Compounds and uses thereof

Abstract

The present disclosure relates to compounds that modulate the activity of transcription factor SOX18. More particularly, due to the modulation of transcription factor SOX18, the compounds present as useful therapies in the treatment of angiogenesis- and lymphangiogenesis- related diseases, disorders, or conditions.

Description

COMPOUNDS AND USES THEREOFRelated application

[0001] This application claims priority from Australian Provisional Patent Application No. 2024903551 filed 31 October 2024, the entire contents of which are incorporated herein by cross-reference.Field

[0002] The present disclosure relates to compounds that modulate the activity of transcription factor SOX18. More particularly, due to the modulation of transcription factor SOX 18, the compounds present as useful therapies in the treatment of angiogenesis- and lymphangiogene- sis-related diseases, disorders, or conditions.Background

[0003] Transcription factor SOX18 is a protein that, in humans, is encoded by the SOX18 gene. SOX18 (SRY-related HMG-box 18), belonging to the group F of SOX proteins along with SOX7 and SOX17, is an important transcription factor involved in the development of cardiovascular and lymphatic vessels during embryonic development. In particular, the SOX18 protein is responsible for the activation of Prospero Homeobox 1 (Prox-1) promoter and, thus, it is involved in the formation of new blood and lymphatic vessels. The initiation of the expression of the SOX18 gene and, therefore, of PROXI, in the early stages of embryogenesis results in changes in the phenotype of endothelial cells, which causes their migration and fusion (which leads to the formation of a network of lymphatic vessels, the protoplasts of the mature lymphatic system). In addition to the involvement of the SOX18 protein in the formation of the cardiovascular system in the embryonic development, its presence has also been demonstrated in many cells and tissues of the mature human body, for example in the heart, the lungs, the skeletal muscles, the stomach, and the intestines.

[0004] It is this role in angiogenesis and lymphangiogenesis that has spurred further investigation into SOX18 as an anticancer target. Indeed, the observed variable levels of SOX18 in different kinds of cancer (stomach, colorectal, ovarian, endometrium or liver cancer) indicate the role of this transcription factor in tumour progression, metastasis, and the development of blood and lymphatic vessels within the tumour.

[0005] However, pharmacological modulation of SOX18, and indeed the majority of transcription factors more broadly, has been met with little success. This is mostly due to the standard drug discovery approaches centred on blocking protein / DNA binding or interfering with post- translational modifications.

[0006] More recently, advances in the field have revealed a central role of protein-protein interaction in the mode of action of transcription factors. It is therefore understood that modulation of transcription factor activity may be best achieved by modulation of its protein-protein interaction, be it with DNA or a partner protein. However, to date, an unexplored aspect of the pharmacological modulation of SOX transcription factors is how these proteins recruit their partners and consequently modulate transcription via a range of protein-protein interactions (PPIs).

[0007] Accordingly, there remains a need to develop tools to further investigate the PPIs of transcription factors, including SOX18, as a means to modulate activity of the transcription factor. In particular, there remains a need for safe and efficacious compounds capable of modulating transcription factor SOX18 activity, particularly wherein the pharmacokinetic / pharma- codynamic properties of the compounds provide for potent and selective therapeutics.Summary

[0008] The present inventors have undertaken extensive research into the development of new compounds and have surprisingly identified that compounds of Formula I as described herein are capable of modulating the activity of transcription factor SOX18. Due to this modulatory activity, the compounds of Formula I may present as useful therapies in the treatment of angiogenesis- and lymphangiogenesis-related diseases, disorders, or conditions.

[0009] Accordingly, in one aspect there is provided a compound of Formula I:Formula I; whereinY1is CH or N;Y2is C(0) or C(OH);R1is -H or -Ci-6-alkyl;Ring X is a 5-membered carbocycle or 5-membered heterocycle; wherein Ring X is optionally substituted with one or more R2; if present, each R2is independently selected from the group consisting of -halogen, -Ci- salkyl, -OH, -O(Ci-3alkyl), -NH2, -N(H)(-Ci-3alkyl), -N(Ci-3alkyl)(Ci-3alkyl), and -CF3;L is a bond or -Ci-8alkylene-;Ring Z is a 5-10-membered carbocyclyl or 5-10-membered heterocyclyl; wherein Ring Z is optionally substituted with one or more R3; if present, each R3is independently selected from the group consisting of -halogen, -Ci- salkyl optionally substituted with one or more R5, -Ci-salkenyl optionally substituted with one or more R5, -Ci-salkynyl optionally substituted with one or more R5, -C(R4)3, -O(R4), -N(R4)2, -OC(R4)3, -Ci-salkyl-O(R4), -O-Ci-salkyl-O(R4), -3-7-membered carbocyclyl optionally substituted with one or more R5, -3-7-membered heterocyclyl optionally substituted with one or more R5, -Ci.8alkyl-N(R4)2, -O-Ci.8alkyl-N(R4)2, -C(O)O(R4), -OC(O)(R4), -CN, -NO2, -S(O)2R4, - S(O)2N(R4)2, -N(H)SO2(R4), -(O), -N(R4)-Ci-8alkyl-N(R4)2, -N(R4)-Ci-8alkyl-O(R4), -N(R4)CI- 4alkyl optionally substituted with one or more R5, -O-Ci-8alkyl-(R4)3, -O-Ci-8alkyl optionally substituted with one or more R5, -O-Ci-8alkenyl-(R4)3, -O-Ci-8alkenyl optionally substituted with one or more R5, O-Ci-8alkynyl-(R4)3, -O-Ci-8alkynyl optionally substituted with one or more R5, and -O-cyclicCi-8alkyl-(R4)3; if present, each R4is independently selected from the group consisting of -H, -halogen, and -Ci-ealkyl; if present, each R5is independently selected from the group consisting of -halogen, - OH, -N(R4)2, -OCi-4alkyl, -C(O)N(R4)2, -C3-6cycloalkyl optionally substituted with one or two R6, 4-6-membered heterocyclyl comprising one or two heteroatoms independently selected from N, O or S and optionally substituted with one or two R6; and if present, each R6is independently selected from the group consisting of -halogen, - OH, -CF3, -halogen, and -Ci-salkyl, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0010] In a further aspect, there is provided a pharmaceutical composition comprising a compound of Formula I as described herein, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0011] In a further aspect, there is provided a method of treating a SOX18-mediated disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a pharmaceutically acceptable amount of a compound of Formula I as described herein, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0012] In some embodiments, the SOX18-mediated disease, disorder, or condition is an angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition.

[0013] In a further aspect, there is provided a method of treating an angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a pharmaceutically acceptable amount of a compound of Formula I as described herein, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0014] In some embodiments, the angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition is a cancer.

[0015] In some embodiments, the angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition is an ophthalmic disease, disorder, or condition.

[0016] In some embodiments, the angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition is a renal disease, disorder, or condition.

[0017] In a further aspect, there is provided a method of modulating SOX18 activity, comprising contacting SOX18 with a compound of Formula I as described herein, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.Brief Description of the Drawings

[0001] Embodiments of the present disclosure will now be described with reference to the following Figure, which is intended to be exemplary only, and in which:

[0002] Figure 1. The anti-tumour activity of compound

[0032] across individual experiments utilising the SVR angiosarcoma model as described in Example 2. Compound

[0032] dose response in Laboratory 1 (A), Compound

[0032] twice daily (BID) versus once-daily (QD) dosing in Laboratory 1 (B), Compound

[0032] at 150mg / kg QD repeat in Laboratory 1 (C) and Compound

[0032] at 150mg / kg QD in Laboratory 2 (D) exhibit statistically significant anti -tumour activity following once-daily or twice-daily administration (p.o.) in the mouse SVR angiosarcoma model. Statistical significance of treatment groups vs vehicle control was determinedusing a two-way ANOVA followed by multiple comparison tests. *=P<0.05, **=P<0.01, ***=P<0.001, ****=P<0.0001. NS - Not statistically significant.DescriptionGeneral Definitions

[0018] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (e.g., chemistry, medicinal chemistry and the like).

[0019] As used herein, the term “and / or”, e.g., “X and / or Y” shall be understood to mean either "X and Y" or "X or Y" and shall be taken to provide explicit support for both meanings or for either meaning.

[0020] As used herein, the term “about”, as applied to one or more values, refers to a value that is similar to a stated reference value. In certain embodiments, unless stated to the contrary, the term “about” refers to ±20%, more preferably ±10%, of the designated value. In certain embodiments, the term "about" refers to a range of values that fall within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% or would be below 0%, of a designated value).

[0021] As used herein, singular forms “a”, “an” and “the” include plural aspects, unless the context clearly indicates otherwise.

[0022] Throughout this specification, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0023] As used herein, the term “subject” refers to any organism susceptible to a disease or condition. For example, the subject can be a mammal, primate, livestock (e.g., sheep, cow, horse, pig), companion animal (e.g., dog, cat), or laboratory animal (e.g., mouse, rabbit, rat, guinea pig, hamster). In one example, the subject is a mammal. In one embodiment, the subject is human.

[0024] As used herein, the term “treating” includes alleviation of the symptoms associated with a specific disorder or condition and eliminating said symptoms. For example, as used herein,the term “treating cancer” refers to alleviating the symptoms associated with cancer and eliminating said symptoms. In one embodiment, the term “treating cancer” refers to an increase in progression-free survival.

[0025] As used herein, the term “prevention” includes prophylaxis of the specific disorder or condition. For example, as used herein, the term “preventing cancer” refers to preventing the onset or duration of the symptoms associated with cancer. In one example, the term “preventing cancer” refers to slowing or halting the progression of the cancer. In one example, the term “preventing cancer” refers to slowing or preventing metastasis.

[0026] As would be understood by the person skilled in the art, a compound of Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, would be administered in a therapeutically effective amount. The term “therapeutically effective amount”, as used herein, refers to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, being administered in an amount sufficient to alleviate or prevent to some extent one or more of the symptoms of the disorder or condition being treated. The result can be the reduction and / or alleviation of the signs, symptoms, or causes of a disease or condition, or any other desired alteration of a biological system. In one embodiment, the term “therapeutically effective amount” refers to a compound of Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, being administered in an amount sufficient to result in a reduction of symptoms associated with cancer. The term, an “effective amount”, as used herein, refers to an amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, effective to achieve a desired pharmacologic effect or therapeutic improvement without undue adverse side effects or to achieve a desired pharmacologic effect or therapeutic improvement with a reduced side effect profile. By way of example only, therapeutically effective amounts may be determined by routine experimentation, including but not limited to a dose escalation clinical trial. The term “therapeutically effective amount” includes, for example, a prophylactically effective amount. In one embodiment, a prophylactically effective amount is an amount sufficient to prevent cancer. It is understood that “an effective amount” or “a therapeutically effective amount” can vary from subject to subject, due to variation in metabolism of the compound and any of age, weight, general condition of the subject, the condition being treated, the severity of the condition being treated, and the judgment of the prescribing physician. Thus, it is not always possible to specify an exact “effective amount”. However, an appropriate “effective amount” in any individual case may be determined by one of ordinary skill in the art using routine experimentation. Wheremore than one therapeutic agent is used in combination, a “therapeutically effective amount” of each therapeutic agent can refer to an amount of the therapeutic agent that would be therapeutically effective when used on its own, or may refer to a reduced amount that is therapeutically effective by virtue of its combination with one or more additional therapeutic agents.

[0027] The compounds of the present disclosure may contain chiral (asymmetric) centers, or the molecule as a whole may be chiral. The individual stereoisomers (enantiomers and diastereoisomers) and mixtures of these are within the scope of the present disclosure.

[0028] The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.

[0029] As used herein, the term “halogen” means fluorine, chorine, bromine, or iodine.

[0030] As used herein, the term “alkyl” encompasses both straight chain (i.e., linear) and branched chain hydrocarbon groups and is intended to encompass monovalent and multivalent (e.g., divalent) alkyl groups. The alkyl group may have from 1 to 8 carbon atoms, denoted Cisalkyl, or it may have from 1 to 6 carbon atoms, denoted Ci-ealkyl, or it may have from 1 to 4 carbon atoms, denoted C alkyl, and so forth. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, pentyl, and hexyl groups. In one example, the alkyl group is of one to eight carbon atoms (i.e. Ci-salkyl). In one example, the alkyl group is of one to six carbon atoms (i.e. Ci-ealkyl).

[0031] As used herein, the term “alkenyl” encompasses both straight and branched chain unsaturated hydrocarbon groups with at least one carbon-carbon double bond and is intended to encompass monovalent and multivalent (e.g., divalent) alkenyl groups. Unless indicated otherwise, the stereochemistry about each double bond may be independently cis or trans, or E or Z, as appropriate. The alkenyl group may have from 2 to 8 carbon atoms, denoted C2-salkenyl, or it may have from 2 to 6 carbon atoms, denoted C2-ealkenyl, or it may have from 1 to 4 carbon atoms, denoted C2-4alkenyl, and so forth. An alkynyl group may include one, two, three, four, or more carbon-carbon double bonds. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl groups. In one example, the alkenyl group is of two to six carbon atoms (i.e. C2-ealkenyl).

[0032] As used herein, the term “alkynyl” encompasses both straight and branched chain unsaturated hydrocarbon groups with at least one carbon-carbon triple bond and is intended to encompass monovalent and multivalent (e.g., divalent) alkynyl groups. The alkynyl group mayhave from 2 to 8 carbon atoms, denoted C2-salkynyl, or it may have from 2 to 6 carbon atoms, denoted C2-ealkynyl, or it may have from 1 to 4 carbon atoms, denoted C2-4alkynyl, and so forth. An alkynyl group may include one, two, three, four, or more carbon-carbon triple bonds. For example, Ce alkynyl may include one or more carbon-carbon triple bonds. Unless otherwise specified, an alkynyl group described herein refers to both unsubstituted and substituted alkynyl groups.

[0033] As used herein, the terms “carbocyclyl” and “carbocycle” refer to a monovalent nonaromatic, saturated, or partially unsaturated, or aromatic ring having carbon atoms, including monocyclic, fused or spiro polycyclic carbocycles, and is intended to encompass monovalent and multivalent carbocyclylic groups. In one example, the carbocyclyl is a 5-7-membered carbocyclyl (i.e., having 5-7 carbon atoms). In one example, the carbocyclyl is a 3-7-membered carbocyclyl (i.e., having 3-7 carbon atoms). A carbocyclyl group may, for example, be mono- cyclic or polycyclic (i.e. bicyclic, tricyclic). A polycyclic carbocyclyl group may contain fused rings. Examples of monocyclic carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1 -cyclopent- 1-enyl, l-cyclopent-2-enyl, 1 -cyclopent-3 -enyl, cyclohexyl, 1 -cyclohex- 1-enyl, l-cyclohex-2-enyl, 1 -cyclohex-3 -enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like. Examples of monocyclic, aromatic carbocyclyl group include, but are not limited to, phenyl and naphthal enyl.

[0034] In some embodiments, the carbocyclyl group is a “cycloalkyl” group. As used herein, the term “cycloalkyl” or “cycloalkyl group” refers to a saturated or partially saturated, mono- cyclic, fused or spiro polycyclic, carbocycle, and is intended to encompass monovalent and multivalent cycloalkyl groups. The cycloalkyl group may have from 3 to 10 carbon atoms per ring, denoted Cs-iocycloalkyl (or -cyclicCs-ioalkyl), from 3 to 8 carbon atoms per ring (or - cyclicCs-salkyl), denoted Cs-scycloalkyl, from 3 to 6 carbon atoms per ring, denoted Cs-ecyclo- alkyl, and the like. Examples of suitable cycoalkyl groups may include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[3.3]heptanyl, decalin and adamantyl.

[0035] In some embodiments, the carbocyclyl group is an “aryl” group. As used herein, the term “aryl” or “aryl group” refers to a monocyclic, or fused polycyclic, aromatic carbocycle (i.e., a ring structure having ring atoms that are all carbon), and is intended to encompass monovalent and multivalent aryl groups. The aryl group may have from 6-10 carbon atoms per ring, denoted Ce-ioaryl. In some embodiments, the aryl group may be a Ce group (i.e., phenyl). Examples of suitable aryl groups may include, but are not limited to, phenyl, naphthyl, phenanthryl. As used herein, the term “aryl” is also intended to encompass optionally substitutedpartially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.

[0036] As used herein, the term “heterocyclyl” refers to an aromatic or non-aromatic cyclic group which is analogous to a carbocyclyl group, but in which from one or more of the carbon atoms is / are replaced by one or more heteroatoms (e.g., from one to four, one to three, or one to two heteroatoms) independently selected from nitrogen (N), oxygen (O), and sulfur (S) , and is intended to encompass monovalent and multivalent heterocyclyl groups. It is to be understood that when the heteratom is a sp3hybridised nitrogen (N), it is substituted with hydrogen (H). A heterocyclyl group may, for example, be monocyclic, polycyclic (e.g. bicyclic) or spi- rocyclic. A polycyclic heterocyclyl may for example contain fused rings. In a bicyclic heterocyclyl group, there may be one or more heteroatoms in each ring, or heteroatoms only in one of the rings. Heterocyclyl groups containing a suitable nitrogen atom include the corresponding N-oxides. In one example, the heterocyclyl group is a 5-7-membered heterocyclyl. In one example, the heterocyclyl group is a 3-7-membered heterocyclyl. Examples of monocyclic non- aromatic heterocyclyl groups include aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyra- zolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, thiomor- pholinyl and azepanyl. Examples of bicyclic heterocyclyl groups in which one of the rings is non-aromatic include, but are not limited to, dihydrobenzofuranyl, indanyl, indolinyl, isoin- dolinyl, tetrahydroisoquinolinyl, tetrahydroquinolyl, and benzoazepanyl. Examples of mono- cyclic aromatic heterocyclyl groups (also referred to as monocyclic heteroaryl groups) include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyra- zolyl, and pyrimidinyl. Examples of bicyclic aromatic heterocyclyl groups (also referred to as bicyclic heteroaryl groups) include, but are not limited to, quinoxalinyl, quinazolinul, pyri- dopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuranyl, indolyl, indazolyl, benzothiazolyl, oxazolyl[4,5-b]pyridyl, pyridopyrimidinyl, iso- quinolinyl, and benzohydroxazole.

[0037] In some embodiments, the heterocyclyl group is a “heterocycloalkyl” group. As used herein, the term “heterocycloalkyl” or “heterocycloalkyl group” refers to a saturated or partially saturated, monocyclic, bicyclic, fused or spiro polycyclic carbocycles comprising one or more heteroatoms (e.g., from one to four heteroatoms, particularly from one to three heteroatoms) independently selected from O, N and S. The heterocycloalkyl group may be a 5-10 memberedheterocycloalkyl. Examples of suitable heterocycloalkyl groups may include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, quinuclidinyl, morpholinyl, diazaspiro[3.3]heptane (e.g., 2,6-diazaspiro[3.3]heptane), tetrahydrothiophenyl, tetrahydrofuranyl and tetrahydropyranyl. The heterocycloalkyl group may be a terminal group or a bridging group and may be attached through a heteroatom or any carbon ring atom.

[0038] In some embodiments, the heterocyclyl group is a “heteroaryl” group. As used herein, the term “aryl” or “aryl group” refers to a monocyclic, or fused polycyclic, aromatic carbocycle (i.e., a ring structure having ring atoms that are all carbon), and is intended to encompass monovalent and multivalent aryl groups. The aryl group may have from 6-10 carbon atoms per ring, denoted Ce-Cio-aryl. In some embodiments, the aryl group may be a Ce group (i.e., phenyl). Examples of suitable aryl groups may include, but are not limited to, phenyl, naphthyl, phenanthryl. As used herein, the term “aryl” is also intended to encompass optionally substituted partially saturated bicyclic aromatic carbocyclic moiety in which a phenyl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as tetrahydronaphthyl, indenyl or indanyl.

[0039] As used herein, the term “saturated” refers to a group where all available valence bonds of the backbone atoms are attached to other atoms. Representative examples of saturated groups include, but are not limited to, butyl, cyclohexyl, piperidine, and the like.

[0040] As used herein, the term “unsaturated” refers to a group where at least one valence bond of two adjacent backbone atoms is not attached to other atoms. Representative examples include, but are not limited to, alkenes (e.g., -CH2-CH2CH=CH), phenyl, pyrrole, and the like.

[0041] As used herein, the term “substituted” refers to a group having one or more hydrogens or other atoms removed from a carbon or suitable heteroatom and replaced with a further group (i.e., substituent).

[0042] As used herein, the term “unsubstituted” refers to a group that does not have any further groups attached thereto or substituted therefore.

[0043] The present disclosure relates to compounds of Formula I, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof. Salts may be formed in the case of embodiments of the compound of Formula I that contain a suitable acidic or basic group. Suitable salts of the compound of Formula I include those formed with organic or inorganic acids or bases.

[0044] As used herein, the phrase “pharmaceutically acceptable salt” refers to pharmaceutically acceptable organic or inorganic salts. Exemplary acid addition salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-tol- uenesulfonate, and pamoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Exemplary base addition salts include, but are not limited to, ammonium salts, alkali metal salts, for example those of potassium and sodium, alkaline earth metal salts, for example those of calcium and magnesium, and salts with organic bases, for example dicyclohexylamine, N-methyl-D- glucomine, morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethyl -propylamine, or a mono-, di- or trihydroxy lower alkylamine, for example mono-, di- or triethanolamine. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion. The counterion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterion. It will also be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the present disclosure since these may be useful as intermediates in the preparation of pharmaceutically acceptable salts or may be useful during storage or transport.

[0045] Those skilled in the art of organic and / or medicinal chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as “solvates”. For example, a complex with water is known as a “hydrate”. As used herein, the phrases “pharmaceutically acceptable solvate” or “solvate” refer to an association of one or more solvent molecules and a compound of the present disclosure. Examples of solvents that form pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. It will be understood that the present disclosure encompasses solvated forms, including hydrates, of the compounds of Formula I and salts thereof.

[0046] As used herein, the term “tautomer” refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another.

[0047] As used herein, the term “stereoisomer” refers to compounds having the same molecular formula and sequence of bonded atoms (i.e., atom connectivity), though differ in the three- dimensional orientations of their atoms in space. As used herein, the term “enantiomers” refers to two compounds that are stereoisomers in that they are non-superimposable mirror images of one another. Relevant stereocenters may be donated with (R)- or (S)- configuration.

[0048] Those skilled in the art of organic and / or medicinal chemistry will appreciate that the compounds of Formula I, or pharmaceutically acceptable salts, solvates, or stereoisomers thereof, may be present in amorphous form, or in a crystalline form. It will be understood that the present disclosure encompasses all forms and polymorphs of the compounds of Formula I or pharmaceutically acceptable salts, solvates, or stereoisomers thereof.Compounds of Formula I

[0049] The present disclosure provides compounds of Formula I:Formula I; wherein Y1is CH or N; Y2is C(O) or C(OH); R1is -H or -Ci-6-alkyl; Ring X is a 5-membered carbocycle or 5-membered heterocycle; wherein Ring X is optionally substituted with one or more R2; if present, each R2is independently selected from the group consisting of -halogen, - Ci-salkyl, -OH, -O(Ci-3alkyl), -NH2, -N(H)(-Ci-3alkyl), -N(Ci-3alkyl)(Ci-3alkyl), and -CF3; L is a bond or -Ci-salkylene-; Ring Z is a 5-10-membered carbocyclyl or 5-10-membered heterocy- clyl; wherein Ring Z is optionally substituted with one or more R3; if present, each R3is independently selected from the group consisting of -halogen, -Ci-salkyl optionally substituted with one or more R5, -Ci-salkenyl optionally substituted with one or more R5, -Ci-salkynyl optionally substituted with one or more R5, -C(R4)3, -O(R4), -N(R4)2, -OC(R4)3, -Ci-8alkyl-O(R4), -O-Ci- salkyl-O(R4), -3-7-membered carbocyclyl optionally substituted with one or more R5, -3-7- membered heterocyclyl optionally substituted with one or more R5, -Ci-8alkyl-N(R4)2, -O-Ci-8alkyl-N(R4)2, -C(O)O(R4), -OC(O)(R4), -CN, -NO2, -S(O)2R4, -S(O)2N(R4)2, -N(H)SO2(R4), -(O), -N(R4)-Ci-8alkyl-N(R4)2, -N(R4)-Ci-8alkyl-O(R4), -N(R4)Ci-4alkyl optionally substituted with one or more R5, -O-Ci-8alkyl-(R4)3, -O-Ci-salkyl optionally substituted with one or more R5, -O-Ci-8alkenyl-(R4)3, -O-Ci-salkenyl optionally substituted with one or more R5, O-Ci-sal- kynyl-(R4)3, -O-Ci-salkynyl optionally substituted with one or more R5, and -O-cyclicCi-salkyl- (R4)S; if present, each R4is independently selected from the group consisting of -H, -halogen, and -Ci-ealkyl; if present, each R5is independently selected from the group consisting of -halogen, -OH, -N(R4)2, -OCi-4alkyl, -C(O)N(R4)2, -C3-6cycloalkyl optionally substituted with one or two R6, 4-6-membered heterocyclyl comprising one or two heteroatoms independently selected from N, O or S and optionally substituted with one or two R6; and if present, each R6is independently selected from the group consisting of -halogen, -OH, -CF3, -halogen, and -Ci- 3alkyl; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0050] In some embodiments, the compound of Formula I is a compound of Formula IA:Formula I A; wherein — is a single or double bond; Y1is CH or N; Y2is C(O) or C(OH); R1is -H or -Ci-6- alkyl; Ring X is a 5-membered carbocycle or 5-membered heterocycle; wherein X1and X4are each independently C or N; X2and X3are each independently CH, CH2, O, S, or N; X5is N, O, CH, CH2, C(O), or S; wherein Ring X is optionally substituted with one or more R2; if present, each R2is independently selected from the group consisting of - -halogen, -Ci-salkyl, -OH, - O(Ci-3alkyl), -NH2, -N(H)(-Ci-3alkyl), -N(Ci-3alkyl)(Ci-3alkyl), and -CF3; L is a bond or -Ci- salkylene-; Ring Z is a 5-10-membered carbocyclyl or 5-10-membered heterocyclyl; wherein Ring Z is optionally substituted with one or more R3; if present, each R3is independently selected from the group consisting of -halogen, -Ci-salkyl, -Ci-salkenyl, -C(R4)3, -O(R4), -N(R4)2, -OC(R4)3, -Ci-8alkyl-O(R4), -O-Ci-8alkyl-O(R4), -3-7-membered carbocyclyl, -3-7-membered heterocyclyl, -Ci.8alkyl-N(R4)2, -O-Ci.8alkyl-N(R4)2, -C(O)O(R4), -OC(O)(R4), -CN, -NO2, - S(O)2R4, -S(O)2N(R4)2, -N(H)SO2(R4), -(O), -N(R4)-Ci.8alkyl-N(R4)2, -N(R4)-Ci.8alkyl-O(R4), -O-Ci-8alkyl-(R4)3, and -O-cyclicCi-8alkyl-(R4)3; wherein each -Ci-salkyl, -Ci-salkenyl, -3-7- membered carbocyclyl, and -3-7-membered heterocyclyl is optionally substituted with one or more -halogen; and if present, each R4is independently selected from the group consisting of -H, -halogen, and -Ci-ealkyl; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0051] It is to be understood that, unless otherwise specified, any reference herein to a group of members, such as a group of substituents (e.g., Y1, Y2, X1, X2, X3, X4, X5, L, R1, R2, R3, Ring X, Ring Z or Ring Z) is intended to be a disclosure of each individual member of that group, as well as any combination or sub-group of any number of members of that group.

[0052] In some embodiments of the compounds of Formula I, — is a single bond. In some embodiments, — is a double bond. In one example, Ring X contains five single bonds. In one example, Ring X contains one double bond and four single bonds. In one example, Ring X contains two double bonds and three single bonds. It is to be understood that each — is to be selected so as to maintain acceptable valency.

[0053] In some embodiments of the compounds of Formula I, Y1is CH or N. In one example, Y1is CH. In one example, Y1is N.

[0054] In some embodiments of the compounds of Formula I, Y2is C(O) or C(OH). In one example, Y2is C(O). In one example, Y2is C(OH).

[0055] In the compounds of Formula I, the 6-membered ring comprising Y1and Y2is termed herein as “Ring Y”. In some embodiments, Ring Y is selected from the group consisting of:Yd, wherein R1is -H or -Ci-ealkyl.

[0056] It will be appreciated that eachdenotes the point of attachment to the remainder of the compound of Formula I.

[0057] In some embodiments, Ring Y is selected from the group consisting of Ya and Yb, wherein R1is -H or -Ci-6-alkyl.

[0058] In some embodiments, Ring Y is selected from the group consisting of Yc; and Yd, wherein R1is -H or -Ci-6-alkyl.

[0059] In some embodiments, R1is -H or -Ci-ealkyl. In some embodiments, R1is -H or -Ci- salkyl. In one example, R1is -H. In one example, R1is -Ci-ealkyl. In one example, R1is -Cialkyl (e.g., -CH3). In one example, R1is -C2alkyl (e.g., -CH2CH3). In one example, R1is -Csalkyl (e.g., -CH2CH2CH3, CH(CH3)2). In one example, R1is -C4alkyl. In one example, R1is -Csalkyl. In one example, R1is -Cealkyl.

[0060] In some embodiments, Ring Y is selected from the group consisting of:

[0061] In some embodiments, Ring Y is selected from the group consisting of Yai, Ybi; Yaii; and Ybii.

[0062] In some embodiments, Ring Y is selected from the group consisting of Yci, Ydi, Ycii, Ydii, and tautomers thereof.

[0063] In some embodiments, Ring Y is Yc, wherein R1is -H or -Ci-6-alkyl. In some embodiments, Ring Y is Yd, wherein R1is -H or -Ci-6-alkyl.

[0064] In some embodiments, Ring Y is Yai. In some embodiments, Ring Y is Ybi. In some embodiments, Ring Y is Yaii. In some embodiments, Ring Y is Ybii.

[0065] In the compounds of Formula I, the 5-membered ring comprising X1, X2, X3, X4, and X5is termed herein as “Ring X”. In some embodiments, Ring X is a 5-membered carbocycle (i.e., each of X1, X2, X3, X4, and X5is C). In some embodiments, Ring X is a 5-membered heterocycle (i.e., at least one of X1, X2, X3, X4, or X5is an atom other than C). It will be appreciated that any suitable combination of X1, X2, X3, X4, and X5substituents may be utilized to form Ring X, provided acceptable atom / bond valency is maintained. That is, Ring X may be saturated, partially saturated, or unsaturated.

[0066] In some embodiments of the compounds of Formula I, X1and X4are each independently C or N. In some embodiments, X1is C or N. In one example, X1is C. In one example, X1is N. In some embodiments, X4is C or N. In one example, X4is C. In one example, X4is N.

[0067] In some embodiments of the compounds of Formula I, X2and X3are each independently CH, CH2, O, S, or N. In some embodiments, X2is CH, CH2, O, S, or N. In one example, X2is CH. In one example, X2is CH2. In one example, X2is O. In one example, X2is S. In one example, X2is N. In some embodiments, X3is CH, CH2, O, S, orN. In one example, X3is CH. In one example, X3is CH2. In one example, X3is O. In one example, X3is S. In one example, X3is N.

[0068] In some embodiments of the compounds of Formula I, X5is N, O, CH, CH2, C(O), or S. In one example, X5is N. In one example, X5is O. In one example, X5is CH. In one example, X5is CH2. In one example, X5is C(O). In one example, X5is S.

[0069] In some embodiments of the compounds of Formula I, Ring X is selected from the group consisting of:Xd; Xe; Xf;Xg; Xh; and Xi; wherein Ring X is optionally substituted with one or more R2; and, if present, each R2is independently selected from the group consisting of -halogen, -Ci-salkyl, -OH, -O(Ci-3alkyl), -NH2, -N(H)(-Ci-3alkyl), -N(Ci-3alkyl)(Ci-3alkyl), and -CF3. In some embodiments, Ring X is not substituted with R2.

[0070] Again, it will be appreciated that eachdenotes the point of attachment to the remainder of the compound of Formula I. It is to be understood that each Ring X may be attached to Ring Y and Ring Z in either orientation. By way of example, when Ring X is Xa, the compound of Formula I may have either orientation as follows:

[0071] In some embodiments, X is selected from the group consisting of Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi.

[0072] In some embodiments of the compounds of Formula I, Ring X is selected from the group consisting of Xa, Xb and Xe, optionally substituted with one or more R2.

[0073] In some embodiments of the compounds of Formula I, Ring X is selected from the group consisting of Xa and Xb.

[0074] In some embodiments of the compounds of Formula I, Ring X is selected from the group consisting of Xa and Xb.

[0075] In some embodiments of the compounds of Formula I, L is a bond or -Ci-salkylene (e.g., Cialkylene, C2alkylene, Csalkylene, C4alkylene, Csalkylene, Cealkylene, C?alkylene, or Csal- kylene). In one example, L is a bond. When L is a bond, it will be appreciated that X4is directly bonded to Ring Z.

[0076] In some embodiments of the compounds of Formula I, Ring Z is a 5-10-membered car- bocyclyl or 5-10-membered heterocyclyl. In one example, Ring Z is a 5-10-membered carbo- cyclyl (e.g., 7-10-, 8-10-, 9-10-, 5-, 6-, 7-, 8-, 9-, or 10-membered carobcycle). In one example, Ring Z is a 5-10-membered heterocyclyl (e.g., 7-10-, 8-10-, 9-10-, 5-, 6-, 7-, 8-, 9-, or 10- membered heterocyclyl).

[0077] In some embodiments of the compounds of Formula I, Ring Z is selected from the groupwherein Ring Z is optionally substituted with one or more R3; if present, R3, R4, R5and R6are as defined herein for Formula I or Formula IA. In some embodiments, Ring Z is not substituted with R3.

[0078] In some embodiments of the compounds of Formula I, Ring Z is a 5-membered carbocycle or 5-membered heterocycle. In one example, Ring Z is a 5-membered carbocycle. In some embodiments, Ring Z is a 5-membered carbocycle of Formula II:Formula II; wherein — is a single or double bond; n is 0-8; and if present, R3is as defined herein for Formula I or Formula IA.

[0079] In one example, in Formula II, n is 0 (i.e., R3is not present). In one example, in Formula II, n is 1-8 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8). In one example, in Formula II, n is 8. It will be appreciated that R3may be substituted at any suitable position, or combination of positions, on the 5-membered carbocycle. In some embodiments, Formula II is selected from the following, nonlimiting examples:

[0080] wherein — is a single or double bond; and each R3is as defined herein for Formula I or Formula lA.In some embodiments of the compounds of Formula I, Ring Z is a 5-membered heterocycle of Formula III:Formula III; wherein — is a single or double bond; n is 0-8; and if present, each R3is as defined herein for Formula I or Formula IA.

[0081] In one example, in Formula III, n is 0 (i.e., R3is not present). In one example, in Formula III, n is 1-8 (e.g., 1, 2, 3, 4, 5, 6, 7 or 8). It will be appreciated that R3may be substituted at any suitable position, or combination of positions, on the 5-membered carbocycle.

[0082] In some embodiments, Formula III is selected from the following, non-limiting examples:wherein — is a single or double bond; X is independently selected from C, N, O, and S, provided at least one of X is not C; and each R3is as defined herein for Formula I or Formula IA. In some embodiments of the compounds of Formula I, Ring Z is a 5-membered heterocycle selected from the group consisting of Za, Zi, Zj, Zn, Zu, Zai, Zaj, Zak, Zal, Zam, Zan, Zao, Zap, and Zaq, optionally substituted with one or more R3; if present, each R3is as defined herein for Formula I or Formula IA.

[0083] In some embodiments of the compounds of Formula I, Ring Z is a 6-membered heterocycle selected from the group consisting of Zb, Zc, Zf, Zg, Zh, Zl, Zo, Zs, Zx, Zag, Zar, and Zas, optionally substituted with one or more R3; if present, each R3is as defined herein for Formula I or Formula IA.

[0084] In some embodiments of the compounds of Formula I, Ring Z is a 9-membered heterocycle selected from the group consisting of Ze, Zk, Zm, Zp, Zq, Zr, Zt, Zv, Zy, Zaa, Zac, Zaf, Zat, Zau, Zav, Zaw, Zax, Zay, Zaz, Zba, Zbb, Zbc, Zbd, Zbe, Zbf, Zbg, Zbh, Zbi, Zbj, Zbk, Zbl, Zbm, Zbn, Zbo, Zbp, Zbq, Zbr, Zbs, Zbt, Zbu, Zbv, Zbw, Zbx, Zby, Zch, Zci, and Zcj, optionally substituted with one or more R3; if present, each R3is as defined herein for Formula I or Formula IA.

[0085] In some embodiments of the compounds of Formula I, Ring Z is a 10-membered heterocycle selected from the group consisting of Zd, Zw, Zz, Zab, Zae, Zbz, Zea, Zeb, Zee, Zed,Zcf, and Zcg, optionally substituted with one or more R3; if present, each R3is as defined herein for Formula I or Formula IA.

[0086] In some embodiments of the compounds of Formula I, Ring Z is optionally substituted with one or more R3. It will be appreciated that when an atom of Ring Z is not optionally substituted with R3, it is implicit hydrogen atoms will instead be bonded to the atom of Ring Z to maintain correct valency. For example, when Ring Z is an unsaturated 6-membered carbocyclyl(i.e., phenyl), Ring Z is optionally substituted (in any position or combination of positions on the cycle) with one to five R3as follows:wherein each R3is as defined herein for Formula I or Formula IA. It will be appreciated that, if present, each R3may be the same or otherwise different.

[0087] In some embodiments of the compounds of Formula I, when R3is -Ci-salkyl, -Ci- salkenyl, -Ci-salkynyl, -O-Ci-salkyl, -O-Ci-salkenyl, -O-Ci-salkynyl, -3-7-membered carbocyclyl, or -3-7-membered heterocyclyl, each -Ci-salkyl, -Ci-salkenyl, -3-7-membered carbocyclyl, or -3-7-membered heterocyclyl is optionally substituted with one or more -halogen (e.g., -Cl, - Br, -F, -I). In one example, R3is optionally substituted with one or more -halogen.

[0088] In the compounds of Formula I, it will be appreciated that, if present, each R4may be the same or otherwise different.

[0089] In the compounds of Formula I, it will be appreciated that, if present, each R5may be the same or otherwise different.

[0090] In the compounds of Formula I, it will be appreciated that, if present, each R6may be the same or otherwise different.

[0091] In some embodiments, the compound of Formula I is not a compound selected from the group consisting of:4-(5-(6-oxo- 1 ,6-dihydropyridazin-3 -yl)- 1,3,4- 3 -(5-(6-oxo- 1 ,6-dihydropyridazin-3 -yl)- 1,3,4- oxadiazol-2-yl)benzoic acid;5-(5-(pyridin-3-yl)-l,2,4-oxadiazol-3-yl)pyri- 5-(3-(4-(tri fluoromethoxy)phenyl)- 1,2,4- din-2(lH)-one; oxadiazol-5-yl)pyridin-2(lH)-one;6-(3-(4-(trifluorom ethoxy )phenyl)- 1,2,4- 6-(3-(4-(2,2,2-trifluoroethyl)phenyl)-l,2,4- oxadiazol-5-yl)pyridazin-3(2H)-one; oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(4-(trifluorom ethoxy )phenyl)- 1,2,4- 6-(3-(4-fluorophenyl)-l,2,4-oxadiazol-5- oxadiazol-5-yl)pyridazin-3(2H)-one; yl)pyridazin-3(2H)-one;6-(3-(o-tolyl)-l,2,4-oxadiazol-5-yl)pyridazin- 6-(3-(m-tolyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one; 3(2H)-one;6-(3-(3-(trifluoromethyl)phenyl)-l,2,4-oxadia- 6-(3-(2-methoxyphenyl)-l,2,4-oxadiazol-5- zol-5-yl)pyridazin-3(2H)-one; yl)pyridazin-3(2H)-one;6-(3 -(3 -methoxyphenyl)- 1 ,2,4-oxadiazol-5- 6-(3-(3-Chlorophenyl)-l,2,4-oxadiazol-5- yl)pyridazin-3(2H)-one; yl)pyridazin-3(2H)-one;6-(3-(4-chlorophenyl)-l,2,4-oxadiazol-5- 3 -(5 -(6-oxo- 1 , 6-dihy dropyridazin-3 -yl)- 1 ,2,4- yl)pyridazin-3(2H)-one; oxadiazol-3-yl)benzoic acid;6-(3-(2-(trifluoromethyl)pyridin-4-yl)- 1,2,4- 6-(3 -(3 -fluorophenyl)- 1 ,2,4-oxadiazol-5 - oxadiazol-5-yl)pyridazin-3(2H)-one; yl)pyridazin-3(2H)-one;6-(3 -(2 -fluorophenyl)- 1, 2, 4-oxadiazol-5- 6-(3-(2-chlorophenyl)-l,2,4-oxadiazol-5- yl)pyridazin-3(2H)-one; yl)pyridazin-3(2H)-one;6-(3-Phenyl-l,2,4-oxadiazol-5-yl)pyridazin- 6-( 1 -Phenyl- lH-pyrazol-4-yl)pyridazin-3(2H)-one; 3(2H)-one;6-(3-(Pyridin-3-yl)-l,2,4-oxadiazol-5- 6-(3 -(pyri din-2 -yl)- 1 ,2,4-oxadiazol-5- yl)pyridazin-3(2H)-one; yl)pyridazin-3(2H)-one;6-(3-(4-(trifluoromethyl)phenyl)- 1,2,4- 6-(3-(4-methoxyphenyl)-l,2,4-oxadiazol-5- oxadiazol-5-yl)pyridazin-3(2H)-one; yl)pyridazin-3(2H)-one;6-(3-(pyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyri- 6-(3-(p-tolyl)-l,2,4-oxadiazol-5-yl)pyridazin- dazin-3(2H)-one; 3(2H)-one;, , hylpropan-2-6-(3-(5-chloropyridin-3-yl)-l,2,4-oxadiazol-5- yl)phenyl]-l,2,4-oxadiazol-5-yl}pyridin- yl)pyridazin-3(2H)-one; 2(lH)-one, , yl)phenyl]- 1 ,2,4-oxadiazol-5-yl Jpyridazin- 6-(3-(4-(difluorom ethoxy )phenyl)- 1,2,4- 3(2H)-one oxadiazol-5-yl)pyridazine-3(2H)-one4-(6-hydroxypyri din-3 -yl)-2-pyri din-2 -yl- 1,2- 6-[3-(l,3-benzodioxol-5-yl)-l,2,4-oxadiazol- dihydro-3H-pyrazol-3-one 5-yl]pyridazine-3(2H)-one; and2-ethyl-6-[3-(l-methyl-lH-pyrazol-5-yl)- l,2,4-oxadiazol-5-yl]pyridazine-3(2H)-one.

[0092] In some embodiments, the compound of Formula I is not a compound as disclosed in any of WO 2023 / 091606 Al, WO 2022 / 261296 Al, WO 2018 / 231745 Al, WO 2020 / 132700 Al, WO 2022 / 035805 Al, US 2014 / 0329797 Al, WO 2014 / 031928 A2, and AU 2006239580 Al, the entire contents of which are incorporated herein by cross-reference.

[0093] In some embodiments, the compound of Formula I is a compound of Formula li:Formula li; wherein Y1, Y2, R1, Ring X, X1, X2, X3, X4, X5, and, if present, R2are as defined herein for Formula IA, and Ring Z and, if present, R3are as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0094] In some embodiments, the compound of Formula I is a compound of Formula la:Formula la; wherein — , Y1, Y2, Ring X, X1, X2, X3, X4, X5, L and and, if present, R2are as defined herein for Formula IA, and Ring Z and, if present, R3are as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0095] In some embodiments, the compound of Formula I is a compound of Formula lai:Formula lai; wherein — , Y1, Y2, Ring X, X1, X2, X3, X4, X5, and, if present, R2are as defined herein for Formula IA, and Ring Z and, if present, R3are as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0096] In some embodiments, the compound of Formula I is a compound of Formula lb:wherein — , Y1, Ring X, X1, X2, X3, X4, X5, L and, if present, R2are as defined herein for Formula IA, and Ring Z and, if present, R3are as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0097] In some embodiments, the compound of Formula I is a compound of Formula Ibi :wherein Y1, Ring X, X1, X2, X3, X4, X5and, if present, R2are as defined herein for Formula IA, and Ring Z and, if present, R3are as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0098] In some embodiments, the compound of Formula I is a compound of Formula Ic:wherein Ring X, X1, X2, X3, X4, X5, L and, if present, R2are as defined herein for Formula IA, and Ring Z and, if present, R3are as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0099] In some embodiments, the compound of Formula I is a compound of Formula Ic:Formula Ic; wherein L and, if present, R2are as defined herein for Formula IA; Ring X is selected from the group consisting of Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi; and Ring Z and, if present, R3are as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0100] In some embodiments, the compound of Formula I is a compound of Formula Ici:wherein Ring X, X1, X2, X3, X4, X5and, if present, R2are as defined herein for Formula IA, and Ring Z and, if present, R3are as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0101] In some embodiments, the compound of Formula I is a compound of Formula Ici:wherein Ring X is selected from the group consisting of Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi;if present, R2is as defined herein for Formula IA; and Ring Z and, if present, R3are as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0102] In some embodiments, the compound of Formula I is a compound of Formula Ici:wherein Ring X is selected from the group consisting of Xa and Xb; if present, R2is as defined herein for Formula IA; and Ring Z and, if present, R3are as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0103] It will be appreciated that any combination of Y, X, and Z, as described herein, may form a compound of Formula I. In one example, Ring Y is Ybi, Ring X is Xa, and the compound of Formula I is a compound of Formula Id:wherein L is as defined herein for Formula IA, and Ring Z and, if present, R3are as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0104] In one example, Ring Y is Ybi, Ring X is Xa, and the compound of Formula I is a compound of Formula Idi:wherein Ring Z is a 5-10-membered carbocyclyl or 5-10-membered heterocyclyl; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0105] In some embodiments, the compound of Formula I is a compound of Formula Idi;Formula Idi; wherein Ring Z is a 5-membered carbocyclyl, a 7-10-membered carbocyclyl, or a 5-10-mem- bered heterocyclyl; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0106] That is, in some embodiments, Ring Z is a 5-membered carbocyclyl, 7-10-membered carbocyclyl, or a 5-10-membered heterocyclyl. In some embodiments, Ring Z is not a 6-mem- bered carbocyclyl.

[0107] In some embodiments, the compound of Formula I is a compound of Formula Ici:wherein Y1, Y2, R1, Ring X, X1, X2, X3, X4, X5and, if present, R2are as defined herein for Formula IA; Ring Z is selected from the group consisting of Za, Zb, Zc, Zd, Ze, Zf, Zg, Zh, Zi, Zj, Zk, Zl, Zm, Zn, Zo, Zp, Zq, Zr, Zs, Zt, Zu, Zv, Zw, Zx, Zy, Zz, Zaa, Zab, Zac, Zad, Zae, Zaf, Zag, Zah, Zai, Zak, Zal, Zao, Zaq, Zat, Zav, Zax, Zay, Zba, Zbc, Zbf, Zbg, Zbh, Zbi, Zbj, Zbk, Zbv, Zbw, Zbz, Zea, Zeb, Zch, Zci, and Zcj; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0108] In some embodiments, the compound of Formula I is a compound of Formula Idi:Formula Idi; wherein Ring Z is a 5-membered carbocyclyl, a 7-10-membered carbocyclyl, a 5-membered heterocyclyl or a 7-10-membered heterocyclyl; R3is as defined herein for Formula I of Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0109] That is, in some embodiments, Ring Z is a 5-membered carbocyclyl, 7-10-membered carbocyclyl, a 5-membered heterocyclyl, or a 7-10-membered heterocyclyl. In some embodiments, Ring Z is not a 6-membered carbocyclyl. In some embodiments, Ring Z is not a 6- membered heterocyclyl.

[0110] In some embodiments, the compound of Formula I is a compound of Formula Ici:Formula Ici;wherein Ring X, X1, X2, X3, X4, X5, and, if present, R2are as defined herein for Formula IA; Ring Z is selected from the group consisting of Za, Zd, Ze, Zi, Zj, Zk, Zm, Zn, Zp, Zq, Zr, Zt, Zu, Zy, Zw, Zy, Zz, Zaa, Zab, Zac, Zad, Zae, and Zaf; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0111] In some embodiments, the compound of Formula I is a compound of Formula Ici:wherein Ring X, X1, X2, X3, X4, X5and, if present, R2are as defined herein for Formula IA; Ring Z is Zu; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0112] In some embodiments, the compound of Formula I is a compound of Formula Ici:wherein Ring X, X1, X2, X3, X4, X5and, if present, R2are as defined herein for Formula IA; Ring Z is Zp; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0113] In some embodiments, the compound of Formula I is a compound of Formula Idi:Formula Idi;wherein Ring X, X1, X2, X3, X4, X5and, if present, R2are as defined herein for Formula IA; Ring Z is Zu; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0114] In some embodiments, the compound of Formula I is a compound of Formula Idi:Formula Idi; wherein Ring X, X1, X2, X3, X4, X5and, if present, R2are as defined herein for Formula IA; Ring Z is Zp; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0115] In some embodiments, the compound of Formula I is a compound of Formula li:Formula li; wherein Y1, Y2, R1, Ring X, X1, X2, X3, X4, X5and, if present, R2are as defined herein for Formula IA; Ring Z is Zu; and, if present, R3are as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0116] In some embodiments, the compound of Formula I is a compound of Formula li:Formula li;wherein Y1, Y2, R1, Ring X, X1, X2, X3, X4, X5and, if present, R2are as defined herein for Formula IA; Ring Z is Zp; and, if present, R3are as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0117] In some embodiments, the compound of Formula I is a compound of Formula Ih:wherein Y1, Y2, R1, and L are as defined herein for Formula IA; Ring Z is Zu; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0118] In some embodiments, the compound of Formula I is a compound of Formula Ih:wherein Y1, Y2, R1, and L are as defined herein for Formula IA; Ring Z is Zp; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0119] In some embodiments, the compound of Formula I is a compound of Formula Ihi:Formula Ihi;wherein Ring Z is Zu; and , if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0120] In some embodiments, the compound of Formula I is a compound of Formula Ihi:Formula Ihi; wherein Ring Z is Zp; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0121] In some embodiments, the compound of Formula I is a compound of Formula Iji:Formula Iji; wherein Y1, Y2and R1are as defined herein for Formula IA; Ring Z is a 5-membered hetero- cyclyl; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0122] In some embodiments, the compound of Formula I is a compound of Formula Iki:Formula Iki; wherein Ring Z is a 5-membered heterocyclyl; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0123] In some embodiments, the compound of Formula I is a compound of Formula Hi:Formula Hi; wherein, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0124] In some embodiments, the compound of Formula I is a compound of Formula Iji:Formula Iji; wherein Y1, Y2and R1are as defined herein for Formula IA Ring Z is a 9-membered heterocy- clyl; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0125] In some embodiments, the compound of Formula I is a compound of Formula Iki:Formula Iki; wherein Ring Z is a 9-membered heterocyclyl; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0126] In some embodiments, the compound of Formula I is a compound of Formula Imi:Formula Imi;wherein, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0127] In some embodiments, the compound of Formula I is a compound of Formula Ini:Formula Ini; wherein Y1, Y2, and R1are as defined herein for Formula IA; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0128] In some embodiments, the compound of Formula I is a compound of Formula loi:Formula loi; wherein Y1, Y2, and R1are as defined herein for Formula IA; and, if present, R3is as defined herein for Formula I or Formula IA; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0129] In some embodiments, the compound of Formula I is a compound of Formula le:wherein:Y1is CH or N;R1is -H or -Ci-6-alkyl;Ring A is 5-membered heterocyclyl comprising from one to three heteroatoms independently selected from N, O or S and optionally substituted with one or two R2; if present, each R2is independently -Ci-salkyl;Ring B is -Ce-ioaryl, or 5-10-membered heterocyclyl comprising from one to four heteroatoms independently selected from N, O or S and optionally substituted with from one to three R3; if present, each R3is independently selected from the group consisting of -halogen, - OH, -N(R4)2, -NO2, -SO2-NH2, -SO2-CH3, -Ci-ealkyl optionally substituted with from one to three R5, -C2-ealkenyl optionally substituted with from one to three R5, -C2-ealkynyl optionally substituted with from one to three R5, -OCi-ealkyl optionally substituted with from one to three R5, -OC2-ealkenyl optionally substituted with from one to three R5, -OC2-6alkynyl optionally substituted with from one to three R5, -C(O)OH, -C(O)OCi-4alkyl, -N(R4)Ci-4alkyl optionally substituted with one R5, -Cs-ecycloalkyl optionally substituted with R7, -O-C3-6cycloalkyl optionally substituted with R7, and 4-6-membered heterocyclyl comprising one or two heteroatoms independently selected from N, O or S and optionally substituted with one R7; if present, each R4is independently selected from the group consisting of H and -Cisalkyl; if present, each R5is independently selected from the group consisting of -halogen, - OH, -N(R4)2, -OCi-4alkyl, -C(O)N(R4)2, -Cs-ecycloalkyl optionally substituted with one or two R6, 4-6-membered heterocyclyl comprising one or two heteroatoms independently selected from N, O or S and optionally substituted with one or two R6; if present, each R6is independently selected from the group consisting of -halogen, - OH, -CF3, and -Ci-salkyl; and if present, each R7is independently selected from the group consisting of -halogen, - OH, -CF3, -Ci-salkyl, and -OCi-salkyl; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0130] In some embodiments of the compounds of Formula le, Y1is N.

[0131] In some embodiments of the compounds of Formula le, R1is selected from the group consisting of -H and -Ci-salkyl. In an embodiment, R1is -H or -CH3. In one example, R1is -H.

[0132] In some embodiments, Ring A is Ring X as defined herein for Formula I, wherein Ring A is optionally substituted with from one to two R2. In some embodiments, Ring A is a 5- membered unsaturated heterocyclyl (i.e., heteroaryl) comprising from one to three heteroatoms independently selected from N, O or S and optionally substituted with one or two R2. In someembodiments, Ring A is selected from the group consisting of Xa, Xb, Xc, Xd, Xe, Xf, Xg, and Xi, wherein Ring A is optionally substituted with one or two R2.

[0133] In some embodiments of the compounds of Formula le, Ring A is selected from the group consisting of Xa, Xc and Xe, wherein Ring A is optionally substituted with one or two R2.

[0134] In some embodiments of the compounds of Formula le, Ring A is Xa, wherein Ring A is optionally substituted with one or two R2.

[0135] In some embodiments of the compounds of Formula le, Ring A is substituted with one R2. In some embodiments, Ring A is substituted with two R2. Each R2may be independently selected from -Ci-salkyl. The -Ci-salkyl may be a straight or branched chain -Ci-salkyl (e.g., methyl, ethyl, n-propyl or isopropyl). In some embodiments in which Ring A is substituted with two R2, each R2is -CEE. In some embodiments, Ring A is substituted with one R2. In some embodiments in which Ring A is substituted with one R2, R2is -CEE. In some embodiments, Ring A is unsubstituted with R2.

[0136] In some embodiments of the compounds of Formula le, Ring B is Ring Z as defined herein for Formula I, wherein Ring B is optionally substituted with from one to three R3. In some embodiments, Ring B is -Ce-ioaryl optionally substituted with from one to three R3. In an embodiment, Ring B is -Cearyl (i.e., phenyl) optionally substituted with from one to three R3.

[0137] In some embodiments of the compounds of Formula le, Ring B is 5-10-membered heterocyclyl comprising from one to four heteroatoms independently selected from N, O or S and optionally substituted with from one to three R3. In some embodiments, the 5-10-membered heterocyclyl comprises from one to three heteroatoms. In some embodiments, the 5-10-mem- bered heterocyclyl comprises one or two heteroatoms. In some embodiments, Ring B is a partially unsaturated or fully unsaturated 5-10-membered heterocyclyl. In some embodiments, Ring B is a 5-6-membered heterocyclyl or an 8-10-membered fused bicyclic heterocyclyl (e.g., 5+5, 6+5 or 6+6 fused bicyclic heterocyclyl).

[0138] In some embodiments of the compounds of Formula le, Ring B is a 5-membered heterocyclyl optionally substituted with from one to three R3. In some embodiments, Ring B is selected from the group consisting of Za, Zi, Zj, Zn, Zu, Zai, Zaj, Zak, Zal, Zam, Zan, Zao, Zap, and Zaq, wherein Ring B is optionally substituted with from one to three R3.

[0139] In an example, Ring B is Zu optionally substituted with one or two R3.

[0140] In some embodiments of the compounds of Formula le s, Ring B is a 6-membered heterocyclyl optionally substituted with from one to three R3. In some embodiments, Ring B is selected from the group consisting of Zb, Zc, Zf, Zg, Zh, Zl, Zo, Zs, Zx, Zag, Zar, and Zas, wherein Ring B is optionally substituted with from one to three R3.

[0141] In some embodiments of the compounds of Formula le, Ring B is an 8-membered fused bicyclic heterocyclyl (e.g., 5+5 fused hetercyclyl) optionally substituted with from one to three R3. In some embodiments, Ring B is Zat, optionally substituted with from one to three R3.

[0142] In some embodiments of the compounds of Formula le, Ring B is a 9-membered fused bicyclic heterocyclyl (e.g., 6+5 fused hetercyclyl) optionally substituted with from one to three R3. In some embodiments, Ring B is selected from the group consisting of Ze, Zk, Zm, Zp, Zq, Zr, Zt, Zv, Zy, Zaa, Zac, Zaf, Zat, Zau, Zav, Zaw, Zax, Zay, Zaz, Zba, Zbb, Zbc, Zbd, Zbe, Zbf, Zbg, Zbh, Zbi, Zbj, Zbk, Zbl, Zbm, Zbn, Zbo, Zbp, Zbq, Zbr, Zbs, Zbt, Zbu, Zbv, Zbw, Zbx, Zby, Zch, Zci, and Zcj, wherein Ring B is optionally substituted with from one to three R3.

[0143] In some embodiments of the compounds of Formula le, Ring B is a 10-membered fused bicyclic heterocyclyl (e.g., 6+6 fused hetercyclyl) optionally substituted with from one to three R3. In some embodiments, Ring B is selected from the group consisting of Zd, Zw, Zz, Zab, Zae, Zbz, Zea, Zeb, Zee, Zed, Zcf, Zcg, Zch, Zci, and Zcj, wherein Ring B is optionally substituted with from one to three R3.

[0144] In some embodiments of the compounds of Formula le, Ring B is substituted with one or two R3. In some embodiments, Ring B is substituted with one R3. In some embodiments, Ring B is substituted with two R3. In some embodiments, Ring B is substituted with three R3. In some embodiments, Ring B is unsubstituted with R3.

[0145] In some embodiments of the compounds of Formula le, R3, R5, R6and / or R7is / are - halogen (i.e., F, Cl, Br or I). In some embodiments, each -halogen is independently selected from F, Cl and Br. In some embodiments, each -halogen is selected from F and Cl.

[0146] In some embodiments of the compounds of Formula le, R3is selected from -Ci-ealkyl optionally substituted with from one to three R5, or one or two R5. For example, the -Ci-ealkyl may be a straight or branched chain -Ci-ealkyl, or a straight or branched chain -Ci-salkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl and t-pentyl). Similarly, in embodiments in which R3is selected from -C2-ealkenylor -C2-6alkynyl optionally substituted with from one to three R5, the -C2-ealkenyl or -C2-ealkynyl may be a straight or branched chain -C2-ealkenyl or -C2-ealkynyl, or a straight or branched chain -C2-ealkenyl or -C2-ealkynyl, or a straight or branched chain -C2-salkenyl or -C2-salkynyl. In some embodiments, each R5is selected from the group consisting of -halogen (e.g., F, Cl, Br or I), -OH, -NH2, -NHCH3, -N(CH3)2, -OCH3, -C(O)OH, -C(O)OCH3, -C(O)N(CH3)2, cyclopropyl, cyclopentyl, oxetanyl, tetrahydrofuranyl, morpholinyl, N-methylmorpholinyl, piperazi- nyl and N-methylpiperazinyl.

[0147] In some embodiments of the compounds of Formula le, R3is selected from the group consisting of -Ci-3alkyl-F (e.g., CH2F), -Ci-3alkyl-F2 (e.g., CHF2) and -Ci-3alkyl-F3(e.g., CF3). In some embodiments, R3is selected from the group consisting of -Ci-salkyl-OH, -Ci-salkyl- OCH3, -Ci-5alkyl-NH2, -Ci-5alkyl-NHCH3and -Ci-5alkyl-N(CH3)2. In some embodiments, R3is selected from the group consisting of -Ci-2alkyl-C(O)NH2, -Ci-2alkyl-C(O)NHCH3and -Ci- 2alkyl-C(O)N(CH3)2. In some embodiments, R3is selected from the group consisting of 2-hy- droxycyclopentylmethyl, 3-hydroxy-n-butanyl, 2,3-dihydroxypropyl, l-methyl-3-oxetanylme- thyl, 3-furanylmethyl, 1 -hydroxy -2 -trifluoroethyl, 2-hydroxy-3-trifluoropropyl, methylethoxylate and carboxymethyl.

[0148] In some embodiments of the compounds of Formula le, R3is -OCi-ealkyl optionally substituted with from one to three R5, or one or two R5. For example, the -OCi-ealkyl may be a straight or branched chain -OCi-ealkyl, preferably a straight or branched chain -OCi-salkyl, more preferably a straight or branched chain -OCi.4alkyl (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy). Similarly, in embodiments in which R3is -OC2- ealkenyl or -OC2-ealkynyl optionally substituted with from one to three R5(or one or two R5), the -OC2-ealkenyl or -OC2-ealkynyl may be a straight or branched chain -OC2-ealkenyl or -OC2- ealkynyl, preferably a straight or branched chain -OC2-salkenyl or -OC2-salkynyl, more preferably a straight or branched chain -OC2-4alkenyl or -OC2-4alkynyl. In some embodiments, each R5may be selected from the group consisting of -halogen (e.g., F, Cl, Br or I), -OH, -NH2, - NHCH3, -N(CH3)2, -OCH3, -C(O)N(CH3)2, tetrahydrofuranyl, N-trifluromethylmorpholinyl, and cyclopropyl.

[0149] In some embodiments of the compounds of Formula le, R3is selected from the group consisting of -OCi-3alkyl-F (e.g., OCH2F), -OCi-3alkyl-F2 (e.g., OCHF2) and -OCF3. In some embodiments, R3is selected from the group consisting of -OCi-salkyl-OH, -OCi-5alkyl-OCH3, -OCi-5alkyl-NH2, -OCi-5alkyl-NHCH3and -OCi-5alkyl-N(CH3)2. In some embodiments, R3isselected from the group consisting of -OCH2C(O)NH2, -OCi-salkyl-NHCHs and OCH2C(O)N(CH3)2. In an example, R3is cyclopropoxy.

[0150] In some embodiments of the compounds of Formula le, R3is -C(O)OCi-4alkyl. In some embodiments, R3is -C(O)OCi-3alkyl. In some embodiments, R3is -C(O)OCi-2alkyl. In an example, R3is -C(O)OCH3.

[0151] In some embodiments of the compounds of Formula le, R3is -N(R4)Ci-4alkyl optionally substituted with one R5. For example, the R3may be -N(R4)Ci-4alkyl, -N(R4)Ci-3alkyl, - N(R4)Ci-2alkyl or -N(R4)Cialkyl, optionally substituted with one R5. In some embodiments, R3is -N(R4)Ci-2alkyl optionally substituted with one R5. In some embodiments, R4is -H or -CH3. In some embodiments, R5may be -OH, morpholinyl optionally N-substituted with -CH3, or 1,4- diazinane.

[0152] In some embodiments of the compounds of Formula le, R3is selected from the group consisting of -NHCi-2alkyl-OH, -N(CH3)HCi-2alkyl-OH, -NHCi-2alkyl-OCH3, -N(CH3)Ci-2al- kyl-OCH3, -NHCi.2alkyl-NH2, -N(CH3)HCi.2alkyl-NH2, -NHCi-2alkyl-N(CH3)2, -N(CH3)HCI- 2alkyl-N(CH3)2, -NHCi.2alkyl-morpholinyl, -N(CH3)HCi-2alkyl-morpholinyl, -NHCi-2alkyl- piperazinyl and -NHCi.2alkyl-N-methyl-piperazinyl.

[0153] In some embodiments of the compounds of Formula le, R3is -C3-6cycloalkyl optionally substituted with one R7. For example, the -C3-6cycloalkyl may be selected from the group consisting of cyclopropyl, cylcobutyl, cyclopentyl or cyclohexyl. In an example, R3is -C3-scy- cloalkyl optionally substituted with one R7. Similarly, in embodiments in which R3is -OC3- ecycloalkyl optionally substituted with one R7, the -C3-6cycloalkyl may be selected from the group consisting of cyclopropoxy, cylcobutoxy, cyclopentoxy or cyclohexoxy. In an example, the -O-C3-6cycloalkyl is cyclopropoxy. In some embodiments, R7is -halogen, OH or CH3. In an example, the -C3-6cycloalkyl is unsubstituted with R7.

[0154] In some embodiments of the compounds of Formula le, R3is a 4-6-membered hetero- cycalkyl comprising one or two heteroatoms independently selected from N, O or S and optionally substituted with R7. By way of example, the 4-6-membered heterocyclyl may be selected from the group consisting of oxetane, azetidineoxetanyl, thietanyl, oxazetidinyl (e.g., 1,2-, 1,3 -oxazetidinyl), thiazetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, im- idazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,3 -ox- athiolanyl, piperidinyl, tetrahydropyranyl, hexahydrothiopyranyl, piperazinyl, diazinanyl (e.g., 1,2-, 1,3-, 1,4-diazinanyl), hexahydropyrazinyl, morpholinyl, and thiomorpholinyl. In anexample, the 4-6-membered heterocyclyl is pyrrolidinyl, morpholinyl, piperazinyl and N- methylpiperazinyl. In some embodiments, R7is -CH3, -CF3, -OCH3, or -OC(O)Ci-4alkyl. In some examples, R3is selected from the group consisting of 3-methoxypyrrolidinyl, t-butylpyr- rolidinyl-N-caboxylate (N-Boc-pyrrolidinyl) and 4-trifluromethylpiperidinyl.

[0155] In the compounds of Formula le, each R4may be -H or -Ci-3alkyl. In embodiments in which R4is -Ci-salkyl, it may be a straight or branched chain -Ci-3alkyl (e.g., methyl, ethyl, n- propyl or isopropyl). In an example, R4is H. In an example, R4is methyl (-CH3).

[0156] In some embodiments of the compounds of Formula le, R5is -N(R4)2. In some embodiments, R5is selected from the group consisting of -NH2, -NHCH3 or -N(CH3)2. In some embodiments, R5is -C(O)N(R4)2. In some embodiments, R5is selected from the group consisting of -C(O)NH2, -C(O)NHCH3or -C(O)N(CH3)2.

[0157] In some embodiments of the compounds of Formula le, R5is -OCi-4alkyl. In an example, R5is methoxy (-OCH3).

[0158] In some embodiments of the compounds of Formula le, R5is -C3-6cycloalkyl optionally substituted with one or two R6, preferably one R6. In some embodiments, each R6is selected from -CH3 or -OH.

[0159] In some embodiments of the compounds of Formula le, R5is 4-6-membered heterocyclyl comprising one or two heteroatoms independently selected from N, O or S and optionally substituted with one or two R6. Suitable examples of 4-6-membered heterocyclyl are as defined herein in the context of R3. In some embodiments, the 4-6-membered heterocyclyl is oxetanyl, tetrahydrofuranyl, or morpholinyl. In some embodiments, R6is -CH3 or -OH (e.g., R5may be 4-methyloxetanyl, N-methylmorpholinyl, or 2-hydroxycyclopentyl).

[0160] In some embodiments of the compounds of Formula le, R6is -Ci-salkyl. In one example, R6is -CH3.

[0161] In some embodiments of the compounds of Formula le, R7is -Ci-3alkyl or -OCi-salkyl. In one example, R7is -CH3. In one example, R7is -OCH3.

[0162] In some embodiments, the compounds of Formula le are compounds of Formula If:wherein R1, Ring A and Ring B are as defined herein for Formula le; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0163] In some embodiments, the compound of Formula I is a compound of Formula Ifa:wherein Ring A and Ring B are as defined herein for Formula le; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0164] In some embodiments, the compound of Formula I is a compound of Formula Ifa orFormula Ifb:Formula Ifa Formula Ifb wherein Ring B is as defined herein for Formula le; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0165] In some embodiments of the compounds of Formula Ifa or Formula Ifb, Ring B is Ring Z as defined herein for Formula I. In some embodiments, Ring B is selected from the group consisting of Zb, Zd, Zf, Zg, Zh, Zi, Zj, Zk, Zm, Zn, Zo, Zp, Zq, Zr, Zs, Zu, Zaf, Zai, Zak, Zal, Zam, Zan, Zao, Zaq, Zar, Zas, Zau, Zav, Zaw, Zax, Zay, Zbb, Zbc, Zbe, Zbf, Zbh, Zbi, Zbj, Zbk, Zbl, Zbm, Zbr, Zbs, Zbv, Zbw, Zbx, Zea, Zeb, Zcg, Zch, Zci, and Zcj, wherein Ring B isoptionally substituted with from one to three R3, and wherein each R3is independently as defined herein for Formula le.

[0166] In other embodiments of the compounds of Formula Ifa and Formula Ifb, Ring B is phenyl optionally substituted with from one to three R3, wherein each R3is independently as defined herein for Formula le.

[0167] In some embodiments, the compound of Formula I is compound of Formula Ifc:Formula Ifc wherein Ring B is as defined herein for Formula le, and R2ais selected from H and R2, wherein R2is as defined herein for Formula le; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0168] In some embodiments of the compounds of Formula Ifc, Ring B is Ring Z as defined herein for Formula I optionally substituted with from one to three R3. In some embodiments. Ring B is selected from the group consisting of Zb, Zi, Zp, Zu, Zw, Zab, Zae, Zbp, Zbq, Zee, and Zed, wherein Ring B is optionally substituted with from one to three R3, wherein each R3is as defined herein for Formula le.

[0169] In other embodiments of the compound of Formula Ifc, Ring B is phenyl optionally substituted with from one to three R3, wherein R3is as defined herein for Formula le.

[0170] In some embodiments, the compound of Formula I is a compound of Formula Ifd:wherein Ring B is as defined herein for Formula le, and R2ais selected from H and R2, wherein R2is as defined herein for Formula le; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0171] In some embodiments of the compounds of Formula Ifd, Ring B is Ring Z as defined herein for Formula I phenyl optionally substituted with from one to three R3. In some embodiments, Ring B is selected from Zu or Zp, optionally substituted with from one to three R3, wherein R3is as defined herein for Formula le. In other embodiments of the compound of Formula Ifd, Ring B is phenyl optionally substituted with from one to three R3, wherein R3is as defined herein for Formula le.

[0172] In some embodiments of the compounds of Formulae le, If and Ifi, Ring B is substituted with three R3. In an embodiment, Ring A is selected from Xa, Xc or Xe. In some embodiments, Ring B is Zu. Thus, in some embodiments, the compound of Formula I is a compound of Formula Ig:Formula Ig wherein Ring A and Ring B are as defined herein for Formula le, and R3a, R3band R3care independently selected from H and R3, wherein R3is as defined herein for Formula le; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0173] In some embodiments of the compounds of Formula Ig, R3a, R3band R3care independently selected from R3, wherein R3is as defined herein for Formula le.

[0174] In some embodiments of the compounds of Formula Ig, each R3a, R3band R3cis independently -Ci-ealkyl optionally substituted with from one to three R5. In some embodiments, R3a, R3band / or R3care -Ci-ealkyl optionally substituted with from one to two R5. In some embodiments, each R5is independently selected from -halogen, -OH, -OCi.4alkyl and -N(R4)2. In embodiments in which R3ais substituted with two or three R5, each R5may be attached to the same carbon atom or to different carbon atoms. R3amay be substituted with from one to three R5at any carbon atom in the alkyl chain (or combination of carbon atoms), preferably a terminal carbon atom in the alkyl chain. The -Ci-ealkyl may be a straight or branched chain -Ci-ealkyl,or a straight or branched chain -Ci-salkyl. In some embodiment, the -Ci-ealkyl is a straight or branched chain Ci-salkyl. In an example, R3ais methyl.

[0175] In some embodiments of the compounds of Formula Ig, R3ais selected from -Ci-salkyl- OH, -Ci-salkyl-OCFF and -Ci-salkyl-NBL. In some embodiments, when R3ais -Ci-salkyl-OH, R3amay be selected from hydroxymethyl, 2-hydroxyethyl, 3 -hydroxy -n-propyl, 2-hydroxyiso- propyl, 4-hydroxy-n-butyl, 3-hydroxy-sec-butyl, 2-hydroxy-t-butyl, 5-hydroxy-n-pentyl, 4-hy- droxyisopentyl, 4-hydroxy-sec-pentyl, 3-hydroxyneopentyl and 3 -hydroxy -t-pentyl, and the like. In some embodiments, when R3ais -Ci-salkyl-OCH , R3amay be selected from methoxymethyl, 2-methoxyethyl, 3 -methoxy -n-propyl, 2-methoxyisopropyl, 4-methoxy-n-butyl, 3- methoxy-sec-butyl, 2-methoxy-t-butyl, 5-methoxy-n-pentyl, 4-methoxyisopentyl, 4-methoxy- sec-pentyl, 3-methoxyneopentyl and 3 -methoxy -t-pentyl, and the like. In some embodiments, when R3ais -Ci-salkyl-NFF, R3ais selected from aminomethyl, 2-aminoethyl, 3 -amino-n -propyl, 2-aminoisopropyl, 4-amino-n-butyl, 3-amino-sec-butyl, 2-amino-t-butyl, 5-amino-n-pen- tyl, 4-aminoisopentyl, 4-amino-sec-pentyl, 3 -aminoneopentyl and 3-amino-t-pentyl, and the like.

[0176] In some embodiments of the compounds of Formula Ig, R3ais -Ci-salkyl-Cs-ecycloal- kyl optionally substituted with one or two R6. In some embodiments, R3ais -C1.5alkyl-C3.6cy- cloalkyl optionally substituted with one R6. In some embodiments, R3ais -Ci.2alkyl-C3-6cyclo- alkyl substituted with one R6. In an example, R6is -OH. By way of example, R3amay be selected from methyl-2-hydroxy-cyclopropyl, methyl-2-hydroxy-cyclobutyl, methyl-2-hydroxy- cyclopentyl, methyl-3-hydroxy-cyclopentyl, ethyl-2-hydroxy-cyclopropyl, ethyl-2-hydroxy- cyclobutyl, ethyl-2-hydroxy-cyclopentyl, ethyl-3-hydroxy-cyclopentyl, and the like.

[0177] In some embodiments of the compounds of Formula Ig, R3band / or R3care independently selected from -halogen, -NO2, -Ci-ealkyl optionally substituted with from one to three R5, -OCi-ealkyl optionally substituted with from one to three R5, and -Cs-ecycloalkyl optionally substituted with R7. In some embodiments, R3band / or R3cis -halogen (i.e., F, Cl, Br or I). In an example, the -halogen is Cl or Br.

[0178] In some embodiments of the compounds of Formula Ig, R3band / or R3care independently selected from -Ci-ealkyl optionally substituted with from one to three R5. In some embodiments, R3band / or R3care -Ci-ealkyl optionally substituted with from one or two R5. In some embodiments, R3band / or R3care -Ci-ealkyl, or -Ci-salkyl, optionally substituted with one-OH or -NH2. In some embodiments of the compound of Formula Ig, R3band / or R3care unsubstituted -Ci-ealkyl. In an example, R3band / or R3care -CH3.

[0179] In some embodiments of the compounds of Formula Ig, R3band / or R3care -OCi-ealkyl optionally substituted with from one to three R5. In some embodiments, R3band / or R3care - OCi-ealkyl optionally substituted with one or two R5. In some embodiments, R3band / or R3care -OCi-ealkyl, or -OCi-salkyl, optionally substituted with from one to three -halogen (e.g., F, Cl, Br).

[0180] In some embodiments of the compounds of Formula Ig, R3a, R3band / or R3care -Ci- ealkyl or -OCi-ealkyl substituted with -halogen (e.g., F, Cl or Br). In an example, R3a, R3band / or R3Care F. In some embodiments, R3a, R3band / or R3care selected from -Ci-salkyl-F, -Ci-salkyl- F2 and -Ci-ealkyl-Fs. By way of example, R3amay be selected from fluoromethyl (CH2F), difluoromethyl (CHF2), trifluoromethyl (CF3), 2-fluoroethyl, 2-difluoroethyl, 2-trifluoroethyl, 3-fluoro-n-propyl, 3-difluoro-n-propyl, 3-trifluoro-n-propyl, 2-fluoroisopropyl, 2-difluoroiso- propyl, 3-trifluoroisopropyl, and the like. In some embodiments, R3a, R3band / or R3care -CH2F, -CHF2 or -CF3. In an example, R3ais 3-fluoro-n-propyl, 3-difluoro-n-propyl or 3-trifluoro-n- propyl. In some embodiments, R3band / or R3care selected from -OCi-salkyl-F, -OCi-5alkyl-F2 and -OCi-6alkyl-F3. By way of example, R3band / or R3cmay be selected from fluoromethoxy (OCH2F), difluoromethoxy (OCHF2), trifluoromethoxy (OCF3), 2-fluoroethoxy, 2-difluoroeth- oxy, 2-trifluoroethoxy, 3-fluoro-n-propoxy, 3-difluoro-n-propoxy, 3-trifluoro-n-propoxy, 2- fluoroisopropoxy, 2-difluoroisopropoxy, 3 -trifluoroisopropoxy, and the like. In an example, R3band / or R3cis -OCH2F, -OCHF2or -OCF3.

[0181] In some embodiments, the compound of Formula I is a compound of Formula Iga or Formula Igb:wherein Ring B is as defined herein for Formula le, R3a, R3band R3care independently selected from H and R3, wherein R3is as defined herein for Formula le; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof. In an embodiment, R3a, R3band R3care independently selected from R3, wherein R3is as defined herein for Formula le.

[0182] In some embodiments, the compound of Formula I is a compound of Formula Igai orFormula Igbi:Formula Igai Formula Igbi wherein R3a, R3band R3care independently selected from H and R3, wherein R3is as defined herein for Formula le; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0183] In some embodiments, the compound of Formula I is compound of Formula Igc:Formula Igc wherein R2ais selected from H and R2, wherein R2is as defined herein for Formula le, Ring B is as defined herein for Formula le, and R3a, R3band R3care independently selected from H and R3, wherein R3is as defined herein for Formula le; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof. In an embodiment, R3a, R3band R3care independently selected from R3, wherein R3is as defined herein for Formula le.

[0184] In some embodiments, the compound of Formula I is a compound of Formula Igci:Formula Igciwherein R2ais selected from H and R2, wherein R2is as defined herein for Formula le, and R3a, R3band R3care independently as defined herein for Formula le; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof. In an embodiment, R3a, R3band R3care independently selected from R3, wherein R3is as defined herein for Formula le.

[0185] In some embodiments, the compound of Formula I is a compound of Formula Igd:Formula Igd wherein R2ais selected from H and R2, wherein R2is as defined herein for Formula le, Ring B is as defined herein for Formula le, and R3a, R3band R3care independently selected from H and R3, wherein R3is as defined herein for Formula le; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof. In an embodiment, R3a, R3band R3care independently selected from R3, wherein R3is as defined herein for Formula le.

[0186] In some embodiments, the compound of Formula I is a compound of Formula Igdi:Formula Igdi wherein R2ais selected from H and R2, wherein R2is as defined herein for Formula le, Ring B is as defined herein for Formula le, and R3a, R3band R3care independently selected from H and R3, wherein R3is as defined herein for Formula le; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof. In an embodiment, R3a, R3band R3care independently selected from R3, wherein R3is as defined herein for Formula le.

[0187] It is to be understood that, unless otherwise specified, any reference herein to compounds of Formula I includes reference to compounds of Formulae IA, la, lai, lb, Ibi, Ic, Ici,Id, Idi, le, If, Ifi, Ifa, Ifb, Ifc, Ifd, Ig, Iga, Igai, Igb, Igbi, Igc, Igci, Igd, Igdi, Ih, Ihi, li, Iji, Iki, Hi, Imi, Ini and loi.

[0188] In some embodiments, the compound of Formula I is selected from the group consisting of:Therapeutic Methods and Uses

[0189] A compound of Formula I (including a compound of Formulae IA, la, lai, lb, Ibi, Ic, Ici, Id, Idi, le, If, Ifi, Ifa, Ifb, Ifc, Ifd, Ig, Iga, Igai, Igb, Igbi, Igc, Igci, Igd, Igdi, Ih, Ihi, li, Iji, Iki, Hi, Imi, Ini or loi), or pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, of the present disclosure, and pharmaceutical compositions comprising a compound of Formula I, or pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, find use in the therapy of diseases, disorders, or conditions. Accordingly, in some embodiments, there is provided a compound of Formula I, or pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, for use in the therapy of a disease, disorder, or condition. In some embodiments, there is provided a compound of Formula I, or pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, for use in the therapy of a SOX18-mediated disease, disorder, or condition.

[0190] Accordingly, in some embodiments, there is provided a method of treating a SOX18- related disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a pharmaceutically acceptable amount of a compound of Formula I as described herein, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0191] In some embodiments, the SOX18-mediated disease, disorder, or condition is an angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition. In one example,the S0X18-mediated disease, disorder, or condition is an angiogenesis-related disease, disorder, or condition. In one example, the SOX 18 -mediated disease, disorder, or condition is a lymphangiogenesis-related disease, disorder, or condition. It will be appreciated that a “SOX18- mediated disease, disorder, or condition” refers to a disease, disorder, or condition in which transcription factor SOX18 is understood to be involved in the pathogenesis of the disease, disorder, or condition. For example, activation or overexpression of SOX18 may result in an increased disease state, and therefore that disease is considered to be mediated by SOX18. As such, it will be appreciated that a compound of Formula I, or pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, finds application in the treatment of a disease, disorder, or condition in which modulation of SOX18 provides a therapeutic effect.

[0192] In some embodiments, there is provided a method of treating an angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a pharmaceutically acceptable amount of a compound of Formula I as described herein, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0193] Accordingly, in some embodiments, the compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, prevents and / or reduces the severity of one or more symptoms of an angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition.

[0194] In some embodiments, the angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition is selected from the group consisting of a cancer, an ophthalmic disease, and a renal disease.

[0195] In one example, the angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition is cancer. In some embodiments, the cancer is selected from the group consisting of prostate cancer, lung cancer, breast cancer, bladder cancer, renal cancer, colon cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, hepatoma, hepatocellular carcinoma, sarcoma, leukemia, lymphoma, and vascular neoplasm. In one example, the sarcoma is angiosarcoma.

[0196] In some embodiments, the compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, treats cancer. It will be appreciated that the term “treating cancer”, and the like, refers to a reduction in one or more markers of cancer or symptoms of cancer. In one example, treatment of cancer comprises slowing the rate of a tumour growth. In one example,treatment of cancer comprises reducing a tumour size. In one example, treatment of cancer comprises preventing and / or inhibiting metastasis of a cancer.

[0197] In one example, the angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition is an ophthalmic disease, disorder, or condition. In some embodiments, the ophthalmic disease, disorder, or condition is selected from the group consisting of age-related macular degeneration, diabetic retinopathy, ischemic retinopathy, retinopathy of prematurity, neo- vascular glaucoma, iritis rubeosis, corneal neovascularization, cyclitis, sickle cell retinopathy, pterygium, and vascular response during corneal injury.

[0198] In one example, the angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition is a renal disease, disorder, or condition. In some embodiments, the renal disease, disorder, or condition is selected from the group consisting of chronic renal transplant dysfunction, primary renal fibrotic disorders, proteinuria, diabetic nephropathy, and renal inflammation.

[0199] In some embodiments, there is provided the use of a compound of Formula I as described herein, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof; in the manufacture of a medicament for the treatment of an angiogenesis- and / or lymphangio- genesis-related disease, disorder, or condition.

[0200] In some embodiments, there is provided a compound of Formula I as described herein, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

[0201] In some embodiments, there is provided a method of modulating SOX18 activity, comprising contacting SOX18 with a compound of Formula I as described herein, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.Compositions

[0202] Whilst a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, may, in some embodiments, be administered alone, it is more typically administered as part of a pharmaceutical composition or formulation. Thus, the present disclosure also provides a pharmaceutical composition comprising a compound of Formula I, or salt, solvate, tautomer or stereoisomer, and a pharmaceutically acceptable excipient. The pharmaceutical compositioncomprises one or more pharmaceutically acceptable diluents, carriers, or excipients (collectively referred to herein as “excipient” materials).

[0203] Accordingly, in some embodiments, there is provided a pharmaceutical composition comprising a compound of Formula I as described herein, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

[0204] The present disclosure also provides pharmaceutical formulations or compositions, both for veterinary and for human medical use, which comprise compounds of Formula I, or salt, solvate, tautomer or stereoisomer thereof, of the present disclosure, with one or more pharmaceutically acceptable carriers, and optionally any other therapeutic ingredients, stabilisers, or the like. The carrier(s) must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the formulation and not unduly deleterious to the recipient thereof.

[0205] Examples of pharmaceutical formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, and intraarticular), inhalation (including fine particle dusts or mists that may be generated by means of various types of metered dose pressurised aerosols), nebulisers or insufflators, rectal, intraperitoneal and topical (including dermal, buccal, sublingual, and intraocular) administration, although the most suitable route may depend upon, for example, the condition and disorder of the recipient.

[0206] The pharmaceutical formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of brining a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, into association with the excipient that constitutes one or more necessary ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired formulation.

[0207] In some embodiments, that composition is formulated for oral delivery. For example, pharmaceutical formulations of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets, pills or tablets each containing a predetermined amount of the active ingredient; as a powder or granules, as a solution or a suspension in an aqueous liquid or non-aqueous liquid, for example as elixirs, tinctures, suspensions or syrups; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. A compound ofFormula I, or salt, solvate, tautomer or stereoisomer thereof, may also be presented as a bolus, electuary, or paste.

[0208] A tablet may be made, for example, by compression or moulding, optionally with one or more accessory ingredients. 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, lubricating, surface active, or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally coated or scored, and may be formulated so as to provide slow or controlled release of the compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof. The compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, can, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release can be achieved by the use of suitable pharmaceutical compositions comprising a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. A compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, may also be administered liposomally.

[0209] For example, in one embodiment, the formulation may be a sterile, lyophilized composition that is suitable for reconstitution in an aqueous vehicle prior to injection. In one embodiment, a formulation suitable for parenteral administration conveniently comprises a sterile aqueous preparation of the compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, which may for example be formulated to be isotonic with the blood of the recipient.

[0210] The compounds of Formula I, or salt, solvate, tautomer or stereoisomer thereof, of the present disclosure may for example be formulated in compositions including those suitable for inhalation to the lung, by aerosol, or parenteral (including intraperitoneal, intravenous, subcutaneous, or intramuscular injection) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, into association with a carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by bringing the compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, into association with a liquid carrier to form a solution or a suspension, or alternatively, bring the compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, into association with formulationcomponents suitable for forming a solid, optionally a particulate product, and then, if warranted, shaping the product into a desired delivery form. Solid formulations of the present disclosure, when particulate, will typically comprise particles with sizes ranging from about 1 nanometer to about 500 microns. In general, for solid formulations intended for intravenous administration, particles will typically range from about 1 nm to about 10 microns in diameter. The composition may contain compounds of Formula I of the present disclosure that are nanoparticulate having a particulate diameter of below 1000 nm, for example, between 5 and 1000 nm, especially 5 and 500 nm, more especially 5 to 400 nm, such as 5 to 50 nm and especially between 5 and 20 nm. In one example, the composition contains compounds of Formula I with a mean size of between 5 and 20nm. In one example, the compound of Formula I is poly dispersed in the composition, with PDI of between 1.01 and 1.8, especially between 1.01 and 1.5, and more especially between 1.01 and 1.2. In one example, the compounds of Formula I are monodispersed in the composition.

[0211] It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example, those suitable for oral administration may include flavouring agents.

[0212] The compositions of the present disclosure may also include polymeric excipients / ad- ditives or carriers, e.g., polyvinylpyrrolidones, derivatised celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (a polymeric sugar), hydroxy ethyl starch (HES), dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-P- cyclodextrin and sulfobutylether-P-cyclodextrin), polyethylene glycols, and pectin. The compositions may further include diluents, buffers, citrate, trehalose, binders, disintegrants, thickeners, lubricants, preservatives (including antioxidants), inorganic salts (e.g., sodium chloride), antimicrobial agents (e.g., benzalkonium chloride), sweeteners, antistatic agents, sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines, fatty acids and fatty esters, steroids (e.g., cholesterol)), and chelating agents (e.g., EDTA, zinc and other such suitable cations). Other pharmaceutical excipients and / or additives suitable for use in the compositions according to the present disclosure are listed in "Remington: The Science & Practice of Pharmacy", 19.sup.th ed., Williams & Williams, (1995), and in the "Physician's Desk Reference", 52. sup. nd ed., Medical Economics, Montvale, N.J. (1998), and in "Handbook of Pharmaceutical Excipients", Third Ed., Ed. A. H. Kibbe, Pharmaceutical Press, 2000.Dosages

[0213] The amount of active ingredient that is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the subject under treatment, including the type, species, age, weight, sex, and medical condition of the subject being treated, and the renal and hepatic function of the subject, and the particular condition, disorder or disease being treated, as well as its severity. An ordinary skilled physician or clinician can readily determine and prescribe the effective amount of the drug required to prevent or treat the disease, disorder, or condition.

[0214] Dosages of a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, when used for the indicated effects, will range between, for example, about 0.01 mg per kg of body weight per day (mg / kg / day) to about 1000 mg / kg / day. In one example, the dosage of a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, is between about 0.01 and 1000, 0.1 and 500, 0.1 and 100, 1 and 50 mg / kg / day. In one example, the dosage of a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, is between about 0.01 and 1000 mg / kg / day. In one example, the dosage of a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, is between about 0.1 and 100 mg / kg / day. In one example, the dosage of a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, is greater than about 0.01, 0.1, 1, 10, 20, 50, 75, 100, 500, 1000 mg / kg / day. In one example, the dosage of a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, is greater than about 0.01 mg / kg / day. In one example, the dosage of a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, is less than about 5000, 1000, 75, 50, 20, 10, 1, 0.1 mg / kg / day. In one example, the dosage of a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, is less than about 1000 mg / kg / day.

[0215] A compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, may for example be administered as a single daily dose, or otherwise the total daily dosage may be administered in divided doses of two, three, or four times daily. In one example, the compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, may be dosed less frequently than once per day, for example once per two days, three days, four days, five days, six days, or once per week.

[0216] If administered intravenously, an infusion of the compound over a period of time may be used, for example. Furthermore, a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, may be administered in intranasal form via topical use of suitable intranasalvehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.Combination Therapy

[0217] Whilst a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, may be used as the sole active agent in a medicament, it is also possible for a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, to be used in combination with one or more further therapeutic agents. Accordingly, in one example, a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, is used in combination with one or more further therapeutic agents. The present disclosure therefore also provides a combination of a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, and a further therapeutic agent. The present disclosure also provides a pharmaceutical composition comprising a combination of a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, a further therapeutic agent, and a pharmaceutically acceptable excipient. Such one or more further therapeutic agents may for example be anti-cancer agents. Drugs are often co-administered with other drugs during chemotherapy. In one example, a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, is used in combination with one or more further anticancer agents. In one example, a compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, is used in combination with one or more further cytotoxic agents.

[0218] The compound of Formula I, or salt, solvate, tautomer or stereoisomer thereof, and the one or more further pharmaceutically active agents may be administered simultaneously, subsequently, or separately. For example, they may be administered as part of the same composition, or by administration of separate compositions.

[0219] The further therapeutic agents, when employed in combination with a compound of Formula I, or salt thereof, may be used for example in those amounts indicated in the Physicians’ Desk Reference or as otherwise determined by one of ordinary skill in the art.Kits

[0220] The compounds of Formula I (or pharmaceutically acceptable salts, solvates, tautomers or stereoisomers thereof) comprising the same as disclosed herein may be contained in a kit. The kit may include, for example, the compound of Formula I or pharmaceuticalcomposition and an additional agent, each packaged or formulated individually, or packaged or formulated in combination. Thus, the compound of Formula I (or pharmaceutically acceptable salts, solvates, tautomers or stereoisomers thereof) or pharmaceutical composition may be present in first container, and the kit can optionally include one or more agents in a second container. The container or containers are placed within a package, and the package can optionally include administration or dosage instructions.

[0221] The kits disclosed herein may comprise the compound of Formula I (or pharmaceutically acceptable salts, solvates, tautomers or stereoisomers thereof) in a form suitable for pulmonary administration (e.g., in a pharmaceutical composition as described herein) and a container or packaging. The kits may optionally comprise instructions describing a method of using the pharmaceutical compositions in one or more of the methods described herein (e.g., for preventing or treating a SOX18-mediated disease, disorder, or condition). The kit may optionally comprise a second pharmaceutical composition comprising one or more additional agents described herein for co-therapy use, a pharmaceutically acceptable carriers, diluents, adjuvants and / or excipients. The pharmaceutical composition comprising the compound Formula I (or pharmaceutically acceptable salts, solvates, tautomers or stereoisomers thereof) and the second pharmaceutical composition contained in the kit may be optionally combined in the same pharmaceutical composition.

[0222] The various features and embodiments of the present invention, referred to in individual sections above apply, as appropriate, to other sections, mutatis mutandis. Consequently, features specified in one section may be combined with features specified in other sections as appropriate.

[0223] Those skilled in the art will be aware that the invention described herein is subject to variations and modifications other than those specifically described. It is to be understood that the invention described herein includes all such variations and modifications. The invention also includes all such steps, features, methods, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

[0224] Certain embodiments of the invention will now be described with reference to the following examples which are intended for the purpose of illustration only and are not intended to limit the scope of the generality hereinbefore described.ExamplesExample 1 : Syntheses of Compounds of Formula IGeneral Experimental

[0225] The following experimental section describes in more detail the characterisation of certain of the compounds of the invention and their efficacy. The intention is to illustrate certain specific embodiments of the compounds of the invention and their efficacy without limiting the invention in any way.Abbreviations

[0226] The following list of abbreviations is utilised throughout the experimental section, and is adhered to herein:Abbreviation Full Description g gram mg milligram wt weight eq equivalents mmol Millimole h hour m / z Mass-to-charge ratio mL MillilitreM Molar concentration’H NMR Proton nuclear magenetic resonance min minutes5 Chemical shiftMHz Mega hertzHz HertzCoupling constantL litre19F NMR Fluorine nuclear magnetic resonance2Me-THF 2-MethyltetrahydrofuranBoc tert-Butoxy carbonylBurgess Reagent 1 -Methoxy -N-triethylammoniosulfonyl-methanimidateCDI 1,1' CarbonyldiimidazoleCPME Cyclopentyl methyl etherDCC N,N' -Di cy cl ohexy 1 carb odii mi deDCM DichloromethaneDIAD Diisopropyl azodi carb oxy lateDIPEA N -Ethyl dii sopropy 1 amineDMAP 4-DimethylaminopyridineDMF N,N-dimethylformamideDMSO DimethylsulfoxideEDC or EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimideEt3N TriethylamineEtOAc Ethyl acetateEtOH EthanolHOBt 1 -Hydroxybenzotri azoleIPA 2-propanolLCMS Liquid chromatography mass spectrometryMeCN AcetonitrileMel lodomethaneMeOH MethanolNaOtBu Sodium tert-butoxidePd(dppf)C12 l,l'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd-118 [l, l'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II)Pd-171 Chloro(crotyl)[2-Dicyclohexylphosphino-2',6'-di-i-sopropoxy- 1,1'- biphenyl]palladium(II)Pd-175 [[3,6-dimethoxy-2',4',6'-tris(l-methylethyl)[l,l'-biphenyl]-2-yl- KC 1 ' ]bi S( 1 , 1 -dimethylethyl)phosphine-KP](r|3 -2-propen- 1 -yl)-, 1,1,1 -trifluoromethanesulfonateTBAF Tetrabutylammonium fluorideTFAA Trifluoroacetic anhydrideTHF TetrahydrofuranTHP Tetrahydropyran or tetrahydropyranylTMS TrimethylsilylSyntheses

[0227] Unless otherwise specified, all reagents were purchased via commercial vendors.• General Method la: Alkylation (NaH)

[0228] To a suspension of NaH (67.1 mg, 60% wt, 1.2 eq, 1.68 mmol) in THF (5.00 mL) cooled at 0 °C was dropped a solution of lH-indazole-6-carbonitrile (200 mg, 1 eq, 1.40 mmol) in DMF (5.00 mL). The reaction mixture was stirred at 0 °C for 1 h, before the addition of Mel (218 mg, 96.1 pL, 1.1 eq, 1.54 mmol). The reaction mixture was stirred for a further 1 h. The reaction mixture was diluted with a saturated solution of NH4CI (25 mL) and transferred into a separating funnel. The layer was extracted with EtOAc (3 x 25 mL). The combined organic layers were collected, dried over Mg2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 1 -methyl- lH-indazole-6-carbonitrile (3951-280-1) (127 mg, 0.80 mmol, 57%, 99% purity) as a pale yellow solid, and 2-methyl-2H-indazole-6-carbonitrile (3951-280-2) (53.0 mg, 0.33 mmol, 24% yield, 99% purity) as a pale yellow solid.

[0229] The following compounds were synthesised by General Method la.3951-280-1

[0230] Starting reagent(s): lH-indazole-6-carbonitrile (200 mg, 1 eq, 1.40 mmol), Mel (218 mg, 1.1 eq, 1.54 mmol), NaH (67 mg, 60% wt, 1.2 eq, 1.68 mmol). l-Methyl-lH-indazole-6- carbonitrile (3951-280-1) (127 mg, 57% yield, 99% purity) as a pale yellow solid. 'H NMR (500 MHz, DMSO) 5 8.39 (d, J= 1.4 Hz, 1H), 8.23 (d, J= 1.2 Hz, 1H), 7.97 (d, J= 8.4 Hz, 1H), 7.46 (dd, J= 8.3, 1.3 Hz, 1H), 4.12 (d, J= 1.0 Hz, 3H). m / z 158.2 [M+H]+.

[0231] Starting reagent(s): lH-indazole-6-carbonitrile (200 mg, 1 eq, 1.40 mmol), Mel (218 mg, 1.1 eq, 1.54 mmol), NaH (67 mg, 60% wt, 1.2 eq, 1.68 mmol). 2-Methyl-2H-indazole-6-carbonitrile (3951-280-2) (53.0 mg, 24% yield, 99% purity) as a pale yellow solid. 'H NMR (500 MHz, DMSO) 5 8.53 (s, 1H), 8.29 (s, 1H), 7.94 - 7.89 (m, 1H), 7.30 - 7.24 (m, 1H), 4.24 (d, J = 1.1 Hz, 3H). m / z 158.2 [M+H]+.4245-48-1

[0232] Starting reagent(s): methyl 3-((tert-butoxycarbonyl)amino)-l-methyl-lH-pyrazole-5- carboxylate (255.0 mg, 96% Wt, 1 Eq, 959.0 pmol), sodium hydride (38.36 mg, 60% Wt, 1 Eq, 959.0 pmol) and iodomethane (204.2 mg, 89.6 pL, 1.5 Eq, 1.438 mmol), methyl 3-((tert- butoxycarbonyl)(methyl)amino)-l-methyl-lH-pyrazole-5-carboxylate (249 mg, 0.91 mmol, 94 %, 98% Purity). 'H NMR (500 MHz, DMSO) 5 6.87 (s, 1H), 4.00 (s, 3H), 3.83 (s, 3H), 3.23 (s, 3H), 1.47 (s, 9H). m / z 214.2 [M- / Bu+2H]+.• General Method lb: Alkylation (carbonate base or DIPEA)

[0233] Starting reagent(s): 4-hydroxybenzonitrile (250 mg, 1 eq, 2.10 mmol), 2-(2 -bromoethoxy )tetrahydro-2H-pyran (609 mg, 1.0 eq, 2.10 mmol), potassium carbonate (870 mg, 3.0 eq, 6.30 mmol). 4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (3952-152) (404 mg, 74% yield, 95% purity). 'H NMR (500 MHz, CDC13) 5 7.62 - 7.55 (m, 2H), 7.01 - 6.95 (m, 2H), 4.69 (dd, J= 3.6, 3.6 Hz, 1H), 4.27 - 4.15 (m, 1H), 4.16 - 3.97 (m, 2H), 3.92 - 3.78 (m, 2H), 3.57 - 3.49 (m, 1H), 1.87 - 1.77 (m, 1H), 1.80 - 1.69 (m, 1H), 1.65 - 1.49 (m, 4H). m / z 248.2 [M+H]+.

[0234] The following compounds were synthesised by General Method lb3912-331

[0235] Starting reagent(s): methyl 3-hydroxy-l-methyl-lH-pyrazole-5-carboxylate (250 mg, 1 eq, 1.60 mmol), potassium carbonate (443 mg, 2 eq, 3.20 mmol), iodomethane (341 mg, 0.150 mL, 1.50 eq, 2.40 mmol). Methyl 3-methoxy-l-methyl-lH-pyrazole-5-carboxylate (3912-331)(216 mg, 67% yield, 85% purity) as a pale yellow solid. 'H NMR (500 MHz, CDCh) 5 6.18 (s, 1H), 4.05 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H). m / z 171.2 [M+H]+.

[0236] Starting reagent(s): methyl 3 -(difluoromethyl)- lH-pyrazole-5-carboxylate (414.0 mg, 98% wt, 1 eq, 2.304 mmol), DIPEA (714 mg, 962 pL, 2.40 eq, 5.52 mmol), iodomethane (785 mg, 345 pL, 2.40 eq, 5.53 mmol). Methyl 3-(difluoromethyl)-l-methyl-lH-pyrazole-5-carbox- ylate (3956-324-1) (270 mg, 52% yield, 99% purity) as a white oil. 'H NMR (500 MHz, CDCh) 5 7.03 (d, J= 1.1 Hz, 1H), 6.67 (t, J= 55.0 Hz, 1H), 4.20 (d, J= 0.8 Hz, 3H), 3.90 (s, 3H). m / z 191.2 [M+H]+.

[0237] Starting reagent(s): methyl 3-(difluoromethyl)-lH-pyrazole-5-carboxylate (414.0 mg, 98% wt, 1 eq, 2.304 mmol), DIPEA (714 mg, 962 pL, 2.40 eq, 5.52 mmol), iodomethane (785 mg, 345 pL, 2.40 eq, 5.53 mmol). Methyl 5-(difluoromethyl)-l-methyl-lH-pyrazole-3-carbox- ylate (3956-324-2) (113 mg, 22% yield, 99% purity) as a white solid. 'H NMR (500 MHz, CDCh) 8 7.03 - 6.99 (m, 1H), 6.73 (t, J= 53.5 Hz, 1H), 4.06 (s, 3H), 3.93 (s, 3H). m / z 191.2 [M+H]+.3953-407-2

[0238] Starting reagent(s): iodomethane (250 mg, 110 pL, 1.92 Eq, 1.76 mmol), cesium carbonate (360 mg, 1.20 Eq, 1.10 mmol) and 2-(tetrahydro-2H-pyran-2-yl)-6-(3-(2,4,5,6-tetrahy- drocyclopenta[c]pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (325 mg, 1 Eq, 917 pmol). 6-(3-(l-methyl-l,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)-2- (tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (89.0 mg, 19 %, 71% Purity). 'H NMR (500 MHz, DMSO) 5 8.05 (d, J = 9.8 Hz, 1H), 7.20 (d, J = 9.8 Hz, 1H), 5.99 (dd, J = 2.3, 10.4 Hz,1H), 4.03 - 3.97 (m, 1H), 3.82 (s, 3H), 3.69 - 3.61 (m, 1H), 2.81 - 2.71 (m, 4H), 2.61 - 2.53 (m, 2H), 2.22 - 2.09 (m, 1H), 2.05 - 1.96 (m, 1H), 1.80 - 1.67 (m, 2H), 1.64 - 1.50 (m, 2H). m / z 369.2 [M+H]+.4245-93-1

[0239] Starting reagent(s): 6-(3-(4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (190 mg, 70% Wt, 1 Eq, 319 pmol), cesium carbonate (156 mg, 1.5 Eq, 479 pmol) and iodomethane (83.8 mg, 1.85 Eq, 590 pmol). 6-(3-(4-chl oro-1 -methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)- 1,2, 4-oxadiazol-5-yl)-2- (tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (61.0 mg, 142 pmol, 44.4 %, 90% Purity). 'H NMR (500 MHz, DMSO) 5 8.13 (d, J= 9.8 Hz, 1H), 7.24 (d, J = 9.8 Hz, 1H), 6.01 (dd, J = 10.2, 2.4 Hz, 1H), 4.25 (s, 3H), 4.01 - 3.98 (m, 1H), 3.67 (td, J= 11.2, 5.4 Hz, 1H), 2.24 - 2.09 (m, 1H), 2.08 - 2.00 (m, 1H), 1.80 - 1.68 (m, 2H), 1.61 - 1.51 (m, 2H). m / z 347.0 / 349.0 [M- THP+2H]+.3912-474-2

[0240] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (3.48 g, 1 Eq, 9.98 mmol), cesium carbonate (4.88 g, 1.5 Eq, 15.0 mmol) and iodomethane (2.28 g, 1.00 mL, 1.61 Eq, 16.1 mmol). 6-(3-(5-chloro-l- methyl-lH-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)- one (0.42 g, 1.1 mmol, 11 %, 98% Purity). 'H NMR (500 MHz, DMSO) 5 8.06 (d, J= 9.8 Hz, 1H), 7.20 (d, J= 9.8 Hz, 1H), 7.08 (s, 1H), 5.99 (dd, J= 10.4, 2.2 Hz, 1H), 4.05 - 3.97 (m, 1H), 3.94 (s, 3H), 3.71 - 3.61 (m, 1H), 2.23 - 2.09 (m, 1H), 2.06 - 1.96 (m, 1H), 1.80 - 1.66 (m, 2H), 1.65 - 1.47 (m, 2H). m / z 363.2 [M+H]+.3901-216-1

[0241] Starting reagent(s): iodomethane (0.23 g, 0.10 mL, 2.1 Eq, 1.6 mmol), cesium carbonate (300 mg, 1.21 Eq, 921 pmol) and 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5- yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (300 mg, 1 Eq, 0.776 mmol). 6-(3-(4- bromo- 1 -methyl- lH-pyrazol-3 -yl)- 1 ,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyri- dazin-3(2H)-one. 'H NMR (500 MHz, CDC13) 5 8.10 (d, J = 9.8 Hz, 1H), 7.58 (s, 1H), 7.06 (d, J = 9.8 Hz, 1H), 6.13 (dd, J = 10.3, 2.5 Hz, 1H), 4.15 (dd, J = 10.9, 3.6 Hz, 1H), 4.04 (s, 3H), 3.78 (td, J = 11.4, 2.7 Hz, 1H), 2.45 - 2.34 (m, 1H), 2.15 - 2.10 (m, 1H), 1.84 - 1.69 (m, 3H), 1.64 - 1.59 (m, 1H). m / z 323 [M-THP+2H]+.3912-82

[0176]

[0242] Starting reagent(s): 6-(3-(p-tolyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (50.0 mg, 1 eq, 197 pmol), potassium carbonate (82.0 mg, 3.02 eq, 593 pmol), iodomethane (34.2 mg, 15.0 pL, 1.23 eq, 241 pmol). 2-Methyl-6-(3-(p-tolyl)-l,2,4-oxadiazol-5-yl)pyridazin- 3(2H)-one (3912-82)

[0176] (38 mg, 70% yield, 98% purity) as a yellow solid. 'H NMR (500 MHz, DMSO) 5 8.11 (d, J = 9.7 Hz, 1H), 8.00 - 7.94 (m, 2H), 7.41 (d, J= 8.0 Hz, 2H), 7.17 (d, J= 9.7 Hz, 1H), 3.81 (s, 3H), 2.40 (s, 3H). m / z 269.2 [M+H]+.3912-145

[0243] Starting reagent(s): 3 -hydroxybenzonitrile (250 mg, 1 eq, 2.10 mmol), 2-(2 -bromoethoxy )tetrahydro-2H-pyran (1.3 g, 0.95 mL, 3.0 eq, 6.3 mmol), potassium carbonate (580 mg, 2 eq, 4.20 mmol). 3-(2-((Tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (3912-145) (475 mg, 82% yield, 90% purity) as a colourless oil. 'H NMR (500 MHz, DMSO) 5 7.52 - 7.43 (m, 2H), 7.42 - 7.37 (m, 1H), 7.34 - 7.28 (m, 1H), 4.68 - 4.61 (m, 1H), 4.26 - 4.15 (m, 2H), 3.96 - 3.88 (m, 1H), 3.80 - 3.68 (m, 2H), 3.48 - 3.39 (m, 1H), 1.76 - 1.57 (m, 2H), 1.55 - 1.35 (m, 4H). m / z 270.2 [M+Na]+.3956-344

[0244] Starting reagent(s): methyl 3-bromo-lH-pyrazole-5-carboxylate (5.00 g, 1 Eq, 24.4 mmol) DIPEA (6.30 g, 8.50 mL, 2 Eq, 48.8 mmol), iodomethane (6.92 g, 3.04 mL, 2 Eq, 48.8 mmol), methyl 3-bromo-l-methyl-lH-pyrazole-5-carboxylate (3.42 g, 63% yield, 99% purity). 'H NMR (500 MHz, CDC13) 5 6.80 (s, 1H), 4.14 (s, 3H), 3.88 (s, 3H). m / z 219.0 [M+H]+.

[0245] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (3.48 g, 1 Eq, 9.98 mmol), cesium carbonate (4.88 g, 1.5 Eq, 15.0 mmol) followed by iodomethane (2.28 g, 1.00 mL, 1.61 Eq, 16.1 mmol). 6-(3-(3- chloro- 1 -methyl- lH-pyrazol-5-yl)- 1 ,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl) yridazine-3(2H)-one (2.53 g, 68% yield, 98% purity). 'H NMR (500 MHz, DMSO) 5 8.09 (d, J = 9.8 Hz, 1H), 7.23 (d, J = 9.8 Hz, 1H), 7.10 (s, 1H), 6.00 (dd, J = 10.3, 2.3 Hz, 1H), 4.16 (s, 3H), 4.05 - 3.95 (m, 1H), 3.71 - 3.61 (m, 1H), 2.22 - 2.09 (m, 1H), 2.07 - 1.95 (m, 1H), 1.83 - 1.66 (m, 2H), 1.65 - 1.50 (m, 2H). m / z 363.2 [M+H]+.3901-218-1

[0246] Starting reagent(s): 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 1 Eq, 636 pmol), cesium carbonate (300 mg, 1.45 Eq, 921 pmol), iodoethane (200 mg, 1.28 mmol). 6-(3-(4-bromo-l-ethyl-lH-pyrazol-5- yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (88.0 mg, 0.21 mmol, 33 %, 99% Purity), m / z 423.0 [M+H]+.3901-218-2

[0247] Starting reagent(s): 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 1 Eq, 636 pmol), cesium carbonate (300 mg,1.45 Eq, 921 pmol), iodoethane (200 mg, 1.28 mmol). 6-(3-(4-bromo-l-ethyl-lH-pyrazol-3- yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (66.0 mg, 0.16 mmol, 24 %, 99% Purity), m / z 421.2 [M+H]+.3901-218-3

[0248] Starting reagent(s): 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 1 Eq, 636 pmol), cesium carbonate (300 mg,1.45 Eq, 921 pmol), l,l-difluoro-2-iodoethane (200 mg, 1.04 mmol). 6-(3-(4-bromo-l-(2,2- difluoroethyl)-lH-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin- 3(2H)-one (45.0 mg, 96 pmol, 15 %, 98% Purity), m / z 479.0 [M+Na]+.3901-218-4

[0249] Starting reagent(s): 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 1 Eq, 636 pmol), cesium carbonate (300 mg,1.45 Eq, 921 pmol), l,l-difluoro-2-iodoethane (200 mg, 1.04 mmol). 6-(3-(4-bromo-l-(2,2- difluoroethyl)-lH-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin- 3(2H)-one (45.0 mg, 96 pmol, 15 %, 98% Purity), m / z 479.0 [M+Na]+.3901-218-5

[0250] Starting reagent(s): 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 1 Eq, 636 pmol), cesium carbonate (300 mg,1.45 Eq, 921 pmol), 2-iodopropane (200 mg, 1.18 mmol). 6-(3-(4-bromo-l-isopropyl-lH-py- razol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (150.0 mg, 345 pmol, 54.2 %, 100% Purity), m / z 435.0 [M+H]+.3901-218-6

[0251] Starting reagent(s): 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 1 Eq, 636 pmol), cesium carbonate (300 mg,1.45 Eq, 921 pmol), 2-iodopropane (200 mg, 1.18 mmol). 6-(3-(4-bromo-l-isopropyl-lH-py- razol-3-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (130.0 mg, 0.30 mmol, 47 %, 99% Purity), m / z 437.0 [M+H]+.3901-225-1

[0252] Starting reagent(s): 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 1 Eq, 636 pmol), cesium carbonate (300 mg,1.45 Eq, 921 pmol) and l-bromo-2-methoxy ethane (200 mg, 135 pL, 2.26 Eq, 1.44 mmol). 6- (3-(4-bromo-l -(2 -methoxy ethyl)- lH-pyrazol-5-yl)- 1,2, 4-oxadiazol-5-yl)-2-(tetrahydro-2H- pyran-2-yl)pyridazin-3(2H)-one (70.0 mg, 0.15 mmol, 23 %, 95% Purity).1HNMR (500 MHz, CDC13) 5 8.00 (d, J = 9.8 Hz, 1H), 7.66 (s, 1H), 7.11 (d, J = 9.7 Hz, 1H), 6.15 (dd, J = 10.3, 2.4 Hz, 1H), 4.76 (t, J = 5.6 Hz, 2H), 4.19 - 4.13 (m, 1H), 3.79 (td, J = 11.4, 2.8 Hz, 1H), 3.75 (t, J = 5.6 Hz, 2H), 3.26 (s, 3H), 2.43 - 2.31 (m, 1H), 2.19 - 2.07 (m, 1H), 1.86 - 1.70 (m, 3H), 1.63 (m, 1H). m / z 451.0 [M+H]+.3901-225-2

[0253] Starting reagent(s): 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 1 Eq, 636 pmol), cesium carbonate (300 mg, 1.45 Eq, 921 pmol), l-bromo-2-methoxy ethane (200 mg, 135 pL, 2.26 Eq, 1.44 mmol). 6-(3- (4-bromo-l-(2-methoxyethyl)-lH-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-py- ran-2-yl)pyridazin-3(2H)-one (80.0 mg, 0.15 mmol, 24 %, 85% Purity). 'H NMR (500 MHz, CDC13) 5 8.10 (d, J = 9.8 Hz, 1H), 7.72 (s, 1H), 7.06 (d, J = 9.8 Hz, 1H), 6.13 (dd, J = 10.3, 2.5 Hz, 1H), 4.44 - 4.38 (m, 2H), 4.18 - 4.12 (m, 1H), 3.84 - 3.71 (m, 3H), 3.38 - 3.34 (m, 3H), 2.47 - 2.31 (m, 1H), 2.15 - 2.08 (m, 1H), 1.83 - 1.69 (m, 4H). m / z 451.0 [M+H]+.3956-316-1

[0254] Starting reagent(s): ethyl 3-bromo-4-methyl-lH-pyrazole-5-carboxylate (300 mg, 1 Eq, 1.29 mmol), DIPEA (333 mg, 448 pL, 2 Eq, 2.57 mmol) and iodomethane (365 mg, 161 pL, 2 Eq, 2.57 mmol), ethyl 3-bromo-l,4-dimethyl-lH-pyrazole-5-carboxylate (142 mg, 0.56 mmol, 44 %, 98% Purity).1H NMR (500 MHz, CDC13) 54.37 (q, J = 7.1 Hz, 2H), 4.11 (s, 3H), 2.22 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H). m / z 247 / 249 [M+H]+.3953-407-1

[0255] Starting reagent(s): iodomethane (250 mg, 110 pL, 1.92 Eq, 1.76 mmol), cesium carbonate (360 mg, 1.20 Eq, 1.10 mmol), 2-(tetrahydro-2H-pyran-2-yl)-6-(3-(2,4,5,6-tetrahydro- cyclopenta[c]pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (325 mg, 1 Eq, 917 pmol). 6-(3-(l-methyl-l,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)-2- (tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (89.0 mg, 19 %, 71% Purity). 'H NMR (500 MHz, DMSO) 5 8.08 (d, J = 9.8 Hz, 1H), 7.22 (d, J = 9.8 Hz, 1H), 5.99 (dd, J = 2.3, 10.2 Hz, 1H), 4.12 (s, 3H), 4.03 - 3.97 (m, 1H), 3.71 - 3.61 (m, 1H), 2.85 - 2.81 (m, 2H), 2.70 - 2.66 (m, 2H), 2.44 - 2.38 (m, 2H), 2.21 - 2.11 (m, 1H), 2.07 - 1.98 (m, 1H), 1.80 - 1.69 (m, 2H), 1.62 - 1.52 (m, 2H). m / z 369.2 [M+H]+.3953-444-1

[0256] Starting reagent(s): iodomethane (333 mg, 147 pL, 1.5 Eq, 2.35 mmol), cesium carbonate (765 mg, 1.5 Eq, 2.35 mmol), 6-(3-(4-bromo-3-(trifluoromethyl)-lH-pyrazol-5-yl)- l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (760 mg, 95% Wt, 1 Eq, 1.57 mmol). 6-(3-(4-bromo-l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadia- zol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (416 mg, 52.7 %, 94.3% Purity). 'H NMR (500 MHz, DMSO) 5 8.12 (d, J = 9.8 Hz, 1H), 7.25 (d, J = 9.8 Hz, 1H), 6.01 (dd, J = 10.2, 2.3 Hz, 1H), 4.24 (s, 3H), 4.05 - 3.98 (m, 1H), 3.71 - 3.62 (m, 1H), 2.21 - 2.11 (m, 1H), 2.06 - 2.00 (m, 1H), 1.81 - 1.69 (m, 2H), 1.62 - 1.52 (m, 2H). m / z 391.0 / 393.0 [M-THP+2H]+.4245-74-1

[0257] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (200 mg, 98% Wt, 1 Eq, 513 pmol), cesium carbonate (251 mg, 1.5 Eq, 769 pmol), l-bromo-2-methoxy ethane (132 mg, 89.1 pL, 1.85 Eq, 948 pmol). 6-(3-(l-(2-methoxyethyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadia- zol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (54.0 mg, 0.12 mmol, 23 %, 97% Purity). 'H NMR (500 MHz, DMSO) 5 8.10 (d, J = 9.8 Hz, 1H), 7.50 (s, 1H), 7.24 (d, J = 9.8 Hz, 1H), 6.00 (dd, J = 10.3, 2.3 Hz, 1H), 4.85 (t, J = 5.4 Hz, 2H), 4.01 (d, J = 11.5 Hz, 1H), 3.80 (t, J = 5.4 Hz, 2H), 3.74 - 3.59 (m, 1H), 3.19 (s, 3H), 2.22 - 2.09 (m, 1H), 2.01 (dd, J = 19.3, 6.9 Hz, 1H), 1.82 - 1.68 (m, 2H), 1.56 (s, 2H). m / z 441.2 [M+H]+.4245-72-1

[0258] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (200 mg, 98% Wt, 1 Eq, 513 pmol), cesium carbonate (251 mg, 1.5 Eq, 769 pmol) and 2-iodopropane (161 mg, 1.85 Eq, 948 pmol). 6-(3-(l-isopropyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro- 2H-pyran-2-yl)pyridazin-3(2H)-one (159 mg, 0.36 mmol, 71 %, 97% Purity). 'H NMR (500 MHz, DMSO) 5 8.09 (d, J= 9.8 Hz, 1H), 7.45 (s, 1H), 7.24 (d, J= 9.8 Hz, 1H), 6.00 (dd, J =10.3, 2.3 Hz, 1H), 5.41 (hept, J = 6.5 Hz, 1H), 4.01 (dq, J= 11.9, 2.5 Hz, 1H), 3.72 - 3.60 (m, 1H), 2.23 - 2.10 (m, 1H), 2.07 - 1.98 (m, 1H), 1.81 - 1.70 (m, 2H), 1.57 (td, J = 9.5, 4.2 Hz, 2H), 1.52 (d, J= 6.6 Hz, 6H).19F NMR (471 MHz, DMSO) 5 -60.58. m / z 425.2 [M+H]+.

[0259] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (200 mg, 98% Wt, 1 Eq, 513 pmol), cesium carbonate (251 mg, 1.5 Eq, 769 pmol) and DMF (3 mL), l,l-difluoro-2-iodoethane (182 mg, 87 pL, 1.85 Eq, 948 pmol). 6-(3-(l-(2,2-difluoroethyl)-3-(trifluoromethyl)-lH-pyrazol-5- yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (164 mg, 0.36 mmol, 70 %, 98% Purity) as a waxy white solid. 'H NMR (500 MHz, DMSO) 5 8.11 (d, J = 9.8 Hz, 1H), 7.65 (s, 1H), 7.26 (d, J = 9.8 Hz, 1H), 6.55 (t, JH-F = 56.0 Hz, 1H), 6.05 - 5.96 (m, 1H), 5.22 (td, J = 14.6, 3.7 Hz, 2H), 4.01 (d, J = 11.7 Hz, 1H), 3.67 (s, 1H), 2.16 (d, J = 13.4 Hz, 1H), 1.99 (s, 1H), 1.77 (d, J = 12.7 Hz, 2H), 1.56 (s, 2H). m / z 447.2 [M+H]+.

[0260] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (230 mg, 98% Wt, 1 Eq, 590 pmol), cesium carbonate (288 mg, 1.5 Eq, 884 pmol), l,l,l-trifluoro-2-iodoethane (229 mg, 1.85 Eq, 1.09 mmol). 2-(tetrahydro-2H-pyran-2-yl)-6-(3-(l-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (149 mg, 0.30 mmol, 51 %, 94% Purity). 'H NMR (500 MHz, DMSO) 5 8.11 (d, J = 9.8 Hz, 1H), 7.73 (s, 1H), 7.26 (d, J = 9.8 Hz, 1H), 6.01 (dd, J = 10.3, 2.4 Hz, 1H), 5.72 (q, J = 8.6 Hz, 2H), 4.00 (m, 1H), 3.73 - 3.61 (m, 1H), 2.21 - 2.10 (m, 1H), 2.07 - 1.99 (m, 1H), 1.83 - 1.69 (m, 2H), 1.61 - 1.49 (m, 2H). m / z 381.0 [M-THP+2H]+.

[0261] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (190 mg, 97% Wt, 1 Eq, 482 pmol), cesium carbonate (236 mg, 1.5 Eq, 723 pmol) and l-iodo-2-methylpropane (164 mg, 1.85 Eq, 892 pmol) 6-(3-(l-isobutyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tet- rahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (88.0 mg, 0.19 mmol, 39 %, 94% Purity). 'H NMR (500 MHz, DMSO) 5 8.08 (d, J= 9.8 Hz, 1H), 7.51 (s, 1H), 7.24 (d, J = 9.8 Hz, 1H), 6.01 (dd, J= 10.3, 2.3 Hz, 1H), 4.49 (d, J= 7.3 Hz, 2H), 4.00 (d, J= 5.2 Hz, 1H), 3.71 - 3.63 (m, 1H), 2.23 (dt, J= 13.8, 6.9 Hz, 1H), 2.19 - 2.11 (m, 1H), 2.04 - 1.99 (m, 1H), 1.81 - 1.70 (m, 2H), 1.56 (t, J= 4.2 Hz, 2H), 0.89 (d, J= 6.7 Hz, 6H). m / z 355.2 [M-THP+H]+.4245-97-1

[0262] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (200 mg, 97% Wt, 1 Eq, 507 pmol), cesium carbonate (248 mg, 1.5 Eq, 761 pmol) and DMF (3 mL) were treated with l-bromo-2-(2- methoxyethoxy)ethane (172 mg, 1.85 Eq, 939 pmol). 6-(3-(l-(2-(2-methoxyethoxy)ethyl)-3- (trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyri- dazin-3(2H)-one (111 mg, 0.21 mmol, 41 %, 90% Purity). 'H NMR (500 MHz, DMSO) 5 8.10 (d, J = 9.8 Hz, 1H), 7.49 (s, 1H), 7.25 (d, J = 9.8 Hz, 1H), 6.00 (dd, J = 10.3, 2.3 Hz, 1H), 4.85(t, J = 5.4 Hz, 2H), 4.01 - 3.98 (m, 1H), 3.85 (t, J = 5.4 Hz, 2H), 3.71 - 3.63 (m, 1H), 3.47 - 3.42 (m, 2H), 3.29 - 3.24 (m, 2H), 3.10 (s, 3H), 2.20 - 2.10 (m, 1H), 2.05 - 1.99 (m, 1H), 1.81 - 1.68 (m, 2H), 1.61 - 1.52 (m, 2H). m / z 485.2 [M+H]+.

[0263] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (200 mg, 97% Wt, 1 Eq, 507 pmol), cesium carbonate (248 mg, 1.5 Eq, 761 pmol), 2-bromoethan-l-ol (117 mg, 1.85 Eq, 939 pmol). 6-(3-(l-(2-hydroxyethyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetra- hydro-2H-pyran-2-yl)pyridazin-3(2H)-one (121 mg, 0.24 mmol, 48 %, 85% Purity). 'H NMR (500 MHz, DMSO) 5 8.10 (d, J = 9.8 Hz, 1H), 7.48 (s, 1H), 7.24 (d, J = 9.8 Hz, 1H), 6.00 (dd, J = 10.3, 2.3 Hz, 1H), 4.91 (s, 1H), 4.74 (t, J = 5.6 Hz, 2H), 4.02 - 3.98 (m, 1H), 3.81 (t, J = 5.7 Hz, 2H), 3.71 - 3.63 (m, 1H), 2.23 - 2.08 (m, 1H), 2.07 - 1.99 (m, 1H), 1.83 - 1.66 (m, 2H), 1.63 - 1.51 (m, 2H). m / z 427.2 [M+H]+.

[0264] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (200 mg, 97% Wt, 1 Eq, 507 pmol), cesium carbonate (248 mg, 1.5 Eq, 761 pmol), 2-bromo-N,N-dimethylacetamide (156 mg, 1.85 Eq, 939 pmol). N,N-dimethyl-2-(5-(5-(6-oxo-l-(tetrahydro-2H-pyran-2-yl)-l,6-dihydro- pyridazin-3-yl)-l,2,4-oxadiazol-3-yl)-3-(trifluoromethyl)-lH-pyrazol-l-yl)acetamide (151 mg, 0.24 mmol, 47 %, 74% Purity). 'H NMR (500 MHz, DMSO) 5 8.03 (d, J = 9.8 Hz, 1H), 7.56 (s, 1H), 7.25 (d, J = 9.8 Hz, 1H), 6.00 (dd, J = 10.4, 2.3 Hz, 1H), 5.68 (s, 2H), 4.01 (d, J = 11.7 Hz, 1H), 3.72 - 3.61 (m, 1H), 3.11 (s, 3H), 2.85 (s, 3H), 2.20 - 2.08 (m, 1H), 2.06 - 1.96 (m, 1H), 1.80 - 1.68 (m, 2H), 1.62 - 1.51 (m, 2H). m / z 468.2 [M+H]+.4245-103

[0265]

[0265] Starting reagent(s): N,N-dimethyl-2-(3-(5-(6-oxo-l-(tetrahydro-2H-pyran-2-yl)-l,6- dihydropyridazin-3-yl)-l,2,4-oxadiazol-3-yl)-5-(trifluoromethyl)-lH-pyrazol-l-yl)acetamide (22.0 mg, 1 Eq, 47.1 pmol), 6M HC1 in IPA (25.7 mg, 118 pL, 6.00 molar, 15 Eq, 706 pmol). N,N-dimethyl-2-(3-(5-(6-oxo-l,6-dihydropyridazin-3-yl)-l,2,4-oxadiazol-3-yl)-5-(trifluoro- methyl)-lH-pyrazol-l-yl)acetamide (4245-103)

[0265] (12.0 mg, 31 pmol, 65 %, 98% Purity). 'H NMR (500 MHz, DMSO) 5 13.89 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 9.9 Hz, 1H), 7.55 (s, 1H), 7.12 (dd, J = 9.8, 1.9 Hz, 1H), 5.48 (s, 2H), 3.08 (s, 3H), 2.87 (s, 3H). m / z 384.2 [M+H]+.3953-434-1

[0266] Starting reagent(s): iodomethane (56.8 mg, 25.0 pL, 2.06 Eq, 400 pmol), cesium carbonate (74.0 mg, 1.17 Eq, 227 pmol), 6-(3-(3,4-dimethyl-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5- yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (70.0 mg, 95% Wt, 1 Eq, 194 pmol). 2- (tetrahydro-2H-pyran-2-yl)-6-(3-(l,3,4-trimethyl-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyri- dazin-3(2H)-one (22.0 mg, 60.9 pmol, 31.3 %, 98.6% Purity), m / z 357.2 [M+H]+.

[0267] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (125 mg, 97% Wt, 1 Eq, 317 pmol), cesium carbonate (155 mg, 1.5 Eq, 476 pmol), 3 -bromopropan- l-ol (83.8 mg, 1.9 Eq, 603 pmol). 6-(3-(l-(3-hydroxypropyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tet- rahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (45.0 mg, 96 pmol, 30 %, 94% Purity), m / z 141.2 = [M+H]+.

[0268] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (125 mg, 97% Wt, 1 Eq, 317 pmol), cesium carbonate (155 mg, 1.5 Eq, 476 pmol), l-bromo-3-methoxypropane (92.2 mg, 1.9 Eq, 603 pmol). 6-(3-(l-(3-methoxypropyl)-5-(trifluoromethyl)-lH-pyrazol-3-yl)-l,2,4-oxadiazol-5- yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (38.0 mg, 73 pmol, 23 %, 87% Purity), m / z 455.2 [M+H]+.

[0269] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (125 mg, 97% Wt, 1 Eq, 317 pmol), cesium carbonate (155 mg, 1.5 Eq, 476 pmol), l-bromo-2,2,2-trifluoroethan-l-ol (108 mg, 1.9 Eq, 603 pmol). 2-(tetrahydro-2H-pyran-2-yl)-6-(3-(l-(3,3,3-trifluoro-2-hydroxypropyl)-3-(tri- fluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (67.0 mg, 0.13 mmol, 41 %, 96% Purity), m / z 411.2 [M-THP+2H]+.4246-89

[0270] Starting reagent(s): 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 90% Wt, 1 Eq, 572 pmol), cesium carbonate (284 mg, 1.52 Eq, 872 pmol) and 2-bromoethan-l-ol (286 mg, 162 pL, 4 Eq, 2.28 mmol). 6- (3-(4-bromo-l-(2 -hydroxy ethyl)-lH-pyrazol-3-yl)-l, 2, 4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (92.0 mg, 0.21 mmol, 36 %, 98% Purity), m / z 439.2 / 437.2 [M+H]+.4246-90-2

[0271] Starting reagent(s): 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 90% Wt, 1 Eq, 572 pmol), cesium carbonate (280 mg, 1.5 Eq, 858 pmol) and 3 -bromopropan- l-ol (159 mg, 103 pL, 2 Eq, 1.14 mmol). 6- (3-(4-bromo-l-(3-hydroxypropyl)-lH-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H- pyran-2-yl)pyridazin-3(2H)-one (86.0 mg, 0.18 mmol, 31 %, 94% Purity), m / z 451.2 / 453.2 [M+H]+.4246-89-2

[0272] Starting reagent(s): 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 90% Wt, 1 Eq, 572 pmol), cesium carbonate (284 mg, 1.52 Eq, 872 pmol) and 2-bromoethan-l-ol (286 mg, 162.0 pL, 4 Eq, 2.28 mmol). 6- (3-(4-bromo-l-(2 -hydroxy ethyl)-lH-pyrazol-3-yl)-l, 2, 4-oxadiazol-5-yl)-2-(tetrahydro-2H-py- ran-2-yl)pyridazin-3(2H)-one (92.0 mg, 0.21 mmol, 36 %, 98% Purity), m / z 439.2 / 437.2 [M+H]+.4245-116-1

[0273] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 97% Wt, 1 Eq, 556 pmol), cesium carbonate (544 mg, 3 Eq, 1.67 mmol) and 3 -bromopropan- l-ol (143 mg, 1.85 Eq, 1.03 mmol). 6-(3-(3- chloro-l-(3-hydroxypropyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran- 2-yl)pyridazin-3(2H)-one (98.0 mg, 0.22 mmol, 40 %, 92% Purity), m / z 407.2 / 409.2 [M+H]+.4245-116-2

[0274] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 97% Wt, 1 Eq, 556 pmol), cesium carbonate (544 mg, 3 Eq, E67 mmol) and 3 -bromopropan- l-ol (143 mg, 1.85 Eq, 1.03 mmol). 6-(3-(5- chloro-l-(3-hydroxypropyl)-lH-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran- 2-yl)pyridazin-3(2H)-one (17.9 mg, 39 pmol, 7.0 %, 89% Purity), m / z 407.2 / 409.2 [M+H]+.4245-116-4

[0275] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 97% Wt, 1 Eq, 556 pmol), cesium carbonate (544 mg, 3 Eq, 1.67 mmol) and l-bromo-3-methoxypropane (85.1 mg, 1 Eq, 556 pmol). 6-(3- (5-chloro-l-(3-methoxypropyl)-lH-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-py- ran-2-yl)pyridazin-3(2H)-one (40.0 mg, 90 pmol, 16 %, 95% Purity), m / z 421.1 / 423.2 [M+H]+.4245-116-3

[0276] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 97% Wt, 1 Eq, 556 pmol), cesium carbonate (544 mg, 3 Eq, 1.67 mmol) and l-bromo-3-methoxypropane (85.1 mg, 1 Eq, 556 pmol). 6-(3- (3-chloro-l-(3-methoxypropyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-py- ran-2-yl)pyridazin-3(2H)-one (160 mg, 0.38 mmol, 68 %, 99% Purity), m / z 421.2 / 423.2 [M+H]+.4245-117-1

[0277] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 97% Wt, 1 Eq, 556 pmol), cesium carbonate (544 mg, 3 Eq, E67 mmol) and 2-bromoethan-l-ol (129 mg, 1.85 Eq, 1.03 mmol). 6-(3-(3- chloro- 1 -(2-hy droxy ethyl)- lH-pyrazol-5-yl)- 1 ,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2- yl)pyridazin-3(2H)-one (48.0 mg, 0.12 mmol, 22 %, 99% Purity), m / z 393.2 / 395.2 [M+H]+.

[0278] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 97% Wt, 1 Eq, 556 pmol), cesium carbonate (544 mg, 3 Eq, 1.67 mmol) and 2-bromoethan-l-ol (129 mg, 1.85 Eq, 1.03 mmol). 6-(3-(5- chloro- 1 -(2-hy droxy ethyl)- lH-pyrazol-3-yl)- 1 ,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2- yl)pyridazin-3(2H)-one (14.0 mg, 33 pmol, 6.0 %, 93% Purity), m / z 393.2 / 395.2 [M+H]+.4245-117-3

[0279] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 97% Wt, 1 Eq, 556 pmol), cesium carbonate (544 mg, 3 Eq, 1.67 mmol) and l-bromo-2-m ethoxy ethane (139 mg, 1.8 Eq, 1.00 mmol). 6-(3- (3 -chloro- 1 -(2-methoxy ethyl)- lH-pyrazol-5-yl)- 1 ,2,4-oxadiazol-5 -yl)-2-(tetrahydro-2H-py- ran-2-yl)pyridazin-3(2H)-one (83.0 mg, 0.20 mmol, 36 %, 99% Purity), m / z 407.2 / 409.2 [M+H]+.4245-117-4

[0280] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 97% Wt, 1 Eq, 556 pmol), cesium carbonate (544 mg, 3 Eq, E67 mmol) and l-bromo-2-m ethoxy ethane (139 mg, 1.8 Eq, 1.00 mmol). 6-(3- (5-chloro- 1 -(2-methoxy ethyl)- lH-pyrazol-3 -yl)- 1 ,2,4-oxadiazol-5 -yl)-2-(tetrahydro-2H-py- ran-2-yl)pyridazin-3(2H)-one (30.0 mg, 72 pmol, 13 %, 97% Purity), m / z 407.2 / 409.2 [M+H]+.4246-96-1

[0281] Starting reagent(s): 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (300 mg, 90% Wt, 1 Eq, 687 pmol), cesium carbonate (447 mg, 2 Eq, 1.37 mmol) and l-bromo-3-methoxypropane (210 mg, 155 pL, 2 Eq, 1.37 mmol). 6-(3-(4-bromo-l-(3-methoxypropyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetra- hydro-2H-pyran-2-yl)pyridazin-3(2H)-one (136 mg, 0.29 mmol, 42 %, 99% Purity), m / z 465.2 / 467.2 [M+H]+.4246-96-2

[0282] Starting reagent(s): 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (300 mg, 90% Wt, 1 Eq, 687 pmol), cesium carbonate (447 mg, 2 Eq, 1.37 mmol) and l-bromo-3-methoxypropane (210 mg, 155 pL, 2 Eq, 1.37 mmol). 6-(3-(4-bromo-l-(3-methoxypropyl)-lH-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)-2-(tetra- hydro-2H-pyran-2-yl)pyridazin-3(2H)-one (177 mg, 0.37 mmol, 54 %, 98% Purity), m / z 465.2 / 467.2 [M+H]+.3953-456-1

[0283] Starting reagent(s): 3 -iodopropan- l-ol (77.7 mg, 40.0 pL, 1.63 Eq, 418 pmol), cesium carbonate (125 mg, 1.5 Eq, 385 pmol) and 6-(3-(3,4-dichloro-lH-pyrazol-5-yl)-l,2,4-oxadia- zol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (100 mg, 98.3% Wt, 1 Eq, 257 pmol). 6-(3-(3,4-dichloro-l-(3-hydroxypropyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tet- rahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (30.0 mg, 65 pmol, 25 %, 96% Purity), m / z 441.2 / 443.2 [M+H]+.3901-294-1

[0284] Starting reagent(s): 6-(3-(4-chloro-3-(difluoromethoxy)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (5.4 g, 95% Wt, 1 Eq, 13.83 mmol), cesium carbonate (5.00 g, 1.1 Eq, 15.3 mmol) and iodomethane (5.70 g, 2.50 mL, 2.9 Eq, 40.2 mmol). 6-(3-(4-chloro-3-(difluoromethoxy)-l-methyl-lH-pyrazol-5-yl)-l,2,4-oxadia- zol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (5.15 g, 11 mmol, 83 %, 95% Purity). 'H NMR (500 MHz, DMSO) 5 8.14 - 8.08 (m, 1H), 7.39 (t, J = 72.3 Hz, 1H), 7.23 (d, J = 9.8 Hz, 1H), 6.00 (dd, J = 10.1, 2.3 Hz, 1H), 4.10 (s, 3H), 4.04 - 3.98 (m, 1H), 3.74 - 3.61 (m, 1H), 2.21 - 2.10 (m, 1H), 2.05 - 1.99 (m, 1H), 1.82 - 1.66 (m, 2H), 1.56 (s, 2H). 19F NMR (471 MHz, DMSO) 5 -83.34. m / z 345.1 [M-THP+2H]+.3956-452-1

[0285] Starting reagent(s): 6-(5-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-3-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (166 mg, 96% Wt, 1 Eq, 457 pmol), cesium carbonate (223 mg, 1.5 Eq, 685 pmol) and methyl iodide (130 mg, 57.1 pL, 2.0 Eq, 914 pmol). 6-(5-(3- chloro- 1 -methyl- lH-pyrazol-5-yl)- 1 ,2,4-oxadiazol-3 -yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (42.0 mg, 0.11 mmol, 24 %, 93% Purity).1H NMR (500 MHz, DMSO) 5 8.03 (d, J = 9.8 Hz, 1H), 7.41 (s, 1H), 7.20 (d, J = 9.7 Hz, 1H), 6.01 - 5.95 (m, 1H), 4.25 (s, 3H), 4.00 (d, J = 11.3 Hz, 1H), 3.69 - 3.63 (m, 1H), 2.21 - 2.13 (m, 1H), 1.99 (d, J = 7.4 Hz, 1H), 1.74 (d, J = 12.6 Hz, 2H), 1.55 (s, 2H). m / z 279.2 [M-THP+2H]+.

[0286] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (125 mg, 97% Wt, 1 Eq, 317 pmol), cesium carbonate (155 mg, 1.5 Eq, 476 pmol) and 3-(bromomethyl)tetrahydrofuran (96.8 mg, 1.85 Eq, 587 pmol). 2-(tetrahydro-2H-pyran-2-yl)-6-(3-(l-((tetrahydrofuran-3-yl)methyl)-3- (trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (72.0 mg, 0.14 mmol, 45 %, 93% Purity), m / z 383.2 [M-THP+H]+.

[0287] Starting reagent(s): 2-(tetrahydro-2H-pyran-2-yl)-6-(5-(4-(trifluoromethyl)-lH-pyra- zol-5-yl)-l,2,4-oxadiazol-3-yl)pyridazin-3(2H)-one (166 mg, 95% Wt, 1 Eq, 413 pmol), cesium carbonate (202 mg, 1.5 Eq, 619 pmol) and methyl iodide (117 mg, 51.6 pL, 2.0 Eq, 825 pmol). 6-(5-(l-methyl-4-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-3-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (44.0 mg, 0.11 mmol, 27 %, 99% Purity). fld NMR in DMSO-d6 4245-460-A was consistent with product structure at 99% purity. 'H NMR (500 MHz, DMSO) 5 8.25 (s, 1H), 8.03 (d, J = 9.8 Hz, 1H), 7.21 (d, J = 9.8 Hz, 1H), 5.99 (dd, J = 10.1, 2.4 Hz, 1H), 4.03 - 3.96 (m, 1H), 3.65 (ddd, J = 11.5, 8.2, 6.3 Hz, 1H), 2.22 - 2.12 (m, 1H), 2.02 (d, J = 13.1 Hz, 1H), 1.79 - 1.68 (m, 2H), 1.55 (d, J = 8.7 Hz, 2H). m / z 313.2 [M- THP+H]+.

[0288] Starting reagent(s): 2-(tetrahydro-2H-pyran-2-yl)-6-(5-(4-(trifluoromethyl)-lH-pyra- zol-5-yl)-l,2,4-oxadiazol-3-yl)pyridazin-3(2H)-one (166 mg, 95% Wt, 1 Eq, 413 pmol), cesium carbonate (202 mg, 1.5 Eq, 619 pmol) and methyl iodide (117 mg, 51.6 pL, 2.0 Eq, 825 pmol). 6-(5-(l-methyl-4-(trifluoromethyl)-lH-pyrazol-3-yl)-l,2,4-oxadiazol-3-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (75.0 mg, 0.19 mmol, 45 %, 98% Purity). 'H NMR (500 MHz, DMSO) 5 8.72 (s, 1H), 7.96 (d, J = 9.8 Hz, 1H), 7.19 (d, J = 9.8 Hz, 1H), 5.98 (dd, J = 10.2, 2.3 Hz, 1H), 4.03 - 3.96 (m, 1H), 3.65 (ddd, J = 11.5, 8.5, 6.2 Hz, 1H), 2.24 - 2.11 (m, 1H), 2.06 - 1.97 (m, 1H), 1.77 - 1.68 (m, 2H), 1.54 (d, J = 8.8 Hz, 2H). m / z; 313.2 [M+H]+.3953-463-1

[0289] Starting reagent(s): 2-bromoethan-l-ol (72.2 mg, 41.0 pL, 1.53 Eq, 577 pmol), cesium carbonate (185 mg, 1.5 Eq, 567 pmol) and 6-(3-(3,4-dichloro-lH-pyrazol-5-yl)-l,2,4-oxadia- zol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (150 mg, 96.6% Wt, 1 Eq, 378 pmol). 6-(3-(3,4-dichloro-l-(2-hydroxyethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetra- hydro-2H-pyran-2-yl)pyridazin-3(2H)-one (46.0 mg, 108 pmol, 28.5 %, 100% Purity), m / z 343.5 / 345.5 [M-THP+2H]+.3953-464-1

[0290] Starting reagent(s): l-bromo-2-methoxy ethane (79.9 mg, 54.0 pL, 1.52 Eq, 575 pmol), cesium carbonate (185 mg, 1.5 Eq, 567 pmol) and 6-(3-(3,4-dichloro-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (150 mg, 96.6% Wt, 1 Eq, 378 pmol). 6-(3-(3, 4-di chi oro-1 -(2 -methoxy ethyl)- lH-pyrazol-5-yl)- 1,2, 4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (85.0 mg, 184 pmol, 48.5 %, 95.3% Purity), m / z 441.2 / 443.2 [M+H]+.3953-465-1

[0291] Starting reagent(s): iodomethane (82.1 mg, 36.0 pL, 1.53 Eq, 578 pmol), cesium carbonate (185 mg, 1.5 Eq, 567 pmol) and 6-(3-(3,4-dichloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (150 mg, 96.6% Wt, 1 Eq, 378 pmol).6-(3-(3, 4-di chi oro-1 -methyl- lH-pyrazol-5-yl)- 1,2, 4-oxadiazol-5-yl)-2-(tetrahy dro-2H-pyran- 2-yl)pyridazin-3(2H)-one (97.0 mg, 244 pmol, 64.6 %, 100% Purity), m / z 313.0 / 315.0 [M- THP+2H]+.4246-107-1

[0292] Starting reagent(s): 6-(3-(4-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 95% Wt, 1 Eq, 681 pmol) and cesium carbonate (462 mg, 2.08 Eq, 1.42 mmol) in anhydrous DMF (2.00 mL) was added 2-bromoethan- l-ol (177 mg, 101 pL, 2.08 Eq, 1.42 mmol). 6-(3-(4-chloro-l-(2-hydroxyethyl)-lH-pyrazol-5- yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (124 mg, 0.31 mmol, 45 %, 97% Purity), m / z 393.2 [M+H]+.

[0293] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (150 mg, 97% Wt, 1 Eq, 381 pmol), cesium carbonate (186 mg, 1.5 Eq, 571 pmol) and 1-iodopropane (120 mg, 1.85 Eq, 704 pmol).6-(3-(l-propyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H- pyran-2-yl)pyridazin-3(2H)-one (77.0 mg, 0.18 mmol, 46 %, 97% Purity), m / z 425.2 [M+H]+.

[0294] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (150 mg, 97% Wt, 1 Eq, 381 pmol), cesium carbonate (186 mg, 1.5 Eq, 571 pmol) and 1 -chlorobutane (66.9 mg, 1.9 Eq, 723 pmol).6-(3-(l-butyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H- pyran-2-yl)pyridazin-3(2H)-one (75.0 mg, 0.17 mmol, 44 %, 98% Purity), m / z 439.2 [M+H]+.4246-108-1

[0295] Starting reagent(s): 6-(3-(4-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 95% Wt, 1 Eq, 681 pmol), cesium carbonate (465 mg, 2.10 Eq, 1.43 mmol) and 3 -bromopropan- l-ol (200 mg, 130 pL, 2.11 Eq, 1.44 mmol). 6-(3-(4-chloro-l-(3-hydroxypropyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro- 2H-pyran-2-yl)pyridazin-3(2H)-one (66.0 mg, 0.14 mmol, 21 %, 88% Purity), m / z 407.2 [M+H]+.4246-109-1

[0296] Starting reagent(s): 6-(3-(4-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 95% Wt, 1 Eq, 681 pmol), cesium carbonate (468 mg, 2.11 Eq, 1.44 mmol) and l-bromo-2-methoxy ethane (210 mg, 142 pL, 2.22 Eq, 1.51 mmol). 6-(3-(4-chl oro-1 -(2 -methoxy ethyl)- lH-pyrazol-5-yl)-l, 2, 4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (95.0 mg, 0.23 mmol, 34 %, 99% Purity), m / z 407.2 [M+H]+.3912-479-1

[0297] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (0.50 g, 98% Wt, 1 Eq, 1.3 mmol), cesium carbonate (0.63 g, 1.5 Eq, 1.9 mmol) and propargyl bromide (0.30 g, 0.22 mL, 80% Wt, 1.6 Eq, 2.1 mmol). 6-(3-(l -(prop-2 -yn-1 -yl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l, 2, 4-oxadiazol-5- yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (155 mg, 0.36 mmol, 28 %, 97% Purity), m / z 337.2 [M-THP+2H]+.4245-131-3

[0298] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (150 mg, 97% Wt, 1 Eq, 381 pmol), cesium carbonate (186 mg, 1.5 Eq, 571 pmol) and 3-(bromomethyl)-3-methyloxetane (62.8 mg, 1 Eq, 381 pmol). 6-(3-(l-((3-methyloxetan-3-yl)methyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)- l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (59.0 mg, 0.11 mmol, 29 %, 88% Purity), m / z 467.2 [M+H]+.Relative Stereochemistry known Mixture of 2 enantiomers (4 diastereoisomers including THP protecting group)3912-531

[0299] Starting reagent(s): 6-(3-(4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 95% Wt, 1 Eq, 456 pmol), cesium carbonate (193 mg, 1.3 Eq, 593 pmol), Mixture of ((lS,2R)-2-hydroxycyclo- pentyl)methyl 4-methylbenzenesulfonate and ((lR,2S)-2-hydroxycyclopentyl)methyl 4- methylbenzenesulfonate (1 : 1 169 mg, 95% Wt, 1.3 Eq, 593 pmol). Mixture of 6-(3-(4-chloro-1-(((lS,2R)-2-hydroxycyclopentyl)methyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one and 6-(3-(4-chloro-l-(((lR,2S)-2-hydroxycy cl opentyl)methyl)-3-(tri fluoromethyl)- lH-pyrazol-5-yl)- 1,2, 4-oxadiazol-5-yl)-2- (tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (1 : 1, 90.0 mg, 169 pmol, 21.1 %, 96.5% Purity).1H NMR (500 MHz, DMSO) 5 8.12 (d, J = 9.8 Hz, 1H), 7.25 (d, J = 9.8 Hz, 1H), 6.01 (d, J = 9.6 Hz, 1H), 4.72 - 4.64 (m, 1H), 4.59 (t, J = 4.8 Hz, 1H), 4.53 - 4.44 (m, 1H), 4.06 - 3.97 (m, 1H), 3.83 - 3.75 (m, 1H), 3.71 - 3.62 (m, 1H), 2.31 - 2.22 (m, 1H), 2.22 - 2.11 (m, 1H), 2.08 - 1.96 (m, 1H), 1.87 - 1.49 (m, 8H), 1.48 - 1.37 (m, 1H), 1.32 - 1.16 (m, 1H). m / z 413.6 [M-DHP-OH]+.3953-462-1

[0300] Starting reagent(s): l-bromo-3-methoxypropane (87.0 mg, 64.0 pL, 1.50 Eq, 569 pmol), cesium carbonate (185 mg, 1.5 Eq, 567 pmol) and 6-(3-(3,4-dichloro-lH-pyrazol-5-yl)- l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (150 mg, 96.6% Wt, 1 Eq, 378 pmol). 6-(3-(3,4-dichloro-l-(3-methoxypropyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5- yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (98.0 mg, 215 pmol, 56.9 %, 100% Purity). m / z 455.2 / 457.2 [M+H]+.3953-460-1

[0301] Starting reagent(s): iodomethane (980 mg, 432 pL, 1.5 Eq, 6.90 mmol), cesium carbonate (2.25 g, 1.5 Eq, 6.90 mmol), 3-methyl-4-nitro-lH-pyrazole-5-carbonitrile (778 mg, 90%Wt, 1 Eq, 4.60 mmol). l,3-dimethyl-4-nitro-lH-pyrazole-5-carbonitrile (466 mg, 2.70 mmol, 58.6 %, 96.2% Purity). 'H NMR (500 MHz, DMSO) 5 3.93 (s, 3H), 2.62 (s, 3H). m / z 165.2 [M-H]-.4246-110-1

[0302] Starting reagent(s): 6-(3-(4-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 95% Wt, 1 Eq, 681 pmol), cesium carbonate (460 mg, 2.07 Eq, 1.41 mmol), l-bromo-3-methoxypropane (221 mg, 162 pL, 2.12 Eq, 1.44 mmol). 6-(3-(4-chl oro-1 -(3-methoxypropyl)- lH-pyrazol-5-yl)- 1,2, 4-oxadiazol-5-yl)-2-(tetra- hydro-2H-pyran-2-yl)pyridazin-3(2H)-one (87.0 mg, 0.20 mmol, 30 %, 98% Purity), m / z 337.3 [M-THP+2H]+.4246-97-1

[0303] Starting reagent(s): 6-(3-(4-bromo-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (300 mg, 90% Wt, 1 Eq, 687 pmol), cesium carbonate (447 mg, 2 Eq, 1.37 mmol), 3 -bromopropan- l-ol (191 mg, 124 pL, 2 Eq, 1.37 mmol). 6-(3-(4- bromo-l-(3-hydroxypropyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran- 2-yl)pyridazin-3(2H)-one (151 mg, 0.30 mmol, 44 %, 90% Purity), m / z 451.2 / 453.2 [M+H]+.4245-108-1

[0304] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (250 mg, 97% Wt, 1 Eq, 634 pmol), cesium carbonate (310 mg, 1.5 Eq, 951 pmol), 2-(3-bromopropyl)isoindoline-l, 3-dione (315 mg, 1.85 Eq, 1.17 mmol). 2-(3-(5-(5-(6-oxo-l-(tetrahydro-2H-pyran-2-yl)-l,6-dihydropyridazin-3- yl)- 1 ,2,4-oxadiazol-3 -y l)-3 -(trifluoromethyl)- IH-pyrazol- 1 -yl)propyl)isoindoline- 1 ,3 -di one (174 mg, 0.27 mmol, 43 %, 90% Purity). 'H NMR (500 MHz, DMSO) 5 7.97 (d, J = 9.9 Hz, 1H), 7.87 - 7.71 (m, 4H), 7.46 (s, 1H), 7.19 (d, J= 9.9 Hz, 1H), 5.99 (dd, J= 10.4, 2.2 Hz, 1H), 4.73 (t, J= 7.2 Hz, 2H), 4.09 (q, J= 5.3 Hz, 2H), 4.02 (d, J= 11.6 Hz, 1H), 3.66 (t, J= 6.5 Hz, 3H), 2.30 (m, 2H), 2.20 - 2.10 (m, 1H), 2.08 - 1.96 (m, 1H), 1.81 - 1.69 (m, 2H), 1.62 - 1.53 (m, 2H). m / z 570.2 [M+H]+.4245-137-1

[0305] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (150 mg, 97% Wt, 1 Eq, 417 pmol), cesium carbonate (204 mg, 1.5 Eq, 626 pmol), 3-bromo-N,N-dimethylpropan-l-amine, HBr (191 mg, 1.85 Eq, 772 pmol). 6-(3-(3-chloro-l-(3-(dimethylamino)propyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5- yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (56.0 mg, 0.13 mmol, 30 %, 98% Purity). m / z 434.2 / 436.2 [M+H]+.4245-137-2

[0306] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (150 mg, 97% Wt, 1 Eq, 417 pmol), cesium carbonate (204 mg, 1.5 Eq, 626 pmol), 3-bromo-2,2-dimethylpropan-l-ol (132 mg, 97.5 pL, 1.9 Eq, 793 pmol), potassium iodide (6.93 mg, 0.1 Eq, 41.7 pmol). 6-(3 -(3 -chi oro-1 -(3 -hydroxy-2, 2-dime- thylpropyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin- 3(2H)-one (30.0 mg, 68 pmol, 16 %, 99% Purity), m / z 435.1 / 437.1 [M+H]+.4245-137-3

[0307] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (150 mg, 97% Wt, 1 Eq, 417 pmol), cesium carbonate (204 mg, 1.5 Eq, 626 pmol), 4-bromo-2-methylbutan-2-ol (90.6 mg, 1.3 Eq, 542 pmol). 6-(3- (3-chloro-l-(3-hydroxy-3-methylbutyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro- 2H-pyran-2-yl)pyridazin-3(2H)-one (95.0 mg, 0.21 mmol, 51 %, 97% Purity). 'H NMR (500 MHz, DMSO) 5 8.06 (d, J = 9.8 Hz, 1H), 7.24 (d, J= 9.8 Hz, 1H), 7.08 (d, J= 1.7 Hz, 1H), 6.00 (dd, J= 10.4, 2.2 Hz, 1H), 4.68 - 4.58 (m, 2H), 4.45 (s, 1H), 4.01 (d, J= 11.9 Hz, 1H), 3.72 - 3.59 (m, 1H), 2.24 - 2.10 (m, 1H), 2.06 - 1.97 (m, 1H), 1.95 - 1.84 (m, 2H), 1.80 - 1.67 (m, 2H), 1.62 - 1.50 (m, 2H), 1.16 (s, 6H). m / z 435.2 [M+H]+.3956-462-1

[0308] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(5 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-3-yl)pyridazin-3(2H)-one (198 mg, 67% Wt, 1 Eq, 347 pmol), cesium carbonate (170 mg, 1.5 Eq, 521 pmol), iodoethane (108 mg, 55.8 pL, 2.0 Eq, 694 pmol). 'H NMR (500 MHz, DMSO) 5 8.03 (d, J = 9.8 Hz, 1H), 7.83 (s, 1H), 7.21 (d, J = 9.8 Hz, 1H), 5.99 (dd, J = 10.1, 2.4 Hz, 1H), 4.78 (q, J = 7.2 Hz, 2H), 4.00 (d, J = 11.5 Hz, 1H), 3.70 - 3.61 (m, 1H), 2.20 - 2.16 (m, 1H), 2.03 (d, J = 13.0 Hz, 1H), 1.79 - 1.74 (m, 2H), 1.56 (d, J = 5.3 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H). m / z 327.2 [M+H]+.4245-143-1

[0309] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (150 mg, 97% Wt, 1 Eq, 417 pmol), cesium carbonate(204 mg, 1.5 Eq, 626 pmol), 3 -hydroxybutyl 4-methylbenzenesulfonate (315 mg, 97% Wt, 3 Eq, 1.25 mmol). 6-(3-(3-chloro-l-(3-hydroxybutyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2- (tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (110 mg, 0.24 mmol, 58 %, 93% Purity), m / z 421.3 [M+H]+.4245-143-2

[0310] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (150 mg, 97% Wt, 1 Eq, 417 pmol), cesium carbonate (204 mg, 1.5 Eq, 626 pmol), 3 -hydroxy -2-methylpropyl 4-methylbenzenesulfonate (315 mg, 97% Wt, 3 Eq, 1.25 mmol). 6-(3-(3-chloro-l-(3-hydroxy-2-methylpropyl)-lH-pyrazol-5-yl)- l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (43.0 mg, 0.10 mmol, 24 %, 99% Purity), m / z 421.4 [M+H]+.4245-88-1

[0311] Starting reagent(s): 2-(tetrahydro-2H-pyran-2-yl)-6-(3-(3-(trifluoromethyl)-lH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (190 mg, 97% Wt, 1 Eq, 482 pmol), cesium carbonate (236 mg, 1.5 Eq, 723 pmol), 4-(2-bromoethyl)morpholine (173 mg, 1.85 Eq, 892 pmol), KI (8.00 mg, 0.1 Eq, 48.2 pmol). 6-(3-(l-(2-morpholinoethyl)-3-(trifluoromethyl)- lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (45.0 mg, 90 pmol, 19 %, 99% Purity), m / z 496.2 [M+H]+.4245-107-1

[0312] Starting reagent(s): 2-(tetrahydro-2H-pyran-2-yl)-6-(3-(3-(trifluoromethyl)-lH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (125 mg, 97% Wt, 1 Eq, 317 pmol), cesium carbonate (155 mg, 1.5 Eq, 476 pmol), tert-butyl (2-(2-(2-(2-bromoethoxy)ethoxy)eth- oxy)ethyl)carbamate (209 mg, 1.85 Eq, 587 pmol). tert-butyl (2-(2-(2-(2-(5-(5-(6-oxo-l-(tetra- hydro-2H-pyran-2-yl)-l,6-dihydropyridazin-3-yl)-l,2,4-oxadiazol-3-yl)-3-(trifluoromethyl)- lH-pyrazol-l-yl)ethoxy)ethoxy)ethoxy)ethyl)carbamate (48.0 mg, 70 pmol, 22 %, 96% Purity). m / z 558.3 [M-Boc+2H]+.3901-246-1

[0313] Starting reagent(s): iodomethane (0.23 g, 0.10 m , 2.5 Eq, 1.6 mmol), ethyl 3-fluoro- lH-pyrazole-5-carboxylate (100 mg, 1 Eq, 632 pmol), cesium carbonate (225 mg, 1.09 Eq, 691 pmol). Used without analysis.4246-114-1

[0314] Starting reagent(s): 6-(3-(4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 96% Wt, 1 Eq, 461 pmol), cesium carbonate (300 mg, 2 Eq, 921 pmol) and 2-bromoethan-l-ol (132.4 mg, 75.2 pL, 2.3 Eq, 1.06 mmol). 6-(3-(4-chloro-l-(2-hydroxyethyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)- l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (98.0 mg, 0.19 mmol, 41 %, 88% Purity), m / z 447.0 [M-THP+2H]+.

[0315] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (150 mg, 97% Wt, 1 Eq, 417 pmol), cesium carbonate (204 mg, 1.5 Eq, 626 pmol) and 3-(bromomethyl)oxetane (113 mg, 1.8 Eq, 751 pmol). 6-(3-(3- chloro- 1 -(oxetan-3 -ylmethyl)- lH-pyrazol-5-yl)- 1 ,2,4-oxadiazol-5 -yl)-2-(tetrahydro-2H-py- ran-2-yl)pyridazin-3(2H)-one (86.0 mg, 0.20 mmol, 48 %, 97% Purity), m / z 419.2 / 421.2 [M+H]+.4245-149-1

[0316] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (120 mg, 97% Wt, 1 Eq, 334 pmol), cesium carbonate (163 mg, 1.5 Eq, 501 pmol) and 4-bromotetrahydro-2H-pyran (99.1 mg, 67.6 pL, 1.8 Eq, 601 pmol). 6-(3-(3-chloro-l-(tetrahydro-2H-pyran-4-yl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)- 2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (93.0 mg, 0.20 mmol, 61 %, 94% Purity), m / z 433.2 / 435.2 [M+H]+.Boc4245-149-2

[0317] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (120 mg, 97% Wt, 1 Eq, 334 pmol), cesium carbonate (163 mg, 1.5 Eq, 501 pmol) and tert-butyl 4-bromopiperidine-l -carboxylate (159 mg, 1.8 Eq, 601 pmol). tert-butyl 4-(3-chloro-5-(5-(6-oxo-l-(tetrahydro-2H-pyran-2-yl)-l,6-dihydropyridazin-3-yl)-l,2,4-oxadiazol-3-yl)-lH-pyrazol-l-yl)piperidine-l-carboxylate (124 mg, 0.23 mmol, 69 %, 99% Purity), m / z 432.2 / 434.2 [M-Boc+2H]+.

[0318] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(5 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-3-yl)pyridazin-3(2H)-one (198 mg, 67% Wt, 1 Eq, 347 pmol), cesium carbonate (170 mg, 1.5 Eq, 521 pmol) and iodoethane (108 mg, 55.8 pL, 2.0 Eq, 694 pmol). 6-(5-(l-ethyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-l,2,4-oxadiazol-3-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (11.0 mg, 27 pmol, 7.6 %, 99% Purity), m / z 327.2 [M- THP+2H]+.3953-478-1

[0319] Starting reagent(s): iodomethane (82.1 mg, 36.0 pL, 1.71 Eq, 578 pmol), cesium carbonate (166 mg, 1.5 Eq, 508 pmol), 6-(3-(4-bromo-3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (150 mg, 96.6% Wt, 1 Eq, 339 pmol).6-(3-(4-bromo-3-chloro-l-methyl-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H- pyran-2-yl)pyridazin-3(2H)-one (105 mg, 225 pmol, 66.4 %, 94.7% Purity). 'H NMR (500 MHz, DMSO) 5 8.11 (d, J = 9.8 Hz, 1H), 7.24 (d, J = 9.8 Hz, 1H), 6.00 (dd, J = 2.4, 10.3 Hz, 1H), 4.15 (s, 3H), 4.05 - 3.97 (m, 1H), 3.70 - 3.63 (m, 1H), 2.21 - 2.11 (m, 1H), 2.05 - 1.99 (m, 1H), 1.80 - 1.69 (m, 2H), 1.62 - 1.50 (m, 2H). m / z 357.0 / 359.0 [M-THP+2H]+.3953-519-1

[0320] Starting reagent(s): 4-bromo-2-methylbutan-2-ol (270 mg, 1 Eq, 1.62 mmol), cesium carbonate (790 mg, 1.5 Eq, 2.42 mmol) and 6-(3-(4-bromo-3-chloro-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)pyridazin-3(2H)-one (1 g, 2.34 mmol). 6-(3 -(4-bromo-3 -chi oro-1 -(3 -hydroxy - 3-methylbutyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyri- dazin-3(2H)-one (252 mg, 465 pmol, 28.7 %, 94.8% Purity). 'H NMR (500 MHz, DMSO) 5 8.07 (d, J = 9.8 Hz, 1H), 7.26 (d, J = 9.8 Hz, 1H), 6.01 (dd, J = 2.3, 10.3 Hz, 1H), 4.66 - 4.57 (m, 2H), 4.44 (s, 1H), 4.05 - 3.98 (m, 1H), 3.71 - 3.63 (m, 1H), 2.24 - 2.11 (m, 1H), 2.08 - 1.98 (m, 1H), 1.95 - 1.85 (m, 2H), 1.75 (td, J = 3.5, 14.1 Hz, 2H), 1.63 - 1.51 (m, 2H), 1.14 (s, 6H). m / z 496.9 [M+H]+.3901-275-1

[0321] Starting reagent(s): 2-(3-bromopropoxy)tetrahydro-2H-pyran (0.66 g, 0.50 mL, 1.4 Eq, 3.0 mmol), cesium carbonate (1.00 g, 1.51 Eq, 3.07 mmol) and 6-(3-(4-bromo-3 -(trifluoromethyl)- lH-pyrazol-5-yl)- 1,2, 4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (1.00 g, 94% Wt, 1 Eq, 2.04 mmol). 6-(3-(4-bromo-l-(3-((tetrahydro-2H-pyran-2- yl)oxy)propyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H- pyran-2-yl)pyridazin-3(2H)-one (900 mg, 1.4 mmol, 70 %, 95% Purity). 'H NMR (500 MHz, DMSO) 5 8.09 (d, J = 9.8 Hz, 1H), 7.25 (d, J = 9.8 Hz, 1H), 6.01 (dd, J = 10.2, 2.3 Hz, 1H), 4.69 (t, J = 6.9 Hz, 2H), 4.44 (t, J = 3.7 Hz, 1H), 4.07 - 3.98 (m, 1H), 3.71 - 3.60 (m, 3H), 3.39 - 3.32 (m, 2H), 2.22 - 2.05 (m, 3H), 2.05 - 2.00 (m, 1H), 1.84 - 1.67 (m, 2H), 1.65 - 1.47 (m, 4H), 1.47 - 1.25 (m, 4H).3956-521-1

[0322] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 99.5% Wt, 1 Eq, 713 pmol), cesium carbonate (349 mg, 1.5 Eq, 1.07 mmol), 4-bromobutan-l-ol (142 mg, 133 pL, 1.3 Eq, 927 pmol), potassium iodide (11.8 mg, 0.1 Eq, 71.3 pmol). 6-(3-(3-chloro-l-(4-hydroxybutyl)-lH-pyrazol- 5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (45.0 mg, 98 pmol, 14 %, 92% Purity). 'H NMR (500 MHz, DMSO) 5 8.07 (d, J = 9.8 Hz, 1H), 7.23 (d, J = 9.8 Hz, 1H), 7.09 (s, 1H), 6.04 - 5.96 (m, 1H), 4.54 (t, J = 7.2 Hz, 2H), 4.43 (t, J = 5.2 Hz, 1H), 4.01 (d, J = 11.5 Hz, 1H), 3.71 - 3.64 (m, 1H), 3.39 (q, J = 6.5 Hz, 2H), 2.21 - 2.11 (m, 1H), 2.01 (d, J = 12.6 Hz, 1H), 1.85 (p, J = 7.3 Hz, 2H), 1.74 (t, J = 14.7 Hz, 2H), 1.56 (s, 2H), 1.42 (p, J = 6.6 Hz, 2H). m / z 421.2 [M+H]+.3956-527-1

[0323] Starting reagent(s): 2-(3-bromopropoxy)tetrahydro-2H-pyran (190 mg, 144 pL, 1.4 Eq, 851 pmol), suspension of cesium carbonate (277 mg, 1.4 Eq, 851 pmol) and 6-(3-(4-chloro- 3-(difluoromethoxy)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2- yl)pyridazin-3(2H)-one (280 mg, 90% Wt, 1 Eq, 608 pmol). 6-(3-(4-chl oro-3 -(difluorom ethoxy)- 1 -(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)- lH-pyrazol-5-yl)- 1 ,2,4-oxadiazol-5-yl)-2- (tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (128 mg, 0.19 mmol, 32 %, 84% Purity). 'H NMR (500 MHz, DMSO) 5 8.09 (d, J = 9.7 Hz, 1H), 7.56 - 7.20 (m, 2H), 6.00 (dd, J = 10.1, 2.3 Hz, 1H), 4.56 (t, J = 6.9 Hz, 2H), 4.45 (t, J = 3.7 Hz, 1H), 4.01 (d, J = 13.4 Hz, 1H), 3.72 - 3.57 (m, 3H), 3.41 - 3.30 (m, 3H), 2.15 (td, J = 12.2, 4.6 Hz, 1H), 2.10 - 2.00 (m, 2H), 1.81 - 1.67 (m, 2H), 1.66 - 1.49 (m, 4H), 1.47 - 1.29 (m, 4H). m / z 389.3 [M+H]+.3912-536-1

[0324] Starting reagent(s): 6-(3-(4-chloro-3-(difluoromethoxy)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (130 mg, 98% Wt, 1 Eq, 307 pmol), cesium carbonate (150 mg, 1.5 Eq, 461 pmol), (R)-3 -hydroxybutyl 4-methylben- zenesulfonate (117 mg, 96.4% Wt, 1.5 Eq, 461 pmol). 6-(3-(4-chloro-3-(difluoromethoxy)-l- ((R)-3-hydroxybutyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2- yl)pyridazin-3(2H)-one (73.0 mg, 0.14 mmol, 45 %, 93% Purity). 'H NMR (500 MHz, DMSO) 5 8.08 (d, .7= 9.8 Hz, 1H), 7.47 (t, J= 72.2 Hz, 1H), 7.24 (d, = 9.7 Hz, 1H), 6.01 (dd, J= 10.1, 2.3 Hz, 1H), 4.58 - 4.55 (m, 1H), 4.52 (t, J= 7.5 Hz, 2H), 4.05 - 3.97 (m, 1H), 3.73 - 3.55 (m, 2H), 2.24 - 2.11 (m, 1H), 2.07 - 1.96 (m, 1H), 1.94 - 1.67 (m, 4H), 1.65 - 1.47 (m, 2H), 1.07 (d, J= 6.2 Hz, 3H). m / z 487.0 [M+H]+.

[0325] Starting reagent(s): 6-(3-(4-chloro-3-(difluoromethoxy)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (130 mg, 98% Wt, 1 Eq, 307 pmol), cesium carbonate (150 mg, 1.5 Eq, 461 pmol), (S)-3 -hydroxybutyl 4-methylben- zenesulfonate (120 mg, 93.6% Wt, 1.5 Eq, 461 pmol). 6-(3-(4-chl oro-3 -(difluoromethoxy)- 1- ((S)-3-hydroxybutyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2- yl)pyridazin-3(2H)-one (101 mg, 0.17 mmol, 54 %, 80% Purity). 'H NMR (500 MHz, DMSO) 5 8.08 (d, .7= 9.8 Hz, 1H), 7.47 (t, J= 72.1 Hz, 1H), 7.24 (d, .7= 9.6 Hz, 1H), 6.00 (dd, J= 10.3, 2.3 Hz, 1H), 4.58 - 4.55 (m, 1H), 4.52 (t, J= 7.5 Hz, 2H), 4.05 - 3.97 (m, 1H), 3.73 - 3.56 (m, 2H), 2.24 - 2.08 (m, 1H), 2.08 - 1.98 (m, 1H), 1.95 - 1.65 (m, 4H), 1.63 - 1.49 (m, 2H), 1.07 (d, J= 6.2 Hz, 3H). m / z 487.0 [M+H]+.

[0326] Starting reagent(s): 6-(3-(4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (400 mg, 95% Wt, 1 Eq, 912 pmol), cesium carbonate (450 mg, 1.51 Eq, 1.38 mmol), (R)-3 -hydroxybutyl 4-methylbenzene- sulfonate (350 mg, 96.4% Wt, 1.51 Eq, 1.38 mmol). 6-(3-(4-chloro-l-((R)-3-hydroxybutyl)-3- (trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyri- dazin-3(2H)-one (195 mg, 0.39 mmol, 43 %, 99% Purity). 'H NMR (500 MHz, DMSO) 5 8.10 (d, J = 9.8 Hz, 1H), 7.25 (dd, J = 9.8, 1.2 Hz, 1H), 6.01 (dd, J = 10.2, 2.3 Hz, 1H), 4.74 - 4.62 (m, 2H), 4.62 - 4.57 (m, 1H), 4.01 (d, J = 11.6 Hz, 1H), 3.71 - 3.61 (m, 2H), 2.22 - 2.12 (m, 1H), 2.07 - 1.99 (m, 1H), 1.99 - 1.90 (m, 1H), 1.90 - 1.80 (m, 1H), 1.80 - 1.68 (m, 2H), 1.56 (s, 2H), 1.08 (d, J = 6.1 Hz, 3H). m / z 404.7 [M-THP+H]+.

[0327] Starting reagent(s): 6-(3-(4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (400 mg, 95% Wt, 1 Eq, 912 pmol), cesium carbonate (450 mg, 1.51 Eq, 1.38 mmol, (S)-3 -hydroxybutyl 4-methylbenzene- sulfonate (360 mg, 93.6% Wt, 1.51 Eq, 1.38 mmol). 6-(3-(4-chloro-l-((S)-3-hydroxybutyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyri- dazin-3(2H)-one (180 mg, 0.36 mmol, 40 %, 98% Purity) m / z 405.3 [M-THP+2H]+.3956-540-1

[0328] Starting reagent(s): 6-(3-(4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (100 mg, 1 Eq, 240 pmol), cesium carbonate (117 mg, 1.5 Eq, 360 pmol), (S)-3 -hydroxy -2-methylpropyl 4-methylbenzene- sulfonate (87.9 mg, 1.5 Eq, 360 pmol). 6-(3-(4-chloro-l-((R)-3-hydroxy-2-methylpropyl)-3- (trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyri- dazin-3(2H)-one (34.0 mg, 53 pmol, 11 %, 76% Purity). 'H NMR (500 MHz, DMSO) 5 8.10 (d, J = 9.8 Hz, 1H), 7.24 (d, J = 9.8 Hz, 1H), 6.05 - 6.00 (m, 1H), 4.75 - 4.58 (m, 2H), 4.41 (ddd, J = 14.0, 8.0, 2.8 Hz, 1H), 4.01 (d, J = 11.4 Hz, 1H), 3.72 - 3.60 (m, 1H), 4.75 - 3.29 (m, 2H) assumed 2.18 (dd, J = 13.5, 8.7 Hz, 2H), 2.02 (d, J = 13.4 Hz, 1H), 1.77 (d, J = 13.0 Hz, 2H), 1.56 (s, 2H), 0.81 (d, J = 6.8 Hz, 3H).

[0329] Starting reagent(s): 6-(3-(4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 95% Wt, 1 Eq, 456 pmol), cesium carbonate (223 mg, 1.5 Eq, 684 pmol), (R)-3-hydroxy-2-methylpropyl 4- methylbenzenesulfonate (250 mg, 89% Wt, 2.0 Eq, 912 pmol). 6-(3 -(4-chl oro-1 -((S)-3-hy- droxy-2-methylpropyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (86.0 mg, 0.16 mmol, 33 %, 90% Purity). 'H NMR (500 MHz, DMSO) 5 8.10 (d, J = 9.8 Hz, 1H), 7.25 (d, J = 9.8 Hz, 1H), 6.01 (dd, J = 10.2, 2.3 Hz, 1H), 4.69 (ddd, J = 13.8, 6.4, 4.1 Hz, 1H), 4.60 (d, J = 5.4 Hz, 1H), 4.41 (ddd, J = 13.7, 7.9, 2.8 Hz, 1H), 4.01 (d, J = 11.5 Hz, 1H), 3.71 - 3.62 (m, 1H), 3.29 (d, J = 5.6 Hz, 2H), 2.22 - 2.11 (m, 2H), 2.02 (d, J = 13.2 Hz, 1H), 1.82 - 1.68 (m, 2H), 1.57 (d, J = 4.7 Hz, 2H), 0.81 (d, J = 6.8 Hz, 3H).3953-542-1

[0330] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 95% Wt, 1 Eq, 545 pmol), cesium carbonate(266 mg, 1.5 Eq, 817 pmol), (R)-3 -hydroxybutyl 4-methylbenzenesulfonate (207 mg, 96.4% Wt, 1.5 Eq, 817 pmol). 6-(3-(3-chloro-l-((R)-3-hydroxybutyl)-lH-pyrazol-5-yl)-l,2,4-oxadia- zol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (132 mg, 0.31 mmol, 57 %, 99% Purity). 'H NMR (500 MHz, DMSO) 5 8.07 (d, J = 9.8 Hz, 1H), 7.24 (d, J = 9.8 Hz, 1H), 7.08 (s, 1H), 6.03 - 5.98 (m, 1H), 4.66 - 4.54 (m, 3H), 4.04 - 3.97 (m, 1H), 3.72 - 3.60 (m, 2H), 2.21 - 2.10 (m, 1H), 2.06 - 1.96 (m, 1H), 1.94 - 1.79 (m, 2H), 1.79 - 1.68 (m, 2H), 1.63 - 1.52 (m, 2H), 1.09 (d, J = 6.2 Hz, 3H). m / z 421.5 / 423.5 [M+H]+.

[0331] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 95% Wt, 1 Eq, 545 pmol), cesium carbonate (266 mg, 1.5 Eq, 817 pmol), (S)-3 -hydroxybutyl 4-methylbenzenesulfonate (213 mg, 93.6% Wt, 1.5 Eq, 817 pmol). 6-(3-(3-chloro-l-((S)-3-hydroxybutyl)-lH-pyrazol-5-yl)-l,2,4-oxadia- zol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (134 mg, 0.32 mmol, 58 %, 99% Purity). 'H NMR (500 MHz, DMSO) 5 8.07 (d, J = 9.7 Hz, 1H), 7.24 (d, J = 9.9 Hz, 1H), 7.08 (s, 1H), 6.04 - 5.96 (m, 1H), 4.66 - 4.53 (m, 3H), 4.05 - 3.97 (m, 1H), 3.72 - 3.60 (m, 2H), 2.23 - 2.10 (m, 1H), 2.07 - 1.96 (m, 1H), 1.96 - 1.79 (m, 2H), 1.79 - 1.67 (m, 2H), 1.56 (s, 2H), 1.09 (d, J = 6.3 Hz, 3H). m / z 421.07 / 423.03 [M+H]+.

[0332] Starting reagent(s): 6-(3-(4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (300 mg, 95% Wt, 1 Eq, 684 pmol) in DMF (1.00 mL), cesium carbonate (290 mg, 1.3 Eq, 889 pmol), l-fluoro-3 -iodopropane (167 mg, 1.3 Eq, 889 pmol). 6-(3-(4-chloro-l-(3-fluoropropyl)-3-(trifluoromethyl)-lH- pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (198 mg, 0.41 mmol, 60 %, 98% Purity). 'H NMR (500 MHz, DMSO) 5 8.10 (d, J = 9.8 Hz, 1H), 7.25 (d, J= 9.7 Hz, 1H), 6.01 (dd, J = 10.2, 2.4 Hz, 1H), 4.73 (t, J= 7.1 Hz, 2H), 4.58 (t, J =5.6 Hz, 1H), 4.49 (t, J= 5.6 Hz, 1H), 4.07 - 3.96 (m, 1H), 3.72 - 3.61 (m, 1H), 2.34 - 2.09 (m, 3H), 2.02 (d, J= 13.1 Hz, 1H), 1.83 - 1.67 (m, 2H), 1.64 - 1.49 (m, 2H). m / z 393.6 [M+H]+.3953-569

[0333] Starting reagent(s): 6-(3-(4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (500 mg, 1 Eq, 1.20 mmol), cesium carbonate (1.17 g, 3.0 Eq, 3.60 mmol), 3-((tert-butoxycarbonyl)amino)-2-methylpropyl 4-methylbenzenesulfonate (620 mg, 86.9% Wt, 1.31 Eq, 1.57 mmol), tert-butyl (3-(4-chloro-5- (5-(6-oxo- 1 -(tetrahydro-2H-pyran-2-yl)- 1 ,6-dihydropyridazin-3 -yl)- 1 ,2,4-oxadiazol-3 -y l)-3 - (trifluoromethyl)-lH-pyrazol-l-yl)-2-methylpropyl)carbamate (338 mg, 0.56 mmol, 47 %, 98% Purity). 'H NMR (500 MHz, DMSO) 5 8.13 (d, J = 9.9 Hz, 1H), 7.24 (d, J = 9.8 Hz, 1H), 6.86 (s, 1H), 6.01 (dd, J = 2.3, 10.2 Hz, 1H), 4.61 (dd, J = 5.9, 13.9 Hz, 1H), 4.35 (dd, J = 8.5, 13.8 Hz, 1H), 4.01 (d, J = 11.6 Hz, 1H), 3.73 - 3.61 (m, 1H), 2.98 - 2.84 (m, 2H), 2.26 - 2.11 (m, 2H), 2.06 - 1.96 (m, 1H), 1.82 - 1.67 (m, 2H), 1.56 (m, 2H), 1.33 (s, 9H), 0.79 (d, J = 6.7 Hz, 3H). m / z 404.2 / 406.2 [M-THP-Boc+4H]+.3956-574

[0334] Starting reagent(s): 6-(3-(4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (180.0 mg, 1 Eq, 431.9 pmol), cesium carbonate (422.2 mg, 3.0 Eq, 1.296 mmol), (R)-3-((tert-butoxycarbonyl)amino)butyl 4- methylbenzenesulfonate (445.0 mg, 3.0 Eq, 1.296 mmol), tert-butyl ((2R)-4-(4-chloro-5-(5-(6-oxo-l-(tetrahydro-2H-pyran-2-yl)-l,6-dihydropyridazin-3-yl)-l,2,4-oxadiazol-3-yl)-3-(tri- fluoromethyl)-lH-pyrazol-l-yl)butan-2-yl)carbamate (98.0 mg, 0.15 mmol, 34 %, 87% Purity). 'H NMR (500 MHz, CDC13) 5 8.06 (d, J = 9.9 Hz, 1H), 7.12 (d, J = 9.7 Hz, 1H), 6.15 (dd, J = 10.1, 2.4 Hz, 1H), 4.70 - 4.58 (m, 2H), 4.47 (s, 1H), 4.17 (s, 1H), 3.86 - 3.73 (m, 2H), 2.39 - 2.32 (m, 1H), 2.10 (d, J = 15.9 Hz, 2H), 1.85 - 1.72 (m, 3H), 1.64 (s, 1H), 1.40 (s, 9H), 1.19 (d, J = 6.7 Hz, 3H). NH proton was not observed, m / z 406.2 [M-THP-Boc+4H]+.3956-572

[0335] Starting reagent(s): 6-(3-(4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (180.0 mg, 1 Eq, 431.9 pmol), cesium carbonate (422.2 mg, 3.0 Eq, 1.296 mmol), (S)-3-((tert-butoxycarbonyl)amino)butyl 4- methylbenzenesulfonate (296.7 mg, 2.0 Eq, 863.8 pmol). tert-butyl ((2S)-4-(4-chloro-5-(5-(6- oxo-l-(tetrahydro-2H-pyran-2-yl)-l,6-dihydropyridazin-3-yl)-l,2,4-oxadiazol-3-yl)-3-(tri- fluoromethyl)-lH-pyrazol-l-yl)butan-2-yl)carbamate (105 mg, 179 pmol, 41.3 %). 'H NMR (500 MHz, DMSO) 5 8.12 (d, J = 9.8 Hz, 1H), 7.24 (d, J = 9.8 Hz, 1H), 6.76 (d, J = 8.3 Hz, 1H), 6.01 (d, J = 10.2 Hz, 1H), 4.69 (s, 1H), 4.53 (s, 1H), 4.02 (t, J = 7.1 Hz, 2H), 3.71 - 3.63 (m, 1H), 3.46 (s, 1H), 2.17 (d, J = 12.2 Hz, 1H), 1.99 (m, 1H), 1.91 (m, 1H), 1.76 (d, J = 13.4 Hz, 2H), 1.56 (s, 2H), 1.31 (d, J = 2.2 Hz, 9H), 1.04 (d, J = 6.6 Hz, 3H). m / z 406.2 [M-THP- Boc+4H]+.

[0336] Starting reagent(s): 6-(3-(4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (176.0 mg, 96% Wt, 1 Eq, 405.4pmol), 3 -bromopropan- l-ol (84.52 mg, 54.99 pL, 1.5 Eq, 608.1 pmol) and Potassium carbonate (84.04 mg, 1.5 Eq, 608.1 pmol). 6-(3-(4-chloro-l-(3-hydroxypropyl)-3-(trifluoromethyl)-lH- pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (166.6 mg, 0.29 mmol, 73 %, 84% Purity), m / z 391.0 / 393.2 [M-THP+2H]+.

[0337] Starting reagent(s): 6-(3-(3,4-dichloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tet- rahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (652 mg, 74% Wt, 1 Eq, 1.26 mmol), cesium carbonate (615 mg, 1.5 Eq, 1.89 mmol) and 4-bromo-2-methylbutan-2-ol (273 mg, 0.21 mL, 1.3 Eq, 1.64 mmol). 6-(3-(3,4-dichloro-l-(3-hydroxy-3-methylbutyl)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (315 mg, 0.62 mmol, 50 %, 93% Purity), m / z 469.2 / 471.2 [M+H]+.

[0338] Starting reagent(s): 6-(3-(4-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (500 mg, 95% Wt, 1 Eq, 1.36 mmol), cesium carbonate (932 mg, 2.1 Eq, 2.86 mmol) and added 4-bromo-2-methylbutan-2-ol (478 mg, 2.1 Eq, 2.86 mmol). 6-(3-(4-chloro- l-(3-hy droxy-3-m ethylbutyl)- lH-pyrazol-5-yl)- 1,2, 4-oxadiazol-5- yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (255 mg, 572 pmol, 42.0 %, 97.5% Purity). m / z 435.2 [M+H]+.3953-499-1

[0339] Starting reagent(s): iodomethane (163 mg, 71.5 pL, 1.8 Eq, 1.15 mmol), cesium carbonate (312 mg, 1.5 Eq, 957 pmol) and 6-(3-(4-bromo-3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (300 mg, 90.9% Wt, 1 Eq, 638 pmol). 6-(3-(4-bromo-3-chl oro-1 -methyl- lH-pyrazol-5-yl)- 1,2, 4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (240 mg, 0.49 mmol, 77 %, 90% Purity). 'H NMR (500 MHz, DMSO) 5 8.11 (d, J = 9.8 Hz, 1H), 7.24 (d, J = 9.8 Hz, 1H), 6.00 (dd, J = 10.2, 2.3 Hz, 1H), 4.15 (s, 3H), 4.04 - 3.97 (m, 1H), 3.71 - 3.62 (m, 1H), 2.22 - 2.10 (m, 1H), 2.06 - 1.98 (m, 1H), 1.82 - 1.66 (m, 2H), 1.64 - 1.52 (m, 2H). m / z 357.0 / 359.0 [M-THP+2]+.3953-498-1

[0340] Starting reagent(s): 3 -bromopropan- l-ol (266 mg, 173 pL, 1.8 Eq, 1.91 mmol), cesium carbonate (519 mg, 1.5 Eq, 1.59 mmol) and 6-(3-(4-bromo-3-chloro-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (500 mg, 90.9% Wt, 1 Eq, 1.06 mmol). 6-(3-(4-bromo-3-chloro-l-(3-hydroxypropyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol- 5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (218 mg, 0.43 mmol, 40 %, 95% Purity). 'H NMR (500 MHz, DMSO) 5 8.09 (d, J = 9.7 Hz, 1H), 7.24 (d, J = 9.8 Hz, 1H), 6.01 (dd, J = 10.3, 2.3 Hz, 1H), 4.62 - 4.51 (m, 3H), 4.04 - 3.98 (m, 1H), 3.70 - 3.63 (m, 1H), 3.45 - 3.38 (m, 2H), 2.23 - 2.10 (m, 1H), 2.06 - 1.99 (m, 1H), 1.98 - 1.91 (m, 2H), 1.81 - 1.67 (m, 2H), 1.62 - 1.52 (m, 2H). No ionization by MS3912-506-1

[0341] Starting reagent(s): 6-(3-(4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (175 mg, 1 Eq, 420 pmol), cesium carbonate (205 mg, 1.5 Eq, 630 pmol) and added 4-bromo-2-methylbutan-2-ol (88.0 mg, 1.25 Eq, 527 pmol). 6-(3-(4-chloro-l-(3-hydroxy-3-methylbutyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (60.0 mg, 0.12 mmol, 15 %, 98% Purity). 'H NMR (500 MHz, DMSO) 5 8.08 (d, J = 9.8 Hz, 1H), 7.26 (d, J = 9.8 Hz, 1H), 6.01 (dd, J = 10.3, 2.3 Hz, 1H), 4.76 - 4.66 (m, 2H), 4.47 (s, 1H), 4.05 - 3.96 (m, 1H), 3.73 - 3.59 (m, 1H), 2.24 - 2.11 (m, 1H), 2.07 - 1.97 (m, 1H), 1.98 - 1.88 (m, 2H), 1.82 - 1.66 (m, 2H), 1.63 - 1.49 (m, 2H), 1.15 (s, 6H). m / z 401.3 [M-THP-H2O+2H]+.

[0342] Starting reagent(s): 2-(tetrahy dro-2H-pyran -2 -yl)-6-(3 -(3 -(trifluoromethyl)- IH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (150 mg, 95% Wt, 1 Eq, 373 pmol), cesium carbonate (200 mg, 1.65 Eq, 614 pmol) and 4-bromo-2-methylbutan-2-ol (90.0 mg, 1.45 Eq, 539 pmol). 6-(3-(l-(3-hydroxy-3-methylbutyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)- l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (115 mg, 0.24 mmol, 65 %, 99% Purity), m / z 469.2 [M+H]+.

[0343] Starting reagent(s): 6-(3-(3-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (6.40 g, 97% Wt, 1 Eq, 17.8 mmol), cesium carbonate (8.70 g, 1.5 Eq, 26.7 mmol) and 4-bromo-2-methylbutan-2-ol (3.87 g, 1.3 Eq, 23.1 mmol). 6- (3-(5-chloro-l-(3-hydroxy-3-methylbutyl)-lH-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahy- dro-2H-pyran-2-yl)pyridazin-3(2H)-one (150 mg, 0.33 mmol, 1.8%, 95% Purity). 'H NMR (500 MHz, DMSO) 5 8.08 (d, J = 9.8 Hz, 1H), 7.21 (d, J = 9.8 Hz, 1H), 7.08 (d, J = 1.0 Hz, 1H), 6.00 (dd, J = 10.5, 2.2 Hz, 1H), 4.56 (s, 1H), 4.39 - 4.29 (m, 2H), 4.02 (d, J = 11.5 Hz, 1H), 3.67 (td, J = 11.2, 3.4 Hz, 1H), 2.25 - 2.11 (m, 1H), 2.10 - 1.99 (m, 1H), 1.95 - 1.88 (m, 2H), 1.75 (t, J = 12.2 Hz, 2H), 1.58 (d, J = 20.5 Hz, 2H), 1.18 (s, 6H).

[0344] Starting reagent(s): 6-(3-(4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadi- azol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 95% Wt, 1 Eq, 456 pmol) in DMF (2.00 mL), cesium carbonate (178 mg, 1.2 Eq, 547 pmol), 3, 3 -difluoropropyl 4- methylbenzenesulfonate (152 mg, 89.8% Wt, 1.2 Eq, 547 pmol). 6-(3-(4-chloro-l-(3,3- difluoropropyl)-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H- pyran-2-yl)pyridazin-3(2H)-one (117 mg, 0.22 mmol, 49 %, 94% Purity). 'H NMR (500 MHz, DMSO) 5 8.10 (d, J = 9.8 Hz, 1H), 7.26 (d, J = 9.8 Hz, 1H), 6.25 (tt, J = 55.9, 4.3 Hz, 1H), 6.01 (dd, J = 10.2, 2.3 Hz, 1H), 4.81 (t, J = 7.1 Hz, 2H), 4.04 - 3.98 (m, 1H), 3.73 - 3.60 (m, 1H), 2.59 - 2.45 (m, 2H), 2.24 - 2.09 (m, 1H), 2.06 - 2.00 (m, 1H), 1.84 - 1.68 (m, 2H), 1.65 - 1.50 (m, 2H).19F NMR (471 MHz, DMSO) 5 -61.21, -116.50. m / z 494.9 [M+H]+.3901-324

[0345] Starting reagent(s): 2-bromoethan-l-ol (176 mg, 100 pL, 2.46 Eq, 1.41 mmol), cesium carbonate (300 mg, 1.61 Eq, 921 pmol), 6-(3-(4-chloro-3-(difluoromethoxy)-lH-pyrazol-5-yl)- l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 95% Wt, 1 Eq, 573 pmol). 6-(3-(4-chloro-3-(difluoromethoxy)-l-(2-hydroxyethyl)-lH-pyrazol-5-yl)- l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (160 mg, 0.33 mmol, 58 %, 95% Purity). 'H NMR (400 MHz, DMSO) 5 8.10 (d, J = 9.8 Hz, 1H), 7.40 (t, J = 72.1 Hz, 1H), 7.24 (d, J = 9.8 Hz, 1H), 6.01 (dd, J = 10.3, 2.3 Hz, 1H), 4.79 (t, J = 5.8 Hz, 1H), 4.54 (t, J = 5.5 Hz, 2H), 4.08 - 3.97 (m, 1H), 3.73 - 3.61 (m, 3H), 2.23 - 2.09 (m, 1H), 2.06 - 1.96 (m, 1H), 1.81 - 1.66 (m, 2H), 1.59 - 1.54 (m, 2H). 19F NMR (376 MHz, DMSO) 5 -83.22. m / z 375 [M-THP+2H]+.3956-595

[0346] Starting reagent(s): 6-(3-(4-chloro-3-(difluoromethoxy)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (300 mg, 1 Eq, 723 pmol), cesium carbonate (707 mg, 3.0 Eq, 2.17 mmol), (R)-3-((tert-butoxycarbonyl)amino)bu- tyl 4-methylbenzenesulfonate (422 mg, 1.7 Eq, 1.23 mmol), tert-butyl ((2R)-4-(4-chl oro-3 - (difluoromethoxy)-5-(5-(6-oxo-l-(tetrahydro-2H-pyran-2-yl)-l,6-dihydropyridazin-3-yl)- l,2,4-oxadiazol-3-yl)-lH-pyrazol-l-yl)butan-2-yl)carbamate (213 mg, 0.35 mmol, 48 %, 95% Purity).1H NMR (500 MHz, DMSO) 5 8.11 (d, J = 9.8 Hz, 1H), 7.47 (d, J = 72.1 Hz, 1H), 7.25 - 7.21 (m, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.05 - 5.94 (m, 1H), 4.55 (s, 1H), 4.38 (dd, J = 14.1, 7.2 Hz, 1H), 4.01 (d, J = 13.3 Hz, 1H), 3.71 - 3.61 (m, 1H), 3.43 (s, 1H), 3.29 (s, 2H), 2.23 - 2.11 (m, 1H), 2.03 (s, 1H), 1.88 (dt, J = 24.2, 7.7 Hz, 2H), 1.74 (t, J = 15.0 Hz, 2H), 1.31 (d, J = 2.5 Hz, 9H), 1.02 (d, J = 6.6 Hz, 3H). m / z 486.0 [M-Boc+2H]+.3953-583

[0347] Starting reagent(s): 6-(3-(4-chloro-3-(difluoromethoxy)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (300 mg, 95% Wt, 1 Eq, 687 pmol), cesium carbonate (291 mg, 1.3 Eq, 893 pmol), l-fluoro-3 -iodopropane (168 mg, 91.4 pL, 1.3 Eq, 893 pmol). 6-(3-(4-chloro-3-(difluoromethoxy)-l-(3-fluoropropyl)-lH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (310 mg, 567 pmol, 82.6 %, 86.9% Purity).XH NMR (500 MHz, DMSO) 5 8.09 (d, J = 9.8 Hz, 1H), 7.40 (t, J = 72.1 Hz, 1H), 7.24 (d, J = 9.8 Hz, 1H), 6.00 (dd, J = 2.3, 10.2 Hz, 1H), 4.64 - 4.53 (m, 3H), 4.50 - 4.44 (m, 1H), 4.01 - 3.98 (m, 1H), 3.71 - 3.60 (m, 1H), 2.26 - 2.12 (m, 3H), 2.06 - 1.99 (m, 1H), 1.80 - 1.66 (m, 2H), 1.63 - 1.52 (m, 2H). m / z 391.0 / 393.0 [M-THP+2H]+.3956-594

[0348] Starting reagent(s): 6-(3-(4-chloro-3-(difluoromethoxy)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 1 Eq, 482 pmol), cesium carbonate (471 mg, 3.0 Eq, 1.45 mmol), (S)-3-((tert-butoxycarbonyl)amino)bu- tyl 4-methylbenzenesulfonate (248 mg, 1.5 Eq, 723 pmol). tert-butyl ((2S)-4-(4-chloro-3- (difluoromethoxy)-5-(5-(6-oxo-l-(tetrahydro-2H-pyran-2-yl)-l,6-dihydropyridazin-3-yl)- l,2,4-oxadiazol-3-yl)-lH-pyrazol-l-yl)butan-2-yl)carbamate (90.0 mg, 0.15 mmol, 30 %, 95% Purity).1H NMR (500 MHz, DMSO) 5 8.11 (d, J = 9.8 Hz, 1H), 7.39 (t, J = 72.1 Hz, 1H), 7.24 (dd, J = 9.8, 1.0 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.01 (dd, J = 10.2, 2.3 Hz, 1H), 4.55 (s, 1H), 4.45 - 4.34 (m, 1H), 3.73 - 3.63 (m, 1H), 3.43 (s, 1H), 2.22 - 2.10 (m, 1H), 1.99 (s, 2H), 1.94 - 1.83 (m, 2H), 1.76 (d, J = 13.2 Hz, 2H), 1.56 (s, 2H), 1.31 (d, J = 2.5 Hz, 9H), 1.02 (d, J = 6.5 Hz, 3H). m / z 402.0 [M-THP-Boc+3H]+.3912-578

[0349] Starting reagent(s): 6-(3-(4-chloro-3-(difluoromethoxy)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (250 mg, 95% Wt, 1 Eq, 573 pmol), cesium carbonate (373 mg, 2 Eq, 1.15 mmol), (R)-3-hydroxy-2-m ethylpropyl 4- methylbenzenesulfonate (182 mg, 92.3% Wt, 1.2 Eq, 687 pmol). 6-(3-(4-chl oro-3 -(difluoromethoxy)- l-((S)-3-hy droxy-2-methylpropyl)-lH-pyrazol-5-yl)-l, 2, 4-oxadiazol-5-yl)-2-(tetra- hydro-2H-pyran-2-yl)pyridazin-3(2H)-one (95.0 mg, 0.17 mmol, 29 %, 85% Purity). 'H NMR (500 MHz, DMSO) 5 8.08 (d, J = 9.8 Hz, 1H), 7.47 (t, J = 72.1 Hz, 1H), 7.24 (d, J= 9.8 Hz, 1H), 6.01 (dd, J= 10.2, 2.4 Hz, 1H), 4.55 - 4.48 (m, 1H), 4.31 - 4.21 (m, 1H), 4.03 - 3.97 (m, 2H), 3.71 - 3.62 (m, 1H), 3.31 - 3.26 (m, 3H), 2.27 - 2.06 (m, 2H), 2.07 - 1.99 (m, 1H), 1.81 - 1.67 (m, 1H), 1.62 - 1.48 (m, 2H), 0.79 (d, J= 6.8 Hz, 3H). m / z 403.3 [M-THP+2H]+.3956-588

[0350] Starting reagent(s): 6-(3-(4-chloro-3-(difluoromethoxy)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (390 mg, 1 Eq, 940 pmol), cesium carbonate (919 mg, 3.0 Eq, 2.82 mmol), (S)-3-((tert-butyldimethylsilyl)oxy)-2- methylpropyl 4-methylbenzenesulfonate (674 mg, 2.0 Eq, 1.88 mmol). 6-(3-(l-((R)-3-((tert- butyldimethylsilyl)oxy)-2-methylpropyl)-4-chloro-3-(difluoromethoxy)-lH-pyrazol-5-yl)- l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (284 mg, 394 pmol, 42.0 %, 83.5% Purity). 'H NMR (500 MHz, DMSO) 5 8.15 - 8.01 (m, 1H), 7.58 - 7.20 (m, 2H), 6.01 (d, J = 10.0 Hz, 1H), 4.39 (d, J = 75.4 Hz, 2H), 4.00 (d, J = 12.7 Hz, 1H), 3.67 (s, 1H), 3.56 - 3.40 (m, 1H), 2.08 (d, J = 91.8 Hz, 4H), 1.83 - 1.50 (m, 4H), 0.90 - 0.74 (m, 12H), 0.05 - 0.10 (m, 6H). m / z 602.2 [M+H]+.3953-585

[0351] Starting reagent(s): 6-(3-(4-chloro-3-(difluoromethoxy)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (300 mg, 97% Wt, 1 Eq, 702 pmol) in DMF (3.00 mL) was added cesium carbonate (297 mg, 1.3 Eq, 912 pmol). The reaction mixture was stirred at ambient temperature for 10 min followed by the addition of a solution of 3, 3 -difluoropropyl 4-methylbenzenesulfonate (254 mg, 89.8% Wt, 1.3 Eq, 912 pmol). 6-(3-(4-chloro-3-(difluoromethoxy)-l-(3,3-difluoropropyl)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (275 mg, 462 pmol, 65.9 %, 82.8% Purity). 'H NMR (500 MHz, DMSO) 5 8.09 (d, J = 9.8 Hz, 1H), 7.42 (t, J = 72.0 Hz, 1H), 7.26 (d, J = 9.8 Hz, 1H), 6.23 (tt, J = 4.4, 56.0 Hz, 1H), 6.01 (dd, J = 2.3, 10.2 Hz, 1H), 4.66 (t, J = 6.9 Hz, 2H), 4.02 - 3.97 (m, 1H), 3.70 - 3.62 (m, 1H), 2.48 - 2.38 (m, 2H), 2.21 - 2.11 (m, 1H), 2.03 (s, 1H), 1.81 - 1.69 (m, 2H), 1.61 - 1.52 (m, 2H). m / z 409.0 / 411.0 [M- THP+2H]+.3956-601

[0352] Starting reagent(s): 6-(3-(4-chloro-3-(difluoromethoxy)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (340 mg, 95% Wt, 1 Eq, 779 pmol), cesium carbonate (761 mg, 3.0 Eq, 2.34 mmol) and triethyl(((2S,3S)-4-iodo-3- methylbutan-2-yl)oxy)silane (799 mg, 2.0 Eq, 1.56 mmol). 6-(3-(4-chl oro-3 -(difluorom ethoxy)- 1-((2R, 3 S)-2-methyl-3-((tri ethylsilyl)oxy)butyl)-lH-pyrazol-5-yl)-l, 2, 4-oxadiazol-5-yl)- 2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (210 mg, 0.31 mmol, 40 %, 92% Purity). 'H NMR (500 MHz, CDC13) 5 8.00 (ddd, J = 9.8, 1.7, 0.7 Hz, 1H), 7.12 - 6.78 (m, 2H), 6.18 - 6.06 (m, 1H), 4.65 - 4.58 (m, 1H), 4.29 - 4.20 (m, 1H), 4.15 (d, J = 12.8 Hz, 1H), 3.79 (t, J = 10.7 Hz, 1H), 3.75 - 3.69 (m, 1H), 2.41 - 2.32 (m, 1H), 2.12 (s, 2H), 1.78 (dt, J = 22.5, 11.2 Hz, 3H), 1.64 (s, 1H), 1.17 - 1.11 (m, 3H), 0.94 - 0.90 (m, 9H), 0.78 (dd, J = 6.8, 2.4 Hz, 3H), 0.55 (q, J = 8.1 Hz, 6H).3953-619

[0353] Starting reagent(s): 6-(3-(4-chloro-3-(difluoromethoxy)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (750 mg, 1 Eq, 1.81 mmol), cesium carbonate (1.77 g, 3.0 Eq, 5.42 mmol), (R)-3-((tert-butoxycarbonyl)amino)-2- methylpropyl 4-methylbenzenesulfonate (1.95 g, 80% Wt, 2.51 Eq, 4.54 mmol), tert-butyl ((2R)-3-(4-chloro-3-(difluoromethoxy)-5-(5-(6-oxo-l-(tetrahydro-2H-pyran-2-yl)-l,6-dihy- dropyridazin-3 -yl)- 1 ,2,4-oxadiazol-3 -yl)- IH-pyrazol- 1 -yl)-2-methylpropyl)carbamate (215 mg, 0.35 mmol, 19 %, 95% Purity). 'H NMR (500 MHz, DMSO) 5 8.11 (d, J = 9.8 Hz, 1H), 7.40 (t, J = 72.1 Hz, 1H), 7.23 (d, J = 9.8 Hz, 1H), 6.87 - 6.81 (m, 1H), 6.01 (dd, J = 2.3, 10.2 Hz, 1H), 4.44 (dd, J = 5.9, 13.9 Hz, 1H), 4.21 (dd, J = 8.3, 13.9 Hz, 1H), 4.04 - 3.97 (m, 1H), 3.70 - 3.63 (m, 1H), 2.95 - 2.81 (m, 2H), 2.22 - 2.11 (m, 2H), 2.07 - 1.97 (m, 1H), 1.80 - 1.66(m, 2H), 1.61 - 1.51 (m, 2H), 1.34 (s, 9H), 0.78 (d, J = 6.8 Hz, 3H). m / z 402.1 [M-Boc- THP+3H]+.3953-613

[0354] Starting reagent(s): potassium l,3-dioxoisoindolin-2-ide (3.87 g, 1.2 Eq, 20.9 mmol), (S)-3-hydroxy-2-methylpropyl 4-methylbenzenesulfonate (5 g, 17.4 mmol). (R)-2-(3 -hydroxy - 2-methylpropyl)isoindoline-l, 3-dione (3.10 g, 11 mmol, 65 %, 80% Purity). 'H NMR (500 MHz, DMSO) 5 7.91 - 7.79 (m, 5H), 4.54 (t, J = 5.2 Hz, 1H), 3.59 (dd, J = 6.5, 13.7 Hz, 1H), 3.41 (dd, J = 8.2, 13.7 Hz, 1H), 3.31 - 3.26 (m, 2H), 2.04 - 1.95 (m, 1H), 0.81 (d, J = 6.8 Hz, 3H). m / z 220.2 [M+H]+.3901-349-1

[0355] Starting reagent(s): 6-(3-(4-chloro-3-(difluoromethoxy)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (125 mg, 1 Eq, 301 pmol), cesium carbonate (120 mg, 1.22 Eq, 368 pmol), (2R,3R)-4-iodo-3-methylbutan-2-ol (75.0 mg, 95% Wt, 1.10 Eq, 333 pmol). 6-(3-(4-chloro-3-(difluoromethoxy)-l-((2S,3R)-3-hydroxy-2- methylbutyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin- 3(2H)-one (75.0 mg, 0.11 mmol, 37 %, 75% Purity). 'H NMR (500 MHz, DMSO) 5 8.08 (d, J = 9.8 Hz, 1H), 7.39 (t, J = 72.2 Hz, 1H), 7.24 (d, J = 9.6 Hz, 1H), 4.61 (dt, J = 13.8, 4.4 Hz, 1H), 4.57 (dd, J = 4.9, 2.5 Hz, 1H), 4.28 (ddd, J = 14.0, 9.4, 4.9 Hz, 1H), 4.07 - 3.94 (m, 1H), 3.71 - 3.62 (m, 1H), 3.50 (m, 1H), 2.23 - 2.11 (m, 1H), 2.00 (m, 2H), 1.80 - 1.69 (m, 2H), 1.58 - 1.55 (m, 3H), 1.05 (dd, J = 6.3, 1.3 Hz, 3H), 0.71 (d, J = 6.8 Hz, 3H). 19F NMR (471 MHz, DMSO) 5 -83.33. m / z 501.3 [M+H]+.General Method 1c: O-Alkylation (NaH)

[0356] 6-(3 -(3 -(hydroxymethyl)- 1 -methyl- lH-pyrazol-5-yl)- 1 ,2,4-oxadiazol-5-yl)-2-(tetra- hydro-2H-pyran-2-yl)pyridazin-3(2H)-one (200 mg, 80% Wt, 1 Eq, 446 pmol) and Mel (127 mg, 55.8 pL, 2 Eq, 893 pmol) were dissolved in THF (3.00 mL). sodium hydride (26.8 mg, 60% Wt, 1.5 Eq, 670 pmol) was added in two portions and the reaction was allowed to stir at room temperature for 1 hour.The reaction was quenched with sat. aq. NH4C1 (3 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 4 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude product was purified by chromatography on silica gel (12 g cartridge, 10-90% EtOAc / isohexane) to afford 6-(3- (3-(methoxymethyl)-l-methyl-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-py- ran-2-yl)pyridazin-3(2H)-one (4245-41) (54.0 mg, 0.14 mmol, 32 %, 98% Purity) as a cream powder. 'H NMR (500 MHz, DMSO) 5 8.10 (d, J = 9.7 Hz, 1H), 7.22 (d, J = 9.8 Hz, 1H), 6.96 (s, 1H), 5.99 (dd, J = 10.3, 2.3 Hz, 1H), 4.40 (s, 2H), 4.16 (s, 3H), 4.05 - 3.97 (m, 1H), 3.66 (td, J = 10.7, 4.0 Hz, 1H), 3.28 (s, 3H), 2.23 - 2.07 (m, 1H), 1.99 (d, J = 7.8 Hz, 1H), 1.83 - 1.67 (m, 2H), 1.56 (s, 2H). m / z 373.4 [M+H]+.• General Method Id: O-Alkylation (trialkyl oxonium salts)4246-78

[0264]

[0357] 6-(3-(4-(hy droxymethyl)-l -methyl- lH-pyrazol-5-yl)-l, 2, 4-oxadiazol-5-yl)-2-(tetra- hydro-2H-pyran-2-yl)pyridazin-3(2H)-one (200.0 mg, 89% Wt, 1 Eq, 496.7 pmol) was dissolved in CH2Q2 (2.5 mL). trimethyloxonium tetrafluoroborate (146.9 mg, 2 Eq, 993.4 pmol) , Nl,Nl,N8,N8-tetramethylnaphthalene-l,8-diamine (212.9 mg, 2 Eq, 993.4 pmol) and Molecular sieves (300 mg, 1 Eq, 496.7 pmol) were added and stirring was continued for 2h at room temperature. The reaction mixture was filtered and the solid residues were washed with CH2C12 (5 mL). The filtrate was collected and the solvent was evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g cartridge, 10-80%EtOAc / isohexane) and the product containing fractions were evaporated under reduced pressure. The residue was co-evaporated with TBME and the Isohexane to afford 6-(3-(4-(m ethoxymethyl)-! -methyl- lH-pyrazol-5-yl)- 1,2, 4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyri- dazin-3(2H)-one (4246-78)

[0264] (125 mg, 0.29 mmol, 59 %, 87% Purity). 'H NMR (500 MHz, DMSO) 5 8.12 (dd, J = 9.7, 0.9 Hz, 1H), 7.66 (s, 1H), 7.23 (d, J = 9.6 Hz, 1H), 6.00 (dd, J = 10.2, 2.3 Hz, 1H), 4.59 (s, 2H), 4.15 (s, 3H), 4.01 (d, J = 11.3 Hz, 1H), 3.71 - 3.62 (m, 1H), 3.28 (s, 3H), 2.22 - 2.11 (m, 1H), 2.07 - 1.98 (m, 1H), 1.81 - 1.68 (m, 2H), 1.61 - 1.51 (m, 2H). m / z 373.2 [M+H]+.• General Method le: Alkylation (cyclic sulfates)3912-588

[0374]

[0358] (R)-4-methyl-l,3,2-dioxathiolane 2,2-dioxide (120 mg, 1.52 Eq, 869 pmol) was added to a suspension of cesium carbonate (466 mg, 2.50 Eq, 1.43 mmol) and 6-(3-(4-chl oro-3 - (difluoromethoxy)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyri- dazin-3(2H)-one (250.0 mg, 95% Wt, 1 Eq, 572.6 pmol) in DMF (1.50 mL). The reaction mixture was stirred at room temperature for 0.5 h. The reaction mixture was then diluted with sulfuric acid (6M in water) (3.68 g, 2.00 mL, 6.00 molar, 21.0 Eq, 12.0 mmol) before it was heated to 80 °C and stirred for 18 hours. The reaction mixture was cooled to room temperature before additional sulfuric acid (1.84 g, 1.00 mL, 32.8 Eq, 18.8 mmol) was added. The reaction mixture was heated to 80 °C and stirred for a further 1 hour. The reaction mixture was cooled to room temperature then diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over MgSCU, filtered and the solvent removed in vacuo. The crude product was purified by flash chromatography on silica gel (0-100% EtOAc / DCM) to afford a white solid. The solid was dissolved in 2.3 mL with DMSO, filtered and purified by reversed phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB prep column, 130A, 5 pm, 30 mm X 100 mm, flow rate 40 mL min-1 eluting with a 0.1% Formic acid in water-MeCN gradient over 17.5 mins using UV across all wavelengths with PDA as well as a QDA and ELS detector. At-column dilutionpump gives 2 mL min-1 Methanol over the entire method, which is included in the following MeCN percentages. Gradient information: 0.0-0.5 min, 17.5% MeCN; 0.5-15.5 min, ramped from 17.5% MeCN to 47.5% MeCN; 15.5-15.6 min, ramped from 47.5% MeCN to 100% MeCN; 15.6-17.5 min, held at 100% MeCN. The clean fractions were evaporated in a Geneva to yield (R)-6-(3-(4-chloro-3-(difluoromethoxy)-l-(2-hydroxypropyl)-lH-pyrazol-5-yl)-l,2,4- oxadiazol-5-yl)pyridazin-3(2H)-one (3912-588)

[0374] (13.1 mg, 33 pmol, 5.8 %, 98% Purity) as a white solid.XH NMR (500 MHz, DMSO) 5 13.92 (s, 1H), 8.07 (d, J = 9.9 Hz, 1H), 7.39 (t, J = 72.1 Hz, 1H), 7.14 (d, J = 9.9 Hz, 1H), 4.79 (d, J = 5.5 Hz, 1H), 4.44 (dd, J = 13.8, 7.6 Hz, 1H), 4.37 (dd, J = 13.8, 4.5 Hz, 1H), 4.00 - 3.87 (m, 1H), 1.04 (d, J = 6.3 Hz, 3H). m / z 388.7 [M+H]+.

[0359] The following compounds were synthesised by General Method le, using the appropriate reagents:3956-615

[0375]

[0360] Starting reagent(s): (S)-4-m ethyl- 1, 3, 2-di oxathiolane 2,2-dioxide (118.7 mg, 1.5 Eq, 859.0 pmol), cesium carbonate (242.5 mg, 1.3 Eq, 744.4 pmol), 6-(3-(4-chl oro-3 -(difluoromethoxy)- lH-pyrazol-5-yl)-l, 2, 4-oxadiazol-5-yl)-2-(tetrahydro-2H-pyran-2-yl)pyridazin- 3(2H)-one (250.0 mg, 95% Wt, 1 Eq, 572.6 pmol), sulfuric acid (1.84 g, 1.00 mL, 50% Wt,16.4 Eq, 9.38 mmol). (S)-6-(3-(4-chloro-3-(difluoromethoxy)-l-(2-hydroxypropyl)-lH-pyra- zol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one (3956-615)

[0375] one (70.0 mg, 180 pmol,31.4 %, 100% Purity) as a white solid.XH NMR (500 MHz, DMSO) 5 13.92 (s, 1H), 8.07 (d, J = 9.9 Hz, 1H), 7.39 (t, J = 72.1 Hz, 1H), 7.14 (d, J = 9.9 Hz, 1H), 4.79 (d, J = 5.6 Hz, 1H), 4.47 - 4.34 (m, 2H), 3.94 (dt, J = 12.3, 6.0 Hz, 1H), 1.04 (d, J = 6.3 Hz, 3H). m / z 389.0 [M+H]+.• General Method 2a: Amide formation (SOCh)

[0361] Thionyl chloride (4.07 g, 2.50 mL, 28.2 eq, 34.3 mmol) was added to 4-(trifluorometh- oxy)benzoic acid (250 mg, 1 eq, 1.21 mmol) and the reaction mixture was stirred at reflux (80 °C) for 2 h. The reaction mixture was concentrated in vacuo and SOCh was co-evaporated twice with toluene. The solid obtained was diluted in DCM (1 mL) then ammonium hydroxide (2.20 g, 2.50 mL, 51.8 eq, 62.8 mmol) was slowly dropped in, the reaction mixture was stirred at 25 °C for 1 h. The reaction mixture was diluted with distilled water (5 mL) and the solid was filtered to afford 4-(trifluoromethoxy)benzamide (3951-268) (254 mg, 0.93 mmol, 77% yield, 75% purity) as a white solid.

[0362] The following compounds were synthesised by General Method 2a.

[0363] Starting reagent(s): (trifluoromethoxy )benzoic acid (250 mg, 1 eq, 1.21 mmol), thionyl chloride (4.07 g, 2.50 mL, 28.2 eq, 34.3 mmol), 4-ammonium hydroxide (2.20 g, 2.50 mL, 51.8 eq, 62.8 mmol). 4-(Trifluoromethoxy)benzamide (3951-268) (254 mg, 77% yield, 75% purity) as a white solid, m / z 206.2 [M+H]+.3951-399

[0364] Starting reagent(s): 3-isopropyl-l-methyl-lH-pyrazole-5-carboxylic acid (100 mg, 1 eq, 595 pmol), thionyl chloride (106 mg, 65.1 pL, 1.5 eq, 892 pmol), ammonium hydroxide (4.40 g, 5.00 mL, 211 eq, 126 mmol). 3 -Isopropyl- 1 -methyl- lH-pyrazole-5-carboxamide (3951-399) (75.0 mg, 74% yield, 98% purity) as a white solid, m / z 168.2 [M+H]+.3912-313-1

[0365] Starting reagent(s): 3,5-dimethylisoxazole-4-carboxylic acid (300 mg, 1 eq, 2.13 mmol), thionyl chloride (7.50 g, 4.60 mL, 29.7 eq, 63.0 mmol), ammonium hydroxide (2.24 g, 2.5 mL, 30 eq, 63.8 mmol). 3,5-Dimethylisoxazole-4-carboxamide (3912-313-1) (247 mg, 82.9% yield) as a white solid. Product was used directly in the next step without further analysis.3956-290

[0366] Starting reagent(s): isothiazole-5-carboxylic acid (300 mg, 1 eq, 2.32 mmol), thionyl chloride (4.07 g, 2.50 mL, 14.7 eq, 34.3 mmol), ammonium hydroxide (1.5 g, 1.70 mL, 18 eq, 43 mmol). Isothiazole-5-carboxamide (3956-290) (198 mg, 63% yield, 95% purity) as an off-white solid.XH NMR (500 MHz, DMSO) 5 8.64 (d, J= 1.8 Hz, 1H), 8.30 (s, 1H), 7.87 (d, J= 1.8 Hz, 1H), 7.83 (s, 1H). m / z 129.2 [M+H]+.

[0367] Starting reagent(s): 3-methoxy-l-methyl-lH-pyrazole-5-carboxylic acid (155 mg, 1 eq, 993 pmol), thionyl chloride (3.26 g, 2.00 mL, 27.6 eq, 27.4 mmol), ammonium hydroxide (1.8 g, 2.00 mL, 51 eq, 50 mmol). 3-Methoxy-l-methyl-lH-pyrazole-5-carboxamide (3912- 335) (155 mg, 86% yield, 85% purity) as a white solid. 'H NMR (500 MHz, CDCL) 8 5.90 (s, 1H), 4.03 (s, 3H), 3.88 (s, 3H). NH2not observed, m / z 177.2 [M+Na]+.3951-343

[0368] Starting reagent(s): 2-(trifluoromethoxy)benzoic acid (500 mg, 1 eq, 2.43 mmol), thionyl chloride (8.15 g, 5.00 mL, 28.2 eq, 68.5 mmol), ammonium hydroxide (4.40 g, 5.00 mL, 51.8 eq, 126 mmol). 2-(Trifhroromethoxy)benzamide (3951-343) (433 mg, 87% yield, 100% purity) as a white solid, m / z 206.1 [M+H]+.

[0369] Starting reagent(s): 2-methyl-2H-indazole-3-carboxylic acid (500 mg, 1 eq, 2.84 mmol), thionyl chloride (675 mg, 414 pL, 2 eq, 5.68 mmol), ammonium hydroxide (4.40 g,5.00 mL, 44.2 eq, 126 mmol). 2-Methyl-2H-indazole-3-carboxamide (3951-352) (263 mg, 53% yield, 100% purity) as a white solid, m / z 176.2 [M+H]+.

[0370] Starting reagent(s): 5-methoxy-2-methylbenzoic acid (500 mg, 1 eq, 3.01 mmol), thi- onyl chloride (787 mg, 483 pL, 2.2 eq, 6.62 mmol), ammonium hydroxide (4.40 g, 5.00 mL, 41.7 eq, 126 mmol). 5-Methoxy-2-methylbenzamide (3951-354) (498 mg, 100% yield, 100% purity) as a white solid, m / z 166.5 [M+H]+.3951-356

[0371] Starting reagent(s): 3 -methoxy-2-m ethylbenzoic acid (500 mg, 1 eq, 3.01 mmol), thi- onyl chloride (787 mg, 483 pL, 2.2 eq, 6.62 mmol), ammonium hydroxide (4.40 g, 5.00 mL, 41.7 eq, 126 mmol). 3 -Methoxy -2-methylbenzamide (3951-356) (165 mg, 32% yield, 97% purity) as a white solid, m / z 166.2 [M+H]+.

[0372] Starting reagent(s): 2,3 -di chlorobenzoic acid (500 mg, 1 eq, 2.62 mmol), thionyl chloride (467 mg, 287 pL, 1.5 eq, 3.93 mmol), ammonium hydroxide (4.40 g, 5.00 mL, 48.0 eq, 126 mmol). 2,3-Dichlorobenzamide (3951-379) (400 mg, 75% yield, 93% purity) as a white solid, m / z 190.1 / 192.1 [M+H]+.3912-233

[0373] Starting reagent(s): 5-chloro-2-methoxyisonicotinic acid (300 mg, 1 eq, 1.60 mmol), thionyl chloride (5.71 g, 3.50 mL, 30 eq, 48.0 mmol), ammonium hydroxide (1.68 g, 1.9 mL,30 eq, 48.0 mmol). 5-Chloro-2-methoxyisonicotinamide (3912-233) (196 mg, 65% yield, 99% purity) as a white solid, m / z 187.2 / 189.2 [M+H]+.3912-242

[0374] Starting reagent(s): 3-fluoro-2-(trifluoromethyl)isonicotinic acid (300 mg, 1 eq, 1.43 mmol), thionyl chloride (5.22 g, 3.20 mL, 30.6 eq, 43.8 mmol), ammonium hydroxide (1.6 g, 1.80 mL, 31 eq, 45 mmol). 3-Fluoro-2-(trifluoromethyl)isonicotinamide (3912-242) (110 mg, 37% yield, 100% purity) as an off-white solid, m / z 209.0 [M+H]+.3951-267

[0375] Starting reagent(s): 3-(trifluoromethoxy)benzoic acid (250 mg, 1 eq, 1.21 mmol), thionyl chloride (4.07 g, 2.50 mL, 28.2 eq, 34.3 mmol), ammonium hydroxide (2.20 g, 2.50 mL, 51.8 eq, 62.8 mmol). 3 -(trifluorom ethoxy )benzamide (3951-267) (267 mg, 83% yield, 77% purity) as a white solid, m / z 206.2 [3956-371

[0376] Starting reagent(s): 2,5-dimethylthiophene-3-carboxylic acid (250 mg, 1 Eq, 1.60 mmol), thionyl chloride (3.26 g, 2.00 mL, 17.1 Eq, 27.4 mmol), ammonium hydroxide (1.5 g, 1.70 mL, 27 Eq, 43 mmol). 2,5-dimethylthiophene-3-carboxamide (219 mg, 84% yield, 95% purity). 'H NMR (500 MHz, DMSO) 5 7.42 (s, 1H), 7.08 (s, 1H), 6.98 (d, J = 1.3 Hz, 1H), 2.54 (d, J = 0.7 Hz, 3H), 2.34 (s, 3H). m / z 156.2 [M+H]+.3912-404

[0377] Starting reagent(s): 3,5-dimethylthiophene-2-carboxamide (219 mg, 86% yield, 98% purity). 'H NMR (500 MHz, DMSO) 5 7.18 (s, 2H), 6.64 (d, J = 1.3 Hz, 1H), 2.38 (d, J = 1.1 Hz, 3H), 2.33 (s, 3H). m / z 156.1 [M+H]+.3912-422-1

[0378] Starting reagent(s): 2,5-dimethylfuran-3-carboxylic acid (250 mg, 1 Eq, 1.78 mmol), thionyl chloride (4.24 g, 2.60 mL, 20 Eq, 35.7 mmol), ammonium hydroxide (1.56 g, 1.8 mL, 25 Eq, 44.6 mmol). 2,5-dimethylfuran-3-carboxamide (157 mg, 60 %, 95% Purity). 'H NMR (500 MHz, DMSO) 5 7.33 (s, 1H), 6.99 (s, 1H), 6.38 (d, J = 1.3 Hz, 1H), 2.43 (s, 3H), 2.19 (s, 3H). m / z 140.2 [M+H]+.3912-436

[0379] Starting reagent(s): l-ethyl-3-methyl-lH-pyrazole-4-carboxylic acid (310 mg, 1 Eq, 2.01 mmol), thionyl chloride (1.63 g, 1.00 mL, 6.81 Eq, 13.7 mmol), 7M ammonia in MeOH (0.15 g, 0.60 mL, 7.00 molar, 2.1 Eq, 4.2 mmol). l-ethyl-3-methyl-lH-pyrazole-4-carboxamide (308 mg, 100 % yield). Product carried forward without analysis or purification.• General Method 2b: Amide Formation (GDI)

[0380] CDI (900 mg, 1.54 eq, 5.55 mmol) was added to a solution of 4-chl oro-2, 2-difhioro- benzo[d][l,3]dioxole-5-carboxylic acid (900 mg, 95% wt, 1 eq, 3.61 mmol) in tetrahydrofuran (10 mL) then stirred at room temperature for 1 h. The mixture was added dropwise to a rapidly stirred flask of ammonium hydroxide (13.2 g, 15.0 mL, 28% wt, 29.2 eq, 105 mmol) then left to stir for a further 2 h at room temperature. The mixture was extracted with ethyl acetate (3 x 15 mL) then the combined organic phases were washed sequentially with 1 M HC1 (2 x 20 mL) and brine (20 mL). The organic phase was dried (ISfeSCU), filtered and concentrated under reduced pressure to yield 4-chloro-2,2-difluorobenzo[d][l,3]dioxole-5-carboxamide (3901- 163) (826 mg, 92% yield, 95% purity) as a cream-white solid.

[0381] The following compounds were synthesised by General Method 2B.3901-163

[0382] Starting reagent(s): 4-chloro-2,2-difluorobenzo[d][l,3]dioxole-5-carboxylic acid (900 mg, 95% wt, 1 eq, 3.61 mmol), CDI (900 mg, 1.54 eq, 5.55 mmol), ammonium hydroxide (13.2 g, 15.0 mL, 28% wt, 29.2 eq, 105 mmol). 4-Chloro-2,2-difluorobenzo[d][l,3]dioxole-5-carbox- amide (3901-163) (826 mg, 92% yield, 95% purity) as a cream-white solid. 'H NMR (500 MHz, DMSO) 5 7.93 (s, 1H), 7.71 (s, 1H), 7.47 (d, J = 8.3 Hz, 1H), 7.37 (d, J= 8.3 Hz, 1H). m / z 236.0 [M+H]+.3953-415-1

[0383] Starting reagent(s): CDI (1.62 g, 1.4 Eq, 9.99 mmol), 3,4-dimethyl-lH-pyrazole-5- carboxylic acid (1.00 g, 1 Eq, 7.14 mmol), ammonium hydroxide (8.04 g, 9.14 mL, 28% Wt, 9 Eq, 64.2 mmol). 3,4-dimethyl-lH-pyrazole-5-carboxamide (800 mg, 5.7 mmol, 80 %, 99% Purity) 3953-415-1. 'H NMR (500 MHz, DMSO) 5 12.65 (s, 1H), 7.21 (s, 1H), 6.94 (s, 1H), 2.14 (s, 3H), 2.09 (s, 3H). m / z 140.2 [M+H]+.3953-451-1

[0384] Starting reagent(s): CDI (1.33 g, 1.4 Eq, 8.18 mmol), 3-methyl-4-nitro-lH-pyrazole- 5-carboxylic acid (1.00 g, 1 Eq, 5.84 mmol), ammonium hydroxide (6.60 g, 7.50 mL, 28% Wt, 9.02 Eq, 52.7 mmol). 3-methyl-4-nitro-lH-pyrazole-5-carboxamide (994 mg, 5.84 mmol, 99.9 %, 100% Purity), m / z 171.2 [M+H]+.3953-322-1

[0385] Starting reagent(s): CDI (293 mg, 1.4 Eq, 1.80 mmol), benzo[c][l,2,5]thiadiazole-5- carboxylic acid (250 mg, 92.9% Wt, 1 Eq, 1.29 mmol), ammonium hydroxide (1.45 g, 1.65 mL,28% Wt, 9 Eq, 11.6 mmol). 'H NMR (500 MHz, DMSO) 5 8.62 (t, J = 1.3 Hz, 1H), 8.32 (s, 1H), 8.15 (d, J = 1.3 Hz, 2H), 7.70 (s, 1H). m / z 180.2 [M+H]+.• General Method 2c: Amide Formation (Ester Aminolysis)

[0386] A solution of methyl 3-cyclopropoxy-l-methyl-lH-pyrazole-5-carboxylate (210 mg, 83% wt, 1 eq, 888 pmol) in 7 MNH? in MeOH (2.36 g, 3.00 mL, 7.00 M, 23.6 eq, 21.0 mmol) was heated to 60 °C in a sealed vessel and stirred for 18 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to afford 3-cyclopropoxy-l-methyl-lH-pyrazole- 5-carboxamide (3912-349) (115 mg, 0.56 mmol, 64% yield, 89% purity) as a pale-yellow oil.

[0387] Starting reagent(s): methyl 3-(difluoromethoxy)-l-methyl-lH-pyrazole-5-carboxylate (107 mg, 96% wt, 1 eq, 498 pmol), 7 M NH3 in MeOH (1.57 g, 2.00 mL, 7.00 molar, 28.1 eq, 14.0 mmol). 3-(Difluoromethoxy)-l-methyl-lH-pyrazole-5-carboxamide (3912-350) (91.0 mg, 94% yield, 98% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 7.98 (s, 1H), 7.62 (s, 1H), 7.21 (t, J = 73.2 Hz, 1H), 6.58 (s, 1H), 3.96 (s, 3H).19F NMR (471 MHz, DMSO) 5 - 83.61. m / z 192.2 [M+H]+.3912-351

[0388] Starting reagent(s): methyl 3-bromo-l-methyl-lH-pyrazole-5-carboxylate (500 mg, 1 eq, 2.28 mmol), 7 M NH3 in MeOH (3.94 g, 5.00 mL, 7.00 molar, 15.3 eq, 35.0 mmol). 3- Bromo-l-methyl-lH-pyrazole-5-carboxamide (3912-351) (471 mg, 98% yield, 97% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 7.97 (s, 1H), 7.65 (s, 1H), 6.95 (s, 1H), 4.02 (s, 3H). m / z 204.1 / 206.1 [M+H]+.

[0389] Starting reagent(s): methyl 3-(difluoromethyl)-l-methyl-lH-pyrazole-5-carboxylate (270 mg, 99% wt, 1 eq, 1.41 mmol), 7 M NH3 in MeOH (3.15 g, 4.00 mL, 7 molar, 19.9 eq, 28.0 mmol). 3-(Difluoromethyl)-l-methyl-lH-pyrazole-5-carboxamide (3956-326) (234 mg, 95% yield) as a white solid. 'H NMR (500 MHz, DMSO) 5 8.04 (s, 1H), 7.64 (s, 1H), 7.12 (s, 1H), 6.95 (t, J= 54.6 Hz, 1H), 4.08 (d, J= 1.0 Hz, 3H). m / z 176.2 [M+H]+.

[0390] Starting reagent(s): methyl 3-ethyl-l-methyl-lH-pyrazole-5-carboxylate (225 mg, 90% Wt, 1 Eq, 1.20 mmol), ammonia in methanol (1.97 g, 2.50 mL, 7 molar, 14.5 Eq, 17.5 mmol). 3-ethyl-l-methyl-lH-pyrazole-5-carboxamide (188 mg, 83% yield, 81% purity). 'H NMR (500 MHz, CDC13) 5 6.34 (s, 1H), 5.94 - 5.60 (m, 2H), 4.12 (s, 3H), 2.64 (q, J = 7.6 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H). m / z 154.2 [M+H]+.3912-372

[0391] Starting reagent(s): methyl l-methyl-lH-l,2,3-triazole-5-carboxylate (300 mg, 1 Eq, 2.13 mmol) and 7M NH3 in MeOH (3.15 g, 4.00 mL, 7.00 molar, 13.2 Eq, 28.0 mmol). 1- methyl-lH-l,2,3-triazole-5-carboxamide (261 mg, 95% yield, 98% purity). 'H NMR (500 MHz, DMSO) 5 8.19 (s, 1H), 8.16 (s, 1H), 7.78 (s, 1H), 4.20 (s, 3H). m / z 147.2 [M+Na]+.3912-465

[0392] Starting reagent(s): methyl 3-chloro-lH-pyrazole-5-carboxylate (4.50 g, 95% Wt, 1 Eq, 26.6 mmol), 7M NH3in MeOH (35.4 g, 45.0 mL, 7.00 molar, 11.8 Eq, 315 mmol). 3-chloro-lH-pyrazole-5-carboxamide (4.14 g, 100% yield, 94% purity). 'H NMR (500 MHz, DMSO) 5 13.72 (s, 1H), 7.96 (s, 1H), 7.62 (s, 1H), 6.84 (s, 1H). m / z 146.2 [M+H]+.3956-361

[0393] Starting reagent(s): methyl l-methyl-3-(((triisopropylsilyl)oxy)methyl)-lH-pyrazole- 5-carboxylate (0.943 g, 90% Wt, 1 Eq, 2.60 mmol) and ammonia in methanol (7.87 g, 10.0 mL, 7 molar, 26.9 Eq, 70.0 mmol). l-methyl-3-(((triisopropylsilyl)oxy)methyl)-lH-pyrazole-5-car- boxamide (854 mg, 84% yield, 80% purity). 'H NMR (500 MHz, DMSO) 5 7.93 (s, 1H), 7.42 (s, 1H), 6.84 (s, 1H), 4.65 (s, 2H), 3.99 (s, 3H), 1.15 - 1.09 (m, 3H), 1.04 (d, J = 6.9 Hz, 18H). m / z 312.2 [M+H]+.4245-49-1

[0394] Starting reagent(s): methyl 3-((tert-butoxycarbonyl)amino)-l-methyl-lH-pyrazole-5- carboxylate (260 mg, 96% Wt, 1 Eq, 978 pmol), ammonia in methanol (333 mg, 2.79 mL, 7 molar, 20 Eq, 19.6 mmol), tert-butyl (5-carbamoyl-l-methyl-lH-pyrazol-3-yl)carbamate (256 mg, 98%, 90% Purity). 'H NMR (500 MHz, DMSO) 5 9.64 (s, 1H), 7.90 (s, 1H), 7.39 (s, 1H), 6.91 (s, 1H), 3.91 (s, 3H), 1.45 (s, 9H). m / z 185.2 [M+H]+.4245-50-1

[0395] Starting reagent(s): methyl 3-((tert-butoxycarbonyl)(methyl)amino)-l-methyl-lH-py- razole-5-carboxylate (241 mg, 98% Wt, 1 Eq, 877 pmol) and ammonia in methanol (299 mg, 2.51 mL, 7 molar, 20 Eq, 17.5 mmol), tert-butyl (5-carbamoyl-l-methyl-lH-pyrazol-3-yl)(me- thyl)carbamate (221 mg, 0.83 mmol, 94 %, 95% Purity). 'H NMR (500 MHz, DMSO) 5 7.94 (s, 1H), 7.45 (s, 1H), 6.95 (s, 1H), 3.96 (s, 3H), 3.21 (s, 3H), 1.47 (s, 9H). m / z 199.2 [M-Bu+2H]+.3953-397-1

[0396] Starting reagent(s): ethyl 2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxylate (500 mg, 1 Eq, 2.77 mmol) and ammonia in methanol (7.87 g, 10.0 mL, 7 molar, 25.2 Eq, 70.0 mmol). 2, 4, 5, 6-tetrahydrocy cl openta[c]pyrazole-3 -carboxamide (417 mg, 94 %, 95% Purity). 'H NMR (500 MHz, DMSO) 5 12.69 (s, 1H), 7.60 - 6.82 (m, 2H), 2.82 - 2.53 (m, 4H), 2.44 (s, 2H). m / z 152.2 [M+H]+.3956-322-1

[0397] Starting reagent(s): methyl 3-bromo-l,4-dimethyl-lH-pyrazole-5-carboxylate (219 mg, 99% Wt, 1.56 Eq, 930 pmol) was added in ammonia in methanol (1.57 g, 2.00 mL, 7 molar, 23.4 Eq, 14.0 mmol). 3-bromo-l,4-dimethyl-lH-pyrazole-5-carboxamide (258 mg, 1.1 mmol, 74 %, 95% Purity). 'H NMR (500 MHz, DMSO) 5 7.81 (d, J = 43.5 Hz, 2H), 3.85 (s, 3H), 2.04 (s, 3H). m / z 218 / 220 [M+H]+.4245-60-1

[0398] Starting reagent(s): ethyl 3-(trifluoromethyl)-lH-pyrazole-5-carboxylate (7.90 g, 1 Eq, 38.0 mmol), ammonia in methanol (12.9 g, 108 mL, 7 molar, 20 Eq, 759 mmol). 3-(trifluoro- methyl)-lH-pyrazole-5-carboxamide (6.78 g, 94 %, 94% Purity). 'H NMR (500 MHz, DMSO) 5 14.59 - 14.21 (m, 1H), 7.95 (s, 1H), 7.54 (s, 1H), 7.15 (s, 1H). m / z 180.2 [M+H]+.4246-44-1

[0399] Starting reagent(s): ethyl 4-chloro-l -methyl- lH-pyrazole-5-carboxylate (250 mg, 1 Eq, 1.33 mmol) and ammonia in methanol (2.36 g, 3.00 mL, 7 molar, 15.8 Eq, 21.0 mmol). 4- chloro-1 -methyl- lH-pyrazole-5-carboxamide (211 mg, 99 %, 99% Purity). 'H NMR (500 MHz, DMSO) 5 7.99 (s, 1H), 7.74 (s, 1H), 7.59 (s, 1H), 3.92 (s, 3H). m / z 160.2 [M+H]+.3901-238-1

[0400] Starting reagent(s): ethyl l-methyl-4-nitro-lH-pyrazole-5-carboxylate (5.00 g, 95% Wt, 1 Eq, 23.8 mmol) and ammonia in methanol (39.4 g, 50.0 mL, 7 molar, 14.7 Eq, 350 mmol). l-methyl-4-nitro-lH-pyrazole-5-carboxamide (4.10 g, 23 mmol, 96 %, 95% Purity). 'H NMR in DMSO-d6 3901-238-1 was consistent with product structure at 95% purity. 'H NMR (500 MHz, DMSO) 5 8.47 (s, 1H), 8.31 (s, 1H), 8.26 (s, 1H), 3.86 (s, 3H). No ionization in MS

[0401] Starting reagent(s): ethyl 3-fluoro-l-methyl-lH-pyrazole-5-carboxylate (109 mg, 95% Wt, 1 Eq, 601 pmol), ammonia in methanol (2.36 g, 3.00 mL, 7 molar, 34.9 Eq, 21.0 mmol). 3- fluoro-l-methyl-lH-pyrazole-5-carboxamide (52.0 mg, 0.35 mmol, 57 %, 95% Purity). 'H NMR (500 MHz, DMSO) 5 7.97 (s, 1H), 7.65 (s, 1H), 6.52 (d, J = 5.9 Hz, 1H), 3.94 (d, J = 0.7 Hz, 3H).3901-282-1

[0402] Starting reagent(s): ammonium hydroxide (22.0 g, 25.0 mL, 79.2 Eq, 628 mmol), methyl 3-(difluoromethoxy)-l-(4-methoxybenzyl)-lH-pyrazole-5-carboxylate (2.50 g, 99% Wt, 1 Eq, 7.93 mmol). 3-(difluoromethoxy)-l-(4-methoxybenzyl)-lH-pyrazole-5-carboxamide (1.54 g, 5.1 mmol, 65 %, 99% Purity).XH NMR (500 MHz, DMSO) 5 8.02 (s, 1H), 7.65 (s, 1H), 7.22 (d, J = 73.0 Hz, 1H), 7.18 - 7.12 (m, 2H), 6.90 - 6.84 (m, 2H), 6.62 (s, 1H), 5.56 (s, 2H), 3.71 (s, 3H). m / z 320.2 [M+Na]+.4246-95-1

[0403] Starting reagent(s): methyl 4-chloro-lH-pyrazole-5-carboxylate (5.00 g, 1 Eq, 31.1 mmol), ammonia in methanol (14.31 g, 120.0 mL, 7.00 molar, 27.0 Eq, 840.0 mmol). 4-chloro- lH-pyrazole-5-carboxamide (4.33 g, 29 mmol, 95 %, 99% Purity). 'H NMR (500 MHz, DMSO) 5 13.47 (brs, 1H), 7.99 (s, 1H), 7.46 (s, 1H), 7.33 (brs, 1H). m / z 144.2 [M-H]'.• General Method 3a: Nitrile Formation (TFAA)

[0404] To the reaction mixture of 3-(trifluoromethoxy)benzamide (267 mg, 77% wt, 1 eq, 1.00 mmol) and triethylamine (152 mg, 210 pL, 1.5 eq, 1.50 mmol) in DCM (2.00 mL) was added TFAA (316 mg, 212 pL, 1.5 eq, 1.50 mmol) slowly at 0°C. The reaction mixture was stirred at 0 °C for 15 min. The reaction was then quenched with H2O (5 mL) and extracted with DCM (10 mL). The organic layer was washed with brine (5.0 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 3-(trifluoro- methoxy)benzonitrile (3951-270) (49.0 mg, 26% yield, 99% purity) as a clear colourless oil.

[0405] The following compounds were synthesised by General Method 3a.3951-271

[0406] Starting reagent(s): 4-(trifluorom ethoxy )benzamide (254 mg, 75% wt, 1 eq, 929 pmol), triethylamine (141 mg, 194 pL, 1.5 eq, 1.39 mmol), TFAA (293 mg, 197 pL, 1.5 eq, 1.39 mmol). 4-(trifluoromethoxy)benzonitrile (3951-271) (28 mg, 16% yield, 99% purity) as a colourless oil. 'H NMR (500 MHz, DMSO) 5 8.07 - 8.00 (m, 2H), 7.63 - 7.58 (m, 2H).19F NMR (471 MHz, DMSO) 5 -56.71.3912-354

[0407] Starting reagent(s): 3-bromo-l-methyl-lH-pyrazole-5-carboxamide (471 mg, 97% wt, 1 eq, 2.24 mmol), triethylamine (0.34 g, 0.47 mL, 1.5 eq, 3.4 mmol), TFAA (0.70 g, 0.47 mL, 1.5 eq, 3.3 mmol). 3-Bromo-l-methyl-lH-pyrazole-5-carbonitrile (3912-354) (398 mg, 91% yield, 95% purity) as a white solid. 5 7.36 (s, 1H), 4.00 (s, 3H).3951-402

[0408] Starting reagent(s): 3 -isopropyl- 1 -methyl- lH-pyrazole-5-carboxamide (75.0 mg, 98% wt, 1 eq, 440 pmol), triethylamine (66.7 mg, 91.9 pL, 1.5 eq, 659 pmol), TFAA (138 mg, 93.1 pL, 1.5 eq, 659 pmol). 3-Isopropyl-l-methyl-lH-pyrazole-5-carbonitrile (3951-402) (72 mg, 93% yield, 85% purity) as a white solid, m / z 150.6 [M+H]+.3901-164

[0409] Starting reagent(s): 4-chloro-2,2-difluorobenzo[d][l,3]dioxole-5-carboxamide (826 mg, 95% wt, 1 eq, 3.33 mmol), triethylamine (1.09 g, 1.50 mL, 3.23 eq, 10.8 mmol), TFAA (1.0 g, 0.70 mL, 1.5 eq, 5.0 mmol). 4-Chloro-2,2-difluorobenzo[d][l,3]dioxole-5-carbonitrile (3901-164) (790 mg, 100% yield, 95% purity) as a yellow solid. 'H NMR (500 MHz, CDCh) 5 7.51 (d, .7= 8.4 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H).3912-315-1

[0410] Starting reagent(s): 3,5-dimethylisoxazole-4-carboxamide (247 mg, 1 eq, 1.76 mmol), triethylamine (0.27 g, 0.37 mL, 1.5 eq, 2.7 mmol), TFAA (0.55 g, 0.37 mL, 1.5 eq, 2.6 mmol). 3,5-Dimethylisoxazole-4-carbonitrile (3912-315-1) (230 mg 100% yield, 95% purity) as a yellow oil. Product was used directly in the next step without further analysis.3956-297

[0411] Starting reagent(s): isothiazole-5-carboxamide (198 mg, 95% wt, 1 eq, 1.47 mmol), triethylamine (238 mg, 327 pL, 1.6 eq, 2.35 mmol), TFAA (493 mg, 332 pL, 1.6 eq, 2.35 mmol). Isothiazole-5-carbonitrile (3956-297) (247 mg, 76% yield, 50% purity) as a brown solid.XH NMR (500 MHz, CDCh) 8 8.60 (d, J= 1.8 Hz, 1H), 7.73 (d, J= 1.8 Hz, 1H).3912-337

[0412] Starting reagent(s): 3-methoxy-l-methyl-lH-pyrazole-5-carboxamide (122 mg, 85% wt, 1 eq, 668 pmol), triethylamine (101 mg, 140 pL, 1.5 eq, 1.00 mmol), TFAA (211 mg, 142 pL, 1.5 eq, 1.00 mmol). 3-Methoxy-l-methyl-lH-pyrazole-5-carbonitrile (3912-337) (179 mg, 98% yield, 50% purity) as a yellow oil. Product was used directly in the next step without further analysis.3912-352

[0413] Starting reagent(s): 3-cyclopropoxy-l-methyl-lH-pyrazole-5-carboxamide (115 mg, 89% wt, 1 eq, 565 pmol), triethylamine (85.7 mg, 118 pL, 1.5 eq, 847 pmol), TFAA (178 mg, 120 pL, 1.5 eq, 847 pmol). 3-Cyclopropoxy-l-methyl-lH-pyrazole-5-carbonitrile (3912-352) (128 mg, 100% yield, 75% purity) as a yellow oil. m / z 164.2 [M+H]+.3956-328

[0414] Starting reagent(s): 3-(difluoromethyl)-l-methyl-lH-pyrazole-5-carboxamide (234 mg, 95% wt, 1 eq, 1.27 mmol), triethylamine (205 mg, 283 pL, 1.6 eq, 2.03 mmol), TFAA (427 mg, 287 pL, 1.6 eq, 2.03 mmol). 3 -(Difluoromethyl)- 1 -methyl- lH-pyrazole-5-carbonitrile(3956-328) (181 mg, 89% yield, 98 purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 7.47 (s, 1H), 7.09 (t, J = 54.1 Hz, 1H), 4.06 (s, 3H).3951-344

[0415] Starting reagent(s): 2-(trifluoromethoxy)benzamide (433 mg, 100% wt, 1 eq, 2.11 mmol), triethylamine (320 mg, 441 pL, 1.5 eq, 3.17 mmol), TFAA (665 mg, 447 pL, 1.5 eq, 3.17 mmol). 2-(Trifluoromethoxy)benzonitrile (3951-344) (543 mg, 100% yield, 75% purity) as a yellow oil.3951-353

[0416] Starting reagent(s): 2-methyl-2H-indazole-3 -carboxamide (263 mg, 100% wt, 1 eq, 1.50 mmol), triethylamine (228 mg, 314 pL, 1.5 eq, 2.25 mmol), TFAA (473 mg, 318 pL, 1.5 eq, 2.25 mmol). 2-Methyl-2H-indazole-3-carbonitrile (3951-353) (171 mg, 73% yield, 100% purity) as a black solid, m / z 158.2 [M+H]+.3951-363

[0417] Starting reagent(s): 3 -methoxy-2-m ethylbenzamide (161 mg, 97% wt, 1 eq, 945 pmol), triethylamine (143 mg, 198 pL, 1.5 eq, 1.42 mmol), TFAA (298 mg, 200 pL, 1.5 eq, 1.42 mmol). 3-Methoxy-2-methylbenzonitrile (3951-363) (138 mg, 95% yield, 96% purity) as a white solid.3951-382

[0418] Starting reagent(s): 2,3-dichlorobenzamide (400 mg, 93% wt, 1 eq, 1.96 mmol), triethylamine (297 mg, 409 pL, 1.5 eq, 2.94 mmol), TFAA (617 mg, 415 pL, 1.5 eq, 2.94 mmol). 2,3 -Dichlorobenzonitrile (3951-382) (335 mg, 98% yield, 99% purity) as a white solid.3912-235

[0419] Starting reagent(s): 5-chloro-2-methoxyisonicotinamide (196 mg, 1 eq, 1.05 mmol), triethylamine (0.16 g, 0.22 mL, 1.5 eq, 1.6 mmol), TFAA (0.33 g, 0.22 mL, 1.5 eq, 1.6 mmol). 5-Chloro-2-methoxyisonicotinonitrile (3912-235) (169 mg, 92% yield, 97% purity) as a yellow solid, m / z 199.2 [M+CH3OH2]+.3912-243

[0420] Starting reagent(s): 3-fluoro-2-(trifluoromethyl)isonicotinamide (110 mg, 1 eq, 529 pmol), tri ethylamine (80 mg, 0.11 mL, 1.5 eq, 0.79 mmol), TFAA (0.16 g, 0.11 mL, 1.5 eq, 0.78 mmol). 3-Fluoro-2-(trifluoromethyl)isonicotinonitrile (3912-243) (78 mg, 75% yield, 97% purity) as a yellow oil. The product was used directly in the next step without further analysis.3956-374

[0421] Starting reagent(s): 2,5-dimethylthiophene-3-carboxamide (210 mg, 95% Wt, 1 Eq, 1.29 mmol), triethylamine (208 mg, 287 pL, 1.6 Eq, 2.06 mmol), 2,2,2-trifluoroacetic anhydride (432 mg, 290 pL, 1.6 Eq, 2.06 mmol). 2,5-dimethylthiophene-3-carbonitrile (152 mg, 82% yield, 95% purity).XH NMR (500 MHz, CDC13) 5 6.79 - 6.65 (m, 1H), 2.57 (s, 3H), 2.41 (s, 3H).

[0422] Starting reagent(s): 3 -ethyl- 1 -methyl- lH-pyrazole-5-carboxamide (188 mg, 81% Wt, 1 Eq, 994 pmol), triethylamine (161 mg, 222 pL, 1.6 Eq, 1.59 mmol), 2,2,2-trifluoroacetic anhydride (334 mg, 225 pL, 1.6 Eq, 1.59 mmol). 3-ethyl-l-methyl-lH-pyrazole-5-carbonitrile (156 mg, 93% yield, 80% purity). 'H NMR (500 MHz, CDC13) 5 6.56 (s, 1H), 3.99 (s, 3H), 2.69 - 2.56 (m, 2H), 1.24 (t, J = 7.6 Hz, 3H).3912-374

[0423] Starting reagent(s): l-methyl-lH-l,2,3-triazole-5-carboxamide (261 mg, 1 Eq, 2.07 mmol), triethylamine (0.31 g, 0.43 mL, 1.5 Eq, 3.1 mmol) and 2,2,2-trifluoroacetic anhydride (0.65 g, 0.44 mL, 1.5 Eq, 3.1 mmol). l-methyl-lH-l,2,3-triazole-5-carbonitrile (554 mg, 74% yield, 30% purity).1HNMR (500 MHz, DMSO) 58.58 (s, 1H), 4.23 (s, 3H). m / z 147.2 [M+K]+.3912-406

[0424] Starting reagent(s): 3,5-dimethylthiophene-2-carboxamide (219 mg, 1 Eq, 1.41 mmol), triethylamine (0.22 g, 0.30 mL, 1.5 Eq, 2.2 mmol), 2,2,2-trifluoroacetic anhydride (0.45 g, 0.30 mL, 1.5 Eq, 2.1 mmol). 3,5-dimethylthiophene-2-carbonitrile (175 mg, 86% yield, 95% purity). 'H NMR (500 MHz, CDC13) 5 6.61 (s, 1H), 2.47 (s, 3H), 2.36 (s, 3H).3956-366

[0425] Starting reagent(s): l-methyl-3-(((triisopropylsilyl)oxy)methyl)-lH-pyrazole-5-car- boxamide (0.854 g, 80% Wt, 1 Eq, 2.19 mmol), triethylamine (355 mg, 489 pL, 1.6 Eq, 3.51 mmol) and 2,2,2-trifluoroacetic anhydride (737 mg, 496 pL, 1.6 Eq, 3.51 mmol), l-methyl-3- (((triisopropylsilyl)oxy)methyl)-lH-pyrazole-5-carbonitrile (0.69 g, 95% yield, 89% purity). 'H NMR (500 MHz, DMSO) 5 6.81 (s, 1H), 4.79 (s, 2H), 4.01 (s, 3H), 1.16 - 1.11 (m, 3H), 1.07 (d, J = 6.9 Hz, 18H). m / z 294.2 [M+H]+.3912-424-1

[0426] Starting reagent(s): 2,5-dimethylfuran-3-carboxamide (157 mg, 95% Wt, 1 Eq, 1.07 mmol), triethylamine (0.16 g, 0.22 mL, 1.5 Eq, 1.6 mmol), 2,2,2-trifluoroacetic anhydride (0.34 g, 0.23 mL, 1.5 Eq, 1.6 mmol). 2,5-dimethylfuran-3-carbonitrile (119 mg, 0.83 mmol, 77 %, 84% Purity). 'H NMR (500 MHz, DMSO) 5 6.39 (s, 1H), 2.40 (s, 3H), 2.24 (s, 3H).3912-438-1

[0427] Starting reagent(s): l-ethyl-3-methyl-lH-pyrazole-4-carboxamide (308 mg, 1 Eq, 2.01 mmol) and triethylamine (0.61 g, 0.84 mL, 3.0 Eq, 6.0 mmol), 2,2,2-trifluoroacetic anhydride (0.64 g, 0.43 mL, 1.5 Eq, 3.0 mmol). l-ethyl-3-methyl-lH-pyrazole-4-carbonitrile (176 mg, 47 % yield, 73% Purity). 'H NMR (500 MHz, CDC13) 5 7.69 (s, 1H), 4.11 (q, J = 7.3 Hz, 2H), 2.36 (s, 3H), 1.47 (t, J = 7.3 Hz, 3H). m / z 136.1 [M+H]+.4245-52-1

[0428] Starting reagent(s): tert-butyl (5-carbamoyl-l-methyl-lH-pyrazol-3-yl)carbamate (256 mg, 90% Wt, 1 Eq, 959 pmol), 2,2,2-trifluoroacetic anhydride (363 mg, 244 pL, 1.8 Eq, 1.73 mmol), tert-butyl (5-cyano-l-methyl-lH-pyrazol-3-yl)carbamate (213 mg). Used without analysis.4245-53-1

[0429] Starting reagent(s): tert-butyl (5-carbamoyl-l-methyl-lH-pyrazol-3-yl)(methyl)carba- mate (221 mg, 95% Wt, 1 Eq, 826 pmol), tri ethylamine (150 mg, 207 pL, 1.8 Eq, 1.49 mmol) and 2,2,2-trifluoroacetic anhydride (312 mg, 210 pL, 1.8 Eq, 1.49 mmol), tert-butyl (5-cyano- l-methyl-lH-pyrazol-3-yl)(methyl)carbamate (110 mg, 55% yield, 97% purity). Used without analysis.3953-399-1

[0430] Starting reagent(s): 2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboxamide (417 mg, 95% Wt, 1 Eq, 2.62 mmol), triethylamine (1.60 g, 2.20 mL, 6.02 Eq, 15.8 mmol) and TFAA(818 mg, 550 pL, 1.49 Eq, 3.89 mmol). 2,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile (550 mg, 97%, 62% purity). No ionization in MS.

[0431] Starting reagent(s): 3-bromo-l,4-dimethyl-lH-pyrazole-5-carboxamide (250 mg, 95% Wt, 1 Eq, 1.09 mmol), triethylamine (334 mg, 460 pL, 3.03 Eq, 3.30 mmol), TFAA (342 mg, 230 pL, 1.50 Eq, 1.63 mmol). 3-bromo-l,4-dimethyl-lH-pyrazole-5-carbonitrile (263 mg, 87% yield, 73% purity). No ionization in MS.

[0432] Starting reagent(s): 4-chl oro-1 -methyl- lH-pyrazole-5-carboxamide (211 mg, 99% Wt, 1 Eq, 1.31 mmol), triethylamine (199 mg, 274 pL, 1.5 Eq, 1.96 mmol) and 2,2,2-trifluoroacetic anhydride (412 mg, 277 pL, 1.5 Eq, 1.96 mmol) 4-chloro-l-methyl-lH-pyrazole-5-carbonitrile (182 mg, 93 %, 95% Purity). 'H NMR (500 MHz, CDC13) 5 7.51 (s, 1H), 4.03 (s, 3H). No product ionization on MS.3901-240-1

[0433] Starting reagent(s): l-methyl-4-nitro-lH-pyrazole-5-carboxamide (4.10 g, 95% Wt, 1 Eq, 22.9 mmol), triethylamine (7.26 g, 10.0 mL, 3.13 Eq, 71.7 mmol) and 2,2,2-trifluoroacetic anhydride (7.44 g, 5.00 mL, 1.55 Eq, 35.4 mmol). l-methyl-4-nitro-lH-pyrazole-5-carbonitrile (3.50 g, 22 mmol, 95 %, 95% Purity). 'H NMR in DMSO-d6 3901-240-1 was consistent with product structure at 95% purity. 'H NMR (500 MHz, DMSO) 5 8.56 (s, 1H), 4.10 (s, 3H). No ionization in MS.3901-250-1

[0434] Starting reagent(s): 3-fluoro-l-methyl-lH-pyrazole-5-carboxamide (50.0 mg, 95% Wt, 1 Eq, 332 pmol), triethylamine (90.8 mg, 125.0 pL, 2.70 Eq, 897 pmol), 2,2,2-trifluoroacetic anhydride (89.2 mg, 60.0 pL, 1.28 Eq, 425 pmol). 3 -fluoro- 1 -methyl- IH-pyra- zole-5-carbonitrile (44.0 mg, 0.35 mmol, 100 %, 99% Purity). Used without analysis.3901-283-1

[0435] Starting reagent(s): 3-(difluoromethoxy)-l-(4-methoxybenzyl)-lH-pyrazole-5-car- boxamide (1.50 g, 99% Wt, 1 Eq, 5.00 mmol), triethylamine (726 mg, 1.00 mL, 1.44 Eq, 7.17 mmol), 2,2,2-trifluoroacetic anhydride (3.12 g, 2.10 mL, 2.98 Eq, 14.9 mmol). 3-(difluorometh- oxy)-l-(4-methoxybenzyl)-lH-pyrazole-5-carbonitrile (1.50 g, 4.8 mmol, 97 %, 90% Purity).XH NMR (500 MHz, DMSO) 5 7.30 (t, J = 72.7 Hz, 1H), 7.23 (d, J = 8.1 Hz, 2H), 7.01 (s, 1H), 6.95 (d, J = 8.1 Hz, 2H), 5.37 (s, 2H), 3.74 (s, 3H). 19F NMR (471 MHz, DMSO) 5 -84.31.

[0436] Starting reagent(s): benzo[c][l,2,5]thiadiazole-5-carboxamide (159 mg, 95% Wt, 1 Eq, 843 pmol), triethylamine (290 mg, 400 pL, 3.40 Eq, 2.87 mmol), TFAA (268 mg, 180 pL, 1.51 Eq, 1.27 mmol).1H NMR (500 MHz, DMSO) 5 8.90 (dd, J = 1.3, 1.3 Hz, 1H), 8.31 (dd, J = 9.1, 0.8 Hz, 1H), 8.00 (dd, J = 9.1, 1.6 Hz, 1H)• General Method 3b: Nitrile Formation (POCh)

[0437] To 3-chloro-lH-pyrazole-5-carboxamide (3.88 g, 94% Wt, 1 Eq, 25.1 mmol) in MeCN (50.0 mL) was added phosphorus oxychloride (11.5 g, 7.00 mL, 3.00 Eq, 75.1 mmol) followed by pyridine (4.11 g, 4.20 mL, 2.07 Eq, 51.9 mmol). The reaction mixture was stirred at room temperature for 18 hours before it was cautiously added dropwise to water (100 mL). The resulting mixture was extracted with DCM (3 x 50 mL) and the combined organic layers were washed with water (5 x 50 mL), brine (50 mL) then dried over MgSO4, filtered and the solvent was removed in vacuo to afford 3 -chloro- lH-pyrazole-5-carbonitrile (3912-470) (2.60 g, 80%yield, 98% purity) as a purple solid. 'H NMR (500 MHz, DMSO) 5 14.77 (s, 1H), 7.21 (s, 1H). m / z 126.0 [M-H]'.

[0438] The following compounds were synthesised by General Method 3b, using the appropriate reagents.

[0439] Starting reagent(s): 3-(trifluoromethyl)-lH-pyrazole-5-carboxamide (6.78 g, 94% Wt, 1 Eq, 35.6 mmol), phosphorus oxychloride (16.4 g, 9.95 mL, 3 Eq, 107 mmol), pyridine (5.63 g, 5.76 mL, 2 Eq, 71.2 mmol). 3-(trifhroromethyl)-lH-pyrazole-5-carbonitrile (5.56 g, 30 mmol, 84 %, 87% Purity). 'H NMR (500 MHz, CDC13) 5 7.09 (s, 1H). Exchangeable -NH not visible in spectrum. No ionization in MS.3953-418-1

[0440] Starting reagent(s): 3,4-dimethyl-lH-pyrazole-5-carboxamide (800 mg, 99% Wt, 1 Eq, 5.69 mmol) was added phosphorus oxychloride (6.58 g, 4.00 mL, 7.54 Eq, 42.9 mmol) followed by pyridine (489 mg, 500 pL, 1.09 Eq, 6.18 mmol). 3,4-dimethyl-lH-pyrazole-5-car- bonitrile (500 mg, 3.9 mmol, 69 %, 95% Purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 13.43 (s, 1H), 2.19 (s, 3H), 2.03 (s, 3H). m / z 122.2 [M+H]+.3953-454-1

[0441] Starting reagent(s): 3-methyl-4-nitro-lH-pyrazole-5-carboxamide (994 mg, 94% Wt, 1 Eq, 5.49 mmol), phosphorus oxychloride (1.97 g, 1.20 mL, 2.34 Eq, 12.9 mmol), pyridine (665 mg, 680 pL, 1.53 Eq, 8.41 mmol). 3-methyl-4-nitro-lH-pyrazole-5-carbonitrile (778 mg, 4.6 mmol, 84 %, 90% Purity). 'H NMR (500 MHz, DMSO) 5 14.77 (s, 1H), 2.57 (s, 3H). m / z 151.2 [M-H]-.4246-100-1

[0442] Starting reagent(s): 4-chloro-lH-pyrazole-5-carboxamide (4.30 g, 99% Wt, 1 Eq, 29.2 mmol), Phosphorus oxychloride (8.97 g, 5.45 mL, 2 Eq, 58.5 mmol), pyridine (6.94 g, 7.10 mL, 3 Eq, 87.7 mmol). 4-chloro-lH-pyrazole-5-carbonitrile (3.53 g, 24 mmol, 83 %, 88% Purity). 'H NMR (500 MHz, DMSO) 5 14.32 (s, 1H), 8.36 (s, 1H). m / z 126.2 [M-H]'.• General Method 3c: Nitrile Formation (Oxime dehydration)

[0443] To a suspension of (E)-4-(((tert-butyldiphenylsilyl)oxy)methyl)-l-methyl-lH-pyra- zole-5-carbaldehyde oxime (305.0 mg, 83% Wt, 1 Eq, 643.2 pmol) in anhydrous MeCN (0.50 mL) was added dimethyl but-2-ynedioate (137.1 mg, 118 pL, 1.5 Eq, 964.8 pmol), followed by triethylamine (97.63 mg, 134 pL, 1.5 Eq, 964.8 pmol). The reaction was stirred at 25 °C for 4 h. More dimethyl but-2-ynedioate (137.1 mg, 118 pL, 1.5 Eq, 964.8 pmol) and triethylamine (97.63 mg, 134 pL, 1.5 Eq, 964.8 pmol) were added and stirring was continued for 2 h. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-70% EtOAc / isohexane) to afford 4-(((tert-butyldiphenylsilyl)oxy)methyl)-l-methyl-lH-pyrazole- 5-carbonitrile (4246-45-1) (229 mg, 0.57 mmol, 89 %, 94% Purity) as a clear colourless oil. 'H NMR (500 MHz, CDC13) 5 7.72 - 7.64 (m, 4H), 7.49 - 7.36 (m, 7H), 4.69 (s, 2H), 4.01 (s, 3H), 1.08 (s, 9H). m / z 376.2 [M+H]+.• General Method 3d: Nitrile Formation (Cyanation)

[0444] A vial containing 7-fluoro-3-iodo-lH-indazole (1.00 g, 1 eq, 3.82 mmol), potassium ferrocyanide (806 mg, 0.5 eq, 1.91 mmol) was added dimethylacetamide (8.00 mL) and water (6.00 mL) which then purged with nitrogen for 5 min. The resultant solution was heated at 80 °C for 18 h. The completion of the reaction is checked by TLC. Water (30 mL) was added followed by 2-methyltetrahydrofuran (2- MeTHF, 30 mL). Then, the mixture was transferred to a separating funnel. The aqueous layer was separated and back-extracted with 2-MeTHF (2 x 10 mL). The combined organic layers are dried over ISfeSCU and concentrated by rotary evaporation under vacuum. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-50% EtOAc / isohexane) to afford 7-fluoro-lH-indazole-3-carbonitrile (3956-295) (398 mg, 3.82 mmol, 61% yield, 95% purity) as a clear white solid.TH NMR (500 MHz, CDC13) 5 7.66 (dd, J= 8.2, 0.7 Hz, 1H), 7.32 (td, J = 8.0, 4.3 Hz, 1H), 7.23 (ddd, J = 10.5, 7.8, 0.7 Hz, 1H). NH proton not observed.• General Method 3e: Cyanation reaction

[0445] To a solution 4-(trifluoromethyl)piperidine (236 mg, 200 pL, 1 eq, 1.54 mmol) in THF (4.00 mL) with DBU (282 mg, 279 pL, 1.2 eq, 1.85 mmol) was added 3-Oxo-l,2-benziodoxole- l(3H)-carbonitrile (505 mg, 1.2 eq, 1.85 mmol), the reaction mixture was stirred for 10 min. The reaction mixture was concentrated in vacuo then the crude product was purified by chromatography on silica gel (12 g cartridge, 0-100% EtOAc / isohexane) to afford 4-(trifluorome- thyl)piperidine-l -carbonitrile (3951-265) (186 mg, 48% yield, 71% purity) as a clear yellow oil. 'H NMR (500 MHz, DMSO) 5 3.48 - 3.42 (m, 2H), 3.08 (ddd, J= 12.8, 2.7 Hz, 2H), 2.54 (m, 1H), 1.85 - 1.78 (m, 2H), 1.50 (dddd, J= 12.3, 12.3, 4.5 Hz, 2H).19F NMR (471 MHz, DMSO) 5 -72.78.• General Method 4: Amidoxime Formation

[0446] To a stirred suspension of 4-methylbenzonitrile (1.00 g, 1 eq, 8.54 mmol) and hydroxylamine, HC1 (890 mg, 1.5 eq, 12.8 mmol) in EtOH (10.0 mL) was added sodium bicarbonate (1.08 g, 1.5 eq, 12.8 mmol). The reaction mixture was heated to 90 °C and stirred for 8 h beforeit was cooled to room temperature and left to stand for 8 h. The reaction mixture was concentrated in vacuo and the resulting residue was diluted with water (30 mL) then filtered. The collected solid was washed with water (2 x 30 mL) and dried in vacuo to afford (Z)-N'-hydroxy- 4-methylbenzimidamide (3912-67) (876 mg, 5.5 mmol, 65% yield, 95% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.52 (s, 1H), 7.61 - 7.50 (m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 5.73 (s, 2H), 2.31 (s, 3H).

[0447] The following compounds were synthesised by General Method 4.3912-305

[0448] Starting reagent(s): 1,3 -dimethyl- lH-pyrazole-5-carbonitrile (1.00 g, 1 eq, 8.54 mmol), hydroxylamine, HC1 (890 mg, 1.5 eq, 12.8 mmol), sodium bicarbonate (1.08 g, 1.5 eq, 12.8 mmol). (Z)-N' -hydroxy-1, 3-dimethyl-lH-pyrazole-5-carboximidamide (3912-305) (79 mg, 38% yield, 98% purity) as a white solid.XH NMR (500 MHz, DMSO) 5 9.76 (s, 1H), 6.33 (s, 1H), 5.78 (s, 2H), 3.84 (s, 3H), 2.12 (s, 3H). m / z 155.2 [M+H]+.3951-405-1

[0449] Starting reagent(s): 3-isopropyl-l-methyl-lH-pyrazole-5-carbonitrile (72.0 mg, 85% wt, 1 eq, 410 pmol), hydroxylamine, HC1 (28.5 mg, 1 eq, 410 pmol), sodium bicarbonate (34.5 mg, 1 eq, 410 pmol). N-Hydroxy-3-isopropyl-l-methyl-lH-pyrazole-5-carboximidamide (3951-405-1). Product was used directly in the next step without further analysis.3912-306

[0450] Starting reagent(s): 1 -methyl- lH-pyrazole-5-carbonitrile (150 mg, 1 eq, 1.40 mmol), hydroxylamine, HC1 (146 mg, 1.5 eq, 2.10 mmol), sodium bicarbonate (176 mg, 1.5 eq, 2.10 mmol). (Z)-N'-Hydroxy-l -methyl- lH-pyrazole-5-carboximidamide (3912-306) (88 mg, 34% yield, 75% purity) as a colourless oil. 'H NMR (500 MHz, DMSO) 5 9.81 (s, 1H), 7.39 (d, J = 0.8 Hz, 1H), 6.57 (d, J= 0.7 Hz, 1H), 5.86 (s, 2H), 3.93 (s, 3H). m / z 141.2 [M+H]+.3901-166

[0451] Starting reagent(s): 4-chloro-2,2-difluorobenzo[d][l,3]dioxole-5-carbonitrile (690 mg, 95% wt, 1 eq, 3.01 mmol), hydroxylamine, HC1 (425 mg, 2.03 eq, 6.12 mmol), triethylamine (0.65 g, 0.90 mL, 2.1 eq, 6.5 mmol). (Z)-4-Chloro-2,2-difluoro-N'-hy- droxybenzo[d][l,3]dioxole-5-carboximidamide (3901-166) (580 mg, 64% yield, 95% purity) as a colourless, crystalline solid, m / z 251.0 [M+H]+.BrNH2-Z N N — OH3951-415

[0452] Starting reagent(s): 4-bromo-l -methyl- lH-pyrazole-5-carbonitrile (500 mg, 98% wt, 1 eq, 2.63 mmol), hydroxylamine, HC1 (220 mg, 1.2 eq, 3.16 mmol), sodium bicarbonate (266 mg, 1.2 eq, 3.16 mmol). 4-Bromo-N-hydroxy-l-methyl-lH-pyrazole-5-carboximidamide (3951-415). Product was used directly in the next step without further analysis.3912-318

[0453] Starting reagent(s): 3,5-dimethylisoxazole-4-carbonitrile (230 mg, 95% wt, 1 eq, 1.79 mmol), hydroxylamine, HC1 (186 mg, 1.5 eq, 2.68 mmol), sodium bicarbonate (225 mg, 1.5 eq, 2.68 mmol). (Z)-N' -Hydroxy-3, 5-dimethylisoxazole-4-carboximidamide (3912-318) (113 mg, 24% yield, 60% purity) as a yellow solid, m / z 156.2 [M+H]+.3956-281

[0454] Starting reagent(s): lH-pyrazole-5-carbonitrile (350 mg, 1 eq, 3.76 mmol), hydroxylamine, HC1 (392 mg, 1.5 eq, 5.64 mmol), sodium bicarbonate (474 mg, 1.5 eq, 5.64 mmol). (Z)-N'-Hydroxy-lH-pyrazole-5-carboximidamide (3956-281) (257 mg, 53% yield, 97% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 12.89 (s, 1H), 9.40 (s, 1H), 7.70 (s, 1H), 6.38 (s, 1H), 5.44 (s, 2H).3956-299

[0455] Starting reagent(s): isothiazole-5-carbonitrile (247 mg, 50% wt, 1 eq, 1.12 mmol), hydroxylamine, HC1 (117 mg, 1.5 eq, 1.68 mmol), sodium bicarbonate (188 mg, 2.0 eq, 2.24 mmol). (Z)-N'-Hydroxyisothiazole-5-carboximidamide (3956-299) (140 mg, 78% yield, 90% purity) as an off-white solid. 'H NMR (500 MHz, DMSO) 5 10.02 (s, 1H), 8.53 (d, J= 1.8 Hz, 1H), 7.70 (d, J = 1.8 Hz, 1H), 6.19 (s, 2H).3956-306

[0456] Starting reagent(s): 4-methylthiazole-5-carbonitrile (250.0 mg, 1 eq, 2.014 mmol), hydroxylamine, HC1 (209.9 mg, 1.5 eq, 3.020 mmol), sodium bicarbonate (253.7 mg, 1.5 eq, 3.020 mmol). (Z)-N'-Hydroxy-4-methylthiazole-5-carboximidamide (3956-306) (305 mg, 81% yield, 84% purity) as a yellow oil. 'H NMR (500 MHz, DMSO) 5 9.79 (s, 1H), 8.91 (s, 1H), 5.85 (s, 2H), 2.50 (s, 3H). m / z 158.2 [M+H]+.3912-339

[0457] Starting reagent(s): 3-methoxy-l-methyl-lH-pyrazole-5-carbonitrile (179 mg, 50% wt, 1 eq, 653 pmol), hydroxylamine, HC1 (68.0 mg, 1.5 eq, 979 pmol), sodium bicarbonate (82.2 mg, 1.5 eq, 979 pmol). (Z)-N'-Hydroxy-3-methoxy-l-methyl-lH-pyrazole-5-carboxim- idamide (3912-339) (133 mg, 89% yield, 74% purity) as a yellow oil. m / z 171.2 [M+H]+.

[0458] Starting reagent(s): 4-methyloxazole-5-carbonitrile (150 mg, 1 eq, 1.39 mmol), hydroxylamine, HC1 (145 mg, 1.5 eq, 2.08 mmol), sodium bicarbonate (175 mg, 1.5 eq, 2.08 mmol). (Z)-N'-Hydroxy-4-methyloxazole-5-carboximidamide (3912-340) (68 mg, 32% yield, 92% purity) as a yellow solid, m / z 142.2 [M+H]+.3956-298

[0459] Starting reagent(s): 7-fluoro-2H-indazole-3-carbonitrile (203 mg, 1 eq, 1.26 mmol), hydroxylamine, HC1 (149 mg, 1.7 eq, 2.14 mmol), sodium bicarbonate (180 mg, 1.7 eq, 2.14 mmol). (Z)-7-Fluoro-N'-hydroxy-2H-indazole-3-carboximidamide (3956-298) (273 mg, 86% yield, 95% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 13.76 (s, 1H), 9.85 (s, 1H), 7.90 (d, .7= 8.1 Hz, 1H), 7.26 - 7.18 (m, 1H), 7.18 - 7.08 (m, 1H), 5.72 (s, 2H).19F NMR (471 MHz, DMSO) 5 -131.42 (dd, J = 11.3, 4.5 Hz).

[0460] Starting reagent(s): l-methyl-4-(trifluoromethyl)-lH-pyrazole-5-carbonitrile (37.0 mg, 1 eq, 211 pmol), hydroxylamine, HC1 (25.0 mg, 1.7 eq, 359 pmol), sodium bicarbonate (30.2 mg, 1.7 eq, 359 pmol). (Z)-N'-Hydroxy-l-methyl-4-(trifluoromethyl)-lH-pyrazole-5-car- boximidamide (3956-304) (35 mg, 26% yield, 33% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 10.02 (s, 1H), 7.87 (s, 1H), 6.13 (s, 2H), 3.83 (s, 3H). m / z 209.2 [M+H]+.3912-355

[0461] Starting reagent(s): 3-cyclopropoxy-l-methyl-lH-pyrazole-5-carbonitrile (128 mg, 75% wt, 1 eq, 588 pmol), hydroxylamine, HC1 (61.3 mg, 1.5 eq, 882 pmol), sodium bicarbonate (74.1 mg, 1.5 eq, 882 pmol). (Z)-3-Cyclopropoxy-N'-hydroxy-l-methyl-lH-pyrazole-5-car- boximidamide (3912-355) (70 mg, 47% yield, 77% purity) as an off-white solid, m / z 197.2 [M+H]+.3912-356

[0462] Starting reagent(s): 3-(difluoromethoxy)-l-methyl-lH-pyrazole-5-carbonitrile (55.0 mg, 92% wt, 1 eq, 292 pmol), hydroxylamine, HC1 (33.0 mg, 1.62 eq, 475 pmol), sodium bicarbonate (40.0 mg, 1.63 eq, 476 pmol). (Z)-3-(Difluoromethoxy)-N'-hydroxy-l-methyl-lH- pyrazole-5-carboximidamide (3912-356) (28 mg, 43% yield, 93% purity) as a white solid, m / z 207.2 [M+H]+.3912-357

[0463] Starting reagent(s): 3-bromo-l-methyl-lH-pyrazole-5-carbonitrile (398 mg, 95% wt, 1 eq, 2.03 mmol), hydroxylamine, HC1 (212 mg, 1.5 eq, 3.05 mmol), sodium bicarbonate (256 mg, 1.5 eq, 3.05 mmol). (Z)-3-Bromo-N'-hydroxy-l-methyl-lH-pyrazole-5-carboximidamide (3912-357) (193 mg, 41% yield, 96% purity) as a white solid, m / z 219.0 / 221.0 [M+H]+.3901-171-1

[0464] Starting reagent(s): 2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridine-4-carbonitrile (250 mg, 1 eq, 1.57 mmol), hydroxylamine, HC1 (220 mg, 2 eq, 3.17 mmol), triethylamine (327 mg, 450 pL, 2 eq, 3.23 mmol). (Z)-N'-Hydroxy-2-oxo-2,3-dihydro-lH-pyrrolo[2,3-b]pyridine-4- carboximidamide (3901-171-1) (270 mg, 85% yield, 95% purity) as a pale, grey solid. 'H NMR (500 MHz, DMSO) 5 11.00 (s, 1H), 10.06 (s, 1H), 8.11 - 8.06 (m, 1H), 7.16 (d, J= 5.6 Hz, 1H), 5.91 (s, 2H), 3.64 (d, J= 0.9 Hz, 2H).3901-171-2

[0465] Starting reagent(s): 8-chloroisoquinoline-5-carbonitrile (100 mg, 1 eq, 530 qmol), hydroxylamine, HC1 (75 mg, 2 eq, 1.08 mmol), tri ethylamine (116 mg, 160 qL, 2 eq, 1.15 mmol). (Z)-8-Chloro-N'-hydroxyisoquinoline-5-carboximidamide (3901-171-2) (25 mg, 21% yield, 98% purity) as a white solid, m / z 222.2 [M+H]+.3901-171-3

[0466] Starting reagent(s): 6-fluoroquinoline-4-carbonitrile (200 mg, 1 eq, 1.16 mmol), hydroxylamine, HC1 (160 mg, 2 eq, 2.3 mmol), triethylamine (232 mg, 320 qL, 2 eq, 2.3 mmol). (Z)-6-Fluoro-N'-hydroxyquinoline-4-carboximidamide (3901-171-3) (110 mg, 46% yield, 99% purity) as a white solid, m / z 206.2 [M+H]+.3956-327

[0467] Starting reagent(s): 3-(difluoromethyl)-l-methyl-lH-pyrazole-5-carbonitrile (181 mg, 98% wt, 1 eq, 1.13 mmol), hydroxylamine, HC1 (118 mg, 1.5 eq, 1.69 mmol), triethylamine (228 mg, 315 pL, 2.0 eq, 2.26 mmol). (Z)-3-(Difluoromethyl)-N'-hydroxy-l-methyl-lH-pyra- zole-5-carboximidamide (3956-327) (204 mg, 90% yield, 95% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.96 (s, 1H), 6.96 (t, J = 54.7 Hz, 1H), 6.85 - 6.83 (m, 1H), 5.98 (s, 2H), 3.98 (s, 3H). m / z 191.2 [M+H]+.3953-316

[0468] Starting reagent(s): 2,3-dihydrobenzofuran-5-carbonitrile (250 mg, 1 eq, 1.72 mmol), hydroxylamine, HC1 (191 mg, 1.6 eq, 2.76 mmol), sodium bicarbonate (231 mg, 1.6 eq, 2.76 mmol). (Z)-N' -Hydroxy-2, 3-dihydrobenzofuran-5-carboximidamide (3953-316) (247 mg, 81% yield, 100% purity) as a white solid, m / z 179.2 [M+H]+.3953-317

[0469] Starting reagent(s): 1 -methyl- lH-benzo[d]imidazole-5-carbonitrile (250 mg, 1 eq, 1.59 mmol), hydroxylamine, HC1 (177 mg, 1.6 eq, 2.54 mmol), sodium bicarbonate (214 mg, 1.6 eq, 2.54 mmol). (Z)-N'-Hydroxy-l-methyl-lH-benzo[d]imidazole-5-carboximidamide (3953-317) (217 mg, 68% yield, 95% purity) as a beige solid, m / z 191.2 [M+H]+.3953-321

[0470] Starting reagent(s): benzo[c][l,2,5]oxadiazole-5-carbonitrile (250 mg, 1 eq, 1.72 mmol), hydroxylamine, HC1 (192 mg, 1.6 eq, 2.76 mmol), sodium bicarbonate (232 mg, 1.6 eq, 2.76 mmol). (Z)-N'-Hydroxybenzo[c][l,2,5]oxadiazole-5-carboximidamide (3953-321) (249 mg, 80% yield, 90% purity) as a yellow solid. 'H NMR (500 MHz, DMSO) 5 10.41 (s, 1H), 8.29 (dd, J= 1.2, 1.2 Hz, 1H), 8.03 (dd, J = 9.6, 1.4 Hz, 1H), 7.97 (dd, J= 9.6, 1.0 Hz, 1H), 6.16 (s, 2H). m / z 179.2 [M+H]+.3951-209

[0471] Starting reagent(s): 6-(trifluoromethyl)nicotinonitrile (250 mg, 1 eq, 1.45 mmol), hydroxylamine, HC1 (151 mg, 1.5 eq, 2.18 mmol), sodium bicarbonate (183 mg, 1.5 eq, 2.18 mmol). (Z)-N'-Hydroxy-6-(trifluoromethyl)nicotinimidamide (3951-209) (254 mg, 85% yield, 100% purity) as a white solid, m / z 206.2 [M+H]+.

[0472] Starting reagent(s): tert-butyl (S)-3-cyanopyrrolidine-l-carboxylate (100 mg, 1 eq, 510 pmol), hydroxylamine, HC1 (53.1 mg, 1.5 eq, 764 pmol), sodium bicarbonate (64.2 mg, 1.5 eq, 764 pmol). Zc / V-Butyl (S,Z)-3-(N'-hydroxycarbamimidoyl)pyrrolidine-l -carboxylate (3951-211) (117 mg, 79% yield, 79% purity) as a colourless oil. m / z 174.2 [M-tBu+H]+.3951-214

[0473] Starting reagent(s): l-methyl-lH-pyrazole-3-carbonitrile (100 mg, 1 eq, 934 pmol), hydroxylamine, HC1 (97.3 mg, 1.5 eq, 1.40 mmol), sodium bicarbonate (118 mg, 1.5 eq, 1.40 mmol). (Z)-N'-Hydroxy-l-methyl-lH-pyrazole-3-carboximidamide (3951-214) (41 mg, 32% yield, 95% purity) as a white solid, m / z 141.2 [M+H]+.3951-216

[0474] Starting reagent(s): lH-indazole-6-carbonitrile (100 mg, 1 eq, 699 pmol), hydroxylamine, HC1 (72.8 mg, 1.5 eq, 1.05 mmol), sodium bicarbonate (88.0 mg, 1.5 eq, 1.05 mmol). (Z)-N'-Hydroxy-lH-indazole-6-carboximidamide (3951-216) (41 mg, 32% yield, 95% purity) as an orange solid, m / z 177.2 [M+H]+.

[0475] Starting reagent(s): 5-chloropicolinonitrile (100 mg, 1 eq, 722 pmol), hydroxylamine, HC1 (75.2 mg, 1.5 eq, 1.08 mmol), sodium bicarbonate (91.0 mg, 1.5 eq, 1.08 mmol). (Z)-5- Chloro-N'-hydroxypicolinimidamide (3951-227) (77 mg, 91% yield, 98% purity) as a white solid, m / z 172.2 [M+H]+.

[0476] Starting reagent(s): 6-chloronicotinonitrile (100 mg, 1 eq, 722 pmol), hydroxylamine, HC1 (75.2 mg, 1.5 eq, 1.08 mmol), sodium bicarbonate (91.0 mg, 1.5 eq, 1.08 mmol) (Z)-6- Chloro-N'-hydroxynicotinimidamide (3951-228) (79 mg, 63% yield, 100% purity) as a white solid, m / z 172.2 [M+H]+.

[0477] Starting reagent(s): 2-chloro-4-(trifluoromethyl)benzonitrile (100 mg, 1 eq, 486 pmol), hydroxylamine, HC1 (50.7 mg, 1.5 eq, 730 pmol), sodium bicarbonate (61.3 mg, 1.5 eq, 730 pmol). (Z)-2-Chloro-N'-hydroxy-4-(trifluoromethyl)benzimidamide (3951-229) (57 mg, 33% yield, 67% purity) as a white solid, m / z 239 [M+H]+.

[0478] Starting reagent(s): 6-methylnicotinonitrile (250 mg, 1 eq, 2.12 mmol), hydroxylamine, HC1 (221 mg, 1.5 eq, 3.17 mmol), sodium bicarbonate (267 mg, 1.5 eq, 3.17 mmol). (Z)- N'-Hydroxy-6-methylnicotinimidamide (3951-244) (204 mg, 64% yield, 100% purity) as a white solid, m / z 152.2 [M+H]+.

[0479] Starting reagent(s): 5-methylpicolinonitrile (250 mg, 1 eq, 2.12 mmol), hydroxylamine, HC1 (221 mg, 1.5 eq, 3.17 mmol), sodium bicarbonate (267 mg, 1.5 eq, 3.17 mmol). (Z)- N'-Hydroxy-5-methylpicolinimidamide (3951-245) (196 mg, 47% yield, 77% purity) as a white solid, m / z 152.2 [M+H]+.3951-246

[0480] Starting reagent(s): 2-methylpyrimidine-5-carbonitrile (250 mg, 1 eq, 2.10 mmol), hydroxylamine, HC1 (219 mg, 1.5 eq, 3.15 mmol), sodium bicarbonate (264 mg, 1.5 eq, 3.15 mmol). (Z)-N'-Hydroxy-2-methylpyrimidine-5-carboximidamide (3951-245) (227 mg, 65% yield, 92% purity) as a white solid, m / z 153.2 [M+H]+.3951-247

[0481] Starting reagent(s): 2-methylpyrimidine-4-carbonitrile (250 mg, 1 eq, 2.10 mmol), hydroxylamine, HC1 (219 mg, 1.5 eq, 3.15 mmol), sodium bicarbonate (264 mg, 1.5 eq, 3.15 mmol). (Z)-N'-Hydroxy-2-methylpyrimidine-4-carboximidamide (3951-247) (222 mg, 70% yield, 100% purity) as a white solid, m / z 153.2 [M+H]+.

[0482] Starting reagent(s): 2-(difluoromethyl)isonicotinonitrile (250 mg, 1 eq, 1.62 mmol), hydroxylamine, HC1 (169 mg, 1.5 eq, 2.43 mmol), sodium bicarbonate (204 mg, 1.5 eq, 2.43 mmol). 2-(Difluoromethyl)-N-hydroxyisonicotinimidamide (3951-258) (263 mg, 87% yield, 100% purity) as a white solid, m / z 188.2 [M+H]+.3951-260

[0483] Starting reagent(s): 5-(trifluoromethyl)picolinonitrile (250 mg, 97% wt, 1 eq, 1.41 mmol), hydroxylamine, HC1 (147 mg, 1.5 eq, 2.11 mmol), sodium bicarbonate (178 mg, 1.5 eq, 2.11 mmol). N-Hydroxy-5-(trifluoromethyl)picolinimidamide (3951-260) (317 mg, 100% yield, 95% purity) as a white solid, m / z 206.2 [M+H]+.

[0484] Starting reagent(s): 4-(trifluoromethyl)piperidine-l -carbonitrile (186 mg, 71% wt, 1 eq, 741 pmol), hydroxylamine, HC1 (77.3 mg, 1.5 eq, 1.11 mmol), sodium bicarbonate (93.4 mg, 1.5 eq, 1.11 mmol). N-Hydroxy-4-(trifluoromethyl)piperidine-l-carboximidamide (3951- 272) (157 mg, 100% yield, 100% purity) as a colourless oil. m / z 212.2 [M+H]+.

[0485] Starting reagent(s): 4-(trifluoromethoxy)benzonitrile (28.0 mg, 99% wt, 1 eq, 148 pmol), hydroxylamine, HC1 (15.4 mg, 1.5 eq, 222 pmol), sodium bicarbonate (18.7 mg, 1.5 eq, 222 pmol). N-Hydroxy-4-(trifluoromethoxy)benzimidamide (3951-275) (32.6 mg, 100% yield, 100% purity) as a white solid, m / z 221.1 [M+H]+.3951-281

[0486] Starting reagent(s): l-methyl-3-(trifluoromethyl)-lH-pyrazole-5-carbonitrile (100 mg, 1 eq, 571 pmol), hydroxylamine, HC1 (59.5 mg, 1.5 eq, 857 pmol), sodium hydrogencarbonate (72.0 mg, 1.5 eq, 857 pmol). N-Hydroxy-l-methyl-3-(trifluoromethyl)-lH-pyrazole-5-car- boximidamide (3951-281) (119 mg, 100% yield, 100% purity) as a white solid, m / z 209.2 [M+H]+.3951-282

[0487] Starting reagent(s): l-methyl-5-(trifluoromethyl)-lH-pyrazole-3-carbonitrile (100 mg,1 eq, 571 pmol), hydroxylamine, HC1 (59.5 mg, 1.5 eq, 857 pmol), sodium hydrogencarbonate(72.0 mg, 1.5 eq, 857 pmol). N-Hydroxy-l-methyl-5-(trifluoromethyl)-lH-pyrazole-3-car- boximidamide (3951-282) (119 mg, 100% yield, 100% purity) as a white solid, m / z 209.2 [M+H]+.

[0488] Starting reagent(s): l-methyl-lH-indazole-6-carbonitrile (127 mg, 99% wt, 1 eq, 800 pmol), hydroxylamine, HC1 (83.4 mg, 1.5 eq, 1.20 mmol), sodium hydrogencarbonate (101 mg, 1.5 eq, 1.20 mmol). N-Hydroxy-1 -methyl- lH-indazole-6-carboximidamide (3951-285) (152 mg, 99% yield, 100% purity) as a white solid, m / z 191.2 [M+H]+.3951-286

[0489] Starting reagent(s): 2-methyl-2H-indazole-6-carbonitrile (53.0 mg, 99% wt, 1 eq, 334 pmol), hydroxylamine, HC1 (34.8 mg, 1.5 eq, 501 pmol), sodium bicarbonate (42.1 mg, 1.5 eq, 501 pmol). N-Hydroxy-2-methyl-2H-indazole-6-carboximidamide (3951-286) (63.5 mg, 100% yield, 100% purity) as a white solid, m / z 191.1 [M+H]+.

[0490] Starting reagent(s): 2-chloro-5-(trifluoromethyl)benzonitrile (250 mg, 100% wt, 1 eq, 1.22 mmol), hydroxylamine, HC1 (84.5 mg, 1 eq, 1.22 mmol), sodium bicarbonate (102 mg, 1 eq, 1.22 mmol). 2-Chloro-N-hydroxy-5-(trifluoromethyl)benzimidamide (3951-291) (290 mg, 100% yield, 100% purity) as a white solid, m / z 239.0 [M+H]+.3951-292

[0491] Starting reagent(s): 2-chloro-3-(trifluoromethyl)benzonitrile (250 mg, 100% wt, 1 eq,1.22 mmol), hydroxylamine, HC1 (84.5 mg, 1 eq, 1.22 mmol), sodium bicarbonate (102 mg, 1eq, 1.22 mmol). 2-Chloro-N-hydroxy-3-(trifluoromethyl)benzimidamide (3951-292) (290 mg, 100% yield, 100% purity) as a white solid, m / z 239.0 [M+H]+.

[0492] Starting reagent(s): 4-(methylsulfonyl)benzonitrile (250 mg, 100% wt, 1 eq, 1.38 mmol), hydroxylamine, HC1 (95.9 mg, 1 eq, 1.38 mmol), sodium bicarbonate (116 mg, 1 eq, 1.38 mmol). N-Hydroxy-4-(methylsulfonyl)benzimidamide (3951-297) (296 mg, 100% yield, 100% purity) as a white solid, m / z 215.2 [M+H]+.3951-299

[0493] Starting reagent(s): 4-cyanobenzenesulfonamide (250 mg, 100% wt, 1 eq, 1.37 mmol), hydroxylamine, HC1 (95.3 mg, 1 eq, 1.37 mmol), sodium bicarbonate (115 mg, 1 eq, 1.37 mmol). N-Hydroxy-4-sulfamoylbenzimidamide (3951-299) (295 mg, 100% yield, 100% purity) as a white solid, m / z 216.2 [M+H]+.3951-317

[0494] Starting reagent(s): 4-(tert-butyl)benzonitrile (250 mg, 100% wt, 1 eq, 1.57 mmol), hydroxylamine, HC1 (109 mg, 1 eq, 1.57 mmol), sodium bicarbonate (132 mg, 1 eq, 1.57 mmol). 4-(tert-Butyl)-N-hydroxybenzimidamide (3951-317) (302 mg, 100% yield, 100% purity) as a white solid, m / z 193.2 [M+H]+.3951-318

[0495] Starting reagent(s): 4-nitrobenzonitrile (250 mg, 100% wt, 1 eq, 1.69 mmol), hydroxylamine, HC1 (117 mg, 1 eq, 1.69 mmol), sodium bicarbonate (142 mg, 1 eq, 1.69 mmol). N- Hydroxy-4-nitrobenzimidamide (3951-318) (306 mg, 100% yield, 100% purity) as a white solid, m / z 182.2 [M+H]+.3951-319

[0496] Starting reagent(s): 3,5-dichlorobenzonitrile (250 mg, 100% wt, 1 eq, 1.45 mmol), hydroxylamine, HC1 (101 mg, 1 eq, 1.45 mmol), sodium bicarbonate (122 mg, 1 eq, 1.45 mmol). 3,5-Dichloro-N-hydroxybenzimidamide (3951-319) (298 mg, 100% yield, 100%) as a white solid, m / z 205.0 / 207.0 [M+H]+.

[0497] Starting reagent(s): 3,5-bis(trifluoromethyl)benzonitrile (250 mg, 100% wt, 1 eq, 1.05 mmol), hydroxylamine, HC1 (72.7 mg, 1 eq, 1.05 mmol), sodium bicarbonate (87.8 mg, 1 eq, 1.05 mmol). N-Hydroxy-3,5-bis(trifluoromethyl)benzimidamide (3951-320) (285 mg, 100% yield, 100% purity) as a white solid, m / z 273 [M+H]+.3912-102

[0498] Starting reagent(s): 4-(trifluoromethyl)benzonitrile (200 mg, 1 eq, 1.17 mmol), hydroxylamine, HC1 (122 mg, 1.5 eq, 1.75 mmol), sodium bicarbonate (147 mg, 1.5 eq, 1.75 mmol). (Z)-N'-Hydroxy-4-(trifluoromethyl)benzimidamide (3912-102) (211 mg, 86% yield, 97% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 5.97 (s, 2H), 7.74 (d, J= 8.3 Hz, 2H), 7.89 (d, J= 8.2 Hz, 2H), 9.91 (s, 1H). m / z 205.2 [M+H]+.3951-332

[0499] Starting reagent(s): 6-chloro-2,2-difluorobenzo[d][l,3]dioxole-5-carbonitrile (152 mg, 100% wt, 1 eq, 699 pmol), hydroxylamine, HC1 (48.5 mg, 1 eq, 699 pmol), sodium bicarbonate (58.7 mg, 1 eq, 699 pmol). 6-Chloro-2,2-difluoro-N-hydroxybenzo[d][l,3]dioxole-5- carboximidamide (3951-332) (175 mg, 100% yield, 100% purity) as a white solid, m / z 351 [M+H]+.3951-333

[0500] Starting reagent(s): 3 -bromobenzonitrile (250 mg, 100% wt, 1 eq, 1.37 mmol), hydroxylamine, HC1 (95.4 mg, 1 eq, 1.37 mmol), sodium bicarbonate (115 mg, 1 eq, 1.37 mmol). 3-Bromo-N-hydroxybenzimidamide (3951-333) (295 mg, 100% yield, 100% purity) as a white solid, m / z 215.0 / 217.0 [M+H]+.3951-334

[0501] Starting reagent(s): 3,4-dimethylbenzonitrile (250 mg, 100% wt, 1 eq, 1.91 mmol), hydroxylamine, HC1 (132 mg, 1 eq, 1.91 mmol), sodium bicarbonate (160 mg, 1 eq, 1.91 mmol). N-Hydroxy-3,4-dimethylbenzimidamide (3951-334) (313 mg, 100% yield, 100% purity) as a white solid, m / z 165.2 [M+H]+.3951-335

[0502] Starting reagent(s): 4-chloro-3-(trifluoromethyl)benzonitrile (250 mg, 100% wt, 1 eq, 1.22 mmol), hydroxylamine, HC1 (84.5 mg, 1 eq, 1.22 mmol), sodium bicarbonate (102 mg, 1 eq, 1.22 mmol). 4-Chloro-N-hydroxy-3-(trifluoromethyl)benzimidamide (3951-335) (290 mg, 100% yield, 100% purity) as a white solid, m / z 239 [M+H]+.3951-357

[0503] Starting reagent(s): 2-(trifluoromethoxy)benzonitrile (543 mg, 75% wt, 1 eq, 2.18 mmol), hydroxylamine, HC1 (151 mg, 1 eq, 2.18 mmol), sodium bicarbonate (183 mg, 1 eq, 2.18 mmol). N-Hydroxy-2-(trifluoromethoxy)benzimidamide (3951-357) (479 mg, 100% yield, 100% purity) as a white solid. Product was used directly in the next step without further analysis.

[0504] Starting reagent(s): 5-methoxy-2-methylbenzonitrile (425 mg, 99% wt, 1 eq, 2.86 mmol), hydroxylamine, HC1 (199 mg, 1 eq, 2.86 mmol), sodium bicarbonate (240 mg, 1 eq, 2.86 mmol). N-Hydroxy-5-methoxy-2-methylbenzimidamide (3951-358) (515 mg, 100% yield, 100% purity) as a white solid. Product was used directly in the next step without further analysis.

[0505] Starting reagent(s): 2-methyl-2H-indazole-3-carbonitrile (171 mg, 99% wt, 1 eq, 1.08 mmol), hydroxylamine, HC1 (74.8 mg, 1 eq, 1.08 mmol), sodium bicarbonate (90.5 mg, 1 eq, 1.08 mmol). N-Hydroxy-2-methyl-2H-indazole-3-carboximidamide (3951-359) (205 mg, 99% yield, 99% purity) as a black solid. Product was used directly in the next step without further analysis.3951-364

[0506] Starting reagent(s): 3 -methoxy-2-m ethylbenzonitrile (138 mg, 99% wt, 1 eq, 928 pmol), hydroxylamine, HC1 (64.5 mg, 1 eq, 928 pmol), sodium bicarbonate (78.0 mg, 1 eq, 928 pmol). N-Hydroxy-3-methoxy-2-methylbenzimidamide (3951-364) (167 mg, 99% yield, 100% purity) as a white solid. Product was used directly in the next step without further analysis.3951-365

[0507] Starting reagent(s): 2,5-difluorobenzonitrile (250 mg, 99% wt, 1 eq, 1.78 mmol), hydroxylamine, HC1 (124 mg, 1 eq, 1.78 mmol), sodium bicarbonate (149 mg, 1 eq, 1.78 mmol). 2,5-Difluoro-N-hydroxybenzimidamide (3951-365) (306 mg, 100% yield, 100% purity) as a white solid. Product was used directly in the next step without further analysis.3951-366

[0508] Starting reagent(s): 2-methyl-5-(trifluoromethyl)benzonitrile (250 mg, 99% wt, 1 eq, 1.34 mmol), hydroxylamine, HC1 (92.9 mg, 1 eq, 1.34 mmol), sodium bicarbonate (112 mg, 1 eq, 1.34 mmol). N-Hydroxy-2-methyl-5-(trifluoromethyl)benzimidamide (3951-366) (292 mg, 100% yield, 100% purity) as a white solid. Product was used directly in the next step without further analysis.3951-367

[0509] Starting reagent(s): 2-methyl-3-(trifluoromethyl)benzonitrile (250 mg, 99% wt, 1 eq, 1.34 mmol), hydroxylamine, HC1 (92.9 mg, 1 eq, 1.34 mmol), sodium bicarbonate (112 mg, 1 eq, 1.34 mmol). N-Hydroxy-2-methyl-3-(trifluoromethyl)benzimidamide (3951-367) (292 mg, 100% yield, 100% purity) as a white solid. Product was used directly in the next step without further analysis.3951-372

[0510] Starting reagent(s): 2-chloro-5-methoxybenzonitrile (250 mg, 1 eq, 1.49 mmol), hydroxylamine, HC1 (104 mg, 1 eq, 1.49 mmol), sodium bicarbonate (125 mg, 1 eq, 1.49 mmol). 2-Chloro-N-hydroxy-5-methoxybenzimidamide (3951-372) (296 mg, 99% yield, 100% purity) as a white solid. Product was used directly in the next step without further analysis.3951-373

[0511] Starting reagent(s): 2-chl oro-3 -methoxybenzonitrile (250 mg, 1 eq, 1.49 mmol), hydroxylamine, HC1 (104 mg, 1 eq, 1.49 mmol), sodium bicarbonate (125 mg, 1 eq, 1.49 mmol). 2-Chloro-N-hydroxy-3-methoxybenzimidamide (3951-373) (296 mg, 99% yield, 100% purity) as a white solid. Product was used directly in the next step without further analysis.3951-383

[0512] Starting reagent(s): 2,3-dichlorobenzonitrile (335 mg, 1 eq, 1.95 mmol), hydroxylamine, HC1 (135 mg, 1 eq, 1.95 mmol), sodium bicarbonate (164 mg, 1 eq, 1.95 mmol). 2,3- Dichloro-N-hydroxybenzimidamide (3951-383) (399 mg, 100% yield, 100% purity) as a white solid. Product was used directly in the next step without further analysis.3951-384

[0513] Starting reagent(s): 5-chloro-2-fluorobenzonitrile (250 mg, 1 eq, 1.61 mmol), hydroxylamine, HC1 (112 mg, 1 eq, 1.61 mmol), sodium bicarbonate (135 mg, 1 eq, 1.61 mmol). 5- Chloro-2-fluoro-N-hydroxybenzimidamide (3951-384) (303 mg, 100% yield, 100% purity) as a white solid. Product was used directly in the next step without further analysis.3951-388

[0514] Starting reagent(s): 2,3-dihydro-[l,4]dioxino[2,3-b]pyridine-8-carbonitrile (100 mg, 1 eq, 617 pmol), hydroxylamine, HC1 (42.9 mg, 1 eq, 617 pmol), sodium bicarbonate (51.8 mg,1 eq, 617 pmol). N-Hydroxy-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine-8-carboximidamide (3951-388) (120 mg, 99% yield, 100% purity) as a white solid. Product was used directly in the next step without further analysis.3951-392

[0515] Starting reagent(s): 2,2-difluorobenzo[d][l,3]dioxole-4-carbonitrile (100 mg, 1 eq, 546 pmol), hydroxylamine, HC1 (37.9 mg, 1 eq, 546 pmol), sodium bicarbonate (45.9 mg, 1 eq, 546 pmol). 2,2-Difluoro-N-hydroxybenzo[d][l,3]dioxole-4-carboximidamide (3951-392) (118 mg, 100% yield, 100% purity) as a white solid, m / z 217.1 [M+H]+.3952-69

[0516] Starting reagent(s): picolinonitrile (1.00 g, 1 eq, 9.61 mmol), hydroxylamine, HC1 (1.00 g, 1.5 eq, 14.4 mmol), sodium bicarbonate (1.21 g, 1.5 eq, 14.4 mmol). (Z)-N' -Hydroxy - picolinimidamide (3952-69) (920 mg, 68% yield, 98% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.91 (s, 1H), 8.58 - 8.53 (m, 1H), 7.88 - 7.83 (m, 1H), 7.83 - 7.76 (m, 1H), 7.40 (ddd, J= 7.3, 4.9, 1.3 Hz, 1H), 5.84 (s, 2H).3952-70

[0517] Starting reagent(s): isonicotinonitrile (1.00 g, 1 eq, 9.61 mmol), hydroxylamine, HC1 (1.00 g, 1.5 eq, 14.4 mmol), sodium bicarbonate (1.21 g, 1.5 eq, 14.4 mmol). (Z)-N' -Hydroxy - isonicotinimidamide (3952-70) (890 mg, 66% yield, 98% purity) as a white solid. 'H NMR (500 MHz, DMSO-d6) 5 10.05 (s, 1H), 8.60 - 8.55 (m, 2H), 7.66 - 7.61 (m, 2H), 6.01 (s, 2H).3952-74

[0518] Starting reagent(s): nicotinonitrile (1.00 g, 1 eq, 9.61 mmol), hydroxylamine, HC1 (1.00 g, 1.5 eq, 14.4 mmol), sodium bicarbonate (1.21 g, 1.5 eq, 14.4 mmol). (Z)-N'-Hy- droxynicotinimidamide (3952-74) (758 mg, 56% yield, 98% purity) as a white solid. 'H NMR (400 MHz, DMSO) 5 9.83 (s, 1H), 8.86 (dd, J= 2.3, 0.9 Hz, 1H), 8.56 (dd, J= 4.8, 1.6 Hz, 1H), 8.05 - 7.97 (m, 1H), 7.40 (ddd, J= 8.0, 4.8, 0.9 Hz, 1H), 5.98 (s, 2H).3952-84

[0519] Starting reagent(s): 4-methylbenzonitrile (10.0 g, 1 eq, 85.4 mmol), hydroxylamine, HC1 (8.90 g, 1.5 eq, 128 mmol), sodium bicarbonate (10.8 g, 1.5 eq, 128 mmol). (Z)-N'-Hy- droxy-4-methylbenzimidamide (3952-84) (12.2 g, 93% yield, 98% purity) as a white solid. 'H NMR (500 MHz, DMSO-d6) 5 9.52 (d, J= 1.1 Hz, 1H), 7.58 - 7.53 (m, 2H), 7.17 (d, J= 7.9 Hz, 2H), 5.73 (s, 2H), 2.30 (s, 3H).3952-95

[0520] Starting reagent(s): 4-chloro-3-fluorobenzonitrile (1.00 g, 1 eq, 6.43 mmol), hydroxylamine, HC1 (670 mg, 1.5 eq, 9.64 mmol), sodium bicarbonate (810 mg, 1.5 eq, 9.64 mmol). (Z)-4-Chloro-3-fluoro-N'-hydroxybenzimidamide (3952-95) (1.10 g, 89% yield, 89% purity) as a white solid. 'H NMR (500 MHz, DMSO-d6) 5 9.87 (s, 1H), 7.65 (dd, J= 11.0, 1.9 Hz, 1H), 7.60 (dd, J= 8.5, 7.4 Hz, 1H), 7.55 (dd, J= 8.5, 1.9 Hz, 1H), 5.95 (s, 2H).3952-105

[0521] Starting reagent(s): 2-methylisonicotinonitrile (900 mg, 1 eq, 7.62 mmol), hydroxylamine, HC1 (794 mg, 1.5 eq, 11.4 mmol), sodium hydrogen carbonate (960 mg, 1.5 eq, 11.4mmol). (Z)-N'-Hydroxy-2-methylisonicotinimidamide (3952-105) (850 mg, 72% yield, 98% purity) as a white solid. 'H NMR (500 MHz, DMSO-d6) 5 9.66 (s, 1H), 8.44 (s, 1H), 8.40 (d, J = 4.9 Hz, 1H), 7.29 (d, J= 4.9 Hz, 1H), 5.88 (s, 2H), 2.35 (s, 3H).3952-112

[0522] Starting reagent(s): 4-isopropoxybenzonitrile (1.00 g, 1 eq, 6.20 mmol), hydroxylamine, HC1 (650 mg, 1.51 eq, 9.35 mmol), sodium bicarbonate (800 mg, 1.54 eq, 9.52 mmol). (Z)-N'-Hydroxy-4-isopropoxybenzimidamide (3952-112) (2.05 g, 76% yield, 89% purity) as a white solid. 'H NMR (500 MHz, DMSO-d6) 5 9.42 (s, 1H), 7.60 - 7.54 (m, 2H), 6.96 - 6.86 (m, 2H), 5.69 (s, 2H), 4.72 - 4.59 (m, 1H), 1.26 (d, J= 6.0 Hz, 6H). m / z 195.2 [M+H]+.3952-116

[0523] Starting reagent(s): 3-methylisonicotinonitrile (1.00 g, 1 eq, 8.46 mmol), hydroxylamine, HC1 (882 mg, 1.50 eq, 12.7 mmol), sodium bicarbonate (1.07 g, 1.50 eq, 12.7 mmol). (Z)-N'-Hydroxy-3-methylisonicotinimidamide (3952-116) (1.06 g, 81% yield, 98% purity) as a white solid. 'H NMR (500 MHz, DMSO-d6) 5 9.66 (s, 1H), 8.44 (s, 1H), 8.40 (d, J= 5.0 Hz, 1H), 7.29 (d, J= 4.9 Hz, 1H), 5.88 (s, 2H), 2.35 (s, 3H). m / z 152.2 [M+H]+.3952-122

[0524] Starting reagent(s): 2,4-dichlorobenzonitrile (1.00 g, 1 eq, 5.81 mmol), hydroxylamine, HC1 (650 mg, 1.61 eq, 9.35 mmol), sodium bicarbonate (800 mg, 1.64 eq, 9.52 mmol). (Z)-2,4-Dichloro-N'-hydroxybenzimidamide (3952-122) (1.02 g, 73% yield, 85% purity) as a white solid. 'H NMR (500 MHz, DMSO-d6) 5 9.54 (s, 1H), 7.65 (dd, J= 6.6, 1.6 Hz, 1H), 7.46 (dd, J= 6.9, 1.6 Hz, 1H), 7.46 - 7.38 (m, 1H), 5.87 (s, 2H).3952-123

[0525] Starting reagent(s): 3, 4-di chlorobenzonitrile (1.00 g, 1 eq, 5.81 mmol), hydroxylamine, HC1 (610 mg, 1.51 eq, 8.78 mmol), sodium bicarbonate (750 mg, 1.54 eq, 8.93 mmol). (Z)-3,4-Dichloro-N'-hydroxybenzimidamide (3952-123) (1.05 g, 86% yield, 98% purity) as a white solid. 'H NMR (500 MHz, DMSO-d6) 5 9.88 (s, 1H), 7.89 (d, J= 1.9 Hz, 1H), 7.70 - 7.61 (m, 2H), 5.96 (s, 2H). m / z 205.1 / 207.0 [M+H]+.3952-127

[0526] Starting reagent(s): 3-isopropoxybenzonitrile (1.00 g, 1 eq, 6.20 mmol), hydroxylamine, HC1 (650 mg, 1.51 eq, 9.35 mmol), sodium bicarbonate (800 mg, 1.54 eq, 9.52 mmol). (Z)-N'-Hydroxy-3-isopropoxybenzimidamide (3952-127) (980 mg, 77% yield, 95% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.61 (s, 1H), 7.28 - 7.16 (m, 3H), 6.93 - 6.87 (m, 1H), 5.78 (s, 2H), 4.69 - 4.58 (m, 1H), 1.26 (d, J= 6.0 Hz, 6H). m / z 195.2 [M+H]+.

[0527] Starting reagent(s): 3-chloroisonicotinonitrile (1.00 g, 1 eq, 7.22 mmol), hydroxylamine, HC1 (752 mg, 1.5 eq, 10.8 mmol), sodium bicarbonate (910 mg, 1.5 eq, 10.8 mmol). (Z)- 3-Chloro-N'-hydroxyisonicotinimidamide (3952-133) (420 mg, 33% yield, 98% purity) as a white solid. 'H NMR (400 MHz, DMSO-d6) 5 9.79 (s, 1H), 8.67 (s, 1H), 8.54 (d, J = 4.9 Hz, 1H), 7.50 - 7.42 (m, 1H), 6.00 (s, 2H). m / z 172.2 [M+H]+.

[0528] Starting reagent(s): 2,3 -difluorobenzonitrile (1.00 g, 1 eq, 7.19 mmol), hydroxylamine, HC1 (750 mg, 1.50 eq, 10.8 mmol), sodium bicarbonate (900 mg, 1.49 eq, 10.7 mmol). (Z)-2,3-Difluoro-N'-hydroxybenzimidamide (3952-177) (850 mg, 67% yield, 98% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.76 (s, 1H), 7.50 - 7.41 (m, 1H), 7.35 - 7.28 (m, 1H), 7.26 - 7.18 (m, 1H), 5.91 (s, 2H). m / z 173.2 [M+H]+.3952-179

[0529] Starting reagent(s): 3-chloro-2-fluorobenzonitrile (1.00 g, 1 eq, 6.43 mmol), hydroxylamine, HC1 (670 mg, 1.5 eq, 9.64 mmol), sodium bicarbonate (810 mg, 1.5 eq, 9.64 mmol). (Z)-3-Chloro-2-fluoro-N'-hydroxybenzimidamide (3952-179) (828 mg, 67% yield, 98% purity) as white solid. 'H NMR (500 MHz, DMSO) 5 9.73 (s, 1H), 7.65 - 7.58 (m, 1H), 7.49 - 7.42 (m, 1H), 7.31 - 7.21 (m, 1H), 5.93 - 5.90 (m, 2H). m / z 189.2 [M+H]+.

[0530] Starting reagent(s): methyl 3-cyano-4-fluorobenzoate (1.00 g, 1 eq, 5.58 mmol), hydroxylamine, HC1 (582 mg, 1.5 eq, 8.37 mmol), sodium bicarbonate (703 mg, 1.5 eq, 8.37 mmol). Methyl (Z)-4-fluoro-3-(N'-hydroxycarbamimidoyl)benzoate (3952-181) (800 mg, 62% yield, 93% purity) as a white solid.1H NMR (500 MHz, DMSO) 5 9.77 (s, 1H), 8.12 - 8.07 (m, 1H), 8.04 - 7.98 (m, 1H), 7.44 - 7.36 (m, 1H), 5.95 - 5.90 (m, 2H), 3.86 (s, 3H). m / z 213.2 [M+H]+.3952-187

[0531] Starting reagent(s): 2-morpholinoisonicotinonitrile (1.00 g, 1 eq, 5.28 mmol), hydroxylamine, HC1 (550 mg, 1.50 eq, 7.91 mmol), sodium bicarbonate (666 mg, 1.5 eq, 7.93 mmol). (Z)-N'-Hydroxy-2-morpholinoisonicotinimidamide (3952-187) (950 mg, 79% yield, 98% purity) as a white solid. 'H NMR (500 MHz, DMSO) 59.87 (s, 1H), 8.08 (d, J= 5.2 Hz, 1H), 7.05 (s, 1H), 6.96 (d, J = 5.2 Hz, 1H), 5.92 (s, 2H), 3.73 - 3.67 (m, 4H), 3.49 - 3.43 (m, 4H). m / z 223.2 [M+H]+.3953-130

[0532] Starting reagent(s): 2-(tetrahydro-2H-pyran-3-yl)acetonitrile (200 mg, 1 eq, 1.60 mmol), hydroxylamine, HC1 (167 mg, 1.5 eq, 2.40 mmol), sodium bicarbonate (201 mg, 1.5 eq, 2.40 mmol). (Z)-N'-Hydroxy-2-(tetrahydro-2H-pyran-3-yl)acetimidamide (3953-130) (138 mg, 25% yield, 47% purity) as a colourless oil. 'H NMR (500 MHz, DMSO) 5 8.72 (s, 1H), 5.33 (s, 2H), 3.78 - 3.67 (m, 2H), 3.30 - 3.22 (m, 1H), 3.00 - 2.93 (m, 1H), 1.88 - 1.71 (m, 4H), 1.62 - 1.40 (m, 2H), 1.17 - 1.07 (m, 1H).3953-131

[0533] Starting reagent(s): 4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (400 mg, 95% wt, 1 eq, 1.54 mmol), hydroxylamine, HC1 (160 mg, 1.5 eq, 2.30 mmol), sodium bicarbonate (194 mg, 1.5 eq, 2.30 mmol). (Z)-N'-Hydroxy-4-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)benzimidamide (3953-131) (430 mg, 75% yield, 75% purity) as a colourless oil. 'H NMR (500 MHz, DMSO) 5 9.44 (s, 1H), 7.62 - 7.56 (m, 2H), 6.96 - 6.91 (m, 2H), 5.71 (s, 2H), 4.67 - 4.62 (m, 1H), 4.17 - 4.12 (m, 2H), 3.94 - 3.88 (m, 1H), 3.80 - 3.74 (m, 1H), 3.74 - 3.68 (m, 1H), 3.48 - 3.41 (m, 1H), 1.74 - 1.66 (m, 1H), 1.66 - 1.59 (m, 1H), 1.53 - 1.39 (m, 4H). m / z 281.25 [M+H]+.3956-163

[0534] Starting reagent(s): 5-chloro-2-methylnicotinonitrile (200 mg, 1 eq, 1.31 mmol), hydroxylamine, HC1 (137 mg, 1.5 eq, 1.97 mmol), sodium bicarbonate (165 mg, 1.5 eq, 1.97 mmol). (Z)-5-Chloro-N'-hydroxy-2-methylnicotinimidamide (3956-163) (198 mg, 50% yield, 62% purity) as an off-white solid. 'H NMR (500 MHz, DMSO) 5 9.65 (s, 1H), 8.51 (d, J= 2.5 Hz, 1H), 7.75 (d, J= 2.5 Hz, 1H), 5.96 (s, 2H), 2.52 (s, 3H). m / z 186.2 [M+H]+.3956-168

[0535] Starting reagent(s): 1 -methyl- lH-pyrazole-4-carbonitrile (800 mg, 1 eq, 7.47 mmol), hydroxylamine, HC1 (778 mg, 1.5 eq, 11.2 mmol), sodium bicarbonate (941 mg, 1.5 eq, 11.2 mmol). (Z)-N'-Hydroxy-l -methyl- lH-pyrazole-4-carboximidamide (3956-168) (290 mg, 24% yield, 85% purity) as a yellow oil. 'H NMR (500 MHz, DMSO) 5 9.12 (s, 1H), 7.88 (s, 1H), 7.61 (s, 1H), 5.60 (s, 2H), 3.81 (s, 3H).3956-171

[0536] Starting reagent(s): 2-fluorobenzonitrile (500 mg, 448 pL, 1 eq, 4.13 mmol), hydroxylamine, HC1 (430 mg, 1.5 eq, 6.19 mmol), sodium bicarbonate (520 mg, 1.5 eq, 6.19 mmol). (Z)-2-Fluoro-N'-hydroxybenzimidamide (3956-171) (615 mg, 88% yield, 91% purity) as a yellow oil. 'H NMR (500 MHz, DMSO) 5 9.62 (s, 1H), 7.54 - 7.47 (m, 1H), 7.47 - 7.38 (m, 1H), 7.27 - 7.17 (m, 2H), 5.80 (s, 2H). m / z 155.2 [M+H]+.3956-172

[0537] Starting reagent(s): 3 -fluorobenzonitrile (500 mg, 441 pL, 1 eq, 4.13 mmol), hydroxylamine, HC1 (430 mg, 1.5 eq, 6.19 mmol), sodium bicarbonate (520 mg, 1.5 eq, 6.19 mmol). (Z)-3-Fluoro-N'-hydroxybenzimidamide (3956-172) (615 mg, 93% yield, 96% purity) as a yellow oil. 'H NMR (500 MHz, DMSO) 5 9.77 (s, 1H), 7.56 - 7.51 (m, 1H), 7.48 - 7.38 (m, 2H), 7.23 - 7.18 (m, 1H), 5.89 (s, 2H). m / z 155.2 [M+H]+.3956-173

[0538] Starting reagent(s): 4-fluorobenzonitrile (500 mg, 1 eq, 4.13 mmol), hydroxylamine, HC1 (430 mg, 1.5 eq, 6.19 mmol), sodium bicarbonate (520 mg, 1.5 eq, 6.19 mmol). (Z)-4-Fluoro-N'-hydroxybenzimidamide (3956-173) (650 mg, 98% yield, 96% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.63 (s, 1H), 7.75 - 7.66 (m, 2H), 7.24 - 7.17 (m, 2H), 5.83 (s, 2H). m / z 155.2 [M+H]+.3956-177

[0539] Starting reagent(s): tert-butyl (tert-butoxycarbonyl)(2-cyano-5-(trifluoromethyl)phe- nyl)carbamate (500 mg, 86% wt, 1 eq, 1.11 mmol), hydroxylamine, HC1 (116 mg, 1.5 eq, 1.67 mmol), sodium bicarbonate (140 mg, 1.5 eq, 1.67 mmol). Zc / V-Butyl (Z)-(2-(N'-hydroxycar- bamimidoyl)-5-(trifluoromethyl)phenyl)carbamate (3956-177) (410 mg, 73% yield, 63% purity) as an off-white solid, m / z 320.2 [M+H]+.3956-179

[0540] Starting reagent(s): 2,2-difluorobenzo[d][l,3]dioxole-5-carbonitrile (350 mg, 1 eq, 1.91 mmol), hydroxylamine, HC1 (199 mg, 1.5 eq, 2.87 mmol), sodium bicarbonate (241 mg, 1.5 eq, 2.87 mmol). (Z)-2,2-Difhroro-N'-hydroxybenzo[d][l,3]dioxole-5-carboximidamide (3956-179) (378 mg, 82% yield, 90% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.75 (s, 1H), 7.62 (d, J= 1.7 Hz, 1H), 7.54 (dd, J= 8.5, 1.7 Hz, 1H), 7.41 (d, J= 8.5 Hz, 1H), 5.89 (d, J= 6.2 Hz, 2H). m / z 217.2 [M+H]+.

[0541] Starting reagent(s): 3-chloro-2-(trifluoromethyl)isonicotinonitrile (145 mg, 90% wt, 1 eq, 632 pmol), hydroxylamine, HC1 (146 mg, 3 eq, 2.11 mmol), triethylamine (218 mg, 0.3 mL, 3 eq, 2.15 mmol). (Z)-3-Chloro-N'-hydroxy-2-(trifluoromethyl)isonicotinimidamide (3956- 190) (83 mg, 53% yield, 97% purity) as a yellow solid, m / z 240 [M+H]+.3956-191

[0542] Starting reagent(s): 5-chloro-2-methylisonicotinonitrile (119 mg, 82% wt, 1 eq, 640 pmol), hydroxylamine, HC1 (163 mg, 3 eq, 2.35 mmol), triethylamine (240 mg, 0.33 mL, 3 eq, 2.37 mmol). (Z)-5-Chloro-N'-hydroxy-2-methylisonicotinimidamide (3956-191) (119 mg, 82% yield, 82% purity) as a pale green solid, m / z 186.2 [M+H]+.3956-196

[0543] Starting reagent(s): 3-chloro-2-methoxyisonicotinonitrile (180 mg, 96% wt, 1 eq, 1.03 mmol), hydroxylamine, HC1 (214 mg, 3 eq, 3.08 mmol), triethylamine (312 mg, 0.43 mL, 3 eq, 3.08 mmol). (Z)-3-Chloro-N'-hydroxy-2-methoxyisonicotinimidamide (3956-196) (200 mg, 86% yield, 89% purity) as a pale green solid, m / z 202.2 [M+H]+.3956-198

[0544] Starting reagent(s): 2-nitrobenzonitrile (1.00 g, 1 eq, 6.75 mmol), hydroxylamine, HC1 (704 mg, 1.5 eq, 10.1 mmol), sodium bicarbonate (851 mg, 1.5 eq, 10.1 mmol). (Z)-N'-Hy- droxy-2-nitrobenzimidamide (3956-198) (364 mg, 29% yield, 98% purity) as a yellow solid.1H NMR (500 MHz, DMSO) 5 9.69 (s, 1H), 7.85 (dd, J= 8.0, 1.2 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.67 - 7.58 (m, 2H), 6.00 (s, 2H). m / z 182.2 [M+H]+.3956-205

[0545] Starting reagent(s): 2-chloroisonicotinonitrile (1.51 g, 90% wt, 1 eq, 9.81 mmol), hydroxylamine, HC1 (1.02 g, 1.41 mL, 1.5 eq, 14.7 mmol), sodium bicarbonate (1.24 g, 1.5 eq,14.7 mmol). (Z)-2-Chloro-N'-hydroxyisonicotinimidamide (3956-205) (1.7 g, 91% yield, 90% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 10.23 (s, 1H), 8.40 (dd, J= 5.3, 0.7 Hz, 1H), 7.73 (dd, J = 1.5, 0.7 Hz, 1H), 7.67 (dd, J = 5.2, 1.5 Hz, 1H), 6.10 (s, 2H). m / z 172.0 [M+H]+.3956-210

[0546] Starting reagent(s): tert-butyl (tert-butoxycarbonyl)(4-cyanopyridin-2-yl)carbamate (490.0 mg, 95% wt, 1 eq, 1.458 mmol), hydroxylamine, HC1 (151.9 mg, 1.5 eq, 2.186 mmol), triethylamine (221.2 mg, 305 pL, 1.5 eq, 2.186 mmol). Zc / V-Butyl (Z)-(tert-butoxycarbonyl)(4- (N'-hydroxycarbamimidoyl)pyridin-2-yl)carbamate (3956-210) (482 mg, 79% yield, 84% purity) as a white solid.XH NMR (500 MHz, DMSO) 5 10.13 (s, 1H), 8.43 (dd, J= 5.1, 1.0 Hz, 1H), 7.60 (dd, J= 6.3, 1.3 Hz, 2H), 6.06 (s, 2H), 1.40 (s, 18H). m / z 353.2 [M+H]+.3956-215

[0547] Starting reagent(s): quinoline-4-carbonitrile (100.0 mg, 1 eq, 648.6 pmol), hydroxylamine, HC1 (67.61 mg, 1.5 eq, 973.0 pmol), triethylamine (98.45 mg, 136 pL, 1.5 eq, 973.0 pmol). (Z)-N'-Hydroxyquinoline-4-carboximidamide (3956-215) (180 mg, 19% yield, 50% purity) as a white solid.1H NMR (500 MHz, DMSO) 59.92 (s, 1H), 8.93 (d, J= 4.4 Hz, 1H), 8.44 - 8.41 (m, 1H), 8.06 - 8.02 (m, 1H), 7.65 - 7.61 (m, 1H), 7.56 (d, J= 4.3 Hz, 2H), 6.14 (s, 2H).3956-218

[0548] Starting reagent(s): 2,6-dimethylisonicotinonitrile (300.0 mg, 1 eq, 2.270 mmol), hydroxylamine, HC1 (236.6 mg, 1.5 eq, 3.405 mmol), sodium bicarbonate (286 mg, 1.5 eq, 3.405mmol). (Z)-N' -Hydroxy-2, 6-dimethylisonicotinimidamide (3956-218) (158 mg, 41% yield, 97% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.88 (s, 1H), 7.29 (s, 2H), 5.88 (s, 2H), 2.42 (s, 6H).3956-219

[0549] Starting reagent(s): 2-fluoroisonicotinonitrile (800.0 mg, 1 eq, 6.552 mmol), hydroxylamine, HC1 (683 mg, 1.5 eq, 9.828 mmol), sodium carbonate (694.4 mg, 1 eq, 6.552 mmol). (Z)-2-Fluoro-N'-hydroxyisonicotinimidamide (3956-219) (1.0 g, 82% yield, 95% purity) as an off-white solid. 'H NMR (500 MHz, DMSO) 5 10.22 (s, 1H), 8.23 (d, J= 5.3 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.39 (s, 1H), 6.10 (s, 2H). m / z 156.2 [M+H]+.3956-237

[0550] Starting reagent(s): tert-butyl (tert-butoxycarbonyl)(4-cyanopyridin-3-yl)carbamate (686.0 mg, 94% wt, 1 eq, 2.019 mmol), hydroxylamine, HC1 (210.5 mg, 1.5 eq, 3.029 mmol), sodium bicarbonate (254.4 mg, 1.5 eq, 3.029 mmol). Zc / V-Butyl (Z)-(tert-butoxycarbonyl)(4- (N'-hydroxycarbamimidoyl)pyridin-3-yl)carbamate (3956-237) (281 mg, 16% yield, 40% purity) as a yellow solid. 'H NMR (500 MHz, DMSO) 5 10.38 (s, 1H), 9.34 (s, 1H), 8.27 (d, J= 5.1 Hz, 1H), 7.58 (dd, J= 5.2, 0.6 Hz, 1H), 6.32 (s, 2H), 1.48 (s, 18H). m / z 353.2 [M+H]+.3956-255

[0551] Starting reagent(s): tert-butyl 4-cyano-lH-pyrrolo[2,3-b]pyridine-l-carboxylate (625 mg, 98% wt, 1 eq, 2.52 mmol), hydroxylamine, HC1 (262 mg, 1.5 eq, 3.78 mmol), sodium bicarbonate (317 mg, 1.5 eq, 3.78 mmol). Zc / V-Butyl (Z)-4-(N'-hydroxycarbamimidoyl)-lH- pyrrolo[2,3-b]pyridine-l-carboxylate (3956-255) (589 mg, 80% yield, 95% purity) as yellow solid, m / z 277.2 [M+H]+.3912-100

[0552] Starting reagent(s): 4-methoxybenzonitrile (200 mg, 1 eq, 1.50 mmol), hydroxylamine, HC1 (157 mg, 1.5 eq, 2.25 mmol), sodium bicarbonate (189 mg, 1.5 eq, 2.25 mmol). (Z)- N' -Hydroxy -4-methoxybenzimidamide (3912-100) (153 mg, 50% yield, 82% purity) as an off- white solid. 'H NMR (500 MHz, DMSO) 5 9.44 (s, 1H), 7.63 - 7.57 (m, 2H), 6.94 - 6.89 (m, 2H), 5.71 (s, 2H), 3.77 (s, 3H). m / z 167.2 [M+H]+.3912-109

[0553] Starting reagent(s): 4-(dimethylamino)benzonitrile (200 mg, 1 eq, 1.37 mmol), hydroxylamine, HC1 (143 mg, 1.5 eq, 2.05 mmol), sodium bicarbonate (172 mg, 1.5 eq, 2.05 mmol). (Z)-4-(Dimethylamino)-N'-hydroxybenzimidamide (3912-109) (72 mg, 28% yield, 94% purity) as a beige solid, m / z 180.2 [M+H]+.3912-147

[0554] Starting reagent(s): benzonitrile (250 mg, 249 pL, 1 eq, 2.42 mmol), hydroxylamine, HC1 (253 mg, 1.5 eq, 3.64 mmol), sodium bicarbonate (306 mg, 1.5 eq, 3.64 mmol). (Z)-N'- Hydroxybenzimidamide (3912-147) (334 mg, 81% yield, 80% purity) as a colourless oil. 'H NMR (500 MHz, DMSO) 5 9.61 (d, = 0.6 Hz, 1H), 7.71 - 7.63 (m, 2H), 7.40 - 7.31 (m, 3H), 5.79 (s, 2H).cr X Y OH NH23912-148

[0555] Starting reagent(s): 3 -chi oro-4-m ethylbenzonitrile (250 mg, 1 eq, 1.65 mmol), hydroxylamine, HC1 (172 mg, 1.5 eq, 2.47 mmol), sodium bicarbonate (208 mg, 1.5 eq, 2.47 mmol). (Z)-3-Chloro-N'-hydroxy-4-methylbenzimidamide (3912-148) (239 mg, 77% yield, 98% purity) as a yellow solid. 'H NMR (500 MHz, DMSO) 5 9.69 (s, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.55 (dd, J= 7.9, 1.8 Hz, 1H), 7.34 (dd, J= 7.9, 0.8 Hz, 1H), 5.85 (s, 2H), 2.33 (s, 3H).3912-155

[0556] Starting reagent(s): 3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)benzonitrile (475 mg, 98% wt, 1 eq, 1.88 mmol), hydroxylamine, HC1 (196 mg, 1.5 eq, 2.82 mmol), sodium bicarbonate (237 mg, 1.5 eq, 2.82 mmol). (Z)-N'-Hydroxy-3-(2-((tetrahydro-2H-pyran-2- yl)oxy)ethoxy)benzimidamide (3912-155) (452 mg, 73% yield, 85% purity) as a yellow solid. 'H NMR (500 MHz, DMSO) 5 9.61 (s, 1H), 7.29 - 7.20 (m, 3H), 6.99 - 6.89 (m, 1H), 5.79 (s, 2H), 4.70 - 4.61 (m, 1H), 4.20 - 4.10 (m, 2H), 3.96 - 3.88 (m, 1H), 3.82 - 3.75 (m, 1H), 3.75 - 3.68 (m, 1H), 3.49 - 3.40 (m, 1H), 1.76 - 1.67 (m, 1H), 1.67 - 1.58 (m, 1H), 1.54 - 1.39 (m, 4H).3912-156

[0557] Starting reagent(s): 2-chlorobenzonitrile (250 mg, 1 eq, 1.82 mmol), hydroxylamine, HC1 (189 mg, 1.5 eq, 2.73 mmol), sodium bicarbonate (229 mg, 1.5 eq, 2.73 mmol). (Z)-2- Chloro-N'-hydroxybenzimidamide (3912-156) (258 mg, 67% yield, 80% purity) as a off-white solid. 1H NMR (500 MHz, DMSO) 5 9.45 (s, 1H), 7.49 - 7.46 (m, 1H), 7.42 - 7.38 (m, 2H), 7.36 (m, 1H), 5.81 (s, 2H).3912-165

[0558] Starting reagent(s): 3 -morpholinobenzonitrile (107 mg, 95% wt, 1 eq, 540 pmol), hydroxylamine, HC1 (59.0 mg, 1.57 eq, 849 pmol), sodium bicarbonate (72.0 mg, 1.59 eq, 857 pmol). (Z)-N'-Hydroxy-3-morpholinobenzimidamide (3912-165) (117 mg, 92% yield, 94% purity) as a white solid. 'H NMR (400 MHz, DMSO) 5 9.53 (s, 1H), 7.24 - 7.17 (m, 2H), 7.12 (m, 1H), 6.98 - 6.91 (m, 1H), 5.76 (s, 2H), 3.79 - 3.67 (m, 4H), 3.18 - 3.02 (m, 4H).3912-174

[0559] Starting reagent(s): 4-morpholinobenzonitrile (206 mg, 83% wt, 1 eq, 908 pmol), hydroxylamine, HC1 (95.0 mg, 1.51 eq, 1.37 mmol), sodium bicarbonate (114 mg, 1.5 eq, 1.36 mmol). (Z)-N'-Hydroxy-4-morpholinobenzimidamide (3912-174) (116 mg, 53% yield, 92% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.36 (s, 1H), 7.56 - 7.50 (m, 2H), 6.94 - 6.87 (m, 2H), 5.64 (s, 2H), 3.76 - 3.70 (m, 4H), 3.17 - 3.09 (m, 4H). m / z 222.2 [M+H]+.3912-176

[0560] Starting reagent(s): tetrahydro-2H-pyran-4-carbonitrile (200 mg, 193 pL, 1 eq, 1.80 mmol), hydroxylamine, HC1 (188 mg, 1.5 eq, 2.70 mmol), sodium bicarbonate (227 mg, 1.5 eq, 2.70 mmol). (Z)-N'-Hydroxytetrahydro-2H-pyran-4-carboximidamide (3912-176) (35 mg, 13% yield, 98% purity) as a yellow solid. 'H NMR (500 MHz, DMSO) 5 8.80 (s, 1H), 5.30 (s, 2H), 3.90 - 3.78 (m, 2H), 3.31 - 3.24 (m, 2H), 2.27 - 2.14 (m, 1H), 1.64 - 1.56 (m, 4H). m / z 145.2 [M+H]+.3912-192

[0561] Starting reagent(s): lH-benzo[d]imidazole-6-carbonitrile (400 mg, 1 eq, 2.79 mmol), hydroxylamine, HC1 (291 mg, 1.5 eq, 4.19 mmol), sodium bicarbonate (352 mg, 1.5 eq, 4.19 mmol). (Z)-N'-Hydroxy-lH-benzo[d]imidazole-6-carboximidamide (3912-192) (242 mg, 48% yield, 98% purity as a beige solid.1H NMR (500 MHz, DMSO) 5 12.52 (s, 1H), 9.51 (s, 1H), 8.23 (s, 1H), 7.99 - 7.78 (m, 1H), 7.65 - 7.44 (m, 2H), 5.80 (s, 2H). m / z 177.2 [M+H]+.

[0562] Starting reagent(s): methyl 3 -cyanobenzoate (250 mg, 95% wt, 1 eq, 1.47 mmol), hydroxylamine, HC1 (154 mg, 1.5 eq, 2.21 mmol), sodium bicarbonate (186 mg, 1.5 eq, 2.21 mmol). Methyl (Z)-3-(N'-hydroxycarbamimidoyl)benzoate (3912-195) (247 mg, 82% yield, 95% purity) as a colourless foam. 'H NMR (500 MHz, DMSO) 5 9.77 (s, 1H), 8.31 - 8.28 (m, 1H), 7.97 - 7.90 (m, 2H), 7.56 - 7.50 (m, 1H), 5.94 (s, 2H), 3.87 (s, 3H).

[0563] Starting reagent(s): 2-(trifluoromethyl)isonicotinonitrile (250 mg, 1 eq, 1.45 mmol), hydroxylamine, HC1 (151 mg, 1.5 eq, 2.18 mmol), sodium bicarbonate (183 mg, 1.5 eq, 2.18 mmol). (Z)-N'-Hydroxy-2-(trifluoromethyl)isonicotinimidamide (3912-198) (179 mg, 59% yield, 98% purity) as an off-white solid. 'H NMR (500 MHz, DMSO) 5 10.30 (s, 1H), 8.77 (d, J= 5.1 Hz, 1H), 8.11 (dd, J= 1.7, 0.8 Hz, 1H), 7.96 (dd, J = 5.2, 1.6 Hz, 1H), 6.21 (s, 2H). m / z 206.2 [M+H]+.3912-201

[0564] Starting reagent(s): 4-chlorobenzonitrile (250 mg, 95% wt, 1 eq, 1.73 mmol), hydrox- ylamine, HC1 (180 mg, 1.5 eq, 2.59 mmol), sodium bicarbonate (218 mg, 1.5 eq, 2.59 mmol). (Z)-4-Chloro-N'-hydroxybenzimidamide (3912-201) (156 mg, 52% yield, 98% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.72 (s, 1H), 7.71 - 7.66 (m, 2H), 7.46 - 7.41 (m, 2H), 5.86 (s, 2H). m / z 171.2 / 173.2 [M+H]+.3912-202

[0565] Starting reagent(s): 3 -chlorobenzonitrile (250 mg, 95% wt, 1 eq, 1.73 mmol), hydroxylamine, HC1 (180 mg, 1.5 eq, 2.59 mmol), sodium bicarbonate (218 mg, 1.5 eq, 2.59 mmol). (Z)-3-Chloro-N'-hydroxybenzimidamide (3912-202) (248 mg, 83% yield, 98% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.79 (s, 1H), 7.71 - 7.68 (m, 1H), 7.67 - 7.62 (m, 1H), 7.46 - 7.37 (m, 2H), 5.90 (s, 2H). m / z 171.2 / 173.2 [M+H]+.3912-205

[0566] Starting reagent(s): 3 -methoxybenzonitrile (250 mg, 1 eq, 1.88 mmol), hydroxylamine, HC1 (196 mg, 1.5 eq, 2.82 mmol), sodium bicarbonate (237 mg, 1.5 eq, 2.82 mmol). (Z)- N'-Hydroxy-3-methoxybenzimidamide (3912-205) (268 mg, 82% yield, 95% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.62 (s, 1H), 7.31 - 7.19 (m, 3H), 6.97 - 6.87 (m, 1H), 5.79 (s, 2H), 3.77 (s, 3H). m / z 167.2 [M+H]+.3912-206

[0567] Starting reagent(s): 2-methoxybenzonitrile (250 mg, 1 eq, 1.88 mmol), hydroxylamine, HC1 (196 mg, 1.5 eq, 2.82 mmol), sodium bicarbonate (237 mg, 1.5 eq, 2.82 mmol). (Z)- N' -Hydroxy -2 -m ethoxyb enzimidamide (3912-206) (256 mg, 70% yield, 85% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.37 (s, 1H), 7.41 - 7.32 (m, 2H), 7.07 - 7.03 (m, 1H), 6.96 - 6.89 (m, 1H), 5.59 (s, 2H), 3.79 (s, 3H). m / z 167.2 [M+H]+.3912-209

[0568] Starting reagent(s): 3-(trifluoromethyl)benzonitrile (0.26 g, 0.20 mL, 1 eq, 1.5 mmol), hydroxylamine, HC1 (0.16 g, 1.5 eq, 2.2 mmol), sodium hydrogencarbonate (0.19 g, 1.5 eq, 2.2 mmol). (Z)-N'-Hydroxy-3-(trifluoromethyl)benzimidamide (3912-209) (286 mg, 84% yield, 90% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.86 (s, 1H), 8.03 - 7.95 (m, 2H), 7.73 (m, 1H), 7.65 - 7.59 (m, 1H), 6.01 (s, 2H).3912-210

[0569] Starting reagent(s): 2-(trifluoromethyl)benzonitrile (0.26 g, 0.20 mL, 1 eq, 1.5 mmol), hydroxylamine, HC1 (0.16 g, 1.5 eq, 2.3 mmol), sodium bicarbonate (0.19 g, 1.5 eq, 2.3 mmol). (Z)-N'-Hydroxy-2-(trifluoromethyl)benzimidamide (3912-210) (75 mg, 24% yield, 98% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.53 (s, 1H), 7.77 - 7.73 (m, 1H), 7.71 - 7.66 (m, 1H), 7.64 - 7.58 (m, 1H), 7.55 - 7.48 (m, 1H), 5.84 (s, 2H). m / z 205.2 [M+H]+.3912-216

[0570] Starting reagent(s): 3 -methylbenzonitrile (247 mg, 250 pL, 1 eq, 2.11 mmol), hydroxylamine, HC1 (220 mg, 1.5 eq, 3.16 mmol), sodium bicarbonate (265 mg, 1.5 eq, 3.16 mmol). (Z)-N'-Hydroxy-3-methylbenzimidamide (3912-216) (301 mg, 90% yield, 95% purity) as a white solid.XH NMR (500 MHz, DMSO) 5 9.56 (s, 1H), 7.49 (d, J= 1.8 Hz, 1H), 7.45 (dd, J= 7.8, 2.0 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.20 - 7.15 (m, 1H), 5.74 (d, J = 6.9 Hz, 2H), 2.31 (s, 3H). m / z 151.2 [M+H]+.

[0571] Starting reagent(s): 2-methylbenzonitrile (247 mg, 250 pL, 1 eq, 2.11 mmol), hydroxylamine, HC1 (220 mg, 1.5 eq, 3.17 mmol), sodium bicarbonate (266 mg, 1.5 eq, 3.17 mmol). (Z)-N'-Hydroxy-2-methylbenzimidamide (3912-217) (189 mg, 42% yield, 70% purity) as a white solid, m / z 151.2 [M+H]+.3912-218

[0572] Starting reagent(s): 2-fluoro-4-(trifluoromethyl)benzonitrile (244 mg, 180 pL, 1 eq, 1.29 mmol), hydroxylamine, HC1 (135 mg, 1.5 eq, 1.94 mmol), sodium bicarbonate (163 mg, 1.5 eq, 1.94 mmol). (Z)-2-Fluoro-N'-hydroxy-4-(trifluoromethyl)benzimidamide (3912-218) (240 mg, 79% yield, 95% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 9.86 (s, 1H), 7.75 - 7.71 (m, 2H), 7.63 - 7.58 (m, 1H), 5.96 (s, 2H). m / z 223.2 [M+H]+.3912-237

[0573] Starting reagent(s): 5-chloro-2-methoxyisonicotinonitrile (169 mg, 96.5% wt, 1 eq, 967 pmol), hydroxylamine, HC1 (134 mg, 2 eq, 1.93 mmol), triethylamine (196 mg, 0.27 mL, 2 eq, 1.93 mmol). (Z)-5-Chloro-N'-hydroxy-2-methoxyisonicotinimidamide (3912-237) (158 mg, 75% yield, 93% purity) as a yellow solid, m / z 202.0 / 204.2 [M+H]+.

[0574] Starting reagent(s): 3-fluoro-2-(trifluoromethyl)isonicotinonitrile (78.0 mg, 96.5% wt, 1 eq, 396 pmol), hydroxylamine, HC1 (41.0 mg, 1.49 eq, 590 pmol), sodium bicarbonate (50.0 mg, 1.50 eq, 595 pmol). (Z)-3-Fluoro-N'-hydroxy-2-(trifluoromethyl)isonicotinimidamide (3912-244) (89 mg, 92% yield, 92% purity) as an off-white solid, m / z 224.2 [M+H]+.

[0575] Starting reagent(s): 2-(((tert-butyldimethylsilyl)oxy)methyl)isonicotinonitrile (350 mg, 1 eq, 1.41 mmol), hydroxylamine, HC1 (147 mg, 1.5 eq, 2.11 mmol), sodium bicarbonate (178 mg, 1.5 eq, 2.11 mmol). (Z)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-N'-hydroxyisonico- tinimidamide (3912-247) (307 mg, 75% yield, 97% purity) as an off-white solid. 'H NMR (500 MHz, DMSO) 5 10.03 (s, 1H), 8.49 (d, J= 5.1 Hz, 1H), 7.76 - 7.70 (m, 1H), 7.50 (dd, J= 5.2, 1.7 Hz, 1H), 6.01 - 5.90 (m, 1H), 4.75 (s, 2H), 0.92 (s, 9H), 0.10 (s, 6H). m / z 282.2 [M+H]+.

[0576] Starting reagent(s): 5-(trifluoromethyl)nicotinonitrile (250 mg, 1 eq, 1.45 mmol), hydroxylamine, HC1 (151 mg, 1.5 eq, 2.18 mmol), sodium bicarbonate (183 mg, 1.5 eq, 2.18 mmol). (Z)-N'-Hydroxy-5-(trifluoromethyl)nicotinimidamide (3912-248) (246 mg, 79% yield, 97% purity) as a white solid.XH NMR (500 MHz, DMSO) 5 10.09 (s, 1H), 9.15 (d, = 2.0 Hz, 1H), 8.99 - 8.94 (m, 1H), 8.41 - 8.31 (m, 1H), 6.25 - 6.11 (m, 1H). m / z 206.2 [M+H]+.

[0577] Starting reagent(s): 2-oxo-l,2-dihydropyridine-4-carbonitrile (250 mg, 98% wt, 1 eq, 2.04 mmol), hydroxylamine, HC1 (213 mg, 1.5 eq, 3.06 mmol), sodium bicarbonate (257 mg, 1.5 eq, 3.06 mmol). (Z)-N'-Hydroxy-2-oxo-l,2-dihydropyridine-4-carboximidamide (3912- 265) (202 mg, 59% yield, 92% purity) as a beige solid, m / z 154.2 [M+H]+.3912-272

[0578] Starting reagent(s): l-methyl-2-oxo-l,2-dihydropyridine-4-carbonitrile (250 mg, 98% wt, 1 eq, 1.83 mmol), hydroxylamine, HC1 (190 mg, 1.5 eq, 2.74 mmol), sodium bicarbonate(230 mg, 1.5 eq, 2.74 mmol). (Z)-N' -Hydroxy- l-methyl-2-oxo- 1,2-dihydropyri dine-4-car- boximidamide (3912-272) (106 mg, 34% yield, 98% purity) as a white solid. 'H NMR (500 MHz, DMSO) 5 10.11 (s, 1H), 7.58 (d, J= 1A Hz, 1H), 6.71 (d, J= 1.9 Hz, 1H), 6.48 (dd, J= 7.1, 2.0 Hz, 1H), 5.86 (s, 2H), 3.39 (s, 3H). m / z 168.2 [M+H]+.3912-273

[0579] Starting reagent(s): 2-methoxyisonicotinonitrile (250 mg, 98% wt, 1 eq, 1.83 mmol), hydroxylamine, HC1 (190 mg, 1.5 eq, 2.74 mmol), sodium hydrogencarbonate (230 mg, 1.5 eq, 2.74 mmol). (Z)-N'-Hydroxy-2-methoxyisonicotinimidamide (3912-273) (239 mg, 77% yield, 98% purity) as a white solid.XH NMR (500 MHz, DMSO) 5 10.01 (s, 1H), 8.13 (d, = 5.4 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.07 (s, 1H), 5.96 (s, 2H), 3.85 (s, 3H). m / z 168.2 [M+H]+.

[0580] Starting reagent(s): 2-cyclopropylisonicotinonitrile (400 mg, 95% wt, 1 eq, 2.64 mmol), hydroxylamine, HC1 (275 mg, 1.5 eq, 3.95 mmol), sodium bicarbonate (350 mg, 1.58 eq, 4.17 mmol). (Z)-2-Cyclopropyl-N'-hydroxyisonicotinimidamide (3901-96) (470 mg, 96% yield, 95% purity) as a colourless oil. 'H NMR (500 MHz, DMSO) 5 9.96 (s, 1H), 8.36 (dd, J = 5.2, 0.8 Hz, 1H), 7.51 (dd, J= 1.7, 0.8 Hz, 1H), 7.36 (dd, J= 5.2, 1.7 Hz, 1H), 5.95 (s, 2H), 2.12 - 2.04 (m, 1H), 0.99 - 0.86 (m, 4H). m / z 178.2 [M+H]+.3901-110-1

[0581] Starting reagent(s): (Z)-N'-hydroxy-lH-indole-3-carboximidamide (60.0 mg, 0.34 mmol, 19%, 98% purity), hydroxylamine, HC1 (150 mg, 1.23 eq, 2.16 mmol) in EtOH (5.00 mL) were added sodium bicarbonate (200 mg, 1.35 eq, 2.38 mmol). (Z)-N'-Hydroxy-lH-in- dole-3-carboximidamide (3901-110-1) (60 mg, 19% yield, 98% purity) as an off-white solid, m / z 176.2 [M+H]+.3901-110-2

[0582] Starting reagent(s): lH-indazole-3 -carbonitrile (252 mg, 1 eq, 1.76 mmol), hydroxylamine, HC1 (150 mg, 1.23 eq, 2.16 mmol), sodium bicarbonate (200 mg, 1.35 eq, 2.38 mmol). (Z)-N'-Hydroxy-lH-indazole-3-carboximidamide (3901-110-2) (110 mg, 34% yield, 97% purity) as an off-white solid, m / z 177.2 [M+H]+.3901-110-3

[0583] Starting reagent(s): benzo[b]thiophene-3-carbonitrile (250 mg, 1 eq, 1.57 mmol), hydroxylamine, HC1 (150 mg, 1.23 eq, 2.16 mmol), sodium bicarbonate (200 mg, 1.35 eq, 2.38 mmol). (Z)-N'-Hydroxybenzo[b]thiophene-3-carboximidamide (3901-110-3) (250 mg, 68% yield, 92% purity) as an off-white solid, m / z 193.2 [M+H]+.3951-274

[0584] Starting reagent(s): 3-(trifluoromethoxy)benzonitrile (49.0 mg, 99% wt, 1 eq, 259 pmol), hydroxylamine, HC1 (27.0 mg, 1.5 eq, 389 pmol), sodium hydrogencarbonate (32.7 mg, 1.5 eq, 389 pmol). Used directly in the next step without analysis.3952-179

[0585] Starting reagent(s): 3-chloro-2-fluorobenzonitrile (1.00 g, 1 eq, 6.43 mmol), hydroxylamine, HC1 (670 mg, 1.5 eq, 9.64 mmol), sodium hydrogen carbonate (810 mg, 1.5 eq, 9.64 mmol). (Z)-3-chloro-2-fluoro-N'-hydroxybenzimidamide (3952-179) (0.828 g, 67% yield, 98% purity) as a white solid. 'H NMR (500 MHz, DMSO-d6) 5 9.73 (s, 1H), 7.65 - 7.58 (m, 1H), 7.45 (ddd, J= 8.0, 6.3, 1.7 Hz, 1H), 7.24 (t, J= 7.9 Hz, 1H), 5.92 (s, 2H). m / z 189.2 [M+H]+.3953-330

[0586] Starting reagent(s): benzo[b]thiophene-5 -carbonitrile (100 mg, 1 Eq, 628 pmol), hydroxylamine, HC1 (69.8 mg, 1.6 Eq, 1.00 mmol), sodium hydrogencarbonate (84.4 mg, 1.6 Eq, 1.00 mmol). (Z)-N'-hydroxybenzo[b]thiophene-5-carboximidamide (115 mg, 90% yield, 95% purity). 'H NMR (500 MHz, DMSO) 5 9.63 (s, 1H), 8.17 (d, J = 1.7 Hz, 1H), 7.98 (d, J = 8.5 Hz, 1H), 7.79 (d, J = 5.4 Hz, 1H), 7.69 (dd, J = 8.5, 1.7 Hz, 1H), 7.48 (dd, J = 5.5, 0.8 Hz, 1H), 5.86 (s, 2H). m / z 193.2 [M+H]+.3953-332

[0587] Starting reagent(s): benzofuran-5-carbonitrile (100 mg, 1 Eq, 699 pmol), hydroxylamine, HC1 (77.7 mg, 1.6 Eq, 1.12 mmol), sodium hydrogencarbonate (93.9 mg, 1.6 Eq, 1.12 mmol). (Z)-N'-hydroxybenzofuran-5-carboximidamide (30 mg, 24% yield, 98% purity), m / z 177.2 [M+H]+.3956-353

[0588] Starting reagent(s): 2,4-dimethylthiazole-5-carbonitrile (136 mg, 98% Wt, 1 Eq, 964 pmol), hydroxylamine hydrochloride (134 mg, 2.0 Eq, 1.93 mmol), triethylamine (195 mg, 269 pL, 2.0 Eq, 1.93 mmol). (Z)-N'-hydroxy-2,4-dimethylthiazole-5-carboximidamide (135 mg, 78% yield, 95% purity). 'H NMR (500 MHz, DMSO) 5 9.72 (s, 1H), 5.76 (s, 2H), 2.56 (s, 3H), 2.40 (s, 3H). m / z 172.2 [M+H]+.3901-190

[0589] Starting reagent(s): 5-fluoroquinoline-8-carbonitrile (100 mg, 1 Eq, 581 pmol), sodium bicarbonate (60.0 mg, 1.23 Eq, 714 pmol), hydroxylamine hydrochloride (50.0 mg, 1.24 Eq, 720 pmol). (Z)-5-fluoro-N'-hydroxyquinoline-8-carboximidamide (42 mg, 32% yield, 91% purity), m / z 206.2 [M+H]+.3953-337

[0590] Starting reagent(s): benzo[b]thiophene-6-carbonitrile (100 mg, 1 Eq, 628 pmol), hydroxylamine, HC1 (70.0 mg, 1.60 Eq, 1.01 mmol), sodium hydrogencarbonate (85.0 mg, 1.61 Eq, 1.01 mmol). (Z)-N'-hydroxybenzo[b]thiophene-6-carboximidamide (80 mg, 66% yield, 99% purity), m / z 193.2 [M+H]+.

[0591] Starting reagent(s): 2-oxoindoline-6-carbonitrile (100 mg, 1 Eq, 632 pmol), hydroxylamine, HC1 (70.0 mg, 1.59 Eq, 1.01 mmol), sodium hydrogencarbonate (85.0 mg, 1.60 Eq, 1.01 mmol). (Z)-N'-hydroxy-2-oxoindoline-6-carboximidamide (107 mg, 84% yield, 95% purity). 'H NMR (500 MHz, DMSO) 5 10.42 (s, 1H), 9.56 (s, 1H), 7.23 (dd, J = 1.6, 7.7 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.12 (d, J = 1.5 Hz, 1H), 5.74 (s, 2H), 3.47 (s, 2H). m / z 192.2 [M+H]+.3953-343

[0592] Starting reagent(s): 1 -methyl- lH-indole-6-carbonitrile (100 mg, 1 Eq, 640 pmol), hydroxylamine, HC1 (70.0 mg, 1.57 Eq, 1.01 mmol), sodium hydrogencarbonate (85.0 mg, 1.58 Eq, 1.01 mmol). (Z)-N'-hydroxy-l-methyl-lH-indole-6-carboximidamide (73 mg, 25% yield, 41% purity), m / z 190.2 [M+H]+.3953-351

[0593] Starting reagent(s): l-oxoisoindoline-5-carbonitrile (100 mg, 1 Eq, 632 pmol), hydroxylamine, HC1 (61.0 mg, 1.39 Eq, 878 pmol), sodium hydrogencarbonate (74.0 mg, 1.39 Eq, 881 pmol). (Z)-N'-hydroxy-l-oxoisoindoline-5-carboximidamide (97 mg, 76% yield, 95% purity). 'H NMR (500 MHz, DMSO) 5 9.81 (s, 1H), 8.58 (s, 1H), 7.87 - 7.83 (m, 1H), 7.78 (dd, J = 7.9, 1.5 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 5.91 (s, 2H), 4.38 (s, 2H). m / z 192.2 [M+H]+.3901-193-1

[0594] Starting reagent(s): hydroxylamine hydrochloride (100 mg, 2.06 Eq, 1.44 mmol), triethylamine (145 mg, 200 pL, 2.05 Eq, 1.43 mmol). (Z)-N'-hydroxy-lH-benzo[d]imidazole-4- carboximidamide (106 mg, 76% yield, 88% purity), m / z 177.2 [M+H]+.3901-193-2

[0595] Starting reagent(s): hydroxylamine hydrochloride (100 mg, 2.06 Eq, 1.44 mmol), triethylamine (145 mg, 200 pL, 2.05 Eq, 1.43 mmol). (Z)-4-fluoro-N'-hydroxy-lH-indazole-7- carboximidamide (106 mg, 86% yield, 98% purity), m / z 195.2 [M+H]+.3901-193-3

[0596] Starting reagent(s): hydroxylamine hydrochloride (100 mg, 2.06 Eq, 1.44 mmol), triethylamine (145 mg, 200 pL, 2.05 Eq, 1.43 mmol). (Z)-N'-hydroxy-2-oxoindoline-4-carboxim- idamide (103 mg, 85% yield, 99% purity), m / z 192.2 [M+H]+.3956-376

[0597] Starting reagent(s): 2,5-dimethylthiophene-3-carbonitrile (152 mg, 95% Wt, 1 Eq, 1.05 mmol), hydroxylamine hydrochloride (146 mg, 2.0 Eq, 2.10 mmol) and triethylamine (213 mg, 293 pL, 2.0 Eq, 2.10 mmol). (Z)-N' -hydroxy-2, 5-dimethylthiophene-3-carboximidamide (111 mg, 55% yield, 88% purity). 'H NMR (500 MHz, DMSO) 5 9.39 (s, 1H), 6.78 (d, J = 1.4 Hz, 1H), 5.61 (s, 2H), 2.43 (s, 3H), 2.34 (s, 3H). m / z 171.2 [M+H]+.3956-378

[0598] Starting reagent(s): 3-ethyl-l-methyl-lH-pyrazole-5-carbonitrile (156 mg, 80% Wt, 1 Eq, 923 pmol), hydroxylamine hydrochloride (128 mg, 2.0 Eq, 1.85 mmol) and triethylamine (187 mg, 257 pL, 2.0 Eq, 1.85 mmol). (Z)-3-ethyl-N'-hydroxy-l -methyl- lH-pyrazole-5-car- boximidamide (175 mg, 85% yield, 75% purity). 'H NMR (500 MHz, DMSO) 5 9.76 (s, 1H), 6.37 (s, 1H), 5.79 (s, 2H), 3.85 (s, 3H), 2.48 (m, 2H), 1.15 (t, J = 7.5 Hz, 3H). m / z 169.2 [M+H]+.3901-181

[0599] Starting reagent(s): Triethylamine (109 mg, 150 pL, 2.07 Eq, 1.08 mmol), hydroxylamine hydrochloride (75.0 mg, 2.07 Eq, 1.08 mmol) and l-(difluoromethyl)-lH-indole-4-car- bonitrile (100 mg, 1 Eq, 520 pmol). (Z)-l-(difluoromethyl)-N' -hydroxy- lH-indole-4-car- boximidamide (102 mg, 78% yield, 90% purity), m / z 226.2 [M+H]+.3912-376

[0600] Starting reagent(s): l-methyl-lH-l,2,3-triazole-5-carbonitrile (554 mg, 30% Wt, 1 Eq, 1.54 mmol), hydroxylamine, HC1 (160 mg, 1.5 Eq, 2.31 mmol) and sodium hydrogencarbonate. (220 mg, 1.7 Eq, 2.61 mmol). (Z)-N'-hydroxy-l-methyl-lH-l,2,3-triazole-5-carboximidamide (120 mg, 54% yield, 98% purity). 'H NMR (500 MHz, DMSO) 5 10.06 (d, J = 0.8 Hz, 1H), 8.00 (d, J = 0.8 Hz, 1H), 6.08 (s, 2H), 4.11 (d, J = 0.9 Hz, 3H). m / z 161.2 [M+NH4]+.3912-408

[0601] Starting reagent(s): 3,5-dimethylthiophene-2-carbonitrile (175 mg, 95% Wt, 1 Eq, 1.21 mmol), hydroxylamine HC1 (126 mg, 1.5 Eq, 1.82 mmol), sodium hydrogencarbonate (153 mg, 1.50 Eq, 1.82 mmol). (Z)-N'-hydroxy-3,5-dimethylthiophene-2-carboximidamide (98 mg, 43% yield, 90% purity). 'H NMR (500 MHz, DMSO) 5 9.54 (s, 1H), 6.58 (s, 1H), 5.59 (s, 2H), 2.35 (s, 3H), 2.24 (s, 3H). m / z 171.2 [M+H]+.3901-186-1

[0602] Starting reagent(s): hydroxylamine hydrochloride (100 mg, 2.22 Eq, 1.44 mmol), triethylamine (152 mg, 210 pL, 2.32 Eq, 1.51 mmol) and isoquinoline-5-carbonitrile (100 mg, 1 Eq, 0.65 mmol). (Z)-N'-hydroxyisoquinoline-5-carboximidamide (95 mg, 74% yield, 94% purity). m / z 188.2 [M+H]+.3953-357

[0603] Starting reagent(s): 1 -methyl- lH-indazole-5-carbonitrile (100 mg, 1 Eq, 636 pmol), hydroxylamine HC1 (61.9 mg, 1.4 Eq, 891 pmol), sodium hydrogencarbonate (74.8 mg, 1.4 Eq,891 pmol). (Z)-N'-hydroxy-l-methyl-lH-indazole-5-carboximidamide (80 mg, 63% yield, 95% purity). 'H NMR (500 MHz, DMSO) 5 9.55 (s, 1H), 8.07 (d, J = 1.0 Hz, 1H), 8.03 (d, J = 1.4 Hz, 1H), 7.76 (dd, J = 8.9, 1.6 Hz, 1H), 7.60 (d, J = 8.9 Hz, 1H), 5.82 (s, 2H), 4.04 (s, 3H). m / z 191.2 [M+H]+.

[0604] Starting reagent(s): lH-indole-4-carbonitrile (100 mg, 1 Eq, 703 pmol), Hydroxylamine hydrochloride (100 mg, 2.05 Eq, 1.44 mmol) and triethylamine (145 mg, 200.0 pL, 2.04 Eq, 1.43 mmol). (Z)-N'-hydroxy-lH-indole-4-carboximidamide (94 mg, 66% yield, 87% purity). m / z 176.2 [M+H]+.3901-186-2

[0605] Starting reagent(s): hydroxylamine hydrochloride (100 mg, 2.22 Eq, 1.44 mmol), triethylamine (152 mg, 210 pL, 2.32 Eq, 1.51 mmol) and lH-indole-7-carbonitril (100 mg, 1 Eq, 0.7 mmol). (Z)-N'-hydroxy-lH-indole-7-carboximidamide (135 mg, 100% yield, 95% purity), m / z 176.2 [M+H]+.3912-471

[0606] Starting reagent(s): 3-chloro-lH-pyrazole-5-carbonitrile (2.70 g, 98% Wt, 1 Eq, 20.7 mmol), hydroxylamine (50% in water) (4.31 g, 4.00 mL, 50% Wt, 3.15 Eq, 65.3 mmol). (Z)-3- chloro-N'-hydroxy-lH-pyrazole-5-carboximidamide (3.70 g, 100% yield, 90% purity). 'H NMR (500 MHz, DMSO) 5 9.74 (s, 1H), 6.59 (s, 1H), 5.87 (s, 2H). m / z 161.2 [M+H]+.4245-5-1

[0607] Starting reagent(s): lH-benzo[d][l,2,3]triazole-5-carbonitrile (100 mg, 1 Eq, 694 pmol), Hydroxylamine hydrochloride (96.4 mg, 2 Eq, 1.39 mmol), triethylamine (140 mg, 193 pL, 2 Eq, 1.39 mmol). (Z)-N'-hydroxy-lH-benzo[d][l,2,3]triazole-6-carboximidamide (78 mg, 62% yield, 98% purity). 'H NMR (500 MHz, DMSO) 5 9.79 (s, 1H), 8.18 (s, 1H), 7.83 (d, J = 9.5 Hz, 2H), 5.98 (s, 2H). m / z 178.2 [M+H]+.4245-2

[0608] Starting reagent(s): lH-indole-5-carbonitrile (100 mg, 1 Eq, 703 pmol) and hydroxylamine, HC1 (78.2 mg, 1.6 Eq, 1.13 mmol) in EtOH (4.00 mL) was added sodium hydrogencarbonate (94.6 mg, 1.6 Eq, 1.13 mmol). (Z)-N'-hydroxy-lH-indole-5-carboximidamide (102 mg, 66% yield, 80% purity).XH NMR (500 MHz, DMSO) 5 11.14 (s, 1H), 9.36 (s, 1H), 7.84 (d, J = 1.7 Hz, 1H), 7.45 (dd, J = 8.6, 1.7 Hz, 1H), 7.37 - 7.32 (m, 2H), 6.51 - 6.38 (m, 1H), 5.68 (d, J = 7.4 Hz, 2H). m / z 176.2 [M+H]+.3956-369

[0609] Starting reagent(s): l-methyl-3-(((triisopropylsilyl)oxy)methyl)-lH-pyrazole-5-car- bonitrile (0.69 g, 89% Wt, 1 Eq, 2.1 mmol), hydroxylamine hydrochloride (0.29 g, 2.0 Eq, 4.2 mmol) and triethylamine (0.42 g, 0.58 mL, 2.0 Eq, 4.2 mmol). (Z)-N'-hydroxy-l-methyl-3- (((triisopropylsilyl)oxy)methyl)-lH-pyrazole-5-carboximidamide (678 mg, 89% yield, 90% purity). 'H NMR (500 MHz, DMSO) 5 9.83 (s, 1H), 6.55 (s, 1H), 5.91 (s, 2H), 4.64 (s, 2H), 3.88 (s, 3H), 1.14 - 1.09 (m, 3H), 1.04 (d, J = 6.8 Hz, 18H). m / z 327.2 [M+H]+.4246-9-1

[0610] Starting reagent(s): 4-methyl-lH-indole-7-carbonitrile (100 mg, 1 Eq, 640 pmol), Hydroxylamine hydrochloride (100 mg, 2.25 Eq, 1.44 mmol) and triethylamine (145 mg, 200.0 pL, 2.24 Eq, 1.43 mmol). (Z)-N' -hydroxy -4-methyl-lH-indole-7-carboximidamide (0.13 g, 640 pmol, 100 %, 93% Purity), m / z 190.2 [M+H]+.4246-9-2

[0611] Starting reagent(s): 4-fluoro-lH-indole-7-carbonitrile (100 mg, 0.975 Eq, 624 pmol), Hydroxylamine hydrochloride (100 mg, 2.25 Eq, 1.44 mmol) and triethylamine (145 mg, 200.0 pL, 2.24 Eq, 1.43 mmol). (Z)-4-fluoro-N'-hydroxy-lH-indole-7-carboximidamide (0.14 g, 640 pmol, 100 %, 91% Purity), m / z 194.2 [M+H]+.4246-3-2

[0612] Starting reagent(s): 2,3-dihydrobenzo[b][l,4]dioxine-5-carbonitrile (100 mg, 1.38 Eq, 621 pmol), Hydroxylamine hydrochloride (100 mg, 3.20 Eq, 1.44 mmol), triethylamine (145 mg, 200.0 pL, 3.19 Eq, 1.43 mmol). (Z)-N'-hydroxy-2,3-dihydrobenzo[b][l,4]dioxine-5-car- boximidamide (119 mg, 93% yield, 95% purity), m / z 195.2 [M+H]+.4246-3-3

[0613] Starting reagent(s): 8-(trifluoromethyl)quinoline-4-carbonitrile (100 mg, 1 Eq, 450 pmol), Hydroxylamine hydrochloride (100 mg, 3.20 Eq, 1.44 mmol) and triethylamine (145mg, 200.0 pL, 3.19 Eq, 1.43 mmol). (Z)-N'-hydroxy-8-(trifluoromethyl)quinoline-4-carboxim- idamide (78 mg, 60% yield, 89% purity), m / z 256.2 [M+H]+.3901-214-1

[0614] Starting reagent(s): 50% hydroxylamine in water (2.70 g, 2.50 mL, 50% Wt, 1.33 Eq, 19.4 mmol) and 4-bromo-lH-pyrazole-5-carbonitrile (2.50 g, 1 Eq, 14.5 mmol. (Z)-4-bromo- N'-hydroxy-lH-pyrazole-5-carboximidamide (2.51 g, 12 mmol, 80 %, 95% Purity) as a white solid.1HNMR (500 MHz, DMSO) 5 13.35 (s, 1H), 9.76 (s, 1H), 7.98 (s, 1H), 5.51 (s, 2H). m / z 205.2 [M+H]+3912-429-1

[0615] Starting reagent(s): 2,5-dimethylfuran-3-carbonitrile (119 mg, 84% Wt, 1 Eq, 825 pmol), sodium hydrogencarbonate (104 mg, 1.5 Eq, 1.24 mmol), hydroxylamine, HC1 (86.0 mg, 1.5 Eq, 1.24 mmol). (Z)-N' -hydroxy-2, 5-dimethylfuran-3-carboximidamide (108 mg, 0.50 mmol, 61 %, 72% Purity). 'H NMR (500 MHz, DMSO) 5 9.26 (s, 1H), 6.19 (s, 1H), 5.48 (s,2H), 2.34 (s, 3H), 2.19 (s, 3H). m / z 155.2 [M+H]+3912-440-1

[0616] Starting reagent(s): l-ethyl-3-methyl-lH-pyrazole-4-carbonitrile (176 mg, 73% Wt, 1 Eq, 951 pmol), sodium hydrogencarbonate (120 mg, 1.5 Eq, 1.43 mmol), hydroxylamine, HC1 (99.0 mg, 1.50 Eq, 1.42 mmol). (Z)-l-ethyl-N'-hydroxy-3-methyl-lH-pyrazole-4-carboximid- amide (0.24 g, 100 % yield, 66% Purity), m / z 169.2 [M+H]+.3901-221-1

[0617] Starting reagent(s): 50% hydroxylamine in water (107.8 mg, 100.0 pL, 50% Wt, 2.93Eq, 775.7 pmol), l-ethyl-4-(trifluoromethyl)-lH-pyrazole-5-carbonitrile (50.0 mg, 1 Eq, 264pmol). (Z)-l-ethyl-N'-hydroxy-4-(trifluoromethyl)-lH-pyrazole-5-carboximidamide (55.0 mg, 84 %, 90% Purity).XH NMR (500 MHz, DMSO) 5 10.00 (s, 1H), 7.89 (d, J = 0.8 Hz, 1H), 6.13 (s, 2H), 4.15 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H). m / z 223.2 [M+H]+.4245-52-1

[0618] Starting reagent(s): tert-butyl (5-cyano-l-methyl-lH-pyrazol-3-yl)carbamate (213,959 umol), triethylamine (175 mg, 241 pL, 1.8 Eq, 1.73 mmol) was added, followed by hydroxylamine, HC1 (133 mg, 2 Eq, 1.92 mmol), tert-butyl (E)-(5-(N'-hydroxycarbamimidoyl)- l-methyl-lH-pyrazol-3-yl)carbamate (101 mg, 40 %, 97% Purity). 'H NMR (500 MHz, DMSO) 5 9.80 (s, 1H), 9.53 (s, 1H), 6.59 (s, 1H), 5.82 (s, 2H), 3.80 (s, 3H), 1.44 (s,...

Claims

CLAIMS1. A compound of Formula I:whereinY1is CH or N;Y2is C(O) or C(OH);R1is -H or -Ci-6-alkyl;Ring X is a 5-membered carbocycle or 5-membered heterocycle; wherein Ring X is optionally substituted with one or more R2; if present, each R2is independently selected from the group consisting of -halogen, -Ci- salkyl, -OH, -O(Ci-3alkyl), -NH2, -N(H)(-Ci-3alkyl), -N(Ci-3alkyl)(Ci-3alkyl), and -CF3;L is a bond or -Ci-8alkylene-;Ring Z is a 5-10-membered carbocyclyl or 5-10-membered heterocyclyl; wherein Ring Z is optionally substituted with one or more R3if present, each R3is independently selected from the group consisting of -halogen, -Ci- salkyl optionally substituted with one or more R5, -Ci-salkenyl optionally substituted with one or more R5, -Ci-salkynyl optionally substituted with one or more R5, -C(R4)3, -O(R4), -N(R4)2, -OC(R4)3, -Ci-salkyl-O(R4), -O-Ci-salkyl-O(R4), -3-7-membered carbocyclyl optionally substituted with one or more R5, -3-7-membered heterocyclyl optionally substituted with one or more R5, -Ci.8alkyl-N(R4)2, -O-Ci.8alkyl-N(R4)2, -C(O)O(R4), -OC(O)(R4), -CN, -NO2, -S(O)2R4, - S(O)2N(R4)2, -N(H)SO2(R4), -(O), -N(R4)-Ci-8alkyl-N(R4)2, -N(R4)-Ci-8alkyl-O(R4), -N(R4)CI- 4alkyl optionally substituted with one or more R5, -O-Ci-8alkyl-(R4)3, -O-Ci-8alkyl optionally substituted with one or more R5, -O-Ci-8alkenyl-(R4)3, -O-Ci-8alkenyl optionally substituted with one or more R5, O-Ci-8alkynyl-(R4)3, -O-Ci-8alkynyl optionally substituted with one or more R5, and -O-cyclicCi-8alkyl-(R4)3; if present, each R4is independently selected from the group consisting of -H, -halogen, and -Ci-ealkyl;if present, each R5is independently selected from the group consisting of -halogen, - OH, -N(R4)2, -OCi-4alkyl, -C(O)N(R4)2, -Cs-ecycloalkyl optionally substituted with one or two R6, 4-6-membered heterocyclyl comprising one or two heteroatoms independently selected from N, O or S and optionally substituted with one or two R6; and if present, each R6is independently selected from the group consisting of -halogen, - OH, -CF3, -halogen, -Ci-salkyl, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof, wherein the compound of Formula I is not a compound selected from the group consisting of 4-(5-(6-oxo-l,6-dihydropyridazin-3-yl)-l,3,4-oxadiazol-2-yl)benzoic acid, 3-(5-(6-oxo- 1 ,6-dihydropyridazin-3 -yl)- 1 ,3 ,4-oxadiazol-2-yl)benzoic acid, 5-(5-(pyri din-3 -yl)- 1 ,2,4-oxadi- azol-3-yl)pyridin-2(lH)-one, 5-(3-(4-(trifluoromethoxy)phenyl)-l,2,4-oxadiazol-5-yl)pyridin- 2(lH)-one, 6-(3-(4-(trifluoromethoxy)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, 6- (3-(4-(2,2,2-trifluoroethyl)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, 6-(3-(4-(trifluo- romethoxy)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, 6-(3-(4-fluorophenyl)- 1,2,4- oxadiazol-5-yl)pyridazin-3(2H)-one, 6-(3-(o-tolyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, 6-(3-(m-tolyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, 6-(3 -(3 -(triflu oromethyl)phenyl)- l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, 6-(3-(2-methoxyphenyl)-l,2,4-oxadiazol-5-yl)pyri- dazin-3(2H)-one, 6-(3-(3-methoxyphenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, 6-(3-(3- Chlorophenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, 6-(3-(4-Chlorophenyl)-l,2,4-oxadi- azol-5-yl)pyridazin-3(2H)-one, 3-(5-(6-oxo-l,6-dihydropyridazin-3-yl)-l,2,4-oxadiazol-3- yl)benzoic acid, 6-(3-(2-(trifluoromethyl)pyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)- one, 6-(3 -(3 -fluorophenyl)- 1 ,2,4-oxadiazol-5-yl)pyridazin-3 (2H)-one, 6-(3 -(2-fluorophenyl)- l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, 6-(3-(2-chlorophenyl)-l,2,4-oxadiazol-5-yl)pyri- dazin-3(2H)-one, 6-(3 -Phenyl- 1, 2, 4-oxadiazol-5-yl)pyridazin-3(2H)-one, 6-(l-Phenyl-lH-py- razol-4-yl)pyridazin-3(2H)-one, 6-(3-(Pyri din-3 -yl)- 1,2, 4-oxadiazol-5-yl)pyridazin-3(2H)- one, 6-(3-(pyridin-2-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, 6-(3-(4-(trifluorome- thyl)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, 6-(3-(4-m ethoxyphenyl)- 1,2, 4-oxadi- azol-5-yl)pyridazin-3(2H)-one, 6-(3-(pyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, 6-(3-(p-tolyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one. 2,2-diethyl-6-[3-(6-hydroxy-3- pyridyl)-l,2,4-oxadiazol-5-yl]chroman-4-one, 6-(3-(5-chl oropyri din-3 -yl)- 1,2, 4-oxadiazol-5- yl)pyridazin-3(2H)-one, 5-{3-[4-(l,l,l-trifhroro-2-methylpropan-2-yl)phenyl]-l,2,4-oxadia- zol-5-yl }pyridin-2(lH)-one, 6-{3-[4-(l,l,l-Trifhroro-2-methylpropan-2-yl)phenyl]-l,2,4- oxadiazol-5-yl}pyridazin-3(2H)-one, 6-(3-(4-(difluoromethoxy)phenyl)-l,2,4-oxadiazol-5- yl)pyridazine-3(2H)-one, 4-(6-hydroxypyri din-3 -yl)-2-pyridin-2-yl-l,2-dihydro-3H-pyrazol-3-one, 6-[3-(l,3-benzodioxol-5-yl)-l,2,4-oxadiazol-5-yl]pyridazine-3(2H)-one; and 2-ethyl-6- [3-(l-methyl-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]pyridazine-3(2H)-one.

2. The compound of claim 1, wherein the compound of Formula I is a compound of Formula I A:Formula I A; wherein— is a single or double bond;Y1is CH or N;Y2is C(O) or C(OH);R1is -H or -Ci-6-alkyl;Ring X is a 5-membered carbocycle or 5-membered heterocycle; wherein X1and X4are each independently C or N;X2and X3are each independently CH, CH2, O, S, or N; andX5is N, O, CH, CH2, C(O), or S; wherein Ring X is optionally substituted with one or more R2; if present, each R2is independently selected from the group consisting of -halogen, -Ci- salkyl, -OH, -O(Ci-3alkyl), -NH2, -N(H)(-Ci-3alkyl), -N(Ci-3alkyl)(Ci-3alkyl), and -CF3;L is a bond or -Ci-8alkylene-;Ring Z is a 5-10-membered carbocyclyl or 5-10-membered heterocyclyl; wherein Ring Z is optionally substituted with one or more R3; if present, each R3is independently selected from the group consisting of -halogen, -Ci- salkyl, -Ci-salkenyl, -C(R4)3, -O(R4), -N(R4)2, -OC(R4)3, -Ci-8alkyl-O(R4), -O-Ci-8alkyl-O(R4), -3-7-membered carbocyclyl, -3-7-membered heterocyclyl, -Ci-8alkyl-N(R4)2, -O-Ci-8alkyl- N(R4)2, -C(O)O(R4), -OC(O)(R4), -CN, -NO2, -S(O)2R4, -S(O)2N(R4)2, -N(H)SO2(R4), -(O), - N(R4)-Ci.8alkyl-N(R4)2, -N(R4)-Ci-8alkyl-O(R4), -O-Ci-8alkyl-(R4)3, and -O-cyclicCi-8alkyl- (R4)3; wherein each -Ci-8alkyl, -Ci-salkenyl, -3-7-membered carbocyclyl, and -3-7- membered heterocyclyl is optionally substituted with one or more -halogen; andif present, each R4is independently selected from the group consisting of -H, - halogen, and -Ci-ealkyl; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

3. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of claim 1 or claim 2, wherein R1is H.

4. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of any one of claims 1 to 3, wherein R1is H and Y2is C(O).

5. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of any one of claims 1 to 4, wherein Y1is N.

6. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of any one of claims 1 to 5, wherein L is a bond.

7. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of any one of claims 1 to 6, wherein Ring X is selected from the group consisting of:wherein Ring X is optionally substituted with one or more R2.

8. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of any one of claims 1 to 7, wherein Ring X is Xa:Xa.

9. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of any one of claims 1 to 8, wherein the compound of Formula I is a compound of Formula Idi:whereinRing Z is a 5-10-membered carbocyclyl or 5-10-membered heterocyclyl; if present, each R3is defined as in claim 1 or claim 2; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

10. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of claim 1, wherein Ring Z is selected from the group consisting of:wherein Ring Z is optionally substituted with one or more R3.

11. The compound of any one of claims 1 to 10, wherein Ring Z is Zu:wherein Ring Z is optionally substituted with one or more R3.

12. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of any one of claims 1 to 10, wherein Ring Z is Zp:wherein Ring Z is substituted with one or more R3.

13. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of claim 1, wherein the compound of Formula I is a compound of Formula le:Formula le whereinY1is CH or N;R1is -H or -Ci-6-alkyl;Ring A is 5-membered heterocyclyl comprising from one to three heteroatoms independently selected from N, O or S and optionally substituted with one or two R2; if present, each R2is independently -Ci-salkyl;Ring B is -Ce-ioaryl, or 5-10-membered heterocyclyl comprising from one to four heteroatoms independently selected from N, O or S and optionally substituted with from one to three R3; if present, each R3is independently selected from the group consisting of -halogen, - OH, -N(R4)2, -NO2, -SO2-NH2, -SO2-CH3, -Ci-ealkyl optionally substituted with from one to three R5, -C2-ealkenyl optionally substituted with from one to three R5, -C2-ealkynyl optionallysubstituted with from one to three R5, -OCi-ealkyl optionally substituted with from one to three R5, -OC2-ealkenyl optionally substituted with from one to three R5, -OC2-6alkynyl optionally substituted with from one to three R5, -C(O)OH, -C(O)OCi-4alkyl, -N(R4)Ci-4alkyl optionally substituted with one R5, -Cs-ecycloalkyl optionally substituted with R7, -O-Cs-ecycloalkyl optionally substituted with R7, and 4-6-membered heterocyclyl comprising one or two heteroatoms independently selected from N, O or S and optionally substituted with one R7; if present, each R4is independently selected from the group consisting of H and -Cisalkyl; if present, each R5is independently selected from the group consisting of -halogen, - OH, -N(R4)2, -OCi-4alkyl, -C(O)N(R4)2, -Cs-ecycloalkyl optionally substituted with one or two R6, 4-6-membered heterocyclyl comprising one or two heteroatoms independently selected from N, O or S and optionally substituted with one or two R6; if present, each R6is independently selected from the group consisting of -halogen, - OH, -CF3, and -Ci-salkyl; and if present, each R7is selected from the group consisting of -halogen, -OH, -CF3, -Ci- 3alkyl, and -OCi-salkyl; or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

14. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of claim 13, wherein Y1is N and R1is -H.

15. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of claim 14 or claim 15, wherein Ring X is selected from the group consisting of:Xa; Xc; and Xe; wherein Ring X is optionally substituted with one R2.

16. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of claim 15, wherein Ring X is Xa:

17. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of any one of claims 13 to 16, wherein Ring Z is Zu:Zu, wherein Ring Z is optionally substituted with from one to three R3.

18. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of any one of claims 13 to 17, wherein Ring Z is substituted with three R3.

19. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of any one of claims 13 to 18, wherein the compound of Formula I is a compound of Formula Igai, Formula Igbi, Formula Igci, and Formula Igd:Formula Igci; Formula Igdi, wherein R3a, R3band R3care independently R3as defined in claim 14.

20. The compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof, of any one of claims 13 to 19, wherein the compound of Formula I is a compound of Formula Igai:Formula Igai; wherein R3a, R3band R3care independently R3as defined in claim 13.

21. The compound of claim 1, wherein the compound is selected from the group consisting of6-(3-(2-fluoro-4-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-Isopropyl-l-methyl-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(4-Bromo-l-methyl-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3,5-dimethylisoxazol-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(lH-Pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(Isothiazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(4-Methylthiazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-Methoxy-l-methyl-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(4-Methyloxazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(7-Fluoro-2H-indazol-3-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(l-Methyl-4-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)- one;6-(3-(2,3-dihydrobenzofuran-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(l-Methyl-lH-benzo[d]imidazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(Benzo[c][l,2,5]oxadiazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(6-(Trifluoromethyl)pyridin-3-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one; tert-Butyl-3-(5-(6-oxo-l,6-dihydropyridazin-3-yl)-l,2,4-oxadiazol-3-yl)pyrrolidine-l-carbox- ylate;6-(3-(l-Methyl-lH-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(lH-Indazol-6-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(5-Chloropyridin-2-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(6-Chloropyridin-3-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Chloro-4-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(5-Methylpyridin-2-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(6-Methylpyridin-3-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Methylpyrimidin-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Methylpyrimidin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-(Difluoromethyl)pyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(5-(Trifluoromethyl)pyridin-2-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(4-(Trifluoromethyl)piperidin-l-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(l-Methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)- one;6-(3-(l-Methyl-5-(trifluoromethyl)-lH-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)- one;6-(3-(l-Methyl-lH-indazol-6-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Methyl-2H-indazol-6-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Chloro-5-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Chloro-3-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(4-(Methylsulfonyl)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;4-(5-(6-Oxo-l,6-dihydropyridazin-3-yl)-l,2,4-oxadiazol-3-yl)benzenesulfonamide;6-(3-(4-(tert-Butyl)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(4-Nitrophenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3,5-bis(Trifluoromethyl)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3,5-Dichlorophenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(6-Chloro-2,2-difluorobenzo[d][l,3]dioxol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)- one;6-(3-(3-Bromophenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3,4-Dimethylphenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(4-Chloro-3-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-(Trifluorom ethoxy )phenyl)-l, 2, 4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(5-Methoxy-2-methylphenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Methyl-2H-indazol-3-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-Methoxy-2-methylphenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2,5-Difluorophenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Methyl-3-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Methyl-5-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Chloro-5-methoxyphenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Chloro-3-methoxyphenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2,3-Dichlorophenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(5-Chloro-2-fluorophenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3 -(2,3 -Dihydro-[ 1 ,4]dioxino[2,3 -b]pyridin-8-yl)- 1 ,2,4-oxadiazol-5-yl)pyridazin-3 (2H)- one;6-(3-(2,2-Difluorobenzo[d][l,3]dioxol-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(4-Chloro-3-fluorophenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Methylpyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(4-Isopropoxyphenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-Methylpyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2,4-Dichlorophenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3,4-Dichlorophenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-Isopropoxyphenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-Chloropyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(4-(2-(Dimethylamino)ethoxy)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3-ol;6-(3-(2, 3 -Difluorophenyl)- 1, 2, 4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-Chloro-2-fluorophenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;Methyl 4-fluoro-3-(5-(6-oxo-l,6-dihydropyridazin-3-yl)-l,2,4-oxadiazol-3-yl)benzoate;6-(3-(2-Morpholinopyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, HC1;6-(3-((Tetrahydro-2H-pyran-3-yl)methyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(6-Chloro-2-methylpyridin-3-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(l-Methyl-lH-pyrazol-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2,2-Difluorobenzo[d][l,3]dioxol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-Chloro-2-(trifluoromethyl)pyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(5-Chloro-2-methylpyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-Chloro-2-methoxypyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Nitrophenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2,6-Dimethylpyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Chloropyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(Quinolin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Fluoropyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(4-(Dimethylamino)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Chloro-4-methylphenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-Chloro-4-methylphenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-(2 -Hydroxy ethoxy)phenyl)-l, 2, 4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-Morpholinophenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(4-Morpholinophenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(Tetrahydro-2H-pyran-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(lH-Benzo[d]imidazol-6-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;Methyl 3-(5-(6-oxo-l,6-dihydropyridazin-3-yl)-l,2,4-oxadiazol-3-yl)benzoate;6-(3-(2-(Trifluoromethyl)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(5-Chloro-2-methoxypyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-Fluoro-2-(trifluoromethyl)pyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-(Hydroxymethyl)pyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(5-(Trifluoromethyl)pyridin-3-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Oxo-l,2-dihydropyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(l-Methyl-2-oxo-l,2-dihydropyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Methoxypyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Cyclopropylpyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, HC1;6-(3-(lH-Indol-3-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(lH-Indazol-3-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(Benzo[b]thiophen-3-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-(Trifluoromethoxy)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-(2-(Dimethylamino)ethoxy)pyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-(2 -Methoxy ethoxy )pyridin-4-yl)-l, 2, 4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-((2 -Hydroxy ethyl)amino)pyridin-4-yl)-l, 2, 4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-(2 -Hydroxy ethoxy)pyridin-4-yl)-l, 2, 4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-(2,2,2-Trifluoroethoxy)pyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-(2 -Hydroxy ethoxy)-4-(trifluoromethyl)phenyl)-l, 2, 4-oxadiazol-5-yl)pyridazin-3(2H)- one;6-(3-(2-(2 -Methoxy ethoxy)-4-(trifluoromethyl)phenyl)-l, 2, 4-oxadiazol-5-yl)pyridazin-3(2H)- one;6-(3-(4-(2 -Hydroxy ethoxy)phenyl)-l, 2, 4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(2-(2,2-Difluorobenzo[d][l,3]dioxol-5-yl)-4-methylthiazol-5-yl)pyridazin-3(2H)-one;6-(2-Phenylthiazol-5-yl)pyridazin-3(2H)-one;6-(3 -(1,3 -Dimethyl- lH-pyrazol-5-yl)- 1 ,2,4-oxadiazol-5-yl)pyridazin-3 (2H)-one hydrochloride;6-(3-(l-Methyl-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one hydrochloride;6-(3-(lH-Indazol-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one hydrochloride;6-(3-(6-Fluoroquinolin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-Cyclopropoxy-l-methyl-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3 -(3 -(Difluoromethoxy)- 1 -methyl- lH-pyrazol-5-yl)-l, 2, 4-oxadiazol-5-yl)pyridazin-3(2H)- one;6-(3-(3-Bromo-l-methyl-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(8-Chloroisoquinolin-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one hydrochloride;4-(5-(6-Oxo-l,6-dihydropyridazin-3-yl)-l,2,4-oxadiazol-3-yl)-l,3-dihydro-2H-pyrrolo[2,3- b]pyridin-2-one hydrochloride;6-(3 -(3 -(Difluoromethyl)- 1 -methyl- lH-pyrazol-5-yl)-l, 2, 4-oxadiazol-5-yl)pyridazin-3(2H)- one;6-(l-(3,4-Dihydro-2H-pyrido[3,2-b][l,4]oxazin-7-yl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one hydrochloride;6-(l-(2,2-Difluorobenzo[d][l,3]dioxol-5-yl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one;6-(l-(Quinolin-4-yl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one hydrochloride;6-(2'-Methyl-5'-(trifluoromethyl)-2'H-[l,3'-bipyrazol]-4-yl)pyridazin-3(2H)-one;6-(2-(4-(Trifluoromethyl)phenyl)thiazol-5-yl)pyridazin-3(2H)-one;6-(2-(3 -(Trifluoromethyl)phenyl)thiazol -5 -yl)pyri dazin-3 (2H)-one;6-(2-(2,2-Difluorobenzo[d][l,3]dioxol-5-yl)thiazol-5-yl)pyridazin-3(2H)-one;6-(l-(4-(Trifluoromethyl)phenyl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one;6-(l-(2-Methylpyrimidin-5-yl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one;6-(l-(5-(Trifluoromethyl)pyridin-2-yl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one;6-(l-(2-Chloro-4-(trifluoromethyl)phenyl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one;6-( 1 -(2-Methylpyridin-4-yl)- 1 H-pyrazol-4-yl)pyri dazin-3 (2H)-one, HC1 ;6-(l-(2-(Difluoromethyl)pyridin-4-yl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one;6-(l-(2-(Trifluoromethyl)pyridin-4-yl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one;6-( 1 -(2-Cy clopropylpyri din-4-yl)- 1 H-py razol -4-yl)pyridazin-3 (2H)-one, HC1 ;6-( 1 -(5 ,6, 7, 8 -T etrahy droquinolin-8-yl)- 1 H-pyrazol-4-yl)pyridazin-3 (2H)-one, HC1 ;6-(l-(6,7-Dihydro-5H-cyclopenta[b]pyridin-7-yl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one, HC1;6-( 1 -(5 ,6, 7, 8 -T etrahy droi soquinolin-5 -yl)- 1 H-pyrazol-4-yl)pyridazin-3 (2H)-one, HC1 ;6-(l-(l-(Pyridin-4-yl)ethyl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one, HC1;6-(l-(2,3-Dihydro-lH-pyrido[2,3-b][l,4]oxazin-7-yl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one, HC1;6-(l-(2-(2-Hydroxyethoxy)pyridin-4-yl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one;6-(l-(5,6,7,8-Tetrahydroquinolin-5-yl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one;6-( 1 -(2,3 -Dihydrofuro[2,3 -b]pyridin-4-yl)- lH-pyrazol-4-yl)pyridazin-3 (2H)-one;6-(l-(Pyridin-4-yl)-lH-pyrazol-4-yl)pyridazin-3(2H)-one hydrochloride;6-(l-(4-(Trifluoromethyl)phenyl)-lH-l,2,3-triazol-4-yl)pyridazin-3(2H)-one;6-(l-(4-(Trifluoromethyl)phenyl)-lH-imidazol-4-yl)pyridazin-3(2H)-one;6-(l -Phenyl- lH-imidazol-4-yl)pyridazin-3(2H)-one;6-(2-Oxo-3-(4-(trifluoromethyl)phenyl)imidazolidin-l-yl)pyridazin-3(2H)-one;6-(5-Phenyloxazol-2-yl)pyridazin-3(2H)-one;6-(3-(4-Chloro-2,2-difluorobenzo[d][l,3]dioxol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)- one;2-Methyl-6-(3-(p-tolyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(2-Aminopyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, HC1;6-(3-(2-(3-Methoxypyrrolidin-l-yl)pyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, HC1;6-(3-(2-Amino-4-(trifluoromethyl)phenyl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-(3-(3-Aminopyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, HC1;6-(3-(lH-Pyrrolo[2,3-b]pyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one, HC1;6-(3-(2-((2-(Dimethylamino)ethyl)(methyl)amino)pyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyri- dazin-3(2H)-one;6-(3-(2-((2-(Dimethylamino)ethyl)amino)pyridin-4-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)- one;6-( 1 -(4-Chlorophenyl)- lH-pyrazol-4-yl)pyridazin-3 (2H)-one;6-( 1 -Phenyl- 1H- 1 ,2,3 -triazol-4-yl)pyridazin-3 (2H)-one;6-(5-(4-(trifluoromethyl)phenyl)-l,3,4-oxadiazol-2-yl)pyridazin-3(2H)-one;6-(5-(p-Tolyl)-l,3,4-oxadiazol-2-yl)pyridazin-3(2H)-one;6-(5-(4-(Trifluoromethyl)phenyl)isoxazol-3-yl)pyridazin-3(2H)-one;3-[3-(2,l,3-benzothiadiazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-(difluoromethyl)indol-4-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(3-methyltriazol-4-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(5-isoquinolyl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(lH-indol-7-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(benzothiophen-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(benzofuran-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(2,4-dimethylthiazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(5-fluoro-8-quinolyl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(benzothiophen-6-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;6-(3-(lH-indazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;6-[5-(6-oxo-lH-pyridazin-3-yl)-l,2,4-oxadiazol-3-yl]indolin-2-one;3-[3-(l-methylindol-6-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;5-[5-(6-oxo-lH-pyridazin-3-yl)-l,2,4-oxadiazol-3-yl]isoindolin-l-one;3-[3-(lH-benzimidazol-4-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(4-fluoro-lH-indazol-7-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;4-[5-(6-oxo-lH-pyridazin-3-yl)-l,2,4-oxadiazol-3-yl]indolin-2-one;3-[3-(2,5-dimethyl-3-thienyl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(5-ethyl-2-methyl-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(3,5-dimethyl-2-thienyl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(l-methylindazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(lH-indol-4-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(3-chloro-l-methyl-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(lH-benzotriazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(lH-indol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(2,3-dihydro-l,4-benzodioxin-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[8-(trifluoromethyl)-4-quinolyl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[5-(hydroxymethyl)-2-methyl-pyrazol-3-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(4-methyl-lH-indol-7-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;6-(3-(4-fluoro-lH-indol-7-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;3-[3-(2,5-dimethyl-3-furyl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(4-bromo-l-methyl-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(4-bromo-l-ethyl-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(4-bromo-l-ethyl-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-bromo-l-(2,2-difluoroethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-bromo-l-(2,2-difluoroethyl)pyrazol-3-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(4-bromo-l-isopropyl-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(4-bromo-l-isopropyl-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[5-(fluoromethyl)-2-methyl-pyrazol-3-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[5-(methoxymethyl)-2-methyl-pyrazol-3-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(l-ethyl-3-methyl-pyrazol-4-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[l-[2,4-dimethyl-5-(trifluoromethyl)pyrazol-3-yl]pyrazol-4-yl]-lH-pyridazin-6-one;3-[3-[l-methyl-3-(2,2,2-trifluoro-l-hydroxy-ethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH- pyridazin-6-one;3-[3-[l-ethyl-4-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(3-amino-l-methyl-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-methyl-3-(methylamino)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-bromo-l-(2-methoxyethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-bromo-l-(2-methoxyethyl)pyrazol-3-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(3-bromo-l,4-dimethyl-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(l-methyl-5,6-dihydro-4H-cyclopenta[d]pyrazol-3-yl)-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-(4-chloro-l-methyl-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[5-[(dimethylamino)methyl]-2-methyl-pyrazol-3-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[2-[l-methyl-3-(trifluoromethyl)pyrazol-5-yl]thiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-ethyl-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-(2,2-difluoroethyl)-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-[l-(2-methoxyethyl)-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-[l-isopropyl-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-bromo-l-methyl-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[5-[l-methyl-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-3-yl]-lH-pyridazin-6-one;3-[3-(2-methyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-3-yl)-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;6-(3-(l-methyl-3-((methylamino)methyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)-one;3-[3-[l-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-[4-(hydroxymethyl)-l-methyl-pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-isobutyl-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-chloro-3-(trifluoromethyl)-lH-pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6- one;3-[3-[4-chloro-l-methyl-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(l-methyl-4-nitro-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[4-methyl-2-[l-methyl-3-(trifluoromethyl)pyrazol-5-yl]thiazol-5-yl]-lH-pyridazin-6-one;3-[3-(5-chloro-l-methyl-pyrazol-3-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-[2-(2 -methoxy ethoxy )ethyl]-3-(trifluoromethyl)pyrazol-5-yl]-l, 2, 4-oxadiazol-5-yl]- lH-pyridazin-6-one;3-[3-[l-(2-hydroxyethyl)-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;N,N-dimethyl-2-[5-[5-(6-oxo-lH-pyridazin-3-yl)-l,2,4-oxadiazol-3-yl]-3-(trifluorome- thyl)pyrazol-l-yl]acetamide;3-[3-[4-(methoxymethyl)-l-methyl-pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;N,N-dimethyl-2-[3-[5-(6-oxo-lH-pyridazin-3-yl)-l,2,4-oxadiazol-3-yl]-5-(trifluorome- thyl)pyrazol-l-yl]acetamide;3-[3-(3,4-dimethyl-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(2,4,5-trimethylpyrazol-3-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-(3-hydroxypropyl)-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-[l-(3-methoxypropyl)-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-[l-(3,3,3-trifluoro-2-hydroxy-propyl)-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5 -y 1 ] - 1 H-py ri dazin-6 -one ;3-[3-(4-amino-l-methyl-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[5-(2,2-difluoro-l,3-benzodioxol-5-yl)-l,2,4-oxadiazol-3-yl]-lH-pyridazin-6-one;3-[3-[l-(2-morpholinoethyl)-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-[l-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4- oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(3-fluoro-l-methyl-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-bromo-l-(2-hydroxyethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-bromo-l-(3-hydroxypropyl)pyrazol-3-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-(fluoromethyl)-l-methyl-pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-bromo-l-(2-hydroxyethyl)pyrazol-3-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[3-chloro-l-(3-hydroxypropyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[5-chloro-l-(3-hydroxypropyl)pyrazol-3-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[5-chloro-l-(3-methoxypropyl)pyrazol-3-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[3-chloro-l-(3-methoxypropyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[3-chloro-l-(2-hydroxyethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[5-chloro-l-(2-hydroxyethyl)pyrazol-3-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[3-chloro-l-(2-methoxyethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[5-chloro-l-(2-methoxyethyl)pyrazol-3-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-bromo-l-(3-methoxypropyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-bromo-l-(3-methoxypropyl)pyrazol-3-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l,4-dimethyl-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6- one;3-[3-[3,4-dichloro-l-(3-hydroxypropyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6- one;3-[3-[4-chloro-3-(difluoromethoxy)-l-methyl-pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[5-(3-chloro-l-methyl-pyrazol-5-yl)-l,2,4-oxadiazol-3-yl]-lH-pyridazin-6-one;3-[3-(3,4-dichloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-(tetrahydrofuran-3-ylmethyl)-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]- lH-pyridazin-6-one;3-[3-[4-cyclopropyl-l-methyl-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[5-[l-methyl-4-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-3-yl]-lH-pyridazin-6-one;3-[5-[l-methyl-4-(trifluoromethyl)pyrazol-3-yl]-l,2,4-oxadiazol-3-yl]-lH-pyridazin-6-one;3-[3-[3, 4-di chi oro-1 -(2 -hydroxy ethyl)pyrazol-5-yl]-l, 2, 4-oxadiazol-5-yl]-lH-pyridazin-6- one;3-[3-[3, 4-di chi oro-1 -(2-methoxyethyl)pyrazol-5-yl]- 1,2, 4-oxadiazol-5-yl]-lH-pyridazin-6- one;3-[3-(3,4-dichloro-l-methyl-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(4-chloro-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-chloro-l-(2-hydroxyethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-propyl-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-butyl-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-(3-aminopropyl)-3-chloro-pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-chloro-l-(3-hydroxypropyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-chloro-l-(2-methoxyethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-prop-2-ynyl-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6- one;3-[3-[l-[(3-methyloxetan-3-yl)methyl]-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5- yl]-lH-pyridazin-6-one;3-[5-(3-bromo-l,4-dimethyl-pyrazol-5-yl)-l,2,4-oxadiazol-3-yl]-lH-pyridazin-6-one;3-[3-[3,4-dichloro-l-(3-methoxypropyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6- one;3-[3-(l,3-dimethyl-4-nitro-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-(aminomethyl)-l-methyl-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH- pyridazin-6-one;3-[3-[4-chloro-l-(3-methoxypropyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-bromo-l-(3-hydroxypropyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-(3-aminopropyl)-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-[3-chloro-l-(3-hydroxy-3-methyl-butyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-(4-amino-l,3-dimethyl-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[5-[l-ethyl-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-3-yl]-lH-pyridazin-6-one;3-[3-[3-chloro-l-(3-hydroxybutyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[3-chloro-l-[3-(methylamino)propyl]pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[3-chloro-l-[3-(dimethylamino)propyl]pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-[4-chl oro-1 -(2-hydroxyethyl)-3-(trifluoromethyl)pyrazol-5-yl]- 1,2, 4-oxadiazol-5-yl]-lH- pyridazin-6-one;3-[3-[3-chloro-l-(oxetan-3-ylmethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-(3-chloro-l-tetrahydropyran-4-yl-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6- one;3-[3-[3-chloro-l-(4-piperidyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[5-[l-ethyl-5-(trifluoromethyl)pyrazol-3-yl]-l,2,4-oxadiazol-3-yl]-lH-pyridazin-6-one;3-[3-(3-chloro-l,4-dimethyl-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[3-chloro-l-(3-hydroxypropyl)-4-methyl-pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-[3-chloro-l-(3-hydroxy-2-methyl-propyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-[3-chloro-l-(2,3-dihydroxypropyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6- one;3-[3-[l-(3-amino-3-methyl-butyl)-3-chloro-pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin- 6-one;3-[3-[3-chl oro-1 -(3-hy droxy-2,2-dimethyl-propyl)pyrazol-5-yl]- 1,2, 4-oxadiazol-5-yl]-lH- pyridazin-6-one;3-[3-[4-chloro-l-(3-hydroxypropyl)-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]- lH-pyridazin-6-one;3-[3-[3, 4-di chi oro-1 -(3-hy droxy-3-methyl-butyl)pyrazol-5-yl]- 1,2, 4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-[4-chl oro-1 -(3-hy droxy-3-methyl-butyl)pyrazol-5-yl]-l, 2, 4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-(4-bromo-3-chloro-l-methyl-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-bromo-3-chl oro-1 -(3-hy droxypropyl)pyrazol-5-yl]- 1,2, 4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-[3-chloro-l-[2-(methylamino)ethyl]pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6- one;3-[3-[l-(3-aminopropyl)-4-chloro-pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-(3-amino-3-methyl-butyl)-4-chloro-pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin- 6-one;3-[3-[4-chl oro-1 -(3-hy droxy-3-methyl-butyl)-3-(trifluoromethyl)pyrazol-5-yl]- 1,2, 4-oxadia- zol-5-yl]-lH-pyridazin-6-one;3-[3-[l-(3-hydroxy-3-methyl-butyl)-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]- lH-pyridazin-6-one;3-[3-[5-chl oro-1 -(3-hy droxy-3-methyl-butyl)pyrazol-3-yl]-l, 2, 4-oxadiazol-5-yl]-lH-pyri- dazin-6-one;3-[3-[4-bromo-3-chl oro-1 -(3-hy droxy-3-methyl-butyl)pyrazol-5-yl]-l, 2, 4-oxadiazol-5-yl]- lH-pyridazin-6-one;3-[3-(3-chloro-4-cyclopropyl-l-methyl-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6- one;3-[3-[l-(3-hydroxypropyl)-4-methyl-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]- lH-pyridazin-6-one;3-[3-[3-chloro-l-(4-hydroxybutyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-chloro-3-(difluoromethoxy)-l-(3-hydroxypropyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]- lH-pyridazin-6-one;3-[3-[4-chloro-3-(difluoromethoxy)-l-[(3R)-3-hydroxybutyl]pyrazol-5-yl]-l,2,4-oxadiazol-5- yl]-lH-pyridazin-6-one;3-[3-[4-chloro-3-(difluoromethoxy)-l-[(3S)-3-hydroxybutyl]pyrazol-5-yl]-l,2,4-oxadiazol-5- yl]-lH-pyridazin-6-one;3-[3-[4-chl oro-1 -[(3R)-3-hydroxybutyl]-3-(trifluoromethyl)pyrazol-5-yl]- 1,2, 4-oxadiazol-5- yl]-lH-pyridazin-6-one;3-[3-[4-chloro-l-[(3S)-3-hydroxybutyl]-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5- yl]-lH-pyridazin-6-one;3-[3-[4-chl oro-1 -[(2R)-3-hy droxy-2-methyl-propyl]-3-(trifluorom ethyl)pyrazol-5-yl]-l, 2,4- oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-chl oro-1 - [(2 S)-3 -hydroxy -2-methyl-propyl]-3-(trifluoromethyl)pyrazol-5-yl]- 1,2,4- oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[3-chloro-l-[(3R)-3-hydroxybutyl]pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6- one;3-[3-[3-chloro-l-[(3S)-3-hydroxybutyl]pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH-pyridazin-6- one;3-[3-[4-chloro-l-(3-fluoropropyl)-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]-lH- pyridazin-6-one;3-[3-[l-(3-amino-2-methyl-propyl)-4-chloro-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadia- zol-5-yl]-lH-pyridazin-6-one;3-[3-[l-[(3R)-3-aminobutyl]-4-chloro-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]- lH-pyridazin-6-one;3-[3-[l-[(3S)-3-aminobutyl]-4-chloro-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]- lH-pyridazin-6-one;3-[3-[4-chloro-l-[[(lS,2R)-2-hydroxycyclopentyl]methyl]-3-(trifluoromethyl)pyrazol-5-yl]- l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-chloro-l-[[(lR,2S)-2-hydroxycyclopentyl]methyl]-3-(trifluoromethyl)pyrazol-5-yl]- l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-chloro-l-(3,3-difluoropropyl)-3-(trifluoromethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]- lH-pyridazin-6-one;3-[3-[4-chloro-3-(difluoromethoxy)-l-(2-hydroxyethyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]- lH-pyridazin-6-one;3 -[3 -[ 1 -[(3R)-3 -aminobutyl]-4-chl oro-3 -(difluoromethoxy)pyrazol-5-yl]- 1 ,2,4-oxadiazol-5- yl]-lH-pyridazin-6-one;3-[3-[4-chloro-3-(difluoromethoxy)-l-(3-fluoropropyl)pyrazol-5-yl]-l,2,4-oxadiazol-5-yl]- lH-pyridazin-6-one;3 -[3 -[ 1 -[(3 S)-3 -aminobutyl]-4-chl oro-3 -(difluoromethoxy)pyrazol-5-yl]- 1 ,2,4-oxadiazol-5- yl]-lH-pyridazin-6-one;3-[3-[4-chl oro-3 -(difluoromethoxy)- l-[(2R)-3-hy droxy-2-methyl-propyl]pyrazol-5-yl]- 1,2,4- oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-chloro-3-(difluoromethoxy)-l-[(2S)-3-hydroxy-2-methyl-propyl]pyrazol-5-yl]-l,2,4- oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-chloro-3-(difluoromethoxy)-l-(3,3-difluoropropyl)pyrazol-5-yl]-l,2,4-oxadiazol-5- yl]-lH-pyridazin-6-one;3-[3-[4-chloro-3-(difluoromethoxy)-l-[(2R,3S)-3-hydroxy-2-methyl-butyl]pyrazol-5-yl]- l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-chloro-3-(difluoromethoxy)-l-[(2R)-2-hydroxypropyl]pyrazol-5-yl]-l,2,4-oxadiazol-5 -y 1 ] - 1 H-py ri dazin-6 -one ;3-[3-[4-chloro-3-(difluoromethoxy)-l-[(2S)-2-hydroxypropyl]pyrazol-5-yl]-l,2,4-oxadiazol-5 -y 1 ] - 1 H-py ri dazin-6 -one ;3-[3-[4-chloro-3-(difluoromethoxy)-l-[(2S,3R)-3-hydroxy-2-methyl-butyl]pyrazol-5-yl]- l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[l-[(2R)-3-amino-2-methyl-propyl]-4-chloro-3-(difluoromethoxy)pyrazol-5-yl]-l,2,4- oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-chloro-3-(difluoromethoxy)-l-[[(l S,2R)-2 -hydroxy cyclobutyl]methyl]pyrazol-5-yl]- l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-chloro-3-(difluoromethoxy)-l-[[(lS,2S)-2-hydroxycyclobutyl]methyl]pyrazol-5-yl]- l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one;3-[3-[4-chloro-3-(difluoromethoxy)-l-[(2S,3S)-3-hydroxy-2-methyl-butyl]pyrazol-5-yl]- l,2,4-oxadiazol-5-yl]-lH-pyridazin-6-one; and4-fluoro-3 -(5-(6-oxo- 1 ,6-dihydropyridazin-3 -yl)- 1 ,2,4-oxadiazol-3 -yl)benzoic acid6-(3 -( 1 - methyl-3-((methylamino)methyl)-lH-pyrazol-5-yl)-l,2,4-oxadiazol-5-yl)pyridazin-3(2H)- one.

22. A pharmaceutical composition comprising a compound of any one of claims 1 to 21, and a pharmaceutically acceptable excipient.

23. A method of treating a SOX18-mediated disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of Formula I:whereinY1is CH or N;Y2is C(O) or C(OH);R1is -H or -Ci-6-alkyl;Ring X is a 5-membered carbocycle or 5-membered heterocycle; wherein Ring X is optionally substituted with one or more R2; if present, each R2is independently selected from the group consisting of -halogen, -Ci- salkyl, -OH, -O(Ci-3alkyl), -NH2, -N(H)(-Ci-3alkyl), -N(Ci-3alkyl)(Ci-3alkyl), and -CF3;L is a bond or -Ci-8alkylene-;Ring Z is a 5-10-membered carbocyclyl or 5-10-membered heterocyclyl; wherein Ring Z is optionally substituted with one or more R3; if present, each R3is independently selected from the group consisting of -halogen, -Ci- salkyl optionally substituted with one or more R5, -Ci-salkenyl optionally substituted with one or more R5, -Ci-salkynyl optionally substituted with one or more R5, -C(R4)3, -O(R4), -N(R4)2, -OC(R4)3, -Ci-salkyl-O(R4), -O-Ci-salkyl-O(R4), -3-7-membered carbocyclyl optionally substituted with one or more R5, -3-7-membered heterocyclyl optionally substituted with one or more R5, -Ci.8alkyl-N(R4)2, -O-Ci.8alkyl-N(R4)2, -C(O)O(R4), -OC(O)(R4), -CN, -NO2, -S(O)2R4, - S(O)2N(R4)2, -N(H)SO2(R4), -(O), -N(R4)-Ci-8alkyl-N(R4)2, -N(R4)-Ci-8alkyl-O(R4), -N(R4)CI- 4alkyl optionally substituted with one or more R5, -O-Ci-8alkyl-(R4)3, -O-Ci-8alkyl optionally substituted with one or more R5, -O-Ci-8alkenyl-(R4)3, -O-Ci-8alkenyl optionally substituted with one or more R5, O-Ci-8alkynyl-(R4)3, -O-Ci-8alkynyl optionally substituted with one or more R5, and -O-cyclicCi-8alkyl-(R4)3; if present, each R4is independently selected from the group consisting of -H, -halogen, and -Ci-ealkyl; if present, each R5is independently selected from the group consisting of -halogen, - OH, -N(R4)2, -OCi-4alkyl, -C(O)N(R4)2, -C3-6cycloalkyl optionally substituted with one or two R6, 4-6-membered heterocyclyl comprising one or two heteroatoms independently selected from N, O or S and optionally substituted with one or two R6; andif present, each R6is independently selected from the group consisting of -halogen, - OH, -CF3, -halogen, and -Ci-salkyl, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

24. The method of claim 23, wherein the SOX18-mediated disease, disorder, or condition is an angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition.

25. A method of treating an angiogenesis- and / or a lymphangiogenesis-related disease, disorder, or condition in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of a compound of Formula I:Formula I; whereinY1is CH or N;Y2is C(O) or C(OH);R1is -H or -Ci-6-alkyl;Ring X is a 5-membered carbocycle or 5-membered heterocycle; wherein Ring X is optionally substituted with one or more R2; if present, each R2is independently selected from the group consisting of -halogen, -Ci- salkyl, -OH, -O(Ci-3alkyl), -NH2, -N(H)(-Ci-3alkyl), -N(Ci-3alkyl)(Ci-3alkyl), and -CF3;L is a bond or -Ci-8alkylene-;Ring Z is a 5-10-membered carbocyclyl or 5-10-membered heterocyclyl; wherein Ring Z is optionally substituted with one or more R3; if present, each R3is independently selected from the group consisting of -halogen, -Ci- salkyl optionally substituted with one or more R5, -Ci-salkenyl optionally substituted with one or more R5, -Ci-salkynyl optionally substituted with one or more R5, -C(R4)3, -O(R4), -N(R4)2, -OC(R4)3, -Ci-salkyl-O(R4), -O-Ci-salkyl-O(R4), -3-7-membered carbocyclyl optionally substituted with one or more R5, -3-7-membered heterocyclyl optionally substituted with one or more R5, -Ci.8alkyl-N(R4)2, -O-Ci.8alkyl-N(R4)2, -C(O)O(R4), -OC(O)(R4), -CN, -NO2, -S(O)2R4, - S(O)2N(R4)2, -N(H)SO2(R4), -(O), -N(R4)-Ci-8alkyl-N(R4)2, -N(R4)-Ci-8alkyl-O(R4), -N(R4)CI- 4alkyl optionally substituted with one or more R5, -O-Ci-8alkyl-(R4)3, -O-Ci-8alkyl optionallysubstituted with one or more R5, -O-Ci-8alkenyl-(R4)3, -O-Ci-salkenyl optionally substituted with one or more R5, O-Ci-salkynyl-(R4)3, -O-Ci-salkynyl optionally substituted with one or more R5, and -O-cyclicCi-8alkyl-(R4)3; if present, each R4is independently selected from the group consisting of -H, -halogen, and -Ci-ealkyl; if present, each R5is independently selected from the group consisting of -halogen, - OH, -N(R4)2, -OCi-4alkyl, -C(O)N(R4)2, -C3-6cycloalkyl optionally substituted with one or two R6, 4-6-membered heterocyclyl comprising one or two heteroatoms independently selected from N, O or S and optionally substituted with one or two R6; and if present, each R6is independently selected from the group consisting of -halogen, - OH, -CF3, -halogen, and -Ci-salkyl, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

26. The method of claim 25, wherein the angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition is a cancer, optionally wherein the cancer is selected from the group consisting of prostate cancer, lung cancer, breast cancer, bladder cancer, renal cancer, colon cancer, gastric cancer, pancreatic cancer, ovarian cancer, melanoma, hepatoma, hepatocellular carcinoma, sarcoma, leukemia, lymphoma, and vascular neoplasm, optionally wherein the sarcoma is angiosarcoma.

27. The method of claim 25, wherein the angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition is an ophthalmic disease, disorder, or condition, optionally wherein the ophthalmic disease, disorder, or condition is selected from the group consisting of age-related macular degeneration, diabetic retinopathy, ischemic retinopathy, retinopathy of prematurity, neovascular glaucoma, iritis rubeosis, corneal neovascularization, cyclitis, sickle cell retinopathy, pterygium, and vascular response during corneal injury.

28. The method of claim 25, wherein the angiogenesis- and / or lymphangiogenesis-related disease, disorder, or condition is a renal disease, disorder, or condition, optionally wherein the renal disease, disorder, or condition is selected from the group consisting of chronic renal transplant dysfunction, primary renal fibrotic disorders, proteinuria, diabetic nephropathy, and renal inflammation.whereinY1is CH or N;Y2is C(O) or C(OH);R1is -H or -Ci-6-alkyl;Ring X is a 5-membered carbocycle or 5-membered heterocycle; wherein Ring X is optionally substituted with one or more R2; if present, each R2is independently selected from the group consisting of -halogen, -Ci- salkyl, -OH, -O(Ci-3alkyl), -NH2, -N(H)(-Ci-3alkyl), -N(Ci-3alkyl)(Ci-3alkyl), and -CF3;L is a bond or -Ci-8alkylene-;Ring Z is a 5-10-membered carbocyclyl or 5-10-membered heterocyclyl; wherein Ring Z is optionally substituted with one or more R3; if present, each R3is independently selected from the group consisting of -halogen, -Ci- salkyl optionally substituted with one or more R5, -Ci-salkenyl optionally substituted with one or more R5, -Ci-salkynyl optionally substituted with one or more R5, -C(R4)3, -O(R4), -N(R4)2, -OC(R4)3, -Ci-salkyl-O(R4), -O-Ci-salkyl-O(R4), -3-7-membered carbocyclyl optionally substituted with one or more R5, -3-7-membered heterocyclyl optionally substituted with one or more R5, -Ci.8alkyl-N(R4)2, -O-Ci.8alkyl-N(R4)2, -C(O)O(R4), -OC(O)(R4), -CN, -NO2, -S(O)2R4, - S(O)2N(R4)2, -N(H)SO2(R4), -(O), -N(R4)-Ci-8alkyl-N(R4)2, -N(R4)-Ci-8alkyl-O(R4), -N(R4)CI- 4alkyl optionally substituted with one or more R5, -O-Ci-8alkyl-(R4)3, -O-Ci-8alkyl optionally substituted with one or more R5, -O-Ci-8alkenyl-(R4)3, -O-Ci-8alkenyl optionally substituted with one or more R5, O-Ci-8alkynyl-(R4)3, -O-Ci-8alkynyl optionally substituted with one or more R5, and -O-cyclicCi-8alkyl-(R4)3; if present, each R4is independently selected from the group consisting of -H, -halogen, and -Ci-ealkyl; if present, each R5is independently selected from the group consisting of -halogen, - OH, -N(R4)2, -OCi-4alkyl, -C(O)N(R4)2, -C3-6cycloalkyl optionally substituted with one or two R6, 4-6-membered heterocyclyl comprising one or two heteroatoms independently selected from N, O or S and optionally substituted with one or two R6; andif present, each R6is independently selected from the group consisting of -halogen, - OH, -CF3, -halogen, and -Ci-salkyl, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof; in the manufacture of a medicament for the treatment of an angiogenesis- and / or a lymphangiogenesis-related disease, disorder, or condition.

30. A method of modulating SOX18 activity, comprising contacting SOX18 with a compound of Formula I:Formula I; whereinY1is CH or N;Y2is C(O) or C(OH);R1is -H or -Ci-6-alkyl;Ring X is a 5-membered carbocycle or 5-membered heterocycle; wherein Ring X is optionally substituted with one or more R2; if present, each R2is independently selected from the group consisting of -halogen, -Ci- salkyl, -OH, -O(Ci-3alkyl), -NH2, -N(H)(-Ci-3alkyl), -N(Ci-3alkyl)(Ci-3alkyl), and -CF3;L is a bond or -Ci-8alkylene-;Ring Z is a 5-10-membered carbocyclyl or 5-10-membered heterocyclyl; wherein Ring Z is optionally substituted with one or more R3; if present, each R3is independently selected from the group consisting of -halogen, -Ci- salkyl optionally substituted with one or more R5, -Ci-salkenyl optionally substituted with one or more R5, -Ci-salkynyl optionally substituted with one or more R5, -C(R4)3, -O(R4), -N(R4)2, -OC(R4)3, -Ci-salkyl-O(R4), -O-Ci-salkyl-O(R4), -3-7-membered carbocyclyl optionally substituted with one or more R5, -3-7-membered heterocyclyl optionally substituted with one or more R5, -Ci.8alkyl-N(R4)2, -O-Ci.8alkyl-N(R4)2, -C(O)O(R4), -OC(O)(R4), -CN, -NO2, -S(O)2R4, - S(O)2N(R4)2, -N(H)SO2(R4), -(O), -N(R4)-Ci-8alkyl-N(R4)2, -N(R4)-Ci-8alkyl-O(R4), -N(R4)CI- 4alkyl optionally substituted with one or more R5, -O-Ci-8alkyl-(R4)3, -O-Ci-8alkyl optionally substituted with one or more R5, -O-Ci-8alkenyl-(R4)3, -O-Ci-8alkenyl optionally substitutedwith one or more R5, O-Ci-8alkynyl-(R4)3, -O-Ci-salkynyl optionally substituted with one or more R5, and -O-cyclicCi-8alkyl-(R4)3; if present, each R4is independently selected from the group consisting of -H, -halogen, and -Ci-ealkyl; if present, each R5is independently selected from the group consisting of -halogen, - OH, -N(R4)2, -OCi-4alkyl, -C(O)N(R4)2, -C3-6cycloalkyl optionally substituted with one or two R6, 4-6-membered heterocyclyl comprising one or two heteroatoms independently selected from N, O or S and optionally substituted with one or two R6; and if present, each R6is independently selected from the group consisting of -halogen, - OH, -CF3, -halogen, and -Ci-salkyl, or a pharmaceutically acceptable salt, solvate, tautomer or stereoisomer thereof.

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