Hedgehog acyltransferase inhibitors

Abstract

The invention relates to a class of compounds useful as Hedgehog Acyltransferase inhibitors, as well as the treatment or prevention of diseases associated with the Hedgehog signalling pathway using the compounds of the present invention. In one aspect, the present invention provides a compound of formula (I) below.

Description

[0001] HEDGEHOG ACYLTRANSFERASE INHIBITORS

[0002] Field of the Invention

[0003] The invention relates to a class of compounds useful as Hedgehog Acyltransferase inhibitors, as well as the treatment or prevention of diseases associated with the Hedgehog signalling pathway using the compounds of the present invention.

[0004] Background of the Invention

[0005] The Hedgehog signalling pathway is a signalling pathway that transmits information to embryonic cells required for cell differentiation. It is one of the key regulators of early development and is present in all bilaterians. The Hedgehog pathway takes its name from an intracellular signalling molecule called Hedgehog, which is found in fruit flies. Fruit fly larvae lacking the Hedgehog gene have a spiky appearance resembling a hedgehog.

[0006] Beyond its role in embryogenesis, dysregulation of the Hedgehog signalling pathway has been implicated in various pathological conditions, including cancer and fibrotic diseases. The Hedgehog signalling pathway plays a critical role in the pathogenesis of cancer and fibrotic diseases, exerting both pro-tumorigenic and pro-fibrotic effects in various tissues. Dysregulation of this signalling cascade can lead to uncontrolled cell proliferation, aberrant tissue remodelling, and the development of malignant tumours or fibrotic lesions. In cancer, aberrant activation of the Hedgehog signalling pathway is frequently observed in a wide range of malignancies, including breast cancer, lung cancer, colon cancer, colorectal cancer, pancreatic cancer, skin cancer, prostate cancer, gliomas, mesothelioma, leukaemia, among others. When aberrantly activated the pathway can promote tumour growth, survival, metastasis and resistance to therapy through multiple mechanisms. The Hedgehog signalling pathway is aberrantly activated in cancers that are responsible for about 25% of cancer-related deaths (e.g., Chahal et al “Hedgehog pathway and smoothened inhibitors in cancer therapies” (2018), Anticancer Drugs, 29, 387-401 , doi: 10.1097 / CAD.0000000000000609) .

[0007] Similarly, aberrant Hedgehog signalling has been implicated in the pathogenesis of fibrotic diseases, including idiopathic pulmonary fibrosis, liver fibrosis, and systemic sclerosis. In these conditions, persistent activation of the pathway leads to excessive deposition of extracellular matrix (ECM) proteins, such as collagen and fibronectin, and the formation of scar tissue, resulting in organ dysfunction and failure. Hedgehog signalling promotes the activation and proliferation of fibroblasts, the primary effector cells responsible for ECM production in fibrotic lesions.

[0008] Hedgehog (HH) signalling is mediated by the three Hedgehog ligands (Sonic Hedgehog- SHH, Desert Hedgehog-DHH, Indian Hedgehog-IHH), which are produced as precursor proteins and undergo a post-translational maturation process, to acquire full signalling activity. This process includes C-terminal autocleavage and cholesterylation as well as N- terminal palmitoylation. The palmitoylation step is catalysed by Hedgehog Acyltransferase (HHAT), a transmembrane protein at the endoplasmic reticulum, using palmitoyl-CoA as the lipid donor. Then, the activated ligands are secreted from cells and bind to the Patched receptor on the receiving cell membrane. Binding relieves inhibition of Smoothened protein which activates the GLI transcription factors, the ultimate effectors of the pathway. However, there are also ‘non-canonical’ versions of Hedgehog signalling which bypass certain components of the pathway which means that blocking the Hedgehog signalling pathway can be challenging.

[0009] Targeting the Hedgehog signalling pathway has emerged as a promising therapeutic strategy. Drug discovery efforts to target Hedgehog signalling have focused on Smoothened protein and have led to the approval of Vismodegib (RTM) and Sonidegib (RTM) against basal cell carcinoma and Glasdegib (RTM) against acute myeloid leukaemia. Taladegib, another Smoothened inhibitor, is also currently evaluated in a Phase 2 clinical trial for treatment of idiopathic pulmonary fibrosis. However, Smoothened protein inhibitors are characterised by certain disadvantages. First, resistance is developed to these drugs, because of mutations in the Smoothened protein or due to alterations in cellular pathways. Second, they cannot inhibit ‘non-canonical’, Smoothened protein-independent Hedgehog signalling, which is present in certain Hedgehog-related diseases. Third, they abrogate T-cell migration and killing activity, thereby compromising anti-tumour immune response. As a result, Smoothened protein inhibitors have failed to show efficacy in clinical trials against other Hedgehog-related cancers, such as pancreatic and colorectal cancer, which are also characterised by a complex fibrotic microenvironment.

[0010] An alternative Hedgehog signalling pathway inhibitor is arsenic trioxide, which targets the GLI transcription factors and is indicated against acute promyelocytic leukaemia. However, this compound is not considered a selective Hedgehog pathway inhibitor, as it affects multiple cellular pathways and its use is accompanied by a severe risk of cardiotoxicity, carcinogenesis, and embryo-foetal toxicity. Several efforts have been made to target other components of the pathway, such as in the case of a monoclonal antibody targeting the Hedgehog ligands; though none of these have reached yet an advanced clinical stage.

[0011] Therefore, there is an urgent need for a new class of agents that target Hedgehog signalling in fibrotic settings and for treatment or prevention of cancers, such as cancers which are not responsive or become resistant to the approved Smoothened protein-inhibitors. As Hedgehog Acyltransferase is responsible for the activation of the Hedgehog ligands and of the pathway, its inhibition blocks pro-tumourigenic and pro-fibrotic Hedgehog signalling, Targeting Hedgehog Acyltransferase by genetic means, effectively reduces the growth and viability of breast, lung, colon and pancreatic cancer cells in vitro and in vivo. However, the lack of selective and metabolically stable Hedgehog Acyltransferase inhibitors has prevented thus far, the therapeutic targeting of this unique component of the Hedgehog pathway. The present invention describes the discovery of high-quality Hedgehog Acyltransferase inhibitors as a novel strategy to block Hedgehog signalling and as a new therapeutic option for Hedgehog-related cancers and fibrotic diseases.

[0012] Summary of the Invention

[0013] The present invention relates to a class of compounds that are useful as Hedgehog Acyltransferase inhibitors. This, in an aspect, the present invention provides a compound of formula (I): where: A is selected from halo, and optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkyl, alkenyl and alkynyl groups;

[0014] B is selected from optionally substituted aryl groups and heteroaryl groups;

[0015] L1is absent or is selected from alkylene, -NR’-, -NR’-alkylene-, -O-, -O- alkylene-, -S- and -S-alkylene-;

[0016] L2is selected from -C(O)NR’-, -(CR’2)I-3-C(O)NR’-, -(CR’2)I-3-NR’-, -(CR’2)I. 3NR’C(O)-, -C(=S)NR’-, -C(=NR’)NR’-, -S(O2)NR’-, -NR’C(O)NR’-, - NR’S(O2)NR’-, -OC(O)NR’-, -CR’F-NR’-, -CF2NR’-, -CR’(CF3)NR’-, -CF=CR’-, -(oxetane)NR’- and heteroarylene groups;

[0017] X is selected from -N- and -CR5-, where R5is selected from H, halo, alkyl, alkenyl, alkynyl and haloalkyl;

[0018] R1and R2are each independently selected from H, halo, alkyl, alkenyl, alkynyl and haloalkyl, or R1and R2together with the carbon atoms to which they are attached form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group;

[0019] R3and R4are each independently selected from H, alkyl, alkenyl, alkynyl and haloalkyl, or R3and R4together with the carbon to which they are attached form a 3 to 6-membered cycloalkyl group; each R’ is independently selected from H and alkyl; or a pharmaceutically acceptable salt thereof.

[0020] In one aspect, compounds of the present invention have the formula (III): where: A, L1, L2, X and R1to R4are as defined above;

[0021] D is selected from optionally substituted arylene and heteroarylene groups; and

[0022] R7is selected from -C(O)R”, -S(O)R”, -S(O)2R”, CH2R”, -CHFR”, -CF2R”, - CH(alkyl)R”, -C(alkyl)2R”, -OR” and -R”, where R” is selected from optionally substituted heterocyclic groups and carbocyclic groups.

[0023] In another aspect, the compound of formula (I) is selected from any one of compounds 4, 5, 9, 14 to 16, 18, 19, 21 to 25, 27, 28, 30, 33, 35, 37 to 57, 60 to 102 or a pharmaceutically acceptable salt thereof.

[0024] In another aspect, the compound of formula (I) is selected from any one of compounds 105 to 120 or a pharmaceutically acceptable salt thereof, or from any one of compounds 91a, 95a, 95b, 96a, 96b, 99a, 101a, 101b, 109a, 109b, 113a, 115a, 115b, and 116a or a pharmaceutically acceptable salt thereof.

[0025] The present invention also provides a compound for use in a method of treating or preventing a disease associated with an aberrantly activated Hedgehog signalling pathway, wherein the compound is a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof.

[0026] The present invention further provides a method of treating or preventing a disease associated with an aberrantly activated Hedgehog (HH) signalling pathway in a patient, said method comprising administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, to the patient. Also provided is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in treating or preventing a disease, preferably associated with an aberrantly activated Hedgehog (HH) signalling pathway.

[0027] Further provided is a pharmaceutical composition which comprises a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, as well as a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, for use as a medicament. In these aspects, the compound of formula (I), or a pharmaceutically acceptable salt thereof, may be further defined as follows:

[0028] R3and R4are each H;

[0029] A is not a cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, or heterocycloalkyl group;

[0030] B is not a heteroaryl group; and

[0031] L2is not a heteroarylene group: provided that the compound is not:

[0032]

[0033] In an aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) selected from any one of compounds 1 to 25, 27 to 35 and 37 to 10 102, or a pharmaceutically acceptable salt thereof. In an aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) selected from any one of compounds 103 to 120, or a pharmaceutical composition comprising a compound of formula (I) selected from any one of compounds 91a, 95a, 95b, 96a, 96b, 99a, 101a, 101b, 109a, 109b, 113a, 115a, 115b, and 116a or a pharmaceutically acceptable salt thereof.

[0034] Brief Description of the Drawings

[0035] Figure 1 depicts the concentration of compound 20 dosed in BALB\c mice i.v. at 0.5 mg / kg and at p.o. at 5 mg / kg.

[0036] Detailed Description of the Invention

[0037] Definition of terms

[0038] As used herein, the term “alkyl” denotes an acyclic saturated linear or branched group consisting of carbon atoms and hydrogen atoms. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, etc. The terms “(Ci-3)alkyl”, “(Ci-6)alkyl”, etc., denote the number of carbon atoms in the alkyl group, i.e., 1 to 3 or 1 to 6.

[0039] The term “haloalkyl” denotes an alkyl group which is substituted by one or more halogens (e.g., independently selected from fluorine, chlorine, bromine and iodide). Exemplary haloalkyl groups include trifluoromethyl, trifluoroethyl, difluoroethyl, pentafluoroethyl, chloromethyl, etc.

[0040] The terms “alkenyl” and “alkynyl” are used to refer to alkyl groups but which comprise at least one double bond or triple bond, respectively.

[0041] As used herein, the term “cyclic group” denotes a saturated, partially or fully unsaturated, or aromatic ring structure. Where a cyclic group is defined as having a certain number of members, the term “members”, “membered” and the like is used to denote the number of ring atoms in said cyclic group. For example, a 5-membered cyclic group (e.g., a 5- membered heterocyclic group) contains 5 ring atoms. It will be appreciated that a cyclic group may be a multicyclic group formed of at least two joined rings in which at least one ring atom is shared by rings for them to be joined (e.g. fused, bridged or spirocyclic rings); in these instances, the number of ring atoms represents the total number of ring atoms across all joined rings (e.g., a naphthalene group is a 10-membered cyclic group, made up of two fused rings).

[0042] The term “cyclic group” is intended to encompass both carbocyclic groups as well as heterocyclic groups. The term “carbocyclic” denotes a cyclic group in which the ring atoms are exclusively carbon. The term “heterocyclic” denotes to a cyclic group having as ring members atoms of at least two different elements, with one of the elements typically being carbon and the other selected independently from the group consisting of nitrogen, sulfur and oxygen.

[0043] The term “spiro” or “spirocyclic” as used herein in relation to cyclic groups denotes a multicyclic system in which first and second cyclic groups share only one common ring atom. For example, the spiro[5.5]undecanyl group comprises two cyclohexane rings which have a single carbon ring atom in common. The term “fused” as used herein in relation to cyclic groups denotes a multicyclic system in which first and second cyclic groups share two adjacent common ring atoms. For example, the bicyclo[4.4.0]decanyl group comprises two cyclohexane rings which have two adjacent carbon ring atoms in common. The term “bridged” as used herein in relation to cyclic groups denotes a multicyclic system in which first and second cyclic groups have more than two adjacent ring atoms in common, i.e., said first and second cyclic groups share three or more common ring atoms. For example, the bicyclo[3.3.1]nonanyl group comprises two cyclohexane rings which have three adjacent carbon ring atoms in common.

[0044] As used herein, the term “cycloalkyl” denotes a carbocyclic group which is saturated and which preferably consists solely of ring carbon atoms and hydrogen. Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0045] As used herein, the term “cycloalkenyl” denotes a cycloalkyl group but which contains one or more double bonds within the ring. The term “cycloalkenyl” is not intended to encompass cyclic groups having aromatic character (those being considered as aryl groups as defined herein). Exemplary cycloalkenyl groups include cyclohexenyl.

[0046] As used herein, the term “aryl” denotes a carbocyclic group which is aromatic and which preferably consists solely of ring carbon atoms and hydrogen. Examples of aryl groups include phenyl and naphthalenyl. As used herein, the term “heterocycloalkyl” denotes a heterocyclic group which does not contain double bonds between atoms within the ring structure. Heterocycloalkyl rings may have oxo substituents (=0) on a ring atom, typically either adjacent to a heteroatom (e.g., 2- oxopyrrolidinyl) or on a ring sulfur (as -S(0)- or -S(0)2-), but otherwise preferably consist of the ring atoms and hydrogen. Exemplary heterocycloalkyl groups include tetrahydrofuranyl, piperidinyl, morpholinyl and piperazinyl.

[0047] As used herein, the term “heterocycloalkenyl” denotes a heterocycloalkyl group but which contains one or more double bonds within the ring. The term “heterocycloalkenyl” is not intended to encompass cyclic groups having aromatic character (those being considered as heteroaryl groups as defined herein). Exemplary heterocycloalkenyl groups include tetrahydropyridyl.

[0048] As used herein, the term “heteroaryl” denotes a heterocyclic group which is aromatic. Heterocycloalkyl rings may have oxo substituents (=0) on a ring atom, typically either adjacent to a heteroatom (e.g., 2-oxopyrrolidinyl) or on a ring sulfur (as -S(0)- or -S(0)2-), but otherwise preferably consist of the ring atoms and hydrogen. Examples of heteroaryl groups include monocyclic groups such as pyridyl and 2-oxopyridinyl, as well as multicyclic groups such as indolyl.

[0049] As used herein, the terms “halo” and “halogen” mean fluorine, chlorine, bromine, or iodine. These terms are used interchangeably and may refer to a halogen free radical group or to a halogen atom as such. Those of skill in the art will readily be able to ascertain the identification of which in view of the context in which this term is used in the present disclosure.

[0050] As used herein, the suffix “-yl” (e.g., alkyl, aryl, etc.) is intended to denote a univalent group and the suffix “-ylene” is intended to denote a divalent group. However, where the suffix “-yl” has been used where a divalent group is clearly intended then the group shall be understood as a divalent group, and vice versa.

[0051] Some of the groups disclosed herein link two distinct parts of the compounds of formula (I). Although these linking groups have been written in one way in the present application, they may in fact be used in their opposite orientation. By way of illustrative example, the group C(O)NH-” may link the groups X and Y as either X-C(O)NH-Y or X-NHC(O)-Y. The compounds of the present disclosure are described, inter alia, by way of structural formulae. It will be appreciated that these formulae typically show only one form (e.g., resonance form, tautomeric form, etc.) of the compound, whereas certain compounds may exist in more than one such form. The present disclosure includes all possible tautomers of the compounds characterised by the structural formulae hereinbefore and below, including as single tautomers, or as any mixture of tautomers in any ratio.

[0052] It will also be appreciated that certain of the present compounds may exist in one or more isomeric (e.g., stereoisomeric) forms. The present disclosure includes all possible stereoisomers, enantiomers, diastereomers, etc. of the compounds described herein, as well as cis- and trans- forms and conformers of the same. The purification and the separation of isomers may be accomplished by methods described below, as well as by techniques known in the art. For example, optical isomers of the compounds can be obtained by resolution of the racemic mixture of diastereoisomeric salts thereof (e.g., using an optically active acid or base, or by the formation of covalent diastereomers). A different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatization. Enzymatic separation, with or without derivatisation, may also be useful, and optically active compounds of the present disclosure can likewise be obtained by chiral syntheses utilizing optically active starting materials. The present disclosure includes all possible stereoisomers of the compounds described herein as single stereoisomers, e.g. (R)- or (S)- isomers, or as any mixture of said stereoisomers in any ratio.

[0053] The compounds of the disclosure may exist in the form of free acids or bases, or may exist as addition salts with suitable acids or bases. For example, basic compounds of formula (I) may be provided as pharmaceutically acceptable acid addition salts with an acid such as HCI. Methods for forming salts are described below and are also known in the art (see, e.g., Berge et al (1977), J Pharm Sci. 66:1-19). As used herein, the term “pharmaceutically acceptable” when used in connection with salts means a salt of a currently disclosed compound that may be administered without any resultant substantial undesirable biological effect(s) or any resultant deleterious interaction(s) with any other component of a pharmaceutical composition in which it may be contained.

[0054] Compounds of Formula (I)

[0055] The present inventors have discovered a class of compounds having inhibitory activity towards Hedgehog signalling at its initial step, by stopping a post-translational modification process which results in the activation of the Hedgehog signalling messengers. As a result, the compounds of the present invention enjoy inhibitory activity towards both ‘canonical’ and ‘non-canonical’ versions of the pathway, which do not rely on Smoothened protein activity. Upstream blocking of the Hedgehog signalling pathway blocks both the Smoothened protein dependent and independent Hedgehog signalling, and thus is effective in cases where traditional Smoothened protein inhibitors cannot be used. Inhibition of Hedgehog Acyltransferase has been demonstrated to stop the production of active Hedgehog signalling messengers, hence it blocks oncogenic and pro-fibrotic Hedgehog signalling, with a distinct mechanism compared to the approved Smoothened inhibitors (e.g., Konitsiotis et al “Attenuation of hedgehog acyltransferase-catalyzed sonic Hedgehog palmitoylation causes reduced signaling, proliferation and invasiveness of human carcinoma cells” (2014), PLoS One, 9, e89899, doi: 10.1371 / journal. pone.0089899).

[0056] Hedgehog signalling can be autocrine, paracrine, or endocrine. Specifically for the long- range signalling, the Hedgehog-ligand post-translational palmitoylation step, which is catalysed by Hedgehog Acyltransferase is essential. Only Hedgehog Acyltransferase inhibition could stop this aspect of oncogenic and pro-fibrotic Hedgehog signalling. As a consequence, targeting Hedgehog Acyltransferase inhibits TGFp-dependent fibroblast activation and and is effective in experimental fibrosis models (e.g., Liang et al “Acyltransferase skinny hedgehog regulates TGFp-dependent fibroblast activation in SSc” (2019), Ann Rheum Dis, 78, 1269-1273. doi: 10.1136 / annrheumdis-2019-215066). It has been shown with proteomics studies that Hedgehog Acyltransferase inhibition only affects the palmitoylation of Hedgehog ligands, without interfering with the palmitoylation modification of other proteins inside the cell. Thus, Hedgehog Acyltransferase inhibition has a low risk of toxicity. See, Rodgers, U. R. et al. “Characterization of Hedgehog Acyltransferase Inhibitors Identifies a Small Molecule Probe for Hedgehog Signaling by Cancer Cells” (2016), ACS Chem Biol, 11 , 3256-3262, doi:10.1021 / acschembio.6b00896. Therefore, Hedgehog Acyltransferase inhibition represents a unique strategy to stop cancer and fibrosis promoting Hedgehog signalling.

[0057] A biochemical assay was used to screen a library of 20,000 compounds against purified Hedgehog Acyltransferase. Subsequent hit validation, selection and optimisation provided a novel Hedgehog Acyltransferase inhibitor series. New cryogenic electron microscopy structures have been obtained for representative compounds of the novel series, which were used to guide the design of analogues. The optimisation of the series has led to the most potent Hedgehog Acyltransferase inhibitors that have discovered thus far and to the first orally bioavailable Hedgehog Acyltransferase inhibitor, confirmed by in vivo pharmacokinetic studies.

[0058] The present invention provides a compound of formula (I): where: A is selected from halo, and optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkyl, alkenyl and alkynyl groups;

[0059] B is selected from optionally substituted aryl groups and heteroaryl groups;

[0060] L1is absent or is selected from alkylene, -NR’-, -NR’-alkylene-, -O-, -O- alkylene-, -S- and -S-alkylene-;

[0061] L2is selected from -C(O)NR’-, -(CR’2)I-3-C(O)NR’-, -(CR’2)I-3-NR’-, -(CR’2)I. 3NR’C(O)-, -C(=S)NR’-, -C(=NR’)NR’-, -S(O2)NR’-, -NR’C(O)NR’-, - NR’S(O2)NR’-, -OC(O)NR’-, -CR’F-NR’-, -CF2NR’-, -CR’(CF3)NR’-, -CF=CR’-, -(oxetane)NR’- and heteroarylene groups;

[0062] X is selected from -N- and -CR5-, where R5is selected from H, halo, alkyl, alkenyl, alkynyl and haloalkyl;

[0063] R1and R2are each independently selected from H, halo, alkyl, alkenyl, alkynyl and haloalkyl, or R1and R2together with the carbon atoms to which they are attached form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group;

[0064] R3and R4are each independently selected from H, alkyl, alkenyl, alkynyl and haloalkyl, or R3and R4together with the carbon to which they are attached form a 3 to 6-membered cycloalkyl group; each R’ is independently selected from H and alkyl; or a pharmaceutically acceptable salt thereof.

[0065] As would be appreciated by a person of skill in the art, a bond depicted as - may be either a double bond or a single bond. In the present invention, the bond is preferably a double bond, and thus the compound is a compound of formula (II): or a pharmaceutically acceptable salt thereof.

[0066] According to the present invention, A is selected from halo (e.g., -Cl, -Br or -F), and optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkyl, alkenyl and alkynyl groups. For the avoidance of doubt, it will be appreciated that “optionally substituted” applies to each of the aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkyl, alkenyl and alkynyl groups.

[0067] In preferred embodiments, A is selected from optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl groups. More preferably, A is selected from optionally substituted aryl, heteroaryl and cycloalkyl, heterocycloalkyl, groups. Most preferably, A is selected from optionally substituted aryl and heteroaryl groups.

[0068] Preferably, the optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkyl, alkenyl, or alkynyl group is an optionally substituted 6 to 12-membered aryl, 5 to 12-membered heteroaryl, 3 to 12-membered cycloalkyl, 5 to 12- membered heterocycloalkyl, 5 to 12-membered cycloalkenyl, 5 to 12-membered heterocycloalkenyl, -C1-12 alkyl, -C2-12 alkenyl, or -C2-12 alkynyl group. More preferred are optionally substituted 6-membered aryl, 5 to 6-membered heteroaryl, 3 to 6-membered cycloalkyl, 5 to 6-membered heterocycloalkyl, 5 to 6-membered cycloalkenyl, 5 to 6- membered heterocycloalkenyl, -Ci_8alkyl, -C2-8 alkenyl, or -C2-8 alkynyl group, respectively.

[0069] For example, A may be an optionally substituted phenyl, pyridyl, pyrimidyl, or pyridazyl group.

[0070] A may be optionally substituted with one or more substituents. For example, A may be mono-substituted, di-substituted, tri-substituted, and so on, where the nature of A allows it. Typically, where A is substituted, it will be substituted with one or two substituents. Preferably, A is unsubstituted or substituted with one substituent. Each optional substituent present on A may be independently selected from halo (e.g., -Cl, - Br or -F), -CN, -NO2, -OR’, -NR’2, -SR’, alkyl, haloalkyl (e.g., -CF3), alkenyl, alkynyl, -O- haloalkyl (e.g. -OCF3), -alkylene-OR’, -alkylene-NR’2, -C(O)OR’, -OC(O)R’, -alkylene- OC(O)R’, -C(O)R’, -alkylene-C(O)R’, -C(O)NR’2, -NR’C(O)R’, -alkylene-NR’C(O)R’, -S(O)R’, -S(O)2R’, -S(O)2OR’, -S(O)NR’2and -S(O)2NR’2. Preferably, each optional substituent present on A may be independently selected from halo (e.g., -Cl, -Br or -F), -CN, -NO2, -OR’, -NR’2, -SR’, -C1-6 alkyl, -Ci_6haloalkyl (e.g., -CF3), -C2.6alkenyl, -C2.6alkynyl, -O-Ci_6haloalkyl (e.g., -OCF3), -CI-6 alkylene-OR’, -Ci_6alkylene-NR’2, -C(O)OR’, -OC(O)R’, -Ci_6alkylene- OC(O)R’, -C(O)R’, -(Ci.6alkylene)C(O)R’, -C(O)NR’2, -NR’C(O)R’, -Ci-6alkylene-NR’C(O)R’, -S(O)R’, -S(O)2R’, -S(O)2OR’, -S(O)NR’2and -S(O)2NR’2. More preferably, each optional substituent present on A may be independently selected from halo (e.g., -Cl, -Br or -F), -CN, -NO2, -OR’, -NR’2, -CI-3alkyl, -Ci-3haloalkyl (e.g., -CF3), -C2.3alkenyl, -C2.3alkynyl, -O-Ci.3haloalkyl (e.g., -OCF3), -C(O)OR’, -OC(O)R’, -C(O)NR’2and -NR’C(O)R’.

[0071] As can be seen from the results of Example 1 , electron withdrawing groups as substituents on group A are particularly suitable for providing high inhibitory activity against Hedgehog Acyltransferase. In preferred compounds, A is substituted with at least one electron withdrawing group, and preferably an electron withdrawing group independently selected from halo (e.g., -Cl, -Br or -F), -CN, -NO2, -Ci-6haloalkyl (e.g., -CF3), -O-Ci-6haloalkyl (e.g., - OCF3), -C(O)OR’, -C(O)NR’2, -S(O)R’, -S(O)2R’, -S(O)2OR’, -S(O)NR’2and -S(O)2NR’2. More preferably, A is substituted with at least one electron withdrawing group independently selected from halo (e.g., -Cl, -Br or -F), -CN, -NO2, -Ci_6haloalkyl (e.g., -CF3) and -O-Ci_6haloalkyl (e.g., -OCF3). Most preferably, the at least one electron withdrawing group is -Cl. Other substituents on A may also be present in addition to an electron withdrawing group, though this is generally less preferred. As can also be seen from the results of Example 1 , in the case that A is a 6-membered aryl group or 6-membered heteroaryl group, electron withdrawing groups as substituents on A at the 4-position relative to L1are particularly suitable for providing high inhibitory activity against Hedgehog Acyltransferase. Thus, in preferred compounds, A is a 6-membered aryl group or 6-membered heteroaryl group and A is substituted with at least one electron withdrawing group at the 4-position relative to L1. In some instances, a second substituent is present on A, such as a second electron withdrawing group, for example, -F, -Cl or -Br. In some instances, A is a 6-membered aryl group or 6-membered heteroaryl group and A is substituted with at least two electron withdrawing groups at the 3-position relative to L1and at the 4-position relative to L1, for example, A may be substituted with -Cl at the 4-position relative to L1, and further substituted with -F at the 3-position relative to L1. Also preferred is for A to be substituted with an alkylenedioxy group (-O-alkylene-O-), such as -O-Ci.3alkylene-O- and more preferably -OCH2O-, where the oxygen atoms of the alkylenedioxy group attach to adjacent ring atoms in A. For instance, in these embodiments, A may be:

[0072] According to the present invention, B is selected from optionally substituted aryl and heteroaryl groups. For the avoidance of doubt, it will be appreciated that “optionally substituted” applies to both aryl and heteroaryl groups.

[0073] In preferred embodiments, B is selected from optionally substituted 6 to 12-membered aryl and 5 to 12-membered heteroaryl groups. More preferably, B is selected from optionally substituted 6-membered aryl and 5 to 6-membered heteroaryl groups. Most preferably, B is selected from optionally substituted 6-membered aryl and 6-membered heteroaryl groups.

[0074] For example, B may be an optionally substituted phenyl, pyridyl, pyrimidyl, or pyrazyl group.

[0075] B may be optionally substituted with one or more substituents. For example, B may be mono-substituted, di-substituted, tri-substituted, and so on, where the nature of B allows it. Typically, where B is substituted, it will be substituted with one or two substituents.

[0076] Each optional substituent present on B may be independently selected from halo (e.g., -Cl, - Br or -F), -CN, -NO2, -OR’, alkyl, haloalkyl (e.g. -CF3), alkenyl, alkynyl, -O-haloalkyl (e.g., - OCF3), -NR’2I-C(O)R’, -C(O)OR’, -OC(O)R’, -S(O)R’, -S(O)2R', -S(O)2OR’, -S(O)NR’2I- S(O)2NR’2, -OS(O)2F, -C(O)NR’2I-NR’C(O)R’, -C(O)R”, -S(O)R” and -S(O)2R”. Preferably, each optional substituent present on B may be independently selected from halo (e.g., -Cl, - Br or -F), -CN, -NO2, -OR’, -Ci_6alkyl, -Ci_6haloalkyl (e.g., -CF3), -C2.6alkenyl, -C2.6alkynyl, - O(Ci-6haloalkyl) (e.g., -OCF3), -NR’2, -C(O)R’, -C(O)OR’, -OC(O)R’, -S(O)R’, -S(O)2R', - S(O)2OR’, -S(O)NR’2, -S(O)2NR’2, -OS(O)2F, -C(O)NR’2, -NR’C(O)R’, -C(O)R”, -S(O)R” and - S(O)2R”. More preferably, each optional substituent present on B may be independently selected from halo (e.g., -Cl, -Br or -F), -CN, -NO2, -OR’, -Ci-3alkyl, -Ci-3haloalkyl (e.g., - CF3), -C2.3alkenyl, -C2.3alkynyl, -O(Ci.3haloalkyl) (e.g., -OCF3), -NR’2, -C(O)OR’, -C(O)NR’2, -NR’C(O)R’, -C(O)R”, -S(O)R” and -S(O)2R”. As can be seen from the results of Example 1 , electron withdrawing groups as substituents on group B are particularly suitable for providing high inhibitory activity against Hedgehog Acyltransferase. In preferred compounds, B is substituted with at least one electron withdrawing group, and preferably, an electron withdrawing group independently selected from halo (e.g., -Cl, -Br or -F), -CN, -NO2, -Ci-6haloalkyl (e.g., -CF3), -O-Ci-6haloalkyl (e.g., - OCF3), -C(O)OR’, -C(O)NR’2I-S(O)R’, -S(O)2R’, -S(O)2OR’, -S(O)NR’2and -S(O)2NR’2, - C(O)R”, -S(O)R” and -S(O)2R”. More preferably, B is substituted with an electron withdrawing group independently selected from halo (e.g., -Cl, -Br or -F), -CN, -NO2, -Ci_6haloalkyl (e.g., -CF3) and -O-Ci_6haloalkyl (e.g., -OCF3). Most preferably, the at least one electron withdrawing group is -CN. Further substituents on B may also be present, for instance as discussed below in relation to compounds of formula (III). As can also be seen from the results of Example 1 , in the case that B is a 6-membered aryl or 6-membered heteroaryl group, electron withdrawing groups as substituents on B at the 3-position and / or 5-position relative to L2are particularly suitable for providing high inhibitory activity against Hedgehog Acyltransferase. In preferred compounds, B is a 6-membered aryl or 6-membered heteroaryl group and B is substituted with an electron withdrawing group, such as -CN, at the 3-position or the 5-position relative to L2.

[0077] In compounds of the present invention, linking group L1is absent or is selected from alkylene, -NR’-, -NR’-alkylene-, -O-, -O-alkylene-, -S- and -S-alkylene-. Preferably, L1is absent or is selected from -NR’-, -NR’-CI.6alkylene-, -O-, -O-Ci_6alkylene-, -S- and -S-Ci_6alkylene-. More preferably, L1is absent or is selected from -NR’-, -NR’-CI.6alkylene-, -O- and -O-Ci-6 alkylene-, and even more preferably, L1is absent or is selected from -NR’- and - O-. Most preferably, L1is absent.

[0078] Linking group L2is selected from -C(O)NR’-, -(CR’2)I.3-C(O)NR’-, -(CR’2)I.3-NR’-, -(CR’2)I.3NR’C(O)-, -C(=S)NR’-, -C(=NR’)NR’-, -S(O2)NR’-, -NR’C(O)NR’-, -NR’S(O2)NR’-, - OC(O)NR’-, -CR’F-NR’-, -CF2NR’-, -CR’(CF3)NR’-, -CF=CR’-, -(oxetane)NR’- and heteroarylene groups. Preferably, L2is selected from -C(O)NR’-, -(CR’2)I.3-C(O)NR’-, - (CR’2)I.3-NR’-, -(CR’2)I.3NR’C(O)- and heteroarylene groups. Most preferably, L2is - C(O)NR’-. In L2groups which contain the -NR’- group, the nitrogen of this group is preferably bonded to B. For instance, where L2is -C(O)NR’-, this group is preferably incorporated into the compound as >N-C(R3)(R4)-C(O)NR’-B rather than >N-C(R3)(R4)- NR’C(O)-B.

[0079] For the avoidance of doubt, the -(oxetane)NR’- has the following structure:

[0080] In many of the Hedgehog Acyltransferase inhibitors of the present invention L2is a secondary amide, i.e. -C(O)NH-. When this group is replaced with an amide bio-isostere in compound 4, inhibitory activity is retained. Bio-isosteres are functional group substitutions that maintain similar biological or pharmacological activity compared to the original molecule. Bio-isosteres are employed in drug design to optimise or modify the properties of a compound while preserving its desired biological function. Various amide bio-isosteres, including -1 ,2,3-triazole-, are outlined in Shikha et al (2020), J. Med. Chem., 63 (21), 12290- 12358.

[0081] Heteroarylene groups are suitable amide bio-isosteres, although 5-membered heteroarylene groups, and preferably, 5-membered heteroarylene groups comprising at least 2 heteroatoms, such as nitrogen, oxygen, or sulphur, are most well suited as bio-isosteres. The heteroarylene group may be selected from imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, oxadiazole, thiadiazole (such as 1 ,2,3-thiadiazole, 1 ,2,4- thiadiazole, 1 ,2,5-thiadiazole, or 1 ,3,4-thiadiazole) and tetrazole; preferably, the heteroarylene group is selected from imidazole, thiazole, triazole (such as 1 ,2,3-triazole or

[0082] 1.2.4-triazole), oxadiazole (such as 1 ,2,3-oxadiazole, 1 ,2,4-oxadiazole, 1 ,2,5-oxadiazole, or

[0083] 1.3.4-oxadiazole) and tetrazole; more preferably, the heteroarylene group is triazole (such as 1 ,2,3-triazole, or 1 ,2,4-triazole).

[0084] In compounds of the present invention, X is selected from -N- and -CR5-. R5is selected from H, halo (e.g., -Cl, -Br or -F), alkyl, alkenyl, alkynyl and haloalkyl (e.g., -CF3). Preferably, R5is selected from H, halo (e.g., -Cl, -Br or -F), -Ci_6alkyl, -C2-6 alkenyl, -C2-6 alkynyl and -Ci_6haloalkyl (e.g., -CF3). More preferably, R5is selected from H, halo (e.g., -Cl, -Br or -F), -Ci-3alkyl, -C2.3alkenyl, -C2.3alkynyl and -Ci-3haloalkyl (e.g., -CF3). Even more preferably, R5is selected from H, halo (e.g., -Cl, -Br or -F) and -Ci-3alkyl, and most preferably, R5is H. Thus, in preferred compounds, X is selected from -N- and -CH-. Most preferably, X is N.

[0085] R1and R2are each independently selected from H, halo (e.g., -Cl, -Br or -F), alkyl, alkenyl, alkynyl and haloalkyl (e.g., -CF3), or R1and R2together with the carbon atoms to which they are attached form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group. Preferably, R1is selected from H, halo (e.g., -Cl, -Br or -F), alkyl, alkenyl, alkynyl and haloalkyl (e.g., -CF3). More preferably, R1is selected from H, halo (e.g., -Cl, -Br or -F), -Ci_6alkyl, -C2-6 alkenyl, -C2-6 alkynyl and -Ci_6haloalkyl (e.g., -CF3), such as from H, halo (e.g., - Cl, -Br or -F), -Ci-3alkyl, -C2.3alkenyl, -C2.3alkynyl and -Ci-3haloalkyl (e.g., -CF3). Even more preferably, R1is selected from H, halo (e.g., -Cl, -Br or -F) and -Ci-3alkyl, and most preferably is H.

[0086] Preferably, R2is selected from H, halo (e.g., -Cl, -Br or -F), alkyl, alkenyl, alkynyl and haloalkyl (e.g., -CF3). More preferably, R2is selected from H, halo (e.g., -Cl, -Br or -F), -Ci_6alkyl, -C2.6 alkenyl, -C2.6alkynyl and -Ci_6haloalkyl (e.g., -CF3), such as from H, halo (e.g., - Cl, -Br or -F), -Ci-3alkyl, -C2.3alkenyl, -C2.3alkynyl and -Ci-3haloalkyl (e.g., -CF3). Even more preferably, R2is selected from H, halo (e.g., -Cl, -Br or -F) and -Ci-3alkyl, and most preferably is H.

[0087] In the case that R1and R2together with the carbon atoms to which they are attached form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group; it is preferable that said aryl, heteroaryl, cycloalkyl or heterocycloalkyl is 5 or 6-membered, and more preferably 6- membered. For example, where R1and R2together with the carbon atoms to which they are attached form a 6-membered aryl group, the compound of formula (I) will have the following structure:

[0088] As would be appreciated, the nature of the bond between the two carbons which are substituted with R1and R2will impact the nature of any cyclic group which is formed therefrom. In the case that R1and R2together with the carbon atoms to which they are attached form an aryl or heteroaryl group, then this bond must be a part of the aromatic ring. Alternatively, In the case that R1and R2together with the carbon atoms to which they are attached form a cycloalkyl or heterocycloalkyl group, then this bond may be a single bond. In compounds of the invention, R3and R4are each independently selected from H, alkyl, alkenyl, alkynyl and haloalkyl (e.g., -CF3), or R3and R4together with the carbon to which they are attached form a 3 to 6-membered cycloalkyl group.

[0089] Preferably, R3is selected from H, halo (e.g., -Cl, -Br or -F), alkyl, alkenyl, alkynyl and haloalkyl (e.g., -CF3). More preferably, R3is selected from H, halo (e.g., -Cl, -Br or -F), -Ci_6alkyl, -C2-6 alkenyl, -C2-6 alkynyl and -Ci_6haloalkyl (e.g., -CF3), such as from H, halo (e.g., - Cl, -Br or -F), -C1-3 alkyl, -C2.3alkenyl, -C2.3alkynyl and -C1-3 haloalkyl (e.g., -CF3). Even more preferably, R3is selected from H, halo (e.g., -Cl, -Br or -F) and -C1-3 alkyl, and most preferably is H.

[0090] Preferably, R4is selected from H, halo (e.g., -Cl, -Br or -F), alkyl, alkenyl, alkynyl and haloalkyl (e.g., -CF3). More preferably, R4is selected from H, halo (e.g., -Cl, -Br or -F), -Ci_6alkyl, -C2.6 alkenyl, -C2.6alkynyl and -Ci_6haloalkyl (e.g., -CF3), such as from H, halo (e.g., - Cl, -Br or -F), -C1-3 alkyl, -C2.3alkenyl, -C2.3alkynyl and -C1-3 haloalkyl (e.g., -CF3). Even more preferably, R4is selected from H, halo (e.g., -Cl, -Br or -F) and -C1-3 alkyl, and most preferably is H.

[0091] Where R3and R4together with the carbon to which they are attached form a 3 to 6- membered cycloalkyl group, the compound of formula (I) will have the following structure: wherein n is either 0, 1 , 2, or 3, to form a 3, 4, 5, or 6-memebred cycloalkyl group, respectively.

[0092] Each R’ is independently selected from H and alkyl. Preferably, each R’ is independently selected from H and -Ci.6alkyl, and more preferably, each R’ is independently selected from H and -C1-3 alkyl, such as from H, methyl and ethyl. Most preferably, each R’ is H. In particular, it is preferable that the R’ group or groups which form part of L2are H.

[0093] According to the present invention, R” is selected from optionally substituted heterocyclic and carbocyclic groups. For the avoidance of doubt, it will be appreciated that “optionally substituted” applies to both heterocyclic and carbocyclic groups. For instance, R” is selected from optionally substituted 4 to 10 membered heterocyclic groups and 4 to 10-membered carbocyclic groups. Preferably, R” is selected from optionally substituted 4 to 10-membered heterocyclic groups, and more preferably, R” is selected from optionally substituted 4 to 10- membered heterocylcoalkyl groups.

[0094] For example, the 4 to 10-membered heterocycloalkyl group may be selected from azetidine, pyrrolidine, piperidine, piperazine, morpholine, or a bridged heterocycloalkyl group, such as 8-oxa-3-azabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane, or 2-oxa-5- azabicyclo[2.2.1]heptane. In preferred compounds, the R” comprises at least one amine group.

[0095] Where R” is substituted, it is preferably substituted with one or more groups selected from halo (e.g., -Cl, -Br or -F), -OR’, -NR’2, -Ci.6alkyl, -C2-6 alkenyl, -C2.6alkynyl, -Ci.6haloalkyl (e.g., -CF3) and -C(O)OR’.

[0096] As can be seen from the results of Example 1 , -C(O)R”, -S(O)R”, -S(O)2R”, -CH2R”, -OR” and -R” substituents on B are particularly suitable for providing high inhibitory activity against Hedgehog Acyltransferase. As can also be seen from the results of Example 1 , -C(O)R”, - S(O)R”, -S(O)2R”, -CH2R”, -OR” and -R” substituents on B also give rise to good solubility and / or tend to provide high metabolic stability. Thus, in one embodiment, the compound of formula (I) is a compound, or a pharmaceutically acceptable salt thereof, having the formula (HI): where: D is selected from optionally substituted arylene and heteroarylene groups; and

[0097] R7is selected from -C(O)R”, -S(O)R”, -S(O)2R”, -CH2R”, -CHFR”, -CF2R”, - CH(alkyl)R”, -C(alkyl)2R”, -OR” and -R”, where R” is selected from optionally substituted heterocyclic groups and carbocyclic groups. In some instances, R7is selected from -C(O)R”, -S(O)R” and -S(O)2R”, where R” is selected from optionally substituted heterocyclic groups and carbocyclic groups.

[0098] In some instances, R7is selected from -CH2R”, -CHFR”, -CF2R”, -CH(alkyl)R”, -C(alkyl)2R”, - OR” and -R”, where R” is selected from optionally substituted heterocyclic groups and carbocyclic groups. In some instances, R7is selected from -CH2R”, -OR”, and -R”, where R” is selected from optionally substituted heterocyclic groups and carbocyclic groups.

[0099] It will be appreciated that, the group “-D-R7” of formula (III) corresponds to group B of formula (I). For the avoidance of any doubt, the groups A, L1, L2, X and R1to R4, including preferred groups, are as defined above.

[0100] D is selected from optionally substituted aryl groups and heteroaryl groups. For the avoidance of doubt, it will be appreciated that “optionally substituted” applies to both aryl and heteroaryl groups. In preferred embodiments, D is selected from optionally substituted 6 to 12-membered arylene and 5 to 12-membered heteroarylene groups. More preferably, D is selected from optionally substituted 6-membered arylene and 5 to 6-membered heteroarylene groups. Most preferably, D is selected from optionally substituted 6- membered arylene and 6-membered heteroarylene groups.

[0101] For example, D may be an optionally substituted phenylene, pyridylene, pyrimidylene, or pyrazylene group.

[0102] In preferred compounds, D is substituted with at least one electron withdrawing group selected from halo (e.g., -Cl, -Br or -F), -CN, -NO2, -Ci_6haloalkyl (e.g., -CF3), -O-Ci.6haloalkyl (-OCF3), -C(O)OR’, -C(O)NR’2, -S(O)R’, -S(O)2R’, -S(O)2OR’, -S(O)NR’2and - S(O)2NR’2, and preferably from halo (e.g., -Cl, -Br or -F), -CN, -NO2, -Ci_6haloalkyl (e.g., - CF3) and -O-Ci_6haloalkyl (e.g., -OCF3). Most preferably, D is substituted with -CN. In the case that D is a 6-membered aryl or 6-membered heteroaryl group, the electron withdrawing group is preferably on B at one of the 3-position or 5-position relative to L2. In preferred embodiments, R7is on B at the other of the 3-position or 5-position relate to L2.

[0103] Preferably, R7is -C(O)R”. Preferably, R7is at the 3-position or the 5-position relative to L2. Preferred R” groups are as defined above. In cases where the bond between the two carbons attached to R1and R2, respectively, is a double bond, then the compound is a compound or a pharmaceutically acceptable salt thereof, having the formula (IV):

[0104] Exemplary compounds of the present invention include:

[0105] Preferred compounds of formula (I) are particularly effective inhibitors of Hedgehog Acyltransferase (HHAT). In some instances, the compound of formula (I) may be selected from compounds 1 , 3, 4, 9, 12, 15, 19, 20, 21 , 24, 25, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 38, 39, 40, 41 , 42, 44, 46, 47, 48, 51 , 53, 54, 55, 56, 57, 58, 59, 60, 61 , 63, 64, 65, 66, 67, 69, 70, 71 , 72, 73, 74, 75, 76, 78, 79, 80, 81 , 82, 83, 84, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96 and 97 or pharmaceutically acceptable salts thereof. In some instances, the compound of formula (I) may be selected from compounds 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 and 120 or pharmaceutically acceptable salts thereof.

[0106] Preferably, the compound of formula (I) is selected from compounds 1 , 3, 15, 19, 20, 24, 25, 28, 29, 30, 31 , 32, 33, 35, 36, 38, 39, 46, 47, 51 , 55, 58, 59, 63, 65, 72, 73, 74, 76, 80, 81 , 82, 83, 86, 87, 88, 89, 90, 91 , 93, 94, 95, 96 and 97 or pharmaceutically acceptable salts thereof. Preferably, the compound of formula (I) is selected from compounds 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 and 120 or pharmaceutically acceptable salts thereof. For instance, the compound of formula (I) may be selected from compounds 20, 28, 29, 31 , 32, 35, 47, 63, 73, 74, 81 , 89, 91 , 93, 95, 96 and 97 or pharmaceutically acceptable salts thereof, or from compounds 98, 99, 100, 101, 102, 103, 105, 106, 107, 108, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119 and 120 or pharmaceutically acceptable salts thereof. Compound 20, or a pharmaceutically acceptable salt thereof, is an example of a particularly preferred compound of formula (I).

[0107] In some instances, the compound of formula (I) may be selected from any one of compounds 4, 5, 9, 14 to 16, 18, 19, 21 to 25, 27, 28, 30, 33, 35, 37 to 57, 60 to 102 or a pharmaceutically acceptable salt thereof, or from any one of compounds 105 to 120 or a pharmaceutically acceptable salt thereof, or from any one of compounds 91a, 95a, 95b, 96a, 96b, 99a, 101a, 101b, 109a, 109b, 113a, 115a, 115b, and 116a or a pharmaceutically acceptable salt thereof. These compounds are believed to be previously unknown in any technical field.

[0108] In some embodiments, in the compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0109] R3and R4are each H;

[0110] A is not a cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, or heterocycloalkyl group;

[0111] B is not a heteroaryl group;

[0112] L2is not a heteroarylene group; and the compound of formula (l)is not:

[0113] Pharmaceutical compositions

[0114] The compounds of the present invention may be used in a pharmaceutical composition. Thus, in some aspects, the present invention provides a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0115] For the avoidance of any doubt, any of the specific limitations to A, B, L1, L2, X, R’, R”, R1, R2and R5and any substituents thereon, defined in the section above relating to “Compounds of Formula (I)”, may also be applied to the compound of formula (I) comprised within the pharmaceutical composition.

[0116] In some embodiments, the pharmaceutical composition comprises a compound of formula (I), wherein:

[0117] R3and R4are each H; wherein A is not a cycloalkyl group, heterocycloalkyl group, cycloalkenyl group, or heterocycloalkyl group; wherein B is not a heteroaryl group; and

[0118] L2is not a heteroarylene group: or a pharmaceutically acceptable salt thereof: provided that the compound is not:

[0119]

[0120] Such pharmaceutical compositions have not previously been disclosed.

[0121] In some instances, the pharmaceutical composition may comprise a compound selected from any one of compounds 1 to 25, 27 to 35 and 37 to 102 or a pharmaceutically acceptable salt thereof. In some instances, the pharmaceutical composition may comprise a compound selected from any one of compounds and 103 to 120 or a pharmaceutically acceptable salt thereof. In some instances, the pharmaceutical composition may comprise a compound selected from any one of compounds 91a, 95a, 95b, 96a, 96b, 99a, 101a, 101b, 109a, 109b, 113a, 115a, 115b, and 116a or a pharmaceutically acceptable salt thereof. A specifically preferred compound is compound 20 or a pharmaceutically acceptable salt thereof.

[0122] The pharmaceutical composition may comprise a compound of formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutically acceptable salt is an HCI salt.

[0123] The pharmaceutical composition will typically comprise one or more pharmaceutically acceptable excipients. For example, the one or more pharmaceutically acceptable excipients may be selected from a detectable agent, label, adjuvant, diluent, binder, stabilizer, filler, buffer, salt, lipophilic solvent, preservative, adjuvant and additive, for example proteins, peptides, amino acids, lipids and carbohydrates.

[0124] In some embodiments, the pharmaceutical composition may comprise at least one further active agent. Preferably, the further active agent is anti-cancer or anti-fibrotic agent.

[0125] The pharmaceutical composition can be formulated as a pharmaceutical composition for oral or parenteral administration. Oral administration may be in the form of a liquid or solid (e.g. tablet or capsule) pharmaceutical composition. Parental administration may be buccal, intravenous, intramuscular, subcutaneous, topical, transdermal, rectal or intranasal administration or in a form suitable for administration by inhalation or insufflation. Typically, the pharmaceutical formulation will be formulated for oral administration or intravenous administration.

[0126] Medical uses of the compounds

[0127] Compounds of formula (I), a pharmaceutically acceptable salts thereof, are particularly useful in methods of treating or preventing a disease associated with an aberrantly activated Hedgehog signalling pathway. Preferably, compounds of formula (I), or pharmaceutically acceptable salts thereof, are used to treat a disease associated with an aberrantly activated Hedgehog signalling pathway. For the avoidance of any doubt, any of the specific limitations to A, B, L1, L2, X, R’, R”, R1, R2and R5and any substituents thereon, defined in the section above relating to “Compounds of Formula (I)” (or indeed “Pharmaceutical Compositions”), may also be applied when it comes to medical uses of the compounds of formula (I). For instance, in some embodiments, the compound of formula (I) may be selected from compounds 1 to 102 and pharmaceutically acceptable salts thereof. For instance, in some embodiments, the compound of formula (I) may be selected from compounds 103 to 120 and pharmaceutically acceptable salts thereof. For instance, in some embodiments, the compound of formula (I) may be selected from compounds 91a, 95a, 95b, 96a, 96b, 99a, 101a, 101b, 109a, 109b, 113a, 115a, 115b, and 116a and pharmaceutically acceptable salts thereof.

[0128] The disease associated with an aberrantly activated Hedgehog signalling pathway may be selected from cancer, fibrotic diseases and chronic obstructive pulmonary disease. Preferably, the disease is selected from cancer and fibrotic diseases, and more preferably the disease is cancer.

[0129] The Hedgehog signalling pathway has been implicated in various forms of cancer. Thus, compounds which disrupt the Hedgehog signalling pathway have also been implicated in the treatment of various forms of cancer (see, e.g., Rimkus et al “Targeting the Sonic Hedgehog Signaling Pathway: Review of Smoothened and GLI Inhibitors” (2016), Cancers- 8(2):22. https: / / doi.org / 10.3390 / cancers8020022). In some instances, the cancer may be selected from medulloblastoma, rhabdomyosarcomas, intracranial meningioma, adenocarcinoma, hepatocellular carcinoma, bone cancer, brain cancer, breast cancer, lung cancer, colon cancer, colorectal cancer, pancreatic cancer, skin cancer (such as basal cell carcinoma), prostate cancer, oesophageal cancer, ovarian cancer, gliomas, mesothelioma and leukaemia (such as myeloid leukemia); preferably, the cancer may be selected from breast cancer, lung cancer, colon cancer, colorectal cancer, pancreatic cancer, leukaemia and basal cell carcinoma.

[0130] In some instances, the cancer may be a dormant cancer, or the cancer is in a dormant stage or quiescent state. In particular, the dormant cancer may be a dormant leukaemia. Dormancy is a stage in cancer progression where the cells cease dividing but survive in a quiescent state while waiting for appropriate environmental conditions to begin proliferation again. Dormant cancer cells are thought to be present in early tumour progression, in micrometastases, or left behind in minimal residual disease after what was thought to be a successful treatment of the primary tumour. Glasdegib (RTM) is a known anticancer drug that has been shown to bind and inhibit Smoothened protein. Glasdegib (RTM) has been shown to abrogate leukaemia-initiation potential and leukaemia stem cell dormancy in chronic myeloid leukaemia and acute myeloid leukaemia cells - see Sadarangani A, et al “GLI2 inhibition abrogates human leukemia stem cell dormancy” (2015), J Transl Med, Mar 21 ;13:98. doi: 10.1186 / sl 2967-015-0453-9. PMID: 25889765; PMCID: PMC4414375. In a similar way, compounds of formula (I) may be used in the treatment or prevention of dormant cancers which may be resistant to traditional treatments.

[0131] Compounds of formula (I), and their pharmaceutically acceptable salts, may also be used in the treatment or prevention of a fibrotic disease. The fibrotic disease may be selected from pulmonary fibrosis, liver fibrosis and systemic sclerosis.

[0132] More broadly, the compounds of formula (I), or a pharmaceutically acceptable salt thereof, may be used as a medicament. Thus, the compounds and salts may be used in therapy, for instance in a method of treating or preventing a disease. In these embodiments, the compound of formula (I) is preferably as described in the section above relating to “Pharmaceutical Compositions”.

[0133] The present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in treating or preventing a disease, preferably associated with an aberrantly activated Hedgehog (HH) signalling pathway.

[0134] The compounds of formula (I) are preferably used for treating a mammalian subject, and more preferably a human subject.

[0135] The compound may be administered to a subject in therapeutically effective amount. For instance, the compound may be administered in a dosage of from 0.01 mg / kg to 100 mg / kg, preferably 0.1 mg / mg to 50 mg / kg.

[0136] In some instances, the compound of formula (I) may be administered one or more times per day. For example, a compound of formula (I) dosage may be dosed once daily, twice daily, or thrice daily. The compound of formula (I) may be administered one or more times per day for a period of at least 3 days, for instance at least 7 days.

[0137] Other dosages and dosage regimes may also be used. A skilled physician would be able to appropriately dose a patient taking into account the relevant factors such as route of administration, patient body mass, sex, age, co-morbidities, etc. It will be appreciated that the compounds of formula (I) will generally be used in medicine in the form of a pharmaceutical composition, such as described in the section above relating to “Pharmaceutical Compositions”.

[0138] The present invention will now be described by way of the following non-limiting examples.

[0139] Example 1 - Hedgehog Acyltransferase (HHAT) Inhibitory Activity

[0140] The evaluation of purified Hedgehog Acyltransferase (HHAT) inhibitors of the present invention was performed using an Acyl-cLIP assay, as described in Lanyon-Hogg et al “Acylation-coupled lipophilic induction of polarisation (Acyl-cLIP): a universal assay for lipid transferase and hydrolase enzymes” (2019), Chem Sci, 10, 8995-9000, doi:10.1039 / c9sc01785b. The N-terminal part of Sonic Hedgehog peptide (SHH - residues 24-33) was labelled with fluorescein (SHH-FAM) or TAMRA (SHH-TAMRA). Upon palmitoylation from HHAT, the palmitoylated SHH peptide binds to macromolecules present in the assay, resulting to slower tumbling and this leads to increased fluorescence polarisation. HHAT inhibition by small molecules blocks the palmitoylation process and as a result stops this increase in fluorescence anisotropy measurements. A range of concentrations was tested for each compound in order to define their inhibitory activity against HHAT.

[0141] The assay shows compounds of the present invention to be active HHAT inhibitors, with compounds 4, 9, 12, 21 , 27, 34, 40, 41 , 42, 44, 48, 53, 54, 56, 57, 60, 61 , 64, 66, 67, 69, 70, 71 , 75, 78, 79, 84, 92 and 109 shown to be good inhibitors (1 pM < IC5o 20 pM), compounds 1 , 3, 15, 19, 24, 25, 30, 33, 36, 38, 39, 46, 51 , 55, 58, 59, 65, 72, 76, 80*, 82, 83, 86, 87, 88, 90, 94, and 104 shown to be very good inhibitors (0.1 pM < IC5o 1 pM), and compounds 20, 28, 29, 31 , 32, 35, 47, 63, 73, 74, 81 , 89, 91 , 93, 95, 96*, 97*, 98, 99, 100, 101*, 102*, 103, 105, 106*, 107, 108*, 110*, 111*, 112*, 113*, 114, 115, 116*, 117, 118, 119 and 120 showing excellent inhibitory activity (IC5o 0.1 pM).

[0142] Example 2 - Biological Evaluation of Hedgehog Acyltransferase Inhibitors

[0143] Selected compounds demonstrating high potency against HHAT in the Acyl-cLIP assay were tested in a cellular assay to evaluate inhibition of HH signalling. As HH signalling is mainly paracrine, two different cell lines were used: HEK293 modified to overexpress SHH (as the signal sending cell line) and NIH-3T3 modified with the Gli-GFP construct (as the signal receiving cell line). In these receiving cells, GFP was genetically incorporated after the Gli promoter, therefore, the stimulated Gli transcription, after HH pathway activation, could also induce GFP transcription and translation to provide a fluorescent readout. The signal sending cell line was incubated with a serial dilution of compound stock solution. After 24 hours, the conditioned media was transferred to the signal receiving cell line. When there is no HHAT inhibition, the conditioned media with large amount of palmitoylated-activated SHH produced by signal sending cells, triggers the transcription of Gli which also produces a GFP signal. After media transfer, the signal receiving cells were incubated in the IncuCyte to measure the level of GFP signal, which is inversely proportional to the inhibitory activity of the compound. This assay imitates HH signalling between cells in disease settings (for example how cancer cells communicate with surrounding fibroblast and immune cells in the tumour microenvironment). The strong inhibitory activity exhibited by several compounds of the invention, supports their use in vivo in HH-related cancer and fibrotic models. Nonlimiting examples of compounds which demonstrate high inhibitory activity in the cellular ‘Gli- GFP’ assay (IC50< 0.5 pM) are 20, 28, 29, 31, 32, 35, 47, 63, 73, 74, 80*, 81, 82, 86, 89, 91, 93, 96*, 98, 99, 100, 101*, 102*, 105, 107, 110*, 111*, 112*, 113*, 114, 115, 116*, 117, 118, 119 and 120.

[0144] Example 3 - Pharmacokinetic Properties of Hedgehog Acyltransferase Inhibitors

[0145] As part of the pharmacokinetic optimisation of this series, in order to discover suitable compounds for in vivo studies, the kinetic solubility in PBS pH 7.4 and metabolic stability in mouse liver microsomal (MLM) assays of selected compounds have been evaluated (see Table 1 below).

[0146] Table 1. Solubility and metabolic stability (MLM) of selected HHAT inhibitors.

[0147] It is evident that many of these compounds have moderate-high solubility and low-moderate clearance, which allows their use in vivo. Based on the in vitro high metabolic stability, a representative compound of this series, compound 20, was selected for in vivo pharmacokinetic studies, as it also showed high permeability in a Caco-2 assay (A>B 22.8 x 106cm / s, efflux ratio 0.75). Compound 20 was dosed in BALB\c mice i.v. at 0.5 mg / kg and p.o. at 5 mg / kg, the results are depicted in Figure

[0148] 1. Post-dosing measurements demonstrated that 20 is orally bioavailable (F 26%) and has low clearance (Clh7.12 ml / min / kg). These results indicate that 20 can be used as an HHAT inhibitor in vivo in HH-related disease models. Compound 20 is the first HHAT inhibitor that has ever been confirmed to be orally bioavailable and have suitable pharmacokinetic properties for use in vivo. Along with its high potency in enzymatic and cellular assays, 20 represents a significantly higher quality HHAT inhibitor than those known to-date.

[0149] Example 4 - Synthesis of Hedgehog Acyltransferase Inhibitors

[0150] Method A (Synthesis of substituted pyridazin-3(2H)-one intermediates) a. (i) Glyoxylic acid, 80 °C; (ii) hydrazine, 100 °C.

[0151] Substituted acetophenone (5.0 mmol) [or 1-(4-chlorophenyl)propan-1-one] and glyoxylic acid solution 50% wt in water (2.0 mmol) were stirred at 80 °C for 3 h. Upon completion, the reaction mixture was cooled down to room temperature and pH was adjusted to 8-9 by adding ammonia solution. The mixture was partitioned between water and ethyl acetate and the aqueous layer was collected for the next step. Hydrazine (8.0 mmol) was added and heated to 100 °C for 18 h. The mixture was cooled down in an ice bath and filtered under reduced pressure to get the pure product.

[0152] 6-(4-Fluorophenyl)pyridazin-3(2H)-one

[0153] The title compound was synthesized according to Method A from 1-(4-fluorophenyl)ethan-1- one. Off-white solid (25%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 13.21 (s, 1 H), 8.04 (d, J = 9.9 Hz, 1 H), 7.95 - 7.88 (m, 2H), 7.33 (t, J = 8.8 Hz, 2H), 7.00 (d, J = 9.9 Hz, 1 H).13C NMR (101 MHz, DMSO-cfe) 5 164.4, 162.0, 160.6, 143.4, 131.9, 131.65, 131.62, 130.7, 128.4, 128.3, 116.4, 116.2.

[0154] 6-(4-Chlorophenyl)pyridazin-3(2H)-one

[0155] The title compound was synthesized according to Method A from 1-(4-chlorophenyl)ethan-1- one. Off-white solid (50%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 13.26 (s, 1 H), 8.05 (d, J = 9.9 Hz, 1 H), 7.93 - 7.84 (m, 2H), 7.58 - 7.50 (m, 2H), 7.00 (d, J = 9.9 Hz, 1 H).13C NMR (101 MHz, DMSO-cfe) 6 160.2, 142.7, 134.0, 133.5, 131.3, 130.2, 128.9, 127.4. ES(+) m / z 207.0 [M+H]+. 6-(4-Bromophenyl)pyridazin-3(2H)-one

[0156] The title compound was synthesized according to Method A from 1-(4-bromophenyl)ethan-1- one. Off-white solid (51%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 0 13.25 (s, 1 H), 8.14 - 7.98 (m, 1 H), 7.82 (d, J = 6.5 Hz, 2H), 7.69 (d, J = 5.8 Hz, 2H), 7.13 - 6.91 (m, 1 H).13C NMR (101 MHz, DMSO-cfe) 0 160.6, 143.3, 134.3, 132.3,

[0157] 131.9, 131.7, 130.7, 128.2, 123.2.

[0158] 6-(4-Methylphenyl)pyridazin-3(2H)-one

[0159] The title compound was synthesized according to Method A from 1-(4-methylphenyl)ethan-1- one. Off-white solid (51%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 0 13.15 (s, 1 H), 8.01 (d, J = 9.9 Hz, 1 H), 7.76 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 9.9 Hz, 1 H), 2.35 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 0 160.7, 144.2, 139.2, 132.3, 131.8, 130.6, 129.9, 126.0, 21.3.

[0160] 6-(4-(Trifluoromethyl)phenyl)pyridazin-3(2H)-one

[0161] The title compound was synthesized according to Method A from 1-(4- (trifluoromethyl)phenyl)ethan-1-one. Off-white solid (45%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-d6) 0 13.36 (s, 1 H), 8.31 - 8.00 (m, 3H), 7.86 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 9.9 Hz, 1 H).13C NMR (101 MHz, DMSO-cfe) 0 160.7, 142.9,

[0162] 138.9, 131.9, 130.7, 126.9, 126.30, 126.26.

[0163] 6-(4-Methoxyphenyl)pyridazin-3(2H)-one

[0164] The title compound was synthesized according to Method A from 1-(4-methoxyphenyl)ethan- 1-one. Off-white solid (59%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 0 13.07 (s, 1 H), 8.00 (d, J = 9.9 Hz, 1 H), 7.81 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 9.9 Hz, 1 H), 3.81 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 0 160.6, 144.1 , 131.8, 130.5, 127.5, 114.8, 55.7.

[0165] 6-(3-Chlorophenyl)pyridazin-3(2H)-one

[0166] The title compound was synthesized according to Method A from 1-(3-chlorophenyl)ethan-1- one. Off-white solid (36%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 0 13.30 (s, 1 H), 8.09 (d, J = 9.9 Hz, 1 H), 7.91 (s, 1 H), 7.84 (d, J = 3.9 Hz, 1 H), 7.52 (d, J = 4.7 Hz, 2H), 7.01 (d, J = 9.9 Hz, 1H).13C NMR (101 MHz, DMSO-cfe) 0 160.7,

[0167] 142.9, 137.2, 134.3, 131.9, 131.3, 130.7, 129.4, 125.8, 124.8.

[0168] 6- i-one The title compound was synthesized according to Method A from 1-(2-fluorophenyl)ethan-1- one. White solid (18%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 0 12.35 (s, 1H), 7.75 (dd, J = 9.9, 2.5 Hz, 1 H), 7.67 (t, J = 7.9 Hz, 1 H), 7.57 - 7.44 (m, 1 H), 7.43 - 7.24 (m, 2H), 6.99 (d, J = 9.8 Hz, 1 H).13C NMR (101 MHz, DMSO-cfe) 0 160.7, 160.0, 158.3, 141.1 , 134.04, 133.98, 131.45, 131.36, 129.9, 129.7, 124.99, 124.96, 123.2, 123.1 , 116.5, 116.2.

[0169] 6-(3,5-Difluorophenyl)pyridazin-3(2H)-one

[0170] The title compound was synthesized according to Method A from 1-(3,5- difluorophenyl)ethan-1-one. Off-white solid (20%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-d6) 0 13.38 (s, 1 H), 8.12 (d, J = 10.0 Hz, 1 H), 7.68 - 7.52 (m, 2H), 7.36 (tt, J = 9.2, 2.2 Hz, 1 H), 7.04 (d, J = 9.9 Hz, 1H).13C NMR (101 MHz, DMSO-cfe) 0 164.6, 162.1 , 160.7, 142.0, 138.7, 131.7, 130.6, 109.4, 105.2, 105.0.

[0171] 6-(Benzo[d][1 ,3ldioxol-5-yl)pyridazin-3(2H)-one

[0172] The title compound was synthesized according to Method A from 1-(benzo[d][1 ,3]dioxol-5- yl)ethan-1-one. White solid (43%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 0 13.10 (s, 1 H), 7.99 (d, J = 9.9 Hz, 1 H), 7.39 (d, J = 11.1 Hz, 2H), 7.02 (d, J = 8.1 Hz, 1 H), 6.95 (d, J = 9.9 Hz, 1 H), 6.09 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 0 160.6, 148.7, 148.5, 143.9, 131.9, 130.5, 129.3, 120.4, 109.0, 106.1 , 101.9.

[0173] 6-(Thiophen-3-yl)pyridazin-3(2H)-one

[0174] The title compound was synthesized according to Method A from 1-(thiophen-3-yl)ethan-1- one. Brown solid (33%). Rf: 0.7 (10% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 0 13.05 (s, 1 H), 8.10 (d, J = 2.7 Hz, 1 H), 8.00 (d, J = 9.8 Hz, 1 H), 7.67 (dd, J =

[0175] 5.1 , 2.9 Hz, 1 H), 7.55 (d, J = 5.0 Hz, 1 H), 6.98 (d, J = 9.8 Hz, 1 H).13C NMR (101 MHz, DMSO-cfe) 0 160.6, 141.4, 137.6, 132.3, 130.6, 128.2, 125.6, 124.4.

[0176] 6-(2,4-Dichlorophenyl)pyridazin-3(2H)-one

[0177] The title compound was synthesized according to Method A from 1-(2,4- dichlorophenyl)ethan-1-one. White solid (25%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 0 12.91 (s, 1 H), 7.85 - 7.75 (m, 1 H), 7.68 (d, J = 9.8 Hz, 1 H), 7.61 - 7.51 (m, 2H), 6.98 (d, J = 9.8 Hz, 1 H).13C NMR (101 MHz, DMSO-cfe) 0 160.5, 143.6,

[0178] 135.1 , 134.9, 134.1 , 133.0, 132.8, 129.9, 129.6, 128.3.

[0179] 6-(3,4-Di> i-one The title compound was synthesized according to Method A from 1-(3,4- dichlorophenyl)ethan-1-one. White solid (27%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 0 13.31 (s, 1 H), 8.11 (dd, J = 5.9, 4.0 Hz, 2H), 7.87 (dd, J = 8.5, 2.0 Hz, 1 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.02 (d, J = 9.9 Hz, 1 H).13C NMR (101 MHz, DMSO-cfe) 0 165.4, 146.8, 140.4, 137.0, 136.4, 135.5, 135.3, 132.7, 132.6, 131.0, 130.9.

[0180] 6-(4-Chlorophenyl)-5-methylpyridazin-3(2H)-one

[0181] The title compound was synthesized according to Method A from 1-(4-chlorophenyl)propan- 1-one. White solid (9%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 0 13.10 (s, 1 H), 7.53 (m, 4H), 6.85 (s, 1 H), 2.12 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 0 160.9, 146.9, 143.6, 135.1 , 134.0, 131.1 , 128.8, 128.8, 20.2.

[0182] Method B (Synthesis of intermediate - 6-(5-chloropyridin-2-yl)pyridazin-3(2H)-one) a. (i) Glyoxylic acid, K2CO3, MeOH, H2O, 80 °C; (ii) acetic acid (gl.), hydrazine, 100 °C.

[0183] To a suspension of 1-(5-chloropyridin-2-yl)ethan-1-one (210 mg, 1.35 mmol) in methanol (2 mL) under nitrogen, was added water (3 mL) and glyoxylic acid solution 50% wt in water (150 uL, 1.35 mmol). Then, potassium carbonate (373 mg, 2.70 mmol) was added and the reaction was heated to 80 °C for 3 h. The mixture was partially concentrated, diluted with water and washed (x2) with ethyl acetate. The aqueous phase was treated carefully with glacial acetic acid (1 mL), then hydrazine monohydrate was added (120 uL, 1.62 mmol) and refluxed for 18 h. After cooling, the mixture was neutralised with sodium bicarbonate, extracted (x3) with ethyl acetate, the combined organic layers were washed with brine and concentrated under reduced pressure. Purification with flash column chromatography (50- 100% ethyl acetate in hexane) afforded 6-(5-chloropyridin-2-yl)pyridazin-3(2H)-one (75 mg, 27%) as an off-white solid.1H NMR (400 MHz, DMSO-cfe) 6 13.37 (s, 1 H), 8.70 (t, J = 1.6 Hz, 1H), 8.23 (d, J = 9.9 Hz, 1 H), 8.08 - 8.01 (m, 2H), 7.02 (d, J = 9.9 Hz, 1H).13C NMR (101 MHz, DMSO-cfe) 5 160.6, 150.5, 147.7, 142.6, 137.3, 131.4, 130.5, 130.2, 120.8. ES(+) m / z 208.1 [M+H]+. Method C (Synthesis of intermediates - 6-(4-chlorophenyl)pyridazin-3(2H)-one and 6-(4- chloro-3-fluorophenyl)pyridazin-3(2H)-one) a. Pd(dppf)CI2, K2CO3, Dioxane / Water 4 / 1 , 100 °C.

[0184] (Alternative synthesis described under Method A) A mixture of 6-bromopyridazin-3(2H)-one (2.00 g, 11.4 mmol), (4-chlorophenyl)boronic acid (1.97 g, 12.6 mmol), potassium carbonate (3.95 g, 28.6 mmol) and [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (836 mg, 1.14 mmol) in dioxane (40 mL) and water (10 ml_), was evacuated and purged with nitrogen, and the reaction was heated to 100 °C for 18 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. Saturated ammonium chloride aqueous solution was added to the residue, and after extraction (x3) with ethyl acetate, the combined layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography (50-100% ethyl acetate in hexane) afforded 6-(4-chlorophenyl)pyridazin-3(2H)-one (1.22 g, 5.90 mmol, 52%) as an off-white solid. Characterization data under Method A.

[0185] 6-(4-chloro-3-fluorophenyl)pyridazin-3(2H)-one was synthesized according to the same procedure using (4-chloro-3-fluorophenyl)boronic acid. Beige solid (40%).1H NMR (400 MHz, DMSO-cfe) 5 13.33 (s, 1 H), 8.08 (d, J = 10.0 Hz, 1 H), 7.89 (dd, J = 10.9, 2.0 Hz, 1 H), 7.78 - 7.65 (m, 2H), 7.02 (d, J = 9.9 Hz, 1 H).19F NMR (377 MHz, DMSO-cfe) 5 -115.4.13C NMR (101 MHz, DMSO-cfe) 6 160.2, 158.8, 156.3, 141.8, 135.8, 135.7, 131.25, 131.18, 130.2, 122.8, 122.8, 120.4, 120.2, 114.1 , 113.8. ES(+) m / z 225.0 [M+H]+.

[0186] Method D (Synthesis of NH-linked pyridazin-3(2H)-one intermediates) a. Amine (neat), 70 °C; b. acetic acid, reflux. A mixture of 3,6-dichloropyridazine (5.0 mmol) and substituted aniline (5.0 mmol) was heated to 70 °C for 3-18 h. The reaction was allowed to return to room temperature, ethanol was added and the mixture was poured into ice-cold water. The precipitate was filtered and dried under reduced pressure to provide the desired product which was used directly in the next step. The product was added to acetic acid (15 mL) and the reaction was heated to reflux for 18 h. The mixture was concentrated under reduced pressure and the residue was purified with flash column chromatography (1-2% methanol in dichloromethane) to afford the desired intermediates, which were used directly in the next step (Method R).

[0187] Method E (Synthesis of intermediate - 6-phenoxypyridazin-3(2H)-one) a. Phenol, NaH, DMF, RT; b. acetic acid, reflux.

[0188] To a mixture of 3,6-dichloropyridazine (5.0 mmol) and phenol (5.0 mmol) in anhydrous DMF (5 mL) under nitrogen, sodium hydride (132 mg, 5.5 mmol) was added portionwise and the reaction stirred at room temperature for 2 h. Ethanol was added and the mixture was poured into ice-cold water. The precipitate was filtered and dried under reduced pressure to provide the desired product, as a white solid, which was used directly in the next step. The product was added to acetic acid (15 mL) and the reaction was heated to reflux for 18 h. The mixture was concentrated under reduced pressure to afford 6-phenoxypyridazin-3(2H)-one, which was used directly in the next step (Method R).

[0189] Method F of substituted chloroacetamide and 2-i intermediates') a. Chloroacetyl chloride or 2-chloropropanoyl chloride, K2CO3, THF or acetone, RT.

[0190] Substituted aniline or indole or thiophene (3.0 mmol) was dissolved in tetra hydrofuran or acetone (10 mL) under nitrogen, potassium carbonate (6.0 mmol) and chloroacetyl chloride (or 2-chloropropanoyl chloride) (3.3 mmol) were added and the reaction was stirred at room temperature for 3-18 h. The mixture was concentrated, the residue was triturated with water and filtered under reduced pressure (or alternatively extracted with ethyl acetate) to provide the desired chloroacetamide and 2-chloropropanamide intermediates.

[0191] 2-Chloro-N-

[0192] The title compound was synthesized according to Method F from aniline and chloroacetyl chloride in acetone. Off-white solid (38%). Rf: 0.7 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 0 10.30 (s, 1 H), 7.59 (d, J = 8.1 Hz, 2H), 7.34 (t, J = 7.8 Hz, 2H), 7.10 (t, J = 7.3 Hz, 1 H), 4.26 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 0 165.1 , 138.9, 129.3, 124.30, 119.8, 44.0.

[0193] 2-Chloro-N-(2-cyanophenyl)acetamide

[0194] The title compound was synthesized according to Method F from 2-aminobenzonitrile and chloroacetyl chloride in acetone. Light yellow solid (36%). Rf: 0.6 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 0 10.51 (s, 1 H), 7.85 (d, J = 7.8 Hz, 1 H), 7.78 - 7.67 (m, 1 H), 7.63 (d, J = 7.0 Hz, 1 H), 7.41 (t, J = 7.6 Hz, 1 H), 4.38 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 0 165.9, 139.8, 134.4, 133.8, 126.7, 126.0, 117.0, 107.8, 43.3.

[0195] 2-Chloro-N-(3-cyanophenyl)acetamide

[0196] The title compound was synthesized according to Method F from 3-aminobenzonitrile and chloroacetyl chloride in acetone. Off-white solid (65%). Rf: 0.6 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.66 (s, 1 H), 8.08 (s, 1 H), 7.82 (s, 1 H), 7.66 - 7.49 (m, 2H), 4.31 (s, 2H).13C NMR (101 MHz, DMSO-d6) 5 165.8, 139.7, 130.9, 127.9, 124.4, 122.5, 119.0, 112.2, 43.9.

[0197] 2-Chloro-N-

[0198] The title compound was synthesized according to Method F from 4-aminobenzonitrile and chloroacetyl chloride in acetone. Off-white solid (79%). Rf: 0.6 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.73 (s, 1 H), 7.84 - 7.73 (m, 4H), 4.31 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.4, 142.7, 133.4, 119.4, 118.9, 105.6, 43.6.

[0199] 2-Chloro-N-(3-vinylphenyl)acetamide

[0200] The title compound was synthesized according to Method F from 3-vinylaniline and chloroacetyl chloride in acetone. Off-white solid (74%). Rf: 0.7 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.42 (s, 1 H), 8.14 (d, J = 9.8 Hz, 1 H), 7.91 (d, J = 6.8 Hz, 2H), 7.75 (s, 1 H), 7.55 - 7.44 (m, 5H), 7.32 (t, J = 7.8 Hz, 1 H), 7.20 (d, J = 7.6 Hz, 1 H), 7.13 (d, J = 9.8 Hz, 1 H), 6.71 (dd, J = 17.6, 10.9 Hz, 1 H), 5.77 (d, J = 17.6 Hz, 1H), 5.28 (d, J = 11.1 Hz, 1 H), 5.01 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 0 165.2, 139.2, 138.1 , 137.0, 129.6, 122.2, 119.5, 117.4, 115.1 , 44.0.

[0201] 2-Chloro-N-(3-ethynylphenyl)acetamide

[0202] The title compound was synthesized according to Method F from 3-ethynylaniline and chloroacetyl chloride in acetone. Off-white solid (69%). Rf: 0.7 (5% methanol in dichloromethane).1H NMR (400 MHz, CDCh) 6 8.26 (s, 1 H), 7.71 (s, 1 H), 7.61 (d, J = 7.0 Hz, 1 H), 7.39 - 7.30 (m, 2H), 4.22 (s, 2H), 3.12 (s, 1 H).13C NMR (101 MHz, CDCI3) 0 163.8, 136.7, 129.2, 128.9, 123.45, 123.1 , 120.5, 82.8, 77.9, 42.8.

[0203] 2-Chloro-N-

[0204] The title compound was synthesized according to Method F from 3-(trifluoromethyl)aniline and chloroacetyl chloride in acetone. Brown solid (55%). Rf: 0.7 (5% methanol in dichloromethane).1H NMR (400 MHz, CDCh) 6 8.37 (s, 1 H), 7.87 (s, 1 H), 7.80 (d, J = 8.0 Hz, 1 H), 7.52 (t, J = 7.9 Hz, 1 H), 7.46 (d, J = 7.8 Hz, 1 H), 4.24 (s, 2H).13C NMR (101 MHz, CDCh) 0 164.0, 137.2, 129.8, 123.1 , 121.9, 121.8, 116.9, 116.8, 42.8.

[0205] Ethyl 3-(2-chloroacetamido)benzoate

[0206] The title compound was synthesized according to Method F from ethyl 3-aminobenzoate and chloroacetyl chloride in acetone. Off-white solid (52%). Rf: 0.7 (5% methanol in dichloromethane).1H NMR (400 MHz, CDCh) 6 8.46 (s, 1H), 8.08 - 8.03 (m, 1 H), 7.96 - 7.90 (m, 1 H), 7.86 - 7.81 (m, 1 H), 7.43 (m, 1 H), 4.37 (q, J = 7.2 Hz, 2H), 4.21 (s, 2H), 1.39 (t, J = 7.2 Hz, 3H).13C NMR (101 MHz, CDCh) 6 166.1 , 164.2, 137.1 , 131.5, 129.4, 126.3, 124.6, 121.1 , 61.4, 43.0, 14.4.

[0207] 2-Chloro-N-

[0208] The title compound was synthesized according to Method F from 4-nitroaniline and chloroacetyl chloride in acetone. The crude mixture was used directly in the next step without further purification.

[0209] 2-Chloro-N-

[0210] The title compound was synthesized according to Method F from 4-chloroaniline and chloroacetyl chloride in acetone. The crude mixture was used directly in the next step without further purification.

[0211] 2-Chloro-N-(3-cyano-4-fluorophenyl)acetamide The title compound was synthesized according to Method F from 5-amino-2- fluorobenzonitrile and chloroacetyl chloride in acetone. Off-white solid (51%). Rf: 0.7 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 11.29 (s, 1 H), 8.61 (d, J = 4.6 Hz, 1 H), 8.34 (s, 1 H), 7.62 (d, J = 4.3 Hz, 1 H), 4.39 (s, 2H).13C NMR (101 MHz, DMSO- cfe) 5 166.6, 152.5, 150.4, 121.9, 121.6, 117.3, 115.6, 43.8.

[0212] 2-Chloro-N-(3-cyano-5-fluorophenyl)acetamide

[0213] The title compound was synthesized according to Method F from 3-amino-5- fluorobenzonitrile and chloroacetyl chloride in acetone. Off-white solid (44%). Rf: 0.7 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.83 (s, 1 H), 7.89 - 7.70 (m, 2H), 7.60 (d, J = 8.2 Hz, 1 H), 4.32 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.1 , 163.4, 161.0, 141.6, 141.5, 119.2, 117.9, 114.8, 114.6, 113.5, 113.4, 111.7, 111.4, 43.9.

[0214] 2-Chloro-N-(4-cyanopyridin-2-yl)acetamide

[0215] The title compound was synthesized according to Method F from 2-aminoisonicotinonitrile and chloroacetyl chloride in THF. Beige solid (37%). Rf: 0.3 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 6 11.29 (s, 1 H), 8.61 (d, J = 4.6 Hz, 1 H), 8.34 (s, 1 H), 7.62 (d, J = 4.3 Hz, 1 H), 4.39 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.6, 152.5, 150.4, 121.9, 121.6, 117.3, 115.5, 43.8. ES(-) m / z 194.0 [M-H]’.

[0216] 2-Chloro-N-(3-fluorophenyl)acetamide

[0217] The title compound was synthesized according to Method F from 3-fluoroaniline and chloroacetyl chloride in THF. Beige solid (99%). Rf: 0.5 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.52 (s, 1 H), 7.58 (d, J = 11.6 Hz, 1 H), 7.42 - 7.33 (m, 1 H), 7.33 - 7.24 (m, 1 H), 6.92 (t, J = 8.5 Hz, 1 H), 4.27 (s, 2H).19F NMR (377 MHz, DMSO-cfe) 5 - 111.80.13C NMR (101 MHz, DMSO-cfe) 5 165.0, 163.3, 160.9, 140.2, 140.1 , 130.6, 130.5, 115.1 , 110.4, 110.2, 106.3, 106.0, 43.5. ES(+) m / z 188.1 [M+H]+.

[0218] 2-Chloro-N-(3-chlorophenyl)acetamide

[0219] The title compound was synthesized according to Method F from 3-chloroaniline and chloroacetyl chloride in THF. Beige solid (98%). Rf: 0.5 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.53 (s, 1 H), 7.80 (s, 1 H), 7.53 - 7.41 (m, 1 H), 7.41 - 7.29 (m, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 4.27 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.0, 139.9, 133.2, 130.6, 123.6, 118.8, 117.8, 43.5. ES(+) m / z 204.0 [M+H]+.

[0220] 3-(2-Chloroacetamido)benzamide The title compound was synthesized according to Method F from 3-aminobenzamide and chloroacetyl chloride in THF. Beige solid (72%). Rf: 0.3 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 6 10.46 (s, 1 H), 8.04 (s, 1 H), 7.97 (s, 1 H), 7.75 (s, 1 H), 7.57 (s, 1H), 7.38 (s, 2H), 4.27 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 6 167.7, 164.8, 138.5, 135.2, 128.7, 122.6, 122.1 , 119.0, 43.6. ES(+) m / z 213.1 [M+H]+.

[0221] 2-Chloro-N-(3-(dimethylamino)phenyl)acetamide

[0222] The title compound was synthesized according to Method F from / V^Af-dimethylbenzene- 1 ,3-diamine dihydrochloride and chloroacetyl chloride in THF. The product was further was purified with flash column chromatography (10-30% ethyl acetate in hexane). Beige solid (16%). Rf: 0.6 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.10 (s, 1 H), 7.11 (t, J = 8.1 Hz, 1 H), 6.99 (t, J = 2.3 Hz, 1 H), 6.91 (dd, J = 7.9, 1.8 Hz, 1 H), 6.46 (dd, J = 8.4, 2.5 Hz, 1 H), 4.22 (s, 2H), 2.87 (s, 6H).13C NMR (101 MHz, DMSO-cfe) 5 164.4, 150.8, 139.2, 129.2, 108.3, 107.5, 103.3, 43.7, 40.1 ,ES(+) m / z 213.1 [M+H]+.

[0223] 2-Chloro-N-(6-cyano-1 H-indol-4-yl)acetamide

[0224] The title compound was synthesized according to Method F from 4-amino-1H-indole-6- carbonitrile and chloroacetyl chloride in THF. Beige solid (95%). Rf: 0.4 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 11.79 (s, 1 H), 10.24 (s, 1 H), 7.98 (s, 1 H), 7.71 (s, 1H), 7.67 - 7.60 (m, 1 H), 6.93 - 6.82 (m, 1H), 4.43 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.5, 135.5, 130.7, 129.0, 123.1 , 120.5, 113.1 , 111.8, 102.4, 99.9, 43.5. ES(-) m / z 231 .9 [M-H]-.

[0225] 2-Chloro-N-(5-cyanothiophen-2-yl)acetamide

[0226] The title compound was synthesized according to Method F from 5-aminothiophene-2- carbonitrile and chloroacetyl chloride in THF. Beige solid (79%). Rf: 0.4 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 12.38 (s, 1 H), 7.76 (d, J = 4.2 Hz, 1 H), 6.84 (d, J = 4.2 Hz, 1 H), 4.41 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 164.6, 145.4, 137.0, 115.4, 112.3, 98.5, 42.2. ES(-) m / z 198.8 [M-H]-.

[0227] 2-Chloro-N-(3-cyano-2-fluorophenyl)acetamide

[0228] The title compound was synthesized according to Method F from 3-amino-2- fluorobenzonitrile and chloroacetyl chloride in THF. Beige solid (80%). Rf: 0.6 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.45 (s, 1 H), 8.27 - 8.14 (m, 1 H), 7.71 (ddd, J = 7.6, 5.8, 1.6 Hz, 1 H), 7.40 (t, J = 8.0 Hz, 1 H), 4.39 (s, 2H).19F NMR (377 MHz, DMSO-cfe) 5 -118.88.13C NMR (101 MHz, DMSO-cfe) 5 165.5, 155.5, 152.9, 129.5, 129.2, 126.6, 126.5, 125.7, 125.6, 113.8, 100.8, 100.6, 43.0. ES(-) m / z 211 .1 [M-H]-. 2-Chloro-N-(5-cyano-2-fluorophenyl)acetamide

[0229] The title compound was synthesized according to Method F from 3-amino-4- fluorobenzonitrile and chloroacetyl chloride in THF. Brown solid (88%). Rf: 0.6 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 6 10.47 (s, 1 H), 8.39 (d, J = 7.1 Hz, 1 H), 7.72 (s, 1 H), 7.55 (t, J = 9.7 Hz, 1 H), 4.40 (s, 2H).19F NMR (377 MHz, DMSO-cfe) 6 -115.00.13C NMR (101 MHz, DMSO-cfe) 0 165.8, 157.1 , 154.6, 130.3, 130.2, 127.2, 127.0, 126.9, 117.9, 117.6, 117.4, 107.72, 107.69, 43.0. ES(-) m / z 211 .1 [M-H]-.

[0230] 2-Chloro-N-(3-cyano-2,4-difluorophenyl)acetamide

[0231] The title compound was synthesized according to Method F from 3-amino-2,6- difluorobenzonitrile and chloroacetyl chloride in THF. Beige solid (77%). Rf: 0.6 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.46 (s, 1 H), 8.18 (td, J = 9.1 , 6.0 Hz, 1H), 7.43 (td, J = 9.0, 1.6 Hz, 1 H), 4.38 (s, 2H).19F NMR (377 MHz, DMSO-cfe) 5 -110.20, - 114.15.13C NMR (101 MHz, DMSO-cfe) 5 165.6, 160.0, 157.4, 155.5, 153.0, 131.3, 131.2, 123.0, 112.65, 112.61 , 112.45, 112.41 , 109.5, 42.9. ES(-) m / z 229.1 [M-H]-.

[0232] 2-Chloro-N-(2-cyanopyridin-4-’

[0233] The title compound was synthesized according to Method F from 4-aminopicolinonitrile and chloroacetyl chloride in THF. Beige solid (78%). Rf: 0.3 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 11.06 (s, 1 H), 8.62 (d, J = 5.6 Hz, 1 H), 8.13 - 8.08 (m, 1 H), 7.79 (dd, J = 5.6, 2.1 Hz, 1 H), 4.37 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.4, 152.3, 146.3, 133.5, 118.1 , 117.5, 116.5, 43.5. ES(-) m / z 194.0 [M-H]-.

[0234] 2-Chloro-N-(5-cyanopyridin-3-yl)acetamide

[0235] The title compound was synthesized according to Method F from 5-aminonicotinonitrile and chloroacetyl chloride in THF. Beige solid (68%). Rf: 0.3 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.90 (s, 1 H), 8.93 (s, 1 H), 8.75 (s, 1 H), 8.48 (s, 1 H), 4.35 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.9, 147.2, 144.5, 135.1 , 128.9, 116.7, 108.9, 43.2. ES(-) m / z 194.1 [M-H]-.

[0236] 2-Chloro-N-(6-cyanopyridin-2-yl)acetamide

[0237] The title compound was synthesized according to Method F from 6-aminopicolinonitrile and chloroacetyl chloride in THF. Beige solid (78%). Rf: 0.3 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 11.30 (s, 1 H), 8.34 (d, J = 8.6 Hz, 1 H), 8.07 (t, J = 7.8 Hz, 1 H), 7.78 (d, J = 7.5 Hz, 1 H), 4.36 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.0, 152.4, 140.4, 130.6, 124.9, 118.0, 116.9, 43.3. ES(-) m / z 194.1 [M-H]-. 2-Chloro-N-(2-chloro-5-cyanophenyl)acetamide

[0238] The title compound was synthesized according to Method F from 3-amino-4- chlorobenzonitrile and chloroacetyl chloride in THF. Beige solid (95%). Rf: 0.6 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 6 10.16 (s, 1 H), 8.21 (s, 1 H), 8.07 - 7.25 (m, 2H), 4.42 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 6 165.7, 135.3, 131.7, 131.2, 130.1 , 128.9, 117.7, 110.4, 43.0. ES(-) m / z 227.0 [M-H]’.

[0239] N-(3-Bromo-5-cyanophenyl)-2-chloroacetamide

[0240] The title compound was synthesized according to Method F from 3-amino-5- bromobenzonitrile and chloroacetyl chloride in THF. Beige solid (99%). Rf: 0.7 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 6 8.12 (s, 1 H), 7.96 (s, 1H), 7.86 (s, 1 H), 4.31 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.6, 140.5, 129.4, 126.3, 122.4, 121.3, 117.2, 113.6, 43.4. ES(-) m / z 272.8 [M-H]’.

[0241] 2-Chloro-N-(3-cyano-5-methoxyphenyl)acetamide

[0242] The title compound was synthesized according to Method F from 3-amino-5- methoxybenzonitrile and chloroacetyl chloride in THF. Brown solid (73%). Rf: 0.7 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.64 (s, 1 H), 7.60 (s, 1 H), 7.47 (s, 1 H), 7.19 (s, 1 H), 4.29 (s, 2H), 3.80 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 5 165.3, 159.9, 140.5, 118.5, 114.8, 112.4, 110.1 , 55.8, 43.5. ES(-) m / z 222.9 [M-H]’.

[0243] Methyl 3-(2-chloroacetamido)-5-cyanobenzoate

[0244] The title compound was synthesized according to Method F from methyl 3-amino-5- cyanobenzoate and chloroacetyl chloride in THF. Beige solid (98%). Rf: 0.5 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 11.38 - 10.98 (br, 1 H), 8.48 (s, 1 H), 8.29 (s, 1 H), 8.00 (s, 1 H), 4.36 (s, 2H), 3.89 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 5 165.7, 164.4, 139.9, 131.6, 127.4, 125.9, 123.9, 117.7, 112.4, 52.8, 43.4. ES(-) m / z 251 .1 [M-H]’.

[0245] 2-Chloro-N-(3-cyanophenyl)propanamide

[0246] The title compound was synthesized according to Method F from 3-aminobenzonitrile and 2- chloropropanoyl chloride in acetone. Brown solid (69%). Rf: 0.7 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.68 (s, 1 H), 8.10 (s, 1 H), 7.91 - 7.78 (m, 1 H), 7.63 - 7.52 (m, 2H), 4.68 (q, J = 6.7 Hz, 1 H), 1.63 (d, J = 6.7 Hz, 3H).13C NMR (101 MHz, DMSO-cfe) 5 168.4, 139.7, 130.9, 128.0, 124.5, 122.6, 119.0, 112.2, 55.0, 21.3. Method G is of intermediate - 3-chloro-N- a. 3-Chloropropanoyl chloride, K2CO3, acetone, RT.

[0247] 3-aminobenzonitrile (350 mg, 2.96 mmol) was dissolved in acetone (10 mL) under nitrogen, potassium carbonate (1.04 g, 7.50 mmol) and 3-chloropropanoyl chloride (0.35 mL, 3.6 mmol) were added and the reaction was stirred at room temperature for 18 h. The reaction mixture was extracted by ethyl acetate and washed with water, saturated ammomium chloride aqueous solution and brine. Then the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude, which was further purified by washing with iced ethyl acetate to afford 3-chloro-N-(3- cyanophenyl)propanamide as an off-white solid (295 mg, 48%). Rf: 0.7 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.45 (s, 1 H), 8.11 (q, J = 1.3 Hz, 1 H), 7.85 - 7.76 (m, 1 H), 7.53 (d, J = 6.5 Hz, 2H), 3.89 (t, J = 6.2 Hz, 2H), 2.86 (t, J = 6.2 Hz, 2H).13C NMR (101 MHz, DMSO-d6) 5 169.1 , 140.2, 130.8, 127.4, 124.1 , 122.1 , 119.1 , 112.1 , 41.0, 39.7. mo- a. EDCI, HOBt, DCM, RT.

[0248] 2-bromo-2-methylpropanoic acid (0.90 g, 5.4 mmol) was dissolved in dichloromethane (25 mL), and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.18 g, 6.0 mmol) and 1- hydroxybenzotriazole (0.41 g, 2.5 mmol) were added to the reaction mixture. Then, 3- aminobenzonitrile (0.59 g, 5.0 mmol) was added and the reaction stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was extracted with ethyl acetate and washed with sodium carbonate aqueous solution, ammonium chloride aqueous solution and brine. Then the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification with flash column chromatography (1-2.5% methanol in dichloromethane) afforded 2-bromo-N-(3- cyanophenyl)-2-methylpropanamide as an off-white solid (364 mg, 29%). Rf: 0.7 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.15 (s, 1 H), 8.14 (s, 1 H), 7.98 (d, J = 4.8 Hz, 1 H), 7.58 (d, J = 5.4 Hz, 2H), 2.01 (s, 6H).13C NMR (101 MHz, DMSO- cfe) 6 170.4, 139.9, 130.6, 127.9, 125.4, 123.6, 119.1 , 111.9, 60.7, 31.0.

[0249] Method I (Synthesis of intermediate - methyl 2-(2-chloroacetamido)-6-cyanoisonicotinate) a. mCPBA, DCM, RT; b. POCI3, 100 °C; c. (i) benzophenone imine, Cs2CO3, Pd2(dba)3, XantPhos, dioxane, 80 °C, (ii) HCI 1M (aq.), THF, RT; d. chloroacetyl chloride, K2CO3, THF, RT.

[0250] To a solution of methyl 2-cyanoisonicotinate (1.00 g, 6.17 mmol) in dichloromethane (20 mL) was added 3-chloroperbenzoic acid (2.13 g, 12.3 mmol) at 0 °C and the reaction mixture stirred at room temperature for 48 h. The mixture was diluted with dichloromethane and washed with sodium bicarbonate saturated aqueous solution (x2) and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification using flash column chromatography (10-100% ethyl acetate in hexane) afforded 2-cyano-4- (methoxycarbonyl)pyridine 1 -oxide (660 mg, 60%) as a white solid. Rf: 0.5 (50% dichloromethane in ethyl acetate).1H NMR (400 MHz, CDCI3) 5 8.29 (d, J = 6.9 Hz, 1 H), 8.25 (d, J = 2.5 Hz, 1 H), 8.03 (dd, J = 7.0, 2.5 Hz, 1 H), 3.98 (s, 3H). ES(+) m / z 179.0 [M+H]+.

[0251] 2-cyano-4-(methoxycarbonyl)pyridine 1 -oxide (660 mg, 3.70 mmol) was added to phosphorus oxychloride (12 mL) at 0 °C and the reaction was heated to 100 °C for 24 h. The mixture was poured into ice, neutralised with sodium hydroxide 20% (aq.) and extracted with dichloromethane (x3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification using flash column chromatography (5-50% ethyl acetate in hexane) afforded methyl 2-chloro-6-cyanoisonicotinate (490 mg, 67%) as a white solid. Rf: 0.5 (30% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 8.47 (d, J = 1.3 Hz, 1 H), 8.23 (d, J = 1.3 Hz, 1 H), 3.93 (s, 3H).13C NMR (101 MHz, DMSO- d6) 5 162.6, 152.1 , 141.9, 133.2, 128.2, 127.4, 115.8, 53.5. ES(+) m / z 197.0 [M+H]+.

[0252] A mixture of methyl 2-chloro-6-cyanoisonicotinate (160 mg, 0.81 mmol), benzophenone imine (0.15 mL, 0.90 mmol), cesium carbonate (530 mg, 1.63 mmol), tris(dibenzylideneacetone)dipalladium(0) (75 mg, 0.081 mmol) and 4,5- bis(diphenylphospheno)-9,9-dimethylxanthene (94 mg, 0.16 mmol) in anhydrous dioxane (10 mL), was evacuated and purged with nitrogen, and the reaction was heated to 80 °C for 1.5 h. Then, the reaction mixture was diluted with ethyl acetate, filtered through celite and the filtrate was washed with brine (x2). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF (8 mL) and HCI 1 M (2 mL) was added dropwise at 0 °C. The reaction stirred at room temperature for 30 min, then the mixture was diluted with water and was extracted with ethyl acetate (x3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (10-100% ethyl acetate in hexane) afforded methyl 2-amino-6-cyanoisonicotinate (100 mg, 69% over two steps) as a white solid. Rf: 0.5 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 7.36 (s, 1H), 7.24 (s, 1 H), 7.02 (s, 2H), 3.86 (s, 3H). ES(+) m / z 178.1 [M+H]+.

[0253] To a solution of methyl 2-amino-6-cyanoisonicotinate (150 mg, 0.85 mmol) in anhydrous THF (10 mL) under nitrogen, was added potassium carbonate (234 mg, 1.69 mmol) and chloroacetyl chloride (0.074 mL, 0.93 mmol) dropwise and the reaction stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, the residue was triturated with water and filtered to provide methyl 3-(2-chloroacetamido)-5- cyanobenzoate (215 mg, 100%) as a light yellow solid. Rf: 0.6 (30% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 6 11.59 (s, 1 H), 8.79 (s, 1 H), 8.14 (s, 1 H), 4.39 (s, 2H), 3.93 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 5 166.4, 163.5, 153.4, 140.8, 131.6, 123.4, 117.0, 116.4, 53.3, 43.3. ES(+) m / z 254.0 [M+H]+.

[0254] Method J of substituted 3-bromo- and 3-chloro- 6- in-1 intermediates / final compounds) a. K2CO3, DMF, RT.

[0255] 2-(3-bromo-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide (22)

[0256] To a solution of 6-bromopyridazin-3(2H)-one (300 mg, 1.71 mmol) in anhydrous DMF (2 mL) under nitrogen, was added potassium carbonate (474 mg, 3.43 mmol). After 10 min, 2- chloro-N-(3-cyanophenyl)acetamide (367 mg, 1.89 mmol) was added and the reaction stirred at room temperature for 18 h. The reaction mixture was diluted with water, and after extraction (x3) with ethyl acetate, the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography (50-100% ethyl acetate in hexane) afforded 2-(3-bromo-6-oxopyridazin- 1(6H)-yl)-N-(3-cyanophenyl)acetamide as an off-white solid (380 mg, 67%). Rf: 0.3 (75% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.72 (s, 1 H), 8.07 - 8.02 (m, 1 H), 7.82 - 7.73 (m, 1 H), 7.69 (d, J = 9.7 Hz, 1 H), 7.60 - 7.51 (m, 2H), 7.02 (d, J = 9.7 Hz, 1 H), 4.90 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.4, 158.4, 139.3, 137.4, 131.6, 130.4, 127.2, 126.4, 123.7, 121.8, 118.6, 111.7, 54.8. HRMS (ES+) m / z calc, for Ci3Hi0BrN4O2[M+H]+: 332.9987, found: 332.9976.

[0257] 2-(3-chloro-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide was synthesized according to the same procedure, using 6-chloropyridazin-3(2H)-one and the product was obtained as a yellow solid (77%). Rf: 0.3 (75% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.72 (s, 1 H), 8.08 - 8.02 (m, 1 H), 7.81 - 7.75 (m, 1 H), 7.65 (d, J = 9.8 Hz, 1 H), 7.59 - 7.51 (m, 2H), 7.13 (d, J = 9.8 Hz, 1 H), 4.90 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.4, 158.5, 139.3, 136.8, 134.8, 132.0, 130.4, 127.2, 123.7, 121.8, 118.6, 111.7, 54.8. ES(+) m / z 311.1 [M+Na]+.

[0258] 3-(3-bromo-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)propanamide (5)

[0259] The title compound was synthesized according to the same procedure using 6- bromopyridazin-3(2H)-one and 3-chloro-N-(3-cyanophenyl)propanamide in acetone as solvent and the product was obtained as an off-white solid (53%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.40 (s, 1 H), 8.04 (m, 1 H), 7.80 - 7.70 (m, 1 H), 7.60 (d, J = 9.7 Hz, 1 H), 7.57 - 7.47 (m, 2H), 6.95 (d, J = 9.7 Hz, 1 H), 4.30 (t, J = 7.0 Hz, 2H), 2.80 (t, J = 7.0 Hz, 2H).13C NMR (101 MHz, DMSO-cfe) 5 169.1 , 158.3, 139.7, 136.7, 131.7, 130.2, 126.8, 126.1 , 123.8, 121.8, 118.7, 111.5, 47.3, 34.8.

[0260] Method of intermediate - 2-(5-bromo-2- cyanophenvDacetamide) a. K2CO3, DMF, RT.

[0261] To a solution of 5-bromopyridin-2(1 H)-one (40 mg, 0.23 mmol) in anhydrous DMF (2 mL) under nitrogen, was added potassium carbonate (64 mg, 0.46 mmol). After 10 min, 2-chloro- N-(3-cyanophenyl)acetamide (49 mg, 0.25 mmol) was added and the reaction stirred at room temperature for 18 h. The reaction mixture was diluted with water, and after extraction (x3) with ethyl acetate, the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography (50-100% ethyl acetate in hexane) afforded 2-(5-bromo-2-oxopyridin-1 (2H)- yl)-N-(3-cyanophenyl)acetamide (40 mg, 52%) as an off-white solid. Rf: 0.3 (75% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 6 10.76 (s, 1 H), 8.13 - 7.96 (m, 2H), 7.86 - 7.73 (m, 1 H), 7.66 - 7.47 (m, 3H), 6.41 (d, J = 9.7 Hz, 1 H), 4.75 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.0, 160.1 , 143.2, 140.2, 139.4, 130.5, 127.1 , 123.6, 121.6, 120.8, 118.6, 111.7, 96.1 , 51.6. ES(+) m / z 354.1 [M+Na]+.

[0262] Method L (Synthesis of final compounds') a. K2CO3, DMF or acetone, RT.

[0263] To a solution of 6-aryl substituted pyridazin-3(2H)-one (0.20 mmol) in anhydrous DMF or acetone (2 mL) under nitrogen, was added potassium carbonate (0.40 mmol) and substituted 2-chloroacetamide or 2-chloropropanamide (0.22 mmol) and the reaction stirred at room temperature for 18 h. Saturated ammonium chloride aqueous solution was added to the reaction mixture, and after extraction (x3) with ethyl acetate, the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Further purification with flash column chromatography, or alternatively by washing with iced ethyl acetate afforded the final compounds.

[0264] N-(3-cyanophenyl)-2-(6-oxo-3-phenylpyridazin-1 (6H)-yl)propanamide (1)

[0265] The title compound was synthesized according to Method L from 6-phenylpyridazin-3-(2H)- one and 2-chloro-N-(3-cyanophenyl)propanamide in acetone and was purified by washing with iced ethyl acetate. White solid (9%). Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.63 (s, 1 H), 8.14 (d, J = 9.7 Hz, 1 H), 8.07 (s, 1 H), 7.91 (d, J = 7.5 Hz, 2H), 7.86 - 7.78 (m, 1 H), 7.59 - 7.42 (m, 5H), 7.10 (d, J = 9.7 Hz, 1 H), 5.49 (q, J = 7.0 Hz, 1 H), 1.72 (d, J = 7.1 Hz, 3H).13C NMR (101 MHz, DMSO-cfe) 5 169.3, 159.1 , 143.1 , 139.7, 134.6, 130.7, 130.3, 129.4, 129.2, 129.0, 127.1 , 125.8, 123.8, 121.9, 118.6, 111.6, 58.5, 15.7. HRMS (ES+) m / z calc, for C20HI7N4O2[M+H]+: 345.1352, found: 345.1364.

[0266] / V-(3-cyanophenyl)-2-(6-oxo-3-phenylpyridazin-1 (6 / - / )-yl)acetamide (3)

[0267] The title compound was synthesized according to Method L from 6-phenylpyridazin-3-(2H)- one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (68%). Rf: 0.5 (10% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.80 - 10.60 (br, 1 H), 8.13 (d, J = 9.8 Hz, 1 H), 8.07 (s, 1 H), 7.90 (d, J = 7.3 Hz, 2H), 7.81 (d, J = 7.0 Hz, 1 H), 7.60 - 7.42 (m, 5H), 7.13 (d, J = 9.7 Hz, 1 H), 5.02 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.9, 159.1 , 143.7, 139.7, 134.2, 131.4, 130.4, 129.7, 129.5, 129.0, 127.0, 125.9, 123.8, 121.8, 118.6, 111.7, 55.3. HRMS (ES+) m / z calc, for CI9HI5N4O2[M+H]+: 331.1195, found: 331.1193.

[0268] N-(2-cyanophenyl)-2-(6-oxo-3-phenylpyridazin-1 (6H)-yl)acetamide (6)

[0269] The title compound was synthesized according to Method L from 6-phenylpyridazin-3-(2H)- one and 2-chloro-N-(2-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (26%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.60 (s, 1 H), 8.12 (d, J = 9.8 Hz, 1 H), 7.94 - 7.87 (m, 2H), 7.87 - 7.81 (m, 1 H), 7.76 - 7.59 (m, 2H), 7.55 - 7.42 (m, 3H), 7.36 (ddd, J = 8.1 , 6.6, 2.0 Hz, 1 H), 7.13 (d, J = 9.7 Hz, 1 H), 5.07 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.9, 159.0, 143.8, 139.6, 134.2, 133.9, 133.4, 131.4, 129.7, 129.5, 128.9, 125.9, 125.9, 125.2, 116.7, 106.6, 54.8. HRMS (ES+) m / z calc, for CI9HI5N4O2[M+H]+: 331.1195, found: 331.1197.

[0270] N-(4-cyanophenyl)-2-(6-oxo-3-phenylpyridazin-1 (6H)-yl)acetamide (7)

[0271] The title compound was synthesized according to Method L from 6-phenylpyridazin-3-(2H)- one and 2-chloro-N-(4-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (63%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 11.16 (s, 1 H), 8.13 (d, J = 9.8 Hz, 1 H), 7.93 - 7.85 (m, 2H), 7.85 - 7.75 (m, 4H), 7.55 - 7.42 (m, 3H), 7.12 (d, J = 9.8 Hz, 1 H), 5.06 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.0, 159.0, 143.7, 143.0, 134.1 , 133.4, 131.5, 129.7, 129.5, 128.9, 125.9, 119.1 , 119.0, 105.2, 55.4. HRMS (ES+) m / z calc, for CI9HI5N4O2[M+H]+: 331.1195, found: 331.1208.

[0272] N-(4- -2-(6-oxo-3-

[0273] The title compound was synthesized according to Method L from 6-phenylpyridazin-3-(2H)- one and 2-chloro-N-(4-chlorophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (65%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.52 (s, 1H), 8.12 (d, J = 9.8 Hz, 1 H), 7.90 (d, J = 7.0 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.52 - 7.45 (m, 3H), 7.38 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 9.7 Hz, 1 H), 4.99 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 0 165.2, 159.0, 143.7, 137.7, 134.2, 131.4, 129.7, 129.5, 128.9, 128.8, 127.0, 125.9, 120.6, 55.3. HRMS (ES+) m / z calc, for C18H15CIN3O2 [M+H]+: 340.0853, found: 340.0860.

[0274] N-(3-ethynylphenyl)-2-(6-oxo-3-phenylpyridazin-1 (6H)-yl)acetamide (9)

[0275] The title compound was synthesized according to Method L from 6-phenylpyridazin-3-(2H)- one and 2-chloro-N-(3-ethynylphenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (39%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.49 (s, 1 H), 8.12 (d, J = 9.8 Hz, 1 H), 7.93 - 7.86 (m, 2H), 7.77 (t, J = 2.0 Hz, 1 H), 7.63 - 7.42 (m, 4H), 7.34 (t, J = 7.9 Hz, 1 H), 7.21 - 7.15 (m, 1 H), 7.12 (d, J = 9.8 Hz, 1 H), 5.00 (s, 2H), 4.18 (s, 1 H).13C NMR (101 MHz, DMSO-cfe) 5 165.4, 159.0, 143.7, 138.9, 134.2, 131.4, 129.7, 129.5, 129.4, 128.9, 126.7, 125.9, 122.1 , 121.9, 119.7, 83.2, 80.7, 55.3. HRMS (ES+) m / z calc, for C20HI6N3O2[M+H]+: 330.1243, found: 330.1244.

[0276] N-(4-nitrophenyl)-2-(6-oxo-3-phenylpyridazin-1 (6H)-yl)acetamide (10)

[0277] The title compound was synthesized according to Method L from 6-phenylpyridazin-3-(2H)- one and 2-chloro-N-(4-nitrophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (33%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 11.02 (s, 1 H), 8.25 (d, J = 8.5 Hz, 2H), 8.14 (d, J = 9.8 Hz, 1 H), 7.90 (d, J = 7.3 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.55 - 7.43 (m, 3H), 7.14 (d, J = 9.7 Hz, 1 H), 5.06 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.2, 159.0, 144.8, 143.8, 142.4, 134.1 , 131.5, 129.7, 129.5, 129.0, 125.9, 125.1 , 118.9, 55.5. HRMS (ES+) m / z calc, for CI8HI5N4O4[M+H]+: 351.1093, found: 351.1100.

[0278] The title compound was synthesized according to Method L from 6-phenylpyridazin-3-(2H)- one and 2-chloro-N-(3-(trifluoromethyl)phenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (14%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.75 (s, 1 H), 8.17 - 8.08 (m, 2H), 7.94 - 7.86 (m, 2H), 7.79 - 7.72 (m, 1 H), 7.58 (t, J = 8.0 Hz, 1H), 7.54 - 7.45 (m, 3H), 7.43 (d, J = 8.0 Hz, 1 H), 7.13 (d, J = 9.8 Hz, 1 H), 5.02 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.8, 159.1 , 143.8, 139.4, 134.2, 131.4, 130.2, 129.7, 129.5, 128.9, 125.9, 122.6, 115.2, 55.3. HRMS (ES+) m / z calc, for CI9HI5F3N3O2[M+H]+: 374.1116, found: 374.1120. The title compound was synthesized according to Method L from 6-phenylpyridazin-3-(2H)- one and ethyl 3-(2-chloroacetamido)benzoate in acetone and was purified by washing with iced ethyl acetate. White solid (39%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.64 (s, 1 H), 8.28 (s, 1 H), 8.13 (d, J = 9.8 Hz, 1 H), 7.90 (d, J = 7.4 Hz, 2H), 7.82 (dd, J = 8.1 , 2.2 Hz, 1 H), 7.67 (d, J = 7.7 Hz, 1 H), 7.55 - 7.42 (m, 4H), 7.13 (d, J = 9.7 Hz, 1 H), 5.01 (s, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).13C NMR (101 MHz, DMSO-cfe) 5 165.5, 165.4, 159.1 , 143.7, 139.0, 134.2, 131.4, 130.5, 129.7, 129.5, 129.3, 128.9, 125.9, 124.1 , 123.5, 119.5, 60.8, 55.3, 14.2. HRMS (ES+) m / z calc, for C21H20N3O4 [M+H]+: 378.1454, found: 378.1439.

[0279] N-(3-cvano-4-fluorophenyl)-2-(6-oxo-3-phenylpyridazin-1 (6H)-yl)acetamide ( 15)

[0280] The title compound was synthesized according to Method L from 6-phenylpyridazin-3-(2H)- one and 2-chloro-N-(3-cyano-4-fluorophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (6%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.78 (s, 1 H), 8.13 (d, J = 9.8 Hz, 1 H), 8.09 (dd, J = 5.7, 2.7 Hz, 1 H), 7.93 - 7.87 (m, 2H), 7.85 (ddd, J = 9.1 , 4.8, 2.8 Hz, 1 H), 7.57 - 7.42 (m, 4H), 7.13 (d, J = 9.7 Hz, 1 H), 5.01 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.7, 159.5, 159.0, 157.0, 143.8, 135.8, 134.2, 131.5, 129.7, 129.5, 128.9, 126.5, 126.4, 125.9, 122.9, 117.4, 117.2, 113.9, 100.1 , 100.0, 55.2. HRMS (ES+) m / z calc, for C19H14FN4O2 [M+H]+: 349.1101 , found: 349.1116.

[0281] 2-(3-(3-acetamido-4-methylphenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide (16)

[0282] The title compound was synthesized according to Method L from N-(2-methyl-5-(6-oxo-1 ,6- dihydropyridazin-3-yl)phenyl)acetamide and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (81%). Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.75 (s, 1 H), 9.44 (s, 1 H), 8.09 - 8.02 (m, 2H), 7.92 (d, J = 2.0 Hz, 1 H), 7.85 - 7.76 (m, 1 H), 7.60 (dd, J = 8.0, 2.0 Hz, 1H), 7.60 - 7.49 (m, 2H), 7.33 (d, J = 8.0 Hz, 1 H), 7.10 (d, J = 9.8 Hz, 1 H), 5.00 (s, 2H), 2.24 (s, 3H), 2.07 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 5 168.4, 165.8, 159.0, 143.5, 139.4, 137.1 , 133.4, 132.0, 131.3, 130.8, 130.4, 129.7, 127.1 , 123.7, 122.6, 122.4, 121.8, 118.6, 111.7, 55.3, 23.3, 17.8. HRMS (ES+) m / z calc, for C22H2oN503[M+H]+: 402.1566, found: 402.1564.

[0283] N-(4-cyanopyridin-2-yl)-2-(6-oxo-3-phenylpyridazin-1 (6H)-yl)acetamide (18)

[0284] The title compound was synthesized according to Method L from 6-phenylpyridazin-3-(2H)- one and 2-chloro-N-(4-cyanopyridin-2-yl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (14%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 0 11.41 (s, 1 H), 8.62 (d, J = 5.2 Hz, 1 H), 8.30 (s, 1 H), 8.13 (d, J = 10.0 Hz, 1 H), 7.90 (d, J = 7.3 Hz, 2H), 7.60 (d, J = 5.1 Hz, 1 H), 7.55 - 7.45 (m, 3H), 7.13 (d, J = 9.8 Hz, 1 H), 5.10 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 0 166.7, 159.0, 152.1 , 149.9, 143.8, 134.1 , 131.5, 129.7, 129.5, 128.9, 125.9, 121.1 , 121.0, 115.0, 55.2. HRMS (ES+) m / z calc, for CI8HI4N5O2[M+H]+: 332.1147, found: 332.1129.

[0285] N-(3-cyanophenyl)-2-(3-(2- in-1

[0286] The title compound was synthesized according to Method L from 6-(2- fluorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (60%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.75 (s, 1 H), 8.10 - 8.04 (m, 1 H), 7.85 (dd, J = 9.7, 2.5 Hz, 1 H), 7.82 - 7.77 (m, 1 H), 7.69 (td, J = 7.9, 1 .8 Hz, 1 H), 7.60 - 7.49 (m, 3H), 7.41 - 7.31 (m, 2H), 7.12 (d, J = 9.7 Hz, 1 H), 5.02 (s, 2H).13C NMR (101 MHz, DMSO- cfe) 5 165.7, 160.8, 158.9, 158.3, 141.0, 139.4, 134.0, 134.0, 131.8, 131.7, 130.4, 130.0, 129.2, 127.1 , 125.0, 125.0, 123.7, 122.8, 122.7, 121.8, 118.6, 116.5, 116.3, 111.7, 55.2. ES(+) m / z 349.1 (M+H)+. HRMS (ES+) m / z calc, for CI9HI4FN4O2[M+H]+: 349.1101 , found: 349.1102.

[0287] 2-(3-(4-li-6-oxopyridazin-1 (6H)-yl)-N-(3-i

[0288] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (57%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.76 (s, 1 H), 8.14 (d, J = 9.7 Hz, 1 H), 8.06 (s, 1H), 7.96 - 7.90 (m, 2H), 7.84 - 7.77 (m, 1 H), 7.61 - 7.52 (m, 4H), 7.14 (d, J = 9.6 Hz, 1 H), 5.02 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.8, 159.0, 142.7, 139.4, 134.3, 133.0, 131.3, 130.4, 129.8, 129.0, 127.7, 127.1 , 123.7, 121.8, 118.6, 111.7, 55.3. HRMS (ES+) m / z calc, for CI9HI4CIN4O2[M+H]+: 365.0805, found: 365.0802.

[0289] N-(3-cyano-5- -2-(6-oxo-3-

[0290] The title compound was synthesized according to Method L from 6-phenylpyridazin-3-(2H)- one and 2-chloro-N-(3-cyano-5-fluorophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (35%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.94 (s, 1 H), 8.14 (d, J = 9.8 Hz, 1 H),

[0291] 7.92 - 7.86 (m, 2H), 7.84 - 7.73 (m, 2H), 7.57 (dt, J = 8.6, 1.8 Hz, 1 H), 7.54 - 7.43 (m, 3H),

[0292] 7.13 (d, J = 9.7 Hz, 1 H), 5.03 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.1 , 163.0, 160.6,

[0293] 159.0, 143.8, 141.3, 141.2, 134.1 , 131.5, 129.7, 129.5, 129.0, 125.9, 118.5, 117.5, 117.5, 114.1 , 113.8, 113.1 , 113.0, 110.9, 110.7, 55.4. HRMS (ES+) m / z calc, for CI9HI4FN4O2[M+H]+: 349.1101 , found: 349.1092.

[0294] N-(3- i-2-(6-oxo-3-(thiophen-3-’ in-1

[0295] The title compound was synthesized according to Method L from 6-(thiophen-3-yl)pyridazin- 3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (30%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.73 (s, 1 H), 8.16 (dd, J = 3.0, 1.3 Hz, 1 H), 8.09 (d, J = 9.7 Hz, 1 H), 8.06 (s, 1 H), 7.85 - 7.75 (m, 1 H), 7.68 (dd, J = 5.1 , 2.9 Hz, 1H), 7.59 - 7.52 (m, 3H), 7.10 (d, J = 9.7 Hz, 1 H), 4.97 (s, 2H).13C NMR (101 MHz, DMSO- cfe) 5 165.8, 158.9, 140.9, 139.4, 136.7, 131.8, 130.4, 129.7, 127.8, 127.1 , 125.3, 124.6, 123.7, 121.7, 118.6, 111.7, 55.3. HRMS (ES+) m / z calc, for CI7HI3N4O2S [M+H]+: 337.0759, found: 337.0762.

[0296] 2-(6-oxo-3-phenylpyridazin-1 (6H)-yl)-N-phenylacetamide (26)

[0297] The title compound was synthesized according to Method L from 6-phenylpyridazin-3-(2H)- one and 2-chloro-N-phenylacetamide in acetone and was purified by washing with iced ethyl acetate. White solid (57%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.38 (s, 1 H), 8.12 (d, J = 9.7 Hz, 1 H), 7.93 - 7.86 (m, 2H), 7.59 (d, J = 7.9 Hz, 2H), 7.55 - 7.42 (m, 3H), 7.32 (t, J = 8.0 Hz, 2H), 7.12 (d, J = 9.7 Hz, 1 H), 7.07 (t, J = 7.4 Hz, 1 H), 4.99 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.0, 159.1 , 143.6, 138.7, 134.2, 131.3, 129.7, 129.4, 128.9, 128.9, 125.9, 123.5, 119.1 , 55.3. HRMS (ES+) m / z calc, for CI8HI6N3O2[M+H]+: 306.1243, found: 306.1234.

[0298] 2-(6-oxo-3-phenylpyridazin-1 (6H)-yl)-N-(3-vinylphenyl)acetamide (27)

[0299] The title compound was synthesized according to Method L from 6-phenylpyridazin-3-(2H)- one and 2-chloro-N-(3-vinylphenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (59%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.41 (s, 1 H), 8.13 (d, J = 9.8 Hz, 1 H), 7.94 - 7.86 (m, 2H), 7.74 (t, J = 2.0 Hz, 1 H), 7.55 - 7.42 (m, 4H), 7.30 (t, J = 7.9 Hz, 1 H), 7.19 (d, J = 7.6 Hz, 1 H), 7.12 (d, J = 9.7 Hz, 1 H), 6.70 (dd, J = 17.6, 10.9 Hz, 1 H), 5.76 (d, J = 17.6 Hz, 1 H), 5.27 (d, J = 11.1 Hz, 1 H), 5.00 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.2, 159.1 , 143.7, 139.0, 137.7, 136.6, 134.2, 131.4, 129.7, 129.5, 129.1 , 128.9, 125.9, 121.5, 118.7, 116.6, 114.5, 55.2. HRMS (ES+) m / z calc, for C20HI8N3O2[M+H]+: 332.1399, found: 332.1407. The title compound was synthesized according to Method L from 6-(3,4- dichlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (51%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.77 (s, 1 H), 8.20 (d, J = 9.8 Hz, 1 H), 8.17 (d, J = 2.2 Hz, 1 H), 8.09 - 8.03 (m, 1 H), 7.91 (dd, J = 8.6, 2.2 Hz, 1 H), 7.85 - 7.74 (m, 2H), 7.60 - 7.51 (m, 2H), 7.15 (d, J = 9.8 Hz, 1 H), 5.04 (s, 2H).13C NMR (101 MHz, DMSO- cfe) 5 165.7, 159.0, 141.5, 139.4, 134.7, 132.1 , 131.9, 131.2, 131.2, 130.4, 129.7, 127.6, 127.1 , 126.0, 123.7, 121.7, 118.6, 111.7, 55.4. HRMS (ES+) m / z calc, for C19H13CI2N4O2 [M+H]+: 399.0416, found: 399.0403.

[0300] 2-(3-(benzo[dl[1 ,3ldioxol-5-yl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide (29)

[0301] The title compound was synthesized according to Method L from 6-(benzo[d][1 ,3]dioxol-5- yl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (65%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 8.10 - 8.04 (m, 2H), 7.85 - 7.77 (m, 1 H), 7.59 - 7.49 (m, 2H), 7.48 - 7.39 (m, 2H), 7.07 (d, J = 9.8 Hz, 1 H), 7.03 (d, J = 8.1 Hz, 1 H), 6.09 (s, 2H), 4.99 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.9, 158.9, 148.4, 148.1 , 143.3, 139.8, 131.3, 130.4, 129.5, 128.4, 126.9, 123.8, 121.8, 120.3, 118.7, 111.6, 108.6, 105.9, 101.6, 55.3. HRMS (ES+) m / z calc, for C20H15N O [M+H]+: 375.1093, found: 375.1092.

[0302] 2-(3-(3-> i-6-oxopyridazin-1 (6H)-yl)-N-(3-i

[0303] The title compound was synthesized according to Method L from 6-(3- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. Off-white solid (31%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.76 (s, 1 H), 8.18 (d, J = 9.8 Hz, 1 H), 8.07 (s, 1 H), 7.97 (s, 1 H), 7.92 - 7.85 (m, 1 H), 7.84 - 7.77 (m, 1 H), 7.60 - 7.51 (m, 4H), 7.14 (d, J = 9.8 Hz, 1 H), 5.04 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.7, 159.0, 142.3, 139.4, 136.2, 133.9, 131.4, 130.9, 130.4, 129.7, 129.3, 127.1 , 125.5, 124.5, 123.7, 121.8, 118.6, 111.7, 55.4. HRMS (ES+) m / z calc, for C19H1 CIN O2 [M+H]+: 365.0805, found: 365.0806.

[0304] N-(3-cyanophenyl)-2-(3-(4-' in-1

[0305] The title compound was synthesized according to Method L from 6-(4- fluorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (67%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-d6) 5 10.75 (s, 1 H), 8.13 (d, J = 9.8 Hz, 1 H), 8.09 - 8.04 (m, 1 H), 7.95 (dd, J = 8.6, 5.6 Hz, 2H), 7.85 - 7.77 (m, 1 H), 7.60 - 7.51 (m, 2H), 7.34 (t, J = 8.8 Hz, 2H), 7.13 (d, J = 9.7 Hz, 1 H), 5.02 (s, 2H).13C NMR (101 MHz, DMSO-d6) 0 165.8, 164.1 , 161.7, 158.9, 142.9, 139.4, 131.4, 130.7, 130.4, 129.7, 128.2, 128.2, 127.1 ,

[0306] 123.7, 121.7, 118.6, 116.0, 115.8, 111.7, 55.3. HRMS (ES+) m / z calc, for CI9HI4FN4O2[M+H]+: 349.1101 , found: 349.1094.

[0307] 2-(3-(4-bromophenyl)-6-oxopyridazin-1(6H)-yl)-N-(3-cyanophenyl)acetamide (32)

[0308] The title compound was synthesized according to Method L from 6-(4- bromophenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (10%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.76 (s, 1 H), 8.14 (d, J = 9.8 Hz, 1 H), 8.09 - 8.04 (m, 1 H), 7.90 - 7.83 (m, 2H), 7.83 - 7.76 (m, 1 H), 7.75 - 7.67 (m, 2H), 7.60 - 7.51 (m, 2H), 7.14 (d, J = 9.8 Hz, 1 H), 5.02 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.7, 159.0, 142.7, 139.4, 133.4, 131.9, 131.2, 130.4, 129.7, 127.9, 127.1 , 123.7, 123.0, 121.7, 118.6, 111.7, 55.3. HRMS (ES+) m / z calc, for Ci9Hi4BrN4O2[M+H]+: 409.0300, found: 409.0285.

[0309] N-(3-cyanophenyl)-2-(6-oxo-3-(4-(trifluoromethyl)phenyl)pyridazin-1 (6H)-yl)acetamide (33)

[0310] The title compound was synthesized according to Method L from 6-(4- (trifluoromethyl)phenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (30%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.78 (s, 1 H), 8.21 (d, J = 9.8 Hz, 1 H), 8.13 (d, J = 8.2 Hz, 2H), 8.09 - 8.04 (m, 1 H), 7.87 (d, J = 8.3 Hz, 2H), 7.84 - 7.77 (m, 1 H), 7.60 - 7.51 (m, 2H), 7.18 (d, J = 9.8 Hz, 1 H), 5.05 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.7, 159.0, 142.4, 139.4, 138.0, 131.4, 130.4, 129.8, 127.1 , 126.6, 125.9,

[0311] 125.8, 123.7, 121.8, 118.6, 111.7, 55.4. HRMS (ES+) m / z calc, for C20HI4F3N4O2[M+H]+: 399.1069, found: 399.1052.

[0312] N-(3-cyanophenyl)-2-(3-(4-

[0313] The title compound was synthesized according to Method L from 6-(4- methoxyphenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (59%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.75 (s, 1 H), 8.12 - 8.04 (m, 2H), 7.87 - 7.83 (m, 2H), 7.82 - 7.78 (m, 1 H), 7.60 - 7.51 (m, 2H), 7.09 (d, J = 9.8 Hz, 1 H), 7.07 - 7.03 (m, 2H), 4.99 (s, 2H), 3.81 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 5 165.9, 160.3,

[0314] 158.9, 143.6, 139.5, 131.3, 130.4, 129.6, 127.3, 127.1 , 126.6, 123.7, 121.7, 118.6, 114.3, 111.7, 55.3, 55.2. HRMS (ES+) m / z calc, for C20HI6N4O3[M+H]+: 361.1301 , found: 361.1313.

[0315] The title compound was synthesized according to Method L from 6-(3,5- difluorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (41%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.77 (s, 1 H), 8.20 (d, J = 9.8 Hz, 1 H), 8.09 - 8.04 (m, 1 H), 7.85 - 7.75 (m, 1 H), 7.73 - 7.62 (m, 2H), 7.60 - 7.49 (m, 2H), 7.38 (tt, J = 9.1 , 2.3 Hz, 1 H), 7.16 (d, J = 9.8 Hz, 1 H), 5.04 (s, 2H).13C NMR (101 MHz, DMSO-d6)

[0316] 165.6, 164.1 , 164.0, 161.7, 161.6, 159.0, 141.4, 139.4, 137.7, 131.2, 130.4, 129.7, 127.2,

[0317] 123.7, 121.8, 118.6, 111.7, 109.2, 109.0, 105.0, 104.8, 104.5, 55.5. HRMS (ES+) m / z calc, for C19H13F2N4O2 [M+H]+: 367.1007, found: 367.1015.

[0318] N-(3-cyanophenyl)-2-(6-oxo-3-(p-tolyl)pyridazin-1 (6H)-yl)acetamide (36)

[0319] The title compound was synthesized according to Method L from 6-(p-tolyl)pyridazin-3(2H)- one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (10%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.74 (s, 1 H), 8.10 (d, J = 9.8 Hz, 1 H), 8.08 - 8.04 (m, 1 H), 7.84 - 7.76 (m, 3H), 7.60 - 7.52 (m, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 9.7 Hz, 1 H), 5.01 (s, 2H), 2.35 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 5 165.9, 159.0, 143.7, 139.5, 139.1 , 131.4, 130.4, 129.6, 129.5, 127.1 , 125.8, 123.7, 121.7, 118.6, 111.7, 55.3, 20.8. HRMS (ES+) m / z calc, for C20H17N4O2 [M+H]+: 345.1352, found: 345.1352.

[0320] The title compound was synthesized according to Method L from 6-(4-chlorophenyl)-5- methylpyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (12%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.70 (s, 1 H), 8.06 (d, J = 2.0 Hz, 1 H),

[0321] 7.82 - 7.75 (m, 1 H), 7.58 - 7.52 (m, 6H), 6.98 (d, J = 1.5 Hz, 1 H), 4.95 (s, 2H), 2.18 (s, 3H).

[0322] 13C NMR (101 MHz, DMSO-cfe) 5 166.0, 159.5, 146.7, 143.6, 139.5, 134.2, 134.0, 130.9, 130.6, 128.6, 128.1 , 127.4, 123.9, 122.0, 118.8, 111.8, 54.7, 19.7. HRMS (ES+) m / z calc, for C20H16CIN4O2 [M+H]+: 379.0962, found: 379.0952.

[0323] The title compound was synthesized according to Method L from 6-(2,4- dichlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide in acetone and was purified by washing with iced ethyl acetate. White solid (57%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.75 (s, 1 H), 8.07 (s, 1 H), 7.84 - 7.75 (m, 3H), 7.60 - 7.52 (m, 4H), 7.11 (d, J = 9.7 Hz, 1 H), 5.00 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 0 165.7, 158.9, 143.1 , 139.4, 134.9, 134.4, 133.1 , 132.6, 132.5, 130.4, 129.5, 128.6, 128.0, 127.2, 123.7, 121.8, 118.6, 111.7, 55.1. HRMS (ES+) m / z calc, for C19H13CI2N4O2 [M+H]+: 399.0416, found: 399.0410.

[0324] 2-(3-(5-chloropyridin-2-yl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide (55)

[0325] The title compound was synthesized according to Method L from 6-(5-chloropyridin-2- yl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide in DMF and was purified by flash column chromatography (50-100% ethyl acetate in hexane). Off-white solid (57%). Rf: 0.3 (75% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.78 (s, 1 H), 8.80 - 8.71 (m, 1 H), 8.32 (d, J = 9.8 Hz, 1 H), 8.13 - 8.03 (m, 3H), 7.83 - 7.78 (m, 1 H), 7.60 - 7.50 (m, 2H), 7.16 (d, J = 9.8 Hz, 1 H), 5.05 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.6, 159.3, 150.0, 147.9, 142.5, 139.4, 137.4, 131.7, 130.5, 130.4, 129.7, 127.2, 123.7, 121.8, 121.1 , 118.6, 111.7, 55.5. HRMS (ES+) m / z calc, for C18H13CIN5O2 [M+H]+: 366.0758, found: 366.0743.

[0326] 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-fluorophenyl)acetamide (58)

[0327] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-fluorophenyl)acetamide in DMF and was purified by flash column chromatography (0-10% methanol in dichloromethane). White solid (29%). Rf: 0.3 (75% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 6 10.61 (s, 1H), 8.14 (d, J = 9.8 Hz, 1 H), 7.96 - 7.89 (m, 2H), 7.60 - 7.53 (m, 3H), 7.37 (td, J = 8.1 , 6.6 Hz, 1 H), 7.29 (dt, J = 8.4, 1.4 Hz, 1 H), 7.13 (d, J = 9.8 Hz, 1 H), 6.91 (td, J = 8.4, 2.5 Hz, 1 H), 5.00 (s, 2H).19F NMR (377 MHz, DMSO-cfe) 6 -111.81.13C NMR (126 MHz, DMSO-cfe) 5 165.4, 163.1 , 161.2, 159.0, 142.6, 140.4, 140.3, 134.3, 133.1 , 131.2, 130.6, 130.5, 129.7, 129.0, 127.7, 114.84, 114.82, 110.1 , 109.9, 106.0, 105.8, 55.3. HRMS (ES+) m / z calc, for C18H14CIFN3O2 [M+H]+: 358.0759, found: 358.0763.

[0328] N-(3-chlorophenyl)-2-(3-(4-i in-1

[0329] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-chlorophenyl)acetamide in DMF and was purified by flash column chromatography (0-10% methanol in dichloromethane). White solid (35%). Rf: 0.3 (75% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.59 (s, 1H), 8.14 (d, J = 9.8 Hz, 1 H), 7.96 - 7.89 (m, 2H), 7.82 - 7.77 (m, 1 H), 7.60 - 7.55 (m, 2H), 7.47 - 7.42 (m, 1 H), 7.36 (t, J = 8.1 Hz, 1 H), 7.17 - 7.10 (m, 2H), 5.00 (s, 2H).13C NMR (126 MHz, DMSO-cfe) 5 165.5, 159.0, 142.6, 140.1 , 134.3, 133.2, 133.0, 131.2, 130.6, 129.7, 129.0, 127.7, 123.2, 118.6, 117.5, 55.3. HRMS (ES+) m / z calc, for CI8HI4CI2N3O2[M+H]+: 374.0463, found: 374.0455.

[0330] 3-(2-(3-(4-> in-1

[0331] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 3-(2-chloroacetamido)benzamide in DMF and was purified by flash column chromatography (0-20% methanol in ethyl acetate). White solid (15%). Rf: 0.5 (10% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.62 (s, 1 H), 8.14 (d, J = 9.8 Hz, 1 H), 8.10 - 8.04 (m, 1 H), 7.99 - 7.88 (m, 3H), 7.77 - 7.71 (m, 1 H), 7.60 - 7.52 (m, 3H), 7.38 (t, J = 7.9 Hz, 1 H), 7.34 (s, 1 H), 7.13 (d, J = 9.8 Hz, 1 H), 5.01 (s, 2H).13C NMR (126 MHz, DMSO-cfe) 5 167.8, 165.2, 159.0, 142.6, 138.7, 135.2, 134.3, 133.1 , 131.2, 129.8, 129.0, 128.7, 127.7, 122.3, 121.8, 118.7, 55.2. HRMS (ES+) m / z calc, for C19H16CIN4O3 [M+H]+: 383.0911 , found: 383.0904.

[0332] 2-(3-(4-i -6-oxopyridazin-1 (6H)-yl)-N-(3-

[0333] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-(dimethylamino)phenyl)acetamide in DMF and was purified by flash column chromatography (0-20% methanol in dichloromethane). Light yellow solid (81 %). Rf: 0.6 (10% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.19 (s, 1 H), 8.13 (d, J = 9.8 Hz, 1 H), 7.97 - 7.88 (m, 2H), 7.61 - 7.52 (m, 2H), 7.15 - 7.04 (m, 3H), 6.87 - 6.82 (m, 1 H), 6.44 (dd, J = 8.3, 2.5 Hz, 1 H), 4.96 (s, 2H), 2.86 (s, 6H).13C NMR (101 MHz, DMSO-cfe) 5 164.8, 159.0, 150.8, 142.5, 139.5, 134.2, 133.1 , 131.1 , 129.7, 129.1 , 129.0, 127.6, 107.9, 107.2, 103.1 , 55.3, 40.1. HRMS (ES+) m / z calc, for C20H20CIN4O2[M+H]+: 383.1275, found: 383.1293.

[0334] 2-(3-(4-i :in-1 (6H)-yl)-N-(3-i

[0335] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyano-2-fluorophenyl)acetamide in DMF and was purified by flash column chromatography (20-100% ethyl acetate in hexane). White solid (47%). Rf: 0.7 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.57 (s, 1 H), 8.25 (td, J = 8.0, 1.6 Hz, 1 H), 8.13 (d, J = 9.8 Hz, 1 H), 7.96 - 7.89 (m, 2H), 7.67 (ddd, J = 7.6, 5.8, 1.6 Hz, 1 H), 7.61 - 7.53 (m, 2H), 7.38 (t, J = 8.1 Hz, 1 H), 7.13 (d, J = 9.8 Hz, 1 H), 5.10 (s, 2H).19F NMR (377 MHz, DMSO-cfe) 5 -119.35.13C NMR (101 MHz, DMSO-cfe) 5 166.0, 159.0, 155.1 , 152.5, 142.7, 134.3, 133.0, 131.3, 129.8, 129.0, 128.9, 128.7, 127.7, 126.8, 126.7, 125.65, 125.60, 113.8, 100.7, 100.6, 55.1. HRMS (ES+) m / z calc, for CI9HI3CIFN4O2[M+H]+: 383.0711 , found: 383.0702. 2-(3-(4-i :in-1 (6H)-yl)-N-(5-i

[0336] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(5-cyano-2-fluorophenyl)acetamide in DMF and was purified by flash column chromatography (20-100% ethyl acetate in hexane). White solid (63%). Rf: 0.7 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 6 10.60 (s, 1 H), 8.43 (dd, J = 7.2, 2.1 Hz, 1 H), 8.14 (d, J = 9.8 Hz, 1 H), 7.98 - 7.86 (m, 2H), 7.70 (ddd, J = 8.6, 4.6, 2.1 Hz, 1 H), 7.61 - 7.51 (m, 3H), 7.14 (d, J = 9.8 Hz, 1 H), 5.11 (s, 2H).19F NMR (377 MHz, DMSO-cfe) 6 -115.52.13C NMR (101 MHz, DMSO-cfe) 5 166.3, 159.0, 156.7, 154.1 , 142.7, 134.3, 133.0, 131.3, 129.8, 129.7, 129.0, 127.7, 127.2, 127.1 , 126.5, 118.0, 117.5, 117.3, 107.68, 107.66, 55.1. HRMS (ES+) m / z calc, for CI9HI3CIFN4O2[M+H]+: 383.0711 , found: 383.0716.

[0337] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyano-2,4-difluorophenyl)acetamide in

[0338] DMF and was purified by flash column chromatography (20-100% ethyl acetate in hexane).

[0339] White solid (30%). Rf: 0.6 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.56 (s, 1 H),

[0340] 8.22 (td, J = 9.1 , 6.0 Hz, 1 H), 8.13 (d, J = 9.8 Hz, 1 H), 7.95 - 7.90 (m, 2H), 7.60 - 7.54 (m,

[0341] 2H), 7.41 (td, J = 9.0, 1.6 Hz, 1 H), 7.13 (d, J = 9.8 Hz, 1 H), 5.08 (s, 2H).19F NMR (377 MHz,

[0342] DMSO-cfe) 5 -110.92, -114.69.13C NMR (101 MHz, DMSO-cfe) 5 166.0, 159.0, 142.7, 134.3, 133.0, 131.3, 130.6, 130.5, 129.8, 129.0, 127.7, 123.3, 123.2, 112.6, 112.4, 109.5, 55.0. HRMS (ES+) m / z calc, for CI9HI2CIF2N4O2[M+H]+: 401 .0617, found: 401 .0631 .

[0343] N-(2-chloro-5-cyanophenyl)-2-(3-(4-

[0344] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(2-chloro-5-cyanophenyl)acetamide in DMF and was purified by flash column chromatography (20-100% ethyl acetate in hexane). White solid (65%). Rf: 0.7 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.28 (s, 1 H), 8.24 (d, J = 2.0 Hz, 1 H), 8.13 (d, J = 9.8 Hz, 1 H), 7.96 - 7.90 (m, 2H), 7.78 (d, J = 8.4 Hz, 1 H), 7.68 (dd, J = 8.4, 2.0 Hz, 1 H), 7.60 - 7.55 (m, 2H), 7.14 (d, J = 9.8 Hz, 1 H), 5.12 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.3, 159.0, 142.8, 135.5, 134.3, 133.0, 131.3, 131.2, 130.9, 129.8, 129.6, 129.0, 128.3, 127.7, 117.8, 110.4, 55.0. HRMS (ES+) m / z calc, for CI9HI3CI2N4O2[M+H]+: 399.0416, found: 399.0428.

[0345] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(6-cyano-1 H-indol-4-yl)acetamide in DMF and was purified by flash column chromatography (50-100% ethyl acetate in hexane). Off- white solid (51%). Rf: 0.5 (75% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 6 11.78 (s, 1 H), 10.35 (s, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 7.99 - 7.91 (m, 3H), 7.70 - 7.67 (m, 1H), 7.65 (t, J = 2.8 Hz, 1 H), 7.60 - 7.54 (m, 2H), 7.15 (d, J = 9.8 Hz, 1 H), 7.00 - 6.94 (m, 1H), 5.17 (s, 2H).13C NMR (126 MHz, DMSO-cfe) 6 165.9, 159.0, 142.6, 135.6, 134.3, 133.1 , 131.2, 131.0, 129.8, 129.0, 128.8, 127.7, 122.9, 120.5, 112.8, 111.5, 102.4, 100.0, 55.3. HRMS (ES+) m / z calc, for C21H15CIN5O2 [M+H]+: 404.0914, found: 404.0912.

[0346] 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(5-cyanothiophen-2-yl)acetamide (68)

[0347] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro- / V-(5-cyanothiophen-2-yl)acetamide in DMF and was purified by flash column chromatography (50-100% ethyl acetate in hexane). Light yellow solid (56%). Rf: 0.5 (75% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 12.42 (s, 1 H), 8.16 (d, J = 9.8 Hz, 1H), 7.96 - 7.90 (m, 2H), 7.77 (d, J = 4.2 Hz, 1 H), 7.60 - 7.55 (m, 2H), 7.15 (d, J = 9.8 Hz, 1 H), 6.81 (d, J = 4.2 Hz, 1 H), 5.09 (s, 2H).13C NMR (126 MHz, DMSO-cfe) 5 165.0, 158.9, 145.4, 142.9, 137.1 , 134.4, 132.9, 131.5, 129.8, 129.0, 127.7, 115.4, 111.8, 98.2, 54.7. HRMS (ES+) m / z calc, for Ci7Hi2CIN4O2S [M+H]+: 371.0370, found: 371.0361.

[0348] 2-(3-(4-l :in-1 (6H)-yl)-N-(3-i

[0349] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(3-cyano-5-methoxyphenyl)acetamide in DMF and was purified by flash column chromatography (0-10% methanol in dichloromethane). White solid (78%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.73 (s, 1H), 8.14 (d, J = 9.8 Hz, 1 H), 7.97 - 7.89 (m, 2H), 7.61 - 7.51 (m, 3H), 7.49 (t, J = 2.2 Hz, 1 H), 7.17 (dd, J = 2.4, 1.3 Hz, 1 H), 7.14 (d, J = 9.8 Hz, 1 H), 5.01 (s, 2H), 3.79 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 5 165.8, 160.0, 159.0, 142.7, 140.7, 134.3, 133.0, 131.3, 129.7, 129.0, 127.7, 118.5, 114.5, 112.4, 112.2, 109.7, 55.7, 55.4. HRMS (ES+) m / z calc, for C2oHi6CIN403[M+H]+: 395.0911 , found: 395.0910.

[0350] N-(3-bromo-5-

[0351] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and N-(3-bromo-5-cyanophenyl)-2-chloroacetamide in DMF and was purified by flash column chromatography (20-100% ethyl acetate in hexane). Off-white solid (74%). Rf: 0.7 (75% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.91 (s, 1 H), 8.19 - 8.08 (m, 2H), 7.98 - 7.88 (m, 3H), 7.85 (s, 1 H), 7.57 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 9.8 Hz, 1 H), 5.02 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.1 , 159.0, 142.8, 140.6, 134.3, 133.0, 131.3, 129.8, 129.1 , 129.0, 127.7, 126.0, 122.4, 121.0, 117.2,

[0352] 113.6, 55.4. HRMS (ES+) m / z calc, for Ci9Hi3BrCIN4O2[M+H]+: 442.9910, found: 442.9892.

[0353] 2-(3-(4-i i-6-oxopyridazin-1 (6H)-yl)-N-(2-i idin-4-'

[0354] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(2-cyanopyridin-4-yl)acetamide in DMF and was purified by flash column chromatography (20-100% ethyl acetate in hexane). White solid (61%). Rf: 0.3 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 6 11.21 (s, 1 H), 8.61 (d, J = 5.7 Hz, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 8.10 (d, J = 2.1 Hz, 1 H), 7.97 - 7.89 (m, 2H), 7.78 (dd, J = 5.6, 2.1 Hz, 1 H), 7.61 - 7.53 (m, 2H), 7.15 (d, J = 9.8 Hz, 1 H), 5.07 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 6 166.9, 159.0, 152.3, 146.3, 142.8, 134.4, 133.5, 133.0, 131.4, 129.8, 129.0, 127.7, 118.0, 117.5, 116.3, 55.5. HRMS (ES+) m / z calc, for CI8HI3CIN5O2 [M+H]+: 366.0758, found: 366.0772.

[0355] 2-(3-(4-i i-6-oxopyridazin-1 (6H)-yl)-N-(5-i idin-3-’

[0356] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(5-cyanopyridin-3-yl)acetamide in DMF and was purified by flash column chromatography (20-100% ethyl acetate in hexane). White solid (52%). Rf: 0.3 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 11.02 (s, 1 H), 8.94 (d, J = 2.5 Hz, 1 H), 8.74 (d, J = 1.8 Hz, 1 H), 8.45 (t, J = 2.2 Hz, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 7.97 - 7.89 (m, 2H), 7.61 - 7.53 (m, 2H), 7.15 (d, J = 9.8 Hz, 1 H), 5.06 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.4, 159.0, 146.9, 144.2, 142.8, 135.2, 134.3, 133.0, 131.4, 129.8, 129.0, 128.5, 127.7, 116.7, 108.9, 55.3. HRMS (ES+) m / z calc, for CI8HI3CIN5O2 [M+H]+: 366.0758, found: 366.0743.

[0357] 2-(3-(4-i i-6-oxopyridazin-1 (6H)-yl)-N-(6-i idin-2-’

[0358] The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(6-cyanopyridin-2-yl)acetamide in DMF and was purified by flash column chromatography (20-100% ethyl acetate in hexane). White solid (64%). Rf: 0.3 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 11.42 (s, 1 H), 8.29 (d, J = 8.6 Hz, 1 H), 8.13 (d, J = 9.8 Hz, 1 H), 8.04 (dd, J = 8.6, 7.4 Hz, 1 H), 7.96 - 7.88 (m, 2H), 7.77 (d, J = 7.5 Hz, 1 H), 7.60 - 7.52 (m, 2H), 7.13 (d, J = 9.8 Hz, 1 H), 5.07 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.5, 159.0, 152.6, 142.7, 140.4, 134.3, 133.0, 131.3, 130.6, 129.7, 129.0, 127.7, 124.7, 117.9, 117.0, 55.3. HRMS (ES+) m / z calc, for CI8HI3CIN5O2[M+H]+: 366.0758, found: 366.0742.

[0359] 2- idin-2-’ The title compound was synthesized according to Method L from 6-(4- chlorophenyl)pyridazin-3(2H)-one and 2-chloro-N-(4-cyanopyridin-2-yl)acetamide in DMF and was purified by flash column chromatography (20-100% ethyl acetate in hexane). White solid (54%). Rf: 0.3 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 6 11.41 (s, 1 H), 8.61 (d, J = 5.1 Hz, 1 H), 8.29 (s, 1 H), 8.14 (d, J = 9.7 Hz, 1 H), 7.92 (d, J = 8.1 Hz, 2H), 7.62 - 7.53 (m, 3H), 7.13 (d, J = 9.6 Hz, 1 H), 5.10 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 6 166.7, 159.0, 152.2, 149.9, 142.8, 134.3, 133.0, 131.3, 129.7, 129.0, 127.7, 121.2, 121.1 , 116.8, 115.1 , 55.3. HRMS (ES+) m / z calc, for CI8HI3CIN5O2[M+H]+: 366.0758, found: 366.0760.

[0360] 2-(3-(benzo[d][1 ,3ldioxol-5-yl)-6-oxopyridazin-1 (6H)-yl)-N-phenylacetamide (104)

[0361] The title compound was synthesized according to Method L from 6-(benzo[d][1 ,3]dioxol-5- yl)pyridazin-3(2H)-one and 2-chloro-N-phenylacetamide in DMF and was purified by flash column chromatography (30-100% ethyl acetate in hexane). White solid (87%). Rf: 0.4 (75% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.35 (s, 1 H), 8.06 (d, J = 9.8 Hz, 1H), 7.64 - 7.53 (m, 2H), 7.46 (d, J = 1.8 Hz, 1 H), 7.43 (dd, J = 8.1 , 1.9 Hz, 1 H), 7.35 - 7.28 (m, 2H), 7.10 - 7.00 (m, 3H), 6.09 (s, 2H), 4.96 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.1 , 159.0, 148.4, 148.1 , 143.2, 138.7, 131.2, 129.5, 128.9, 128.4, 123.5, 120.3, 119.1 , 108.6, 105.9, 101.6, 55.2. HRMS (ES+) m / z calc, for CI9HI6N3O4[M+H]+: 350.1141 , found: 350.1133.

[0362] Method M (Synthesis of final compounds') a. Pd(dppf)CI2, K2CO3, Dioxane / Water 4 / 1 , 100 °C.

[0363] A mixture of 2-(3-bromo-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide (0.12 mmol), substituted aryl boronic acid (0.18 mmol), potassium carbonate (0.30 mmol) and [1 ,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.012 mmol) in dioxane (3.2 mL) and water (0.8 mL), was evacuated and purged with nitrogen, and the reaction was heated to 100 °C for 18 h. Then, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. Water was added to the residue, and after extraction (x3) with ethyl acetate, the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography afforded the final compounds.

[0364] N-(3-cyanophenyl)-2-(6-oxo-3-(m-tolyl)pyridazin-1 (6H)-yl)acetamide (46)

[0365] The title compound was synthesized according to Method M from 2-(3-bromo-6- oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide and m-tolylboronic acid and was purified by flash column chromatography (50-100% ethyl acetate in hexane). Off-white solid (74%). Rf: 0.3 (75% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.75 (s, 1 H), 8.11 (d, J = 9.8 Hz, 1 H), 8.07 (s, 1 H), 7.83 - 7.77 (m, 1 H), 7.72 (s, 1 H), 7.68 (d, J = 7.8 Hz, 1H), 7.60 - 7.51 (m, 2H), 7.39 (t, J = 7.7 Hz, 1 H), 7.28 (d, J = 7.6 Hz, 1 H), 7.11 (d, J = 9.7 Hz, 1 H), 5.02 (s, 2H), 2.37 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 5 165.8, 159.1 , 143.8,

[0366] 139.5, 138.2, 134.1 , 131.5, 130.4, 130.1 , 129.6, 128.9, 127.1 , 126.4, 123.7, 123.1 , 121.7,

[0367] 118.6, 111.7, 55.3, 21.1. HRMS (ES+) m / z calc, for C20HI7N4O2[M+H]+: 345.1352, found: 345.1326.

[0368] 2-(3-(4-chloro-3- -6-oxopyridazin-1 (6H)-yl)-N-(3-i

[0369] The title compound was synthesized according to Method M from 2-(3-bromo-6- oxopyridazin-1(6H)-yl)-N-(3-cyanophenyl)acetamide and (4-chloro-3-fluorophenyl)boronic acid and was purified by flash column chromatography (75-100% ethyl acetate in hexane). Off-white solid (78%). Rf: 0.4 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.76 (s, 1 H), 8.19 (d, J = 9.8 Hz, 1 H), 8.06 (s, 1 H), 7.97 (d, J = 10.8 Hz, 1 H), 7.84 - 7.77 (m, 2H), 7.73 (t, J = 8.0 Hz, 1 H), 7.59 - 7.52 (m, 2H), 7.16 (d, J = 9.7 Hz, 1 H), 5.03 (s, 2H).19F NMR (377 MHz, DMSO-cfe) 5 -115.36.13C NMR (101 MHz, DMSO-d6) 5 165.7, 159.0, 158.8, 156.3,

[0370] 141.6, 139.4, 135.33, 135.25, 131.25, 131.19, 130.4, 129.7, 127.2, 123.7, 123.02, 122.99, 121.8, 120.7, 120.5, 118.6, 114.3, 114.0, 111.7, 55.4. HRMS (ES+) m / z calc, for CI9HI3CIFN4O2[M+H]+: 383.0711 , found: 383.0724.

[0371] 2-(3-(4-chloro-3-methoxyphenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide (48) The title compound was synthesized according to Method M from 2-(3-bromo-6- oxopyridazin-1(6H)-yl)-N-(3-cyanophenyl)acetamide and (4-chloro-3-methoxyphenyl)boronic acid and was purified by flash column chromatography (75-100% ethyl acetate in hexane). Off-white solid (72%). Rf: 0.4 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.76 (s, 1 H), 8.21 (d, J = 9.8 Hz, 1 H), 8.07 (s, 1 H), 7.84 - 7.77 (m, 1 H), 7.62 - 7.47 (m, 5H), 7.15 (d, J = 9.7 Hz, 1H), 5.03 (s, 2H), 3.94 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 5 165.8, 159.0, 154.8, 142.9, 139.4, 134.5, 131.6, 130.4, 130.3, 129.6, 127.1 , 123.7, 122.4, 121.7, 119.0, 118.6,

[0372] 111.7, 110.0, 56.3, 55.5. HRMS (ES+) m / z calc, for C20HI6CIN4O3[M+H]+: 395.0911 , found: 395.0916. 2-(3-(6-aminopyridin-3-yl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide (49)

[0373] The title compound was synthesized according to Method M from 2-(3-bromo-6- oxopyridazin-1(6H)-yl)-N-(3-cyanophenyl)acetamide and (6-aminopyridin-3-yl)boronic acid and was purified by flash column chromatography (0-20% methanol in ethyl acetate). Off- white solid (77%). Rf: 0.2 (10% methanol in ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.79 (s, 1 H), 8.46 (s, 1 H), 8.07 (s, 1 H), 8.03 (d, J = 9.9 Hz, 1 H), 7.87 (d, J = 8.9 Hz, 1 H), 7.81 (d, J = 7.0 Hz, 1 H), 7.55 (m, 2H), 7.04 (d, J = 9.7 Hz, 1 H), 6.52 (d, J = 8.8 Hz, 1 H), 6.40 (s, 2H), 4.96 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.9, 160.4, 158.9, 146.1 , 142.8, 139.5, 134.4, 130.8, 130.4, 129.6, 127.1 , 123.7, 121.7, 118.6, 118.2, 111.7, 108.0, 55.1. HRMS (ES+) m / z calc, for CI8HI5N6O2[M+H]+: 347.1256, found: 347.1231.

[0374] 2-(3-(2-aminopyrimidin-5-yl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide (50)

[0375] The title compound was synthesized according to Method M from 2-(3-bromo-6- oxopyridazin-1(6H)-yl)-N-(3-cyanophenyl)acetamide and (2-aminopyrimidin-5-yl)boronic acid and was purified by flash column chromatography (0-20% methanol in dichloromethane). Off-white solid (45%). Rf: 0.2 (10% methanol in ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.72 (s, 1 H), 8.74 (s, 2H), 8.09 - 8.02 (m, 2H), 7.85 - 7.75 (m, 1 H), 7.61 - 7.51 (m, 2H), 7.10 (m, 3H), 4.97 (s, 2H).13C NMR (126 MHz, DMSO-cfe) 5 165.8, 163.6, 158.9, 155.8, 141.0, 139.5, 130.6, 130.4, 129.8, 127.1 , 123.7, 121.8, 118.6, 116.8, 111.7, 55.2. HRMS (ES+) m / z calc, for CI7HI4N7O2[M+H]+: 348.1209, found: 348.1188.

[0376] 2-(3-(4-chloro-3-methylphenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide (51)

[0377] The title compound was synthesized according to Method M from 2-(3-bromo-6- oxopyridazin-1(6H)-yl)-N-(3-cyanophenyl)acetamide and (4-chloro-3-methylphenyl)boronic acid and was purified by flash column chromatography (75-100% ethyl acetate in hexane). Off-white solid (56%). Rf: 0.4 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.75 (s, 1 H), 8.13 (d, J = 9.8 Hz, 1 H), 8.09 - 8.04 (m, 1 H), 7.91 (d, J = 2.3 Hz, 1 H), 7.80 (m, 1 H), 7.75 (dd, J = 8.4, 2.3 Hz, 1 H), 7.60 - 7.51 (m, 3H), 7.13 (d, J = 9.8 Hz, 1 H), 5.02 (s, 2H), 2.40 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 5 165.8, 159.0, 142.8, 139.5, 136.1 , 134.5, 133.0, 131.3, 130.4, 129.7, 129.4, 128.5, 127.1 , 125.0, 123.7, 121.7, 118.6, 111.7, 55.4, 19.7. HRMS (ES+) m / z calc, for C20HI6CIN4O2[M+H]+: 379.0962, found: 379.0972.

[0378] The title compound was synthesized according to Method M from 2-(3-bromo-6- oxopyridazin-1(6H)-yl)-N-(3-cyanophenyl)acetamide and (3-carbamoylphenyl)boronic acid and was purified by flash column chromatography (0-20% methanol in ethyl acetate). Off- white solid (42%). Rf: 0.3 (10% methanol in ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 0 10.79 (s, 1 H), 8.38 (s, 1 H), 8.19 (d, J = 9.8 Hz, 1 H), 8.13 (s, 1 H), 8.07 (s, 1 H), 8.05 (d, J = 8.2 Hz, 1 H), 7.95 (d, J = 7.7 Hz, 1 H), 7.85 - 7.77 (m, 1 H), 7.63 - 7.49 (m, 4H), 7.17 (d, J = 9.7 Hz, 1 H), 5.04 (s, 2H).13C NMR (126 MHz, DMSO-cfe) 0 167.4, 165.8, 159.0, 143.3, 139.4, 135.0, 134.3, 131.5, 130.4, 129.7, 129.0, 128.5, 128.4, 127.1 , 125.0, 123.7, 121.8, 118.6, 111.7, 55.4. HRMS (ES+) m / z calc, for C2oHi6N503[M+H]+: 374.1253, found: 374.1254.

[0379] 4-(1-(2-((3-cyanophenyl)amino)-2-oxoethyl)-6-oxo-1 ,6-dihydropyridazin-3-yl)benzamide (53)

[0380] The title compound was synthesized according to Method M from 2-(3-bromo-6- oxopyridazin-1(6H)-yl)-N-(3-cyanophenyl)acetamide and (4-carbamoylphenyl)boronic acid and was purified by flash column chromatography (0-20% methanol in ethyl acetate). Off- white solid (65%). Rf: 0.3 (10% methanol in ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.78 (s, 1 H), 8.20 (d, J = 9.8 Hz, 1 H), 8.12 - 8.04 (m, 2H), 7.99 (s, 4H), 7.84 - 7.79 (m, 1H), 7.57 - 7.53 (m, 2H), 7.48 (s, 1 H), 7.15 (d, J = 9.7 Hz, 1 H), 5.04 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 167.2, 165.8, 159.0, 143.0, 139.4, 136.6, 134.8, 131.5, 130.4, 129.7, 128.1 , 127.1 , 126.7, 125.7, 123.7, 121.8, 118.6, 111.7, 55.4. HRMS (ES+) m / z calc, for C20H16N5O3 [M+H]+: 374.1253, found: 374.1269.

[0381] 2-(3-(2-aminopyridin-4-yl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide (54)

[0382] The title compound was synthesized according to Method M from 2-(3-bromo-6- oxopyridazin-1(6H)-yl)-N-(3-cyanophenyl)acetamide and (2-aminopyridin-4-yl)boronic acid and was purified by flash column chromatography (0-20% methanol in dichloromethane). Off-white solid (63%). Rf: 0.2 (10% methanol in ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.77 (s, 1 H), 8.10 - 8.04 (m, 1 H), 8.02 (d, J = 5.6 Hz, 1 H), 7.99 (d, J = 9.8 Hz, 1 H), 7.84 - 7.77 (m, 1 H), 7.59 - 7.52 (m, 2H), 7.14 (d, J = 9.7 Hz, 1 H), 6.94 (dd, J = 5.4, 1.6 Hz, 1 H), 6.89 (d, J = 1.6 Hz, 1 H), 6.13 (s, 2H), 5.02 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 6 165.7, 160.5, 159.2, 148.9, 142.4, 142.2, 139.4, 131.1 , 130.4, 129.7, 127.2, 123.7, 121.8, 118.6, 111.7, 108.5, 103.8, 55.4. HRMS (ES+) m / z calc, for Ci8Hi5N6O2 [M+H]+: 347.1256, found: 347.1242.

[0383] N-(3- in-1

[0384] The title compound was synthesized according to Method M from 2-(3-bromo-6- oxopyridazin-1(6H)-yl)-N-(3-cyanophenyl)acetamide and (3,4-dimethylphenyl)boronic acid and was purified by flash column chromatography (30-100% ethyl acetate in hexane). Beige solid (67%). Rf: 0.4 (75% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.74 (s, 1H), 8.09 (d, J = 9.8 Hz, 1 H), 8.08 - 8.05 (m, 1 H), 7.84 - 7.77 (m, 1 H), 7.69 (d, J = 2.0 Hz, 1H), 7.61 (dd, J = 8.0, 2.0 Hz, 1 H), 7.58 - 7.51 (m, 2H), 7.25 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 9.8 Hz, 1 H), 5.01 (s, 2H), 2.28 (s, 3H), 2.26 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 0 165.9, 159.0, 143.9, 139.5, 137.9, 136.9, 131.7, 131.4, 130.4, 130.0, 129.6, 127.1 , 126.7, 123.7, 123.3, 121.7, 118.6, 111.7, 55.3, 19.5, 19.2. HRMS (ES+) m / z calc, for C2IHI9N4O2[M+H]+: 359.1508, found: 359.1514.

[0385] Method N (Synthesis of final compounds) a. Chloroacetic acid, NaH, DMF, RT; b. (i) ethyl chloroformate, triethylamine, THF, -5 °C to RT, (ii) substituted aniline, THF, RT.

[0386] To a stirred solution of sodium hydride (11 mmol, 40% purity) in anhydrous DMF (30 mL) under nitrogen, was added 6-phenylpyridazin-3(2H)-one (2.8 mmol) portion-wise, then chloroacetic acid (2.8 mmol) was added dropwise, and the reaction stirred overnight at room temperature. The mixture was added to ice-cooled water and the precipitate was filtered. The filtrate was acidified and the precipitate was filtered to afford 2-(6-oxo-3-phenylpyridazin- 1 (6H)-yl)acetic acid (22%), which was used in the next step without further purification.

[0387] To a suspension of 2-(6-oxo-3-phenylpyridazin-1 (6H)-yl)acetic acid (0.13 mmol) in tetrahydrofuran (1 mL) at -5°C was added triethylamine (0.52 mmol). The reaction mixture stirred for 30 min, then warmed to 0°C, ethyl chloroformate (0.14 mmol) was added and stirred for a further 1 h. Substituted aniline (0.26 mmol) was added and stirred at room temperature for 18 h. The suspension was diluted with water and filtered to afford the final compounds.

[0388] N-(4-hydroxyphenyl)-2-(6-oxo-3-phenylpyridazin-1(6H)-yl)acetamide (2)

[0389] The title compound was synthesized according to Method N using 4-aminophenol. White solid (11% over two steps). Rf: 0.1 (40% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.09 (s, 1 H), 9.23 (s, 1H), 8.11 (d, J = 9.8 Hz, 1H), 7.89 (d, J = 7.0 Hz, 2H), 7.55 - 7.42 (m, 3H), 7.36 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 9.8 Hz, 1 H), 6.70 (d, J = 8.8 Hz, 2H), 4.93 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 6 164.3, 159.1 , 153.5, 143.6, 134.3, 131.3, 130.4, 129.7, 129.4, 128.93, 125.8, 120.8, 115.1 , 55.1. HRMS (ES+) m / z calc, for CI8HI6N3O3[M+H]+: 322.1192, found: 322.1188.

[0390] N-(4-methoxyphenyl)-2-(6-oxo-3-phenylpyridazin-1 (6H)-yl)acetamide (17)

[0391] The title compound was synthesized according to Method N using 4-methoxyaniline. White solid (10% over two steps). Rf: 0.3 (40% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.22 (s, 1H), 8.11 (d, J = 9.7 Hz, 1 H), 7.93 - 7.85 (m, 2H), 7.55 - 7.41 (m, 5H), 7.11 (d, J = 9.7 Hz, 1 H), 6.94 - 6.85 (m, 2H), 4.96 (s, 2H), 3.72 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 6 164.5, 159.1 , 155.3, 143.6, 134.2, 131.9, 131.3, 129.7, 129.4, 128.9, 125.9, 120.6, 113.9, 55.2, 55.1. HRMS (ES+) m / z calc, for CI9HI8N3O3[M+H]+: 336.1348, found: 336.1347.

[0392] Method O (Synthesis of final compound - N-(3-cyanophenyl)-3-(6-oxo-3-phenylpyridazin- a. K2CO3, acetone, RT.

[0393] 6-phenylpyridazin-3(2H)-one (90 mg, 0.53 mmol) was dissolved in acetone (5 ml_), then potassium carbonate (183 mg, 1.33 mmol) and 3-chloro-N-(3-cyanophenyl)propanamide (98 mg, 0.47 mmol) were added and the reaction stirred at room temperature for 18 h. The reaction mixture was extracted by ethyl acetate and washed with water, saturated ammonium chloride aqueous solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Further purification by washing with iced ethyl acetate afforded N-(3-cyanophenyl)-3-(6-oxo-3-phenylpyridazin- 1(6H)-yl)propanamide as an off-white solid (83 mg, 51%). Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.46 (s, 1 H), 8.10 - 8.01 (m, 2H), 7.83 - 7.73 (m, 3H), 7.54 - 7.46 (m, 2H), 7.42 - 7.29 (m, 3H), 7.07 (d, J = 9.6 Hz, 1 H), 4.44 (t, J = 6.6 Hz, 2H), 2.90 (t, J = 6.6 Hz, 2H).13C NMR (101 MHz, DMSO-cfe) 5 169.7, 158.9, 143.3, 139.9, 134.3, 130.5, 130.2, 129.6, 129.3, 128.7, 126.7, 125.7, 123.6, 121.7, 118.7, 111.5, 47.0, 34.9. HRMS (ES+) m / z calc, for C20HI7N4O2[M+H]+: 345.1352, found: 345.1351. phenylpyridazin-1 (6H)-yl)propanamide (21)) a. K2CO3, acetone, RT.

[0394] 6-phenylpyridazin-3(2H)-one (86 mg, 0.50 mmol) was dissolved in acetone (5 ml_), then potassium carbonate (173 mg, 1.25 mmol) and 2-bromo-N-(3-cyanophenyl)-2- methylpropanamide (275 mg, 1.00 mmol) were added and the reaction was stirred at room temperature for 18 h. The reaction mixture was extracted by ethyl acetate and washed with water, saturated ammonium chloride aqueous solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Further purification by washing with iced ethyl acetate afforded N-(3-cyanophenyl)-2-methyl- 2-(6-oxo-3-phenylpyridazin-1 (6H)-yl)propanamide as a white solid (11 mg, 6%). Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 9.73 (s, 1 H), 8.16 (d, J = 9.7 Hz, 1 H), 8.05 - 7.97 (m, 3H), 7.90 - 7.81 (m, 1 H), 7.62 - 7.44 (m, 5H), 7.03 (d, J = 9.7 Hz, 1H), 1.73 (s, 6H).13C NMR (101 MHz, DMSO-cfe) 5 170.8, 158.8, 143.0, 140.1 , 134.8, 130.6, 130.1 , 129.9, 129.4, 129.0, 126.7, 125.8, 124.8, 123.0, 118.7, 111.2, 67.9, 24.0. HRMS (ES+) m / z calc, for C2IHI9N4O2[M+H]+: 359.1508, found: 359.1522. a. Pd(dppf)CI2, K2CO3, Dioxane / Water 4 / 1 , 100 °C.

[0395] A mixture of 2-(5-bromo-2-oxopyridin-1 (2H)-yl)-N-(3-cyanophenyl)acetamide (20 mg, 0.060 mmol), (4-chlorophenyl)boronic acid (10 mg, 0.066 mmol), potassium carbonate (21 mg, 0.15 mmol) and [1 ,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (4.4 mg, 0.0060 mmol) in dioxane (2.4 mL) and water (0.6 ml_), was evacuated and purged with nitrogen, and the reaction was heated to 100 °C for 18 h. Then, the reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. Water was added to the residue, and after extraction (x3) with ethyl acetate, the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. Purification with flash column chromatography (50-100% ethyl acetate in hexane) afforded 2-(5-(4- chlorophenyl)-2-oxopyridin-1 (2H)-yl)-N-(3-cyanophenyl)acetamide (7.0 mg, 32%) as an off- white solid. Rf: 0.3 (75% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.77 (s, 1H), 8.19 (d, J = 2.7 Hz, 1 H), 8.11 - 8.03 (m, 1 H), 7.91 (dd, J = 9.5, 2.7 Hz, 1H), 7.84 - 7.77 (m, 1 H), 7.64 - 7.48 (m, 6H), 6.53 (d, J = 9.5 Hz, 1 H), 4.84 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.2, 160.8, 139.5, 139.3, 138.0, 134.8, 131.6, 130.5, 129.0, 127.1 , 126.9, 123.5, 121.6, 119.4, 118.6, 116.4, 111.7, 52.0. HRMS (ES+) m / z calc, for C20HI5CIN3O2[M+H]+: 364.0853, found: 364.0838.

[0396] Method R (Synthesis of final compounds') a. K2CO3, acetone, 45 °C.

[0397] 6-substituted pyridazin-3(2H)-one (0.11 mmol) was dissolved in acetone (10 ml_), then potassium carbonate (0.17 mmol) and 2-chloro-N-(3-cyanophenyl)acetamide (0.11 mmol) were added and the reaction was heated to 45 °C for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Purification with flash column chromatography afforded the final compounds.

[0398] N-(3-cyanophenyl)-2-(6-oxo-3-(phenylamino)pyridazin-1 (6H)-yl)acetamide (40)

[0399] The title compound was synthesized according to Method R using 6-(phenylamino)pyridazin- 3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide and was purified by flash column chromatography (0-5% methanol in dichloromethane). White solid (29%). Rf: 0.2 (2.5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.65 (s, 1 H), 9.06 (s, 1 H), 8.08 (t, J = 1.5 Hz, 1 H), 7.82 (dt, J = 7.1 , 2.4 Hz, 1 H), 7.59 - 7.48 (m, 4H), 7.25 (d, J = 9.8 Hz, 1 H), 7.23 - 7.17 (m, 2H), 6.94 (d, J = 9.8 Hz, 1 H), 6.88 (tt, J = 7.3, 1.1 Hz, 1 H), 4.80 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.3, 157.5, 144.1 , 140.8, 139.6, 130.9, 130.4, 128.9, 128.7, 127.1 , 123.7, 121.8, 120.9, 118.7, 117.4, 111.7, 54.3. HRMS (ES+) m / z calc, for C19H16N5O2 [M+H]+: 346.1304, found: 346.1292.

[0400] N-(3- in-1

[0401] The title compound was synthesized according to Method R using 6- (cyclohexylamino)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide and was purified by flash column chromatography (0-5% methanol in dichloromethane). Yellow solid (34%). Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.53 (s, 1H), 8.08 - 8.03 (m, 1 H), 7.78 (dt, J = 7.1 , 2.4 Hz, 1 H), 7.59 - 7.48 (m, 2H), 6.99 (d, J = 9.8 Hz, 1 H), 6.75 (d, J = 9.7 Hz, 1 H), 6.29 (d, J = 7.2 Hz, 1 H), 4.64 (s, 2H), 1 .95 - 1 .82 (m, 2H), 1.68 - 1.61 (m, 2H), 1.56 - 1.49 (m, 1 H), 1.31 - 1.03 (m, 6H).13C NMR (101 MHz, DMSO- cfe) 5 166.5, 157.5, 146.5, 139.6, 130.3, 130.2, 128.3, 126.9, 123.6, 121.7, 118.7, 111.6, 54.1 , 49.0, 31.8, 25.5, 24.4. HRMS (ES+) m / z calc, for C19H22N5O2 [M+H]+: 352.1774, found: 352.1775.

[0402] N-(3- -2-(6-oxo-3-

[0403] The title compound was synthesized according to Method R using 6-phenoxypyridazin- 3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide and was purified first by flash column chromatography (0-5% methanol in dichloromethane), then by preparative HPLC (2-98% acetonitrile in water). White solid (18%). Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.71 (s, 1 H), 8.04 (d, J = 1.7 Hz, 1 H), 7.81 - 7.74 (m, 1 H), 7.57 - 7.50 (m, 2H), 7.48 (d, J = 9.8 Hz, 1 H), 7.40 (t, J = 7.9 Hz, 2H), 7.23 - 7.11 (m, 4H), 4.72 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.7, 158.7, 153.6, 151.4, 139.4, 133.2, 130.4, 129.9, 128.2, 127.1 , 124.8, 123.7, 121.8, 119.7, 118.6, 111.6, 54.3. HRMS (ES+) m / z calc, for C19H15N4O3 [M+H]+: 347.1144, found: 347.1135.

[0404] The title compound was synthesized according to Method R using 6-(hexylamino)pyridazin- 3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide and was purified by flash column chromatography (0-5% methanol in dichloromethane). White solid (41%). Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.57 (s, 1 H), 8.10 - 8.02 (m, 1 H), 7.83 - 7.73 (m, 1 H), 7.58 - 7.49 (m, 2H), 7.00 (d, J = 9.8 Hz, 1 H), 6.76 (d, J = 9.7 Hz, 1 H), 6.43 (t, J = 5.3 Hz, 1 H), 4.66 (s, 2H), 3.00 (q, J = 6.6 Hz, 2H), 1.48 (p, J = 7.2 Hz, 2H), 1.29 - 1.22 (m, 6H), 0.83 (t, J = 6.6 Hz, 3H).13C NMR (126 MHz, DMSO-cfe) 5 166.4, 157.6, 147.4, 139.6, 130.3, 130.2, 128.0, 126.9, 123.6, 121.7, 118.7, 111.6, 54.0, 41.0, 31.1 , 28.1 , 26.3, 22.1 , 13.9. HRMS (ES+) m / z calc, for C19H24N5O2 [M+H]+: 354.1930, found: 354.1927. 2-(3-((4-chlorophenyl)amino)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide (44)

[0405] The title compound was synthesized according to Method R using 6-((4- chlorophenyl)amino)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide and was purified by flash column chromatography (0-5% methanol in dichloromethane). White solid (25%). Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.66 (s, 1H), 9.23 (s, 1 H), 8.10 - 8.05 (m, 1 H), 7.87 - 7.77 (m, 1 H), 7.60 - 7.51 (m, 4H), 7.27 - 7.21 (m, 3H), 6.96 (d, J = 9.8 Hz, 1 H), 4.80 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.3, 157.5, 143.8, 139.7, 139.5, 131.1 , 130.4, 128.8, 128.5, 127.1 , 124.2, 123.7, 121.8, 118.9, 118.6, 111.7, 54.4. HRMS (ES+) m / z calc, for C19H15CIN5O2 [M+H]+: 380.0914, found: 380.0915.

[0406] 2-(3-((4-chlorobenzyl)amino)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide (45)

[0407] The title compound was synthesized according to Method R using 6-((4- chlorobenzyl)amino)pyridazin-3(2H)-one and 2-chloro-N-(3-cyanophenyl)acetamide and was purified by flash column chromatography (0-5% methanol in dichloromethane). White solid (40%). Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.50 (s, 1H), 8.05 (s, 1 H), 7.81 - 7.74 (m, 1 H), 7.59 - 7.51 (m, 2H), 7.38 - 7.27 (m, 4H), 7.06 (d, J = 9.8 Hz, 1 H), 6.99 (t, J = 5.7 Hz, 1 H), 6.81 (d, J = 9.7 Hz, 1 H), 4.65 (s, 2H), 4.22 (d, J = 5.7 Hz, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.3, 157.7, 146.9, 139.6, 138.3, 131.3, 130.5, 130.3, 129.7, 128.1 , 127.9, 127.0, 123.6, 121.7, 118.7, 111.6, 54.0, 44.0. HRMS (ES+) m / z calc, for C20H17CIN5O2 [M+H]+: 394.1071 , found: 394.1082. yl)pyridazin-1 (6H)-yl)acetamide (57)) a. Piperidine, DIPEA, 120 °C.

[0408] To a solution of 2-(3-chloro-6-oxopyridazin-1 (6H)-yl)-N-(3-cyanophenyl)acetamide (25 mg, 0.089 mmol) in N,N-diisopropylethylamine (2 mL) under nitrogen, was added piperidine (0.043 mL, 0.43 mmol) and the reaction was heated to 120 °C for 48 h. N,N- diisopropylethylamine (1 mL) and piperidine (0.043 mL, 0.43 mmol) were added and the reaction was heated to 120 °C for another 24 h. The mixture was concentrated under reduced pressure and purification using flash column chromatography (0-10% methanol in ethyl acetate) afforded N-(3-cyanophenyl)-2-(6-oxo-3-(piperidin-1-yl)pyridazin-1 (6H)- yl)acetamide (7.0 mg, 24%) as a light yellow solid. Rf: 0.3 (ethyl acetate).1H NMR (400 MHz, MeOD) 0 8.07 - 8.01 (m, 1 H), 7.83 - 7.76 (m, 1 H), 7.57 - 7.41 (m, 3H), 6.90 (d, J = 10.0 Hz, 1H), 4.85 (s, 2H), 3.35 - 3.32 (m, 4H), 1.66 - 1.61 (m, 6H).13C NMR (101 MHz, MeOD) 0 167.9, 160.6, 151.9, 140.7, 131.2, 131.0, 128.7, 128.6, 125.2, 123.9, 119.4, 113.8, 56.0, 26.4, 25.4. HRMS (ES+) m / z calc, for C18H20N5O2 [M+H]+: 338.1617, found: 338.1602.

[0409] Method T (Synthesis of final compound - 3-cyano-N-(2-(6-oxo-3-phenylpyridazin-1 (6H)- yl)ethyl)benzamide (11)) a. EDCI, HOBt, DCM, RT.

[0410] 3-cyanobenzoic acid (147 mg, 1.0 mmol) was dissolved in dichloromethane (10 ml_), and 1- ethyl-3-(3-dimethylaminopropyl)carbodiimide (210 mg, 1.1 mmol) and 1- hydroxybenzotriazole (68 mg, 0.50 mmol) were added to the reaction mixture. Then, 2- (aminoethyl)-6-phenylpyridazin-3(2H)-one (215 mg, 1.0 mmol) was added and the reaction stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was extracted with ethyl acetate and washed with sodium carbonate aqueous solution, ammonium chloride aqueous solution and brine. Then the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification with flash column chromatography (1-2.5% methanol in dichloromethane) afforded 3-cyano- N-(2-(6-oxo-3-phenylpyridazin-1 (6H)-yl)ethyl)benzamide as an off-white solid (100 mg, 29%). Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 8.84 (t, J = 5.9 Hz, 1H), 8.14 - 8.09 (m, 1 H), 8.08 - 8.00 (m, 2H), 7.95 (dt, J = 7.7, 1.4 Hz, 1 H), 7.78 - 7.72 (m, 2H), 7.61 (t, J = 7.8 Hz, 1 H), 7.45 - 7.33 (m, 3H), 7.05 (d, J = 9.7 Hz, 1 H), 4.33 (t, J = 5.7 Hz, 2H), 3.71 (q, J = 5.8 Hz, 2H).13C NMR (101 MHz, DMSO-cfe) 5 172.0, 164.8,

[0411] 159.2, 143.3, 135.4, 134.6, 134.3, 131.9, 130.7, 130.6, 129.7, 129.6, 129.2, 128.7, 125.6,

[0412] 118.2, 111.4, 50.5, 37.9. HRMS (ES+) m / z calc, for C2oHi7N402[M+H]+: 345.1352, found: 345.1364. al -2-(1 -oxo-4- a. EDCI, HOBt, DCM, RT.

[0413] 2-(1-oxo-4-phenylphthalazin-2(1 H)-yl)acetic acid (280 mg, 1.0 mmol) was dissolved in dichloromethane (10 ml_), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (210 mg, 1.1 mmol) and 1 -hydroxybenzotriazole (68 mg, 0.50 mmol) were added to the reaction mixture. Then, 3-aminobenzonitrile (118 mg, 1.0 mmol) was added and the reaction stirred at room temperature for 18 h. The reaction mixture was concentrated and the residue was extracted with ethyl acetate and washed with sodium carbonate aqueous solution, ammonium chloride aqueous solution and brine. Then the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification with flash column chromatography (1-2.5% methanol in dichloromethane) afforded N-(3-cyanophenyl)-2-(1- oxo-4-phenylphthalazin-2(1 H)-yl)acetamide as a white solid (98 mg, 26%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.70 (s, 1 H), 8.43 - 8.34 (m, 1 H), 8.10 - 8.05 (m, 1 H), 8.01 - 7.90 (m, 2H), 7.85 - 7.77 (m, 1 H), 7.77 - 7.71 (m, 1 H), 7.64 - 7.52 (m, 7H), 5.07 (s, 2H).13C NMR (101 MHz, DMSO-d6) 5 166.3, 158.4, 146.4, 139.5, 134.5, 133.8, 132.1 , 130.4, 129.4, 129.2, 128.8, 128.6, 127.4, 127.1 , 126.7, 126.5, 123.8, 121.9, 118.6, 111.7, 54.5. HRMS (ES+) m / z calc, for C23Hi7N4O2 [M+H]+: 381 .1352, found: 381.1343. a. Ethyl hydrazinoacetate, NaOAc, EtOH, reflux; b. 6N NaOH (aq.), 80 °C; c. (i) ethyl chloroform ate, triethylamine, THF, -5 °C to RT, (ii) substituted aniline, THF, RT. A suspension of benzoyl propionic acid (100 mg, 0.56 mmol), ethyl aminoglycinate hydrochloride (87 mg, 0.56 mmol) and sodium acetate (92 mg, 1.1 mmol) in ethanol (5 mL) was refluxed for 18 h. The solvent was removed under reduced pressure and the residue was suspended in water. The precipitate was filtered to afford the desired ester intermediate (82 mg, 55%), which was used in the next step without further purification. Then, a suspension of the ester (62 mg, 0.24 mmol) in 6N NaOH (aq.) was heated to 80°C for 2 h. The mixture was acidified with 6N HCI (aq.) and the precipitate was filtered to afford 2-(6- oxo-3-phenyl-5,6-dihydropyridazin-1 (4H)-yl)acetic acid as a white solid (42 mg, 81%).1H NMR (400 MHz, CDCI3) 5 7.79 (ddd, J = 6.2, 3.2, 1 .4 Hz, 2H), 7.45 - 7.38 (m, 3H), 4.55 (d, J = 1 .4 Hz, 2H), 3.12 - 3.03 (m, 2H), 2.69 - 2.59 (m, 2H).

[0414] To a suspension of 2-(6-oxo-3-phenyl-5,6-dihydropyridazin-1 (4H)-yl)acetic acid (30 mg, 0.13 mmol) in tetra hydrofuran (1 mL) at -5 °C was added triethylamine (73 pL, 0.52 mmol). The reaction mixture stirred for 30 min, then warmed to 0°C, ethyl chloroformate (14 pL, 0.14 mmol) was added and stirred for a further 1 h, then aniline (23 pL, 0.26 mmol) was added and stirred for 18 h. The suspension was diluted with water and filtered to afford 2-(6-oxo-3- phenyl-5,6-dihydropyridazin-1 (4H)-yl)-N-phenylacetamide as a white solid (6.9 mg, 17%). Rf: 0.3 (40% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 6 10.10 (s, 1H), 7.80 - 7.72 (m, 2H), 7.62 - 7.55 (m, 2H), 7.43 (dd, J = 5.1 , 2.0 Hz, 3H), 7.30 (t, J = 7.8 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1 H), 4.57 (s, 2H), 3.05 (t, J = 8.2 Hz, 2H), 2.60 (t, J = 8.2 Hz, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.1 , 165.8, 150.5, 138.8, 135.4, 129.6, 128.8, 128.5, 125.9, 123.3, 119.1 , 51.9, 26.2, 22.5.

[0415] Method W (Synthesis of final compoun

[0416] R: H, Cl a. Propargyl bromide, K2CO3, acetone, RT; b. 3-azidobenzonitrile, CuSO4, sodium ascorbate, MeOH, RT.

[0417] To a solution of 6-aryl pyridazin-3(2H)-one (1.0 mmol) in acetone (10 mL), was added propargyl bromide 80% w / v in toluene (2.0 mmol) and the reaction stirred at room temperature for 18 h. The mixture was concentrated, the residue was re-suspended in ethyl acetate and washed with water and brine. Purification using flash column chromatography afforded the intermediate product which was then used directly in the next step. To a solution of the alkyne derivative (0.5 mmol) in methanol (8 ml_), 3-azidobenzonitrile (0.5 mmol), copper sulfate (0.1 mmol) and sodium ascorbate (0.2 mmol) were added and the reaction stirred at room temperature for 18 h. Then, the mixture was filtered and the filtrate was concentrated under reduced pressure. Purification using flash column chromatography afforded the final compounds.

[0418] 3-(4-((6-oxo-3-phenylpyridazin-1 (6H)-yl)methyl)-1 H-1 ,2,3-triazol-1-yl)benzonitrile (4)

[0419] The title compound was synthesized according to Method W using 6-phenylpyridazin-3-(2H)- one and was purified by flash column chromatography (0-10% methanol in dichloromethane). White solid (85% over two steps). Rf: 0.2 (5% methanol in dichloromethane).1H NMR (400 MHz, CDCI3) 6 8.25 (s, 1 H), 8.07 (t, J = 1.8 Hz, 1 H), 8.00 (ddd, J = 8.1 , 2.3, 1.2 Hz, 1 H), 7.84 - 7.76 (m, 2H), 7.76 - 7.67 (m, 2H), 7.64 (t, J = 7.9 Hz, 1H), 7.51 - 7.38 (m, 3H), 7.04 (d, J = 9.7 Hz, 1 H), 5.62 (s, 2H).13C NMR (101 MHz, CDCI3) 5

[0420] 159.7, 145.1 , 144.0, 137.6, 134.4, 132.2, 131.0, 130.3, 129.8, 129.1 , 126.2, 124.6, 123.8, 122.1 , 117.5, 114.3, 48.6. HRMS (ES+) m / z calc, for C20HI5N6O [M+H]+: 355.1307, found: 355.1302.

[0421] 3-(4-((3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)methyl)-1 H-1 , 2, 3-triazol-1-yl) benzonitrile (37)

[0422] The title compound was synthesized according to Method W using 6-(4- chlorophenyl)pyridazin-3(2H)-one. White solid (43% over two steps). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 8.90 (s, 1 H), 8.44 (t, J = 1.9 Hz, 1 H), 8.28 (ddd, J = 8.3, 2.3, 1.1 Hz, 1 H), 8.11 (d, J = 9.8 Hz, 1 H), 7.98 - 7.89 (m, 3H), 7.78 (t, J = 8.0 Hz, 1 H), 7.60 - 7.51 (m, 2H), 7.13 (d, J = 9.8 Hz, 1 H), 5.50 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 158.6, 143.8, 142.9, 136.9, 134.3, 133.1 , 132.3, 131.3, 131.0, 130.1 , 129.0,

[0423] 127.7, 124.7, 123.5, 122.3, 117.8, 112.7, 46.9. HRMS (ES+) m / z calc, for C20HI4CIN6O [M+H]+: 389.0912, found: 389.0902.

[0424] Method X (Synthesis of final compounds') a. BBr3, DCM, 0 °C to RT; b. R = SO2F: AISF, Cs2CO3, DMSO, RT; R = 4-THP: 4- bromotetrahydro-2H-pyran, K2CO3, DMF, 90 °C.

[0425] 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5-hydroxyphenyl)acetamide (74) To a suspension of 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5- methoxyphenyl)acetamide (30 mg, 0.076 mmol) in anhydrous dichloromethane (2.5 mL) under nitrogen, was added boron tribromide solution 1.0 M in dichloromethane (2.5 mL, 2.5 mmol) dropwise at 0 °C, and the reaction stirred at room temperature for 4 h. Then, boron tribromide solution 1.0 M in dichloromethane (2.5 mL, 2.5 mmol) was added at 0 °C and the reaction stirred at room temperature for another 16 h. Methanol was added carefully dropwise and the mixture was concentrated. Saturated sodium bicarbonate solution (20 mL) was added to the residue and the mixture was stirred at room temperature for 20 min. Then, the aqueous phase was extracted (x3) with ethyl acetate and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography (0-10% methanol in dichloromethane) afforded the title compound (13 mg, 45%) as a white solid. Rf: 0.5 (10% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.62 (s, 1 H), 10.33 (s, 1 H), 8.14 (d, J = 9.8 Hz, 1 H), 7.97 - 7.89 (m, 2H), 7.61 - 7.53 (m, 2H), 7.45 (t, J = 1.6 Hz, 1 H), 7.35 (t, J = 2.1 Hz, 1 H), 7.13 (d, J = 9.8 Hz, 1 H), 6.88 - 6.83 (m, 1 H), 4.99 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 6 165.6, 159.0, 158.4, 142.7, 140.7, 134.3, 133.0, 131.3, 129.7, 129.0, 127.7, 118.7, 113.7, 112.9, 112.1 , 110.7, 55.4. HRMS (ES+) m / z calc, for CI8HI3CIN5O2[M+H]+: 381.0754, found: 381.0736.

[0426] 3-(2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-5-cyanophenyl sulfurofluoridate (83)

[0427] To a solution of 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5- hydroxyphenyl)acetamide (11 mg, 0.029 mmol) in anhydrous DMSO (1 mL) under nitrogen, was added 4-(acetylamino)phenyl]imidodisulfuryl difluoride (14 mg, 0.043 mmol) and cesium carbonate (28 mg, 0.087 mmol) and the reaction stirred at room temperature for 2 h. Saturated ammonium chloride aqueous solution was added to the reaction mixture and after extraction (x3) with ethyl acetate, the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography (10-100% ethyl acetate in hexane) afforded the title compound (6.5 mg, 49%) as a white solid. Rf: 0.6 (70% ethyl acetate in hexane).1H NMR (500 MHz, DMSO-cfe) 5 11.16 (s, 1 H), 8.18 (t, J = 2.2 Hz, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 8.03 (t, J = 1.6 Hz, 1 H), 8.01 (dd, J = 2.4, 1.3 Hz, 1 H), 7.95 - 7.91 (m, 2H), 7.59 - 7.55 (m, 2H), 7.14 (d, J = 9.8 Hz, 1 H), 5.05 (s, 2H).19F NMR (377 MHz, DMSO-cfe) 6 39.86.13C NMR (126 MHz, DMSO-cfe) 5 166.4, 159.0, 149.4, 142.8, 141.3, 134.4, 133.0, 131.4, 129.8, 129.0, 127.7, 122.7, 119.7, 116.9, 116.1 , 113.7, 55.4. HRMS (ES+) m / z calc, for CI9HI3CIFN4O5S [M+H]+: 463.0279, found: 463.0262.

[0428] 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5-((tetrahydro-2H-pyran-4-

[0429] To a solution of 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5- hydroxyphenyl)acetamide (13 mg, 0.034 mmol) in anhydrous DMF (2 mL) under nitrogen, was added potassium carbonate (24 mg, 0.17 mmol) and 4-bromotetrahydro-2H-pyran (19 uL, 0.17 mmol) at 0 °C and the reaction was heated to 90 °C for 6 h. Then, potassium carbonate (24 mg, 0.17 mmol) and 4-bromotetrahydro-2H-pyran (19 uL, 0.17 mmol) were added at 0 °C and the reaction was heated to 90 °C for another 18 h. Saturated ammonium chloride aqueous solution was added to the reaction mixture and after extraction (x3) with ethyl acetate, the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography (0-10% methanol in dichloromethane) afforded 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5- ((tetrahydro-2H-pyran-4-yl)oxy)phenyl)acetamide (10 mg, 63%) as an off-white solid. Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.68 (s, 1 H), 8.14 (d, J = 9.8 Hz, 1 H), 7.93 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.54 (s, 1 H), 7.51 (s, 1 H), 7.25 (s, 1 H), 7.14 (d, J = 9.8 Hz, 1 H), 5.00 (s, 2H), 4.61 (s, 1 H), 3.86 - 3.80 (m, 2H), 3.47 (t, J = 10.7 Hz, 2H), 1.99 - 1.93 (m, 2H), 1.61 - 1.52 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 165.8, 159.0, 157.7, 142.7, 140.7, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 118.5, 114.6, 113.7, 112.5, 111.5, 72.2, 64.4, 55.3, 31.5. HRMS (ES+) m / z calc, for C24H20CIN4O4 [M-H]’ : 463.1179, found: 463.1195.

[0430] -6-oxopvridazin-1 (6H)-vl)-N- a. 4-Methoxybenzyl mercaptan, DIPEA, Pd2(dba)3, XantPhos, Toluene, 120 °C; b. (i) 1 ,3- dichloro-5,5-dimethylhydantoin, acetic acid, water, acetonitrile, -5 °C, (ii) morpholine, DIPEA, THF, RT.

[0431] A mixture of / V-(3-bromo-5-cyanophenyl)-2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6 / - / )- yl)acetamide (110 mg, 0.25 mmol), 4-methoxybenzyl mercaptan (41 uL, 0.30 mmol), / V, / V- diisopropylethylamine (0.13 ml_, 0.74 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol) and 4,5-bis(diphenylphospheno)-9,9-dimethylxanthene (29 mg, 0.050 mmol) in toluene (6 ml_), was evacuated and purged with nitrogen, and the reaction was heated to 120 °C for 18 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (10- 100% ethyl acetate in hexane) afforded 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3- cyano-5-((4-methoxybenzyl)thio)phenyl)acetamide as a yellow solid, which was used directly in the next step. Rf: 0.7 (ethyl acetate), ES(-) m / z 515.0 [M-H]-. To a suspension of the thioether intermediate (20 mg, 0.039 mmol) in acetonitrile (5 mL) at -5 °C, was added water (0.5 mL), acetic acid (0.25 mL) and 1 ,3-dichloro-5,5-dimethylhydantoin (73 mg, 0.37 mmol) and the reaction stirred at -5 °C for 2 h. The reaction mixture was diluted with ethyl acetate and washed (x3) with brine to afford the intermediate sulfonyl chloride as a yellow solid, which was used directly in the next step. The product was dissolved in anhydrous THF (8 mL) under nitrogen and / V, / V-diisopropylethylamine (42 uL, 0.024 mmol) and morpholine (8.4 pL, 0.010 mmol) were added dropwise at 0 °C. The reaction then stirred at room temperature for 2 h. The mixture was concentrated and ammonium chloride saturated aqueous solution was added to the residue. After extraction with ethyl acetate (x3), the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (30- 100% ethyl acetate in hexane) afforded the title compound (9.0 mg, 7% over three steps) as a white solid. Rf: 0.4 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 11.12 (s, 1 H), 8.28 (t, J = 1.9 Hz, 1 H), 8.23 (t, J = 1.7 Hz, 1 H), 8.16 (d, J = 9.8 Hz, 1 H), 7.96 - 7.92 (m, 2H), 7.90 (t, J = 1.5 Hz, 1 H), 7.60 - 7.55 (m, 2H), 7.15 (d, J = 9.8 Hz, 1 H), 5.05 (s, 2H), 3.67 - 3.60 (m, 4H), 2.97 - 2.90 (m, 4H).13C NMR (126 MHz, DMSO-cfe) 5 166.3, 159.0, 142.8, 140.3, 136.8, 134.3, 133.0, 131.4, 129.8, 129.0, 127.7, 125.9, 125.4, 121.6, 117.3, 113.4, 65.2, 55.4, 45.8. HRMS (ES+) m / z calc, for C23H21CIN5O5S [M+H]+: 514.0952, found: 514.0942.

[0432] Method Z (Synthesis of final compounds') a. (i) K2CO3, DMF, RT, (ii) NaOH 2M (aq.) or LiOH 1 M (aq.), THF, RT; b. (i) amine, HATU or T3P, DIPEA, DMF, RT, (ii) HCI in dioxane 4N, dioxane or DCM, TFA, RT (for Boc-protected compounds).

[0433] To a solution of 6-aryl pyridazin-3(2H)-one (0.45 mmol) in anhydrous DMF (5 mL) under nitrogen, was added potassium carbonate (0.90 mmol) and the corresponding ester derivative (0.50 mmol) and the reaction stirred at room temperature for 3 h. Then, saturated ammonium chloride aqueous solution was added to the reaction mixture, the formed precipitate was filtered, washed with water, and dried under reduced pressure to afford the ester product, which was used directly in the next step. To a suspension of the ester product in THF (6 mL), sodium hydroxide aqueous solution 2M (6 mL) or lithium hydroxide aqueous solution 1 M (4 mL) was added dropwise at 0 °C and the reaction stirred at room temperature for 1 h. The mixture was diluted with ethyl acetate and water, then the aqueous layer was collected, acidified with hydrochloric acid aqueous solution 1 N to pH 2 and was extracted (x4) with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated under reduced pressure and the residue was triturated with dichloromethane to afford the carboxylic acid product.

[0434] Methyl 3-(2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-5-cyanobenzoate (62) Before the ester hydrolysis step, a small amount was further purified with flash column chromatography (20-100% ethyl acetate in hexane) to afford the product as white solid, pure for evaluation in biological assays. Rf: 0.5 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 6 10.98 (s, 1 H), 8.46 (t, J = 1.8 Hz, 1 H), 8.24 (t, J = 1.8 Hz, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 8.02 (t, J = 1.5 Hz, 1 H), 7.97 - 7.90 (m, 2H), 7.61 - 7.51 (m, 2H), 7.15 (d, J = 9.8 Hz, 1 H), 5.04 (s, 2H), 3.88 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 6 166.1 , 164.4, 159.0, 142.8, 139.9, 134.3, 133.0, 131.7, 131.3, 129.8, 129.0, 127.7, 127.2, 125.7, 123.7, 117.7, 112.5, 55.4, 52.8.

[0435] HRMS (ES+) m / z calc, for C2I HI6CIN4O4[M+H]+: 423.0860, found: 423.0863.

[0436] 3-(2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-5-cyanobenzoic acid (77)

[0437] The title compound was synthesized according to Method Z from 6-(4- chlorophenyl)pyridazin-3(2H)-one and methyl 3-(2-chloroacetamido)-5-cyanobenzoate and the ester was then hydrolysed using sodium hydroxide aqueous solution 2M. Off-white solid (53% over two steps). A small amount of the product was further purified by preparative HPLC (5-98% acetonitrile in water with 1% formic acid) for biological evaluation.1H NMR (400 MHz, DMSO-cfe) 6 10.89 (s, 1 H), 8.34 (s, 1 H), 8.21 (s, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 7.94 (d, J = 8.0 Hz, 3H), 7.58 (d, J = 8.4 Hz, 2H), 7.15 (d, J = 9.8 Hz, 1 H), 5.04 (s, 2H).13C NMR (126 MHz, DMSO-cfe) 5 165.9, 165.6, 159.0, 142.7, 139.4, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 127.4, 124.2, 123.8, 118.4, 111.5, 55.3. HRMS (ES-) m / z calc, for C2OHI2CIN404[M-H]-: 407.0552, found: 407.0553.

[0438] 2-(2-(3-(4-chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-6-cyanoisonicotinic acid

[0439] The title compound was synthesized according to Method Z from 6-(4-chloro-3- fluorophenyl)pyridazin-3(2H)-one and methyl 2-(2-chloroacetamido)-6-cyanoisonicotinate and the ester was then hydrolyzed using lithium hydroxide aqueous solution 1 M. Off-white solid (51% over two steps).1H NMR (400 MHz, DMSO-cfe) 5 14.21 - 13.81 (br, 1 H), 11.67 (s, 1H), 8.75 (s, 1 H), 8.19 (d, J = 9.8 Hz, 1 H), 8.08 (s, 1 H), 7.97 (dd, J = 10.8, 2.1 Hz, 1 H), 7.83 - 7.68 (m, 2H), 7.16 (d, J = 9.8 Hz, 1 H), 5.11 (s, 2H).19F NMR (377 MHz, DMSO-cfe) 5 - 115.37. ES(+) m / z 428.1 [M+H]+.

[0440] 3-(2-(3-(4-chloro-3-fluorophenyl)-6-oxopyridazin-1 (6 / - / )-yl)acetamido)-5-cyanobenzoic acid

[0441] The title compound was synthesized according to Method Z from 6-(4-chloro-3- fluorophenyl)pyridazin-3(2H)-one and methyl 3-(2-chloroacetamido)-5-cyanobenzoate and the ester was then hydrolyzed using lithium hydroxide aqueous solution 1 M. Off-white solid (54% over two steps).1H NMR (400 MHz, DMSO-cfe) 5 11.01 (s, 1 H), 8.41 (s, 1 H), 8.23 (s, 1H), 8.17 (d, J = 9.8 Hz, 1 H), 7.99 - 7.91 (m, 2H), 7.82 - 7.68 (m, 2H), 7.15 (d, J = 9.8 Hz, 1H), 5.05 (s, 2H).19F NMR (377 MHz, DMSO-cfe) 5 -115.33.13C NMR (101 MHz, DMSO-cfe) 5 166.0, 165.6, 159.1 , 158.8, 156.4, 141.8, 139.8, 135.35, 135.28, 133.7, 131.3, 129.8, 127.5, 125.2, 124.1 , 123.08, 123.05, 120.8, 120.6, 118.0, 114.3, 114.1 , 112.2, 55.5. ES(+) m / z 427.1 [M+H]+.

[0442] Amide coupling step (Method I using HATU as the coupling reagent): A mixture of the carboxylic acid (0.10 mmol), amine (0.15 mmol), HATU (0.12 mmol) and N,N-diisopropylethylamine (0.30 mmol) in anhydrous DMF (2 mL) under nitrogen, stirred at room temperature for 18 h. Saturated ammonium chloride aqueous solution was added to the reaction mixture and after extraction (x3) with ethyl acetate, the combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography afforded the final products.

[0443] Amide coupling step (Method II using T3P as the coupling reagent):

[0444] A mixture of the carboxylic acid (0.10 mmol), amine (0.15 mmol), 1-propanephosphonic anhydride 50% in DMF (0.12 mmol) and N,N-diisopropylethylamine (0.30 mmol) in anhydrous DMF (2 mL) under nitrogen, stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate and washed with lithium chloride 5% sol. (x2) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography afforded the final products.

[0445] Deprotection step for Boc-protected compounds:

[0446] To a solution of Boc-protected compound (0.040 mmol) in dioxane (2 mL), was added HCI in dioxane 4 M (2 mL) dropwise at 0 °C and the reaction stirred at room temperature for 1-6 h. The mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to afford the deprotected final compound as the hydrochloride salt.

[0447] Only for compounds 101 and 115, a mixture of dichloromethane and trifluoroacetic acid was used for Boc-deprotection as described in the procedures below.

[0448] 3-(2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-5-cvano-N-methylbenzamide (75)

[0449] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and methylamine solution in THF 2.0 M (5 equiv) using HATU as the coupling reagent and was purified by flash column chromatography (0-20% methanol in dichloromethane). White solid (26%). Rf: 0.3 (ethyl acetate).1H NMR (500 MHz, DMSO-cfe) 6 10.89 (s, 1 H), 8.65 (q, J = 4.5 Hz, 1 H), 8.27 (t, J = 1.9 Hz, 1 H), 8.18 (t, J = 1.7 Hz, 1 H), 8.14 (d, J = 9.8 Hz, 1 H), 7.96 (t, J = 1.5 Hz, 1 H), 7.95 - 7.92 (m, 2H), 7.59 - 7.56 (m, 2H), 7.14 (d, J = 9.7 Hz, 1 H), 5.03 (s, 2H), 2.79 (d, J = 4.4 Hz, 3H).13C NMR (126 MHz, DMSO-cfe) 6 165.9, 164.5, 159.0, 142.7, 139.7, 136.5, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.1 , 123.9, 122.8, 118.2, 111.8, 55.3, 26.4. HRMS (ES+) m / z calc, for C2iHi7CIN5O3[M+H]+: 422.1020, found: 422.1026. 3-(2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-5-cyano-N,N-

[0450] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and dimethylamine solution in THF 2.0 M (5 equiv) using HATU as the coupling reagent and was purified by flash column chromatography (0-20% methanol in dichloromethane). White solid (27%). Rf: 0.3 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 6 10.86 (s, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 8.04 (t, J = 1.8 Hz, 1 H), 7.95 - 7.91 (m, 2H), 7.86 (t, J = 1.7 Hz, 1 H), 7.61 (t, J = 1.5 Hz, 1 H), 7.59 - 7.56 (m, 2H), 7.14 (d, J = 9.8 Hz, 1 H), 5.03 (s, 2H), 2.98 (s, 3H), 2.89 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 5 166.0, 159.0, 142.7, 138.5, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.2, 122.5, 121.9, 118.1 , 111.9, 55.3, 34.8. HRMS (ES+) m / z calc, for C22HI9CIN5O3[M+H]+: 436.1176, found: 436.1168. tert-butyl 4-(3-(2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-5- cyanobenzoyl) piperazine- 1 -carboxylate (79)

[0451] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and 1-boc-piperazine using HATU as the coupling reagent and was purified by flash column chromatography (50-100% ethyl acetate in hexane). White solid (35%). Rf: 0.3 (70% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.87 (s, 1 H), 8.14 (d, J = 9.8 Hz, 1 H), 8.05 (t, J = 1.8 Hz, 1 H), 7.97 - 7.90 (m, 2H), 7.88 (t, J = 1.8 Hz, 1 H), 7.61 (t, J = 1.5 Hz, 1 H), 7.60 - 7.55 (m, 2H), 7.14 (d, J = 9.8 Hz, 1 H), 5.03 (s, 2H), 3.58 (s, 2H), 3.39 (s, 2H), 1.40 (s, 9H) (piperazine-H obscured by water peak)13C NMR (126 MHz, DMSO-cfe) 5 166.8, 166.0, 159.0, 153.8, 142.7, 139.6, 137.8, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.2, 122.7, 121.9, 118.0, 112.1 , 79.2, 55.4, 46.8, 41.5, 28.0. HRMS (ES+) m / z calc, for C29H30CIN6O5 [M+H]+: 577.1966, found: 577.1953.

[0452] 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5-(piperazine-1-

[0453] Deprotection of tert-butyl 4-(3-(2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-5- cyanobenzoyl)piperazine-1 -carboxylate according to Method Z (reaction time: 3 h) afforded the title compound. Off-white solid (93%).1H NMR (400 MHz, DMSO-cfe) 5 11.11 (s, 1 H), 9.22 (s, 2H), 8.14 (d, J = 9.8 Hz, 1 H), 8.07 (t, J = 1.8 Hz, 1 H), 7.98 (t, J = 1.8 Hz, 1 H), 7.95 - 7.91 (m, 2H), 7.68 (t, J = 1.5 Hz, 1 H), 7.59 - 7.56 (m, 2H), 7.14 (d, J = 9.8 Hz, 1 H), 5.05 (s, 2H), 3.79 (s, 2H), 3.54 (s, 2H), 3.14 (s, 4H).13C NMR (101 MHz, DMSO-cfe) 5 166.9, 166.0, 159.0, 142.8, 139.7, 137.0, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.3, 123.0, 122.2, 118.0, 112.0, 55.3, 42.4. HRMS (ES+) m / z calc, for C24H22CIN6O3[M+H]+: 477.1442, found: 477.1439.

[0454] 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5-(morpholine-4-

[0455] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and morpholine using HATU as the coupling reagent and was purified by flash column chromatography (0-20% methanol in dichloromethane). White solid (31%). Rf: 0.4 (10% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.88 (s, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 8.05 (t, J = 1.8 Hz, 1 H), 7.96 - 7.90 (m, 2H), 7.88 (t, J = 1.8 Hz, 1 H), 7.62 (t, J = 1.4 Hz, 1 H), 7.60 - 7.55 (m, 2H), 7.14 (d, J = 9.8 Hz, 1 H), 5.03 (s, 2H), 3.67 - 3.51 (m, 6H) (morpholine-H obscured by water peak).13C NMR (126 MHz, DMSO-cfe) 5 166.7, 166.0, 159.0, 142.8, 139.6, 137.7, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.3, 122.7, 121.9, 118.0, 112.1 , 66.0, 55.4, 47.6, 42.1. HRMS (ES+) m / z calc, for C24H2iCIN5O4[M+H]+: 478.1282, found: 478.1287.

[0456] 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cvano-5-(4-methylpiperazine-1-

[0457] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and 1 -methylpiperazine using HATU as the coupling reagent and was purified by flash column chromatography (0-20% methanol in dichloromethane). Off-white solid (55%). Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.97 (s, 1 H), 8.14 (d, J = 9.9 Hz, 1 H), 8.07 - 8.04 (m, 1 H), 7.96 - 7.90 (m, 2H), 7.88 - 7.84 (m, 1 H), 7.60 - 7.54 (m, 3H), 7.14 (d, J = 9.9 Hz, 1 H), 5.04 (s, 2H), 3.60 (s, 2H), 2.37 - 2.23 (m, 4H), 2.18 (s, 3H) (methylpiperazine-H obscured by water peak).13C NMR (101 MHz, DMSO-cfe) 5 166.6, 166.0, 159.0, 142.8, 139.6, 138.0, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.1 , 122.6, 121.6, 118.0, 112.1 , 55.4, 54.7, 54.2, 47.0, 45.6, 41.6. HRMS (ES+) m / z calc, for C25H2 CIN6O3[M+H]+: 491.1598, found: 491.1601.

[0458] 3-(2-(3-(4-i i-6-oxopyridazin-1

[0459] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and ammonium chloride (10 equiv) using HATU as the coupling reagent and was purified by flash column chromatography (0- 20% methanol in dichloromethane). White solid (20%). Rf: 0.3 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.89 (s, 1 H), 8.27 (t, J = 1.9 Hz, 1 H), 8.19 (t, J = 1.8 Hz, 1 H), 8.15 (d, J = 9.6 Hz, 2H), 8.01 (d, J = 1 .5 Hz, 1 H), 7.96 - 7.91 (m, 2H), 7.65 (s, 1 H), 7.59 - 7.55 (m, 2H), 7.14 (d, J = 9.8 Hz, 1 H), 5.03 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 0 165.9, 165.7, 159.0,

[0460] 142.7, 139.6, 136.4, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.6, 124.1 , 123.1 , 118.2,

[0461] 111.7, 55.3. HRMS (ES+) m / z calc, for C20HI5CIN5O3[M+H]+: 408.0863, found: 408.0877.

[0462] 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5-(piperidine-1-

[0463] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and piperidine using HATU as the coupling reagent and was purified by flash column chromatography (0-20% methanol in dichloromethane). White solid (29%). Rf: 0.3 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 6 10.87 (s, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 8.02 (d, J = 1.8 Hz, 1 H), 7.97 - 7.89 (m, 2H), 7.85 (d, J = 1.8 Hz, 1 H), 7.58 (d, J = 8.5 Hz, 3H), 7.14 (d, J = 9.7 Hz, 1 H), 5.03 (s, 2H), 3.57 (s, 2H), 3.23 (s, 2H), 1.63 - 1.43 (m, 6H).13C NMR (101 MHz, DMSO-cfe) 5 166.5, 166.0, 159.0,

[0464] 142.7, 139.5, 138.6, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 124.9, 122.4, 121.3, 118.0, 112.1 , 55.4, 48.0, 42.4, 25.9, 25.2, 23.9. HRMS (ES+) m / z calc, for C25H23CIN5O3[M+H]+: 476.1489, found: 476.1490.

[0465] 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cvano-5-(pyrrolidine-1-

[0466] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and pyrrolidine using HATU as the coupling reagent and was purified by flash column chromatography (0-20% methanol in ethyl acetate). White solid (24%). Rf: 0.3 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.87 (s, 1H), 8.15 (d, J = 9.8 Hz, 1 H), 8.04 (t, J = 1.8 Hz, 1 H), 7.99 (t, J = 2.0 Hz, 1 H), 7.96 - 7.90 (m, 2H), 7.71 - 7.67 (m, 1 H), 7.62 - 7.54 (m, 2H), 7.14 (d, J = 9.8 Hz, 1 H), 5.03 (s, 2H), 3.45 (t, J = 6.7 Hz, 2H), 3.37 (t, J = 6.3 Hz, 2H), 1 .90 - 1 .77 (m, 4H).13C NMR (126 MHz, DMSO- cfe) 5 166.0, 165.8, 159.0, 142.7, 139.4, 139.1 , 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.4, 122.8, 122.1 , 118.1 , 111.9, 55.3, 48.8, 46.1 , 25.9, 23.9. HRMS (ES+) m / z calc, for C24H2ICIN5O3[M+H]+: 462.1333, found: 462.1331.

[0467] N-(3-(azetidine-1-carbonyl)-5-cvanophenvl)-2-(3-(4-chlorophenvl)-6-oxopyridazin-1

[0468] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and azetidine using HATU as the coupling reagent and was purified by flash column chromatography (0-20% methanol in ethyl acetate). White solid (18%). Rf: 0.3 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.89 (s, 1H), 8.15 (d, J = 9.8 Hz, 1 H), 8.11 (d, J = 1.5 Hz, 2H), 7.97 - 7.89 (m, 2H), 7.73 (t, J = 1.5 Hz, 1 H), 7.58 (d, J = 8.6 Hz, 2H), 7.14 (d, J = 9.8 Hz, 1 H), 5.03 (s, 2H), 4.32 (t, J = 7.7 Hz, 2H), 4.05 (t, J = 7.8 Hz, 2H), 2.26 (p, J = 7.7 Hz, 2H).13C NMR (126 MHz, DMSO-cfe) 0 166.3, 166.0, 159.0, 142.8, 139.6, 135.2, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.8, 123.7, 122.6, 118.1 , 112.1 , 55.4, 53.0, 48.8, 15.5. HRMS (ES+) m / z calc, for C23Hi9CIN5O3[M+H]+: 448.1176, found: 448.1164.

[0469] 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5-(4,4-difluoropiperidine-1-

[0470] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and 4,4-difluoropiperidine hydrochloride using HATU as the coupling reagent and was purified by flash column chromatography (0-20% methanol in dichloromethane). White solid (29%). Rf: 0.7 (10% methanol in ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 6 10.88 (s, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 8.06 (s, 1 H), 7.96 - 7.91 (m, 2H), 7.90 (s, 1 H), 7.68 (s, 1H), 7.60 - 7.54 (m, 2H), 7.14 (d, J = 9.8 Hz, 1 H), 5.03 (s, 2H), 3.70 (s, 2H), 3.39 (s, 2H), 2.04 (s, 4H).19F NMR (376 MHz, DMSO-cfe) 5 -95.76.13C NMR (126 MHz, DMSO-cfe) 5 166.8, 166.0, 159.0, 142.7, 139.6, 137.7, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.1 , 122.8, 121.7, 118.0, 112.1 , 55.4, 43.9, 38.6, 33.5, 33.2, 33.0. HRMS (ES+) m / z calc, for C25H2iCIF2N5O3[M+H]+: 512.1301 , found: 512.1317.

[0471] 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cvano-5-(4-hvdroxypiperidine-1-

[0472] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and 4-hydroxypiperidine using HATU as the coupling reagent and was purified by flash column chromatography (0-20% methanol in dichloromethane). White solid (17%). Rf: 0.2 (10% methanol in ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.87 (s, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 8.03 (s, 1 H), 7.93 (d, J = 8.6 Hz, 2H), 7.85 (s, 1 H), 7.61 - 7.54 (m, 3H), 7.14 (d, J = 9.8 Hz, 1 H), 5.03 (s, 2H), 4.82 (d, J = 3.9 Hz, 1 H), 4.04 - 3.90 (m, 1 H), 3.73 (dt, J = 11.6, 4.0 Hz, 1 H), 3.47 - 3.39 (m, 1 H), 3.27 - 3.17 (m, 1 H), 3.16 - 3.03 (m, 1 H), 1.85 - 1.74 (m, 1 H), 1.74 - 1.62 (m, 1 H), 1.42 - 1.28 (m, 2H).13C NMR (126 MHz, DMSO-cfe) 5 166.5, 166.0, 159.0, 142.7, 139.5, 138.4, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.0, 122.4, 121.3, 118.1 , 112.2, 65.3, 55.4, 44.6, 34.4, 33.7. HRMS (ES+) m / z calc, for C25H23CIN5O4[M+H]+: 492.1439, found: 492.1433.

[0473] N-(3-((1S,4S)-2-oxa-5-azabicyclo[2.2.1lheptane-5-carbonyl)-5-cvanophenyl)-2-(3-(4- in-1 The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and (1S,4S)-2-oxa-5- azabicyclo[2.2.1]heptane hydrochloride using HATU as the coupling reagent and was purified by flash column chromatography (0-20% methanol in ethyl acetate). White solid (27%). Rf: 0.3 (10% methanol in ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.93 (s, 1H), 8.16 (d, J = 9.8 Hz, 1 H), 8.12 (s, 0.5H), 8.06 (s, 0.5H), 8.04 (s, 0.5H), 7.97 - 7.91 (m, 2.5H), 7.75 (s, 0.5H), 7.67 (s, 0.5H), 7.62 - 7.56 (m, 2H), 7.15 (d, J = 9.7 Hz, 1 H), 5.04 (d, J = 4.2 Hz, 2H), 4.84 (s, 0.5H), 4.67 (s, 0.5H), 4.58 (s, 0.5H), 4.39 (s, 0.5H), 3.88 (d, J = 7.6 Hz, 0.5H), 3.81 (d, J = 7.4 Hz, 0.5H), 3.76 (d, J = 7.4 Hz, 0.5H), 3.68 (d, J = 7.3 Hz, 0.5H), 3.53 - 3.48 (m, 1 H), 3.31 - 3.24 (m, 1 H), 1.94 - 1.73 (m, 2H).13C NMR (126 MHz, DMSO- cfe) 5 166.0, 165.3, 159.0, 142.7, 139.6, 139.5, 138.2, 137.7, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.6, 125.4, 123.2, 123.0, 122.4, 122.1 , 118.1 , 112.2, 112.0, 75.5, 75.0, 73.5, 72.9, 59.8, 57.5, 56.3, 55.4, 54.4, 36.7, 35.0. HRMS (ES+) m / z calc, for C25H2iCIN5O4[M+H]+: 490.1282, found: 490.1292.

[0474] N-(3-(8-oxa-3-azabicyclo[3.2.1loctane-3-carbonvl)-5-cvanophenvl)-2-(3-(4-chlorophenyl)-6- oxopyridazin-1 (6H)-yl)acetamide (93)

[0475] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride using HATU as the coupling reagent and was purified by flash column chromatography (0-20% methanol in ethyl acetate). White solid (41%). Rf: 0.4 (10% methanol in ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 6 10.87 (s, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 8.03 (t, J = 1.8 Hz, 1 H), 7.97 - 7.90 (m, 2H), 7.87 (t, J = 1.8 Hz, 1 H), 7.62 - 7.52 (m, 3H), 7.14 (d, J = 9.8 Hz, 1 H), 5.03 (s, 2H), 4.38 (s, 1 H), 4.19 (s, 1 H), 4.13 (d, J = 13.2 Hz, 1 H), 3.14 (d, J = 12.8 Hz, 1 H), 2.99 (d, J = 13.1 Hz, 1 H), 1.85 - 1.56 (m, 4H) (1 H obscured by water peak).13C NMR (126 MHz, DMSO-cfe) 5 168.1 , 166.0, 159.0, 142.7, 139.7, 138.0, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.1 , 122.6, 121.7, 118.0, 112.2, 73.1 , 72.8, 55.4, 53.0, 47.5, 27.2, 27.0. HRMS (ES+) m / z calc, for C26H23CIN5O4[M+H]+: 504.1439, found: 504.1421.

[0476] 2-(3-(4-chlorophenyl)-6-oxopvridazin-1 (6H)-vl)-N-(3-cvano-5-(4-hydroxv-4-

[0477] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and 4-methylpiperidin-4-ol using HATU as the coupling reagent and was purified by flash column chromatography (0-20% methanol in ethyl acetate). White solid (38%). Rf: 0.2 (10% methanol in ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 10.85 (s, 1 H), 8.15 (d, J = 9.8 Hz, 1 H), 8.04 (t, J = 1.8 Hz, 1 H), 7.97 - 7.89 (m, 2H), 7.83 (t, J= 1.8 Hz, 1H), 7.62 - 7.54 (m, 3H), 7.14 (d, J= 9.8 Hz, 1H), 5.03 (s, 2H), 4.45 (s, 1H), 4.06 (d, J= 12.7 Hz, 1H), 3.32 - 3.14 (m, 3H), 1.58 - 1.40 (m, 4H), 1.14 (s, 3H).13C NMR (126 MHz, DMSO-cfe) 0166.4, 166.0, 159.0, 142.7, 139.5, 138.6, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.0, 122.4, 121.4, 118.1, 112.1, 66.1, 55.4, 43.7, 38.5, 38.2, 37.8, 29.8. HRMS (ES+) m / z calc, for C26H25CIN5O4[M+H]+: 506.1595, found: 506.1598.

[0478] 2-(3-(4-chlorophenyl)-6-oxopyridazin-1(6H)-yl)-N-(3-cyano-5-((2S,6R)-2,6- dimethylmorpholine-4-carbonyl)phenyl)acetamide (95)

[0479] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and cis-2,6-dimethylmorpholine using HATU as the coupling reagent and was purified by flash column chromatography (0- 20% methanol in ethyl acetate). White solid (28%). Rf: 0.3 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 510.95 (s, 1H), 8.15 (d, J= 9.9 Hz, 1H), 8.09 - 8.04 (m, 1H), 7.96 - 7.90 (m, 2H), 7.88-7.82 (m, 1H), 7.62-7.55 (m, 3H), 7.14 (d, J= 9.8 Hz, 1H), 5.03 (s, 2H), 4.33 (d, J= 13.0 Hz, 1H), 3.52 (s, 3H), 2.88 - 2.73 (m, 2H), 1.14 (s, 1H), 0.99 (s, 3H) (2H obscured by solvent and water peaks).13C NMR (126 MHz, DMSO-cfe) 6 166.5, 166.0, 159.0, 142.7, 139.8, 137.8, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.2, 122.7, 121.9, 118.1, 112.1, 71.3, 71.0, 55.4, 52.3, 46.9, 18.6, 18.3. HRMS (ES+) m / z calc, for C26H25CIN5O4[M+H]+: 506.1595, found: 506.1601. t-3,5-

[0480] The Boc-protected intermediate was synthesized according to Method Z from 3-(2-(3-(4- chlorophenyl)-6-oxopyridazin-1(6H)-yl)acetamido)-5-cyanobenzoic acid and (2R,6S)-tert- butyl 2,6-dimethylpiperazine-1 -carboxylate using HATU as the coupling reagent and was purified by flash column chromatography (0-10% methanol in dichloromethane). ES(+) m / z 627.1 [M+Na]+. Then, deprotection (reaction time: 4 h) afforded the title compound. White solid (74% over two steps).1H NMR (400 MHz, DMSO-cfe) 611.06 (s, 1H), 9.61 -9.49 (br, 1H), 9.10-9.00 (br, 1H), 8.15 (d, J= 9.8 Hz, 1H), 8.08 (t, J= 1.8 Hz, 1H), 7.98 - 7.89 (m, 3H), 7.66 (t, J= 1.5 Hz, 1H), 7.62- 7.54 (m, 2H), 7.14 (d, J= 9.8 Hz, 1H), 5.05 (s, 2H), 4.62-4.48 (br, 1H), 3.74-3.58 (br, 1H), 3.24-3.10 (br, 1H), 2.89 -2.77 (br, 1H), 1.35 - 1.06 (m, 6H) (piperazine-H obscured by water peak).13C NMR (126 MHz, DMSO-cfe) 5 166.8, 166.0, 159.0, 142.7, 139.7, 136.9, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.4, 123.1, 122.2, 118.1, 112.1, 55.3, 50.7, 49.2, 43.9, 15.4. HRMS (ES+) m / z calc, for C26H26CIN6O3[M+H]+: 505.1755, found: 505.1760. anophenyl)-2-(3-(4-chlorophenyl)-6-

[0481] The Boc-protected intermediate was synthesized according to Method Z from 3-(2-(3-(4- chlorophenyl)-6-oxopyridazin-1 (6 / - / )-yl)acetamido)-5-cyanobenzoic acid and 8-t- butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane using HATU as the coupling reagent and was purified by flash column chromatography (0-20% methanol in ethyl acetate). ES(+) m / z 625.3 [M+Na]+. Then, deprotection (reaction time: 4 h) afforded the title compound. White solid (15% over two steps).1H NMR (400 MHz, MeOD) 5 8.12 - 8.05 (m, 2H), 7.97 (s, 1 H), 7.90 (d, J = 8.3 Hz, 2H), 7.60 (s, 1 H), 7.50 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 9.9 Hz, 1 H), 5.12 (s, 2H), 3.76 - 3.62 (m, 6H), 2.13 - 1.95 (m, 4H).13C NMR (126 MHz, MeOD) 5 171.3, 167.8, 162.0, 146.1 , 141.1 , 137.9, 136.9, 134.4, 133.0, 130.8, 130.2, 128.8, 127.1 , 125.3, 123.6, 118.5, 114.9, 72.5, 71.5, 68.1 , 56.9, 25.8. HRMS (ES+) m / z calc, for C26H24CIN6O3[M+H]+: 503.1598, found: 503.1603.

[0482] 2-(3-(4-chloro-3-

[0483] 1- idin-2-’

[0484] The title compound was synthesized according to Method Z from 2-(2-(3-(4-chloro-3- fluorophenyl)-6-oxopyridazin-1(6H)-yl)acetamido)-6-cyanoisonicotinic acid and 4,4- difluoropiperidine hydrochloride using 1-propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by flash column chromatography (50-100% ethyl acetate in hexane). White solid (32%). Rf: 0.4 (70% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 11.63 (s, 1 H), 8.29 (s, 1 H), 8.18 (d, J = 9.9 Hz, 1 H), 7.96 (dd, J = 10.8, 2.0 Hz, 1H), 7.89 (d, J = 1.3 Hz, 1 H), 7.79 (dd, J = 8.6, 2.0 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.15 (d, J = 9.8 Hz, 1 H), 5.10 (s, 2H), 3.74 - 3.65 (m, 2H), 2.11 - 1.94 (m, 4H) (2H obscured by water peak).19F NMR (377 MHz, DMSO-cfe) 5 -95.88, -115.37.13C NMR (126 MHz, DMSO- d6) 5 166.7, 165.1 , 158.9, 158.5, 156.6, 152.9, 147.1 , 141.71 , 141.69, 135.3, 135.2, 131.23, 131.15, 129.7, 124.5, 123.02, 122.99, 122.6, 121.9, 120.7, 120.5, 116.7, 115.1 , 114.3, 114.1 , 55.4, 43.6, 38.4, 33.5, 33.4, 33.2, 32.9, 32.7, 32.6. HRMS (ES+) m / z calc, for C24Hi9CIF3N6O3[M+H]+: 531.1159, found: 531.1151.

[0485] N-(4-((1S,4S)-2-oxa-5-i .2.1 ]heptane-5-carbonyl)-6-cyanopyridin-2-yl)-2-(3-(4- chloro-3- in-1

[0486] The title compound was synthesized according to Method Z from 2-(2-(3-(4-chloro-3- fluorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-6-cyanoisonicotinic acid and (1S,4S)-2- oxa-5-azabicyclo[2.2.1]heptane hydrochloride using 1-propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by flash column chromatography (0-10% methanol in dichloromethane). White solid (39%). Rf: 0.5 (10% methanol in ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 0 11.63 (s, 1 H), 8.35 (s, 0.5H), 8.30 (s, 0.5H), 8.18 (d, J = 9.8 Hz, 1 H), 7.96 (dd, J = 10.8, 2.0 Hz, 1 H), 7.93 (s, 0.5H), 7.88 (s, 0.5H), 7.79 (dd, J = 8.6, 2.0 Hz, 1 H), 7.73 (t, J = 8.0 Hz, 1 H), 7.15 (d, J = 9.8 Hz, 1 H), 5.10 (s, 2H), 4.84 (s, 0.5H), 4.65 (s, 0.5H), 4.57 (s, 0.5H), 4.38 (s, 0.5H), 3.84 (d, J = 7.7 Hz, 0.5H), 3.78 (d, J = 7.4 Hz, 0.5H), 3.73 (d, J = 7.4 Hz, 0.5H), 3.62 (d, J = 7.5 Hz, 0.5H), 3.49 - 3.42 (m, 1 H), 3.30 - 3.23 (m, 1H), 1.94 - 1.85 (m, 1 H), 1.81 (d, J = 10.1 Hz, 0.5H), 1.74 (d, J = 10.0 Hz, 0.5H).19F NMR (377 MHz, DMSO-cfe) 0 -115.36.13C NMR (126 MHz, DMSO-cfe) 0 166.7, 164.4, 163.7, 158.9, 158.5, 156.6, 152.9, 147.3, 146.8, 141.7, 135.3, 135.2, 131.3, 131.2, 129.7, 123.0, 122.4, 122.2, 120.7, 120.5, 116.8, 116.7, 115.6, 115.4, 114.3, 114.1 , 75.5, 74.9, 73.4, 72.8, 59.6, 57.0, 56.3, 55.41 , 55.35, 54.4, 36.6, 34.9. HRMS (ES+) m / z calc, for C24HI9CIFN6O4[M+H]+: 509.1140, found: 509.1151. idin-2-yl)-2-(3-(4-chloro-3-

[0487] The title compound was synthesized according to Method Z from 2-(2-(3-(4-chloro-3- fluorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-6-cyanoisonicotinic acid and 8-oxa-3- azabicyclo[3.2.1]octane hydrochloride using 1-propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by flash column chromatography (0-10% methanol in dichloromethane). White solid (44%). Rf: 0.6 (10% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 11.63 (s, 1 H), 8.22 (s, 1 H), 8.18 (d, J = 9.8 Hz, 1 H), 7.97 (dd, J =

[0488] 10.8, 2.0 Hz, 1 H), 7.85 (d, J = 1.2 Hz, 1 H), 7.81 - 7.71 (m, 2H), 7.15 (d, J = 9.8 Hz, 1 H), 5.09 (s, 2H), 4.37 (d, J = 6.0 Hz, 1H), 4.17 (d, J = 5.8 Hz, 1 H), 4.08 (d, J = 13.1 Hz, 1 H), 3.12 (d, J = 12.8 Hz, 1 H), 2.98 (d, J = 12.9 Hz, 1 H), 1.84 - 1.71 (m, 2H), 1.70 - 1.55 (m, 2H) (1 H obscured by water peak).19F NMR (377 MHz, DMSO-cfe) 5 -115.36.13C NMR (101 MHz, DMSO-cfe) 5 166.7, 166.5, 158.9, 158.8, 156.3, 152.9, 147.3, 141.73, 141.71 , 135.3, 135.2, 131.3, 131.2, 129.7, 123.03, 123.00, 122.1 , 120.7, 120.5, 116.7, 115.0, 114.3, 114.1 , 73.0,

[0489] 72.8, 55.4, 52.6, 47.4, 27.2, 27.0. HRMS (ES+) m / z calc, for C25H2ICIFN6O4[M+H]+: 523.1297, found: 523.1302. ,5R)-3,5-

[0490] The Boc-protected intermediate was synthesized according to Method Z from 2-(2-(3-(4- chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-6-cyanoisonicotinic acid and (2R,6S)-tert-butyl 2,6-dimethylpiperazine-1 -carboxylate using 1-propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by flash column chromatography (0-10% methanol in dichloromethane). ES(+) m / z 646.3 [M+Na]+. Then, the intermediate was added to a mixture of dichloromethane / trifluoroacetic acid (4 / 1) and the reaction stirred at room temperature for 1 h. The reaction mixture was concentrated, and the residue was treated with sodium hydroxide aq. sol. 0.1 M. After extraction (x4) with ethyl acetate, the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (0-10% methanol in dichloromethane) afforded the product as the free base. To convert to the desired HCI salt, the product was added to dioxane (2 ml_), then HCI in dioxane 4 M (0.1 mL) was added dropwise at 0 °C and the mixture stirred at room temperature for 15 min. The mixture was concentrated under reduced pressure to afford the title compound. White solid (48% over two steps).1H NMR (400 MHz, DMSO-cfe) 6 11.66 (s, 1 H), 9.67 - 9.47 (br, 1 H), 9.18 - 8.98 (br, 1 H), 8.30 (s, 1 H), 8.19 (d, J = 9.8 Hz, 1 H), 7.97 (dd, J = 10.8, 2.0 Hz, 1 H), 7.87 (d, J = 1.2 Hz, 1 H), 7.81 - 7.70 (m, 2H), 7.16 (d, J = 9.8 Hz, 1 H), 5.11 (s, 2H), 4.53 (d, J = 13.6 Hz, 1H), 3.60 (d, J = 12.6 Hz, 1 H), 3.12 (t, J = 12.1 Hz, 1 H), 2.81 (t, J = 12.3 Hz, 1 H), 1.29 (d, J = 6.4 Hz, 3H), 1 .12 (d, J = 6.4 Hz, 3H) (piperazine-H obscured by water peak).19F NMR (377 MHz, DMSO-cfe) 5 -115.36.13C NMR (101 MHz, DMSO-cfe) 5 166.7, 165.0, 159.0, 158.8, 156.3, 152.9, 146.4, 141.71 , 141.69, 135.3, 135.2, 131.2, 131.1 , 129.7, 123.02, 122.99, 122.2, 120.7, 120.5, 116.8, 115.5, 114.3, 114.0, 55.4, 50.8, 50.4, 48.9, 43.7, 15.6, 15.2. HRMS (ES+) m / z calc, for C25H24CIFN7O3 [M+H]+: 524.1613, found: 524.1637. . idin-2-yl)-2-(3-(4-chloro-3- in-1

[0491] The Boc-protected intermediate was synthesized according to Method Z from 2-(2-(3-(4- chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-6-cyanoisonicotinic acid and 8-t- butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane using 1-propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by preparative thin layer chromatography (0- 10% methanol in dichloromethane). ES(+) m / z 644.3 [M+Na]+. After deprotection according to Method Z (HCI in dioxane 4M / dioxane: 1 / 1 , reaction time: 6 h), the reaction mixture was concentrated, and the residue was treated with sodium carbonate sat. aq. sol. and extracted (x4) with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (0-10% methanol in dichloromethane) afforded the product as the free base. To convert to the desired HCI salt, the product was added to dioxane (2 mL) then HCI in dioxane 4 M (0.1 mL) was added dropwise at 0 °C and the mixture stirred at room temperature for 15 min. The mixture was concentrated under reduced pressure to afford the title compound. White solid (13% over two steps).1H NMR (400 MHz, DMSO-cfe) 6 11.68 (s, 1 H), 9.35 - 9.05 (br, 2H), 8.26 (s, 1 H), 8.19 (d, J = 9.9 Hz, 1 H), 7.97 (d, J = 10.9 Hz, 1 H), 7.93 (s, 1 H), 7.82 - 7.71 (m, 2H), 7.15 (d, J = 9.7 Hz, 1 H), 5.10 (s, 2H), 4.33 (d, J = 13.8 Hz, 1 H), 4.08 (s, 1 H), 3.86 (s, 1H), 3.56 (d, J = 14.4 Hz, 1 H), 3.41 (d, J = 14.7 Hz, 1 H), 3.22 (d, J = 14.2 Hz, 1 H), 2.00 - 1.83 (m, 2H), 1.83 - 1.59 (m, 2H).19F NMR (377 MHz, DMSO-cfe) 0 -115.36.13C NMR (126 MHz, DMSO-cfe) 0 166.8, 166.7, 158.9, 158.5, 156.6, 152.9, 146.4, 141.7, 135.3, 135.2, 131.3, 131.2, 129.7, 123.02, 123.00, 122.2, 120.7, 120.5, 116.7, 115.2, 114.3, 114.1 , 55.3, 53.6, 53.5, 49.7, 44.7, 24.7, 24.6. HRMS (ES+) m / z calc, for C25H22CIFN7O3 [M+H]+: 522.1457, found: 522.1462.

[0492] 2-(3-(4-Chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(6-cyano-4-(morpholine-4- carbonyl)pyridin-2-yl)acetamide (105)

[0493] The title compound was synthesized according to Method Z from 2-(2-(3-(4-chloro-3- fluorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-6-cyanoisonicotinic acid and morpholine using 1-propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by flash column chromatography (0-10% methanol in dichloromethane). White solid (56%). Rf: 0.4 (10% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 11.62 (s, 1 H), 8.24 (s, 1 H), 8.18 (d, J = 9.8 Hz, 1 H), 7.96 (dd, J = 10.8, 2.0 Hz, 1 H), 7.85 (d, J = 1.2 Hz, 1H), 7.81 - 7.70 (m, 2H), 7.15 (d, J = 9.8 Hz, 1 H), 5.09 (s, 2H), 3.66 - 3.56 (m, 4H), 3.54 - 3.48 (m, 2H), 3.29 - 3.24 (m, 2H).19F NMR (377 MHz, DMSO-cfe) 5 -115.36.13C NMR (101 MHz, DMSO-cfe) 5 166.7, 165.0, 159.9, 159.0, 156.4, 152.9, 147.0, 141.74, 141.72, 135.3, 135.2, 131.3, 131.2, 129.7, 123.05, 123.02, 122.2, 120.7, 120.5, 116.7, 115.2, 114.3, 114.1 , 66.0, 65.7, 55.4, 47.2, 41.9. HRMS (ES+) m / z calc, for C23Hi9CIFN6O4[M+H]+: 497.1140, found: 497.1129.

[0494] 2-(3-(4-chloro-3- in-1 >-4-(piperazine-1-

[0495] The Boc-protected intermediate was synthesized according to Method Z from 2-(2-(3-(4- chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-6-cyanoisonicotinic acid and 1- Boc-piperazine using 1-propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by flash column chromatography (0-10% methanol in dichloromethane). ES(+) m / z 618.2 [M+Na]+. After deprotection according to Method Z (HCI in dioxane 4M / dioxane: 1 / 1 , reaction time: 1 h), the reaction mixture was concentrated, and the residue was treated with sodium carbonate sat. aq. sol. and extracted (x4) with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (0-10% methanol in dichloromethane) afforded the product as the free base. To convert to the desired HCI salt, the product was added to dioxane (2 mL) then HCI in dioxane 4 M (0.1 mL) was added dropwise at 0 °C and the mixture stirred at room temperature for 15 min. The mixture was concentrated under reduced pressure to afford the title compound. White solid (28% over two steps).1H NMR (400 MHz, DMSO-cfe) 6 11.65 (s, 1 H), 9.18 - 8.98 (br, 2H), 8.32 (s, 1 H), 8.18 (d, J = 9.8 Hz, 1 H), 7.97 (dd, J = 10.8, 2.1 Hz, 1 H), 7.88 (d, J = 1.3 Hz, 1 H), 7.81 - 7.71 (m, 2H), 7.15 (d, J = 9.8 Hz, 1 H), 5.10 (s, 2H), 3.78 (s, 2H), 3.48 (s, 2H), 3.17 (s, 2H), 3.07 (s, 2H).19F NMR (377 MHz, DMSO-cfe) 0 -115.35.13C NMR (101 MHz, DMSO-cfe) 0 166.7, 165.1 , 159.0, 158.8, 156.3, 152.9, 146.4, 141.72, 141.70, 135.3, 135.2, 131.2, 131.1 , 129.7, 123.02, 122.99, 122.2, 120.7, 120.5, 116.7, 115.5, 114.3, 114.0, 55.4, 43.7, 42.5, 42.2, 38.5. HRMS (ES+) m / z calc, for C23H2oCIFN703[M+H]+: 496.1300, found: 496.1309. oxopyridazin-1 (6H)-yl)-N-(3-cyano-5-(morpholine-4-

[0496] The title compound was synthesized according to Method Z from 3-(2-(3-(4-chloro-3- fluorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-5-cyanobenzoic acid and morpholine using 1-propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by flash column chromatography (0-10% methanol in dichloromethane). White solid (65%). Rf: 0.4 (10% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.88 (s, 1 H), 8.19 (d, J = 9.9 Hz, 1 H), 8.07 - 8.02 (m, 1 H), 7.97 (dd, J = 10.9, 2.0 Hz, 1 H), 7.90 - 7.84 (m, 1H), 7.83 - 7.70 (m, 2H), 7.65 - 7.59 (m, 1 H), 7.16 (d, J = 9.8 Hz, 1 H), 5.04 (s, 2H), 3.70 - 3.49 (m, 6H) (morpholine-H obscured by water peak).19F NMR (377 MHz, DMSO-cfe) 6 - 115.36.13C NMR (126 MHz, DMSO-cfe) 5 166.7, 165.9, 159.0, 158.6, 156.6, 141.69, 141.67, 139.6, 137.7, 135.3, 135.2, 131.3, 131.2, 129.7, 125.3, 123.02, 122.99, 122.7, 121.9, 120.7, 120.5, 118.0, 114.3, 114.1 , 112.1 , 66.0, 55.4, 47.6, 42.1. HRMS (ES+) m / z calc, for C24H2OCIFN504[M+H]+: 496.1188, found: 496.1176.

[0497] 2-(3-(4-Chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5-(piperazine-1-

[0498] The Boc-protected intermediate was synthesized according to Method Z from 3-(2-(3-(4- chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-5-cyanobenzoic acid and 1-Boc- piperazine using 1-propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by flash column chromatography (0-10% methanol in dichloromethane). ES(+) m / z 617.3 [M+Na]+. Then, deprotection according to Method Z (HCI in dioxane 4M / dioxane: 1 / 1 , reaction time: 2 h) afforded the title compound. White solid (40% over two steps).1H NMR (400 MHz, DMSO-cfe) 5 11.15 (s, 1 H), 9.27 (s, 2H), 8.19 (d, J = 9.8 Hz, 1 H), 8.11 - 8.05 (m, 1 H), 8.02 - 7.93 (m, 2H), 7.83 - 7.70 (m, 2H), 7.70 - 7.65 (m, 1 H), 7.16 (d, J = 9.8 Hz, 1 H), 5.06 (s, 2H), 3.80 (s, 2H), 3.64 - 3.47 (m, 2H), 3.14 (s, 4H).19F NMR (377 MHz, DMSO-cfe) 5 -115.35.13C NMR (101 MHz, DMSO-cfe) 5 166.9, 165.9, 159.0, 158.8, 156.4, 141.71 , 141.69, 139.8, 137.0, 135.3, 135.2, 131.3, 129.8, 125.3, 123.0, 122.2, 120.7, 120.5, 118.1 , 114.3, 114.1 , 112.1 , 55.4, 42.4. HRMS (ES+) m / z calc, for C24H2iCIFN6O3[M+H]+: 495.1348, found: 495.1344.

[0499] The Boc-protected compound (109) was synthesized according to Method Z from 3-(2-(3-(4- chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-5-cyanobenzoic acid and (2R,6S)-tert-butyl 2,6-dimethylpiperazine-1 -carboxylate using 1-propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by flash column chromatography (0-10% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.91 (s, 1 H), 8.19 (d, J = 9.8 Hz, 1 H), 8.07 - 8.03 (m, 1 H), 7.97 (dd, J = 10.9, 2.0 Hz, 1 H), 7.94 - 7.89 (m, 1 H), 7.83 - 7.71 (m, 2H), 7.68 - 7.63 (m, 1 H), 7.17 (d, J = 9.8 Hz, 1 H), 5.05 (s, 2H), 4.30 (m, 1 H), 4.16 (s, 1 H), 3.96 (s, 1 H), 2.99 (s, 1 H), 1.40 (s, 9H), 1.17 (s, 3H), 1.01 (s, 3H).19F NMR (377 MHz, DMSO-cfe) 5 -115.36.13C NMR (101 MHz, DMSO-cfe) 5 168.0, 165.9, 159.0, 156.3, 153.6, 141.7, 139.7, 137.8, 135.3, 135.2, 131.2, 129.7, 125.2, 123.0, 122.6, 121.8, 120.7, 120.5, 118.0, 114.3, 114.0, 112.2, 79.0, 55.4, 50.5, 46.2, 45.4, 28.0, 20.2, 19.5. HRMS (ES+) m / z calc, for C3I H33CIFN6O5 [M+H]+: 623.2185, found 623.2161. Then, deprotection according to Method Z (HCI in dioxane 4M / dioxane: 1 / 1 , reaction time: 2 h) afforded the title compound (110). White solid (43% over two steps).1H NMR (400 MHz, DMSO-cfe) 5 11.13 (s, 1 H), 9.67 (s, 1 H), 9.19 (s, 1 H), 8.19 (d, J = 9.8 Hz, 1 H), 8.13 - 8.05 (m, 1 H), 8.00 - 7.91 (m, 2H), 7.83 - 7.69 (m, 2H), 7.66 (s, 1 H), 7.16 (d, J = 9.7 Hz, 1 H), 5.06 (s, 2H), 4.54 (s, 1H), 3.73 - 3.57 (m, 1 H), 3.20 (s, 1 H), 2.87 (s, 1 H), 1.35 - 1.11 (m, 6H) (piperazine-H obscured by water peak).19F NMR (377 MHz, DMSO-cfe) 5 -115.35.13C NMR (126 MHz, DMSO-cfe) 5 166.8, 165.9, 159.0, 158.5, 156.6, 141.67, 141.66, 139.7, 136.9, 135.3, 135.2, 131.3, 131.2, 129.7, 125.4, 123.04, 123.02, 122.99, 122.2, 120.7, 120.5, 118.1 , 114.2, 114.1 , 112.1 , 55.4, 50.7, 49.2, 43.9, 15.5, 15.2. HRMS (ES+) m / z calc, for C26H25CIFN6O3[M+H]+: 523.1661 , found: 523.1652. i-2-(3-(4-Chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5-(3-

[0500] The Boc-protected intermediate was synthesized according to Method Z from 3-(2-(3-(4- chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-5-cyanobenzoic acid and tertbutyl (R)-2-methylpiperazine-1 -carboxylate using 1-propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by flash column chromatography (0-10% methanol in dichloromethane). ES(+) m / z 631.3 [M+Na]+. Then, deprotection according to Method Z (HCI in dioxane 4M / dioxane: 1 / 1 , reaction time: 2 h) afforded the title compound. White solid (52% over two steps).1H NMR (400 MHz, DMSO-cfe) 5 11.08 (s, 1 H), 9.45 - 9.29 (br, 1 H), 9.28 - 9.12 (br, 1 H), 8.19 (d, J = 9.8 Hz, 1 H), 8.10 - 8.03 (m, 1 H), 8.02 - 7.93 (m, 2H), 7.84 - 7.78 (m, 1 H), 7.77 - 7.71 (m, 1 H), 7.68 (s, 1 H), 7.16 (d, J = 9.8 Hz, 1H), 5.06 (s, 2H), 4.40 (s, 1 H), 3.72 - 3.55 (m, 1 H), 3.21 (s, 2H), 3.14 - 2.92 (m, 2H), 1.29 - 1.10 (m, 3H) (piperazine-H obscured by water peak).19F NMR (377 MHz, DMSO-cfe) 5 -115.35.13C NMR (126 MHz, DMSO-cfe) 5 166.9, 165.9, 159.0, 158.6, 156.6, 141.67, 141.66, 139.7, 137.0, 135.3, 135.2, 131.3, 131.2, 129.7, 125.4, 123.02, 123.00, 122.2, 120.7, 120.5, 118.1 , 114.2, 114.1 , 112.1 , 55.4, 50.1 , 42.0, 15.3. HRMS (ES+) m / z calc, for C25H23CIFN6O3[M+H]+: 509.1504, found: 509.1505. i-2-(3-(4-Chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5-(3-

[0501] The Boc-protected intermediate was synthesized according to Method Z from 3-(2-(3-(4- chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-5-cyanobenzoic acid and tertbutyl (S)-2-methylpiperazine-1 -carboxylate using 1-propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by flash column chromatography (0-10% methanol in dichloromethane). ES(+) m / z 631.3 [M+Na]+. Then, deprotection according to Method Z (HCI in dioxane 4M / dioxane: 1 / 1 , reaction time: 2 h) afforded the title compound. White solid (39% over two steps).1H NMR (400 MHz, DMSO-cfe) 6 11.07 (s, 1 H), 9.46 - 9.36 (br, 1 H), 9.20 - 9.10 (br, 1 H), 8.19 (d, J = 9.8 Hz, 1 H), 8.07 (s, 1 H), 8.01 - 7.92 (m, 2H), 7.82 - 7.77 (m, 1 H), 7.77 - 7.71 (m, 1 H), 7.68 (s, 1 H), 7.16 (d, J = 9.7 Hz, 1H), 5.06 (s, 2H), 4.40 (s, 1 H), 3.72 - 3.57 (m, 1 H), 3.21 (s, 2H), 3.14 - 2.93 (m, 2H), 1.29 - 1.11 (m, 3H) (piperazine-H obscured by water peak).19F NMR (377 MHz, DMSO-cfe) 5 -115.35.13C NMR (126 MHz, DMSO-cfe) 5 166.9, 165.9, 159.0, 158.5, 156.6, 141.68, 141.66, 139.7, 137.0, 135.3, 135.2, 131.3, 131.2, 129.7, 125.4, 123.0, 122.2, 120.7, 120.5, 118.1 , 114.2, 114.1 , 112.1 , 55.4, 50.1 , 42.1 , 15.3. HRMS (ES+) m / z calc, for C25H23CIFN6O3[M+H]+: 509.1504, found: 509.1495.

[0502] The Boc-protected intermediate was synthesized according to Method Z from 3-(2-(3-(4- chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-5-cyanobenzoic acid and (2R,6R)-tert-butyl 2,6-dimethylpiperazine-1 -carboxylate using 1-propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by flash column chromatography (0-10% methanol in dichloromethane). ES(+) m / z 645.3 [M+Na]+. Then, deprotection according to Method Z (HCI in dioxane 4M / dioxane: 1 / 1 , reaction time: 2 h) afforded the title compound. White solid (30% over two steps).1H NMR (400 MHz, DMSO- cfe) 5 11.06 (s, 1 H), 9.31 (s, 2H), 8.19 (d, J = 9.8 Hz, 1 H), 8.08 (d, J = 2.0 Hz, 1 H), 7.97 (dd, J = 10.8, 2.0 Hz, 1H), 7.93 (s, 1 H), 7.83 - 7.71 (m, 2H), 7.68 (s, 1 H), 7.16 (d, J = 9.8 Hz, 1H), 5.06 (s, 2H), 3.90 - 3.48 (m, 4H), 1.32 - 1.11 (m, 6H) (piperazine-H obscured by water peak).19F NMR (377 MHz, DMSO-cfe) 5 -115.35.13C NMR (126 MHz, DMSO-d6) 5 167.6, 165.9, 159.0, 158.6, 156.6, 141.68, 141.67, 139.7, 136.9, 135.3, 135.2, 131.3, 131.2, 129.7, 125.3, 123.0, 122.1 , 120.7, 120.5, 118.0, 114.2, 114.1 , 112.2, 55.4, 49.0, 46.0, 43.7, 14.3. HRMS (ES+) m / z calc, for C26H25CIFN6O3[M+H]+: 523.1661 , found: 523.1677.

[0503] 2- (3- (4-' -6-oxopyridazin-1 (6H)-yl)-N-(6-cyano-4-

[0504] 2-yl)acetamide (114)

[0505] The title compound was synthesized according to Method Z from 2-(2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)acetamido)-6-cyanoisonicotinic acid and morpholine using 1- propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by flash column chromatography (0-10% methanol in dichloromethane). White solid (40%). Rf: 0.4 (10% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 11.62 (s, 1 H), 8.25 (s, 1 H), 8.14 (d, J = 9.8 Hz, 1 H), 7.96 - 7.88 (m, 2H), 7.85 (d, J = 1.2 Hz, 1 H), 7.61 - 7.53 (m, 2H), 7.13 (d, J = 9.8 Hz, 1 H), 5.08 (s, 2H), 3.66 - 3.56 (m, 4H), 3.54 - 3.47 (m, 2H), 3.31 - 3.24 (m, 2H).13C NMR (126 MHz, DMSO-cfe) 5 166.8, 165.0, 159.0, 152.9, 147.0, 142.8, 134.3, 133.0, 131.3, 131.2, 129.7, 129.0, 127.7, 122.2, 116.7, 115.2, 66.0, 65.7, 55.3, 47.2, 41.9. HRMS (ES+) m / z calc, for C23H2oCIN604[M+H]+: 479.1235, found: 479.1251.

[0506] 2-(3-(4-Chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(6-cyano-4-((3R,5S)-3,5- dimethylpiperazine-1-carbonyl)pyridin-2-yl)acetamide (115)

[0507] The Boc-protected intermediate was synthesized according to Method Z from 2-(2-(3-(4- chlorophenyl)-6-oxopyridazin-1 (6H)-yl)acetamido)-6-cyanoisonicotinic acid and (2R,6S)-tert- butyl 2,6-dimethylpiperazine-1 -carboxylate using 1-propanephosphonic anhydride 50% in DMF as the coupling reagent and was purified by flash column chromatography (0-10% methanol in dichloromethane). ES(+) m / z 628.3 [M+Na]+. Then, the intermediate was added to a mixture of dichloromethane / trifluoroacetic acid (1 / 1) and the reaction stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and the residue was treated with sodium hydroxide aq. sol. 0.1 M. After extraction (x4) with ethyl acetate, the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. Purification by flash column chromatography (0-10% methanol in dichloromethane) afforded the title compound as a white solid (28% over two steps).1H NMR (400 MHz, MeOD) 5 8.35 (s, 1 H), 8.08 (d, J = 9.8 Hz, 1 H), 7.93 - 7.87 (m, 2H), 7.64 (s, 1H), 7.52 - 7.46 (m, 2H), 7.14 (d, J = 9.7 Hz, 1 H), 5.16 (s, 2H), 4.47 (d, J = 12.9 Hz, 1 H), 3.43 (d, J = 12.0 Hz, 1 H), 2.86 - 2.69 (m, 3H), 2.42 (t, J = 12.0 Hz, 1 H), 1.13 (d, J = 6.3 Hz, 3H), 0.96 (d, J = 5.8 Hz, 3H).13C NMR (126 MHz, MeOD) 5 168.2, 167.5, 162.0, 154.3, 148.3, 146.1 , 136.9, 134.4, 133.7, 133.0, 130.8, 130.2, 128.8, 123.3, 117.5, 116.4, 56.8, 54.5, 52.4, 51.6, 19.0, 18.6. HRMS (ES+) m / z calc, for C25H25CIN7O3[M+H]+: 506.1707, found: 506.1700.

[0508] Method AA. Synthesis of final compounds - alternative synthesis of 2-(3-(4-chlorophenyl)-6- oxopyridazin-1 (6H)-yl)-N-(3-cvano-5-((3S,5R)-3,5-dimethylpiperazine-1- carbonvDphenvDacetamide hydrochloride (96) and 2-(3-(4-chloro-3-fluorophenyl)-6- oxopyridazin-1 (6H)-yl)-N-(3-cvano-5-((3R,5S)-3,5-dimethylpiperazine-1- carbonyl)phenyl)acetamide (110). a. LiOH 1 M (aq.), THF, RT; b. (2R,6S)-tert-Butyl 2, 6-dimethylpiperazine-1 -carboxylate, T3P, DIPEA, DMF, RT; c. chloroacetyl chloride, K2CO3, THF, RT; d. (i) 6-(4-chlorophenyl)pyridazin- 3(2H)-one or 6-(4-chloro-3-fluorophenyl)pyridazin-3(2H)-one, K2CO3, DMF, RT, (ii) HCI in dioxane 4M, dioxane, RT.

[0509] To a solution of methyl 3-amino-5-cyanobenzoate (600 mg, 3.41 mmol) in THF (12 ml_), was added lithium hydroxide aqueous solution 1 M (8 mL) dropwise at 0 °C and the reaction stirred at room temperature for 2 h. The mixture was partially concentrated, then acidified with HCI 1M to pH 2 and the aqueous phase was extracted (x3) with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 3-amino-5-cyanobenzoic acid (450 mg, 82%) as a light brown solid.1H NMR (400 MHz, DMSO-cfe) 6 13.91 - 12.35 (brs, 1 H), 7.43 (s, 1 H), 7.32 (s, 1 H), 7.05 (s, 1H), 5.90 (s, 2H).13C NMR (101 MHz, DMSO-cfe) 5 166.3, 149.9, 132.8, 119.2, 119.0, 118.8, 118.7, 111.9. ES(+) m / z 163.1 [M+H]+.

[0510] To a solution of 3-amino-5-cyanobenzoic acid (75 mg, 0.46 mmol) in anhydrous DMF (4 mL) under nitrogen, was added (2R,6S)-tert-Butyl 2,6-dimethylpiperazine-1 -carboxylate (149 mg, 0.69 mmol), 1-propanephosphonic anhydride 50% in DMF (0.32 mL, 0.56 mmol) and N,N- diisopropylethylamine (0.24 mL, 1 .39 mmol) and the reaction stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate and washed with lithium chloride 5% aqueous solution (x2) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography (0- 10% methanol in dichloromethane) afforded tert-butyl (2R,6S)-4-(3-amino-5-cyanobenzoyl)- 2, 6-dimethylpiperazine-1 -carboxylate (115 mg, 69%) as a white solid. Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 6.93 - 6.90 (m, 1H), 6.88 (t, J = 1.4 Hz, 1 H), 6.85 - 6.82 (m, 1H), 5.85 (s, 2H), 4.27 (s, 1 H), 4.14 (s, 1 H), 3.96 (s, 1 H), 2.94 (s, 1H), 1.40 (s, 9H), 1.14 (s, 3H), 1.01 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 0 169.0, 153.6, 149.8, 137.8, 118.9, 116.6, 116.5, 116.2, 111.8, 79.0, 54.9, 50.3, 46.2, 45.2, 28.1 , 20.1 , 19.6. ES(+) m / z 381.2 [M+Na]+.

[0511] To a solution of tert-butyl (2R,6S)-4-(3-amino-5-cyanobenzoyl)-2,6-dimethylpiperazine-1- carboxylate (105 mg, 0.29 mmol) in anhydrous THF (5 mL) under nitrogen, was added potassium carbonate (81 mg, 0.59 mmol) and chloroacetyl chloride (26 uL, 0.32 mmol) dropwise at 0 °C and the reaction stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, water was added to the residue and after extraction with ethyl acetate (x3), the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl (2R,6S)-4-(3-(2- chloroacetamido)-5-cyanobenzoyl)-2,6-dimethylpiperazine-1 -carboxylate (120 mg, 94%) as an off-white solid. Rf: 0.4 (70% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.77 (s, 1 H), 8.06 (t, J = 1.8 Hz, 1 H), 7.90 (t, J = 1.8 Hz, 1 H), 7.67 (t, J = 1.5 Hz, 1 H), 4.32 (s, 3H), 4.16 (s, 1 H), 3.96 (s, 1 H), 2.99 (s, 1 H), 1.40 (s, 9H), 1.17 (s, 3H), 1.01 (s, 3H).13C NMR (101 MHz, DMSO-cfe) 5 168.0, 165.5, 153.6, 139.5, 137.8, 125.5, 122.9, 122.0, 118.0, 112.2, 79.1 , 50.5, 46.2, 45.4, 43.4, 28.0, 20.2, 19.4. ES(+) m / z 457.2 [M+Na]+.

[0512] To a solution of 6-(4-chlorophenyl)pyridazin-3(2H)-one (15 mg, 0.073 mmol) in anhydrous DMF (2 mL) under nitrogen, was added potassium carbonate (20 mg, 0.15 mmol) and tertbutyl (2R,6S)-4-(3-(2-chloroacetamido)-5-cyanobenzoyl)-2,6-dimethylpiperazine-1- carboxylate (35 mg, 0.080 mmol) and the reaction stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate and washed with lithium chloride 5% aqueous solution (x2) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography (0-10% methanol in dichloromethane) afforded the Boc-protected compound (30 mg, 68%) as a white solid. ES(+) m / z 627.3 [M+Na]+. Then, to a solution of the Boc-protected compound (30 mg, 0.050 mmol) in dioxane (3 mL), was added HCI in dioxane 4 M (3 mL) dropwise at 0 °C and the reaction stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to afford 2-(3-(4-chlorophenyl)-6- oxopyridazin-1 (6H)-yl)-N-(3-cyano-5-((3S,5R)-3,5-dimethylpiperazine-1- carbonyl)phenyl)acetamide hydrochloride (26 mg, 97%) as a white solid. Characterization data are provided under Method Z.

[0513] To a solution of 6-(4-chloro-3-fluorophenyl)pyridazin-3(2H)-one (40 mg, 0.18 mmol) in anhydrous DMF (2 mL) under nitrogen, was added potassium carbonate (49 mg, 0.36 mmol) and tert-butyl (2R,6S)-4-(3-(2-chloroacetamido)-5-cyanobenzoyl)-2,6-dimethylpiperazine-1- carboxylate (85 mg, 0.20 mmol) and the reaction stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate and washed with lithium chloride 5% aqueous solution (x2) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography (0-10% methanol in dichloromethane) afforded the Boc-protected compound (85 mg, 77%) as a white solid. Characterization data are provided under Method Z. Then, to a solution of the Boc-protected compound (75 mg, 0.12 mmol) in dioxane (3 mL), was added HCI in dioxane 4 M (3 mL) dropwise at 0 °C and the reaction was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to afford 2-(3-(4-chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5-((3R,5S)-3,5- dimethylpiperazine-1-carbonyl)phenyl)acetamide hydrochloride (65 mg, 97%) as a white solid. Characterization data are provided under Method Z.

[0514] Method AB. Synthesis of final compound - alternative synthesis of 2-(3-(4-chloro-3- fluorophenyl)-6-oxopyridazin-1 (6 / - / )-yl)- / V-(3-cvano-5-(morpholine-4- carbonvDphenvDacetamide (107). a. Morpholine, T3P, DIPEA, DMF, RT; b. chloroacetyl chloride, K2CO3, THF, RT; c. 6-(4- chloro-3-fluorophenyl)pyridazin-3(2H)-one, K2CO3, DMF, RT.

[0515] To a solution of 3-amino-5-cyanobenzoic acid (75 mg, 0.46 mmol, synthesis described under Method AA) in anhydrous DMF (4 mL) under nitrogen, was added morpholine (61 pL, 0.69 mmol), 1-propanephosphonic anhydride 50% in DMF (0.32 mL, 0.56 mmol) and N,N- diisopropylethylamine (0.24 mL, 1 .39 mmol) and the reaction stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate and washed with lithium chloride 5% aqueous solution (x2) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography (0- 10% methanol in dichloromethane) afforded 3-amino-5-(morpholine-4- carbonyl)benzonitrile (50 mg, 47%) as a white solid. Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 6.94 - 6.89 (m, 1 H), 6.89 - 6.85 (m, 1 H), 6.84 - 6.80 (m, 1 H), 5.83 (s, 2H), 3.69 - 3.48 (br, 6H), 3.33 - 3.25 (br, 2H).13C NMR (101 MHz, DMSO-cfe) 6 167.7, 149.7, 137.7, 118.9, 116.65, 116.60, 116.3, 111.8, 66.0, 47.6, 42.0. ES(+) m / z 232.1 [M+H]+.

[0516] To a solution of 3-amino-5-(morpholine-4-carbonyl)benzonitrile (45 mg, 0.19 mmol) in anhydrous THF (4 mL) under nitrogen, was added potassium carbonate (54 mg, 0.39 mmol) and chloroacetyl chloride (17 uL, 0.21 mmol) dropwise at 0 °C and the reaction stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, water was added to the residue and after extraction with ethyl acetate (x3), the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2-chloro-N-(3-cyano-5-(morpholine-4-carbonyl)phenyl)acetamide (56 mg, 94%) as a white solid. Rf: 0.3 (70% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 5 10.77 (s, 1 H), 8.09 - 8.03 (m, 1 H), 7.91 - 7.86 (m, 1 H), 7.67 - 7.60 (m, 1 H), 4.32 (s, 2H), 3.59 (m, 6H) (morpholine-H obscured by water peak).13C NMR (101 MHz, DMSO-cfe) 6 166.7, 165.5, 139.5, 137.6, 125.6, 123.0, 122.2, 118.0, 112.1 , 66.0, 47.6, 43.4, 42.1. ES(+) m / z 308.1 [M+H]+.

[0517] To a solution of 6-(4-chloro-3-fluorophenyl)pyridazin-3(2H)-one (30 mg, 0.13 mmol) in anhydrous DMF (2 mL) under nitrogen, was added potassium carbonate (37 mg, 0.27 mmol) and 2-chloro-N-(3-cyano-5-(morpholine-4-carbonyl)phenyl)acetamide (45 mg, 0.15 mmol) at 0 °C and the reaction stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate and washed with lithium chloride 5% aqueous solution (x2) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography (0-10% methanol in dichloromethane) afforded 2-(3-(4-chloro-3-fluorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3- cyano-5-(morpholine-4-carbonyl)phenyl)acetamide (60 mg, 91%) as a white solid. Characterization data are provided under Method Z.

[0518] Method AC. Synthesis of final compound - alternative synthesis for 2-(3-(4-chlorophenyl)-6- oxopyridazin-1(6H)-yl)-N-(6-cvano-4-(morpholine-4-carbonyl)pyridin-2-yl)acetamide (114). a. LiOH 1M (aq.), THF, 0 °C; b. morpholine, T3P, DIPEA, DMF, RT; c. (i) benzophenone imine, Cs2CO3, Pd2(dba)3, XantPhos, dioxane, 80 °C, (ii) HCI 1 M (aq.), THF, RT; d. chloroacetyl chloride, K2CO3, THF, RT; e. 6-(4-chlorophenyl)pyridazin-3(2H)-one, K2CO3, DMF, RT. To a solution of methyl 2-chloro-6-cyanoisonicotinate (110 mg, 0.56 mmol) in THF (6 ml_), was added lithium hydroxide aqueous solution 1 M (4 mL) dropwise and the reaction was stirred at 0 °C for 1 h. The mixture was partially concentrated, then acidified with HCI 1 M to pH 2 and was extracted (x3) with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 2-chloro-6- cyanoisonicotinic acid (90 mg, 88%) as a white solid.1H NMR (400 MHz, DMSO-cfe) 6 8.41 (d, J = 1.2 Hz, 1 H), 8.18 (d, J = 1.2 Hz, 1 H) (-COOH very broad peak).13C NMR (101 MHz, DMSO-cfe) 5 163.5, 152.0, 143.4, 133.1 , 128.3, 127.6, 116.0. ES(+) m / z 183.0 [M+H]+.

[0519] To a solution of 2-chloro-6-cyanoisonicotinic acid (100 mg, 0.55 mmol) in anhydrous DMF (4 mL) under nitrogen, was added morpholine (58 pL, 0.66 mmol), 1-propanephosphonic anhydride 50% in DMF (0.38 mL, 0.66 mmol) and N,N-diisopropylethylamine (0.29 mL, 1.64 mmol) and the reaction stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate and washed with lithium chloride 5% aqueous solution (x2) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography (10-100% ethyl acetate in hexane) afforded 6-chloro-4-(morpholine-4-carbonyl)picolinonitrile (85 mg, 62%) as a white solid. Rf: 0.4 (50% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 6 8.18 (d, J = 1 .2 Hz, 1 H), 7.99 (d, J = 1 .2 Hz, 1 H), 3.68 - 3.64 (m, 2H), 3.63 - 3.58 (m, 2H), 3.57 - 3.52 (m, 2H), 3.28 (m, 2H).13C NMR (101 MHz, DMSO-d6) 5 163.7, 151.5, 148.1 , 132.7, 126.5, 126.2, 116.1 , 65.9, 65.7, 47.1 , 41 .9. ES(+) m / z 252.0 [M+H]+.

[0520] A mixture of 6-chloro-4-(morpholine-4-carbonyl)picolinonitrile (200 mg, 0.79 mmol), benzophenone imine (0.15 mL, 0.90 mmol), cesium carbonate (518 mg, 1.59 mmol), tris(dibenzylideneacetone)dipalladium(0) (73 mg, 0.080 mmol) and 4,5- bis(diphenylphospheno)-9,9-dimethylxanthene (92 mg, 0.16 mmol) in anhydrous dioxane (10 mL), was evacuated and purged with nitrogen, and the reaction was heated to 80 °C for 1.5 h. Then, the reaction mixture was diluted with ethyl acetate, filtered through celite and the filtrate was washed with brine (x2). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF (16 mL) and HCI 1 M (4 mL) was added dropwise at 0 °C. The reaction stirred at room temperature for 30 min, then the mixture was partially concentrated, diluted with brine and was extracted with ethyl acetate (x3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (10- 100% ethyl acetate in hexane) afforded 6-amino-4-(morpholine-4-carbonyl)picolinonitrile (90 mg, 49% over two steps) as a light yellow solid. Rf: 0.3 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 6 7.08 (d, J = 1 .2 Hz, 1 H), 6.84 (s, 2H), 6.65 (d, J = 1 .2 Hz, 1 H), 3.66 - 3.50 (m, 6H), 3.32 - 3.25 (m, 2H).13C NMR (101 MHz, DMSO-cfe) 5 165.8, 160.4, 145.2, 130.9, 117.7, 114.5, 110.3, 66.1 , 65.8, 47.2, 41.8. ES(+) m / z 233.1 [M+H]+.

[0521] To a solution of 6-amino-4-(morpholine-4-carbonyl)picolinonitrile (35 mg, 0.15 mmol) in anhydrous THF (5 mL) under nitrogen, was added potassium carbonate (42 mg, 0.31 mmol) and chloroacetyl chloride (13 uL, 0.17 mmol) dropwise at 0 °C and the reaction stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure and ammonium chloride saturated aqueous solution was added to the residue. After extraction (x3) with ethyl acetate, the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (10-100% ethyl acetate in hexane) afforded 2- ch loro- N- (6- cyan o-4- (morpholine-4-carbonyl)pyridin-2-yl)acetamide (33 mg, 71%) as a white solid. Rf: 0.7 (ethyl acetate). ES(+) m / z 309.1 [M+H]+.

[0522] To a solution of 6-(4-chlorophenyl)pyridazin-3(2H)-one (10 mg, 0.048 mmol) in anhydrous DMF (2 mL) under nitrogen, was added potassium carbonate (13 mg, 0.097 mmol) and 2- chloro-N-(6-cyano-4-(morpholine-4-carbonyl)pyridin-2-yl)acetamide (30 mg, 0.097 mmol) at 0 °C and the reaction was stirred at room temperature for 3 h. The reaction mixture was diluted with ethyl acetate, washed (x2) with lithium chloride aqueous solution 5% and brine, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification using flash column chromatography (0-10% methanol in dichloromethane) afforded 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(6-cyano-4- (morpholine-4-carbonyl)pyridin-2-yl)acetamide (16 mg, 69%) as a white solid. Characterization data are provided under Method Z.

[0523] Method AD. Synthesis of final compound - (R)-2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)- yl)-N-(3-cvano-5-(3-methylpiperazine-1-carbonyl)phenyl)acetamide (116) a. (2R,6S)-tert-Butyl 2, 6-dimethylpiperazine-1 -carboxylate, T3P, DIPEA, DMF, RT; b. chloroacetyl chloride, K2CO3, THF, RT; c. (i) 6-(4-chlorophenyl)pyridazin-3(2H)-one, K2CO3, DMF, RT, (ii) HCI in dioxane 4M, dioxane, RT. To a solution of 3-amino-5-cyanobenzoic acid (65 mg, 0.40 mmol, synthesis described under Method AA) in anhydrous DMF (3 mL) under nitrogen, was added tert-butyl (R)-2- methylpiperazine-1 -carboxylate (120 mg, 0.60 mmol), 1-propanephosphonic anhydride 50% in DMF (0.28 mL, 0.48 mmol) and N,N-diisopropylethylamine (0.21 mL, 1.2 mmol) and the reaction stirred at room temperature for 18 h. The mixture was diluted with ethyl acetate and washed with lithium chloride 5% aqueous solution (x2) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography (0-10% methanol in dichloromethane) afforded tert-butyl (R)-4-(3- amino-5-cyanobenzoyl)-2-methylpiperazine-1 -carboxylate (95 mg, 69%) as a white solid. Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 6.94 - 6.75 (m, 3H), 5.84 (s, 2H), 4.35 - 4.03 (m, 2H), 3.84 - 3.44 (m, 2H), 3.10 - 2.95 (m, 2H), 1.40 (s, 9H), 1.11 - 0.92 (m, 3H).13C NMR (101 MHz, DMSO-cfe) 5 168.6, 153.7, 149.7, 137.8, 118.9, 116.6,

[0524] 116.5, 116.1 , 111.8, 79.2, 54.9, 50.6, 46.5, 45.4, 28.0, 15.0. ES(+) m / z 367.2 [M+Na]+.

[0525] To a solution of tert-butyl (R)-4-(3-amino-5-cyanobenzoyl)-2-methylpiperazine-1 -carboxylate (80 mg, 0.23 mmol) in anhydrous THF (4 mL) under nitrogen, was added potassium carbonate (64 mg, 0.46 mmol) and chloroacetyl chloride (20 uL, 0.26 mmol) dropwise at 0 °C and the reaction stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, water was added to the residue and after extraction with ethyl acetate (x3), the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl (R)-4-(3-(2-chloroacetamido)-5- cyanobenzoyl)-2-methylpiperazine-1 -carboxylate (60 mg, 61 %) as a white solid. Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 5 10.77 (s, 1 H), 8.17 - 8.00 (m, 1 H), 7.88 (s, 1 H), 7.76 - 7.52 (m, 1 H), 4.33 (s, 2H), 4.29 - 4.19 (m, 1 H), 3.85 - 3.60 (m, 1H), 3.17 - 2.79 (m, 3H), 1.41 (s, 9H), 1.17 - 0.94 (m, 3H).13C NMR (101 MHz, DMSO-cfe) 5

[0526] 167.5, 165.5, 153.7, 139.5, 137.7, 125.5, 123.0, 122.0, 118.0, 112.2, 79.2, 54.9, 50.6, 46.7,

[0527] 45.5, 43.4, 28.0, 15.0. ES(+) m / z 443.1 [M+Na]+.

[0528] To a solution of 6-(4-chlorophenyl)pyridazin-3(2H)-one (15 mg, 0.073 mmol) in anhydrous DMF (2 mL) under nitrogen, was added potassium carbonate (20 mg, 0.15 mmol) tert-butyl (R)-4-(3-(2-chloroacetamido)-5-cyanobenzoyl)-2-methylpiperazine-1 -carboxylate (34 mg, 0.080 mmol) and the reaction stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate and washed with lithium chloride 5% aqueous solution (x2) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification with flash column chromatography (0-10% methanol in dichloromethane) afforded the Boc-protected compound as a white solid. ES(+) m / z 613.3 [M+Na]+. Then, to a solution of the Boc-protected compound (20 mg, 0.034 mmol) in dioxane (3 mL), was added HCI in dioxane 4 M (3 mL) dropwise at 0 °C and the reaction stirred at room temperature for 4 h. The mixture was concentrated under reduced pressure and the residue was triturated with diethyl ether to afford (R)-2-(3-(4-chlorophenyl)-6-oxopyridazin- 1(6H)-yl)-N-(3-cyano-5-(3-methylpiperazine-1-carbonyl)phenyl)acetamide hydrochloride (18 mg, 47% over two steps) as a white solid.1H NMR (400 MHz, DMSO-cfe) 6 11.07 (s, 1 H), 9.42 - 9.12 (br, 2H), 8.15 (d, J = 9.8 Hz, 1 H), 8.07 (t, J = 1.7 Hz, 1 H), 7.97 (s, 1 H), 7.95 - 7.90 (m, 2H), 7.68 (s, 1 H), 7.61 - 7.52 (m, 2H), 7.14 (d, J = 9.8 Hz, 1H), 5.05 (s, 2H), 4.45 - 4.35 (br, 1H), 3.70 - 3.58 (m, 1 H), 3.29 - 3.15 (br, 2H), 3.13 - 2.93 (m, 2H), 1.29 - 1.12 (m, 3H).13C NMR (126 MHz, DMSO-cfe) 5 166.9, 166.0, 159.0, 142.7, 139.7, 137.0, 134.3, 133.0, 131.3, 129.8, 129.0, 127.7, 125.3, 123.0, 122.2, 118.1 , 112.1 , 55.3, 50.1 , 42.0, 15.3. HRMS (ES+) m / z calc, for C20HI7N4O2[M+H]+: 491.1598, found: 491.1599.

[0529] Method AE. Synthesis of final compound - 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-

[0530] (3-cyano-5-(morpholinomethyr)phenyr)acetamide (117) a. (i) MsCI, Et3N, THF, 0 °C, (ii) morpholine, THF, reflux; b. (i) benzophenone imine, Cs2CO3, Pd2(dba)3, XantPhos, dioxane, 100 °C, (ii) HCI 1 M (aq.), THF, RT; c. chloroacetyl chloride, K2CO3, THF, RT; d. 6-(4-chlorophenyl)pyridazin-3(2H)-one, K2CO3, DMF, RT.

[0531] To a solution of 3-chloro-5-(hydroxymethyl)benzonitrile (300 mg, 1.79 mmol) in anhydrous THF (10 mL) was added triethylamine (0.37 ml_, 2.7 mmol) and methanesulfonyl chloride (0.17 mL, 2.1 mmol) and the reaction was stirred at 0 °C for 1 h. Then, morpholine (0.47 mL, 5.4 mmol) was added to the mixture and the reaction was heated to reflux for 1 h. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The aqeuous phase was further extracted (x2) with ethyl acetate and the combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (0-10% methanol in dichloromethane) afforded 3-chloro-5-(morpholinomethyl)benzonitrile (270 mg, 64%) as a light yellow oil. Rf: 0.6 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 7.94 (s, 1 H), 7.75 (s, 1 H), 7.74 (s, 1 H), 3.60 - 3.55 (m, 4H), 3.52 (s, 2H), 2.41 - 2.29 (m, 4H). ES(+) m / z 237.1 [M+H]+.

[0532] A mixture of 3-chloro-5-(morpholinomethyl)benzonitrile (250 mg, 1.06 mmol), benzophenone imine (195 uL, 1.16 mmol), cesium carbonate (688 mg, 2.11 mmol), tris(dibenzylideneacetone)dipalladium(0) (97 mg, 0.11 mmol) and 4,5- bis(diphenylphospheno)-9,9-dimethylxanthene (122 mg, 0.21 mmol) in anhydrous dioxane (10 ml_), was evacuated and purged with nitrogen, and the reaction was heated to 100 °C for 24 h. Then, the reaction mixture was diluted with ethyl acetate, filtered through celite and the filtrate was washed with brine (x2). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF (28 ml_), HCI 1M (7 mL) was added dropwise at 0 °C and the reaction stirred at room temperature for 30 min. Then, the mixture was partially concentrated and pH was adjusted to 10 with NaOH 1 M. After extraction with ethyl acetate (x3), the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (50-100% ethyl acetate in hexane) afforded 3-amino-5- (morpholinomethyl)benzonitrile (120 mg, 52% over two steps) as a colourless oil which slowly crystallised. Rf: 0.8 (10% methanol in dichloromethane).1H NMR (400 MHz, DMSO- cfe) 6 6.83 (s, 1 H), 6.79 (s, 1 H), 6.74 (s, 1 H), 5.60 (s, 2H), 3.61 - 3.50 (m, 4H), 2.38 - 2.27 (m, 4H) (CH2obscured by water peak). ES(+) m / z 218.1 [M+H]+.

[0533] To a solution of 3-amino-5-(morpholinomethyl)benzonitrile (110 mg, 0.51 mmol) in anhydrous THF (5 mL) under nitrogen, was added potassium carbonate (140 mg, 1.01 mmol) and chloroacetyl chloride (44 uL, 0.56 mmol) dropwise at 0 °C and the reaction stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, water was added to the residue and after extraction with ethyl acetate (x3), the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (0-10% methanol in dichloromethane) afforded 2-chloro-N-(3-cyano-5-(morpholinomethyl)phenyl)acetamide (120 mg, 81%) as a white solid. Rf: 0.4 (5% methanol in dichloromethane).1H NMR (400 MHz, DMSO-cfe) 6 10.65 (s, 1 H), 8.00 (s, 1 H), 7.78 (s, 1 H), 7.47 (s, 1 H), 4.28 (s, 2H), 3.61 - 3.53 (m, 4H), 3.49 (s, 2H), 2.41 - 2.30 (m, 4H). ES(+) m / z 294.1 [M+H]+.

[0534] To a solution of 6-(4-chlorophenyl)pyridazin-3(2H)-one (30 mg, 0.15 mmol) in anhydrous DMF (2 mL) under nitrogen, was added potassium carbonate (40 mg, 0.29 mmol) and 2- chloro-N-(3-cyano-5-(morpholinomethyl)phenyl)acetamide (47 mg, 0.16 mmol) and the reaction stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate, washed with lithium chloride aqueous solution 5% (x2) and brine, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification using flash column chromatography (0-10% methanol in dichloromethane) afforded 2-(3-(4- chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5-(morpholinomethyl)phenyl)acetamide (50 mg, 74%) as a white solid. Rf: 0.3 (5% methanol in dichloromethane).1H NMR (500 MHz, MeOD) 5 8.07 (d, J = 9.8 Hz, 1 H), 7.99 (s, 1 H), 7.93 (t, J = 1 .8 Hz, 1 H), 7.92 - 7.87 (m, 2H), 7.52 (s, 1 H), 7.51 - 7.47 (m, 2H), 7.14 (d, J = 9.7 Hz, 1 H), 5.10 (s, 2H), 3.91 - 3.81 (br, 2H), 3.76 (s, 4H), 2.82 - 2.72 (br, 4H).13C NMR (126 MHz, MeOD) 5 167.6, 162.0, 146.1 , 141.0, 136.9, 134.4, 133.0, 130.8, 130.2, 129.9, 128.8, 126.7, 123.7, 119.1 , 114.3, 66.8, 62.3, 56.9, 54.0. HRMS (ES+) m / z calc, for C24H23CIN5O3[M+H]+: 464.1489, found: 464.1496.

[0535] Method AF. Synthesis of final compound - 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N- a. Morpholine, DMSO, 120 °C; b. (i) benzophenone imine, Cs2CO3, Pd2(dba)3, XantPhos, dioxane, 100 °C, (ii) HCI 1 M (aq.), THF, RT; c. chloroacetyl chloride, K2CO3, THF, RT; d. 6-(4- chlorophenyl)pyridazin-3(2H)-one, K2CO3, DMF, RT.

[0536] To a solution of 3-chloro-5-fluorobenzonitrile (680 mg, 4.37 mmol) in DMSO (3 mL) was added morpholine (0.96 mL, 11 mmol) and the reaction was heated to 120 °C for 16 h. Brine was added to the reaction mixture and the formed precipitate was filtered, washed with water and dried under reduced pressure to afford 3-chloro-5-morpholinobenzonitrile (820 mg, 84%) as a brown solid. Rf: 0.2 (20% ethyl acetate in hexane).1H NMR (400 MHz, DMSO-cfe) 6 7.35 (s, 1 H), 7.32 - 7.26 (m, 2H), 3.74 - 3.67 (m, 4H), 3.26 - 3.19 (m, 4H). ES(+) m / z 223.1 [M+H]+.

[0537] A mixture of 3-chloro-5-morpholinobenzonitrile (800 mg, 3.59 mmol), benzophenone imine (0.66 mL, 3.9 mmol), cesium carbonate (2.34 g, 7.19 mmol), tris(dibenzylideneacetone)dipalladium(0) (329 mg, 0.36 mmol) and 4,5- bis(diphenylphospheno)-9,9-dimethylxanthene (416 mg, 0.72 mmol) in anhydrous dioxane (20 mL), was evacuated and purged with nitrogen, and the reaction was heated to 100 °C for 24 h. Then, the reaction mixture was diluted with ethyl acetate, filtered through celite and the filtrate was washed with brine (x2). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF (32 mL), HCI 1M (8 mL) was added dropwise at 0 °C and the reaction stirred at room temperature for 30 min. Then, the mixture was partially concentrated and pH was adjusted to 10 with NaOH 1 M. After extraction with ethyl acetate (x3), the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (50-100% ethyl acetate in hexane) afforded 3-amino-5- morpholinobenzonitrile (300 mg, 41% over two steps) as a light brown solid. Rf: 0.7 (ethyl acetate).1H NMR (400 MHz, DMSO-cfe) 5 6.49 (s, 1 H), 6.39 (s, 1 H), 6.33 (s, 1H), 5.42 (s, 2H), 3.73 - 3.64 (m, 4H), 3.09 - 3.00 (m, 4H). ES(+) m / z 204.1 [M+H]+.

[0538] To a solution of 3-amino-5-morpholinobenzonitrile (250 mg, 1.23 mmol) in anhydrous THF (10 ml_) under nitrogen, was added potassium carbonate (340 mg, 2.46 mmol) and chloroacetyl chloride (108 uL, 1.35 mmol) dropwise at 0 °C and the reaction stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, water was added to the residue and after extraction with ethyl acetate (x3), the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (10-100% ethyl acetate in hexane) afforded 2-chloro-N-(3-cyano-5-morpholinophenyl)acetamide (270 mg, 78%) as a light yellow solid. Rf: 0.6 (70% ethyl acetate in hexane). ES(+) m / z 280.1 [M+H]+.

[0539] To a solution of 6-(4-chlorophenyl)pyridazin-3(2H)-one (30 mg, 0.15 mmol) in anhydrous DMF (2 mL) under nitrogen, was added potassium carbonate (40 mg, 0.29 mmol) and 2- chloro-N-(3-cyano-5-morpholinophenyl)acetamide (45 mg, 0.16 mmol) and the reaction stirred at room temperature for 18 h. The reaction mixture was diluted with ethyl acetate, washed (x2) with lithium chloride aqueous solution 5% and brine, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification using flash column chromatography (0-10% methanol in dichloromethane) afforded 2-(3-(4- chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(3-cyano-5-morpholinophenyl)acetamide (40 mg, 61%) as a white solid. Rf: 0.4 (5% methanol in dichloromethane).1H NMR (500 MHz, DMSO- d6) 5 10.58 (s, 1 H), 8.13 (d, J = 9.8 Hz, 1 H), 7.96 - 7.89 (m, 2H), 7.60 - 7.54 (m, 2H), 7.46 (t, J = 2.1 Hz, 1 H), 7.36 (t, J = 1.5 Hz, 1 H), 7.16 - 7.10 (m, 2H), 4.99 (s, 2H), 3.74 - 3.69 (m, 4H), 3.17 - 3.11 (m, 4H).13C NMR (126 MHz, DMSO-cfe) 5 165.6, 159.0, 151.8, 142.7,

[0540] 140.3, 134.3, 133.0, 131.2, 129.7, 129.0, 127.7, 119.1 , 113.3, 112.1 , 112.0, 109.0, 65.8,

[0541] 55.3, 47.5. HRMS (ES+) m / z calc, for C23H2iCIN5O3[M+H]+: 450.1333, found: 450.1314.

[0542] Method AG. Synthesis of final i-6-oxopyridazin-1 (6H)-yl)-N- а. mCPBA, DCM, RT; b. POCI3, 90 °C; c. NBS, benzoyl peroxide, CCI4, reflux; d. morpholine, THF, reflux; e. (i) benzophenone imine, Cs2CO3, Pd2(dba)3, XantPhos, dioxane, 80 °C, (ii) HCI 1 M (aq.), THF, RT; f. chloroacetyl chloride, K2CO3, THF, RT; g. 6-(4- chlorophenyl)pyridazin-3(2H)-one, K2CO3, DMF, RT.

[0543] To a solution of 4-methylpicolinonitrile (1.00 g, 8.46 mmol) in dichloromethane (20 mL) was added 3-chloroperbenzoic acid (2.92 g, 16.9 mmol) at 0 °C and the reaction mixture stirred at room temperature for 24 h. The mixture was diluted with dichloromethane and washed with sodium bicarbonate saturated aqueous solution (x2), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification using flash column chromatography (0-10% methanol in dichloromethane) afforded 2-cyano-4-methylpyridine 1 -oxide (510 mg, 45%) as an off-white solid. Rf: 0.2 (ethyl acetate).1H NMR (400 MHz, CDCI3) 5 8.16 (d, J = б.8 Hz, 1 H), 7.46 (d, J = 2.5 Hz, 1 H), 7.26 (m, 1 H), 2.39 (s, 3H).13C NMR (101 MHz, CDCI3) 5 139.6, 136.6, 131.5, 130.1 , 125.5, 111.9, 20.3. ES(+) m / z 135.1 [M+H]+.

[0544] 2-cyano-4-methylpyridine 1 -oxide (500 mg, 3.73 mmol) was added to phosphorus oxychloride (10 mL) at 0 °C and the reaction was heated to 90 °C for 18 h. The mixture was partially concentrated, then neutralised with sodium bicarbonate saturated aqueous solution and was extracted with dichloromethane (x3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification using flash column chromatography (10-50% ethyl acetate in hexane) afforded 6-chloro-4- methylpicolinonitrile (350 mg, 61%) as a white solid. Rf: 0.5 (30% ethyl acetate in hexane).1H NMR (400 MHz, CDCI3) 5 7.46 (s, 1 H), 7.38 (s, 1H), 2.44 (s, 3H). ES(+) m / z 153.0 [M+H]+.

[0545] To a solution of 6-chloro-4-methylpicolinonitrile (100 mg, 0.66 mmol) in anhydrous tetrachloromethane (5 mL) was added N-bromosuccinimide (140 mg, 0.79 mmol) and dibenzoyl peroxide (16 mg, 0.066 mmol) at 0 °C and the reaction was heated to reflux for 12 h. Then, N-bromosuccinimide (140 mg, 0.79 mmol) and dibenzoyl peroxide (16 mg, 0.066 mmol) were added again at 0 °C and the reaction was heated to reflux for another 4 h. The reaction mixture was diluted with dichloromethane and washed with sodium thiosulfate 10% and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification using flash column chromatography (5-30% ethyl acetate in hexane) afforded 4-(bromomethyl)-6-chloropicolinonitrile (30 mg, 20%) as a colourless oil which slowly crystallised. Rf: 0.6 (20% ethyl acetate in hexane).1H NMR (400 MHz, CDCI3) 5 7.65 (d, J = 1.4 Hz, 1 H), 7.57 (d, J = 1.4 Hz, 1 H), 4.38 (s, 2H).13C NMR (101 MHz, CDCI3) 0

[0546] 153.3, 150.9, 134.0, 128.1 , 127.4, 115.8, 27.9. ES(+) m / z 232.9 [M+H]+.

[0547] To a solution of 4-(bromomethyl)-6-chloropicolinonitrile (30 mg, 0.13 mmol) in anhydrous THF (4 mL) was added morpholine (34 uL, 0.39 mmol) and the reaction was heated to reflux for 1 h. The reaction mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The aqueous layer was further extracted (x2) with ethyl acetate and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification using flash column chromatography (0-10% methanol in dichloromethane) afforded 6-chloro-4-(morpholinomethyl)picolinonitrile (22 mg, 71%) as a light yellow oil, which slowly crystallised. Rf: 0.7 (5% methanol in dichloromethane).1H NMR (400 MHz, CDCI3) 5 7.68 (d, J = 1 .3 Hz, 1 H), 7.55 (d, J = 1 .4 Hz, 1 H), 3.77 - 3.70 (m, 4H), 3.54 (s, 2H), 2.49 - 2.43 (m, 4H).13C NMR (101 MHz, CDCI3) 5 153.2, 153.0, 133.5, 127.9,

[0548] 127.4, 116.2, 66.9, 61.0, 53.7. ES(+) m / z 238.0 [M+H]+.

[0549] A mixture of 6-chloro-4-(morpholinomethyl)picolinonitrile (22 mg, 0.93 mmol), benzophenone imine (17 uL, 0.10 mmol), cesium carbonate (61 mg, 0.19 mmol), tris(dibenzylideneacetone)dipalladium(0) (8.5 mg, 0.093 mmol) and 4,5- bis(diphenylphospheno)-9,9-dimethylxanthene (11 mg, 0.19 mmol) in anhydrous dioxane (4 mL), was evacuated and purged with nitrogen, and the reaction was heated to 80 °C for 18 h. Then, the reaction mixture was diluted with ethyl acetate, filtered through celite and the filtrate was washed with brine (x2). The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF (4 mL), HCI 1M (1 mL) was added dropwise at 0 °C and the reaction stirred at room temperature for 30 min. Then, the mixture was partially concentrated and pH was adjusted to 10 with NaOH 1 M. After extraction with ethyl acetate (x3), the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (50-100% ethyl acetate in hexane) afforded 6-amino-4- (morpholinomethyl)picolinonitrile (11 mg, 54% over two steps) as a light yellow solid. Rf: 0.3 (ethyl acetate).1H NMR (400 MHz, CDCI3) 5 7.08 (s, 1 H), 6.67 (s, 1H), 4.78 (s, 2H), 3.75 - 3.68 (m, 4H), 3.40 (s, 2H), 2.47 - 2.40 (m, 4H).13C NMR (101 MHz, CDCI3) 5 159.2, 150.5, 131.8, 119.6, 117.8, 112.3, 67.0, 61.6, 53.7. ES(+) m / z 219.1 [M+H]+. To a solution of 6-amino-4-(morpholinomethyl)picolinonitrile (10 mg, 0.046 mmol) in anhydrous THF (3 mL) under nitrogen, was added potassium carbonate (13 mg, 0.092 mmol) and chloroacetyl chloride (4.0 uL, 0.050 mmol) dropwise at 0 °C and the reaction stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, water was added to the residue and after extraction with ethyl acetate (x3), the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography (0-10% methanol in dichloromethane) afforded 2-chloro-N-(3-cyano-5-(morpholinomethyl)phenyl)acetamide (5.0 mg, 37%) as an off-white solid. Rf: 0.5 (5% methanol in dichloromethane).1H NMR (400 MHz, CDCh) 5 8.91 (s, 1 H), 8.41 (s, 1 H), 7.59 (s, 1 H), 4.21 (s, 2H), 3.77 - 3.70 (m, 4H), 3.56 (s, 2H), 2.50 - 2.43 (m, 4H). ES(+) m / z 295.1 [M+H]+.

[0550] To a solution of 6-(4-chlorophenyl)pyridazin-3(2H)-one (3.0 mg, 0.015 mmol) in anhydrous DMF (2 mL) under nitrogen, was added potassium carbonate (4.0 mg, 0.029 mmol) and 2- chloro-N-(6-cyano-4-(morpholinomethyl)pyridin-2-yl)acetamide (4.3 mg, 0.015 mmol) at 0 °C and the reaction stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with lithium chloride aqueous solution 5% (x2) and brine, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification using flash column chromatography (0-10% methanol in dichloromethane) and additional purification using preparative thin layer chromatography (5% methanol in dichloromethane) afforded 2-(3-(4-chlorophenyl)-6-oxopyridazin-1 (6H)-yl)-N-(6-cyano-4- (morpholinomethyl)pyridin-2-yl)acetamide (3.0 mg, 45%) as a white solid. Rf: 0.3 (5% methanol in dichloromethane).1H NMR (400 MHz, CDCh) 6 9.02 (s, 1 H), 8.38 (s, 1 H), 7.79 - 7.73 (m, 3H), 7.52 (d, J = 1.2 Hz, 1 H), 7.48 - 7.42 (m, 2H), 7.18 (d, J = 9.7 Hz, 1H), 5.11 (s, 2H), 3.74 - 3.68 (m, 4H), 3.50 (s, 2H), 2.48 - 2.37 (m, 4H).13C NMR (126 MHz, CDCh) 6 165.6, 160.3, 152.5, 152.1 , 145.1 , 136.4, 132.6, 131.7, 131.3, 130.7, 129.4, 127.6, 125.0, 117.8, 117.0, 67.0, 61.7, 57.3, 53.7. HRMS (ES-) m / z calc, for C23H2oCIN603[M-H]- : 463.1291 , found: 463.1298.

Claims

Claims1. A compound for use in a method of treating or preventing a disease associated with an aberrantly activated Hedgehog (HH) signalling pathway, wherein the compound has the formula (I):where: A is selected from halo, and optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, alkyl, alkenyl and alkynyl groups;B is selected from optionally substituted aryl groups and heteroaryl groups;L1is absent or is selected from alkylene, -NR’-, -NR’-alkylene-, -O-, -O- alkylene-, -S- and -S-alkylene-;L2is selected from -C(O)NR’-, -(CR’2)I-3-C(O)NR’-, -(CR’2)I-3-NR’-, -(CR’2)I. 3NR’C(O)-, -C(=S)NR’-, -C(=NR’)NR’-, -S(O2)NR’-, -NR’C(O)NR’-, - NR’S(O2)NR’-, -OC(O)NR’-, -CR’F-NR’-, -CF2NR’-, -CR’(CF3)NR’-, -CF=CR’-, -(oxetane)NR’- and heteroarylene groups;X is selected from -N- and -CR5-, where R5is selected from H, halo, alkyl, alkenyl, alkynyl and haloalkyl;R1and R2are each independently selected from H, halo, alkyl, alkenyl, alkynyl and haloalkyl, or R1and R2together with the carbon atoms to which they are attached form an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group;R3and R4are each independently selected from H, alkyl, alkenyl, alkynyl and haloalkyl, or R3and R4together with the carbon to which they are attached form a 3 to 6-membered cycloalkyl group; each R’ is independently selected from H and alkyl; or a pharmaceutically acceptable salt thereof.

2. The compound for use according to claim 1 , wherein the compound is a compound of formula (II):or a pharmaceutically acceptable salt thereof.

3. The compound for use according to claim 1 or claim 2, wherein X is selected from -island -CH-, and preferably wherein X is N.

4. The compound for use according to any one of the preceding claims, wherein L1is absent or is selected from -NH- and -O-, and preferably wherein L1is absent.

5. The compound for use according to any one of the preceding claims, wherein L2is selected from -C(O)NH-, -CH2C(O)NH-, -CH2NH-, and a 5-membered heteroaryl group, and preferably wherein L2is -C(O)NH-.

6. The compound for use according to any one of the preceding claims, wherein R1and R2are each independently selected from H and Ci_6alkyl, and preferably wherein both R1and R2are H.

7. The compound for use according to any one of the preceding claims, wherein R3and R4are each independently selected from H and Ci_6alkyl, and preferably wherein both R3and R4are H.

8. The compound for use according to any one of the preceding claims, wherein A is: selected from optionally substituted aryl and heteroaryl groups, and preferably is optionally substituted phenyl; and / or substituted with at least one substituent selected from halo, -Ci_6haloalkyl, -CN, and -NO2, and preferably wherein at least one of the substituents is Cl preferably at the 4- position relative to L1.

9. The compound for use according to any one of the preceding claims, wherein B is:selected from optionally substituted aryl and heteroaryl groups, preferably from optionally substituted phenyl and 6-membered heteroaryl groups, and more preferably is an optionally substituted phenyl; and / or substituted with at least one substituent selected from halo, -Ci_6haloalkyl, -CN, - OR’, -C(O)NR’2, -C(O)R”, -OS(O)2F and -NO2where R” is selected from optionally substituted heterocyclic groups and carbocyclic groups, and preferably wherein at least one of the substituents is -CN preferably at the 3-position relative to L2.

10. The compound for use according to any one of the preceding claims, wherein the compound has a structure selected from:or a pharmaceutically acceptable salt thereof; and preferably wherein the compound has the following structure:or a pharmaceutically acceptable salt thereof.11 . The compound for use according to any one of claims 1 to 9, wherein the compound has a structure selected from:or a pharmaceutically acceptable salt thereof.

12. The compound for use according to any one of the preceding claims, wherein the disease is selected from cancer, fibrotic diseases and chronic obstructive pulmonary disease, and preferably wherein the disease is cancer.

13. The compound for use according to claim 12, wherein the cancer is a dormant cancer.

14. The compound for use according to claim 12 or claim 13, wherein the cancer is selected from medulloblastoma, rhabdomyosarcomas, intracranial meningioma, adenocarcinoma, hepatocellular carcinoma, bone cancer, brain cancer, breast cancer, lung cancer, colon cancer, colorectal cancer, pancreatic cancer, skin cancer (such as basal cell carcinoma), prostate cancer, oesophageal cancer, ovarian cancer, gliomas, mesothelioma and leukaemia (such as myeloid leukemia).

15. A method of treating or preventing a disease associated with an aberrantly activated Hedgehog (HH) signalling pathway in a patient, said method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) as defined in any of claims 1 to 11 , or a pharmaceutically acceptable salt thereof, and wherein the disease is preferably as defined in any of claims 12 to 14.

16. A pharmaceutical composition which comprises a compound of formula (I) as defined in any of claims 1-11 , wherein:R3and R4are each H; wherein A is not a cycloalkyl group, heteroclycloalkyl group, cycloalkenyl group, or heterocycloalkyl group; wherein B is not a heteroaryl group; andL2is not a heteroarylene group: or a pharmaceutically acceptable salt thereof, provided that the compound is not:

17. A compound, or pharmaceutically acceptable salt thereof, for use as a medicament, wherein the compound of formula (I) is as defined in claim 16.

18. A compound, or a pharmaceutically acceptable salt thereof, having the formula (III):where: A, L1, L2, X and R1to R4are as defined in any one of claims 1 to 10;D is selected from optionally substituted arylene and heteroarylene groups; andR7is selected from -C(O)R”, -S(O)R”, -S(O)2R”, -CH2R”, -CHFR”, -CF2R”, - CH(alkyl)R”, -C(alkyl)2R”, -OR” and -R”, where R” is selected from optionally substituted heterocyclic groups and carbocyclic groups.

19. The compound of Claim 18, or a pharmaceutically acceptable salt thereof, wherein R7is selected from -C(O)R”, -S(O)R” and -S(O)2R”.

20. The compound of claim 18 or claim 19, or a pharmaceutically acceptable salt thereof, having the formula (IV):21 . The compound of any one of claims 18 to 20, wherein D is: selected from optionally substituted phenylene and 6-membered heteroarylene groups, and more preferably is an optionally substituted phenylene; and / or substituted with at least one substituent selected from halo, -Ci.6haloalkyl, -CN and - NO2, and preferably wherein at least one of the substituents is -CN preferably at the 3- position or 5-position relative to L2.

22. The compound of any of claims 18, 20, or 21 , wherein R7is -C(O)R”.

23. The compound of any of claims 18 to 22, wherein R7is at the 3-position or 5-position relative to L2.

24. The compound of any of claims 18 to 23, wherein R” is: selected from heterocycloalkyl groups, and more preferably from azetidine, pyrrolidine, piperidine, piperazine, morpholine, and bridged heterocycloalkyl groups, such as 8-oxa-3-azabicyclo[3.2.1]octane, 3,8-diazabicyclo[3.2.1]octane, or 2-oxa-5- azabicyclo[2.2.1]heptane; and / or optionally substituted with one or more substituents selected from halo, -OR’, -NR’2, - C1-6 alkyl, -C2-6 alkenyl, -C2-6 alkynyl, -Ci.6haloalkyl and -C(O)OR’.

25. A compound selected from:or a salt thereof.

26. A compound selected from:or a salt thereof.

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