesis of the specific compounds described in the following examples. Abbreviations ACN acetonitrile CT column temperature DCE 1,2-dichloroethane DCM dichloromethane DIAD diisopropylazodicarboxylate DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide EA ethyl acetate FA formic acid F-TEDA-BF41-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]octane bis(tetrafluoroborate) h hour(s) IPA propan-2-ol mCPBA 3-chloroperbenzoic acid MeI methyl iodide NBS N-bromosuccinimide Pd(dtbpf)Cl2dichloro[1,1-bis(di-t-butylphosphino)ferrocene]palladium(II) (CAS:95408-45- PE petroleum ether Prep-HPLC preparative high-performance liquid chromatography RT room temperature (~17-21oC) SFC supercritical fluid chromatography TFA trifluoroacetic acid THF tetrahydrofuran Synthetic Method A Example 1 - 7-methyl-8-phenyl-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one Step 1: α-acetyl-benzeneacetonitrile

[0111] To a stirred solution of phenylacetonitrile (11.7 g, 99.9 mmol) in THF (200 mL) was added NaH (7.43 g, 185 mmol, 60% in mineral oil) in portions at 0 °C under N2. The resulting mixture was stirred for 15 minutes at 0 °C under N2. To the above mixture was added EA (35 g, 400 mmol) at 0 °C. The resulting mixture was stirred overnight at room temperature. The reaction was quenched with 2 N HCl (100 mL), the resulting mixture was extracted with EA (3 x 100 mL), the combined organic layers were washed with brine (80 mL), dried over Na2SO4. After filtration, the filtrate was concentrated to get the crude product, which was purified on silica gel (PE / EA = 10 / 1) to afford the title compound (14.8 g, 93%) as an off white solid. LCMS (ES, m / z): [M-H]- =158. Step 2: 5-methyl-4-phenyl-2H-pyrazol-3-amine

[0112] To a stirred solution of α-acetyl-benzeneacetonitrile (3.18 g, 20.0 mmol) in EtOH (30 mL) was added N2H4-H2O (2.5 g, 40 mmol, 80% wt.) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was concentrated under reduced pressure and diluted with water (50 mL), the resulting mixture was extracted with EA (3 x 70 mL), the combined organic layers were washed with brine (2 x 40 mL), dried over Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (3.07 g, 89%) which was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+=174. Step 3: ethyl N-[(5-methyl-4-phenyl-2H-pyrazol-3-yl)carbamothioyl]carbamate

[0113] To a stirred solution of 5-methyl-4-phenyl-2H-pyrazol-3-amine (3.07 g, 17.7 mmol) in DMF (53 mL) was added ethyl N-carbothioylcarbamate (930 mg, 7.09 mmol) at RT. The resulting mixture was stirred for 1 h. The resulting mixture was poured into ice-cold water (400 mL). The precipitated solids were collected by filtration and washed with water (3 x 20 mL). The solid was dried under vacuum to afford the title compound (2.58 g, 48%) as a yellow solid which was used in the next step without further purification. LCMS (ES, m / z): [M+H]+=305. Step 4: 7-methyl-8-phenyl-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0114] To a stirred solution of ethyl N-[(5-methyl-4-phenyl-2H-pyrazol-3- yl)carbamothioyl]carbamate (2.15 g, 7.06 mmol) in EtOH (30 mL) was added EtONa (5.54 mL, 14.1 mmol, 20% wt in EtOH) at RT. The resulting mixture was refluxed at 80 °C for 0.5 h. The resulting mixture was filtered, the filter cake was dissolved in water (20 mL) and acidified to pH 5 with 2 N HCl (8 mL). The precipitated solids were collected by filtration and washed with water (2 x 15 mL) to afford the title compound (1.66 g, 91%) which was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+ =259 Step 5: 7-methyl-8-phenyl-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4- one (Example 1)

[0115] To a stirred mixture of 7-methyl-8-phenyl-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (400 mg, 1.55 mmol) and K2CO3(642 mg, 4.65 mmol) in DMF (5 mL) was added propargyl bromide (111 mg, 0.929 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The resulting mixture was filtered, the filter cake was washed with DMF (2 x 2 mL). The filtrate was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 36% B to 59% B in 8 min, 59% B; Wave Length: 220 nm; RT1(min): 6.13) to afford the title compound (287 mg, 62.54%) as a white solid. LCMS (ES, m / z): [M+H]+= 297. 1H NMR (400 MHz, DMSO-d6): δ 12.95 (s, 1H), 7.77 – 7.75 (m, 2H), 7.47 – 7.43 (m, 2H), 7.32 – 7.28 (m, 1H), 4.01 (d, J = 2.6 Hz, 2H), 3.28 – 3.27 (t, J = 2.6 Hz, 1H), 2.47 (s, 3H).

[0116] Examples in Table A were synthesized using Synthetic Method A Table A

[0004] Example 85 - 2-[(2-fluorophenyl)sulfanyl]-7-methyl-8-phenyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0117] To a mixture of 7-methyl-8-phenyl-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (100 mg, 0.387 mmol) and 2-fluorophenylboronic acid (163 mg, 1.16 mmol) in dry DCE (2 mL) were added Cu(OAc)2 (70 mg, 0.39 mmol) and 1,10-phenanthroline (140 mg, 0.774 mmol) at RT. The final reaction mixture was irradiated with microwave radiation for 10 min at 85 °C under N2. The reaction was cooled down to RT. The resulting mixture was filtered, the filter cake was washed with DCE (2 x 2 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: Xcelect CSH F-pheny OBD Column, 19*250 mm, 5μm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 38% B to 64% B in 8 min, 64% B; Wave Length: 254 nm; RT1(min): 6.77) to afford the title compound (120 mg, 88%) as a white solid. LCMS (ES, m / z): [M+H]+=353.1H NMR (400 MHz, DMSO-d6): δ 13.21 (s, 1H), 7.72 – 7.70 (m, 2H), 7.49 (m, 1H), 7.41 – 7.36 (m, 3H), 7.26 – 7.18 (m, 3H), 2.45 (s, 3H). Example 86 - 8-(4-fluorophenyl)-2-(pyridin-2-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0118] To a stirred mixture of 8-(4-fluorophenyl)-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (100 mg, 0.381 mmol), K2CO3 (158 mg, 1.14 mmol) and CuI (808 mg, 0.42 mmol) in DMF (2 mL) was added 2-iodopyridine (31 mg, 0.15 mmol) at RT. The resulting mixture was stirred at 120 °C for 1 h. The mixture was allowed to cool down to RT. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (3 x 10 mL), the combined organic layers were washed with water (2 x 10 mL) and brine (10 mL), dried over anhydrous Na2SO4. After filtration the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: water (0.05% FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 37% B to 53% B in 8 min, 53% B; Wave Length: 220 nm; RT1(min): 7.13) to afford the title compound (37 mg, 29%) as a white solid. LCMS (ES, m / z): [M+H]+=340.1H NMR (400 MHz, DMSO-d6): δ 8.70 – 8.68 (m, 1H), 8.51 (s, 1H), 8.03 – 8.01 (m, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.70 – 7.62 (m, 3H), 7.11 – 7.07 (m, 2H). Example 87 - 2-[(4-hydroxybut-2-yn-1-yl)sulfanyl]-7-methyl-8-phenyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one Step 1: 4-bromobut-2-yn-1-ol

[0119] To a solution of butynediol (3.5 g, 41 mmol), triethylamine (1.32 g, 13.0 mmol) and triethylamine hydrochloride (0.11 g, 0.81 mmol) in ACN (30 mL) at 0 °C was added p- toluenesulfonyl chloride (1.78 g, 9.35 mmol) in one portion. The reaction mixture was stirred at 0 °C for 40 min, warmed to RT, and quenched with water (150 mL) and EA (150 mL). The aqueous layer was extracted with EA (100 mL). The combined organics were washed with aqueous NH4Cl (80 mL) and brine (100 mL) and dried over Na2SO4. The solvent was evaporated in vacuo, and the crude material was purified by column chromatography (EA / PE=3 / 7) to yield the intermediate mono-tosyl diol as a light yellow oil. This was dissolved in acetone (10 mL), then added LiBr (1.41 g, 16.3 mmol) added at RT. The mixture was stirred for 1 h and then diluted with Et2O (50 mL) and water (25 mL). The organic layer was washed with brine (5 mL) and dried over Na2SO4. The solvent was evaporated under reduced pressure, no mass signal could be detected, and the crude material the title compound (1.5 g, 25%) was used in the next step without further purification. Step 2: 2-[(4-hydroxybut-2-yn-1-yl)sulfanyl]-7-methyl-8-phenyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0120] To a stirred solution of 7-methyl-8-phenyl-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (180 mg, 0.697 mmol) in DMF (3.5 mL) was added K2CO3(289 mg, 2.09 mmol) followed by the addition of 4-bromobut-2-yn-1-ol (52 mg, 0.35 mmol) dropwise under N2 at RT. The resulting mixture was stirred for 1 h under N2 at RT. The resulting mixture was filtered, the filtrate was purified by Prep-HPLC with the following condition (Column: XSelect CSH Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 19% B to 51% B in 8 min, 51% B; Wave Length: 254 / 220 nm; RT1(min): 6.88) to afford the title compound (110 mg, 48%) as a white solid. LCMS (ES, m / z): [M+H]+ =327. 1H NMR (400 MHz, DMSO- d6): δ 12.95 (s, 1H), 7.75 (d, J = 7.7 Hz, 2H), 7.46 (t, J = 7.3 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 5.19 (s, 1H), 4.09 (s, 2H), 4.06 (d, J = 2.4 Hz, 2H), 2.56 (s, 3H). Example 88 - 8-(4-fluorophenyl)-7-isopropyl-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 2-(4-fluorophenyl)-4-methyl-3-oxopentanenitrile

[0121] To a stirred solution of 4-fluoro-benzeneacetonitrile (30 g, 222 mmol) in THF (300 ml) was added NaH (16.5 g, 688 mmol) in portions at 0 °C. The resulting mixture was stirred for 20 min at 0 °C. To the above mixture was added ethyl isobutyrate (103 g, 888 mmol) dropwise at °C. The resulting mixture was stirred for an additional overnight at RT. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 6 with 2N HCl. The resulting mixture was extracted with EA (3 x 100 ml). The combined organic layers were washed with brine (2 x 100 ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford the title compound (32 g, 70%) as a yellow oil. LCMS (ES, m / z): [M-H]- =204. Step 2: 4-(4-fluorophenyl)-5-isopropyl-2H-pyrazol-3-amine

[0122] To a stirred solution of 2-(4-fluorophenyl)-4-methyl-3-oxopentanenitrile (32 g, 156 mmol) in EtOH (320 mL) was added hydrazine hydrate (80%) (15.6 g, 312 mmol) at RT. The resulting mixture was stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.05% NH3·H2O), 30% to 40% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (10 g, 29%) as a yellow solid. LCMS (ES, m / z): [M+H]+=220. Step 3: ethyl N-{[4-(4-fluorophenyl)-5-isopropyl-2H-pyrazol-3- yl]carbamothioyl}carbamate

[0123] To a stirred solution of 4-(4-fluorophenyl)-5-isopropyl-2H-pyrazol-3-amine (17 g, 78 mmol) in DMF (170 mL) was added ethyl N-carbothioylcarbamate (15.3 g, 116 mmol) at RT. The resulting mixture was stirred for 2h at RT. The mixture was poured into water / ice (200 mL). The precipitated solids were collected by filtration and washed with water (4 x 20 mL). This resulted in the title compound (24.5 g, 87%) as a yellow solid. LCMS (ES, m / z): [M+H]+=352. Step 4: 8-(4-fluorophenyl)-7-isopropyl-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0124] To a stirred solution of ethyl N-{[4-(4-fluorophenyl)-5-isopropyl-2H-pyrazol-3- yl]carbamothioyl}carbamate (24.5 g, 70 mmol) in EtOH (245 mL) was added EtONa (9.52 g, 140 mmol) at RT. The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 6 with 2N HCl. The precipitated solids were collected by filtration and washed with water. This resulted in the title compound (22.5 g, 99%) as a yellow solid. LCMS (ES, m / z): [M+H]+=305. Step 5: 8-(4-fluorophenyl)-7-isopropyl-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0125] To a stirred solution of 8-(4-fluorophenyl)-7-isopropyl-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (25.2 g, 82.8 mmol) in DMF (120 mL) were added K2CO3 (22.9 g, 166 mmol) and propargyl bromide (7.39 g, 62.1 mmol) in portions at RT. The resulting mixture was stirred for 2 h at RT. The mixture was allowed to cool down to 0 °C and poured into water at 0 C. The precipitated solids were collected by filtration and washed with water (3 x 30 mL). The resulting solid was dried under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (12:1) to afford a yellow solid (20 g crude). The 15g residue was purified by trituration with EA (24 mL) at 65°C. The mixture was allowed to cool down to 0 °C. The precipitated solids were collected by filtration, washed with EA (4 x 5 mL) and dried under reduced pressure. This resulted in the title compound (9.6 g, 34%) as an off-white solid. LCMS (ES, m / z): [M+H]+=343. 1H NMR (400 MHz, DMSO-d6) δ 12.95 (s, 1H), δ 7.70 – 7.61 (m, 2H), 7.28 (td, J = 8.9, 2.2 Hz, 2H), 3.97 (d, J = 2.6 Hz, 2H), 3.31 (sept, J = 6.8 Hz, 1H), 3.22 (s, 1H), 1.25 (d, J = 6.8 Hz, 6H). Example 89 - 8-cyclohexyl-7-methyl-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one Step 1: 2-cyclohexyl-3-oxobutanenitrile

[0126] To a stirred solution of 2-cyclohexylacetonitrile (2.46 g, 20 mmol) in THF (29 mL) was added NaH (1.49 g, 62 mmol) and EA (7.0 g, 80 mmol) in portions at 0 °C under N2. The resulting mixture was stirred overnight at 60 °C. The reaction was acidified to pH=6, the resulting mixture was extracted with EA (3 x 80 mL), washed with brine (50 mL), dried over Na2SO4, filtered to get the title compound (3.66 g, 99%), which was used in the next step without further purification. No mass signal could be detected. Step 2: 4-cyclohexyl-5-methyl-2H-pyrazol-3-amine

[0127] To a stirred solution of 2-cyclohexyl-3-oxobutanenitrile (20 mmol) in EtOH (60 mL) was added hydrazine hydrate (80%, 2.0 mL, 41 mmol) in portions at RT. The resulting mixture was stirred overnight at 80 °C under N2. The reaction mixture was cooled down to RT, concentrated under vacuum, diluted with water (80 mL), and extracted with EA (3 x 60 mL). The combined organic layer was washed with brine (40 mL), dried over anhydrous Na2SO4, and concentrated to afford the title compound (2.0 g, 56%) which was used in the next step without further purification. LCMS (ES, m / z): [M+H]+ =180. Step 3: ethyl N-[(4-cyclohexyl-5-methyl-2H-pyrazol-3-yl)carbamothioyl]carbamate

[0128] To a stirred solution of 4-cyclohexyl-5-methyl-2H-pyrazol-3-amine (2.0 g, 4.5 mmol) in dimethylformamide (40 mL) was added ethyl N-carbothioylcarbamate (0.59 g, 4.5 mmol) dropwise at RT under N2. The resulting mixture was stirred for 1 h. The resulting mixture was diluted with cold water (400 mL), filtered to afford the title compound (3.2 g, 92%) which was used in the next step without further purification. LCMS (ES, m / z): [M+H]+ =311. Step 4: 8-cyclohexyl-7-methyl-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0129] To a solution of ethyl N-[(4-cyclohexyl-5-methyl-2H-pyrazol-3- yl)carbamothioyl]carbamate (3.2 g, 10 mmol) in EtOH (40 mL) was added EtONa (20% in EtOH)(6.8 mL, 20 mmol) at RT. The resulting mixture was stirred for 1 h at 80 °C. The precipitated solids were collected by filtration. The residue was dissolved in water (80 mL). The residue was acidified to pH 6 with 1 M HCl. The precipitated solids were collected by filtration and washed with water (2 x 80 mL) to leave the title compound (2.0 g, 73%) which was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+ =265. Step 5: 8-cyclohexyl-7-methyl-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0130] To a stirred solution of 8-cyclohexyl-7-methyl-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (1.0 g, 3.8 mmol) in DMF (5 mL) was added K2CO3(400 mg, 2.89 mmol) in portions and propargyl bromide (180 mg, 1.51 mmol) dropwise under N2 at RT. The resulting mixture was stirred for 1 h under N2 at RT. The resulting mixture was filtered, the filtrate was purified by Prep-HPLC with the following condition (Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 47% B to 52% B in 12 min, 52% B; Wave Length: 220 nm; RT1(min): 9.80) to afford the title compound (31.9 mg, 3%) as an off-white solid. LCMS (ES, m / z): [M+H]+ =303. 1H NMR (400 MHz, DMSO-d6): δ 12.66 (s, 1H), 3.99 (d, J = 2.6 Hz, 2H), 3.19 (t, J = 2.6 Hz, 1H), 2.60 – 2.51 (m, 1H), 2.26 (s, 3H), 1.92-1.64 (m, 7H), 1.39-1.20 (m, 3H). Synthetic Method B Example 90 - 8-(4-fluorophenyl)-7-methoxy-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0005] Step 1: ethyl 2-cyano-2-(4-fluorophenyl)acetate

[0131] To a stirred solution of 4-fluoro-benzeneacetonitrile (1.0 g, 7.4 mmol) in diethyl carbonate (10 mL, 85 mmol) was added sodium ethoxide (1.01 g, 14.8 mmol) at RT. The resulting mixture was stirred overnight at 90 °C. The mixture was acidified to pH 6 with 2N HCl. The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8:1) to afford the title compound (1.3 g, 85%) as a yellow oil. LCMS (ES, m / z): [M-H]- =206. Step 2: 5-amino-4-(4-fluorophenyl)-1,2-dihydropyrazol-3-one

[0132] To a stirred solution of ethyl 2-cyano-2-(4-fluorophenyl)acetate (7.74 g, 37.4 mmol) in EtOH(80 mL) was added hydrazine hydrate (80%) (3.74 g, 74.7 mmol) at RT. The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EA (3 x 70 mL). The combined organic layers were washed with brine (2 x 70 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (4.8 g, 67%) as a white solid. LCMS (ES, m / z): [M+H]+=194. Step 3: tert-butyl 5-amino-4-(4-fluorophenyl)-3-oxo-2H-pyrazole-1-carboxylate

[0133] To a stirred solution of 5-amino-4-(4-fluorophenyl)-1,2-dihydropyrazol-3-one (4.7 g, 24 mmol) in MeOH (47 mL) were added (Boc)2O (6.37 g, 29.2 mmol) and Na2CO3 (3.1 g, 29 mmol) in portions at RT. The resulting mixture was stirred for 3 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water. The resulting mixture was extracted with DCM (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford the title compound (5.98 g, 84%) as a white solid. LCMS (ES, m / z): [M+H]+=294. Step 4: tert-butyl 5-amino-4-(4-fluorophenyl)-3-methoxypyrazole-1-carboxylate

[0134] To a stirred solution of tert-butyl 5-amino-4-(4-fluorophenyl)-3-oxo-2H-pyrazole-1- carboxylate (500 mg, 1.71 mmol) and K2CO3 (707 mg, 5.12 mmol) in DMF (10 mL) was added MeI (266 mg, 1.88 mmol) at RT. The resulting mixture was stirred overnight at RT. To the above mixture was added MeI (484 mg, 3.41 mmol) at RT. The resulting mixture was stirred for an additional 6 h at RT. The residue was dissolved in water. The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (30 mg, 5.7%) and the title compound (292 mg 56%) both as off-white solids. LCMS (ES, m / z): [M+H]+=308. Step 5: 4-(4-fluorophenyl)-5-methoxy-2H-pyrazol-3-amine

[0135] To a stirred solution of tert-butyl 5-amino-4-(4-fluorophenyl)-3-methoxypyrazole-1- carboxylate (360 mg, 1.17 mmol) in DCM (8 mL) was added TFA (1.5 mL) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (144 mg, 59%) as a yellow solid. LCMS (ES, m / z): [M+H]+=208. Step 6: ethyl N-{[4-(4-fluorophenyl)-5-methoxy-2H-pyrazol-3- yl]carbamothioyl}carbamate

[0136] To a stirred solution of 4-(4-fluorophenyl)-5-methoxy-2H-pyrazol-3-amine (100 mg, 0.483 mmol) in DMF (2 mL) was added ethyl N-carbothioylcarbamate (50.6 mg, 0.386 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The reaction was poured into water at 0 C. The resulting mixture was filtered, the filter cake was washed with water. The solids were dried under vacuum. This resulted in the title compound (200 mg, 85%) as a yellow solid. LCMS (ES, m / z): [M+H]+=339. Step 7: 8-(4-fluorophenyl)-7-methoxy-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0137] To a stirred solution of ethyl N-{[4-(4-fluorophenyl)-5-methoxy-2H-pyrazol-3- yl]carbamothioyl}carbamate (200 mg, 0.591 mmol) in EtOH (4 mL) was added EtONa (80.5 mg, 1.18 mmol) at RT. The resulting mixture was stirred for 1 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 6 with 2N HCl. The resulting mixture was filtered, the filter cake was washed with water. The solid was dried under vacuum. This resulted in the title compound (196 mg, 96%) as a yellow solid. LCMS (ES, m / z): [M+H]+=293. Step 8: 8-(4-fluorophenyl)-7-methoxy-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0138] To a stirred mixture of 8-(4-fluorophenyl)-7-methoxy-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (198 mg, 0.676 mmol) and K2CO3 (280 mg, 2.03) in DMF (4 mL) was added propargyl bromide (64.3 mg, 0.541 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 30% to 80% gradient in 10 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 65% B in 8 min, 65% B; Wave Length: 220 nm; RT1(min): 9.23) to afford the title compound (55 mg, 25%) as a white solid. LCMS (ES, m / z): [M+H]+=331. 1H NMR (300 MHz, DMSO-d6) δ 12.98 (s, 1H), 8.16 – 8.04 (m, 2H), 7.29 – 7.15 (m, 2H), 4.08-4.04 (m, 5H), 3.27 (t, J = 2.6 Hz, 1H).

[0139] Examples in Table B were synthesized using Synthetic Method B: Table B Example 93 - 8-(4-fluorophenyl)-6-methyl-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazine-4,7-dione Step 1: tert-butyl 5-amino-4-(4-fluorophenyl)-2-methyl-3-oxo-2,3-dihydro-1H-pyrazole- 1-carboxylate

[0140] To a stirred solution of tert-butyl 5-amino-4-(4-fluorophenyl)-3-oxo-2H-pyrazole-1- carboxylate (500 mg, 1.71 mmol) and K2CO3 (707 mg, 5.12 mmol) in DMF (10 mL) was added MeI (266 mg, 1.88 mmol) at RT. The resulting mixture was stirred overnight at RT. To the above mixture was added MeI (484 mg, 3.41 mmol) at RT. The resulting mixture was stirred for an additional 6h at RT. The residue was dissolved in water. The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted the title compound (292 mg 56%) as an off-white solid. LCMS (ES, m / z): [M+H]+=308. Step 2: 5-amino-4-(4-fluorophenyl)-2-methyl-1,2-dihydro-3H-pyrazol-3-one

[0141] To a stirred solution of tert-butyl 5-amino-4-(4-fluorophenyl)-2-methyl-3-oxo-2,3- dihydro-1H-pyrazole-1-carboxylate (2.42 g, 7.87 mmol) in DCM (24 mL) was added TFA (6 mL) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (1.46 g, 89%) as a white solid. LCMS (ES, m / z): [M+H]+=208. Step 3: ethyl N-{[4-(4-fluorophenyl)-1-methyl-5-oxo-2H-pyrazol-3- yl]carbamothioyl}carbamate

[0142] To a stirred solution of 5-amino-4-(4-fluorophenyl)-2-methyl-1,2-dihydro-3H- pyrazol-3-one (1.34 g, 6.47 mmol) in DMF (13 mL) was added ethyl N-carbothioylcarbamate (1.27 g, 9.70 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The reaction was poured into water at 0 °C. The resulting mixture was filtered, the filter cake was washed with water. The filtrate was concentrated under reduced pressure. This resulted in the title compound (1.0 g, 46%) as a yellow solid. LCMS (ES, m / z): [M+H]+=339. Step 4: 8-(4-fluorophenyl)-6-methyl-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazine-4,7- dione

[0143] To a stirred solution of ethyl N-{[4-(4-fluorophenyl)-1-methyl-5-oxo-2H-pyrazol-3- yl]carbamothioyl}carbamate (1.0 g, 3.0 mmol) in EtOH (10 mL) was added EtONa (402 mg, 5.91 mmol) at RT. The resulting mixture was stirred for 1 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 6 with 2N HCl. The resulting mixture was filtered, the filter cake was washed with water. The filtrate was concentrated under reduced pressure. This resulted in the title compound (872 mg, 91%) as a yellow solid. LCMS (ES, m / z): [M+H]+=293. Step 5: 8-(4-fluorophenyl)-6-methyl-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazine-4,7-dione

[0144] To a stirred mixture of 8-(4-fluorophenyl)-6-methyl-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazine-4,7-dione (200 mg, 0.684 mmol) and K2CO3 (284 mg, 2.05 mmol) in DMF (4 mL) was added propargyl bromide (65 mg, 0.55 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 35% B to 57% B in 8 min, 57% B; Wave Length: 220 nm; RT1(min): 5.85) to afford the title compound (54 mg, 24%) as a white solid. LCMS (ES, m / z): [M-H]−=329.1H NMR (300 MHz, DMSO-d6) δ 8.45 – 8.32 (m, 2H), 7.25 – 7.11 (m, 2H), 4.07 (d, J = 2.6 Hz, 2H), 3.55 (s, 3H), 3.31 (t, J = 2.5 Hz, 1H). Synthetic method C Example 94 - 7-chloro-8-(4-fluorophenyl)-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one Step 1: 4-bromo-5-chloro-2H-pyrazol-3-amine

[0145] To a stirred mixture of 5-chloro-2H-pyrazol-3-amine (120 mg, 1.02 mmol) in DCM (4 mL) was added NBS (363 mg, 2.04 mmol) in portions at RT. The resulting mixture was stirred overnight at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 0.1%FA, 10% to 100% gradient in 10 min; detector, UV 254 nm to afford the title compound (45 mg, 22%) as a yellow solid. LCMS (ES, m / z): [M+H]+=196, 198. Step 2: 5-chloro-4-(4-fluorophenyl)-2H-pyrazol-3-amine)

[0146] To a stirred mixture of 4-bromo-5-chloro-2H-pyrazol-3-amine (320 mg, 0.407 mmol) and 4-fluorophenylboronic acid (85 mg, 0.61 mmol) in dioxane (0.7 mL) were added K2CO3 (169 mg, 1.22 mmol) and Pd(dtbpf)Cl2(26 mg, 0.041 mmol) in portions at RT under N2. The resulting mixture was stirred overnight at 100oC under N2. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 0.1%FA, 10% to 100% gradient in 10 min; detector, UV 220 nm to afford the title compound (40 mg, 12%) as a yellow solid. LCMS (ES, m / z): [M+H]+=212. Step 3: ethyl N-{[5-chloro-4-(4-fluorophenyl)-2H-pyrazol-3- yl]carbamothioyl}carbamate

[0147] To a stirred mixture of 5-chloro-4-(4-fluorophenyl)-2H-pyrazol-3-amine (50 mg, 0.047 mmol) in dimethylformamide (2 mL) was added ethyl N-carbothioylcarbamate (6.2 mg, 0.047 mmol) at RT. The resulting mixture was stirred for 2h at RT. The mixture was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 0.1%FA, 0% to 100% gradient in 10 min; detector, UV 254 nm to afford the title compound (10 mg, 12%) as a yellow solid. LCMS (ES, m / z): [M+H]+=343. Step 4: 7-chloro-8-(4-fluorophenyl)-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0148] To a stirred mixture of ethyl N-{[5-chloro-4-(4-fluorophenyl)-2H-pyrazol-3- yl]carbamothioyl}carbamate (70 mg, 0.204 mmol) in ethyl alcohol (2 mL) was added sodium ethoxide (28 mg, 0.41 mmol) in portions at RT. The resulting mixture was stirred for 2h at 80 °C. The mixture was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 0.1%FA, 0% to 100% gradient in 10 min; detector, UV 254 nm to afford the title compound (50 mg, 83%) as a yellow solid. LCMS (ES, m / z): [M+H]+=297. Step 5: 7-chloro-8-(4-fluorophenyl)-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0149] To a stirred mixture of 7-chloro-8-(4-fluorophenyl)-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (60 mg, 0.20 mmol) and K2CO3(56 mg, 0.40 mmol) in DMF (2 mL) was added propargyl bromide (19 mg, 0.16 mmol) dropwise at RT. The resulting mixture was stirred for 2 h at RT. The mixture was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 52% B to 60% B in 8 min, 60% B; Wave Length: 254 nm; RT1(min): 6.05) to afford the title compound (10 mg, 15%) as a white solid. LCMS (ES, m / z): [M+H]+= 335.1H NMR (300 MHz, DMSO-d6) δ7.85 – 7.56 (m, 2H), 7.32 (m, 2H), 4.01 (s, 2H), 3.22 (s, 1H).

[0150] Example 95 was synthesized using Synthetic Method C: LCMS (ES, m / z): [M+H]+= 379. 1H NMR (400 MHz, DMSO-d6) δ 7.95 – 7.93 (m, 2H), 7.65 – 7.56 (m, 2H), 4.33 (q, 2H). Example 96 - 8-(4-fluorophenyl)-7-hydroxy-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one Step 1: 5-amino-4-(4-fluorophenyl)-1H-pyrazol-3-ol

[0151] To a stirred solution of 2-cyano-2-(4-fluorophenyl)-N,N-dimethylacetamide (1.39 g, 6.74 mmol) in EtOH (20 mL) was added hydrazine hydrate (80%, 0.40 mL, 8.2 mmol) at RT. The resulting mixture was stirred 2 h at 80 °C. resulting mixture was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (0.80 g, 61%) as a light yellow oil. LCMS (ES, m / z): [M+H]+=194. Step 2: ethyl N-{[4-(4-fluorophenyl)-5-hydroxy-2H-pyrazol-3- yl]carbamothioyl}carbamate

[0152] A mixture of 5-amino-4-(4-fluorophenyl)-1H-pyrazol-3-ol (500 mg, 2.59 mmol) and ethyl N-carbothioylcarbamate (306 mg, 2.33 mmol) in DMF (8 mL) was stirred at RT for 2 h. The resulting mixture was filtered, the filter cake was washed with water (3 x 20 mL). The solid was dried under vacuum. This resulted in the title compound (230 mg, 27%) as a yellow solid. LCMS (ES, m / z): [M+H]+=325. Step 3: 8-(4-fluorophenyl)-7-hydroxy-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0153] To a stirred solution of ethyl N-{[4-(4-fluorophenyl)-5-hydroxy-2H-pyrazol-3- yl]carbamothioyl}carbamate (110 mg, 0.339 mmol) in EtOH (2 mL) was added EtONa (46 mg, 0.68 mmol) at 80 °C. The resulting mixture was stirred 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 6 with 2N HCl. The precipitated solids were collected by filtration and washed with water. The solid was dried under vacuum. This resulted in the title compound (65 mg, 69%) as a yellow solid. LCMS (ES, m / z): [M+H]+=279. Step 4: 8-(4-fluorophenyl)-7-hydroxy-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0154] To a stirred solution of 8-(4-fluorophenyl)-7-hydroxy-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (50 mg, 0.18 mmol) and K2CO3 (75 mg, 0.54 mmol) in DMF (2.0 mL) was added propargyl bromide (11 mg, 0.090 mmol) at RT for 2h. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 20% to 50% gradient in 10 min; detector, UV 254 nm to afford 76 mg crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: Atlantis HILIC OBD Column, 19*150mm*5μm; Mobile Phase A: water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 41% B to 49% B in 8 min, 49% B; Wave Length: 220 nm; RT1(min): 5.47) to afford the title compound (10 mg, 18%) as a white solid. LCMS (ES, m / z): [M+H]+=317.1H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 11.93 (s, 1H), 8.25 – 8.15 (m, 2H), 7.27 – 7.16 (m, 2H), 4.07 (d, J = 2.6 Hz, 2H), 3.30 – 3.27 (t, J = 2.6 Hz, 1H). Synthetic Method G Example 97 - 8-(4-fluorophenyl)-2-(prop-2-yn-1-ylsulfanyl)-7-(trifluoromethyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 4-bromo-5-(trifluoromethyl)-2H-pyrazol-3-amine

[0155] To a stirred solution of 5-(trifluoromethyl)-2H-pyrazol-3-amine (950 mg, 6.29 mmol) in ACN (20 mL) was added NBS (1.12 g, 6.29 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure and diluted with water. The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (500 mg, 35%) as a yellow solid. LCMS (ES, m / z): [M+H]+=230, 232. Step 2: 4-(4-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-amine

[0156] To a stirred mixture of 4-bromo-5-(trifluoromethyl)-2H-pyrazol-3-amine (400 mg, 1.74 mmol) and 4-fluorophenylboronic acid (292 mg, 2.09 mmol) in 1,4-dioxane (7 mL) and WATER (1 mL) were added K2CO3(721 mg, 5.22 mmol) and Pd(Dtbpf)Cl2(113 mg, 0.174 mmol) at RT. The final reaction mixture was irradiated with microwave radiation for 4 h at 80 °C. The mixture was acidified to pH 6 with 2N HCl. The resulting mixture was extracted with EA (3 x 8 mL). The combined organic layers were washed with water (8 ml) and brine (2 x 8 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 30% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (230 mg, 54%) as a yellow solid. LCMS (ES, m / z): [M+H]+=246. Step 3: ethyl N-{[4-(4-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3- yl]carbamothioyl}carbamate

[0157] To a stirred solution of 4-(4-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-amine (173 mg, 0.706 mmol) in DMF (4 mL) was added ethyl N-carbothioylcarbamate (93 mg, 0.71 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was poured into water at 0 C (5 mL). The precipitated solids were collected by filtration and washed with water (2 x 1 mL). The solid was dried under vacuum. This resulted in the title compound (252 mg, 95%) as a yellow solid. LCMS (ES, m / z): [M+H]+=377. Step 4: 8-(4-fluorophenyl)-2-sulfanyl-7-(trifluoromethyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0158] To a stirred solution of ethyl N-{[4-(4-fluorophenyl)-5-(trifluoromethyl)-2H-pyrazol- 3-yl]carbamothioyl}carbamate (387 mg, 1.03 mmol) in EtOH (8 mL) was added EtONa (210 mg, 3.08 mmol) at RT. The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 6 with 2N HCl (aq.). The precipitated solids were collected by filtration and washed with water (2 x 1 mL). The solid was dried under vacuum. This resulted in the title compound (275 mg, 81%) as a yellow solid. LCMS (ES, m / z): [M-H]- =329. Step 5: 8-(4-fluorophenyl)-2-(prop-2-yn-1-ylsulfanyl)-7-(trifluoromethyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0159] To a stirred mixture of 8-(4-fluorophenyl)-2-sulfanyl-7-(trifluoromethyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (130 mg, 0.394 mmol) and K2CO3(163 mg, 1.18 mmol) in DMF (3 mL) was added propargyl bromide (47 mg, 0.39 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was filtered, the filter cake was washed with DMF (2 x 1 mL). The filtrate was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: water (0.05%TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 49% B to 61% B in 8 min, 61% B; Wave Length: 254 / 220 nm; RT1(min): 7.38) to afford the title compound (31 mg, 21%) as an off-white solid. LCMS (ES, m / z): [M-H]- =367.1H NMR (300 MHz, DMSO-d6) δ 7.71 – 7.60 (m, 2H), 7.39 – 7.26 (m, 2H), 3.98 (d, = 2.6 Hz, 2H), 3.29(t, J = 2.6 Hz, 1H).

[0160] Example 98 was synthesized using Synthetic Method G: LCMS (ES, m / z): [M+H]+= 413. 1H NMR (300 MHz, DMSO-d6) δ 7.58 – 7.53 (m, 2H), 7.35 – 7.29 (m, 2H), 4.19 (q, J = 10.2 Hz, 2H). Example 99 - 7-methyl-8-(piperidin-1-yl)-2-[(2,2,2-trifluoroethyl)sulfanyl]-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: ethyl N-[(5-methyl-2H-pyrazol-3-yl)carbamothioyl]carbamate

[0161] A solution of 5-methyl-2H-pyrazol-3-amine (1.0 g, 10 mmol) and ethyl N- carbothioylcarbamate (1.08 g, 8.24 mmol) in DMF (20 mL) was stirred for 2 h at RT. The reaction was quenched by the addition of ice water (50 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to leave the title compound (1.0 g, 43%) as a light yellow solid. LCMS (ES, m / z): [M+H]+= 229. Step 2: 7-methyl-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0162] A solution of ethyl N-[(5-methyl-2H-pyrazol-3-yl) carbamothioyl] carbamate (1.6 g, 7.0 mmol) and EtONa (954 mg, 14.0 mmol) in EtOH (16 mL) was stirred overnight at 80 °C. The mixture was acidified to pH 6 with conc. HCl. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. The resulted in the title compound (1.0 g, 78%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=183. Step 3: 7-methyl-2-[(2,2,2-trifluoroethyl)sulfanyl]-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0163] A solution of 7-methyl-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (1.0 g, 5.5 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.04 g, 8.78 mmol) and K2CO3 (2.28 g, 16.5 mmol) in DMF (16 mL) was stirred for 2 h at RT. The reaction was quenched by the addition of ice water (50 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (1.0 g, 69%) as a white solid. LCMS (ES, m / z): [M+H]+=265. Step 4: 3-(methoxymethyl)-7-methyl-2-[(2,2,2-trifluoroethyl)sulfanyl]pyrazolo[1,5- a][1,3,5]triazin-4-one

[0164] A solution of 7-methyl-2-[(2,2,2-trifluoroethyl)sulfanyl]-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (1.0 g, 3.8 mmol), chloromethyl methyl ether (609 mg, 7.57 mmol) and N,N-diisopropylethylamine (1.47 g, 11.4 mmol) in DMF (20 mL) was stirred overnight at 50 °C under N2. The reaction was quenched by the addition of ice water (50 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, ACN in water, 10% to 100% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (1.0 g, 86%) as a white solid. LCMS (ES, m / z): [M+H]+=309. Step 5: 6-methyl-7-nitro-2-[(2,2,2-trifluoroethyl)sulfanyl]-3H,4aH-pyrrolo[3,2- d]pyrimidin-4-one

[0165] To a stirred solution of 3-(methoxymethyl)-6-methyl-2-[(2,2,2- trifluoroethyl)sulfanyl]-4aH-pyrrolo[3,2-d]pyrimidin-4-one (500 mg, 1.63 mmol) in DCM (10 mL) was added fuming HNO3 (0.17 mL, 4.1 mmol) dropwise at -20 °C. The resulting mixture was stirred for 2 days at RT. The residue was basified to pH 7 with saturated Na2CO3 (aq.). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, ACN in water, 10% to 100% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (230 mg, 46%) as a yellow solid. LCMS (ES, m / z): [M+H]+=310. Step 6: 8-amino-7-methyl-2-[(2,2,2-trifluoroethyl)sulfanyl]-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0166] A solution of 7-methyl-8-nitro-2-[(2,2,2-trifluoroethyl)sulfanyl]-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (220 mg, 0.711 mmol) and Pd / C (100 mg, 45%wt) in THF (5 mL) was stirred overnight at RT under hydrogen atmosphere. The filtrate was collected by filtration and used in the next step directly without further purification. This resulted in the title compound (overweight, crude) as a brown liquid. LCMS (ES, m / z): [M+H]+=280. Step 7: 7-methyl-8-(piperidin-1-yl)-2-[(2,2,2-trifluoroethyl)sulfanyl]-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0167] To a stirred solution of 8-amino-7-methyl-2-[(2,2,2-trifluoroethyl)sulfanyl]-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (0.711 mmol) and 1,5-dibromo-pentane (198 mg, 0.859 mmol) in THF (3 mL) was added N,N-diisopropylethylamine (278 mg, 2.15 mmol) and NaI (322 mg, 2.15 mmol) in portions at RT. The resulting mixture was stirred for 4 h at 75 °C. The reaction was quenched by the addition of ice water (5 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 31% B to 46% B in 6 min, 46% B; Wave Length: 254 / 220 nm; RT1(min): 5.08) to afford the title compound (32 mg, 13%) as a yellow solid. LCMS (ES, m / z): [M+H]+=348.1H NMR (300 MHz, DMSO-d6) δ 12.50 (s, 1H), 4.21 (q, J = 10.4 Hz, 2H), 3.12 – 3.00 (m, 4H), 2.20 (s, 3H), 1.65 – 1.48 (m, 6H). Synthetic Method J Example 100 - 7-methyl-8-(6-methylpyridin-3-yl)-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 4-bromo-5-methyl-2H-pyrazol-3-amine

[0168] To a stirred solution of 5-methyl-2H-pyrazol-3-amine (10.0 g, 103 mmol) and AIBN (1.69 g, 10.3 mmol) in ACN (100 mL) was added NBS (18.3 g, 103 mmol) at RT. The resulting mixture was stirred overnight at RT. The resulting mixture was concentrated and diluted with water (50 mL), extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, which resulted in the title compound (overweight) as a red solid. LCMS (ES, m / z): [M+H]+ =176. Step 2: ethyl N-[(4-bromo-5-methyl-2H-pyrazol-3-yl)carbamothioyl]carbamate

[0169] To a stirred solution of 4-bromo-5-methyl-2H-pyrazol-3-amine (103 mmol) in DMF (200 mL) was added ethyl N-carbothioylcarbamate (14.9 g, 114 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was diluted with ice water (400 mL). The precipitated solids were collected by filtration and washed with water (3 x 50 mL). The resulting solid was dried under vacuum to afford the title compound (overweight) as a yellow crude solid, which was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+=307. Step 3: 8-bromo-7-methyl-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0170] To a stirred solution of ethyl N-[(4-bromo-5-methyl-2H-pyrazol-3- yl)carbamothioyl]carbamate (103 mmol) in EtOH (350 mL) was added EtONa (15.5 g, 228 mmol) at RT. The resulting mixture was stirred for an additional 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (200 mL). The mixture was acidified to pH 6 with 2 N HCl (aq.). The precipitated solids were collected by filtration and washed with water (3 x 50 mL). This resulted in the title compound (24 g, 81%) as a yellow solid. LCMS (ES, m / z): [M+H]+=261. Step 4: 8-bromo-3-[(4-methoxyphenyl)methyl]-2-{[(4-methoxyphenyl)methyl]sulfanyl}- 7-methylpyrazolo[1,5-a][1,3,5]triazin-4-one

[0171] To a stirred solution of 8-bromo-7-methyl-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (1.46 g, 5.59 mmol) in DMF (20 mL) were added K2CO3(2.32 g, 16.8 mmol) and 4-methoxybenzyl chloride (3.50 g, 22.4 mmol) at RT under N2. The resulting mixture was stirred overnight at 50 °C. The product was precipitated by the addition of ice water. The precipitated solids were collected by filtration and washed with water (3 x 50 mL). The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10 / 1). This resulted in the title compound (605 mg, 22%) as a white solid. LCMS (ES, m / z): [M+H]+=501. Step 5: 3-[(4-methoxyphenyl)methyl]-2-{[(4-methoxyphenyl)methyl]sulfanyl}-7-methyl- 8-(6-methylpyridin-3-yl)pyrazolo[1,5-a][1,3,5]triazin-4-one

[0172] To a solution of 8-bromo-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-7-methylpyrazolo[1,5-a][1,3,5]triazin-4-one hydrobromide (300 mg, 0.515 mmol) and 6-methylpyridin-3-ylboronic acid (106 mg, 0.772 mmol) in dioxane (5 mL) and WATER (1 mL) were added K2CO3 (142 mg, 1.03 mmol) and Pd(dtbpf)Cl2 (34 mg, 0.052 mmol). After stirring overnight at 80 °C under a N2, the resulting mixture was allowed to cool down to RT. The resulting mixture was diluted with water (20 mL), extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash column chromatography, eluted with ACN / WATER (0.05% FA) (0% to 70% in 10 minutes) to afford the title compound (144 mg, 54%) as a brown solid. LCMS (ES, m / z): [M+H]+=514. Step 6: 7-methyl-8-(6-methylpyridin-3-yl)-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4- one

[0173] A stirred solution of 3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-7-methyl-8-(6-methylpyridin-3-yl)pyrazolo[1,5- a][1,3,5]triazin-4-one (144 mg, 0.280 mmol) in TFA (3 mL) was stirred for 2 h at 72 °C. The resulting mixture was concentrated under vacuum to afford the title compound (overweight), which was used in the next step without further purification. LCMS (ES, m / z): [M+H]+=274. Step 7: 7-methyl-8-(6-methylpyridin-3-yl)-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0174] To a stirred mixture of 7-methyl-8-(6-methylpyridin-3-yl)-2-sulfanyl-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (100 mg, 0.366 mmol) and K2CO3 (152 mg, 1.10 mmol) in DMF (2 mL) was added propargyl bromide (35 mg, 0.29 mmol) dropwise at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was filtered, the filtrate was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 5% B to 28% B in 7 min, 28% B; Wave Length: 254 / 220 nm; RT1(min): 5.08) to afford the title compound (25 mg, 22%) as a white solid. LCMS (ES, m / z): [M+H]+= 312.1H NMR (400 MHz, DMSO-d6): δ 13.21 (s, 1H), 8.83 (d, J = 2.3 Hz, 1H), 8.07 (dd, J = 8.1, 2.4 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 4.01 (d, J = 2.6 Hz, 2H), 3.27 (t, J = 2.6 Hz, 1H), 2.51 (s, 3H), 2.49 (s, 3H).

[0175] Examples in Table J were synthesized using Synthetic Method J: Table J

[0006] Example 109 - 8-[4-(hydroxymethyl)phenyl]-7-methyl-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 8-[4-(hydroxymethyl)phenyl]-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-7-methylpyrazolo[1,5-a][1,3,5]triazin-4-one

[0176] To a solution of 8-bromo-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-7-methylpyrazolo[1,5-a][1,3,5]triazin-4-one (300 mg, 0.598 mmol) and 4-(hydroxymethyl)phenylboronic acid (182 mg, 1.20 mmol) in dioxane (4 mL) and WATER (1 mL) were added K2CO3(165 mg, 1.20 mmol) and Pd(dtbpf)Cl2(39 mg, 0.060 mmol). After stirring overnight at 80 °C under a N2, the resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (180 mg, 57%) as a brown solid. LCMS (ES, m / z): [M+H]+=529. Step 2: (4-{7-methyl-4-oxo-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-8- yl}phenyl)methyl 2,2,2-trifluoroacetate

[0177] A solution of 8-[4-(hydroxymethyl)phenyl]-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-7-methylpyrazolo[1,5-a][1,3,5]triazin-4-one (150 mg, 0.284 mmol) in TFA (3 mL) was stirred for 2 h at 72 °C. The resulting mixture was concentrated under vacuum to afford the title compound (70 mg, 64%). The crude product was used in the next step directly without further purification. LCMS (ES, m / z): [M-H]- =383 Step 3: 8-[4-(hydroxymethyl)phenyl]-7-methyl-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0178] To a stirred mixture of (4-{7-methyl-4-oxo-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-8-yl}phenyl)methyl 2,2,2-trifluoroacetate (70 mg, 0.18 mmol) in MeOH (5 mL) was added NH3·WATER (1 mL) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure to afford the title compound (overweight) as an off-white solid. LCMS (ES, m / z): [M-H]- =287. Step 4: 8-[4-(hydroxymethyl)phenyl]-7-methyl-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0179] To a stirred mixture of 8-[4-(hydroxymethyl)phenyl]-7-methyl-2-sulfanyl-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (0.182 mmol) and K2CO3(173 mg, 1.25 mmol) in DMF (3 mL) was added propargyl bromide (40 mg, 0.33 mmol) dropwise at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was filtered, the filtrate was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, Sunfire prep C18 column, 30*150 mm, 5µm; mobile phase, Water (0.1%FA) and ACN (23% ACN up to 37% in 7 min) to afford the title compound (22 mg, 37%) as a white solid. LCMS (ES, m / z): [M+H]+=327.1H NMR (400 MHz, DMSO-d6): δ 12.94 (s, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 5.19 (s, 1H), 4.53 (s, 2H), 4.01 (d, J = 2.7 Hz, 2H), 3.28 (t, J = 2.7 Hz, 1H), 2.46 (s, 3H). Synthetic Method K Example 141 - 8-(4-fluorophenyl)-7-methyl-2-[(2,2,3,3-tetrafluoropropyl)sulfanyl]-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: ethyl 2-(4-fluorophenyl)-3-oxobutanenitrile

[0180] To a stirred solution of 4-fluorophenylacetonitrile (10 g, 74 mmol) in THF (50 mL) was added NaH (60% in mineral oil) (5.50 g, 229 mmol) at 0 °C under N2. The resulting mixture was stirred for 1 h at 0 °C under N2. To the above mixture was added EA (26.1 g, 296 mmol) dropwise at 0 °C. The resulting mixture was stirred for an additional overnight at RT. The mixture was acidified to pH 5 with HCl (aq.). The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. The resulted in the title compound (11 g, 84%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=178. Step 2: 4-(4-fluorophenyl)-5-methyl-2H-pyrazol-3-amine

[0181] 2-(4-Fluorophenyl)-3-oxobutanenitrile (9.67 g, 54.6 mmol) in EtOH (100 mL) was added hydrazine hydrate (80%; 5.46 g, 109 mmol) at RT. The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in EA (100 mL). The organic layers were washed with water (3x80 mL) and brine (150 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. The resulted in the title compound (7.46 g, 72%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=192. Step 3: ethyl N-[[4-(4-fluorophenyl)-5-methyl-2H-pyrazol-3- yl]carbamothioyl]carbamate)

[0182] To a stirred mixture of 4-(4-fluorophenyl)-5-methyl-2H-pyrazol-3-amine (5.00 g, 26.1 mmol) in DMF (40 mL) was added ethyl N-carbothioylcarbamate (3.43 g, 26.1 mmol) dropwise at RT, the resulting mixture was stirred for 1 h at RT. The reaction was quenched by the addition of water (50 mL) at 0 °C. The resulting mixture was extracted with EA (3x50 mL). The combined organic layers were washed with water (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The resulted in the title compound (6.0 g, 71%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=323. Step 4: 8-(4-fluorophenyl)-7-methyl-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0183] A solution of ethyl N-{[4-(4-fluorophenyl)-5-methyl-2H-pyrazol-3- yl]carbamothioyl}carbamate (7.0 g, 22 mmol) and sodium ethoxide (4.43 g, 65.1 mmol) in ethanol (70 mL) was stirred for 4 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (100 mL). The residue was neutralised to pH 6 with conc. HCl. The resulting mixture was extracted with EA (3x100 mL). The combined organic layers were washed with water (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (4.4 g, 73%) as an off-white solid. LCMS (ES, m / z): [M+H]+=277. Step 5: 8-(4-fluorophenyl)-7-methyl-2-[(2,2,3,3-tetrafluoropropyl)sulfanyl]-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0184] To a stirred solution of 8-(4-fluorophenyl)-7-methyl-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (100 mg, 0.362 mmol) and 2,2,3,3-tetrafluoropropanol (72 mg, 0.54 mmol) in THF (2 mL) were added DIAD (146 mg, 0.724 mmol) and PPh3(190 mg, 0.724 mmol) dropwise at 0 °C under N2. The resulting mixture was stirred for 5 h at 65 °C under N2. The resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 49% B to 59% B in 7 min, 59% B; Wave Length: 254 / 220 nm; RT1(min): 5.50) to afford the title compound (48 mg, 34%) as a white solid. LCMS (ES, m / z): [M+H]+=391. 1H NMR (300 MHz, DMSO-d6) δ 13.15 (s, 1H), 7.89 – 7.50 (m, 2H), 7.44 – 7.04 (m, 2H), 6.60 (tt, J = 52.3, 4.0 Hz, 1H), 4.08 (t, J = 17.5 Hz, 2H), 2.46 (s, 3H).

[0185] Examples in Table K were synthesized using Synthetic Method K: Table K

[0007] Example 152 - 8-(4-fluorophenyl)-2-[(5-hydroxypent-2-yn-1-yl)sulfanyl]-7-methyl-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 8-(4-fluorophenyl)-7-methyl-2-{[5-(oxan-2-yloxy)pent-2-yn-1-yl]sulfanyl}-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0186] To a stirred solution of 5-(oxan-2-yloxy)pent-2-yn-1-ol (Synthesized using procedure described in Org. Biomol. Chem., 2011, 9, 8000-8002; 100 mg, 0.543 mmol), 8-(4- fluorophenyl)-7-methyl-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (180 mg, 0.652 mmol) and PPh3 (285 mg, 1.09 mmol) in THF (2 mL) was added DIAD (220 mg, 1.09 mmol) dropwise at 0 °C under N2. The resulting mixture was stirred for 2 h at 65 °C under N2. The resulting mixture was diluted with water (5 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in ACN (3 mL). The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.05% FA), 20% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (31 mg, 13%) as a white solid. LCMS (ES, m / z): [M-H]- =441. Step 2: 8-(4-fluorophenyl)-2-[(5-hydroxypent-2-yn-1-yl)sulfanyl]-7-methyl-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0187] A solution of 8-(4-fluorophenyl)-7-methyl-2-{[5-(oxan-2-yloxy)pent-2-yn-1- yl]sulfanyl}-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (31 mg, 0.070 mmol) and 2N hydrogen chloride (2 mL) was stirred at RT for 2h. The residue was neutralized to pH 7 with saturated NaHCO3 (aq.). The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 33% B to 45% B in 7 min, 45% B; Wave Length: 254 / 220 nm; RT1(min): 6.38) to afford the title compound (4.5 mg, 18%) as a white solid. LCMS (ES, m / z): [M+H]+=359. 1H NMR (300 MHz, DMSO-d6) δ 12.9 (s,1H), 7.84-.76 (m, 2H), 7.30-7.24 (m, 2H), 4.80 (s, 1H), 3.99 (t, J = 2.4 Hz, 2H), 3.45 (m, 2H), 2.45 (s, 3H), 2.38 – 2.27 (m, 2H). Example 153 - 2-[(4-fluorobut-2-yn-1-yl)sulfanyl]-8-(4-fluorophenyl)-7-methyl-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 8-(4-fluorophenyl)-2-[(4-hydroxybut-2-yn-1-yl)sulfanyl]-7-methyl-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0188] To a stirred mixture of 8-(4-fluorophenyl)-7-methyl-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (200 mg, 3.62 mmol) and butynediol (93 mg, 5.4 mmol) in THF (4 mL) were added PPh3 (380 mg, 7.24 mmol) at RT. To the mixture was added DIAD (292 mg, 7.24 mmol) dropwise at 0 °C under N2. The resulting mixture was stirred for an additional 2 h at RT. The resulting mixture was concentrated under reduced pressure. To the above mixture was added water (5 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, ACN in water, 10% to 40% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (90 mg, 36%) as an off-white solid. LCMS (ES, m / z): [M+H]+=345. Step 2: 8-(4-fluorophenyl)-2-[(4-hydroxybut-2-yn-1-yl)sulfanyl]-3-[(4- methoxyphenyl)methyl]-7-methylpyrazolo[1,5-a][1,3,5]triazin-4-one

[0189] To a stirred solution of 8-(4-fluorophenyl)-2-[(4-hydroxybut-2-yn-1-yl)sulfanyl]-7- methyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (350 mg, 1.02 mmol) in DMF (7 mL) were added TEA (134 mg, 1.32 mmol) and 4-methoxybenzyl chloride (175 mg, 1.12 mmol) in portions at RT. The resulting mixture was stirred for 2 h at 100 °C. To the mixture was added water (10 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, ACN in water, 30% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (103 mg, 22%) as a yellow solid. LCMS (ES, m / z): [M+H]+=465. Step 3: 2-[(4-fluorobut-2-yn-1-yl)sulfanyl]-8-(4-fluorophenyl)-3-[(4- methoxyphenyl)methyl]-7-methylpyrazolo[1,5-a][1,3,5]triazin-4-one

[0190] To a stirred solution of 8-(4-fluorophenyl)-2-[(4-hydroxybut-2-yn-1-yl)sulfanyl]-3- [(4-methoxyphenyl)methyl]-7-methylpyrazolo[1,5-a][1,3,5]triazin-4-one (106 mg, 0.228 mmol) in DCM (2 mL) was added DAST (110 mg, 0.684 mmol) dropwise at -78°C under N2. The resulting mixture was stirred overnight at RT under N2. The reaction was quenched with sat. aq. sodium bicarbonate at 0 °C. The resulting mixture was extracted with DCM (3 x 3 mL). The combined organic layers were washed with brine (2 x 3 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, ACN in water, 35% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (33 mg, 31%) as a yellow oil. LCMS (ES, m / z): [M+H]+=467. Step 4: 2-[(4-fluorobut-2-yn-1-yl)sulfanyl]-8-(4-fluorophenyl)-7-methyl-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0191] To a stirred solution of 2-[(4-fluorobut-2-yn-1-yl)sulfanyl]-8-(4-fluorophenyl)-3-[(4- methoxyphenyl)methyl]-7-methylpyrazolo[1,5-a][1,3,5]triazin-4-one (33 mg, 0.071 mmol) in TFA (1 mL) at RT. The resulting mixture was stirred for 4 h at 70 °C. The resulting mixture was concentrated under reduced pressure. To the above mixture was added THF (3 mL). The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm to afford crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 45% B to 59% B in 7 min, 59% B; Wave Length: 254 / 220 nm; RT1(min): 5.55) to afford the title compound (3.6 mg, 15%) as an off-white solid. LCMS (ES, m / z): [M+H]+=347.1H NMR (300 MHz, DMSO-d6) δ 7.78 (dd, J = 8.6, 5.6 Hz, 2H), 7.26 (t, J = 8.8 Hz, 2H), 5.25-5.00 (d, J = 47.1 Hz, 2H), 4.11 (d, J = 7.4 Hz, 2H), 2.45 (s, 3H). Example 154 - 8-(4-fluorophenyl)-7-(hydroxymethyl)-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: ethyl 5-amino-4-bromo-1H-pyrazole-3-carboxylate

[0192] To a stirred solution of ethyl 5-amino-1H-pyrazole-3-carboxylate (5.0 g, 32 mmol) in ACN (50 mL) was added NBS (6.31 g, 35.5 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford the title compound (6.0 g, 80%) as a brown oil. LCMS (ES, m / z): [M+H]+=234. Step 2: (5-amino-4-bromo-1H-pyrazol-3-yl)methanol

[0193] To a stirred solution of ethyl 5-amino-4-bromo-1H-pyrazole-3-carboxylate (6.0 g, 34 mmol) in THF (100 mL) was added LiBH4 (20.5 mL, 41 mmol, 2M in THF) dropwise at 0 °C under N2. The resulting mixture was stirred overnight at 60 °C under N2. The mixture was allowed to cool down to RT. The reaction was quenched with sat. NH4Cl (aq.) at 0 °C. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford (the title compound (3.6 g, 73%) as a brown oil. LCMS (ES, m / z): [M+H]+=192. Step 3: [5-amino-4-(4-fluorophenyl)-1H-pyrazol-3-yl]methanol

[0194] To a stirred solution of (5-amino-4-bromo-1H-pyrazol-3-yl)methanol (600 mg, 3.13 mmol) in dioxane (6 mL) and water (0.6 mL) was added Pd(dtbpf)Cl2 (204 mg, 0.313 mmol) and KHCO3(626 mg, 6.25 mmol) and 4-fluorophenylboronic acid (874 mg, 6.25 mmol) at RT under N2. The resulting mixture was stirred overnight at 85 °C under N2. The mixture was allowed to cool down to RT. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions (column, C18; mobile phase A: water (0.1% NH3.H2O), mobile phase B: ACN, 5% to 50% gradient in 10 min; detector, UV 254 nm) to afford the title compound (150 mg, 23.08%) as an orange solid. LCMS (ES, m / z): [M+H]+=208. Step 4: ethyl N-{[4-(4-fluorophenyl)-5-(hydroxymethyl)-2H-pyrazol-3- yl]carbamothioyl}carbamate

[0195] To a stirred solution of [5-amino-4-(4-fluorophenyl)-1H-pyrazol-3-yl]methanol (180 mg, 0.869 mmol) in DMF (2 mL) was added ethyl N-carbothioylcarbamate (125 mg, 0.956 mmol) at RT under N2. The resulting mixture was stirred for 2 h at RT under N2. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (200 mg, 68%) as an orange solid. LCMS (ES, m / z): [M+H]+=339. Step 5: 8-(4-fluorophenyl)-7-(hydroxymethyl)-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0196] To a stirred solution of ethyl N-{[4-(4-fluorophenyl)-5-(hydroxymethyl)-2H-pyrazol- 3-yl]carbamothioyl}carbamate (200 mg, 0.591 mmol) in EtOH (4 mL) was added sodium ethoxide (121 mg, 1.77 mmol) in portions at 0 °C under N2. The resulting mixture was stirred for 2 h at 80 °C under N2. The mixture was allowed to cool down to RT. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (5 mL). The mixture was acidified to pH 5 with conc. HCl. The precipitated solids were collected by filtration and washed with water (2 x 2 mL). The resulting solid was dried under vacuum to afford the title compound (150 mg, 87%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=293. Step 6: 8-(4-fluorophenyl)-7-(hydroxymethyl)-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0197] To a stirred solution of 8-(4-fluorophenyl)-7-(hydroxymethyl)-2-sulfanyl-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (50 mg, 0.17 mmol) in DMF (2 mL) was added propargyl bromide (16 mg, 0.14 mmol) and K2CO3(71 mg, 0.51 mmol) at RT under N2. The resulting mixture was stirred for 2 h at RT under N2. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 28% B to 52% B in 7 min, 52% B; Wave Length: 254 / 220 nm; RT1(min): 6.03) to afford the title compound (12.7 mg, 22%) as a white solid. LCMS (ES, m / z): [M+H]+=331. 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 8.06-7.97 (m, 2H), 7.23-7.29 (m, 2H), 5.56 (s, 1H), 4.59 (s, 2H), 4.02 (d, J = 2.6 Hz, 2H), 3.28 (t, J = 2.6 Hz, 1H). Example 155 - 7-(difluoromethyl)-8-(4-fluorophenyl)-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 8-(4-fluorophenyl)-4-oxo-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazine-7-carbaldehyde

[0198] To a stirred solution of 8-(4-fluorophenyl)-7-(hydroxymethyl)-2-(prop-2-yn-1- ylsulfanyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (60 mg, 0.18 mmol) in THF (2 mL) was added Dess-Martin periodinane (231 mg, 0.546 mmol) at RT under N2. The resulting mixture was stirred overnight at RT under N2. The reaction was quenched by the addition of sat. NaHCO3(aq.) (5 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 3 mL). The combined organic layers were washed with brine (2 x 3 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (50 mg, 84%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=329. Step 2: 7-(difluoromethyl)-8-(4-fluorophenyl)-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0199] To a stirred solution of 8-(4-fluorophenyl)-4-oxo-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazine-7-carbaldehyde (50 mg, 0.15 mmol) in DCM (2 mL) was added DAST (74 mg, 0.46 mmol) at -40 °C under N2. The resulting mixture was stirred overnight at RT under N2. The reaction was quenched by the addition of sat. NaHCO3 (aq.) (5 mL) at 0 °C. The resulting mixture was extracted with DCM (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: water (0.05%NH3H2O), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 19% B to 47% B in 7 min, 47% B; Wave Length: 220 nm; RT1(min): 5.63) to afford 7 the title compound (8.4 mg, 16%) as a light yellow solid. LCMS (ES, m / z): [M+H]+ =351. 1H NMR (400 MHz, DMSO-d6) δ 7.84 – 7.75 (m, 2H), 7.31 – 7.19 (m, 2H), 6.97 (t, 1H), 3.89 (d, J = 2.7 Hz, 2H), 3.15 (t, J = 2.6 Hz, 1H). Synthetic Method E Example 156 - 8-(4-fluorophenyl)-7-(morpholin-2-yl)-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0008] Step 1: tert-butyl 2-[2-cyano-2-(4-fluorophenyl)acetyl]morpholine-4-carboxylate

[0200] To a stirred solution of 4-fluoro-benzeneacetonitrile (2.7 g, 20 mmol) in THF (50 mL) was added NaH (1.49 g, 37.2 mmol, 60% in mineral oil) at 0 °C. To the above mixture was added 4-tert-butyl 2-methyl morpholine-2,4-dicarboxylate (7.35 g, 30 mmol) at 0 °C. The resulting mixture was stirred overnight at RT. The reaction was quenched with sat. NH4Cl(aq.) (30 mL) at RT. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford the title compound (6.7 g, 96%) as a yellow oil. LCMS (ES, m / z): [M-Boc+H]+=249. Step 2: tert-butyl 2-[5-amino-4-(4-fluorophenyl)-1H-pyrazol-3-yl]morpholine-4- carboxylate

[0201] To a stirred solution of tert-butyl 2-[2-cyano-2-(4-fluorophenyl)acetyl]morpholine-4- carboxylate (3.48 g, 10 mmol) in EtOH (60 mL) was added hydrazine hydrate (80%) (135 mg, 2.16 mmol) at RT. The resulting mixture was stirred for 2 h at 45 °C. The mixture was allowed to cool down to RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (538 mg, 15%) as a yellow oil. LCMS (ES, m / z): [M-H]- =361. Step 3: tert-butyl 2-[5-({[(ethoxycarbonyl)amino]methanethioyl}amino)-4-(4- fluorophenyl)-1H-pyrazol-3-yl]morpholine-4-carboxylate

[0202] To a stirred solution of tert-butyl 2-[5-amino-4-(4-fluorophenyl)-1H-pyrazol-3- yl]morpholine-4-carboxylate (538 mg, 1.49 mmol) in DMF (3 mL) was added ethyl N- carbothioylcarbamate (136 mg, 1.04 mmol) dropwise at RT. The resulting mixture was stirred for 2 h at RT. The reaction was quenched by the addition of water (50 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (898 mg, overweight) as a yellow oil. LCMS (ES, m / z): [M+H]+494. Step 4: tert-butyl 2-[8-(4-fluorophenyl)-4-oxo-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-7-yl]morpholine-4-carboxylate

[0203] To a stirred solution of tert-butyl 2-[5- ({[(ethoxycarbonyl)amino]methanethioyl}amino)-4-(4-fluorophenyl)-1H-pyrazol-3- yl]morpholine-4-carboxylate (742 mg, 1.50 mmol) in EtOH (7 mL) was added sodium ethoxide (205 mg, 3.01 mmol) in portions, the resulting mixture was refluxed at 80 °C for 1 h. The residue was filtered, the precipitate was dissolved in water (40 mL), acidified to pH 7 with 2N HCl. The resulting mixture was extracted with EA (3 x 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (360 mg, 54%) as a yellow oil. LCMS (ES, m / z): [M+H]+=392. Step 5: tert-butyl 2-[8-(4-fluorophenyl)-4-oxo-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-7-yl]morpholine-4-carboxylate

[0204] To a stirred mixture of tert-butyl 2-[8-(4-fluorophenyl)-4-oxo-2-sulfanyl-3H- pyrazolo[1,5-a][1,3,5]triazin-7-yl]morpholine-4-carboxylate (304 mg, 0.679 mmol) and K2CO3 (282 mg, 2.04 mmol) in DMF (2 mL) was added propargyl bromide (48 mg, 0.41 mmol) dropwise at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was filtered and purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, XBridge Prep C18 OBD Column, 30*50 mm, 5µm 13nm; mobile phase, Water (10 mmol / L NH4HCO3) and ACN (15% ACN up to 40% in 8 min) to afford the title compound (70 mg, 21%) as a white solid. LCMS (ES, m / z): [M-H]- =484. Step 6: 8-(4-fluorophenyl)-7-(morpholin-2-yl)-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0205] A solution of tert-butyl 2-[8-(4-fluorophenyl)-4-oxo-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-7-yl]morpholine-4-carboxylate (44 mg, 0.091 mmol) in DCM (4 mL) and TFA (2 mL) was stirred for 2 h at RT and concentrated under vacuum to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, Sunfire prep C18 column, 30*150 mm, 5µm; mobile phase, Water (0.1%FA) and ACN (17% ACN up to 32% in 7 min) to afford the title compound (13 mg, 37%) as a white solid. LCMS (ES, m / z): [M+H]+=386.1H NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.79 – 7.70 (m, 2H), 7.31 – 7.22 (m, 2H), 4.90 (d, J = 10.4 Hz, 1H), 4.14 – 4.06 (m, 1H), 3.93 (s, 1H), 3.97 – 3.83 (m, 2H), 3.83 – 3.70 (m, 1H), 3.52 (d, J = 12.6 Hz, 1H), 3.35 – 3.28 (m, 2H), 3.09 (t, J = 2.6 Hz, 1H).

[0206] Examples in Table E were synthesized using Synthetic Method E: Table E

[0207] Using Synthetic Method E, racemic 8-(4-chlorophenyl)-7-(morpholin-2-yl)-2-(prop-2- yn-1-ylsulfanyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (500 mg) was synthesized. The enantiomers were separated by SFC with the following conditions (Column: N--(S, S)- Whelk-O1 (Ser#76233), 4.6*100mm, 3.5um; Mobile Phase B: MeOH(20mMNH3); Flow rate: 3 mL / min; Gradient: isocratic 40% B; Wave Length: 220 nm; Injection Volume: 3 mL) to afford enantiomer 1 (130 mg) and enantiomer 2 (60 mg). These were purified individually by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 20% B to 38% B in 8 min; Wave Length: 254 / 220 nm; RT1(min): 6.27) to afford the title compound TFA salt (Example 159, enantiomer 1, 130 mg) as an off white solid. LCMS (ES, m / z): [M+H]+ =402. 1H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 9.21 (s, 1H), 9.02 (s, 1H), 7.79 (d, J = 13.8 Hz, 2H), 7.55 (d, J = 12.4, 11.2 Hz, 2H), 4.95 – 4.93 (m, 1H), 4.13 – 3.91 (m, 4H), 3.62 – 3.51 (m, 3H), 3.30 – 3.26 (m, 3H) and the title compound TFA salt (Example 160, enantiomer 2, 60 mg) as a light yellow solid. LCMS (ES, m / z): [M+H]+ =402. 1H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 9.22 (s, 1H), 9.03 (s, 1H), 7.79 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.3 Hz, 2H), 4.95 – 4.93 (dd, J = 10.8, 2.4 Hz, 1H), , 4.19 – 3.91 (m, 4H), 3.62 – 3.39 (m, 3H), 3.33 – 3.23 (m, 3H). Example 161 - 8-(4-fluorophenyl)-7-(4-methylmorpholin-2-yl)-2-(prop-2-yn-1-ylsul- fanyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0208] To a stirred solution of 8-(4-fluorophenyl)-7-(morpholin-2-yl)-2-(prop-2-yn-1- ylsulfanyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (Example 156, 150 mg, 0.389 mmol) in ACN (3 mL) was added HCHO (95 mg, 1.12 mmol, 37%wt in H2O) at 0 °C under N2. The resulting mixture was stirred for 1 h at RT. To the above mixture was added NaBH3CN (73 mg, 1.2 mmol) at RT. The resulting mixture was stirred for an additional overnight at RT. The resulting mixture was quenched with 2M HCl (0.5 mL). The resulting mixture was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 13% B to 37% B in 7 min; Wave Length: 254 / 220 nm; RT1(min): 5.40) to afford the title compound (19.7 mg, 13%) as a white solid. LCMS (ES, m / z): [M+H]+=400.1H-NMR(400 MHz, DMSO-d6) δ 10.43 (s, 1H), 7.77 – 7.74 (m, 2H), 7.28 – 7.23 (m, 2H), 4.78 (d, J = 10.3 Hz, 1H), 4.10 (d, J = 12.3 Hz, 1H), 3.92 – 3.82 (m, 3H), 3.53 – 3.50 (m, 2H), 3.32 –3.29 (m, 1H), 3.12 (t, J = 2.6 Hz, 1H), 2.99 – 2.98 (m, 1H), 2.77 (s, 3H). Synthetic Method X Example 162 - 8-(4-fluorophenyl)-7-(4-isopropylmorpholin-2-yl)-2-(prop-2-yn-1- ylsulfanyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0209] To a stirred mixture of 8-(4-fluorophenyl)-7-(morpholin-2-yl)-2-(prop-2-yn-1- ylsulfanyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (Example 156, 50 mg, 0.13 mmol) and K2CO3 (54 mg, 0.39 mmol) in DMF (2 mL) was added 2-iodopropane (26.5 mg, 0.156 mmol) at RT. The resulting mixture was stirred overnight at 65 °C. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 2 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 10% to 80% gradient in 10 min; detector, UV 254 nm to afford crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: X Bridge Shield RP18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: water (0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 19% B to 40% B in 7 min; Wave Length: 220 nm; RT1(min): 5.91) to afford the title compound (5.4 mg, 10%) as an off-white solid. LCMS (ES, m / z): [M+H]+=428.1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.76 – 7.72 (m, 2H), 7.29 – 7.25 (m, 2H), 4.90 (d, J = 10.3 Hz, 1H), 4.17(d, J = 12.5 Hz, 1H), 3.95 – 3.87 (m, 3H), 3.58 – 3.50 (m, 2H), 3.44 – 3.35 (m, 2H), 3.13 (sept, J = 6.8 Hz, 1H), 3.12 – 3.11 (m, 1H), 1.25 (d, J = 6.5 Hz, 6H).

[0210] Examples in Table X were synthesized using Synthetic Method X: Table X Synthetic Method F Examples 165 and 166 - 8-(4-fluorophenyl)-7-[oxolan-3-yl]-2-(prop-2-yn-1-ylsulfanyl)- 3H-pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 2-(4-fluorophenyl)-3-oxo-3-(oxolan-3-yl)propanenitrile

[0211] To a stirred solution of 4-fluoro-benzeneacetonitrile (2.0 g, 15 mmol) in THF (20 mL) was added NaH (0.71 g, 30 mmol, 60% in mineral oil) at 0 °C under N2. The resulting mixture was stirred for 30 min at 0 °C under N2. To the above mixture was added methyl oxolane-3-carboxylate (3.85 g, 29.6 mmol) at 0 °C. The resulting mixture was stirred for an additional overnight at RT. The mixture was acidified to pH 6 with 2N HCl (aq.). The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8:1) to afford the title compound (2.74 g, 79%) as a yellow oil. LCMS (ES, m / z): [M-H]- =232. Step 2: 4-(4-fluorophenyl)-5-(oxolan-3-yl)-2H-pyrazol-3-amine

[0212] To a stirred solution of 2-(4-fluorophenyl)-3-oxo-3-(oxolan-3-yl)propanenitrile (14 g, 60 mmol) in EtOH (31 ml) was added hydrazine hydrate (7.51 g, 120 mmol, 80%wt) at RT. The resulting mixture was stirred overnight at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (100 mL). The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, ACN in water (0.05% NH3H2O), 30% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (1.13 g, 8%) as a yellow solid. LCMS (ES, m / z): [M+H]+=248. Step 3: ethyl N-{[4-(4-fluorophenyl)-5-(oxolan-3-yl)-2H-pyrazol-3- yl]carbamothioyl}carbamate

[0213] To a stirred solution of 4-(4-fluorophenyl)-5-(oxolan-3-yl)-2H-pyrazol-3-amine (1.0 g, 4.0 mmol) in DMF (10 mL) was added ethyl N-carbothioylcarbamate (530 mg, 4.04 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The mixture was poured into water (30 mL) at 0 °C. The precipitated solids were collected by filtration and washed with water (2 x 10 mL). The solid was dried under vacuum. This resulted in the title compound (1.2 g, 78%) as a yellow solid. LCMS (ES, m / z): [M+H]+ =379. Step 4: 8-(4-fluorophenyl)-7-(oxolan-3-yl)-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4- one

[0214] To a stirred solution of ethyl N-{[4-(4-fluorophenyl)-5-(oxolan-3-yl)-2H-pyrazol-3- yl]carbamothioyl}carbamate (1.2 g, 3.2 mmol)in EtOH (12 mL) was added sodium ethoxide (432 mg, 6.34 mmol) at RT. The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The mixture was acidified to pH 6 with 2N HCl (aq.). The precipitated solids were collected by filtration and washed with water (2 x 5 mL). The solid was dried under vacuum. This resulted in the title compound (1.08 g, 87%) as a yellow solid. LCMS (ES, m / z): [M+H]+ =333. Step 5: 8-(4-fluorophenyl)-7-[oxolan-3-yl]-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (Enantiomer 1 = Example 165; Enantiomer 2 = Example 166)

[0215] To a stirred solution of 8-(4-fluorophenyl)-7-(oxolan-3-yl)-2-sulfanyl-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (1.08 g, 3.25 mmol) in DMF (11 mL) were added K2CO3 (1.35 g, 9.75 mmol) and propargyl bromide (0.31 g, 2.6 mmol) in portions at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was filtered, the filter cake was washed with DMF (3 x 2 mL). The filtrate was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, ACN in water, 30% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in 8-(4-fluorophenyl)-7-(oxolan-3-yl)-2-(prop-2- yn-1-ylsulfanyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (540 mg) as a yellow solid. The product was purified by SFC with the following conditions: (Column: CHIRALPAK IG, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: IPA--HPLC; Flow rate: 60 mL / min; Gradient: isocratic 35% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 206 nm; RT1(min): 7.22; RT2(min): 9.35; Sample Solvent: MeOH: DCM=1: 1-- HPLC; Injection Volume: 1.6 mL; Number Of Runs: 14) gave 2 separate enantiomer that were further purified by prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 19% B to 45% B in 8 min, 45% B; Wave Length: 220 nm; RT1(min): 6.18) to afford the title compound (Enantiomer 1: 206 mg, 17%) LCMS (ES, m / z): [M+H]+= 371.1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 7.74 – 7.64 (m, 2H), 7.34 – 7.23 (m, 2H), 4.08 – 3.99 (m, 1H), 3.97 (d, J = 2.7 Hz, 2H), 3.87 (td, J = 8.1, 5.6 Hz, 1H), 3.83 – 3.70 (m, 3H), 3.27 (t, J = 2.6 Hz, 1H), 2.31 – 2.11 (m, 2H) and the title compound (Enantiomer 2: 208 mg, 17%) as an off-white solid. LCMS (ES, m / z): [M+H]+= 371.1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 7.74 – 7.64 (m, 2H), 7.34 – 7.23 (m, 2H), 4.08 – 3.99 (m, 1H), 3.97 (d, J = 2.7 Hz, 2H), 3.87 (td, J = 8.1, 5.6 Hz, 1H), 3.83 – 3.70 (m, 3H), 3.27 (t, J = 2.6 Hz, 1H), 2.31 – 2.11 (m, 2H).

[0216] Examples in Table F were synthesized using Synthetic Method F: Table F

[0009] Examples 173 and 174 - 8-(4-fluorophenyl)-7-[oxan-2-yl]-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 2-(4-fluorophenyl)-3-(oxan-2-yl)-3-oxopropanenitrile

[0217] A solution of 4-fluoro-benzeneacetonitrile (51 g, 377 mmol) in THF (500 mL) was treated with NaH (18.1 g, 755 mmol) for 30 min at 0 °C under N2 followed by the addition of methyl oxane-2-carboxylate (65.3 g, 453 mmol) at 0 °C. The resulting mixture was stirred overnight at RT. The mixture was acidified to pH 6 with 2N HCl. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9:1) to afford the title compound (90 g, 96%) as a yellow oil. LCMS (ES, m / z): [M+H]+=248. Step 2: 4-(4-fluorophenyl)-5-(oxan-2-yl)-2H-pyrazol-3-amine

[0218] To a stirred solution of 2-(4-fluorophenyl)-3-(oxan-2-yl)-3-oxopropanenitrile (92 g, 372 mmol) in EtOH (900 mL) was added 80% hydrazine hydrate (23.3 g, 465 mmol) and TFA (42.4 g, 372 mmol) at RT. The resulting mixture was stirred for 2 h at 60 °C. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude title compound was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+=262. Step 3: ethyl N-{[4-(4-fluorophenyl)-5-(oxan-2-yl)-2H-pyrazol-3- yl]carbamothioyl}carbamate

[0219] To a stirred solution of 4-(4-fluorophenyl)-5-(oxan-2-yl)-2H-pyrazol-3-amine (150 g, 574 mmol) in DMF (500 mL) was added ethyl N-carbothioylcarbamate (75.3 g, 574 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The product was precipitated by the addition of water / ice(4 L). The precipitated solids were collected by filtration, washed with water (4 x 100 mL) and dried under reduced. This resulted in the title compound (200 g, 89%) as a yellow solid. LCMS (ES, m / z): [M+H]+=393. Step 4: 8-(4-fluorophenyl)-7-(oxan-2-yl)-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4- one

[0220] To a stirred solution of ethyl N-{[4-(4-fluorophenyl)-5-(oxan-2-yl)-2H-pyrazol-3- yl]carbamothioyl}carbamate (200 g, 510 mmol) in EtOH (1.3 L) was added sodium ethoxide (104 g, 1529 mmol) at RT. The resulting mixture was stirred for 3h at 80 °C. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in water (500 mL). The mixture was acidified to pH 6 with 2N HCl. The precipitated solids were collected by filtration and washed with water (2 x 40 mL). This resulted in the title compound (110 g, 62%) as a yellow solid. LCMS (ES, m / z): [M+H]+=347. Step 5: 8-(4-fluorophenyl)-7-(oxan-2-yl)-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (Example 173 and Example 174)

[0221] To a stirred solution of 8-(4-fluorophenyl)-7-(oxan-2-yl)-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (25 g, 72 mmol) in DMF (250 mL) were added K2CO3(29.9 g, 217 mmol) and propargyl bromide (6.87 g, 57.7 mmol) in portions at RT. The resulting mixture was stirred for 2h at RT. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with water (2 x 100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford the title compound as a yellow solid. The racemic mixture was purified by SFC with the following conditions (Column: NB_ASA CHIRALPAK IG_2, 5*30cm, 10um; Mobile Phase A: CO2, Mobile Phase B: MeOH--HPLC; Flow rate: 200 mL / min; Gradient: isocratic 55% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 290 nm; RT1(min): 4.04; RT2(min): 6.28; Sample Solvent: MeOH: DCM=1: 2; Injection Volume: 6.5 mL; Number Of Runs: 26) to afford enantiomer 1 (6.5 g) and enantiomer 2 (8.0 g) as light yellow solids. Enantiomer 1 (Example 173) was further purified by trituration with ACN (20 mL) to yield the title compound (5.6 g, 20%) as an off-white solid. LCMS (ES, m / z): [M+H]+ =385. 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 7.89 – 7.79 (m, 2H), 7.33 – 7.22 (m, 2H), 4.50 (dd, J = 11.1, 2.3 Hz, 1H), 3.99 (m, 3H), 3.57 (m, 1H), 3.27 (t, J = 2.6 Hz, 1H), 2.12 – 2.01 (m, 1H), 1.90 (m, 1H), 1.73 (br d, J = 13.2 Hz, 1H), 1.54-1.64 (m, 3H). Enantiomer 2 (Example 174) was purified by reverse flash chromatography with the following conditions (column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 50% to 70% gradient in 5 min; detector, UV 254 nm), concentrated under reduced pressure and further purified by trituration with ACN (12 mL) to yield the title compound (5.65 g, 20%) as an off-white solid. LCMS (ES, m / z): [M+H]+ =385. 1H NMR (400 MHz, DMSO-d6) δ 13.06 (s, 1H), 7.89 – 7.79 (m, 2H), 7.33 – 7.22 (m, 2H), 4.50 (dd, J = 11.1, 2.3 Hz, 1H), 3.99 (m, 3H), 3.57 (m, 1H), 3.27 (t, J = 2.6 Hz, 1H), 2.12 – 2.01 (m, 1H), 1.90 (m, 1H), 1.73 (br d, J = 13.2 Hz, 1H), 1.54-1.64 (m, 3H). Example 175 - 7-methyl-8-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}-2-(prop-2-yn-1- ylsulfanyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0010] Step 1: 8-(4-hydroxyphenyl)-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-7-methylpyrazolo[1,5-a][1,3,5]triazin-4-one

[0222] To a stirred mixture of 8-bromo-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-7-methylpyrazolo[1,5-a][1,3,5]triazin-4-one (3.0 g, 6.0 mmol) and 4-hydroxyphenylboronic acid (0.99 g, 7.2 mmol) in dioxane (45 mL) and WATER (15 mL) were added K2CO3 (2.48 g, 17.9 mmol) and Pd(Dtbpf)Cl2 (0.39 g, 0.60 mmol, CAS:95408-45-0) at RT. The resulting mixture was stirred overnight at 80 °C under N2. The residue was dissolved in water (60 mL). The resulting mixture was extracted with EA (3 x 60 mL). The combined organic layers were washed with water (2 x 60 mL) and brine (60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford 8-(4-hydroxyphenyl)-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-7-methylpyrazolo[1,5-a][1,3,5]triazin-4-one (1.68 g, 55%) as a brown solid. LCMS 229-1: (ES, m / z): [M+H]+=515. Step 2: 3-[(4-methoxyphenyl)methyl]-2-{[(4-methoxyphenyl)methyl]sulfanyl}-7-methyl- 8-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}pyrazolo[1,5-a][1,3,5]triazin-4-one

[0223] To a stirred solution of 8-(4-hydroxyphenyl)-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-7-methylpyrazolo[1,5-a][1,3,5]triazin-4-one (800 mg, 1.56 mmo) and 1-methyl-4-piperidinol (1.79 g, 15.6 mmol) in THF (16 mL) was added PPh3 (816 mg, 3.11 mmol) at RT. To the above mixture was added DIAD (629 mg, 3.11 mmol) dropwise at 0 °C under N2. The resulting mixture was stirred for an additional overnight at RT under N2. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% NH3.H2O), 30% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (915 mg, 96%) as a yellow solid. LCMS (ES, m / z): [M+H]+=612. Step 3: 7-methyl-8-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0224] A solution of 3-[(4-methoxyphenyl)methyl]-2-{[(4-methoxyphenyl)methyl]sulfanyl}- 7-methyl-8-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}pyrazolo[1,5-a][1,3,5]triazin-4-one (915 mg, 1.50 mmol) in TFA (5 mL) was stirred for 2 h at 70 °C . The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 30% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (547 mg, 98%) as a brown solid. LCMS (ES, m / z): [M+H]+=372. Step 4: 7-methyl-8-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}-2-(prop-2-yn-1-ylsulfanyl)- 3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0225] To a stirred solution of 7-methyl-8-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}-2- sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (547 mg, 1.47 mmol) in DMF (10 mL) were added K2CO3 (611 mg, 4.42 mmol) and propargyl bromide (88 mg, 0.74 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The resulting mixture was filtered, the filter cake was washed with DMF (3 x 1 mL). The filtrate was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 20% to 50% gradient in 10 min; detector, UV 254 nm to afford crude product. The crude product was purified by Prep- HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 12% B to 29% B in 7 min, 29% B; Wave Length: 254 / 220 nm; RT1(min): 4.05) to afford the title compound (41 mg, 7%) as a white solid. LCMS (ES, m / z): [M+H]+=410. 1H NMR (400 MHz, DMSO-d6) δ 7.67 – 7.65 (m, 2H), 7.04 – 7.02 (m, 2H), 4.61 (m, 1H), 3.89 (d, J = 2.7 Hz, 2H), 3.27 (m, 2H), 3.10 – 3.09 (m, 3H), 2.75 (s, 3H), 2.39 (s, 3H), 2.08 (t, J = 11.7 Hz, 2H), 1.92 (t, J = 11.7 Hz, 2H). Synthetic Method M Example 176 - 8-(4-chlorophenyl)-7-isopropyl-2-(prop-2-yn-1-yloxy)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0011] Step 1: 2-(4-chlorophenyl)-4-methyl-3-oxopentanenitrile

[0226] To a stirred solution of 4-chlorobenzyl cyanide (2.74 g, 18.1 mmol) in THF (30 mL) was added NaH (1.24 g, 51.65 mmol, 60% in mineral oil) at 0 °C under N2. The resulting mixture was stirred for 30 min at 0 °C under N2. To the above mixture was added ethyl isobutyrate (3.00 g, 25.8 mmol) at 0 °C. The resulting mixture was stirred for an additional overnight at RT. The mixture was acidified to pH 6 with 2M HCl (aq.), diluted with water (20 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9:1) to afford the title compound (3.66 g, 64%) as a yellow liquid. LCMS (ES, m / z): [M-H]- =220. Step 2: 3-nitro-4-phenylpyridine

[0227] To a stirred solution of 2-(4-chlorophenyl)-4-methyl-3-oxopentanenitrile (3.56 g, 16.1 mmol) in EtOH (35 mL) were added hydrazine hydrate (2.01 g, 32.1 mmol, 80% wt) and TFA (3.66 g, 32.1 mmol) at RT. The resulting mixture was stirred for 2 h at 80 °C and concentrated under reduced pressure. The residue was dissolved in THF (10 mL) and purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% NH3.H2O), 30% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (3.57 g, 94%) as yellow oil. LCMS (ES, m / z): [M+H]+=236. Step 3: ethyl N-{[4-(4-chlorophenyl)-5-isopropyl-2H-pyrazol-3- yl]carbamothioyl}carbamate

[0228] To a stirred solution of 4-(4-chlorophenyl)-5-isopropyl-2H-pyrazol-3-amine (1.9 g, 8.1 mmol) in DMF (19 mL) was added ethyl N-carbothioylcarbamate (1.06 g, 8.06 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was poured into ice / water (40 mL). The precipitated solids were collected by filtration, washed with water (3 x 5 mL) and dried under vacuum. This resulted in the title compound (2.5 g, 85%) as a yellow solid. LCMS (ES, m / z): [M+H]+=367. Step 4: 3-nitro-4-phenylpyridine

[0229] To a stirred solution of ethyl N-{[4-(4-chlorophenyl)-5-isopropyl-2H-pyrazol-3- yl]carbamothioyl}carbamate (2.4 g, 6.5 mmol) in EtOH (24 mL) was added EtONa (891 mg, 13.1 mmol) at RT. The resulting mixture was stirred for 2 h at 80 °C and concentrated under reduced pressure. The residue was dissolved in water (20 mL) and acidified to pH 6 with 2M HCl (aq.). The precipitated solids were collected by filtration, washed with water (3 x 5 mL) and dried under vacuum. This resulted in the title compound (2.0 g, 95%) as a yellow solid. LCMS (ES, m / z): [M+H]+=321. Step 5: 8-(4-chlorophenyl)-7-isopropyl-2-(methylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0230] To a stirred solution of 8-(4-chlorophenyl)-7-isopropyl-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (2.1 g, 6.55 mmol) in DMF (21 mL) were added K2CO3 (2.71 g, 19.6 mmol) and MeI (1.02 g, 7.20 mmol) at room temperature. The resulting mixture was stirred for 1 h at room temperature. The residue was dissolved in water (20 mL). The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL) and brine (2 x 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:2) to afford the title compound (900 mg, 41.06%) as an off-white solid. LCMS (ES, m / z): [M+H]+=335. Step 6: 8-(4-chlorophenyl)-7-isopropyl-2-methanesulfonyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one and 8-(4-chlorophenyl)-7-isopropyl-2- (methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one

[0231] To a stirred solution of 8-(4-chlorophenyl)-7-isopropyl-2-(methylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (990 mg, 2.96 mmol) in DCM (20 mL) was added mCPBA (1020 mg, 5.91 mmol) in portions at 0 ℃. The resulting mixture was stirred for 15 min at 0 oC and stirred for 2 h at RT, and then concentrated under reduced pressure. The residue was dissolved in THF (10 mL). The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 30% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in the mixture of the title compounds (880 mg, 81%) as an off-white solid. LCMS (ES, m / z): [M+H]+=351 and 367. Step 7: 8-(4-chlorophenyl)-7-isopropyl-2-(prop-2-yn-1-yloxy)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0232] To a stirred solution of propargyl alcohol (60 mg, 1.06 mmol) in DMF (2.6 mL) was added NaH (28 mg, 0.71 mmol, 60% in mineral oil) in portions at 0oC. The resulting mixture was stirred for 30 min at 0 ℃. To the above mixture was added the mixture of 8-(4- chlorophenyl)-7-isopropyl-2-methanesulfonyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one and 8- (4-chlorophenyl)-7-isopropyl-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (130 mg, 0.354 mmol) at RT. The resulting mixture was stirred for an additional 2 h at RT. The mixture was acidified to pH 7 with 1 M HCl (aq.). The mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 30% to 80% gradient in 10 min; detector, UV 254 nm to afford the crude product. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 45% B to 70% B in 8 min, 70% B; Wave Length: 254 / 220 nm; RT1(min): 7.05) to afford the title compound (53 mg, 43%) as a white solid. LCMS (ES, m / z): [M+H]+= 343.1H NMR (400 MHz, DMSO- d6) δ 12.85 (s, 1H), 7.60 – 7.58 (m, 2H), 7.51 – 7.49 (m, 2H), 5.03 – 5.02 (d, J = 2.5 Hz, 2H), 3.73 – 3.71 (t, J = 2.4 Hz, 1H), 3.33 – 3.24 (m, 1H), 1.24 – 1.16 (d, J = 6.8 Hz, 6H). Examples in Table M were synthesized using Synthetic Method M: Table M

[0012] Example 239 - 7-(difluoromethyl)-2-(prop-2-yn-1-yloxy)-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0013] Step 1: 4,4-difluoro-3-oxo-2-(3,4,5-trifluorophenyl)butanenitrile

[0233] To a stirred solution of 2-(3,4,5-trifluorophenyl)acetonitrile (5.0 g, 29 mmol) in THF (50 mL) was added NaH (3.51 g, 87. 7 mmol, 60% in mineral oil) in portions at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. To the above mixture was added ethyl 2,2- difluoroacetate (10.9 g, 87.7 mmol) at 0 °C. The resulting mixture was stirred for an additional 4 h at RT. The mixture was acidified to pH 5 with 2N HCl (2 ml). The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (5:1) to afford the title compound rile (4.9 g, 67%) as a pink solid. LCMS (ES, m / z): =248. Step 2: 5-(difluoromethyl)-4-(3,4,5-trifluorophenyl)-2H-pyrazol-3-amine

[0234] To a stirred solution of 4,4-difluoro-3-oxo-2-(3,4,5-trifluorophenyl)butanenitrile (3.0 g, 12 mmol) in EtOH (30 mL) were added hydrazine hydrate (3.01 g, 48.2 mmol, 80%wt.) and TFA (8.24 g, 72.2 mmol) at RT. The resulting mixture was stirred for 3 h at 60 °C. The resulting mixture was concentrated under reduced pressure. To the above mixture was added water (100 ml). The resulting mixture was extracted with EA (3 x 120 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (3.4 g, overweight) as a yellow oil was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+ =264. Step 3: ethyl N-{[5-(difluoromethyl)-4-(3,4,5-trifluorophenyl)-2H-pyrazol-3- yl]carbamothioyl}carbamate

[0235] To a stirred solution of 5-(difluoromethyl)-4-(3,4,5-trifluorophenyl)-2H-pyrazol-3- amine (12 mmol) in DMF (34 mL) was added ethyl N-carbothioylcarbamate (1.69 g, 12.9mmol) at RT. The resulting mixture was stirred for 1 h at RT. To the above mixture was added ice water (400 ml). The precipitated solids were collected by filtration and washed with water (2 x 20 mL). This resulted in the title compound (5.0 g, overweight) as an off- white solid was used in the next step directly without further purification. LCMS (ES, m / z): [M-H]- =393. Step 4: 7-(difluoromethyl)-2-sulfanyl-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0236] A solution of ethyl N-{[5-(difluoromethyl)-4-(3,4,5-trifluorophenyl)-2H-pyrazol-3- yl]carbamothioyl}carbamate (12 mmol) in 2 N NaOH (100 mL) was stirred for 1 h at RT. The mixture was acidified to pH 6 with 2 N HCl (25 ml). The precipitated solids were collected by filtration and washed with water (2 x 10 mL). This resulted in the title compound (3.0 g, 72% (3 steps)) as an off-white solid was used in the next step directly without further purification. LCMS (ES, m / z): [M-H]- =347. Step 5: 7-(difluoromethyl)-2-(methylsulfanyl)-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0237] To a stirred solution of 7-(difluoromethyl)-2-sulfanyl-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (470 mg, 1.35 mmol) in DMF (5 mL) were added K2CO3 (560 mg, 4.05 mmol) and methyl iodide (172 mg, 1.22 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with water (20 mL) and brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 55% to 75% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (480 mg, 98%) as a white solid. LCMS (ES, m / z): [M+H]+=363. Step 6: 7-(difluoromethyl)-2-methanesulfonyl-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0238] To a stirred solution of 7-(difluoromethyl)-2-(methylsulfanyl)-8-(3,4,5- trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (480 mg, 1.33 mmol) in DCM (5 mL) was added mCPBA (457 mg, 2.65 mmol) at 0 °C. The resulting mixture was stirred for 15 min at 0 °C and 2 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 50% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (400 mg, 77%) as a white solid. LCMS (ES, m / z): [M-H]-=393. Step 7: 7-(difluoromethyl)-2-(prop-2-yn-1-yloxy)-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0239] To a stirred solution of propargyl alcohol (43 mg, 0.76 mmol) in DMF (4 mL) was added NaH (61mg, 1.5 mmol, 60% in mineral oil) at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. To the above mixture was added 7-(difluoromethyl)-2-methanesulfonyl-8- (3,4,5-trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (200 mg, 0.507 mmol) at 0 °C. The resulting mixture was stirred for an additional 2 h at RT. The mixture was acidified to pH 5 with 2N HCl (0.4 ml). The resulting mixture was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 70% to 90% gradient in 10 min; detector, UV 254 nm. The crude product (180 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 43% B to 58% B in 9 min; Wave Length: 254 / 220 nm; RT1(min): 7.80) to afford the title compound (87.6 mg, 47%) as a white solid. LCMS (ES, m / z): [M+H]+=371. 1H NMR (400 MHz, DMSO-d6) δ 13.37 (s, 1H), 7.64 - 7.59 (m, 2H), 7.35 (t, J = 53.0 Hz, 1H), 5.12 (d, J = 2.4 Hz, 2H), 3.78 (t, J = 2.4 Hz, 1H), 2.09 (s, 1H). Example 240 - 2-(2,2-difluoroethoxy)-7-(difluoromethyl)-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0240] To a stirred solution of 2,2-difluoroethanol (31 mg, 0.381mmol) in DMF (2 mL) was added NaH (30mg, 0.76 mmol, 60% in mineral oil) at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. To the above mixture was added 7-(difluoromethyl)-2-methanesulfonyl-8- (3,4,5-trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (100 mg, 0.254 mmol) at 0 °C. The resulting mixture was stirred for an additional 2 h at RT. The mixture was acidified to pH 5 with 2N HCl (0.4 ml). The resulting mixture was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 70% to 90% gradient in 10 min; detector, UV 254 nm. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.05%TFA), Mobile Phase B: MeOH--HPLC; Flow rate: 60 mL / min mL / min; Gradient: 63%83% B in 10 min; Wave Length: 254nm / 220nm nm; RT1(min): 10.07) to afford the title compound (67.3 mg, 67%) as a white solid. LCMS (ES, m / z): [M+H]+=397. 1H NMR (400 MHz, DMSO-d6) δ 13.57 (s, 1H), 7.57 – 7.53 (m, 2H), 7.35 (t, J = 53.0 Hz, 1H), 6.45 (tt, J = 53.7, 3.0 Hz, 1H), 4.74 (td, J = 15.2, 3.0 Hz, 2H). Example 241 - 8-{4-[2-(dimethylamino)ethoxy]phenyl}-7-methoxy-2-(prop-2-yn-1- ylsulfanyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 2-(5-hydroxy-2H-pyrazol-3-yl)isoindole-1,3-dione

[0241] To a stirred solution of 5-amino-1H-pyrazol-3-ol (10.0 g, 101 mmol) in acetic acid (100 mL) was added phthalic anhydride (17.9 g, 121 mmol) at RT under N2. The resulting mixture was stirred for 2 h at 130 °C. The mixture was allowed to cool down to RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with EA (50 mL). The resulting solid was dried under vacuum to afford the title compound (20 g, 87%) as an orange solid. LCMS (ES, m / z): [M+H]+ =230. Step 2: 2-(5-methoxy-2H-pyrazol-3-yl)isoindole-1,3-dione

[0242] To a stirred mixture of 2-(5-hydroxy-2H-pyrazol-3-yl)isoindole-1,3-dione (20 g, 87 mmol) and methanol (20 mL) in THF (200 mL) was added PPh3(34.3 g, 131 mmol) at 0 °C under N2. The resulting mixture was stirred for 5 min at 0 °C. To the above mixture was added DIAD (51.9 mL, 262 mmol) at 0 °C. The resulting mixture was stirred for an additional overnight at 60 °C. The mixture was allowed to cool down to RT. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford the title compound (10 g, 48%) as an orange solid. LCMS (ES, m / z): [M+H]+ =244. Step 3: 2-(4-bromo-5-methoxy-2H-pyrazol-3-yl)isoindole-1,3-dione

[0243] To a stirred solution of 2-(5-methoxy-2H-pyrazol-3-yl)isoindole-1,3-dione (4.0 g, 16 mmol) in ACN (40 mL) were added NBS (2.93 g, 16.4 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2 the title compound (3.0 g, 57%) as a brown solid. LCMS (ES, m / z): [M+H]+=322. Step 4: 4-bromo-5-methoxy-2H-pyrazol-3-amine

[0244] To a stirred solution of 2-(4-bromo-5-methoxy-2H-pyrazol-3-yl)isoindole-1,3-dione (3.0 g, 9.3 mmol) in EtOH (30 mL) was added hydrazine hydrate (80%) (2.91 g, 46.6 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% NH3-H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (500 mg, 28%) as a yellow solid. LCMS (ES, m / z): [M+H]+=192. Step 5: ethyl N-[(4-bromo-5-methoxy-2H-pyrazol-3-yl)carbamothioyl]carbamate

[0245] To a stirred solution of 4-bromo-5-methoxy-2H-pyrazol-3-amine (500 mg, 2.60 mmol) in DMF (10 mL) was added ethyl N-carbothioylcarbamate (376 mg, 2.86 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (640 mg, 76%) as an orange solid. LCMS (ES, m / z): [M+H]+=323. Step 6: 8-bromo-7-methoxy-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0246] To a stirred solution of ethyl N-[(4-bromo-5-methoxy-2H-pyrazol-3- yl)carbamothioyl]carbamate (640 mg, 1.98 mmol) in EtOH (12 mL) was added EtONa (270 mg, 3.96 mmol) at 0 °C. The resulting mixture was stirred for 1 h at 80 °C. The mixture was allowed to cool down to RT. The resulting mixture was diluted with water (10 mL). The mixture was acidified to pH 5 with 2M HCl. The precipitated solids were collected by filtration and washed with water (3 x 1 mL). The resulting solid was dried under vacuum to afford the title compound (450 mg, 82%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=277. Step 7: 8-bromo-7-methoxy-2-{[(4-methoxyphenyl)methyl]sulfanyl}-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0247] To a stirred mixture of 8-bromo-7-methoxy-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (450 mg, 1.62 mmol) and K2CO3 (673 mg, 4.87 mmol) in DMF (10 mL) were added PMBCl (763 mg, 4.87 mmol) at RT. The resulting mixture was stirred overnight at RT. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (520 mg, 81%) as a brown solid. LCMS (ES, m / z): [M+H]- =395. Step 8: 8-bromo-7-methoxy-3-(methoxymethyl)-2-{[(4- methoxyphenyl)methyl]sulfanyl}pyrazolo[1,5-a][1,3,5]triazin-4-one

[0248] To a stirred solution of 8-bromo-7-methoxy-2-{[(4-methoxyphenyl)methyl]sulfanyl}- 3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (520 mg, 1.31 mmol) in DMF (10 mL) was added NaH (60% in mineral oil, 63 mg, 2.6 mmol) in portions at 0 °C. The resulting mixture was stirred for 20 min at 0 °C. To the above mixture was added bromomethyl methyl ether (649 mg, 5.24 mmol) at 0 °C. The resulting mixture was stirred for an additional overnight at RT. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 10% to 100% gradient in 10 min; detector, UV 254 nm to afford the title compound (300 mg, 52%) as a yellow solid. LCMS (ES, m / z): [M+H]+=441. Step 9: dimethyl({2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenoxy]ethyl})amine

[0249] To a stirred mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (1.0 g, 4.5 mmol), dimethylaminoethanol (0.61 g, 6.8 mmol)and PPh3 (1.79 g, 6.82 mmol) in THF (20 mL) was added DIAD (1.38 g, 6.82 mmol) at 0 °C under N2. The resulting mixture was stirred overnight at RT under N2. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford the title compound (600 mg, 45%) as a white solid. LCMS (ES, m / z): [M+H]+=292. Step 10: 8-{4-[2-(dimethylamino)ethoxy]phenyl}-7-methoxy-3-(methoxymethyl)-2-{[(4- methoxyphenyl)methyl]sulfanyl}pyrazolo[1,5-a][1,3,5]triazin-4-one

[0250] To a stirred mixture of 8-bromo-7-methoxy-3-(methoxymethyl)-2-{[(4- methoxyphenyl)methyl]sulfanyl}pyrazolo[1,5-a][1,3,5]triazin-4-one (300 mg, 0.680 mmol) and dimethyl({2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]ethyl})amine (396 mg, 1.36 mmol) in dioxane (6 mL) and WATER (0.6 mL) was added KHCO3 (136 mg, 1.36 mmol) and Pd(dtbpf)Cl2(67 mg, 0.10 mmol) at RT under N2. The resulting mixture was stirred overnight at 80 °C under N2. The mixture was allowed to cool down to RT. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (110 mg, 20%) as a white solid. LCMS (ES, m / z): [M+H]+=526. Step 11: 8-{4-[2-(dimethylamino)ethoxy]phenyl}-7-methoxy-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0251] A solution of 8-{4-[2-(dimethylamino)ethoxy]phenyl}-7-methoxy-3- (methoxymethyl)-2-{[(4-methoxyphenyl)methyl]sulfanyl}pyrazolo[1,5-a][1,3,5]triazin-4-one (110 mg, 0.209 mmol) in TFA (2 mL) was stirred for 1 h at 70 °C under N2. The mixture was allowed to cool down to RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (20 mg, 26%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=362. Step 12: 8-{4-[2-(dimethylamino)ethoxy]phenyl}-7-methoxy-2-(prop-2-yn-1-ylsulfanyl)- 3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0252] To a stirred mixture of 8-{4-[2-(dimethylamino)ethoxy]phenyl}-7-methoxy-2- sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (20 mg, 0.055 mmol) and K2CO3 (23 mg, 0.17 mmol) in DMF (1 mL) was added propargyl bromide (4.0 mg, 0.033 mmol) dropwise at RT under N2. The resulting mixture was stirred for 1 h at RT under N2. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 8% B to 35% B in 7 min, 35% B; Wave Length: 254 / 220 nm; RT1(min): 4.40) to afford the title compound (1.1 mg, 5%) as a white solid. LCMS (ES, m / z): [M+H]+=400. 1H NMR (300 MHz, DMSO-d6) 8.02 (d, J = 8.2 Hz, 2H), 6.95 (d, J = 8.3 Hz, 2H), 4.18 (t, 2H), 4.06 (s, 3H), 3.96 (s, 2H), 3.09 (m, 3H), 2.53 (s, 6H). Example 242 - 8-(4-fluorophenyl)-7-(1H-imidazol-4-yl)-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: ethyl 1-{[2-(trimethylsilyl)ethoxy]methyl}imidazole-4-carboxylate

[0253] To a stirred solution of ethyl 1H-imidazole-4-carboxylate (500 mg, 3.57 mmol) in DMF (10 mL) was added NaH (285 mg, 7.14 mmol, 60% in mineral oil) in portions at 0 °C. The resulting mixture was stirred for 1 h at 0 °C. To the above mixture was added SEMCl (1.78 g, 10.7 mmol) at RT. The resulting mixture was stirred for an additional 2 h at RT. The reaction was quenched with Water / Ice(20 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL) and brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 30% to 80% gradient in 10 min; detector, UV 254 nm to afford the title compound (705 mg, 73%) as a red oil. LCMS (ES, m / z): [M+H]+=271. Step 2: 2-(4-fluorophenyl)-3-oxo-3-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-4- yl)propanenitrile

[0254] To a stirred solution of 4-fluoro-benzeneacetonitrile, (240 mg, 1.78 mmol) in THF (12 mL) was added NaH (178 mg, 4.44 mmol, 60% in mineral oil) in portions at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. To the above mixture was added ethyl 1-{[2- (trimethylsilyl)ethoxy]methyl}imidazole-4-carboxylate (600 mg, 2.22 mmol) at RT. The resulting mixture was stirred for an additional overnight at RT. The reaction was quenched by the addition of water (20 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 40% to 90% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (320 mg, 40%) as a yellow solid. LCMS (ES, m / z): [M+H]+=360. Step 3: 4-(4-fluorophenyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-4-yl)-2H- pyrazol-3-amine

[0255] To a stirred solution of 2-(4-fluorophenyl)-3-oxo-3-(1-{[2- (trimethylsilyl)ethoxy]methyl}imidazol-4-yl)propanenitrile (270 mg, 0.751 mmol) in EtOH (5.4 mL) were added hydrazine hydrate (75 mg, 0.22 mmol, 80% wt.) and TFA (171 mg, 1.50 mmol) at RT. The resulting mixture was stirred overnight at 40 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 30% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (211 mg, 75%) as a brown solid. LCMS (ES, m / z): [M+H]+=374. Step 4: ethyl N-{[4-(4-fluorophenyl)-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-4- yl)-2H-pyrazol-3-yl]carbamothioyl}carbamate

[0256] To a stirred solution of 4-(4-fluorophenyl)-5-(1-{[2- (trimethylsilyl)ethoxy]methyl}imidazol-4-yl)-2H-pyrazol-3-amine (160 mg, 0.428 mmol) in DMF (3.2 mL) was added ethyl N-carbothioylcarbamate (56 mg, 0.43 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (3 x 15 mL). The combined organic layers were washed with water (2 x 15 mL) and brine (2 x 15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (160 mg, 74%) as a brown oil. The crude resulting was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+= 505. Step 5: 8-(4-fluorophenyl)-2-sulfanyl-7-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-4- yl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0257] A solution of ethyl N-{[4-(4-fluorophenyl)-5-(1-{[2- (trimethylsilyl)ethoxy]methyl}imidazol-4-yl)-2H-pyrazol-3-yl]carbamothioyl}carbamate (160 mg, 0.317 mmol) in 2M NaOH (3 mL) was stirred for 30 min at RT. The residue was acidified to pH 6 with 2M HCl (2 ml) and purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 30% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (105 mg, 72%) as a brown solid. LCMS (ES, m / z): [M+H]+=459. Step 6: 8-(4-fluorophenyl)-2-(prop-2-yn-1-ylsulfanyl)-7-(1-{[2- (trimethylsilyl)ethoxy]methyl}imidazol-4-yl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0258] To a stirred solution of 8-(4-fluorophenyl)-2-sulfanyl-7-(1-{[2- (trimethylsilyl)ethoxy]methyl}imidazol-4-yl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (105 mg, 0.229 mmol) in DMF (2.8 mL) were added K2CO3 (95 mg, 0.69 mmol) and propargyl bromide (24 mg, 0.21 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was filtered, the filter cake was washed with DMF (3 x 1 mL). The filtrate was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 30% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (84 mg, 74%) as a brown solid. LCMS (ES, m / z): [M+H]+=497. Step 7: 8-(4-fluorophenyl)-7-(1H-imidazol-4-yl)-2-(prop-2-yn-1-ylsulfanyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0259] A stirred solutionof 8-(4-fluorophenyl)-2-(prop-2-yn-1-ylsulfanyl)-7-(1-{[2- (trimethylsilyl)ethoxy]methyl}imidazol-4-yl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (64 mg, 0.13 mmol) in HCl (4.5 mL, 4M in 1,4-dioxane) was stirred overnight at RT. The reaction was quenched with water at 0 °C. The resulting mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 15% B to 33% B in 7 min, 33% B; Wave Length: 254 / 220 nm; RT1(min): 5.40) to afford the title compound (14 mg, 30%) as a white solid. LCMS (ES, m / z): [M+H]+=367. 13.21 (s, 1H), 8.05 (s, 1H), 7.67 – 7.63 (m, 2H), 7.27 (s, 1H), 7.22 – 7.17 (m, 2H), 3.93 (d, J = 2.6 Hz, 2H), 3.19 (t, J = 2.7 Hz, 1H). Example 243 - 2-(2,2-difluoroethoxy)-7-isopropyl-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 4-methyl-3-oxo-2-(3,4,5-trifluorophenyl) pentanenitrile

[0260] A solution of 2-(3,4,5-trifluorophenyl)acetonitrile (1.00 g, 5.84 mmol) in THF (20 mL) was treated with NaH (0.28 g, 12 mmol, 60% in mineral oil) for 30 min at 0 °C followed by the addition of isobutyryl chloride (1.87 g, 17.5 mmol) dropwise at 0 °C. The resulting mixture was stirred for 1 h at RT. The reaction was quenched by the addition of water (20 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with water (30 mL), dried over anhydrous Na2SO4. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford the title compound (1.00 g, 71%) as a yellow solid. LCMS (ES, m / z): [M-H]- =240. Step 2: 5-isopropyl-4-(3,4,5-trifluorophenyl)-2H-pyrazol-3-amine

[0261] A solution of 4-methyl-3-oxo-2-(3,4,5-trifluorophenyl) pentanenitrile (1.10 g, 4.56 mmol), hydrazine hydrate (0.46 g, 9.12 mmol) and TFA (0.7 mL, 9.12 mmol) in EtOH (20 mL) was stirred for 2 h at 65 °C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (1.20 g, overweight) as a yellow oil. LCMS (ES, m / z): [M+H]+=257. Step 3: ethyl N-{[5-isopropyl-4-(3,4,5-trifluorophenyl)-2H-pyrazol-3- yl]carbamothioyl}carbamate

[0262] A solution of 5-isopropyl-4-(3,4,5-trifluorophenyl)-2H-pyrazol-3-amine (4.56 mmol) and ethyl N-carbothioylcarbamate (0.45 g, 3.45 mmol) in DMF (20 mL) was stirred for 2 h at RT. The reaction was quenched by the addition of Water / Ice (50 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with water (50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (1.50 g, 85%) as a yellow oil that solidified on standing. LCMS (ES, m / z): [M+H]+=387 Step 4: 7-isopropyl-2-sulfanyl-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin- 4-one

[0263] A solution of ethyl N-{[5-isopropyl-4-(3,4,5-trifluorophenyl)-2H-pyrazol-3- yl]carbamothioyl}carbamate (4.50 g, 11.7 mmol) in NaOH (aq. 2M, 50 mL) was stirred for 2 h at RT. The mixture was acidified to pH 6 with conc. HCl. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (1.90 g, 48%) as a yellow solid. LCMS (ES, m / z): [M+H]+=341. Step 5: 7-isopropyl-2-(methylsulfanyl)-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0264] A solution of 7-isopropyl-2-sulfanyl-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (400 mg, 1.17 mmol), MeI (100 mg, 0.70 mmol) and K2CO3 (487 mg, 3.52 mmol) in DMF (4 mL) was stirred for 2 h at RT. The reaction was quenched with water (10 mL) at RT. The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (200 mg, 48%) as an off-white solid. LCMS (ES, m / z): [M+H]+=355. Step 6: 7-isopropyl-2-methanesulfonyl-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one and 7-isopropyl-2-methanesulfinyl-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0265] A solution of 7-isopropyl-2-(methylsulfanyl)-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (300 mg, 0.85 mmol) and mCPBA (292 mg, 1.69 mmol) in DCM (6 mL) was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL). The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in the title compounds (150 mg, 46%) as an off-white solid. LCMS (ES, m / z): [M+H]+=371 and 387. Step 7: 2-(2,2-difluoroethoxy)-7-isopropyl-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0266] To a stirred solution of 2,2-difluoroethanol (32 mg, 0.39 mmol) in DMF (1 mL) was added NaH (9.0 mg, 0.39 mmol, 60% in mineral oil) in portions at 0oC. The resulting mixture was stirred for 30 min at 0 ℃. To the above mixture was added the mixture of 7- isopropyl-2-methanesulfonyl-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4- one and 7-isopropyl-2-methanesulfinyl-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (50 mg, 0.13 mmol, Mw: 386) at RT. The resulting mixture was stirred for 1 h at RT. The mixture was acidified to pH 7 with 1 M HCl (aq.). The mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 30% to 80% gradient in 10 min; detector, UV 254 nm to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150 mm 5 μm, n; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 45% B to 57% B in 10 min, 57% B; Wave Length: 254 / 220 nm; RT1(min): 9.28) to afford the title compound (25 mg, 50%) as a white solid. LCMS (ES, m / z): [M+H]+=389.1H NMR (400 MHz, DMSO-d6) δ 13.07 (s, 1H), 7.49 – 7.45 (m, 2H), 6.42 (tt, J = 53.8, 3.1 Hz, 1H), 4.66 (td, J = 15.1, 3.1 Hz, 2H), 3.32 (sept, J = 6.8 Hz, 1H), 1.22 (d, J = 6.8 Hz, 6H). Example 244 - 7-isopropyl-2-(prop-2-yn-1-yloxy)-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0267] To a stirred solution of propargyl alcohol (30 mg, 0.54 mmol) in DMF (1 mL) was added NaH (13 mg, 0.54 mmol, 60% in mineral oil) in portions at 0oC. The resulting mixture was stirred for 30 min at 0oC. To the above mixture was added the mixture of 7-isopropyl-2- methanesulfonyl-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one and 7- isopropyl-2-methanesulfinyl-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (70 mg, 0.18 mmol, Mw: 386) at RT. The resulting mixture was stirred for 1 h at RT. The mixture was acidified to pH 7 with 1 M HCl (aq.). The mixture was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 30% to 80% gradient in 10 min; detector, UV 254 nm to afford the crude product. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150 mm 5 μm, n; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 44% B to 57% B in 10 min, 57% B; Wave Length: 254 / 220 nm; RT1(min): 9.02) to afford the title compound (20 mg, 30%) as an off-white solid. LCMS (ES, m / z): [M+H]+=363.1H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 7.52 – 7.48 (m, 2H), 5.05 (d, J = 2.5 Hz, 2H), 3.73 (t, J = 2.5 Hz, 1H), 3.34 (sept, J = 6.7 Hz, 1H), 1.21 (d, J = 6.8 Hz, 6H). Synthetic Method Q Example 245 - 2-(2,2-difluoroethoxy)-7-methyl-8-[4-(pyrrolidine-1-carbonyl)phenyl]- 3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0014] Step 1: 3-[(4-methoxyphenyl)methyl]-2-{[(4-methoxyphenyl)methyl]sulfanyl}-7-methyl- 8-[4-(pyrrolidine-1-carbonyl)phenyl]pyrazolo[1,5-a][1,3,5]triazin-4-one

[0268] To a mixture of 8-bromo-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-7-methylpyrazolo[1,5-a][1,3,5]triazin-4-one (1.0 g, 2.0 mmol) and 4-(pyrrolidine-1-carbonyl)phenylboronic acid (655 mg, 2.99 mmol) in dioxane (8 mL) and water (2 mL) were added K2CO3 (827 mg, 5.98 mmol) and Pd(dtbpf)Cl2 (130 mg, 0.199 mmol). The resulting mixture was stirred overnight at 80 °C. To the above mixture was added water (20 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 10% to 80% gradient in 10 min; detector, UV 254 nm to afford the title compound (470 mg, 40%) as an off-white solid. LCMS (ES, m / z): [M+H]+=596. Step 2: 7-methyl-8-[4-(pyrrolidine-1-carbonyl)phenyl]-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0269] A solution of 3-[(4-methoxyphenyl)methyl]-2-{[(4-methoxyphenyl)methyl]sulfanyl}- 7-methyl-8-[4-(pyrrolidine-1-carbonyl)phenyl]pyrazolo[1,5-a][1,3,5]triazin-4-one (530 mg, 0.890 mmol) in TFA (4 mL) was stirred for 4 h at 72 °C. The resulting mixture was concentrated under vacuum to afford the title compound (560 mg, overweight). The resulting mixture was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+=356. Step 3: 7-methyl-2-(methylsulfanyl)-8-[4-(pyrrolidine-1-carbonyl)phenyl]-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0270] To a stirred mixture of 7-methyl-8-[4-(pyrrolidine-1-carbonyl)phenyl]-2-sulfanyl-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (0.890 mmol) and K2CO3 (350 mg, 2.53 mmol) in DMF (3 mL) was added methyl iodide (66 mg, 0.46 mmol) at RT .The resulting mixture was stirred overnight at RT. The resulting mixture was filtered, the filtrate was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 40% to 50% gradient in 5 min; detector, UV 254 nm to afford the title compound (113 mg, 34%) as a white solid. LCMS (ES, m / z): [M+H]+=370. Step 4: 2-methanesulfonyl-7-methyl-8-[4-(pyrrolidine-1-carbonyl)phenyl]-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0271] To a stirred solution of 7-methyl-2-(methylsulfanyl)-8-[4-(pyrrolidine-1- carbonyl)phenyl]-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (112 mg, 0.303 mmol) in DCM (3 mL) was added mCPBA (105 mg, 0.606 mmol) at 0 °C. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water, ACN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (105 mg, 86%) as a white solid. LCMS (ES, m / z): [M+H]+=402. Step 5: -(2,2-difluoroethoxy)-7-methyl-8-[4-(pyrrolidine-1-carbonyl)phenyl]-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0272] To a stirred solution of 2-methanesulfonyl-7-methyl-8-[4-(pyrrolidine-1- carbonyl)phenyl]-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (105 mg, 0.262 mmol) in DMF (2 mL) was added NaH (31 mg, 0.79 mmol, 60% in mineral oil) at 0 °C. To the above mixture was added 2,2-difluoroethanol (64 mg, 0.79 mmol) at 0 °C. The resulting mixture was stirred for an additional 3 h at RT. To the above mixture was added water (10 mL). The mixture was acidified to pH 5 with 2N HCl (0.5 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-01)): Column, Sunfire prep C18 column, 30*150 mm, 5µm; mobile phase, water (0.1% FA) and ACN (25% ACN up to 45% in 7 min) to afford the title compound (66 mg, 63%) as a white solid. LCMS (ES, m / z): [M+H]+=404.1H NMR (400 MHz, DMSO-d6): δ 13.00 (s, 1H), 7.71 (d, J = 8.1 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 6.43 (tt, J = 53.9, 3.2 Hz, 1H), 4.70 (td, J = 15.1, 3.2 Hz, 2H), 3.48 (m, 4H), 2.48 (s, 3H), 1.90 – 1.81 (m, 4H). Examples in Table Q were synthesized using Synthetic Method Q: Table Q

[0015] Example 273 - 2-ethoxy-7-isopropyl-8-[3-fluoro-4-cyano-5-ethoxyphenyl]-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0273] 2-Methanesulfonyl-7-isopropyl-8-(4-cyano-3,5-difluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (synthesized via Synthetic Method Q) was treated with sodium ethoxide (5 eq) in DMF to afford the title compound as a white solid. LCMS (ES, m / z): [M+H]+= 386. 1H-NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.33 – 7.22 (m, 2H), 4.43 (q, J = 7.1 Hz, 2H), 4.28 (q, J = 7.0 Hz, 2H), 3.41 (sept, J = 6.8 Hz, 1H), 1.41 (t, J = 7.0 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.27 (d, J = 6.8 Hz, 6H). Synthetic Method W Example 272 - 8-(4-chlorophenyl)-4-oxo-2-(prop-2-yn-1-yloxy)-3H-pyrazolo[1,5- a][1,3,5]triazine-7-carbonitrile Step 1: ethyl 5-amino-4-bromo-1H-pyrazole-3-carboxylate

[0274] To a stirred solution of ethyl 5-amino-1H-pyrazole-3-carboxylate (15 g, 97 mmol) in ACN (100 mL) was added NBS (18.9 g, 106 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. This resulted in the title compound (34.5 g, overweight) as a dark green solid. LCMS (ES, m / z): [M+H]+=236. Step 2: (5-amino-4-bromo-1H-pyrazol-3-yl)methanol

[0275] To a stirred solution of (5-amino-4-bromo-1H-pyrazol-3-yl)methanol (97 mmol) in THF (300 mL) was added LiBH4(75 mL, 150 mmol, 2M in THF) dropwise at 0oC. The resulting mixture was stirred overnight at 60oC under N2. The reaction was quenched by the addition of sat. NH4Cl (80 mL) at 0oC. The resulting mixture was extracted with DCM (3 x 100 mL), the combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (7:1) to afford the title compound (17.3 g, 93% (2 steps)) as a dark green oil. LCMS (ES, m / z): No mass ion. Step 3: ethyl N-{[4-bromo-5-(hydroxymethyl)-2H-pyrazol-3- yl]carbamothioyl}carbamate

[0276] To a stirred solution of (5-amino-4-bromo-1H-pyrazol-3-yl)methanol (17.3 g, 90.1 mmol) in DMF (90 mL) was added ethyl N-carbothioylcarbamate (11.9 g, 90.7 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The resulting mixture was poured into ice / cold water (180 mL). The precipitated solids were collected by filtration and washed with water (3 x 20 mL). The solid was dried under vacuum. This resulted in the title compound (15.8 g, 54%) as a yellow solid. LCMS (ES, m / z): [M+H]+=323, 325. Step 4: 8-bromo-7-(hydroxymethyl)-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0277] To a stirred solution of ethyl N-{[4-bromo-5-(hydroxymethyl)-2H-pyrazol-3- yl]carbamothioyl}carbamate (15.8 g, 48.9 mmol) in EtOH (158 mL) was added sodium ethanoxide (33.4 g, 98.3 mmol, 20% wt in EtOH) at RT. The resulting mixture was stirred for 2 h at 80oC. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The mixture was acidified to pH 6 with 2M HCl (40 mL) at 0oC. The precipitated solids were collected by filtration and washed with water (3 x 20 mL). The solid was dried under vacuum. This resulted in the title compound (11.5 g, 85%) as a brown yellow solid. LCMS (ES, m / z): [M-H]- =277. Step 5: 8-bromo-7-(hydroxymethyl)-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}pyrazolo[1,5-a][1,3,5]triazin-4-one

[0278] To a stirred solution of 8-bromo-7-(hydroxymethyl)-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (5.0 g, 18 mmol) in DMF (50 mL) were added K2CO3(7.5 g, 54 mmol) and 4-methoxybenzyl chloride (8.5 g, 54 mmol) at RT. The resulting mixture was stirred overnight at 50oC. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with water (3 x 30 mL) and brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford the title compound (3.7 g, 40%) as a brown yellow solid. LCMS (ES, m / z): [M+H]+=517. Step 6: 8-(4-chlorophenyl)-7-(hydroxymethyl)-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}pyrazolo[1,5-a][1,3,5]triazin-4-one

[0279] To a stirred mixture of 8-bromo-7-(hydroxymethyl)-3-[(4-methoxyphenyl)methyl]-2- {[(4-methoxyphenyl)methyl]sulfanyl}pyrazolo[1,5-a][1,3,5]triazin-4-one (3.2 g, 6.2 mmol) and p-chloro-benzeneboronic acid, (1.93 g, 12.4 mmol) in dioxane (30 mL) were added WATER (3 mL), K2CO3(1.71 g, 12.4 mmol) and Pd(Dtbpf)Cl2(414 mg, 0.635 mmol) at RT. The resulting mixture was stirred overnight at 80oC under N2. The resulting mixture was filtered, the filter cake was washed with 1,4-dioxane (3 x 5 mL). The resulting mixture was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 50% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (1.3 g, 38%) as a brown yellow oil. LCMS (ES, m / z): [M+H]+=549. Step 7: 8-(4-chlorophenyl)-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-4-oxopyrazolo[1,5-a][1,3,5]triazine-7-carbaldehyde

[0280] To a stirred solution of 8-(4-chlorophenyl)-7-(hydroxymethyl)-3-[(4- methoxyphenyl)methyl]-2-{[(4-methoxyphenyl)methyl]sulfanyl}pyrazolo[1,5- a][1,3,5]triazin-4-one (1.3 g, 2.4 mmol) in THF (13 mL) was added Dess-Martin periodinane (4.2 g, 9.9 mmol) at 0oC. The resulting mixture was stirred for 2 h at RT. The reaction was quenched by the addition of sat. sodium bicarbonate (30 mL) at 0oC. The resulting mixture was extracted with EA (3 x 30 mL), the combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford the title compound (1.08 g, 83%) as a yellow solid. LCMS (ES, m / z): [M+H]+=547. Step 8: 8-(4-chlorophenyl)-7-[(1E)-(hydroxyimino)methyl]-3-[(4- methoxyphenyl)methyl]-2-{[(4-methoxyphenyl)methyl]sulfanyl}pyrazolo[1,5- a][1,3,5]triazin-4-one

[0281] A mixture of AcOH (10.8 mL) and water (3.6 mL) were added 8-(4-chlorophenyl)-3- [(4-methoxyphenyl)methyl]-2-{[(4-methoxyphenyl)methyl]sulfanyl}-4-oxopyrazolo[1,5- a][1,3,5]triazine-7-carbaldehyde (1.08 g, 1.97 mmol) and NH2OH.HCl (274 mg, 3.95 mmol) at RT. The resulting mixture was stirred for 4 h at 60oC. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 30% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (882 mg, 79%) as a yellow solid. LCMS (ES, m / z): [M+H]+=562. Step 9: 8-(4-chlorophenyl)-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-4-oxopyrazolo[1,5-a][1,3,5]triazine-7-carbonitrile

[0282] To a stirred solution of 8-(4-chlorophenyl)-7-[(1E)-(hydroxyimino)methyl]-3-[(4- methoxyphenyl)methyl]-2-{[(4-methoxyphenyl)methyl]sulfanyl}pyrazolo[1,5- a][1,3,5]triazin-4-one (882 mg, 1.57 mmol) in DCM (89 mL) were added TEA (1.6 g, 16 mmol) and TFAA (3.3 g, 16 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The resulting mixture was diluted with water (30 mL). The resulting mixture was extracted with DCM (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (1.5 g, overweight) as a yellow solid. LCMS (ES, m / z): [M+H]+=544. Step 10: 8-(4-chlorophenyl)-4-oxo-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazine-7- carbonitrile

[0283] A solution of 8-(4-chlorophenyl)-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-4-oxopyrazolo[1,5-a][1,3,5]triazine-7-carbonitrile (1.5 g, 2.8 mmol) in TFA (15 mL) was stirred for 2 h at 80oC. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 50% to 70% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (547 mg, 65%) as a brown yellow oil. LCMS (ES, m / z): [M-H]- =302. Step 11: 8-(4-chlorophenyl)-2-(methylsulfanyl)-4-oxo-3H-pyrazolo[1,5-a][1,3,5]triazine- 7-carbonitrile

[0284] To a stirred solution of 8-(4-chlorophenyl)-4-oxo-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazine-7-carbonitrile (491 mg, 1.62 mmol) in DMF (10 mL) were added K2CO3 (670 mg, 4.85 mmol) and MeI (229 mg, 1.62 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with water (2 x 20 mL) and brine (2 x 20 mL), dried over anhydrous Na2SO4. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 40% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (168 mg, 33%) as a yellow solid. LCMS (ES, m / z): [M-H]- =316. Step 12: 8-(4-chlorophenyl)-2-methanesulfonyl-4-oxo-3H-pyrazolo[1,5-a][1,3,5]triazine- 7-carbonitrile and 8-(4-chlorophenyl)-2-(methylsulfinyl)-4-oxo-3,4-dihydropyrazolo[1,5- a][1,3,5]triazine-7-carbonitrile

[0285] To a stirred solution of 8-(4-chlorophenyl)-2-(methylsulfanyl)-4-oxo-3H- pyrazolo[1,5-a][1,3,5]triazine-7-carbonitrile (168 mg, 0.529 mmol) in DCM (4 mL) was added mCPBA (183 mg, 1.061 mmol) at 0oC. The resulting mixture was stirred for 15 min at 0oC and stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 50% to 80% gradient in 10 min; detector, UV 254 nm. This resulted in the title compounds (170 mg, 92%) as a yellow solid. LCMS (ES, m / z): [M-H]- =332 and 348. Step 13: 8-(4-chlorophenyl)-4-oxo-2-(prop-2-yn-1-yloxy)-3H-pyrazolo[1,5- a][1,3,5]triazine-7-carbonitrile

[0286] To a stirred solution of 2,2-difluoroethanol (33.8 mg, 0.412 mmol) in DMF (4 mL) was added NaH (25 mg, 0.62 mmol, 60% in mineral oil) at 0oC. The resulting mixture was stirred for 30 min at 0oC. To the above mixture were added 8-(4-chlorophenyl)-2- methanesulfonyl-4-oxo-3H-pyrazolo[1,5-a][1,3,5]triazine-7-carbonitrile and 8-(4- chlorophenyl)-2-(methylsulfinyl)-4-oxo-3,4-dihydropyrazolo[1,5-a][1,3,5]triazine-7- carbonitrile (72 mg, 0.206 mmol, Mw: 349.0) at RT. The resulting mixture was stirred for an additional 2 h at RT. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with water (2 x 10 mL) and brine (10 mL), dried over anhydrous Na2SO4. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 30% to 80% gradient in 10 min; detector, UV 254 nm to obtained the crude. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 46% B to 57% B in 10 min, 57% B; Wave Length: 254 / 220 nm; RT1(min): 8.30) to afford the title compound (23.8 mg, 27%) as a white solid. LCMS (ES, m / z): [M-H]- =350.1H NMR-371-0: (400 MHz, DMSO-d6) δ 7.90 – 7.88 (m, 2H), 7.62 – 7.60 (m, 2H), 6.58 – 6.31 (tt, J = 53.7, 3.1 Hz, 1H), 4.78 – 4.70 (td, J = 15.2, 3.1 Hz, 2H).

[0287] Examples in Table W were synthesized using Synthetic Method W: Table W Synthetic Method P Examples 276 and 277 - 2-(2,2-difluoroethoxy)-7-[oxan-2-yl]-8-(3,4,5-trifluorophenyl)- 3H-pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 3-(oxan-2-yl)-3-oxo-2-(3,4,5-trifluorophenyl)propanenitrile

[0288] To a stirred solution of 2-(3,4,5-trifluorophenyl)acetonitrile (3.0 g, 18 mmol) in THF (30 mL) was added NaH (1.40 g, 35.1 mmol, 60% in mineral oil) in portions at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. To the above mixture was added methyl oxane-2-carboxylate (7.58 g, 52.6 mmol) at 0 °C. The resulting mixture was stirred overnight at RT. The reaction was quenched by the addition of water (60 mL) at 0 °C. The resulting mixture was extracted with EA (3 x 60 mL). The combined organic layers were washed with brine (2 x 60 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford the title compound (4.5 g, 88%) as a brown oil. LCMS (ES, m / z): [M-H]- =282. Step 2: 5-(oxan-2-yl)-4-(3,4,5-trifluorophenyl)-2H-pyrazol-3-amine

[0289] To a stirred solution of 3-(oxan-2-yl)-3-oxo-2-(3,4,5-trifluorophenyl)propanenitrile (4.5 g, 16 mmol) in EtOH (45 mL) were added hydrazine hydrate (1.99 g, 31.8 mmol, 80%wt.) and TFA (3.6 g, 32 mmol) at RT. The resulting mixture was stirred for 2 h at 80 °C. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (80 mL). The resulting mixture was extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford the title compound (4.6 g, 97%) as a brown oil. The crude product mixture was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+=298. Step 3: ethyl N-{[5-(oxan-2-yl)-4-(3,4,5-trifluorophenyl)-2H-pyrazol-3- yl]carbamothioyl}carbamate

[0290] To a stirred solution of 5-(oxan-2-yl)-4-(3,4,5-trifluorophenyl)-2H-pyrazol-3-amine (4.6 g, 15 mmol) in DMF (46 mL) was added ethyl N-carbothioylcarbamate (2.03 g, 15.5 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The resulting mixture was poured into water at 0 C (80 mL). The precipitated solids were collected by filtration and washed with water (2 x 10 mL). The solid was dried under vacuum. This resulted in the title compound (5.5 g, 83%) as a yellow solid. The crude product was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+=429. Step 4: 7-(oxan-2-yl)-2-sulfanyl-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0291] A solution of ethyl N-{[5-(oxan-2-yl)-4-(3,4,5-trifluorophenyl)-2H-pyrazol-3- yl]carbamothioyl}carbamate (5.5 g, 13 mmol) in 2M NaOH (55 mL) was stirred for 1 h at RT. The mixture was acidified to pH 6 with 2M HCl (25 mL). The precipitated solids were collected by filtration and washed with water (2 x 10 mL). The solid was dried under vacuum. This resulted in the title compound (4.7 g, 96%) as an off-white solid. The crude product was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+=383. Step 5: 2-(methylsulfanyl)-7-(oxan-2-yl)-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0292] To a stirred solution of 7-(oxan-2-yl)-2-sulfanyl-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (4.7 g, 12 mmol) in DMF (47 mL) were added K2CO3 (5.10 g, 36.9 mmol) and MeI (1.40 g, 9.83 mmol) at RT .The resulting mixture was stirred for 1 h at RT. The resulting mixture was poured into ice / water (80 mL). The precipitated solids were collected by filtration and washed with water (2 x 10 mL). The resulting solid was dried under vacuum. This resulted in the title compound (5.4 g, overweight) as an off-white solid. The crude product was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+=397. Step 6: 2-methanesulfonyl-7-(oxan-2-yl)-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0293] To a stirred solution of 2-(methylsulfanyl)-7-(oxan-2-yl)-8-(3,4,5-trifluorophenyl)- 3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (12 mmol) in DCM (54 mL) was added mCPBA (4.70 g, 27.2 mmol) in portions at 0 °C. The resulting mixture was stirred for 15 min at 0 °C and stirred for 2 h at RT, and then concentrated under reduced pressure. The resulting mixture was diluted with water (80 mL). The resulting mixture was extracted with EA (3 x 80 mL). The combined organic layers were washed with brine (2 x 80 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (9 g, overweight) as a yellow solid. The crude product was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+=429. Step 7: 2-(2,2-difluoroethoxy)-7-[oxan-2-yl]-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (enantiomer 1: Example 276, enantiomer 2: Example 277)

[0294] To a stirred solution of 2,2-difluoroethanol (236 mg, 2.88 mmol) in DMF (8 mL) was added NaH (77 mg, 1.9 mmol, 60% in mineral oil) at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. To the above mixture was added 2-methanesulfonyl-7-(1- methoxypropyl)-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (400 mg, 0.961 mmol) at RT. The resulting mixture was stirred for an additional 2 h at RT. The mixture was acidified to pH 7 with 2M HCl (0.5 mL). The resulting mixture was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 50% to 80% gradient in 10 min; detector, UV 254 nm. The racemic mixture (180 mg) was purified by SFC with the following conditions (Column: (S, S)-Whelk-O 15μm Kromasil, 3*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH--HPLC; Flow rate: 100 mL / min; Gradient: isocratic 55% B; Column Temperature(℃): 35; Back Pressure(bar): 100; Wave Length: 210 / 276 nm; RT1(min): 2.8; RT2(min): 4.2; Sample Solvent: MeOH--HPLC; Injection Volume: 1 mL) to afford the title compound with RT1(min): 2.8 (enantiomer 1: 70 mg) and the title compound with RT2(min): 4.2 (enantiomer 2, 90 mg) as a white solid. The enantiomer 1 crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 58% B to 73% B in 8 min; Wave Length: 254 / 220 nm; RT1(min): 5.50) to afford the title compound (enantiomer 1, 28 mg, 7%) as a white solid. LCMS (ES, m / z): [M+H]+=431.1H NMR (400 MHz, DMSO- d6) δ 13.23 (s, 1H), 7.68 – 7.62 (m, 2H), 6.45 (tt, J = 53.9, 3.0 Hz, 1H), 4.71 (tdd, J = 15.2, 4.8, 2.9 Hz, 2H), 4.54 (dd, J = 11.0, 2.3 Hz, 1H), 4.01 (d, J = 11.2 Hz, 1H), 3.65 – 3.54 (m, 1H), 2.09 – 2.06 (qm, 1H), 1.92 – 1.90 (m, 1H), 1.78 – 1.75 (m, 1H), 1.64 – 1.55 m, 3H). The enantiomer 2 crude product (90 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 49% B to 65% B in 8 min; Wave Length: 254 / 220 nm; RT1(min): 7.25) to afford the title compound (49 mg, 12%) as a white solid. LCMS (ES, m / z): [M+H]+=431.1H NMR (400 MHz, DMSO-d6) δ 13.25 (s, 1H), 7.68 – 7.63 (m, 2H), 6.44 (tt, J = 53.8, 3.1 Hz, 1H), 4.72 (tdd, J = 15.2, 4.9, 2.9 Hz, 2H), 4.53 (dd, J = 11.1, 2.3 Hz, 1H), 4.01 (d, J = 11.2 Hz, 1H), 3.62 – 3.56 (m, 1H), 2.09 – 2.01 (m, 1H), 2.00– 1.90 (m, 1H), 1.78 – 1.75 (m, 1H), 1.64 – 1.58 (m, 3H). Examples in Table P were synthesized using Synthetic Method P: Table P

[0016] Example 288 - 8-(4-chlorophenyl)-2-(difluoromethoxy)-7-(oxan-2-yl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0295] 8-(4-chlorophenyl)-2-methanesulfonyl-7-(oxan-2-yl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one was synthesized using Synthetic Method E. Step 1: 8-(4-chlorophenyl)-2-hydroxy-7-(oxan-2-yl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4- one

[0296] To a stirred solution of 8-(4-chlorophenyl)-2-methanesulfonyl-7-(oxan-2-yl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (synthesized using Synthetic Method P; 1.0 g, 2.4 mmol) in dioxane (10 mL) was added 2 M NaOH (5 mL) at RT. The resulting mixture was stirred for 2 h at RT. The mixture was acidified to pH 5 with 2 M HCl (6 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 50% to 90% gradient in 10 min; detector, UV 254 nm. This resulted in the title compound (0.52 g, 62%) as a yellow solid. LCMS (ES, m / z): [M+H]+=347. Step 2: 8-(4-chlorophenyl)-2-(difluoromethoxy)-7-(oxan-2-yl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0297] To a stirred solution of 8-(4-chlorophenyl)-2-hydroxy-7-(oxan-2-yl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (250 mg, 0.721 mmol) in DMF (2 mL) were added ethyl 2-bromo-2,2- difluoroacetate (293 mg, 1.44 mmol) and Cs2CO3 (705 mg, 2.16 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was diluted with water (10 mL). The mixture was acidified to pH 5 with 2 M HCl. The resulting mixture was extracted with EA (3 x 15 mL). The combined organic layers were washed with water (2 x 15 mL) and brine (15 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 50% to 100% gradient in 10 min; detector, UV 254 nm. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 57% B to 74% B in 9 min, 74% B; Wave Length: 254 / 220 nm; RT1(min): 5.23) to afford the title compound (8.7 mg, 3%) as a white solid. LCMS (ES, m / z): [M+H]+= 397. 1H NMR (400 MHz, DMSO-d6) δ 7.72 (t, J = 76.0 Hz, 1H), 7.72 – 7.69 (m, 2H), 7.55 – 7.49 (m, 2H), 4.50 (dd, J = 11.1, 2.2 Hz, 1H), 3.99 – 3.96 (m, 1H), 3.59 – 3.53 (m, 1H), 2.10 – 2.00 (m, 1H), 1.92 – 1.87 (m, 1H), 1.77 – 1.69 (m, 1H), 1.63 – 1.54 (m, 3H).

[0298] Using the same method, Example 289 was synthesized: LCMS (ES, m / z): [M+H]+= 390. 1H NMR (400 MHz, DMSO-d6) δ 8.60 (m, 1H), 8.05 – 8.01 (m, 1H), 7.91 – 7.74 (m, 2H), 7.56 – 7.52 (m, 1H), 7.43 – 7.14 (m, 4H).

[0299] Using the same method, Example 290 was synthesized: LCMS (ES, m / z): [M+H]+= 375. 1H NMR (400 MHz, DMSO-d6) δ 7.72 (t, J = 70.3 Hz, 1H), 7.48 – 7.42 (m, 2H), 3.34 (sept, J = 6.8 Hz, 1H), 1.31 (d, J = 6.7 Hz, 6H). Synthetic Method Z Example 291 - 7-(4-fluorophenyl)-6-methyl-2-(prop-2-yn-1-ylsulfanyl)-3H-imidazo[2,1- f][1,2,4]triazin-4-one

[0017] Step 1: ethyl 4-methyl-1H-imidazole-2-carboxylate

[0300] To a stirred solution of methylglyoxal (10.0 g, 139 mmol, 40% w / w in WATER) in MeOH (100 mL) was added ethyl glyoxylate (14.2 g, 139 mmol, 50% w / w toluene) and NH3- H2O (19.5 g, 555 mmol) at RT. The resulting mixture was stirred overnight at RT. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (3.0 g, 14%) as a purple solid. LCMS (ES, m / z): [M+H]+=155. Step 2: ethyl 1-amino-4-methylimidazole-2-carboxylate

[0301] To a stirred solution of ethyl 4-methyl-1H-imidazole-2-carboxylate (1.80 g, 11.7 mmol) in DMF (20 mL) was added t-BuOK (1.57 g, 14.0 mmol) at RT under N2. The resulting mixture was stirred for 30 min at RT. To the above mixture was added amino 4- nitrobenzoate (4.25 g, 23.4 mmol) at RT. The resulting mixture was stirred overnight at RT. The resulting mixture was diluted with water (50 mL). The mixture was basified to pH 9 with saturated NaHCO3(aq.). The resulting mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (2 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (900 mg, 46%) as a yellow solid. LCMS (ES, m / z): [M+H]+=170. Step 3: ethyl 1-amino-5-bromo-4-methylimidazole-2-carboxylate

[0302] To a stirred solution of ethyl 1-amino-4-methylimidazole-2-carboxylate (400 mg, 2.36 mmol) in ACN (8 mL) was added NBS (463 mg, 2.60 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% NH3.H2O), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (120 mg, 21%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=248. Step 4: ethyl 1-amino-5-(4-fluorophenyl)-4-methylimidazole-2-carboxylate

[0303] To a stirred mixture of ethyl 1-amino-5-bromo-4-methylimidazole-2-carboxylate (200 mg, 0.806 mmol) and 4-fluorophenylboronic acid (226 mg, 1.61 mmol) in dioxane (4 mL) and WATER (0.4 mL) was added Pd(PPh3)4 (93 mg, 0.081 mmol) and K2CO3 (223 mg, 1.61 mmol) at RT under N2. The final reaction mixture was irradiated with microwave radiation for 2 h at 110 °C. The mixture was allowed to cool down to RT. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EA (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (120 mg, 56%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=264. Step 5: ethyl 1-({[(ethoxycarbonyl)amino]methanethioyl}amino)-5-(4-fluorophenyl)-4- methylimidazole-2-carboxylate

[0304] To a stirred solution of ethyl 1-amino-5-(4-fluorophenyl)-4-methylimidazole-2- carboxylate (120 mg, 0.456 mmol) in DMF (2 mL) was added ethyl N-carbothioylcarbamate (66 mg, 0.50 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (130 mg, 72%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=395. Step 6: 7-(4-fluorophenyl)-6-methyl-2-sulfanyl-3H-imidazo[2,1-f][1,2,4]triazin-4-one

[0305] To a stirred solution of ethyl 1-({[(ethoxycarbonyl)amino]methanethioyl}amino)-5- (4-fluorophenyl)-4-methylimidazole-2-carboxylate (130 mg, 0.330 mmol) in water (2 mL) was added NaOH (2 M, 2 mL) at RT. The resulting mixture was stirred for 1 h at 85 °C. The mixture was allowed to cool down to RT. The mixture was acidified to pH 5 with conc. HCl. The precipitated solids were collected by filtration and washed with water (3 x 1 mL). The resulting solid was dried under vacuum to afford the title compound (50 mg, 55%) as a white solid. LCMS (ES, m / z): [M+H]+ =277. Step 7: -(4-fluorophenyl)-6-methyl-2-(prop-2-yn-1-ylsulfanyl)-3H-imidazo[2,1- f][1,2,4]triazin-4-one

[0306] To a stirred mixture of 7-(4-fluorophenyl)-6-methyl-2-sulfanyl-3H-imidazo[2,1- f][1,2,4]triazin-4-one (50 mg, 0.18 mmol) and K2CO3 (50 mg, 0.36 mmol) in DMF (1 mL) was added propargyl bromide (8.6 mg, 0.072 mmol) at RT under N2. The resulting mixture was stirred for 1 h at RT under N2. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EA (3 x 5 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire prep C18 column, 30*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 32% B to 58% B in 7 min, 58% B; Wave Length: 254 / 220 nm; RT1(min): 5.60) to afford the title compound (7 mg, 12%) as a white solid. LCMS (ES, m / z): [M+H]+=315. 1H NMR (400 MHz, DMSO- d6) δ 12.80 (s, 1H), 7.84 – 7.75 (m, 2H), 7.40 – 7.31 (m, 2H), 3.91 (d, J = 2.6 Hz, 2H), 3.28 (t, , J = 2.6 Hz, 1H), 2.39 (s, 3H). Examples in Table Z were synthesized using Synthetic Method Z: Table Z

[0018] Example 296 - 7-(4-chlorophenyl)-2-(2,2-difluoroethoxy)-6-isopropyl-3H-imidazo[2,1- f][1,2,4]triazin-4-one Step 1: 3 ethyl 1-aminoimidazole-2-carboxylate

[0307] To a stirred solution of ethyl 1H-imidazole-2-carboxylate (10 g, 71 mmol) in THF (200 mL) was added NaH (5.71 g, 143 mmol, 60% in mineral oil) in portions at 0 °C. The resulting mixture was stirred for 2 h at RT. To the above mixture was added amino diphenylphosphinate (33.3 g, 143 mmol) at RT. The resulting mixture was stirred for an additional overnight at 65 °C. The mixture was allowed to cool down to RT. The reaction was quenched by the addition of water (30 mL) at 0 °C. The resulting mixture was filtered, the filter cake was washed with THF (3 x 30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (10:1) to afford the title compound (6.0 g, 54%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=156. Step 2: ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate

[0308] To a stirred solution of ethyl 1-aminoimidazole-2-carboxylate (6.0 g, 39 mmol) in THF (120 mL) were added di-tert-butyl dicarbonate (10.1 g, 46.4 mmol) and DMAP (0.94 g, 7.7 mmol) at RT. The resulting mixture was stirred overnight at 65 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford the title compound (3.4 g, 34. %) as a light yellow solid. LCMS (ES, m / z): [M+H]+=256. Step 3: ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate

[0309] To a stirred solution of ethyl 1-[(tert-butoxycarbonyl)amino]imidazole-2-carboxylate (3.0 g, 12 mmol) in ACN (60 mL) was added NBS (1.26 g, 7.05 mmol) in portions at 0 °C. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford the title compound (2.0 g, 51%) as a yellow oil. LCMS (ES, m / z): [M+H]+=334. Step 4: ethyl 1-[(tert-butoxycarbonyl)amino]-4-(prop-1-en-2-yl)imidazole-2-carboxylate

[0310] To a stirred solution of ethyl 4-bromo-1-[(tert-butoxycarbonyl)amino]imidazole-2- carboxylate (2.0 g, 6.0 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (4.02 g, 23.9 mmol) in dioxane (40 mL) and WATER (4 mL) were added Pd(PPh3)4 (0.69 g, 0.60 mmol) and K2CO3(1.65 g, 12.0 mmol) at RT under N2. The resulting mixture was stirred overnight at 90 °C under N2. The mixture was allowed to cool down to RT. The resulting mixture was diluted with water (80 mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 40% to 60% gradient in 10 min; detector, UV 254 nm to afford the title compound (600 mg, 34%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=296. Step 5: ethyl 1-[(tert-butoxycarbonyl)amino]-4-isopropylimidazole-2-carboxylate

[0311] To a stirred solution of ethyl 1-[(tert-butoxycarbonyl)amino]-4-(prop-1-en-2- yl)imidazole-2-carboxylate (600 mg, 2.03 mmol) in MeOH (12 mL) was added 10% Pd / C (300 mg, 2.82 mmol) at RT under N2. The resulting mixture was stirred overnight at RT under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (5 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford the titlecompound(500 mg, 83%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=298. Step 6: ethyl 1-amino-4-isopropylimidazole-2-carboxylate

[0312] To a stirred solution of ethyl 1-[(tert-butoxycarbonyl)amino]-4-isopropylimidazole-2- carboxylate (500 mg, 1.68 mmol) in DCM (10 mL) was added TFA (3.3 mL) at RT. The resulting mixture was stirred for 1 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 10% to 30% gradient in 10 min; detector, UV 254 nm to affordthe title compound(300 mg, 91%) as a light yellow solid. LCMS (ES, m / z): [M+H]+=198. Step 7: ethyl 1-amino-5-bromo-4-isopropylimidazole-2-carboxylate

[0313] To a stirred solution of ethyl 1-amino-4-isopropylimidazole-2-carboxylate (250 mg, 1.27 mmol) in ACN (6 mL) was added NBS (248 mg, 1.40 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% NH3.H2O), 30% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compound (200 mg, 57%) as a yellow solid. LCMS (ES, m / z): [M+H]+=276. Step 8: ethyl 1-amino-5-(4-chlorophenyl)-4-isopropylimidazole-2-carboxylate

[0314] To a stirred solution of ethyl 1-amino-5-bromo-4-isopropylimidazole-2-carboxylate (150 mg, 0.543 mmol) and p-chloro-benzeneboronic acid, (170 mg, 1.09 mmol) in dioxane (3 mL) and WATER (0.3 mL) were added Pd(PPh3)4 (63 mg, 0.054 mmol) and K2CO3 (150 mg, 1.09 mmol) at RT under N2. The resulting mixture was stirred for 3 h at 90 °C under N2. The mixture was allowed to cool down to RT. The resulting mixture was filtered, the filter cake was washed with 1,4-dioxane (3 x 1 mL). The filtrate was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 40% to 60% gradient in 10 min; detector, UV 254 nm to afford the title compound (110 mg, 66%) as a brown solid. LCMS (ES, m / z): [M+H]+=308. Step 9: ethyl 5-(4-chlorophenyl)-1-({[(ethoxycarbonyl)amino]methanethioyl}amino)-4- isopropylimidazole-2-carboxylate

[0315] To a stirred solution of ethyl 1-amino-5-(4-chlorophenyl)-4-isopropylimidazole-2- carboxylate (110 mg, 0.357 mmol) in DMF (2 mL) was added ethyl N-carbothioylcarbamate (52 mg, 0.39 mmol) at RT. The resulting mixture was stirred for 2 h at RT. The resulting mixture was dissolved in water (5 mL) at 0 °C. The precipitated solids were collected by filtration and washed with water (2 x 1 mL). The resulting solid was dried under vacuum to afford the title compound (90 mg, 57%) as a yellow solid. LCMS (ES, m / z): [M+H]+=439. Step 10: 7-(4-chlorophenyl)-6-isopropyl-2-sulfanyl-3H-imidazo[2,1-f][1,2,4]triazin-4-one

[0316] A solution of ethyl 5-(4-chlorophenyl)-1- ({[(ethoxycarbonyl)amino]methanethioyl}amino)-4-isopropylimidazole-2-carboxylate (90 mg, 0.21 mmol) in 2M NaOH (2 mL) at RT. The resulting mixture was stirred for 2 h at 85 °C. The mixture was allowed to cool down to RT. The resulting mixture was diluted with water (10 mL). The mixture was acidified to pH 5 with 2M HCl (3 mL). The precipitated solids were collected by filtration and washed with water (3 x 2 mL). The resulting solid was dried under vacuum to afford the title compound (60 mg, 91%) as a yellow solid. LCMS (ES, m / z): [M+H]+=321. Step 11: 7-(4-chlorophenyl)-6-isopropyl-2-(methylsulfanyl)-3H-imidazo[2,1- f][1,2,4]triazin-4-one

[0317] To a stirred solution of 7-(4-chlorophenyl)-6-isopropyl-2-sulfanyl-3H-imidazo[2,1- f][1,2,4]triazin-4-one (90 mg, 0.28 mmol) in DMF (2 mL) were added MeI (24 mg, 0.17 mmol) and K2CO3 (78 mg, 0.56 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The resulting mixture was filtered, the filter cake was washed with DMF (2 x 1 mL). The filtrate was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 40% to 50% gradient in 10 min; detector, UV 254 nm to afford the titlecompound(50 mg, 53%) as a white solid. LCMS (ES, m / z): [M+H]+=335. Step 12: 7-(4-chlorophenyl)-6-isopropyl-2-methanesulfonyl-3H-imidazo[2,1- f][1,2,4]triazin-4-one

[0318] To a stirred solution of 7-(4-chlorophenyl)-6-isopropyl-2-(methylsulfanyl)-3H- imidazo[2,1-f][1,2,4]triazin-4-one (50 mg, 0.15 mmol) in DCM (1 mL) was added mCPBA (52 mg, 0.30 mmol) at RT. The resulting mixture was stirred overnight at RT. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase flash chromatography using C18 silica gel; ACN in water (0.1% FA), 40% to 50% gradient in 10 min; detector, UV 254 nm to afford the title compounds (40 mg mixture, 73%) as a white solid. LCMS (ES, m / z): [M+H]+=367. Step 13: 7-(4-chlorophenyl)-2-(2,2-difluoroethoxy)-6-isopropyl-3H-imidazo[2,1- f][1,2,4]triazin-4-one

[0319] To a stirred solution of 2,2-difluoroethanol (13.4 mg, 0.164 mmol) in DMF (1 mL) was added NaH (6.5 mg, 0.16 mmol, 60% in mineral oil) at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. To the above mixture was added 7-(4-chlorophenyl)-6-isopropyl-2- methanesulfonyl-3H-imidazo[2,1-f][1,2,4]triazin-4-one (30 mg, 0.082 mmol) at 0 °C. The resulting mixture was stirred for an additional 2 h at 50 °C. The mixture was allowed to cool down to RT. The mixture was neutralized to pH 7 with 2M HCl (0.1 mL). The mixture was purified by reverse-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water (0.1% FA), 40% to 50% gradient in 10 min; detector, UV 254 nm to afford a residue that was further purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B to 52% B in 10 min, 52% B; Wave Length: 254 / 220 nm; RT1(min): 9.35) to afford the title compound (8 mg, 27%) as a white solid. LCMS (ES, m / z): [M+H]+=369.1H NMR (400 MHz, DMSO- d6) δ 12.86 (s, 1H), 7.64 – 7.57 (m, 4H), 6.39 (tt, J = 3.2 Hz, 1H), 4.49 (td, J = 15.0, 3.2 Hz, 2H), 3.10 (sept, J = 6.7 Hz, 1H), 1.23(d, J = 6.8 Hz, 6H).

[0320] Using the same procedure, Example 297 was synthesized: LCMS (ES, m / z): [M+H]+= 343. 1H NMR (400 MHz, DMSO-d6) δ 12.74 (s, 1H), 7.67 – 7.64 (m, 2H), 7.59 – 7.57 (m, 2H), 4.90 (d, J = 2.5 Hz, 2H), 3.73 (d, J = 2.6 Hz, 1H), 3.10 (sept J = 6.7 Hz, 1H), 1.23 (d, J = 6.8 Hz, 6H). Example 341 - 8-methyl-7-phenyl-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (Example 11388) Step 1: 2-methyl-3-oxo-3-phenylpropanenitrile

[0321] To a stirred solution of benzoyl acetonitrile (4.35 g, 30.0 mmol) in DMF (43.5 mL) was added NaH (1.2 g, 30 mmol, 60% in mineral oil) in portions at 0oC. The resulting mixture was stirred for 15 minutes at 0oC, then CH3I (4.25 g, 30.0 mmol) was added dropwise at 0oC. The resulting mixture was stirred for 1 h at RT. The reaction was quenched with water (50 mL) and extracted with EA (3 x 40 mL). The combined organic layers were washed with brine (40 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8:2) to afford the title compound (2.77 g, 58%) as a yellow oil. LCMS (ES, m / z): [M-H]- =158. Step 2: 4-methyl-5-phenyl-2H-pyrazol-3-amine

[0322] To a stirred solution of 2-methyl-3-oxo-3-phenylpropanenitrile (2.3 g, 14 mmol) in EtOH (23 mL) was added hydrazine hydrate (1.45 g, 28.9 mmol, 80%wt.) at RT. The resulting mixture was stirred overnight at 80oC. The resulting mixture was concentrated under reduced pressure, and the residue was diluted with water (50 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in the title compound (2.2 g, 88%) as a brown oil. The crude resulting was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+=174. Step 3: ethyl N-[(4-methyl-5-phenyl-2H-pyrazol-3-yl)carbamothioyl]carbamate

[0323] To a stirred solution of 4-methyl-5-phenyl-2H-pyrazol-3-amine (2.2 g, 13 mmol) in DMF (48 mL) was added ethyl N-carbothioylcarbamate (1.66 g, 12.7 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The resulting mixture was poured into ice / water (350 mL). The precipitated solids were collected by filtration and washed with water (3 x 20 mL). The resulting solid was dried under reduced pressure. This resulted in precipitate the title compound (3.3 g, 85 %) as a yellow solid. LCMS (ES, m / z): [M+H]+=305. Step 4: 8-methyl-7-phenyl-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0324] A solution of Na (0.76 g, 33 mmol) in EtOH (64 mL) was stirred for 1 h at 0oC. To the above mixture was added ethyl N-[(4-methyl-5-phenyl-2H-pyrazol-3- yl)carbamothioyl]carbamate (5.0 g, 16 mmol) at RT. The resulting mixture was stirred for an additional 1h at 80 ℃. The resulting mixture was filtered, the filter cake was dissolved in water (50 mL), The mixture was acidified to pH 6 with 1N HCl (35 mL). The precipitated solids were collected by filtration and washed with water (3 x 10 mL). The resulting solid was dried under reduced pressure. This resulted in 8 the title compound (2.9 g, 74%) as a yellow solid. The crude resulting was used in the next step directly without further purification. LCMS (ES, m / z): [M+H]+=259. Step 5: 8-methyl-7-phenyl-2-(prop-2-yn-1-ylsulfanyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4- one

[0325] To a stirred mixture of 8-methyl-7-phenyl-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (320 mg, 1.24 mmol) and K2CO3 (514 mg, 3.72 mmol) in DMF (5 mL) was added propargyl bromide (59 mg, 0.50 mmol) at RT. The resulting mixture was stirred for 1 h at RT. The resulting mixture was filtered, the filtrate was purified by Prep-HPLC with the following condition (Column: SunFire Prep C18 OBD Column, 19*150 mm, 5μm; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient: 38% B to 58% B in 8 min; Wave Length: 220 nm; RT1(min): 7.43) to afford the title compound (220 mg, 60%) as a white solid. LCMS (ES, m / z): [M+H]+=297.1H NMR (400 MHz, DMSO-d6): δ 12.87 (s, 1H), 7.83 – 7.81 (m, 2H), 7.54 – 7.46 (m, 3H), 4.13(d, J = 2.6 Hz, 2H), 3.30 (t, J = 2.6 Hz, 1H), 2. 30 (s, 3H). Synthetic Method G-M

[0326] 7-(trifluoromethyl)-2-sulfanyl-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one was synthesized using Synthetic Method G, then converted using Synthetic Method M to Example 342: LCMS (ES, m / z): [M+H]+= 415. 1H NMR (400 MHz, DMSO-d6) δ 7.43 – 7.39 (m, 2H), 6.45 (tt, J = 53.7, 3.0 Hz, 1H), 4.69 (td, J = 15.2, 3.0 Hz, 2H). Examples in Table G-M were synthesized using Synthetic Method G-M: Table G-M Example 380 and Example 381 - 2-ethoxy-7-[oxan-2-yl]-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0327] To a stirred solution of 2-methanesulfonyl-7-(oxan-2-yl)-8-(3,4,5-trifluorophenyl)- 3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (800 mg, 1.87 mmol) in DMF (8 mL) was added sodium ethoxide (1.9 g, 5.6 mmol, 20%wt. in EtOH) at RT. The resulting mixture was stirred for 2 h at RT, then acidified to pH 6 with 2N HCl. The mixture was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 60%-90% gradient in 10 min; UV 254 nm to afford racemic mixture (330 mg). SFC purification (Column: CHIRALPAK IG 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MeOH; flow rate: 100 mL / min; isocratic 20% B; CT (℃): 35; pressure (bar): 100; wavelength: 274 / 224 nm; RT1 (min): 5.38; RT1 (min): 6.88; MeOH:DCM, 1:1; injection volume: 2.5 mL) afforded enantiomer 1 RT1 (min): 5.38 (140 mg) and enantiomer 2 with RT1 (min): 6.88 (140 mg) as yellow solids.

[0328] Enantiomer 1 (140 mg) was purified by Prep-HPLC (Column: Sunfire prep C18 30*150 mm, 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 47%-67% B in 10 min; wavelength: 254nm / 220nm; RT1 (min): 10.53) to afford the title compound (91 mg, 12%) as an off-white solid. LCMS (ES, m / z): [M+H]+395.1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 7.66-7.62 (m, 2H), 4.51 (dd, J 11.1, 2.2 Hz, 1H), 4.45 (q, J 7.2 Hz, 2H), 4.00 (d, J 11.1 Hz, 1H), 3.59 (m, 1H), 2.08 (m, 1H), 1.97 (m, 1H), 1.76 (d, J 13.4 Hz, 1H), 1.64-1.58 (m, 3H), 1.38 (t, J 7.1 Hz, 3H).

[0329] Enantiomer 2 (140 mg) was purified by Prep-HPLC (Column: Sunfire prep C18 30*150 mm, 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 47%-67% B in 10 min; wavelength: 254nm / 220nm; RT1 (min): 10.6) to afford the title compound (98 mg, 13%) as an off-white solid. LCMS (ES, m / z): [M+H]+395.1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 7.67-7.63 (m, 2H), 4.54 (dd, J 11.1, 2.3 Hz, 1H), 4.46 (q, J 7.1, 2H), 4.01 (d, J 11.1 Hz, 1H), 3.59 (m, 1H), 2.06 (m, 1H), 1.97 (m, 1H), 1.77 (d, J 13.4 Hz, 1H), 1.64-1.58 (m, 3H), 1.38 (t, J 7.1 Hz, 3H). Synthetic Method AA Example 382 - 8-[4-(difluoromethyl)phenyl]-7-(pyridin-2-yl)-2-(2,2,2-trifluoroethoxy)- 3H-pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 5-(pyridin-2-yl)-2H-pyrazol-3-amine

[0330] To a stirred solution of 3-oxo-3-(pyridin-2-yl)propanenitrile (10.0 g, 68.4 mmol) in EtOH (100 mL) were added hydrazine hydrate (8.56 g, 137 mmol, 80% wt) and TFA (15.60 g) in portions at RT. The resulting mixture was stirred at 80 °C for 2 h. The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with DCM / MeOH (10:1) to afford the title compound (10.6 g, 97%) as a yellow solid. LCMS (ES, m / z): [M+H]+161. Step 2: 4-bromo-5-(pyridin-2-yl)-2H-pyrazol-3-amine

[0331] To a stirred solution of 5-(pyridin-2-yl)-2H-pyrazol-3-amine (6.0 g, 37 mmol) in ACN (30 mL) and THF (30 mL) was added NBS (6.67 g, 37.5 mmol) at RT. The resulting mixture was stirred for 1 h at RT then concentrated under reduced pressure to afford the title compound (9 g, overweight) as a brown solid. LCMS (ES, m / z): [M+H]+239, 241. Step 3: ethyl N-{[4-bromo-5-(pyridin-2-yl)-2H-pyrazol-3-yl]carbamothioyl}carbamate

[0332] To a stirred solution of 4-bromo-5-(pyridin-2-yl)-2H-pyrazol-3-amine (assume 37 mmol) in DMF (90 mL) was added ethyl N-carbothioylcarbamate (4.94 g, 37.6 mmol) at RT and the resulting mixture stirred at RT for 1 h. Water (150 mL) was added then the mixture was extracted with EA (3 × 100 mL). The combined organic layers were washed with water (2 × 50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (11 g, 80% (2 steps)) as a yellow oil. LCMS (ES, m / z): [M+H]+372, 374. Step 4: 8-bromo-7-(pyridin-2-yl)-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0333] To a stirred solution of ethyl N-{[4-bromo-5-(pyridin-2-yl)-2H-pyrazol-3- yl]carbamothioyl}-carbamate (6.0 g crude, 16 mmol) in EtOH (50 mL) at RT was added EtONa (11.0 g, 32.4 mmol, 20% wt. in EtOH) then the resulting mixture stirred at 80 °C for 2 h. The resulting mixture was concentrated under reduced pressure, re-dissolved in water (100 mL), acidified to pH 6 with 2N HCl and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with DCM / MeOH (8:1) to afford the title compound (600 mg, 11%) as a yellow solid. LCMS (ES, m / z): [M+H]+326, 328. Step 5: 8-bromo-2-(methylsulfanyl)-7-(pyridin-2-yl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4- one

[0334] To a stirred solution of 8-bromo-7-(pyridin-2-yl)-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (1.6 g, 4.9 mmol) in DMF (16 mL) were added K2CO3 (2.05 g, 14.8 mmol) and MeI (560 mg, 3.95 mmol) at RT. The resulting mixture was stirred for 1 h at RT, then filtered and the filter cake washed with DMF (3 × 2 mL). The filtrate was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 40%-70% gradient in 10 min; UV 254 nm to afford the title compound (530 mg, 32%) as a yellow solid. LCMS (ES, m / z): [M+H]+338, 340. Step 6: 8-bromo-2-methanesulfonyl-7-(pyridin-2-yl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4- one and 8-bromo-2-(methylsulfinyl)-7-(pyridin-2-yl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)- one

[0335] To a stirred solution of 8-bromo-2-(methylsulfanyl)-7-(pyridin-2-yl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (420 mg, 1.24 mmol) in DCM (10 mL) was added mCPBA (429 mg, 2.48 mmol) at 0 °C. The resulting mixture was stirred at 0 °C for 15 min and at RT for 2 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 30%-70% gradient in 10 min; UV 254 nm to afford the title compounds (355 mg mixture, 77%) as a yellow solid. LCMS (ES, m / z): [M+H]+354, 356 and 370, 372. Step 7: 8-bromo-7-(pyridin-2-yl)-2-(2,2,2-trifluoroethoxy)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0336] To a stirred solution of trifluoroethanol (81 mg, 0.81 mmol) in DMF (2.00 mL) was added NaH (32 mg, 0.81 mmol, 60% in mineral oil) at 0 °C under N2and the resulting mixture stirred for 30 min at 0 °C. 8-Bromo-2-methanesulfonyl-7-(pyridin-2-yl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one and 8-bromo-2-(methylsulfinyl)-7-(pyridin-2- yl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (100 mg mixture, 0.270 mmol) was added at 0 °C and the resulting mixture stirred for 2 h at RT. Water (10 mL) was added, then the mixture acidified to pH 5 with 2N HCl (0.5 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with water (2 × 10 mL), brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (113 mg, overweight) as a yellow solid. LCMS (ES, m / z): [M+H]+390, 392. Step 8: 8-[4-(difluoromethyl)phenyl]-7-(pyridin-2-yl)-2-(2,2,2-trifluoroethoxy)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0337] To a stirred mixture of 8-bromo-7-(pyridin-2-yl)-2-(2,2,2-trifluoroethoxy)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (113 mg, 0.290 mmol) and 4- (difluoromethyl)phenylboronic acid (99 mg, 0.58 mmol) in dioxane (2 mL) and H2O (0.5 mL) were added K2CO3(120 mg, 0.870 mmol) and Pd(dtbpf)Cl2(19 mg, 0.029 mmol) at RT. The resulting mixture was stirred overnight at 80 °C under N2. To the above mixture was added water (20 mL), then the mixture extracted with EA (3 × 20 mL). The combined organic layers were washed with water (2 × 10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 30%-80% gradient in 10 min; UV 254 nm. The crude product (25 mg) was purified by Prep-HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 39%-59% B in 8 min; wavelength: 254nm / 220nm; RT1 (min): 6.48) to afford the title compound (11.6 mg, 9%) as an off-white solid. LCMS (ES, m / z): [M+H]+438. NMR: (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 8.54 (d, J 4.8 Hz, 1H), 7.95 (m, 1H), 7.85 (d, J 7.8 Hz, 1H), 7.55-7.50 (m, 4H), 7.46 (dd, J 7.6, 4.9 Hz, 1H), 7.03 (t, J 56.1 Hz, 1H), 5.10 (q, J 8.8 Hz, 2H). Examples in Table AA were synthesized using Synthetic Method AA. Table AA Example 385 - 8-[4-(difluoromethyl)phenyl]-2-(prop-2-yn-1-ylsulfanyl)-7-(pyridin-2-yl)- 3H-pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 8-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-7-(pyridin-2-yl)pyrazolo[1,5-a][1,3,5]triazin-4-one

[0338] To a stirred solution of 8-(4-bromophenyl)-7-(pyridin-2-yl)-2-sulfanyl-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (synthesized using Synthetic Method A; 320 mg, 0.800 mmol) in DMF (6 mL) were added K2CO3(331 mg, 2.40 mmol) and 4-methoxybenzyl chloride (376 mg, 2.40 mmol) at RT, then the mixture stirred at 50 °C overnight. The mixture was cooled, filtered and the filter cake washed with DMF (3 × 2 mL). The filtrate was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 50%-100% gradient in 10 min; UV 254 nm to afford the title compound (340 mg, 66%) as a yellow solid. LCMS (ES, m / z): [M+H]+640, 642. Step 2: 8-[4-(difluoromethyl)phenyl]-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-7-(pyridin-2-yl)pyrazolo[1,5-a][1,3,5]triazin-4-one

[0339] To a stirred mixture of 8-(4-bromophenyl)-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-7-(pyridin-2-yl)pyrazolo[1,5-a][1,3,5]triazin-4-one (320 mg, 0.500 mmol) and [1,3-bis[2,6-bis(isopropyl)phenyl]-2- imidazolidinylidene]difluoromethylsilver(I) (CAS: 1643366-13-5; 270 mg, 0.750 mmol) in toluene (6 mL) were added {2-[2-(diphenylphosphino)phenoxy]phenyl}diphenylphosphine (CAS: 166330-10-5; 27 mg, 0.050 mmol) and Pd(dba)2(29 mg, 0.050 mmol) at RT. The resulting mixture was stirred overnight at 80 °C under N2. The cooled mixture was concentrated under reduced pressure, suspended in water (20 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 40%-100% gradient in 10 min; UV 254 nm to afford the title compound (134 mg, 44%) as a yellow solid. LCMS (ES, m / z): [M+H]+612. Step 3: 8-[4-(difluoromethyl)phenyl]-7-(pyridin-2-yl)-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0340] A solution of 8-[4-(difluoromethyl)phenyl]-3-[(4-methoxyphenyl)methyl]-2-{[(4- methoxyphenyl)methyl]sulfanyl}-7-(pyridin-2-yl)pyrazolo[1,5-a][1,3,5]triazin-4-one (113 mg, 0.185 mmol) in TFA (2 mL) was stirred at 80 °C for 2 h, then the cooled mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 30%-80% gradient in 10 min; UV 254 nm to afford the title compound (68 mg, 99%) as a yellow solid. LCMS (ES, m / z): [M+H]+372. Step 4: 8-[4-(difluoromethyl)phenyl]-2-(prop-2-yn-1-ylsulfanyl)-7-(pyridin-2-yl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0341] To a stirred solution of 8-[4-(difluoromethyl)phenyl]-7-(pyridin-2-yl)-2-sulfanyl-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (70 mg, 0.19 mmol) in DMF (2 mL) were added K2CO3 (78 mg, 0.56 mmol) and propargyl bromide (16 mg, 0.13 mmol) at RT. The resulting mixture was stirred at RT for 1 h, then water (20 mL) was added. The mixture was extracted with EA (3 × 20 mL), then the combined organic layers were washed with water (2 × 10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 30%-80% gradient in 10 min; UV 254 nm. The crude product (40 mg) was purified by Prep-HPLC (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 35%-50% B in 8 min; wavelength: 254nm / 220nm; RT1 (min): 8.58) to afford the title compound (26 mg, 34%) as a white solid. LCMS (ES, m / z): [M+H]+410. NMR: (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 8.56 (d, J 4.7 Hz, 1H), 7.95 (m, 1H), 7.86 (d, J 7.8 Hz, 1H), 7.64 (d, J 8.0 Hz, 2H), 7.51-7.45 (m, 3H), 7.03 (t, J 56.1 Hz, 1H), 4.03 (d, J 2.7 Hz, 2H), 3.31 (t, J 2.6 Hz, 1H). Example 386 - 2-(prop-2-yn-1-yloxy)-7-(pyrimidin-2-yl)-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 8-bromo-2-{[(4-methoxyphenyl)methyl]sulfanyl}-7-(pyrimidin-2-yl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0342] To a stirred solution of 8-bromo-7-(pyrimidin-2-yl)-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (synthesized using Synthetic Method AA, 1.80 g, 5.54 mmol) in DMF (20 mL) were added 4-methoxybenzyl chloride (2.60 g, 16.6 mmol) and K2CO3 (2.30 g, 16.6 mmol) at RT and mixture stirred overnight at RT. The mixture was diluted with water (40 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with water (2 × 20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 40%-60% gradient in 10 min; UV 254 nm to afford the title compound (2.1 g, 85%) as a yellow solid. LCMS (ES, m / z): [M+H]+445, 447. Step 2: 2-{[(4-methoxyphenyl)methyl]sulfanyl}-7-(pyrimidin-2-yl)-8-(3,4,5- trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0343] To a stirred mixture of 8-bromo-2-{[(4-methoxyphenyl)methyl]sulfanyl}-7- (pyrimidin-2-yl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (2.0 g, 4.5 mmol) and 3,4,5- trifluorophenylboronic acid (3.95 g, 22.5 mmol) in dioxane (20 mL) and H2O (2 mL) were added Pd(dtbpf)Cl2 (0.29 g, 0.45 mmol) and K2CO3 (1.24 g, 8.98 mmol) at RT under N . The resulting mixture was stirred overnight at 85 °C under N2. The cooled mixture was diluted with water (40 mL) and extracted with EA (3 × 20 mL). The combined organic layers were washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 60%-80% gradient in 10 min; UV 254 nm to afford the title compound (240 mg, 11%) as a light yellow solid. LCMS (ES, m / z): [M+H]+497. Step 3: 7-(pyrimidin-2-yl)-2-sulfanyl-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0344] A solution of 2-{[(4-methoxyphenyl)methyl]sulfanyl}-7-(pyrimidin-2-yl)-8-(3,4,5- trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (240 mg, 0.483 mmol) in TFA (4 mL) was stirred for 2 h at 70 °C. The cooled mixture was concentrated under reduced pressure and the residue purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 40%-60% gradient in 10 min; UV 254 nm to afford the title compound (80 mg, 44%) as a light yellow solid. LCMS (ES, m / z): [M+H]+377. Step 4: 2-(methylsulfanyl)-7-(pyrimidin-2-yl)-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0345] To a stirred solution of 7-(pyrimidin-2-yl)-2-sulfanyl-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (80 mg, 0.21 mmol) in DMF (2 mL) were added MeI (15 mg, 0.11 mmol) and K2CO3(59 mg, 0.43 mmol) at RT and the resulting mixture stirred at RT for 1 h . The mixture was filtered and the filter cake was washed with DMF (2 × 1 mL). The filtrate was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 40%-50% gradient in 10 min; UV 254 nm to afford the title compound (40 mg, 48%) as a white solid. LCMS (ES, m / z): [M+H]+391. Step 5: 2-methanesulfinyl-7-(pyrimidin-2-yl)-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one and 2-methanesulfonyl-7-(pyrimidin-2-yl)-8-(3,4,5- trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0346] To a stirred solution of 2-(methylsulfanyl)-7-(pyrimidin-2-yl)-8-(3,4,5- trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (50 mg, 0.13 mmol) in DCM (2 mL) was added mCPBA (44 mg, 0.26 mmol) at RT. The resulting mixture was stirred overnight at RT, then filtered and the filter cake was washed with DCM (2 × 1 mL). The filtrate was concentrated under reduced pressure and the residue purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 40%-70% gradient in 10 min; UV 254 nm to afford the title compounds (30 mg mixture, 71%) as a white solid. LCMS (ES, m / z): [M−H]−405 and 421. Step 6: 2-(prop-2-yn-1-yloxy)-7-(pyrimidin-2-yl)-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0347] To a stirred solution of propargyl alcohol (5.5 mg, 0.098 mmol) in DMF (1 mL) was added NaH (3.9 mg, 0.098 mmol, 60% in mineral oil) at 0 °C. The resulting mixture was stirred for 30 min at 0 °C. 2-Methanesulfinyl-7-(pyrimidin-2-yl)-8-(3,4,5-trifluorophenyl)- 3H-pyrazolo[1,5-a][1,3,5]triazin-4-one and 2-methanesulfonyl-7-(pyrimidin-2-yl)-8-(3,4,5- trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (30 mg mixture, 0.049 mmol) were added at 0 °C, then the mixture was stirred for 1 h at RT. The mixture was neutralized to pH 7 with 2M HCl (0.3 mL) then purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 40%-50% gradient in 10 min; UV 254 nm. The crude product was purified by Prep-HPLC (Column: Sunfire Prep C18 Column 30*150 mm, 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 32%-50% B in 10 min; wavelength: 254nm / 220nm; RT1 (min): 10.05) to afford the title compound (9 mg, 46%) as a white solid. LCMS (ES, m / z): [M+H]+399.1H NMR: (300 MHz, DMSO-d6) δ 13.25 (s, 1H), 8.94-8.93 (m, 2H), 7.61-7.59 (m, 1H), 7.33 (t, J 8.4 Hz, 2H), 5.11 (d, J 2.2 Hz, 2H), 3.76 (t, J 2.2 Hz, 1H). Synthetic Method BB Example 867 - 7-[1-(benzyloxy)ethyl]-2-ethoxy-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0019] Step 1: 4-(benzyloxy)-3-oxo-2-(3,4,5-trifluorophenyl)pentanenitrile

[0348] To a stirred solution of 2-(3,4,5-trifluorophenyl)acetonitrile (2.0 g, 12 mmol) in THF (30 mL) was added NaH (1.40 g, 35.1 mmol, 60% in mineral oil) at 0 °C. The mixture was stirred for 30 min at 0 °C, then methyl (2S)-2-(benzyloxy)propanoate (2.72 g, 14.0 mmol) added at 0 °C and the resulting mixture stirred overnight at RT. The mixture was acidified to pH 5 with 2 M HCl at 0 °C, diluted with water (50 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (4.08 g, overweight) as a yellow solid. LCMS (ES, m / z): [M−H]−332. Step 2: 3-(1-(benzyloxy)ethyl)-4-(3,4,5-trifluorophenyl)-1H-pyrazol-5-amine

[0349] To a stirred solution of 4-(benzyloxy)-3-oxo-2-(3,4,5-trifluorophenyl)pentanenitrile (assume 12 mmol) in EtOH (40 mL) were added N2H4.H2O (1.61 g, 25.7 mmol, 80% wt.) and TFA (5.9 g, 51 mmol) at 0 °C, then the mixture was stirred at 80 °C for 4 h. The cooled solution was diluted with water (80 mL) and extracted with EA (3 × 80 mL). The combined organic layers were washed with brine (2 × 80 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the racemic title compound (4.91 g, overweight) as a yellow solid. LCMS (ES, m / z): [M+H]+348. Step 3: 1-(3-(1-(benzyloxy)ethyl)-4-(3,4,5-trifluorophenyl)-1H-pyrazol-5-yl)-3- (ethoxymethyl)thiourea

[0350] To a stirred solution of 3-(1-(benzyloxy)ethyl)-4-(3,4,5-trifluorophenyl)-1H-pyrazol- 5-amine (assume 12 mmol) in DMF (50 mL) was added ethyl N-carbothioylcarbamate (3.71 g, 28.3 mmol) at RT under N2. The resulting mixture was stirred for 1 h at RT, then diluted with water (100 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with water (2 × 100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (6.84 g, overweight) as a yellow oil. LCMS (ES, m / z): [M+H]+479. Step 4: 7-(1-(benzyloxy)ethyl)-2-mercapto-8-(3,4,5-trifluorophenyl)pyrazolo[1,5- a][1,3,5]triazin-4(3H)-one

[0351] A solution of ethyl 1-(3-(1-(benzyloxy)ethyl)-4-(3,4,5-trifluorophenyl)-1H-pyrazol-5- yl)-3-(ethoxymethyl)thiourea (6.84 g, 14.3 mmol) in 2 N NaOH (70 mL) was stirred for 1 h at 50 °C. The mixture was acidified to pH 6 with 2M HCl (75 mL) at 0 °C, diluted with water (150 mL) and extracted with EA (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 30%-80% gradient in 60 min; UV 254 nm to afford the title compound (1.32 g, 25% over 4 steps) as a light yellow solid. LCMS (ES, m / z): [M+H]+433. Step 5: 7-(1-(benzyloxy)ethyl)-2-(methylthio)-8-(3,4,5-trifluorophenyl)pyrazolo[1,5- a][1,3,5]triazin-4(3H)-one

[0352] To a stirred solution of 7-(1-(benzyloxy)ethyl)-2-mercapto-8-(3,4,5- trifluorophenyl)pyrazolo[1,5-a][1,3,5]triazin-4(3H)-one (1.27 g, 2.94 mmol) in DMF (15 mL) were added K2CO3 (1.22 g, 8.81 mmol) and MeI (0.67 g, 4.7 mmol) at RT. The resulting mixture was stirred for 1 h at RT, then acidified to pH 6 with 2 M HCl (10 mL) at 0 °C, diluted with water (25 mL) and extracted with EA (3 × 25 mL). The combined organic layers were washed with water (2 × 25 mL) and brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.05% TFA), 30%-80% gradient in 30 min; UV 254 nm to afford the title compound (891 mg, 68%) as a white solid. LCMS (ES, m / z): [M+H]+447. Step 6: 7-[1-(benzyloxy)ethyl]-2-methanesulfinyl-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0353] To a stirred solution of 7-[(1S)-1-(benzyloxy)ethyl]-2-(methylsulfanyl)-8-(3,4,5- trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (4.0 g, 9.0 mmol) in AcOH (80 mL) was added a solution of oxone (6.61 g, 10.8 mmol) in 20 mL H2O at RT. The resulting mixture was stirred for 1 h at RT, then diluted with water (100 mL) and extracted with EA (2 × 70 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford the title compound (1.22 g, 29%) as a brown oil. LCMS (ES, m / z): [M+H]+463. Step 7: 7-[1-(benzyloxy)ethyl]-2-ethoxy-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0354] A mixture of 7-[1-(benzyloxy)ethyl]-2-methanesulfinyl-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (100 mg, 0.216 mmol) and EtONa (220 mg, 0.648 mmol, 20% wt in EtOH) in DMF (3 mL) was stirred for 1 h at RT. The resulting mixture was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 40%-80% gradient in 10 min; UV 254 nm to obtain a crude product. The crude product (80 mg) was purified by Prep-HPLC (Column: Sunfire prep C18 column 30*150 mm, 5μm; mobile phase A: Water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 57%-75 % B in 10 min; wavelength: 254nm / 220nm; RT1 (min): 9.17) to afford the title compound (23 mg, 24%) as a white solid. LCMS (ES, m / z): [M+H]+445.1H NMR: (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 7.71-7.67 (m, 2H), 7.33-7.19 (m, 5H), 4.95 (q, J 6.6 Hz, 1H), 4.49-4.37 (m, 4H), 1.51 (d, J 6.7 Hz, 3H), 1.36 (t, J 7.1 Hz, 3H). Examples in Table BB were synthesized using Synthetic Method BB. Table BB

[0020] Synthetic Method DD Example 391 - 2-ethoxy-7-(1-hydroxyethyl)-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0355] To a solution of 7-[1-(benzyloxy)ethyl]-2-ethoxy-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (synthesized using Synthetic Method BB, 500 mg, 1.13 mmol) in 10 mL MeOH was added 10%Pd / C (1.2 g) in a pressure tank and the mixture was hydrogenated at RT under 30 atm of hydrogen overnight. The mixture was filtered through a Celite pad and concentrated under reduced pressure to afford a residue that was purified by Prep-HPLC (Column: Xselect CSH F-Phenyl OBD column 30*250 mm, 5μm; mobile phase A: water (0.1% FA), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 10%-28% B in 10 min; wavelength: 254nm / 220nm; RT1 (min): 19.5) to afford the title compound (18 mg, 5%) as a white solid. LCMS (ES, m / z): [M+H]+355.1H NMR: (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.87–7.83 (m, 2H), 5.70 (d, J 5.8 Hz, 1H), 4.91 (quin, J 6.1 Hz, 1H), 4.45 (q, J 7.0 Hz, 2H), 1.50 (d, J 6.5 Hz, 3H), 1.37 (t, J 7.1 Hz, 3H). Examples in Table DD were synthesized using Synthetic Method DD. Table DD

[0021] Example 394 - 7-(1-hydroxyethyl)-2-(prop-2-yn-1-yloxy)-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one

[0356] To a solution of 7-[1-(benzyloxy)ethyl]-2-(prop-2-yn-1-yloxy)-8-(3,4,5- trifluorophenyl)-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one (prepared using synthetic method BB; 700 mg, 1.54 mmol) in DCM (14 mL) was added boron trichloride (1 M in hexane, 1.7 mL) at 0 °C. The resulting mixture was stirred for 5 h at 0 °C then the reaction quenched with water (30 mL) at 0 °C. The precipitated solids were filtered and washed with water (2 × 5 mL). The residue (100 mg) was purified by Prep-HPLC (Column: Xselect CSH F-Phenyl OBD column 30*250 mm, 5μm; mobile phase A: water (0.1% FA), mobile phase B: MeOH; flow rate: 60 mL / min; gradient: 44%-59% B in 10 min; wavelength: 254nm / 220nm; RT(min): 11.08) to afford the title compound (27.6 mg, 5%) as a white solid. LCMS (ES, m / z): [M−H]−363.1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 7.92-7.88 (m, 2H), 5.72 (s, 1H), 5.11 (d, J 2.5 Hz, 2H), 4.92 (q, J 6.5 Hz, 1H), 3.75 (t, J 2.4 Hz, 1H), 1.49 (d, J 6.6 Hz, 3H). Synthetic Method FF Example 395 - 2-ethoxy-7-(1-fluoroethyl)-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one Step 1: 2-ethoxy-7-(1-fluoroethyl)-8-(3,4,5-trifluorophenyl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0357] To a stirred solution of 2-ethoxy-7-(1-hydroxyethyl)-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (120 mg, 0.339 mmol) in DCM (6 mL) at 0 °C was added diethylaminosulfur trifluoride (164 mg, 1.02 mmol) and the resulting mixture stirred at 0 °C for 1 h. Water (5 mL) at 0 °C was added and the mixture extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 30%-100% gradient in 10 min; UV 254 nm to afford the title compound. The racemic mixture (74 mg) was purified by SFC (Column: (S, S)-Whelk-O 15μm Kromasil, 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: IPA: ACN 1:1 (0.1% 2M NH3-MeOH); flow rate: 100 mL / min; isocratic 40% B; CT (℃): 25; pressure (bar): 120; wavelength: 272 / 250 nm; RT1 (min): 2.58; RT1 (min): 3.85; MeOH; injection volume: 0.8 mL) to afford enantiomer 1 (30 mg) and enantiomer 2 (30 mg, crude) as white solids.

[0358] Enantiomer 1 crude product was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 10%-50% gradient in 10 min; UV 254 nm to afford the title compound (enantiomer 1, 21 mg, 17%) as a white solid. LCMS (ES, m / z): [M+H]+357.1H NMR: (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 7.57–7.53 (m, 2H), 6.03 (dq, J 47.5, 6.4 Hz, 1H), 4.45 (q, J 7.1 Hz, 1H), 1.72 (dd, J 24.1, 6.4 Hz, 3H), 1.39 (t, J 7.1 Hz, 3H).

[0359] Enantiomer 2 crude product was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 10%-50% gradient in 10 min; UV 254 nm to afford the title compound (enantiomer 2, 18 mg, 15%) as a white solid. LCMS (ES, m / z): [M+H]+357.1H NMR: (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 7.57–7.53 (m, 2H), 6.03 (dq, J 47.5, 6.4 Hz, 1H), 4.44 (q, J 7.1 Hz, 1H), 1.72 (dd, J 24.1, 6.4 Hz, 3H), 1.36 (t, J 7.1 Hz, 3H). Examples in Table FF were synthesized using Synthetic Method FF. Table FF

[0022] Example 402 - 7-(pyridazin-3-yl)-2-(2,2,2-trifluoroethoxy)-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one Step 1: 3-oxo-3-(pyridazin-3-yl)propanenitrile

[0360] To a stirred solution of ACN (5.94 g, 145 mmol) in THF (100 mL) was added NaH (4.34 g, 109 mmol, 60% in mineral oil) at 0 °C, then the mixture was stirred at 0 °C for 30 min. Methyl pyridazine-3-carboxylate (5.0 g, 36 mmol) was added then the resulting mixture stirred at RT overnight. The mixture was concentrated under reduced pressure to afford the title compound (8 g) which was used in the next step directly without further purification. Step 2: 5-(pyridazin-3-yl)-2H-pyrazol-3-amine

[0361] To a stirred solution of 3-oxo-3-(pyridazin-3-yl)propanenitrile (8.0 g, 54 mmol) in EtOH (150 mL) were added hydrazine hydrate (10.2 g, 163 mmol, 80% wt.) and AcOH (13.1 g, 217 mmol) at 0 °C. The resulting mixture was stirred at 50 °C for 2 h, then concentrated under reduced pressure and the residue purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% NH3.H2O), 0%-10% gradient in 10 min; UV 254 nm to afford the title compound (3.0 g, 34%) as a yellow oil. LCMS (ES, m / z): [M+H]+162. Step 3: tert-butyl 5-amino-3-(pyridazin-3-yl)pyrazole-1-carboxylate

[0362] To a stirred solution of 5-(pyridazin-3-yl)-2H-pyrazol-3-amine (3.0 g, 19 mmol) in THF (90 mL) was added DMAP (227 mg, 1.86 mmol) at RT then Boc2O (6.09 g, 27.9 mmol) at 0 °C. The mixture stirred at 65 °C for 2 h, then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 20%-30% gradient in 10 min; UV 254 nm to afford the title compound (2.0 g, 41%) as a yellow solid. LCMS (ES, m / z): [M+H]+262. Step 4: tert-butyl N-[4-bromo-5-(pyridazin-3-yl)-2H-pyrazol-3-yl]carbamate

[0363] To a stirred solution of tert-butyl N-[5-(pyridazin-3-yl)-2H-pyrazol-3-yl]carbamate (2.0 g, 7.7 mmol) in ACN (40 mL) was added NBS (1.36 g, 7.65 mmol) at 0 °C and the resulting mixture stirred at RT for 2 h. The mixture was concentrated under reduced pressure, suspended in water (50 mL) and extracted with EA (3 × 50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (1.8 g, 69%) as a yellow solid. LCMS (ES, m / z): [M+H]+340, 342. Step 5: 4-bromo-5-(pyridazin-3-yl)-2H-pyrazol-3-amine

[0364] To a stirred solution of tert-butyl N-[4-bromo-5-(pyridazin-3-yl)-2H-pyrazol-3- yl]carbamate (1.8 g, 5.3 mmol) in DCM (9 mL) was added TFA (3 mL) at 0 °C. The resulting mixture was stirred at RT for 2 h, then concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 40%-50% gradient in 10 min; UV 254 nm to afford the title compound (1.1 g, 87%) as a yellow solid. LCMS (ES, m / z): [M+H]+240, 242. Step 6: ethyl N-{[4-bromo-5-(pyridazin-3-yl)-2H-pyrazol-3-yl]carbamothioyl}carbamate

[0365] To a stirred solution of 4-bromo-5-(pyridazin-3-yl)-2H-pyrazol-3-amine (1.1 g, 4.6 mmol) in DMF (10 mL) was added ethyl N-carbothioylcarbamate (0.60 g, 4.6 mmol) and the resulting mixture stirred at RT for 2 h. Water (50 mL) was added then the mixture extracted with EA (3 × 50 mL). The combined organic layers were washed with water (3 × 20 mL) and brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (1.1 g, 64%) as a yellow oil. LCMS (ES, m / z): [M+H]+371, 373. Step 7: 8-bromo-7-(pyridazin-3-yl)-2-sulfanyl-3H-pyrazolo[1,5-a][1,3,5]triazin-4-one

[0366] To a stirred solution of ethyl N-{[4-bromo-5-(pyridazin-3-yl)-2H-pyrazol-3- yl]carbamothioyl}-carbamate (1.1 g, 3.0 mmol) in EtOH (20 mL) was added EtONa (2.02 g, 5.93 mmol, 20% wt in EtOH) at RT, then the mixture was stirred at 40 °C for 1 h. The mixture was concentrated under reduced pressure and the residue purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 10%-50% gradient in 10 min; UV 254 nm to afford the title compound (520 mg, 54%) as a yellow solid. LCMS (ES, m / z): [M+H]+325, 327. Step 8: 8-bromo-2-(methylsulfanyl)-7-(pyridazin-3-yl)-3H-pyrazolo[1,5-a][1,3,5]triazin- 4-one

[0367] To a stirred mixture of 8-bromo-7-(pyridazin-3-yl)-2-sulfanyl-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (400 mg, 1.23 mmol) and K2CO3(510 mg, 3.69 mmol) in DMF (6 mL) was added MeI (87 mg, 0.62 mmol), then the mixture was stirred at RT for 1 h. Water (20 mL) was added and the mixture extracted with EA (3 × 20 mL). The combined organic layers were washed with water (3 × 30 mL), brine (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 10%-50% gradient in 10 min; UV 254 nm to afford the title compound (150 mg, 36%) as a yellow solid. LCMS (ES, m / z): [M+H]+341. Step 9: 8-bromo-2-methanesulfonyl-7-(pyridazin-3-yl)-3H-pyrazolo[1,5-a][1,3,5]triazin- 4-one

[0368] To a stirred solution of 8-bromo-2-(methylsulfanyl)-7-(pyridazin-3-yl)-3H- pyrazolo[1,5-a][1,3,5]triazin-4-one (180 mg, 0.531 mmol) in AcOH (6 mL) at RT was added oxone (719 mg, 1.17 mmol, in 2 mL H2O) then the mixture stirred at RT for 1 h. The mixture was neutralized to pH 7 with 2M NaOH (0.1 mL), diluted with water (20 mL) and extracted with EA (3 × 15 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (200 mg, overweight) as a white solid. LCMS (ES, m / z): [M−H]−369, 371. Step 10: 8-bromo-7-(pyridazin-3-yl)-2-(2,2,2-trifluoroethoxy)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one

[0369] To a stirred solution of trifluoroethanol (85 mg, 0.85 mmol) in DMF (2 mL) was added NaH (34 mg, 0.85 mmol, 60% in mineral oil) at 0 °C under N2, then the mixture stirred at 0 °C for 30 min. 8-Bromo-2-methanesulfinyl-7-(pyridazin-3-yl)-3H-pyrazolo[1,5- a][1,3,5]triazin-4-one (100 mg, 0.282 mmol) was added at 0 °C, then the mixture stirred at RT for 2 h. The reaction was quenched with 2N HCl at 0 °C, then diluted with water (10 mL) and extracted with EA (3 × 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography: C18 silica gel; ACN in water (0.1% FA), 10%-50% gradient in 10 min; UV 254 nm to afford the title compound (50 mg, 45%) as a white solid. LCMS (ES, m / z): [M+H]+391, 393. Step 11: 7-(pyridazin-3-yl)-2-(2,2,2-trifluoroethoxy)-8-(3,4,5-trifluorophenyl)-3H- pyrazolo[1,5-a][1,3,5]tria...

Claims

Claims 1. A compound of Formula (I) or Formula (II)or a pharmaceutically acceptable salt thereof wherein R1is hydrogen or optionally substituted C1-C3 alkyl; R2is -S-L2-R2aor -O-L2-R2a; L2is a bond or optionally substituted C1-C3alkylene; R2ais selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, wherein R2ais substituted with n instances of R2b; each R2bis independently selected from the group consisting of halogen, -OH, -ORc, - NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, - C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6 alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of R2bare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; R3is selected from the group consisting of optionally substituted C1-C6alkyl, optionally substituted 3-7 membered carbocyclyl, , optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, optionally substituted naphthyl, optionally substituted 5-10 membered heteroaryl, wherein R3is substituted with m instances of R3a;each R3ais independently selected from the group consisting of halogen, -OH, -ORc, - NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, - C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6 alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of R3aare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; R4is selected from the group consisting of hydrogen, halogen, -CN, -OH, -ORc, -(CH2)1-3Rc, optionally substituted C2-C6alkyl, optionally substituted C3-C6carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, wherein R4is substituted with p instances of R4a; each R4ais independently selected from the group consisting of halogen, -OH, -ORc, - NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, - C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of R4aare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; each Rcis independently selected from the group consisting of optionally substituted C1- C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of Rcare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; n is 0, 1, 2, 3, 4, or 5; and m is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, 4, or 5.

2. A compound of Formula (I) or Formula (II)(I) (II), or a pharmaceutically acceptable salt thereof wherein R1is hydrogen or optionally substituted C1-C3 alkyl; R2is -S-L2-R2aor -O-L2-R2a; L2is a bond or optionally substituted C1-C3alkylene; R2ais selected from the group consisting of C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-6-membered heteroaryl, wherein R2ais substituted with n instances of R2b; each R2bis independently selected from the group consisting of halogen, -OH, -ORc, - NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, - C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6 alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-10 membered heterocyclyl, or two instances of R2bare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; R3is selected from the group consisting of optionally substituted C1-C6 alkyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substited phenyl, optionally substituted naphthyl, optionaly subsubstituted 5-10 membered heteroaryl, wherein R3is substituted with m instances of R3a; each R3ais independently selected from the group consisting of halogen, -OH, -ORc, - NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, - C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of R3aare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; R4is selected from the group consisting of hydrogen, halogen, -CN, -OH, -ORc, -(CH2)1- 3Rc, optionally substituted C1-C6alkyl, optionally substituted C3-C6carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, wherein R4is substituted with p instances of R4a; each R4ais independently selected from the group consisting of halogen, -OH, -ORc, - NH2, -CN, -NO2, -C(O)OH, -C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, - C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6 alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of R4aare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; each Rcis independently selected from the group consisting of optionally substituted C1- C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl, or two instances of Rcare optionally taken together along with their intervening atoms to form an optionally substituted 4-7 membered heterocyclyl; n is 0, 1, 2, 3, 4, or 5; and m is 0, 1, 2, 3, 4, or 5; and p is 0, 1, 2, 3, 4, or 5 wherein when R2is -S-CH2-pyridinyl or -S-CH(CH3)-phenyl, R4is not methyl.

3. The compound of claim 1, wherein R2is -S-L2-R2a.

4. The compound of claim 1, wherein R2is -O-L2-R2a.

5. The compound of any of claims 1-4, wherein L2is a bond.

6. The compound of any of claims 1-4, wherein L2is -CH2-.

7. The compound of any of claims 1-6, wherein R2ais selected from the group consisting of optionally substituted C1-C3alkyl, optionally substituted C2-C3alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3-6 membered carbocyclyl, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl, wherein R2ais substituted with n instances of R2b.

8. The compound of claim 7, wherein R2ais optionally substituted C1-C3 alkyl, wherein R2ais substituted with n instances of R2b.

9. The compound of claim 8, wherein Rais selected from the group consisting of optionally substituted methyl, optionally substituted ethyl, and optionally n-propyl.

10. The compond of claim 7, wherein R2ais optionally substituted C2-C3 alkenyl, wherein R2ais substituted with n instances of R2b.

11. The compound of claim 10, wherein R2ais optionally substituted allyl.

12. The compound of claim 7, wherein R2ais optionally substituted C2-C4 alkynyl, wherein R2ais substituted with n instances of R2b.

13. The compound of claim 12, wherein R2ais optionally substituted propargyl.

14. The compond of claim 7, wherein R2ais optionally substituted optionally substituted 3- 6 membered carbocyclyl, wherein R2ais substituted with n instances of R2b.

15. The compound of claim 14, wherein R2ais optionally substituted cyclopropyl or optionally substituted cyclopropyl.

16. The compound of claim 1, R2is selected from the group consisting of.

17. The compound of any of claim 1-5, wherein R3is an optionally substituted phenyl or optionally substituted 6-membered heteroaryl.

18. The compound of claim 17, wherein R3is an optionally substituted phenyl or optionally substituted pyridinyl.

19. The compound of any of claim 1-5, wherein R3is optionally substituted 3-7 membered carbocyclyl.

20. The compound of any of claim 1-5, wherein R3is optionally substituted 3-7 membered heterocyclyl.

21. The compound of any of claims 1-17, wherein the compound is of formula (I-a) or formula (II-a)(I-a) (II-a), or a pharmaceutically acceptable salt thereof.

22. The compound of any of claims 1-21, wherein R1is hydrogen 23. The compound of any of claims 1-2221, wherein each R3ais independently selected from the group consisting of halogen, -OH, -ORc, -NH2, -CN, -NO2, -C(O)OH, - C(O)ORc, -C(O)Rc, -NHRc, -N(Rc)2, -C(O)NHRc, -C(O)N(Rc)2, -S(O)2Rc, -(CH2)1-3Rc, optionally substituted C1-C6alkyl, optionally substituted C2-C6alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-10 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-10 membered heteroaryl.

24. The compound of claim 23, wherein R3ais halogen.

25. The compound of claim 24, wherein R3ais chloro or fluoro.

26. The compound of claim 23, wherein R3ais -ORc.

27. The compound of claim 26, wherein R3ais -OMe.

28. The compound of claim 26, wherein Rcis optionally substituted 5-6-memebered heterocyclyl.

29. The compound of claim 23, wherein R3ais optionally substituted C1-C6alkyl.

30. The compound of claim 29, wherein R3ais optionally substituted methyl.

31. The compound of claim 23, wherein R3ais -(CH2)1-3Rc.

32. The compound of claim 31, wherein Rcis optionally substituted 6-memebered heterocyclyl.

33. The compound of claim 23, wherein R3ais -S(O)2Rc.

34. The compound of claim 33, wherein Rcis optionally substituted C1-C3 alkyl.

35. The compound of claim 23, wherein R3ais -C(O)N(Rc)2.

36. . The compound of claim 23, wherein R3ais -CN.

37. The compound of any of claims 1-22, wherein m is 2, and the two instances of Rcare taken together along with their intervening atoms to form optionally substituted 4-7 membered heterocyclyl.

38. The compound of claim 37, wherein the two instances of Rcare taken together along with their intervening atoms to form optionally substituted 5-membered heterocyclyl.

39. The compound of any of claims 1-23, wherein R4is selected from the group consisting of halogen, -CN, -OH, -ORc, -CH2Rc, optionally substituted C2-C4alkyl, optionally substituted C3-C4 carbocyclyl, optionally substituted 3-7 membered heterocyclyl, optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl, wherein R4is substituted with p instances of R4a.

40. The compound of any of claims 1-23, wherein R4is optionally substituted C1-C4 alkyl.

41. The compound of claim 40, wherein R4is optionally substituted methyl.

42. The compound of claim 39, wherein R4is optionally substituted C2-C4alkyl.

43. The compound of claim 42, wherein R4is optionally substituted ethyl, optionally substituted iso-propyl, optionally substituted tert-butyl, and optionally substituted sec- butyl.

44. The compound of claim 39, wherein R4is optionally substituted 3-7 membered heterocyclyl.

45. The compound of claim 44, wherein R4is optionally substituted 5-7 membered heterocyclyl.

46. The compound of claim 44, wherein R4is selected from the group consisting of optionally substituted tetrahydrofuranyl, optionally substituted tetrahydropyranyl, optionally substituted piperidinyl, optionally subsistuted morpholinyl, and optionally substituted oxazepanyl.

47. The compound of claim 39, wherein R4is optionally substituted phenyl.

48. The compound of claim 39, wherein R4is optionally substituted 5-6 membered heteroaryl.

49. The compound of claim 48, wherein R4is selected from the group consisting of optionally substituted imidazolyl, optionally substituted pyridinyl, optionally substituted pyrimidinyl, and optionally substituted pyrazinyl.

50. The compound of any of claims 1-23, wherein R4is selected from the group consisting of hydrogen, methyl,.

51. A compound selected from the group consisting of those found in Table 1 or a pharmaceutically acceptable salt thereof.

52. A pharmaceutical composition comprising a compound of any of claims 1-51 and a pharmaceutically acceptable adjuvant.

53. A method of treating or preventing a disease or condition associated with protein misfolding comprising administering a therapeutically effective amount of a compound of any of claims 1-51 or a pharmaceutical composition of claim 52 to a subject in need thereof.

54. The method of claim 53, wherein the protein misfolding disease is Parkinson’s disease.

55. The method of claim 53, wherein the protein misfolding disease or condition is selected from a group consisting of Parkinson’s disease, dementia with Lewy Bodies, or multiple system atrophy.

56. The method of claim 53, wherein the protein misfolding disease or condition is selected from a group consisting of synucleinopathies, amyloidosis, tauopathies, prion disease, Creutzfeldt-Jakob disease, spongiform encephalopathies, neurodegenerative disease, Down syndrome, or cystic fibrosis.

57. The method of claim 53, wherein the disease or condition associated with protein misfolding is selected from a group consisting of Lewy body disease, Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer’s disease, familial Alzheimer’s disease, Lewy body variant of Alzheimer’s disease, a combination of Alzheimer’s and Parkinson’s disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy,Gaucher's disease, juvenile-onset generalized neuroaxonal dystrophy, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

58. The method of claim 53, wherein the disease or condition associated with protein misfolding is selected from a group consisting of Lewy body disease, Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer's disease, familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden-Spatz disease, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

59. The method of claim 52, wherein the disease or condition associated with protein misfolding is Lewy body disease, Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic and familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden-Spatz disease, pure autonomic failure, neurodegeneration in combination with brain iron accumulation type-1, a broadly neurodegenerative disease, synucleinopathy, pure autonomic nerve failure, dementia, tauopathy, argyrophilic grain disease, Pick’s disease, Down syndrome, chronic leukemia, lymphoma, schizophrenia, psychosis, or Creutzfeldt-Jakob’s disease.

60. A method of treating or preventing a disease or condition associated with neurodegeneration comprising administering a therapeutically effective amount of a compound of any of claims 1-51 or a pharmaceutical composition of claim 52 to a subject in need thereof.

61. The method of claim 60, disease or condition associated with neurodegeneration is Parkinson’s disease.

62. The method of claim 60, wherein the disease or condition associated with neurodegeneration is selected from a group consisting of synucleinopathies, amyloidosis, tauopathies, prion disease, Creutzfeldt-Jakob disease, spongiform encephalopathies, Down syndrome, or cystic fibrosis.

63. The method of claim 60, wherein the disease or condition associated with neurodegeneration is from Parkinson’s disease, dementia with Lewy Bodies, or multiple system atrophy.

64. The method of claim 60, wherein the disease or condition associated with neurodegeneration is selected from a group consisting of Lewy body disease, Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer’s disease, familial Alzheimer’s disease, Lewy body variant of Alzheimer’s disease, a combination of Alzheimer’s and Parkinson’s disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

65. The method of claim 60, wherein the disease or condition associated with neurodegeneration is selected from a group consisting of Lewy body disease, Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer's disease, familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden-Spatz disease, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

66. The method of claim 60, wherein the disease or condition associated with neurodegeneration is selected from a group consisting of Lewy body disease, Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic and familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson'sdisease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden- Spatz disease, pure autonomic failure, neurodegeneration in combination with brain iron accumulation type-1, synucleinopathy, pure autonomic nerve failure, dementia, tauopathy, argyrophilic grain disease, Pick’s disease, Down syndrome, chronic leukemia, lymphoma, schizophrenia, psychosis, or Creutzfeldt-Jakob’s disease.

67. A method of treating a disease or condition associated with misfolding of alpha- synuclein protein comprising administering a therapeutically effective amount of a compound of any of claims 1-51 or a pharmaceutical composition of claim 52 to a subject in need thereof.

68. The method of claim 67, wherein the disease or condition associated with misfolding of alpha-synuclein protein is Parkinson’s disease.

69. The method of claim 67, wherein the disease or condition associated misfolding of alpha-synuclein protein is selected from a group consisting of synucleinopathies, amyloidosis, tauopathies, prion disease, Creutzfeldt-Jakob disease, spongiform encephalopathies, neurodegenerative disease, Down syndrome, or cystic fibrosis.

70. The method of claim 67, wherein the disease or condition associated misfolding of alpha-synuclein protein is selected from a group consisting of Lewy body disease, Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer’s disease, familial Alzheimer’s disease, Lewy body variant of Alzheimer’s disease, a combination of Alzheimer’s and Parkinson’s disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

71. The method of claim 67, wherein disease or condition associated misfolding of alpha- synuclein protein is selected from a group consisting of Parkinson’s disease, dementia with Lewy Bodies, or multiple system atrophy.

72. The method of claim 67, wherein the disease or condition associated misfolding of alpha-synuclein protein is selected from a group consisting of Lewy body disease, Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer's disease, familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden-Spatz disease, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

73. The method of claim 67, wherein the disease or condition associated misfolding of alpha-synuclein protein is selected from a group consisting of Lewy body disease, Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic and familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden- Spatz disease, pure autonomic failure, neurodegeneration in combination with brain iron accumulation type-1, a broadly neurodegenerative disease, synucleinopathy, pure autonomic nerve failure, dementia, tauopathy, argyrophilic grain disease, Pick’s disease, Down syndrome, chronic leukemia, lymphoma, schizophrenia, psychosis, or Creutzfeldt-Jakob’s disease.

74. A method of treating or preventing a disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates comprising administering a therapeutically effective amount of a compound of any of claims 1-51 or a pharmaceutical composition of claim 52 to a subject in need thereof.

75. The method of claim 74, wherein the disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates is Parkinson’s disease.

76. The method of claim 74, wherein the disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates is selected from a group consisting of Parkinson’s disease, dementia with Lewy Bodies, or multiple system atrophy.

77. The method of claim 74, wherein the disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates is selected from a group consisting of synucleinopathies, amyloidosis, tauopathies, prion disease, Creutzfeldt-Jakob disease, spongiform encephalopathies, neurodegenerative disease, Down syndrome, or cystic fibrosis.

78. The method of claim 74, wherein the disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates is selected from a group consisting of Lewy body disease, Parkinson’s disease, Parkinson’s disease dementia, dementia with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer’s disease, familial Alzheimer’s disease, Lewy body variant of Alzheimer’s disease, a combination of Alzheimer’s and Parkinson’s disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

79. The method of claim 74, wherein the disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates is selected from a group consisting of Lewy body disease, Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic Alzheimer's disease, familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden-Spatz disease, pure autonomic failure, or neurodegeneration in combination with brain iron accumulation type-1.

80. The method of claim 74 wherein the disease or condition associated with formation, deposition, accumulation, or persistence of alpha-synuclein oligomers, proto-fibrils, fibrils, or aggregates is selected from a group consisting of Parkinson's disease, Parkinson's disease dementia, dementia in combination with Lewy bodies, diffuse Lewy body disease, sporadic and familial Alzheimer's disease, Lewy body variant of Alzheimer's disease, a combination of Alzheimer's and Parkinson's disease, multiple system atrophy or Shy-Drager syndrome, frontotemporal dementia, frontotemporal lobal degeneration, familial dementia, progressive supranuclear palsy, Gaucher's Disease, juvenile-onset generalized neuroaxonal dystrophy, Hallervorden-Spatz disease, pure autonomic failure, neurodegeneration in combination with brain iron accumulation type-1, a broadly neurodegenerative disease, synucleinopathy, pure autonomic nerve failure, dementia, tauopathy, argyrophilic grain disease, Pick’s disease, Down syndrome, chronic leukemia, lymphoma, schizophrenia, psychosis, or Creutzfeldt-Jakob’s disease.

Images