2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer

Abstract

The present invention encompasses 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4- carboxamide compounds of general formula (I), wherein X, R 1 , R 2 , R 3 , R 4 and R 5 Processes for preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions comprising said compounds and combinations, and the use of said compounds as the sole medicament or in combination with other active ingredients for the preparation of a pharmaceutical composition for the treatment or prevention of a disease, in particular cancer or a condition with dysregulated immune response or other disorders associated with aberrant AHR signaling, as defined herein.

Description

[0001] This application is a divisional application of the application patent application No. 201880024008.8 entitled "2-Heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for use in the treatment of cancer". The original application corresponds to International application PCT / EP2018 / 052627, filed on February 2, 2018, with a priority date of February 9, 2017. TECHNICAL FIELD

[0002] The present application includes 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4- carboxamide compounds of general formula (I) as described and defined herein, methods of making said compounds, intermediate compounds useful for making said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease, in particular a cancer or an immune response disorder condition, as the sole agent or in combination with other active ingredients. BACKGROUND

[0003] AHR (aryl hydrocarbon receptor) is a ligand-activated transcription factor belonging to the basic helix-loop-helix / Per-Arnt-Sim (bHLH / PAS) family and is located in the cytosol. Upon ligand binding, AHR translocates to the nucleus where it forms a heterodimer with ARNT (AHR nuclear translocator) and then interacts with the DRE (dioxin response element) of AHR responsive genes to regulate their transcription. AHR is most famously associated with binding environmental toxins and inducing metabolic machinery, such as cytochrome P 450 enzymes (e.g. CYP1A1, CYP1A2 and CYP1B1), needed for their elimination (Reyes et al., Science, 1992, 256(5060): 1193-5). Activation of AHR by biogenic xenobiotics has demonstrated its role in many cellular processes such as embryogenesis, tumorigenesis and inflammation.

[0004] AHR is expressed in many cells of the immune system, including dendritic cells (DCs), macrophages, T cells, and NK cells, and plays an important role in immune regulation (Nguyen et al., Front Immunol, 2014, 5:551). For example, the classic exogenous AHR ligands TCDD and 3-methylcholanthrene are known to induce profound immune suppression, promote carcinogenesis, and induce tumor growth (Gramatzki et al., Oncogene, 2009, 28(28):2593-605; Bui et al., Oncogene, 2009, 28(41):3642-51; Esser et al., Trends Immunol, 2009, 30:447-454). In the context of immune suppression, AHR activation promotes regulatory T cell generation, directly and indirectly suppresses Th1 and Th17 differentiation, and reduces activation and maturation of DCs (Wang et al., Clin Exp Immunol, 2014, 177(2):521-30; Mezrich et al., J Immunol, 2010, 185(6):3190-8; Wei et al., Lab Invest, 2014, 94(5):528-35; Nguyen et al., PNAS, 2010, 107(46):19961-6). AHR activation modulates innate immune responses, and constitutive AHR expression has been shown to negatively regulate type I interferon responses to viral infection (Yamada et al., Nat Immunol, 2016). Additionally, mice with constitutively active AHR spontaneously develop tumors (Andersson et al., PNAS, 2002, 99(15):9990-5).

[0005] In addition to biogenic xenobiotics, AHR can also bind to metabolites of tryptophan degradation. Tryptophan metabolites, such as kynurenine and kynurenic acid, are endogenous AHR ligands that activate AHR under physiological conditions (DiNatale et al., Toxicol Sci, 2010, 115(1):89-97; Mezrich et al., J Immunol, 2010, 185(6):3190-8; Opitz et al., Nature, 2011, 478(7368):197-203). Other endogenous ligands are known to bind AHR, although their physiological roles are currently unknown (Nguyen & Bradfield, Chem Res Toxicol, 2008, 21(1):102-116).

[0006] The immunosuppressive properties of kynurenine and tryptophan degradation have been well described and are associated with cancer-related immunosuppression. The enzymes indoleamine-2,3-dioxygenase 1 and 2 (IDOl / ID02) and tryptophan-2,3-dioxygenase 2 (TDO2) are responsible for catalyzing the first rate-limiting step of tryptophan metabolism. IDOl / 2-mediated degradation of tryptophan in tumors and tumor-draining lymph nodes decreases the anti-tumor immune response, and inhibition of IDO can inhibit tumor formation in animal models (Uyttenhove et al., Nat Med, 2003, 9(10): 1269-74; Liu et al., Blood, 2005, 115(17):3520-30; Muller et al., Nat Med, 11(3):312-9; Metz, Cancer Res, 2007, 67(15):7082-7).

[0007] TDO2 is also strongly expressed in cancer and can lead to the production of immunosuppressive kynurenine. In gliomas, downstream of TDO-mediated tryptophan degradation, kynurenine activation of AHR can enhance tumor growth as a result of suppressing the anti-tumor immune response as well as directly promoting tumor cell survival and motility (Opitz et al., Nature, 2011, 478(7368): 197-203). Thus, AHR ligands produced by tumor cells act on tumor cells and lymphocytes in an autocrine and paracrine manner, respectively, to promote tumor growth.

[0008] The present invention includes 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamide compounds of general formula (I) that inhibit AHR.

[0009] WO 2010 / 059401 relates to compounds and compositions for expanding the number of CD34+ cells for transplantation. In particular, WO 2010 / 059401 relates inter alia to heterocyclic compounds capable of down-regulating the activity and / or expression of AHR.

[0010] WO 2012 / 015914 relates to compositions and methods for modulating AHR activity. In particular, WO 2012 / 015914 relates inter alia to heterocyclic compounds that modulate AHR activity for use in therapeutic compositions.

[0011] WO 2007 / 058392 relates to novel heterocyclic compounds and their pharmaceutical use. In particular, WO 2007 / 058392 relates inter alia to heterocyclic compounds having an inhibitory activity against hepatitis C virus cell infection.

[0012] WO 2002 / 022587 relates to novel compounds exhibiting inhibitory activity against AMPA receptors and / or kainate receptors. In particular, WO 2002 / 022587 relates inter alia to pyridazinone and triazinone compounds.

[0013] US 5,418,233 relates to heteroaromatic derivatives which inhibit cell-cell aggregation and cell-matrix interactions. In particular, US 5,418,233 relates to heteroaromatic derivatives as histamine receptor antagonists.

[0014] WO 2015 / 143164 relates to antimicrobial agents and screening methods. In particular, WO 2015 / 143164 relates inter alia to pyridazinone compounds as antibiotics.

[0015] WO 2009 / 142732 relates to substituted pyridazinone derivatives and their use as H3 antagonists / inverse agonists.

[0016] However, the prior art does not describe the 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4- carboxamide compounds of general formula (I) of the present application as described and defined herein. SUMMARY

[0017] It has now been found that the compounds of the present application have surprising and advantageous properties and this constitutes the basis of the present application.

[0018] In particular, it has surprisingly been found that the compounds of the present application effectively inhibit AHR (data inhibiting AHR are given in the biological experiments section) and are thus useful for the treatment or prevention of cancer or other conditions or diseases wherein exogenous and endogenous AHR ligands induce a dysregulated immune response, uncontrolled cell growth, proliferation and / or survival of tumor cells, immune suppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly diseases wherein uncontrolled cell growth, proliferation and / or survival of tumor cells, immune suppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses are mediated by AHR, such as liquid and solid tumors, and / or metastases thereof, e.g. head and neck tumors (including brain tumors and brain metastases), thoracic tumors (including non-small cell and small cell lung tumors), gastrointestinal tumors (including colon tumors, colorectal tumors and pancreatic tumors), liver tumors, endocrine tumors, breast tumors and other gynecological tumors, urinary tract tumors (including kidney, bladder and prostate tumors), skin tumors and sarcomas, and / or metastases thereof.

[0019] According to a first aspect, the present application encompasses compounds of general formula (I): (I)

[0020]

[0021] their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, and their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein

[0022] R 1 represents C2-C6-hydroxyalkyl, wherein said C2-C6-hydroxyalkyl is optionally substituted one time with cyano, -COOR 10 , -CONR 11 R 12 ,

[0023] C1-C4-alkoxy or C3-C6-cycloalkyl, which is substituted one time with hydroxy and optionally one time with C1-C3-alkyl and / or one to three times with halogen, or

[0024] C3-C6-cycloalkyl, which is substituted one time with hydroxy and optionally one time with C1-C3-alkyl and / or one to three times with halogen, or

[0025] C3-C6-cycloalkyl-C1-C3-alkyl, which is substituted one time with hydroxy and optionally one time with C1-C3-alkyl and / or one to three times with halogen, or

[0026] (C3-C6-cycloalkyl)2-C1-C3-alkyl, which is substituted one time with hydroxy and optionally one time with C1-C3-alkyl and / or one to three times with halogen, or

[0027] 4- to 6-membered heterocycloalkyl, which is substituted one time with hydroxy and optionally one time with C1-C3-alkyl and / or one to three times with halogen;

[0028] R 2 represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

[0029] R 3 represents hydrogen, fluorine, chlorine or methyl;

[0030] R 4 represents hydrogen or fluorine;

[0031] R 5 represents monocyclic heteroaryl, which is optionally substituted one to three times, independently from each other, with R 6 ;

[0032] R 6 represents C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen or cyano;

[0033] X represents CH or N;

[0034] R 10 Indicates C1-C4 alkyl;

[0035] R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or

[0036] Together with the nitrogen atoms to which they are attached, they form 4- to 6-membered nitrogen-containing heterocycles, said rings optionally containing an additional nitrogen atom selected from O, S, NH, NR. a heteroatoms, of which R a It indicates a C1-C4 alkyl group.

[0037] Furthermore, the present invention includes the use of these drugs in combination with other anticancer drugs such as immunotherapeutic agents, targeted anticancer agents, or chemotherapy. Attached Figure Description

[0038] Figure 1 The sequence listing of the TPP-3911 antibody light chain (anti-PD-L1-mIgG1Kappa_RG7446 chimera | light chain | pTT5-anti-PD-L1-huVH-muIgG1-CH1-CH3-kappa-chimera) is described.

[0039] Figure 2 The sequence listing of the TPP-3911 antibody heavy chain (anti-PD-L1-mIgG1Kappa_RG7446 chimera|heavy chain|pTT5-anti-PD-L1-huVH-muIgG1-CH1-CH3-kappa-chimera) is described. Detailed Implementation

[0040] definition

[0041] The term "substituted" means that one or more hydrogen atoms on a specified atom or group are selectively replaced by the indicated group, provided that the replacement does not exceed the normal valence of the specified atom in its existing environment. Combinations of substituents and / or variables are permitted.

[0042] The term "optionally substituted" means that the number of substituents may be equal to or not equal to zero. Unless otherwise stated, an optionally substituted group can be substituted with as many optional substituents as possible by replacing hydrogen atoms with non-hydrogen substituents on any available carbon atom. Typically, the number of optional substituents can be 1, 2, or 3, when present.

[0043] When used in the specification, the term "comprising" includes "consisting of".

[0044] If in the present text any item is referred to as "as mentioned herein", it means that it can be mentioned anywhere in the present text.

[0045] The terms mentioned in the present text have the following meanings:

[0046] The term "halogen" means fluorine, chlorine, bromine or iodine, in particular fluorine, chlorine or bromine atoms.

[0047] The term "C1-C6-haloalkyl" means a straight chain or branched saturated monovalent hydrocarbon group, wherein the term "C1-C6-alkyl" is as defined above, and wherein one or more hydrogen atoms are replaced by halogen atoms, identically or differently, particularly fluorine atoms. The C1-C6-haloalkyl is for example fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoroprop-2-yl. Particularly, the group has 1, 2, 3 or 4 carbon atoms ("C1-C4-haloalkyl"), more particularly 1, 2 or 3 carbon atoms ("C1-C3-haloalkyl"), for example fluoromethyl, difluoromethyl or trifluoromethyl.

[0048] The term "C1-C6-haloalkyl" means a straight chain or branched saturated monovalent hydrocarbon group, wherein the term "C1-C6-alkyl" is as defined above, and wherein one or more hydrogen atoms are replaced by halogen atoms, identically or differently, particularly fluorine atoms. The C1-C6-haloalkyl is for example fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3-difluoroprop-2-yl. Particularly, the group has 1, 2, 3 or 4 carbon atoms ("C1-C4-haloalkyl"), more particularly 1, 2 or 3 carbon atoms ("C1-C3-haloalkyl"), for example fluoromethyl, difluoromethyl or trifluoromethyl.

[0049] The term "C2-C6-hydroxyalkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group, wherein the term "C2-C6-alkyl" is as defined supra, and wherein 1 or 2 hydrogen atoms are replaced with a hydroxy group, for example, 1 -hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1 -hydroxypropyl, 1 -hydroxyprop-2-yl, 2-hydroxyprop-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxyprop-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1 -hydroxy-2-methyl-propyl.

[0050] The term "C1-C4-alkoxy" refers to a straight-chain or branched saturated monovalent group of formula (C1-C4-alkyl)-O- representing methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, or t-butoxy.

[0051] The term "C3-C6-cycloalkyl" refers to a saturated monovalent monocyclic hydrocarbon ring containing 3, 4, 5, or 6 carbon atoms ("C3-C6-cycloalkyl"). The C3-C6-cycloalkyl is a monocyclic hydrocarbon ring, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0052] The term "C2-C7-alkylene" refers to a straight-chain or branched saturated divalent hydrocarbon group, wherein the term "C2-C7-alkyl" is as defined supra, and wherein 2 hydrogen atoms are removed from different carbon atoms to form a bivalent radical.

[0053] The term "4- to 6-membered heterocycloalkyl" refers to a monocyclic saturated heterocyclic ring having a total of 4, 5, or 6 ring atoms, which contains one or two identical or different ring heteroatoms from the series N and O, which heterocycloalkyl group can be attached to the remainder of the molecule by any one of the carbon atoms or, if present, the nitrogen atom.

[0054] The heterocycloalkyl group is not limited thereto, and can be a 4-membered ring, for example, azetidinyl or oxetanyl; or a 5-membered ring, for example, tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, or 1,3-oxazolidinyl; or a 6-membered ring, for example, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl, or 1,2-oxazinanyl.

[0055] In particular, "4- to 6-membered heterocycloalkyl" refers to a 4- to 6-membered heterocycloalkyl group as defined supra, which contains one ring oxygen atom and optionally one additional ring heteroatom from the series N, O. More particularly, "5- or 6-membered heterocycloalkyl" refers to a monocyclic saturated heterocyclic ring having a total of 5 or 6 ring atoms and containing one ring oxygen atom.

[0056] The term "monocyclic heteroaryl" refers to a monovalent aromatic ring having 5 or 6 ring atoms ("5- or 6-membered heteroaryl"), which contains at least one ring heteroatom and optionally one or two further ring heteroatoms from the series N, O and / or S, and which is bound via a ring carbon atom or, optionally, via a ring nitrogen atom, if valence allows.

[0057] The heteroaryl group can be a 5-membered heteroaryl group, such as thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, or tetrazolyl; or a 6-membered heteroaryl group, such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

[0058] Generally, unless otherwise stated, a heteroaryl or heteroarylene group includes all possible isomeric forms thereof, e.g. tautomers and positional isomers with respect to the point of attachment to the rest of the molecule. Thus, for some illustrative, non-limiting examples, the term pyridyl includes pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.

[0059] In particular, the heteroaryl group is isothiazolyl, pyrazolyl, pyridyl, pyridazinyl, or pyrimidinyl.

[0060] When the plural form of the words, compounds, salts, polymorphs, hydrates, solvates, etc. is used herein, this also means a single compound, salt, polymorph, isomer, hydrate, solvate, etc.

[0061] A "stable compound" or "stable structure" is meant to refer to a compound that is sufficiently robust to survive isolation to useful purity from a reaction mixture and formulation into an efficacious therapeutic agent.

[0062] The compounds of the present application optionally contain one or more asymmetric centers, depending on the position and nature of the various substituents required. One or more asymmetric carbon atoms can exist in the (R) or (S) configuration, which in the case of a single asymmetric center can result in a racemic mixture, and in the case of multiple asymmetric centers can result in a mixture of diastereomers. In certain cases, asymmetry can also exist due to restricted rotation about a given bond, e.g. the bond that is central to two substituted aromatic rings of the specified compound.

[0063] Preferred compounds are those that produce more desirable biological activity. Isolated, purified or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present application are also included within the scope of the present application. Purification and isolation of these substances can be accomplished by standard techniques known in the art.

[0064] The preferred isomer is the isomer that produces the more desirable biological activity. These isolated, purified or partially purified isomers or racemic mixtures of the compounds of the present application are also within the scope of the present application. Purification and separation of these materials can be accomplished by standard techniques known in the art.

[0065] Optical isomers can be obtained by resolution of racemic mixtures according to conventional processes, for example, by the formation of diastereomeric salts or complexes using an optically active acid or base, or formation of covalent diastereomers. Examples of appropriate acids are tartaric acids, diacetyltartaric acid, mandelic acid, and camphorsulfonic acid. The mixture of diastereomers can be separated into the individual diastereomers by conventional means, for example, by fractional crystallization or chromatography, based on their physical and / or chemical differences. The optically active bases or acids are then liberated from the separated diastereomeric salts. A variety of methods are known to effect this transformation. Enantiomeric mixtures of the compounds of the present application can be separated based on their difference in physical and / or chemical properties. Different methods useful for separating enantiomeric mixtures include, but are not limited to, chiral phase chromatography (e.g., HPLC column using a chiral phase), chiral phase electrophoresis, and chiral phase centrifugation. Suitable HPLC columns using chiral phases are commercially available, for example, those manufactured by Daicel, for example, Chiracel OD and Chiracel OJ, among others, all of which are routinely selected. Enzymatic resolution, either derivatized or not, is also useful. The optically active compounds of the present application can also be obtained by chiral synthesis using optically active starting materials.

[0066] To distinguish between the different types of isomers from each other, reference is made to the IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

[0067] The present application includes all possible stereoisomers of the compounds of the present application either as the single stereoisomers, or as any mixture in any proportion of said stereoisomers, for example, as mixtures of (R)- and (S)-isomers. Separation of the single stereoisomers of the compounds of the present application (e.g., single enantiomers or single diastereomers) can be achieved by any appropriate prior art method, for example, chromatography, especially chiral chromatography.

[0068] In addition, the compounds of the present application can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present application is oxidized. The present application includes all such possible N-oxides.

[0069] The present application also includes useful forms of the compounds of the present application, for example, metabolites, hydrates, solvates, prodrugs, salts, particularly pharmaceutically acceptable salts, and / or co-precipitates.

[0070] The compounds of the present application can exist in a hydrate or solvate form, wherein the compounds of the present application contain a polar solvent, in particular water, methanol or ethanol, for example as a structural element of the crystal lattice of the compound. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts. In the case of stoichiometric solvates, for example, hemi-, (hemi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates are possible. The present application includes all such hydrates or solvates.

[0071] Furthermore, the compounds of the present application can exist in free form, for example, as a free base, or as a free acid, or as a zwitterion, or in the form of a salt. The salt can be any salt, an organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt, which is commonly used in the pharmaceutical industry, or for example for isolating or purifying the compounds of the present application.

[0072] The term "pharmaceutically acceptable salt" refers to an inorganic or organic acid addition salt of a compound of the present application. For example, see S. M. Berge et al. "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

[0073] A suitable pharmaceutically acceptable salt of a compound of the present application can be, for example, an acid addition salt of a compound of the present application which carries a nitrogen atom in a chain or ring, for example, having sufficient basicity, for example, an acid addition salt with an inorganic acid or "mineral acid", such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, bisulfuric acid, phosphoric acid or nitric acid, or for example, an acid addition salt with an organic acid, such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene- disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid or thiocyanic acid.

[0074] Further, another suitable pharmaceutically acceptable salt of a compound of the present application having sufficient basicity is an alkali metal salt such as a sodium or potassium salt, an alkaline earth metal salt such as a calcium, magnesium, or strontium salt, or an aluminum or zinc salt, or an ammonium salt derived from ammonia or an organic primary, secondary, or tertiary amine having from 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1,2-ethanediamine, N-methylpiperidine, N-methyl-glucamine, N,N-dimethyl-glucamine, N-ethyl-glucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butantriol, or a salt with a quaternary ammonium ion having 1 to 20 carbon atoms such as tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline, or benzalkonium.

[0075] The skilled person will further recognize that acid addition salts of the claimed compounds can be prepared by reacting a compound with the appropriate inorganic or organic acid by any of a number of known methods. Alternatively, alkali and alkaline earth metal salts of acidic compounds of the present application are prepared by reacting the compound of the present application with the appropriate base by a variety of known methods.

[0076] The present application includes all possible salts of the compounds of the present application, either as single salts or any mixture of said salts in any ratio.

[0077] In the present text, especially in the experimental part, for the synthesis of intermediates and examples of the present application, when a compound is mentioned in the form of a salt with a corresponding base or acid, the exact stoichiometric composition of said salt form obtained by the respective preparation and / or purification method is in most cases not known.

[0078] Unless otherwise indicated, the suffixes to the chemical names or structural formulae relating to salts, such as “hydrochloride”, “trifluoroacetate”, “sodium salt” or “x HC1”, “x CF3COOH”, “x Na + ”, for example, refer to the salt form without specifying the stoichiometry of said salt form.

[0079] This applies analogously to the case where a synthetic intermediate or example compound of the present application or a salt thereof is obtained as a solvate, such as a hydrate, by said preparation and / or purification method, if the stoichiometry is not defined.

[0080] Furthermore, the present application encompasses all possible crystalline forms or polymorphs of the compounds of the present application, either as single polymorph or as a mixture of more than one polymorph in any ratio.

[0081] Furthermore, the present application also encompasses prodrugs of the compounds according to the present application. The term "prodrug" denotes a compound which, upon its in vivo

[0082] The present application further encompasses all possible crystalline and polymorphic forms of the compounds of the present application, wherein the polymorphs are present as single polymorph or as a mixture of several polymorphs in all concentrations.

[0083] According to a second embodiment of the first aspect, the present application covers the above-mentioned compounds of general formula (I), their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as physiologically acceptable salts of them and solvates of those salts, and mixtures thereof, wherein:

[0084] R 1 represents C2-C6-hydroxyalkyl, wherein said C2-C6-hydroxyalkyl is optionally substituted one time with cyano, -COOR 10 , -CONR 11 R 12 , C1-C4-alkoxy or C3-C6-cycloalkyl, and optionally one to three times with halogen, or

[0085] C3-C6-cycloalkyl, which is substituted one time with hydroxy and optionally one to three times with halogen, or

[0086] C3-C6-cycloalkyl-C1-C3-alkyl, which is substituted one time with hydroxy and optionally one to three times with halogen, or

[0087] (C3-C6-cycloalkyl)2-C1-C3-alkyl, which is substituted one time with hydroxy and optionally one to three times with halogen, or 4- to 6-membered heterocycloalkyl, which is substituted one time with hydroxy and optionally one to three times with halogen;

[0088] R 2 represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

[0089] R 3 represents hydrogen, fluorine, chlorine or methyl;

[0090] R 4 represents hydrogen or fluorine;

[0091] R 5 This indicates a monocyclic heteroaryl group, whose optional R 6 Each can replace the other one to three times independently;

[0092] R 6 It can represent C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen, or cyano;

[0093] X represents CH or N;

[0094] R 10 Indicates C1-C4 alkyl;

[0095] R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or

[0096] Together with the nitrogen atoms to which they are attached, they form 4- to 6-membered nitrogen-containing heterocycles, said rings optionally containing an additional nitrogen atom selected from O, S, NH, NR. a heteroatoms, of which R a It indicates a C1-C4 alkyl group.

[0097] According to a third embodiment of the first aspect, the present invention covers compounds of the above general formula (I), their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as physiologically acceptable salts and solvates of these salts, and mixtures thereof, wherein:

[0098] R 1 This represents a C2-C6-hydroxyalkyl group, wherein the C2-C6-hydroxyalkyl group is optionally prefixed with a cyano group or a -COOR group. 10 -CONR 11 R 12 The alkyl group is substituted once with a C1-C4-alkoxy or C3-C6-cycloalkyl group, and optionally substituted with a halogen one to three times.

[0099] C3-C6-cycloalkyl, which is substituted once with a hydroxyl group and optionally substituted once with a C1-C3-alkyl group and / or substituted once to three times with a halogen, or

[0100] C3-C6-cycloalkyl-C1-C3-alkyl, which is substituted once with a hydroxyl group and optionally substituted once with a C1-C3-alkyl group and / or substituted once to three times with a halogen, or

[0101] (C3-C6-cycloalkyl)2-C1-C3-alkyl, which is substituted once with a hydroxyl group and optionally substituted once with a C1-C3-alkyl group and / or substituted once to three times with a halogen, or

[0102] 4- to 6-membered heterocycloalkyl, which is substituted once by hydroxyl and optionally substituted once by Ci-C3-alkyl and / or one to three times by halogen;

[0103] R 2 represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

[0104] R 3 represents hydrogen, fluorine, chlorine or methyl;

[0105] R 4 represents hydrogen or fluorine;

[0106] R 5 represents monocyclic heteroaryl, which is optionally substituted one to three times, independently from each other, by R 6 one to three times, independently from each other;

[0107] R 6 represents Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C4-alkoxy, halogen or cyano;

[0108] X represents CH or N.

[0109] According to a fourth embodiment of the first aspect, the present application covers compounds of general formula (I) as mentioned above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0110] R 1 represents C2-C5-hydroxyalkyl, wherein said C2-C5-hydroxyalkyl is optionally substituted once by cyano, -COOCH3, -CONH2, methoxy or cyclopropyl and optionally one to three times by fluorine, or

[0111] C4-C6-cycloalkyl, which is substituted once by hydroxyl and optionally substituted once by methyl and / or one to two times by fluorine, or

[0112] C3-C4-cycloalkyl-methyl, which is substituted once by hydroxyl, or

[0113] 5- or 6-membered heterocycloalkyl, which is substituted once by hydroxyl, said heterocycloalkyl containing one oxygen atom;

[0114] R 2 represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

[0115] R 3 represents hydrogen or fluorine;

[0116] R 4 Indicates hydrogen or fluorine;

[0117] R 5 This indicates a monocyclic heteroaryl group, whose optional R 6 Each can replace the other one to three times independently;

[0118] R 6 It indicates methyl, difluoromethyl, methoxy, halogen, or cyano;

[0119] X represents CH or N;

[0120] R 10 Indicates C1-C4 alkyl;

[0121] R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or

[0122] Together with the nitrogen atoms to which they are attached, they form 4- to 6-membered nitrogen-containing heterocycles, said rings optionally containing an additional nitrogen atom selected from O, S, NH, NR. a heteroatoms, of which R a It indicates a C1-C4 alkyl group.

[0123] According to a fifth embodiment of the first aspect, the present invention covers compounds of the above general formula (I), their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as physiologically acceptable salts and solvates of these salts, and mixtures thereof, wherein:

[0124] R 1 The term represents a C2-C5-hydroxyalkyl group, wherein the C2-C5-hydroxyalkyl group is optionally substituted once with a cyano, -COOCH3, -CONH2, methoxy, or cyclopropyl group, and optionally substituted once to three times with fluorine.

[0125] C4-C6-cycloalkyl, which is substituted once with a hydroxyl group and optionally substituted once with a methyl group and / or substituted once or twice with a fluorine group, or

[0126] C3-C4-cycloalkyl-methyl, which is substituted once by a hydroxyl group, or

[0127] 5- or 6-membered heterocyclic alkyl group, which is substituted once with a hydroxyl group, wherein the heterocyclic alkyl group contains one oxygen atom;

[0128] R 2 It represents chlorine, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy;

[0129] R 3 represents hydrogen;

[0130] R 4 represents hydrogen or fluorine;

[0131] R 5 represents a group selected from:

[0132]

[0133] wherein * represents the point of attachment of the group to the rest of the molecule;

[0134] R 6a represents hydrogen, methyl, fluorine or chlorine;

[0135] X represents CH or N.

[0136] According to a sixth embodiment of the first aspect, the present application covers compounds of general formula (la):

[0137]

[0138] their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof,

[0139] wherein

[0140] R 2 represents chlorine, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy;

[0141] R 7 represents hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethyl, isopropyl, cyclopropyl, cyano, -COOCH3 or -CONH2;

[0142] R 8 represents hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl or methoxymethyl,

[0143] wherein R 7 and R 8 are different from hydrogen, or

[0144] R 7 and R 8 together form a cyclopentyl or cyclohexyl ring optionally substituted one to two times by fluorine, or a heterocycloalkyl ring containing one oxygen atom;

[0145] R 9 represents hydrogen or methyl, or

[0146] R 8 and R 9 together form a cyclopropyl or cyclobutyl ring.

[0147] According to a seventh embodiment of the first aspect, the present application covers compounds of general formula (lb):

[0148]

[0149] their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof,

[0150] wherein

[0151] R 2 represents chlorine, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy or trifluoromethoxy;

[0152] R 5 represents a group selected from:

[0153]

[0154] wherein * represents the point of attachment of the group to the rest of the molecule;

[0155] R 6a represents hydrogen, methyl, fluorine or chlorine;

[0156] R 7 represents hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethyl, isopropyl or cyclopropyl;

[0157] R 8 represents hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl or methoxymethyl,

[0158] wherein one of R 7 and R 8 is different from hydrogen, or

[0159] R 7 and R 8 together form a cyclopentyl or cyclohexyl ring, optionally substituted one to two times by fluorine, or a heterocycloalkyl ring containing one oxygen or sulfur atom;

[0160] R 9 represents hydrogen or methyl, or

[0161] R 8 and R 9 together form a cyclopropyl or cyclobutyl ring.

[0162] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0163] R 1 represents C2-C6-hydroxyalkyl, wherein said C2-C6-hydroxyalkyl is optionally substituted one time with cyano, -COOR 10 , -CONR 11 R 12 ,

[0164] C1-C4-alkoxy or C3-C6-cycloalkyl, which is substituted one time with hydroxy and optionally one time with C1-C3-alkyl and / or one to three times with halogen, or

[0165] C3-C6-cycloalkyl, which is substituted one time with hydroxy and optionally one time with C1-C3-alkyl and / or one to three times with halogen, or

[0166] C3-C6-cycloalkyl-C1-C3-alkyl, which is substituted one time with hydroxy and optionally one time with C1-C3-alkyl and / or one to three times with halogen, or

[0167] (C3-C6-cycloalkyl)2-C1-C3-alkyl, which is substituted one time with hydroxy and optionally one time with C1-C3-alkyl and / or one to three times with halogen, or

[0168] 4- to 6-membered heterocycloalkyl, which is substituted one time with hydroxy and optionally one time with C1-C3-alkyl and / or one to three times with halogen.

[0169] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0170] R 1 represents C2-C5-hydroxyalkyl, wherein said C2-C5-hydroxyalkyl is optionally substituted one time with cyano, -COOCH3, -CONH2, methoxy or cyclopropyl and optionally one to three times with fluorine, or

[0171] C4-C6-cycloalkyl, which is substituted one time with hydroxy and optionally one time with methyl and / or one to two times with fluorine, or

[0172] C3-C4-cycloalkyl-methyl, which is substituted one time with hydroxy, or

[0173] 5- or 6-membered heterocycloalkyl, which is substituted once by hydroxy, said heterocycloalkyl containing one oxygen atom.

[0174] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I), as mentioned above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0175] R 1 represents C2-C6-hydroxyalkyl, wherein said C2-C6-hydroxyalkyl is optionally substituted once by cyano, -COOR 10 , -CONR 11 R 12 , C1-C4-alkoxy or C3-C6-cycloalkyl, and optionally one to three times by halogen, or

[0176] C3-C6-cycloalkyl, which is substituted once by hydroxy and optionally one to three times by halogen, or

[0177] C3-C6-cycloalkyl-C1-C3-alkyl, which is substituted once by hydroxy and optionally one to three times by halogen, or

[0178] (C3-C6-cycloalkyl)2-C1-C3-alkyl, which is substituted once by hydroxy and optionally one to three times by halogen, or

[0179] 4- to 6-membered heterocycloalkyl, which is substituted once by hydroxy and optionally one to three times by halogen.

[0180] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I), as mentioned above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0181] R 1 represents C2-C6-hydroxyalkyl, wherein said C2-C6-hydroxyalkyl is optionally substituted once by C1-C4-alkoxy or C3-C6-cycloalkyl and optionally one to three times by halogen, or

[0182] C3-C6-cycloalkyl, which is substituted once by hydroxy and optionally one to three times by methyl and / or halogen, or

[0183] C3-C6-cycloalkyl-C1-C3-alkyl, which is substituted once with hydroxyl and optionally one to three times with halogen, or

[0184] (C3-C6-cycloalkyl)2-C1-C3-alkyl, which is substituted once with hydroxyl and optionally one to three times with halogen, or 4- to 6-membered heterocycloalkyl, which is substituted once with hydroxyl and optionally one to three times with halogen.

[0185] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I), supra, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0186] R 1 represents C2-C6-hydroxyalkyl, wherein said C2-C6-hydroxyalkyl is optionally substituted once with C1-C2-alkoxy or cyclopropyl and optionally one to three times with halogen, or

[0187] C4-C6-cycloalkyl, which is substituted once with hydroxyl and optionally one time with methyl and / or one to three times with halogen, or

[0188] C3-C6-cycloalkyl-methyl, which is substituted once with hydroxyl and optionally one to three times with halogen, or

[0189] (C3-C6-cycloalkyl)2-methyl, which is substituted once with hydroxyl and optionally one to three times with halogen, or

[0190] 5- or 6-membered heterocycloalkyl, which is substituted once with hydroxyl and optionally one to three times with halogen.

[0191] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I), supra, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0192] R 1 represents C2-C5-hydroxyalkyl, wherein said C2-C5-hydroxyalkyl is optionally substituted once with methoxy or cyclopropyl and optionally one to three times with fluorine, or

[0193] C4-C6-cycloalkyl, which is substituted once with hydroxyl and optionally one time with methyl and / or one to two times with fluorine, or C3-C4-cycloalkyl-methyl, which is substituted once with hydroxyl, or

[0194] 5- or 6-membered heterocycloalkyl, which contains one oxygen atom, substituted once by hydroxy.

[0195] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I), supra, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0196] R 1 represents C2-C5-hydroxyalkyl, wherein said C2-C5-hydroxyalkyl is optionally substituted one time by methoxy or cyclopropyl and optionally one to three times by fluorine, or

[0197] C4-C6-cycloalkyl, which is substituted one time by hydroxy and optionally one time by methyl or one to two times by fluorine, or C3-C4-cycloalkyl-methyl, which is substituted one time by hydroxy, or

[0198] 5- or 6-membered heterocycloalkyl, which contains one oxygen atom, substituted once by hydroxy.

[0199] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I), supra, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0200] R 2 represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy.

[0201] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I), supra, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0202] R 2 represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy.

[0203] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures of them, wherein:

[0204] R 3 denotes hydrogen, fluorine, chlorine or methyl.

[0205] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures of them, wherein:

[0206] R 3 denotes hydrogen or fluorine.

[0207] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures of them, wherein:

[0208] R 3 denotes hydrogen.

[0209] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures of them, wherein:

[0210] R 4 denotes hydrogen or fluorine.

[0211] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures of them, wherein:

[0212] R 4 denotes hydrogen.

[0213] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0214] R 5 represents a monocyclic heteroaryl group, which is optionally substituted one to three times, independently from each other, with R 6 independently from each other, with R

[0215] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0216] R 5 represents a group selected from:

[0217]

[0218] wherein * indicates the point of attachment of the group to the rest of the molecule.

[0219] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0220] R 5 represents a group selected from:

[0221]

[0222] wherein * indicates the point of attachment of the group to the rest of the molecule.

[0223] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0224] R 5 represents a group selected from:

[0225]

[0226] wherein * indicates the point of attachment of the group to the rest of the molecule.

[0227] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I), supra, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0228] R 5 represents a group selected from:

[0229]

[0230] wherein * indicates the point of attachment of the group to the rest of the molecule.

[0231] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I), supra, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0232] R 6 represents Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C4-alkoxy, halogen or cyano.

[0233] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I), supra, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0234] R 6 represents Ci-C4-alkyl, C3-C6-cycloalkyl, Ci-C4-alkoxy, halogen or cyano.

[0235] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I), supra, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures thereof, wherein:

[0236] R 6 represents methyl, methoxy, halogen or cyano.

[0237] According to a further embodiment of the first aspect, the present invention covers compounds of the above general formula (I), their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as physiologically acceptable salts and solvates of these salts, and mixtures thereof, wherein:

[0238] R 6a It indicates hydrogen, methyl, fluorine, or chlorine.

[0239] According to a further embodiment of the first aspect, the present invention covers compounds of the above general formula (I), their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as physiologically acceptable salts and solvates of these salts, and mixtures thereof, wherein:

[0240] R 10 It indicates a C1-C4 alkyl group.

[0241] According to a further embodiment of the first aspect, the present invention covers compounds of the above general formula (I), their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as physiologically acceptable salts and solvates of these salts, and mixtures thereof, wherein:

[0242] R 10 It indicates methyl.

[0243] According to a further embodiment of the first aspect, the present invention covers compounds of the above general formula (I), their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as physiologically acceptable salts and solvates of these salts, and mixtures thereof, wherein:

[0244] R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or

[0245] Together with the nitrogen atoms to which they are attached, they form 4- to 6-membered nitrogen-containing heterocycles, said rings optionally containing an additional nitrogen atom selected from O, S, NH, NR. a heteroatoms, of which R a It indicates a C1-C4 alkyl group.

[0246] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures of the same, wherein:

[0247] R 11 and R 12 are the same or different and independently from each other represent hydrogen or Ci-C3-alkyl, or

[0248] form together with the nitrogen atom to which they are attached a 4- to 6-membered nitrogen containing heterocyclic ring.

[0249] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures of the same, wherein:

[0250] R 11 and R 12 are the same or different and independently from each other represent hydrogen or Ci-C3-alkyl.

[0251] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures of the same, wherein:

[0252] R 11 and R 12 are the same or different and independently from each other represent hydrogen or methyl.

[0253] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures of the same, wherein:

[0254] X represents CH or N.

[0255] According to a further embodiment of the first aspect, the present application covers compounds of general formula (I) as described above, their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates, as well as their physiologically acceptable salts and solvates of such salts, and mixtures of the same, wherein:

[0256] X represents CH.

[0257] In a particularly further embodiment of the first aspect, the present application encompasses a combination of two or more of the above-mentioned embodiments under the heading "Further embodiments of the first aspect of the application".

[0258] The present application encompasses any sub-combination within any of the embodiments or aspects of the compounds of general formula (I) of the present application described above.

[0259] The present application encompasses any sub-combination within any of the embodiments or aspects of the intermediate compounds of general formula (VII) of the present application. The present application encompasses the compounds of general formula (I) disclosed in the example section hereinafter.

[0260] The compounds according to the present application of general formula (I) can be prepared according to the following Scheme 1. The schemes and procedures described below illustrate synthetic routes to the compounds of general formula (I) of the present application and are not intended to be limiting. It will be apparent to those skilled in the art that the sequence of transformations illustrated in Scheme 1 can be modified in various ways. Thus, the sequence of transformations illustrated in this scheme is not intended to be limiting. Furthermore, the interconversion of any substituents R 1 , R 2 , R 3 , R 4 , R 5 or R 6 may be achieved before and / or after the transformations illustrated. These modifications can be, for example, the introduction of a protecting group, the cleavage of a protecting group, the reduction or oxidation of a functional group, halogenation, metallation, metal catalysed coupling reactions, substitution or other reactions known to the skilled person. These transformations include transformations which introduce a functional group which allows further interconversion of substituents. Suitable protecting groups and their introduction and cleavage are well known to the skilled person. Specific examples are described in the subsequent paragraphs.

[0261] Scheme 1 shows a route to the preparation of compounds of general formula (I), wherein X, R 1 , R 2 , R 3 , R 4 , R 5 and R 6with the meanings given above for general formula (I). The keto-malonates, which are represented as intermediates according to formula (III), are in some cases commercially available or can be synthesized from a-halo-acetophenones (II) according to procedures known to the person skilled in the art. The relevant a-halo-acetophenones are generally commercially available. The conversion of such a-halo-acetophenones with malonates in the presence of a suitable base in a suitable solvent leads to the formation of non-commercial keto-malonates according to formula (III). R in formula (III), (V) and (VI) represents a suitable alkyl group, such as methyl, ethyl, propyl or other homologous groups. Suitable solvents can be, but shall not be limited to, acetonitrile, DMF, DMA, DMSO or THF, or even mixtures of these or other solvents. Suitable bases can be, but shall not be limited to, potassium carbonate, sodium hydride, cesium carbonate or potassium hexamethyldisilazane.

[0262] The formation of dihydropyridazinones according to formula (V) from intermediates (III) and suitable arylhydrazines (IV), which are in many cases commercially available, can be accomplished by the reaction of these components in a suitable solvent at elevated temperature. Suitable solvents can be, but shall not be limited to, ethanol or acetic acid.

[0263]

[0264] Scheme 1 : Route for the preparation of compounds of general formula (I), wherein X, R 1 , R 2 , R 3 , R 4 and R 5 have the meanings given above for general formula (I), Hal represents halogen and R represents C1-C4-alkyl.

[0265] Dihydropyridazinones according to formula (V) can be converted to pyridazinones according to formula (VI). This can be accomplished by using suitable reagents such as copper dichloride at elevated temperature.

[0266] The resulting pyridazinones according to formula (VI) with ester functionality can be converted to pyridazinone carboxylic acids (VII) by methods known to the person skilled in the art, for example by basic hydrolysis with for example aqueous alkali hydroxide, or by acidic hydrolysis using for example hydrogen chloride / dioxane or trifluoroacetic acid.

[0267] These acids can be converted by coupling with amines of formula (VIII) (wherein R 1 is as defined for general formula (I)). Coupling reagents and methods for such synthesis of carboxamides from carboxylic acids and amines are known to the person skilled in the art. Examples which can be mentioned here include the use of HATU, HBTU, PyBOB or T3P with the addition of a suitable base. The conversion of carboxylic acids to their amides is described in general terms in reference books.

[0268]

[0269] Scheme 2: Approach for the preparation of compounds of general formula (I), wherein X, R 1 , R 2 , R 3 , R 4 and R 5 have the meanings as given above for general formula (I), Hal represents halogen, R represents Ci-C4-alkyl and R' and R" represent simultaneously H or Ci-C4-alkyl or together form a C2-C7-alkylene as part of a 1,2- or 1,3-diol boronate or a -CO-CH2-(NCH3)-CH2-CO- group.

[0270] Ketomalonates represented as intermediates according to formula (III) are in some cases commercially available or can be synthesized from a-halo-acetophenones (II) according to procedures known to the skilled person. Relevant a-halo-acetophenones are generally commercially available. The conversion of such a-halo-acetophenones with malonates in the presence of a suitable base in a suitable solvent leads to the formation of non-commercial ketomalonates according to formula (III). R in formula (III), (IX), (X) and (VI) represents a suitable alkyl group such as methyl, ethyl, propyl or other homologous groups. Suitable solvents can be but shall not be limited to acetonitrile, DMF, DMA, DMSO or THF or even mixtures of these or other solvents. Suitable bases can be but shall not be limited to potassium carbonate, sodium hydride, cesium carbonate or potassium hexamethyldisilazane.

[0271] The formation of dihydropyridazinones according to formula (IX) from intermediates (III) and hydrazine can be accomplished by the reaction of these components in a suitable solvent at elevated temperature. Suitable solvents can be but shall not be limited to ethanol or acetic acid.

[0272] Dihydropyridazinones according to formula (IX) can be converted to pyridazinones according to formula (X). This can be accomplished by the use of suitable reagents. Suitable reagents can be but shall not be limited to copper dichloride at elevated temperature.

[0273] Substituted pyridazinones according to formula (VI) can be prepared by Chan-Lam coupling reactions of pyridazinones according to formula (X) using boron derivatives such as boric acid, pinacolboronic acid and tetrafluoroborate with suitable solvents at room temperature or elevated temperature. Suitable solvents can be but shall not be limited to acetonitrile, dichloromethane, pyridine or DMF. Suitable catalysts can be but shall not be limited to copper (II) acetate. Suitable basic additives can be but shall not be limited to trimethylamine, 2,2-bipyridine, sodium carbonate or cesium carbonate.

[0274] The obtained substituted pyridazinones according to formula (VI) with ester functionality can be converted to pyridazinone carboxylic acids (VII) by methods known to the person skilled in the art, for example by basic hydrolysis with for example aqueous alkali hydroxide, or by acidic hydrolysis using for example hydrogen chloride / dioxane or trifluoroacetic acid.

[0275] These can be converted by amine coupling with amines of formula (VIII) (wherein R 1 as defined for general formula (I). Coupling reagents and methods for such synthesis of carboxamides from carboxylic acids and amines are known to the person skilled in the art. Examples which can be mentioned here include the use of HATU, HBTU, PyBOB or T3P with the addition of a suitable base. The conversion of carboxylic acids to their amides is described in general terms in reference books.

[0276]

[0277] Scheme 2a: Route for the preparation of intermediates of general formula (X), wherein X, R 1 , R 2 , R 3 and R 4 have the meanings given above as for general formula (I) and R represents C1-C4-alkyl.

[0278] Compounds of general formula (IIa) are commercially available and can be reacted with a ketomalonate dialkyl ester, wherein R represents C1-C4-alkyl. Diethyl ketomalonate as reagent is commercially available. Ketomalonate dialkyl esters can be prepared from the corresponding malonic acid dialkyl ester with p-toluenesulfonyl azide and dioxirane (see for example: Synth. Commun. 1994, 24, 695) or bromine and potassium acetate (see for example: J. Org. Chem. 1981, 46, 2598). Heating of the phenacyl ketone of general formula (IIa) and the ketomalonate dialkyl ester at 95-100 °C neat or with a solvent like pyridine at reflux. Then, the intermediates of formula (IIIa) are reacted with hydrazine hydrate / acetic acid at reflux or with hydrazine dihydrochloride / ethanol at reflux to give intermediates (X).

[0279]

[0280] Scheme 3: Further routes for the preparation of compounds of general formula (I), wherein X, R 1 , R 2 , R 3 , R 4 and R 5with the above given meanings for general formula (I), R represents C1-C4-alkyl, and R' and R" simultaneously represent H or C1-C4-alkyl or together form a C2-C7-alkylene as part of a 1,2- or 1,3-diol boronic ester or a -CO-CH2-(NCH3)-CH2-CO- group.

[0281] 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester [CAS 89581-64-6] is commercially available. The conversion of 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester with an organic boron derivative (boronic acid, pinacol boronic acid ester, MIDA boronic ester, organic trifluoroborates) in the presence of a suitable palladium(0) catalyst, a suitable base and in a suitable solvent at room temperature or elevated temperature leads to the formation of 6-aryl substituted 3-oxo-2,3-dihydropyridazine-4-carboxylic acids of formula (XI). The used organic boron derivatives are commercially available or can be synthesized from organic halides. Methods for such syntheses are known to the person skilled in the art. Suitable catalysts can be, but shall not be limited to, palladium-phosphine complexes like Pd(PPh3)4, PdCl2(PPh3)2 or palladium catalysts which can be prepared in situ from precursors like Pd(OAc)2 or Pd2(dba)3 CHCl3 with an appropriate amount of phosphine or cyclopalladation catalysts like e.g. the second generation RuPhos precatalyst "chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1 '-biphenyl)[2-(2'-amino-1,1 '-biphenyl)]palladium(II)" (RuPhos-Pd-G2). Suitable bases can be, but shall not be limited to, potassium phosphate, potassium carbonate, potassium tert-butoxide, cesium carbonate and triethylamine. Suitable solvents can be, but shall not be limited to, dioxane, toluene, THF and dimethylformamide or even mixtures of these or other solvents.

[0282] 3-oxo-2,3-dihydropyridazine-4-carboxylic acids (XI) can be converted to amides (XII) by coupling with amines of formula (VIII). Coupling reagents and methods for such synthesis of carboxamides from carboxylic acids and amines are known to the person skilled in the art. Examples which can be mentioned herein include the use of HATU, HBTU, PyBOB or T3P with the addition of a suitable base. The conversion of carboxylic acids to their amides is described in general in reference books.

[0283] Substituted pyridazinones of formula (I) can be prepared by Chan-Lam coupling reaction using boronic acid derivatives (boronic acid, pinacol boronic acid ester, MIDA boronic ester and organic trifluoroborates) in a suitable solvent at room temperature or elevated temperature. Suitable solvents can be, but shall not be limited to, acetonitrile, dichloromethane, pyridine and DMF. Suitable catalysts can be, but shall not be limited to, copper(II) acetate. Suitable basic additives can be, but shall not be limited to, trimethylamine, 2,2-bipyridine, sodium carbonate or cesium carbonate.

[0284]

[0285] Scheme 4: Alternative approach for the preparation of compounds of general formula (I), wherein X, R 1 , R 2 , R 3 , R 4 and R 5 have the meanings given above for general formula (I), R represents C1-C4-alkyl, and R' and R" simultaneously represent H or C1-C4-alkyl or together form a C2-C7-alkylene as part of a 1,2- or 1,3-diol boronic ester or a -CO-CH2-(NCH3)-CH2-CO- group.

[0286] 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylic acid [CAS 50681-26-0] is commercially available and can be converted to the amide of formula (XIII) by coupling with an amine of formula (VIII). Coupling reagents and methods for such synthesis of carboxamides from carboxylic acids and amines are known to the person skilled in the art. Examples which can be mentioned herein include the use of HATU, HBTU, PyBOB or T3P with the addition of a suitable base.

[0287] 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylic acid [CAS 50681-26-0] is commercially available and can be converted to the amide of formula (XIII) by coupling with an amine of formula (VIII). Coupling reagents and methods for such synthesis of carboxamides from carboxylic acids and amines are known to the person skilled in the art. Examples which can be mentioned herein include the use of HATU, HBTU, PyBOB or T3P with the addition of a suitable base.

[0288] The substituted pyridazinones according to Formula (I) can be prepared by a Chan-Lam coupling reaction of 6-aryl substituted 3-oxo-2,3-dihydropyridazine-4-carboxamides according to Formula (XII) with boronic acid derivatives (boronic acid, pinacol boronic acid ester, MIDA boronic acid ester and organotrifluoroborates) using a suitable solvent at room temperature or elevated temperature. Suitable solvents can be, but shall not be limited to, acetonitrile, dichloromethane, pyridine and DMF. Suitable catalysts can be, but shall not be limited to, copper (II) acetate. Suitable basic additives can be, but shall not be limited to, trimethylamine, 2,2-bipyridine, sodium carbonate or cesium carbonate.

[0289] As will be appreciated by those skilled in the art, the compounds can be commercially available or can be prepared according to procedures available from the public domain. Specific examples are described in the experimental section.

[0290] According to a second aspect, the present application encompasses a process for the preparation of a compound of general Formula (I) as defined above, said process comprising the step of reacting an intermediate compound of general Formula (VII)

[0291]

[0292] wherein

[0293] R 2 represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

[0294] R 3 represents hydrogen, fluorine, chlorine or methyl;

[0295] R 4 represents hydrogen or fluorine;

[0296] R 5 represents monocyclic heteroaryl, which is optionally substituted one to three times, independently from each other, with R 6 independently from each other, with R

[0297] R 6 represents C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen or cyano;

[0298] X represents CH or N;

[0299] with a compound of general Formula (VIII):

[0300] H2N-R 1

[0301] (VIII),

[0302] wherein

[0303] R1 This represents a C2-C6-hydroxyalkyl group, wherein the C2-C6-hydroxyalkyl group is optionally prefixed with a cyano group or a -COOR group. 10 -CONR 11 R 12 ,

[0304] C1-C4-alkoxy or C3-C6-cycloalkyl substitution once, and optionally halogen substitution one to three times, or

[0305] C3-C6-cycloalkyl, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen, or

[0306] C3-C6-cycloalkyl-C1-C3-alkyl, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen, or

[0307] (C3-C6-cycloalkyl)2-C1-C3-alkyl, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen, or

[0308] 4- to 6-membered heterocyclic alkyl groups, which are substituted once with a hydroxyl group and optionally substituted once to three times with a halogen;

[0309] R 10 Indicates C1-C4 alkyl;

[0310] R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or

[0311] Together with the nitrogen atoms to which they are attached, they form 4- to 6-membered nitrogen-containing heterocycles, said rings optionally containing an additional nitrogen atom selected from O, S, NH, NR. a heteroatoms, of which R a Indicates C1-C4-alkyl;

[0312] This yields compounds of general formula (I):

[0313]

[0314] Among them, X and R 1 R 2 R 3 R 4 and R 5 As defined above.

[0315] This invention covers a method for preparing compounds of general formula (I), the method comprising the steps described in the experimental section herein.

[0316] According to a third aspect, the present invention covers intermediate compounds that can be used to prepare compounds of the above general formula (I).

[0317] In particular, this invention covers intermediate compounds of general formula (VII):

[0318]

[0319] in

[0320] R 2 It represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

[0321] R 3 Indicates hydrogen, fluorine, chlorine, or methyl;

[0322] R 4 Indicates hydrogen or fluorine;

[0323] R 5 This indicates a monocyclic heteroaryl group, whose optional R 6 Each can replace the other one to three times independently;

[0324] R 6 It can represent C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen, or cyano;

[0325] X represents CH or N.

[0326] According to the fourth aspect, the present invention covers the use of the intermediate compound for the preparation of compounds of general formula (I) as defined above.

[0327] In particular, this invention covers the use of intermediate compounds of general formula (VII) for the preparation of compounds of general formula (I) as defined above:

[0328]

[0329] in

[0330] R 2 It represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

[0331] R 3 Indicates hydrogen, fluorine, chlorine, or methyl;

[0332] R 4 Indicates hydrogen or fluorine;

[0333] R 5 This indicates a monocyclic heteroaryl group, whose optional R 6 Each can replace the other one to three times independently;

[0334] R 6represents C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen or cyano;

[0335] X represents CH or N.

[0336] According to a fifth aspect, the present application covers a process for the preparation of a compound of general formula (I) as defined above, said process comprising the step of reacting an intermediate compound of general formula (XII):

[0337]

[0338] wherein

[0339] R 1 represents C2-C6-hydroxyalkyl, wherein said C2-C6-hydroxyalkyl is optionally substituted one time with cyano, -COOR 10 , -CONR 11 R 12 , C1-C4-alkoxy or C3-C6-cycloalkyl, and optionally one to three times with halogen, or

[0340] C3-C6-cycloalkyl, which is substituted one time with hydroxy and optionally one to three times with halogen, or

[0341] C3-C6-cycloalkyl-C1-C3-alkyl, which is substituted one time with hydroxy and optionally one to three times with halogen, or

[0342] (C3-C6-cycloalkyl)2-C1-C3-alkyl, which is substituted one time with hydroxy and optionally one to three times with halogen, or

[0343] 4- to 6-membered heterocycloalkyl, which is substituted one time with hydroxy and optionally one to three times with halogen;

[0344] R 2 represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

[0345] R 3 represents hydrogen, fluorine, chlorine or methyl;

[0346] R 4 represents hydrogen or fluorine;

[0347] X represents CH or N.

[0348] R 10 represents C1-C4-alkyl;

[0349] R 11 and R 12identically or differently and independently of one another, denote hydrogen or C1-C3-alkyl, or

[0350] together with the nitrogen atom to which they are attached form a 4- to 6-membered nitrogen- containing heterocyclic ring, which optionally contains one further heteroatom selected from O, S, NH, NR a denotes C1-C4-alkyl; a denotes C1-C4-alkyl;

[0351] with a compound of general formula (XIV):

[0352]

[0353] wherein

[0354] R 5 denotes monocyclic heteroaryl, which is optionally substituted one to three times, independently of one another, by R 6 denotes C1-C4-alkyl;

[0355] R 6 denotes C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen or cyano;

[0356] R', R" simultaneously denote H or C1-C4-alkyl or together form a C2-C7-alkylene group as part of a 1,2- or 1,3-diol boronic ester or a -CO-CH2-(NCH3)-CH2-CO- group;

[0357] to thereby obtain a compound of general formula (I):

[0358]

[0359] wherein X, R 1 , R 2 , R 3 , R 4 and R 5 are as defined above.

[0360] The present application encompasses a process for preparing a compound of the present application of general formula (I), said process comprising the steps described in the experimental part herein.

[0361] According to a sixth aspect, the present application encompasses intermediate compounds useful for the preparation of a compound of general formula (I) as described above.

[0362] In particular, the present application encompasses an intermediate compound of general formula (XII):

[0363]

[0364] wherein

[0365] R 1This represents a C2-C6-hydroxyalkyl group, wherein the C2-C6-hydroxyalkyl group is optionally prefixed with a cyano group or a -COOR group. 10 -CONR 11 R 12 The alkyl group is substituted once with a C1-C4-alkoxy or C3-C6-cycloalkyl group, and optionally substituted with a halogen one to three times.

[0366] C3-C6-cycloalkyl, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen, or

[0367] C3-C6-cycloalkyl-C1-C3-alkyl, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen, or

[0368] (C3-C6-cycloalkyl)2-C1-C3-alkyl, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen, or

[0369] 4- to 6-membered heterocyclic alkyl groups, which are substituted once with a hydroxyl group and optionally substituted once to three times with a halogen;

[0370] R 2 It represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

[0371] R 3 Indicates hydrogen, fluorine, chlorine, or methyl;

[0372] R 4 Indicates hydrogen or fluorine;

[0373] X represents CH or N;

[0374] R 10 Indicates C1-C4 alkyl;

[0375] R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or

[0376] Together with the nitrogen atoms to which they are attached, they form 4- to 6-membered nitrogen-containing heterocycles, said rings optionally containing an additional nitrogen atom selected from O, S, NH, NR. a heteroatoms, of which R a It indicates a C1-C4 alkyl group.

[0377] According to the seventh aspect, the present invention covers the use of the intermediate compound for the preparation of compounds of general formula (I) as defined above.

[0378] In particular, this invention covers the use of intermediate compounds of general formula (XII) for the preparation of compounds of general formula (I) as defined above:

[0379]

[0380] wherein

[0381] R 1 represents C2-C6-hydroxyalkyl, wherein said C2-C6-hydroxyalkyl is optionally substituted one time with cyano, -COOR 10 , -CONR 11 R 12 , C1-C4-alkoxy or C3-C6-cycloalkyl, and optionally one to three times with halogen, or

[0382] C3-C6-cycloalkyl, which is substituted one time with hydroxy and optionally one to three times with halogen, or

[0383] C3-C6-cycloalkyl-C1-C3-alkyl, which is substituted one time with hydroxy and optionally one to three times with halogen, or

[0384] (C3-C6-cycloalkyl)2-C1-C3-alkyl, which is substituted one time with hydroxy and optionally one to three times with halogen, or

[0385] 4- to 6-membered heterocycloalkyl, which is substituted one time with hydroxy and optionally one to three times with halogen;

[0386] R 2 represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy;

[0387] R 3 represents hydrogen, fluorine, chlorine or methyl;

[0388] R 4 represents hydrogen or fluorine;

[0389] X represents CH or N;

[0390] R 10 represents C1-C4-alkyl;

[0391] R 11 and R 12 are the same or different and independently from each other represent hydrogen or C1-C3-alkyl, or

[0392] form together with the nitrogen atom to which they are attached a 4- to 6-membered nitrogen-containing heterocyclic ring, which optionally contains one further heteroatom selected from O, S, NH, NR a , wherein R a represents C1-C4-alkyl.

[0393] The present application includes the intermediate compounds disclosed in the example section hereinafter.

[0394] The present application includes any subcombination within any embodiment or aspect of the intermediate compounds of general formula (VII) of the present application described above.

[0395] The compounds of general formula (I) of the present application can be converted into any salt as described herein, preferably a pharmaceutically acceptable salt, by any method known to the skilled person. Similarly, any salt of the compounds of general formula (I) of the present application can be converted into the free compound by any method known to the skilled person.

[0396] The compounds of general formula (I) of the present application show a valuable spectrum of pharmacological effects, which cannot be predicted. It was surprisingly found that the compounds of the present application effectively inhibit AHR, and thus said compounds are useful for the treatment or prevention of diseases in humans and animals, preferably cancers associated with aberrant AHR signaling or conditions with dysregulated immune responses or other disorders.

[0397] Disorders and conditions which are particularly suitable for treatment with the AHR inhibitors of the present application are liquid and solid tumors, such as breast cancer, respiratory tract cancer, cancer of the brain, cancer of the reproductive organs, cancer of the digestive tract, cancer of the urinary tract, cancer of the eye, cancer of the liver, cancer of the skin, cancer of the head and neck, cancer of the thyroid gland, cancer of the parathyroid gland and their distant metastases. Those disorders also include lymphomas, sarcomas and leukemias.

[0398] Examples of breast cancer include, but are not limited to, triple-negative breast cancer, invasive ductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ and lobular carcinoma in situ.

[0399] Examples of respiratory tract cancer include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenoma and pleuropulmonary blastoma.

[0400] Examples of cancer of the brain include, but are not limited to, brain stem and hypothalamic glioma, cerebellar and cerebral astrocytoma, glioblastoma, medulloblastoma, ependymal tumors, as well as neuroectodermal and pineal tumors.

[0401] Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer.

[0402] Tumors of the female reproductive organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer and vulvar cancer, as well as uterine sarcoma.

[0403] Examples of ovarian cancer include, but are not limited to, serous tumors, endometrioid tumors, mucinous cystadenocarcinomas, granulosa cell tumors, Sertoli-Leydig cell tumors and androblastomas.

[0404] Examples of cervical cancer include, but are not limited to, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumor, clear cell carcinoma and villoglandular adenocarcinoma.

[0405] Gastrointestinal tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small bowel cancer, and salivary gland cancer.

[0406] Examples of esophageal cancer include, but are not limited to, esophageal cell carcinoma and adenocarcinoma, as well as squamous cell carcinoma, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, and lymphoma.

[0407] Examples of gastric cancer include, but are not limited to, intestinal and diffuse type gastric adenocarcinoma.

[0408] Examples of pancreatic cancer include, but are not limited to, ductal adenocarcinoma, adenosquamous carcinoma, and pancreatic endocrine tumors.

[0409] Urinary tract tumors include, but are not limited to, bladder, penis, kidney, renal pelvis, ureter, urethra, and human papillary renal carcinoma.

[0410] Examples of kidney cancer include, but are not limited to, renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal oncocytoma, Bellini duct carcinoma, renal clear cell sarcoma, mesoblastic nephroma, and nephroblastoma.

[0411] Examples of bladder cancer include, but are not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma.

[0412] Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0413] Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variant), cholangiocarcinoma (intrahepatic bile duct carcinoma), and mixed hepatocellular cholangiocarcinoma.

[0414] Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0415] Head and neck cancers include, but are not limited to, head and neck squamous cell carcinoma, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer, and squamous cell carcinoma.

[0416] Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and central nervous system lymphoma.

[0417] Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0418] Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia.

[0419] The term "treating" or "treatment" is used throughout the present text in the conventional sense, e.g. to manage or care for a subject for the purpose of combating, reducing, diminishing, alleviating, ameliorating the condition of a disease or disorder, e.g. cancer.

[0420] The compounds of the present application are particularly useful for the treatment and prevention, i.e. prophylaxis, of tumor growth and metastasis, especially in solid tumors in all indications and stages with or without pre-treatment of tumor growth.

[0421] Generally, the use of a chemotherapeutic agent and / or anticancer agent in combination with the compounds or pharmaceutical compositions of the present application will help to:

[0422] 1. produce better efficacy in reducing tumor growth or even eliminating tumors compared to administration of either agent alone,

[0423] 2. provide for administration of less of the chemotherapeutic agent,

[0424] 3. provide for well-tolerated chemotherapy in patients with fewer adverse pharmacological complications than observed with single agent chemotherapy and certain other combination therapies,

[0425] 4. provide for a broader range of different cancer types to be treated in mammals, especially humans,

[0426] 5. provide for a higher response rate in treated patients,

[0427] 6. provide for a longer survival time in treated patients compared to standard chemotherapy treatments,

[0428] 7. provide for a longer time to tumor progression, and / or

[0429] 8. result in at least as good efficacy and tolerability results as the agents used alone compared to the known situation of antagonistic effects with other cancer agents.

[0430] In addition, the compounds of general formula (I) of the present application can also be used in combination with radiotherapy and / or surgery.

[0431] In another embodiment of the present application, the compounds of general formula (I) of the present application can be used to sensitize cells to radiation, i.e. the cells are treated with a compound of the present application prior to the radiation treatment of the cells, such that the cells are more sensitive to DNA damage and cell death compared to cells that have not been treated with a compound of the present application at all. In one aspect, the cells are treated with at least one compound of general formula (I) of the present application.

[0432] Thus, the present application also provides a method of killing cells, wherein the cells are administered one or more compounds of the present application in combination with conventional radiotherapy.

[0433] The present application also provides methods of sensitizing a cell to cell death, wherein the cell is treated with one or more compounds of the present application of general formula (I) prior to treating the cell to cause or induce cell death. In one aspect, the cell is treated with at least one compound, or at least one method, or a combination thereof, to cause DNA damage after the cell is treated with one or more compounds of the present application of general formula (I) in order to inhibit the function of a normal cell or to kill the cell.

[0434] In other embodiments of the present application, the cell is killed by treating the cell with at least one DNA damaging agent, i.e., after the cell is treated with one or more compounds of the present application of general formula (I) to sensitize the cell to cell death, the cell is treated with at least one DNA damaging agent to kill the cell. DNA damaging agents useful in the present application include, but are not limited to, chemotherapeutic agents (e.g., cisplatin), ionizing radiation (X-rays, ultraviolet radiation), carcinogens, and mutagens.

[0435] In other embodiments, the cell is killed by treating the cell with at least one method to cause or induce DNA damage. Such methods include, but are not limited to, activating a cellular signaling pathway that results in DNA damage when the pathway is activated, inhibiting a cellular signaling pathway that results in DNA damage when the pathway is inhibited, and inducing a biochemical change in the cell wherein the change results in DNA damage. By way of non-limiting example, a DNA repair pathway in the cell can be inhibited, thereby preventing repair of DNA damage and resulting in abnormal accumulation of DNA damage in the cell.

[0436] In one aspect of the present application, a compound of the present application of general formula (I) is administered to the cell prior to radiation or other cellular DNA damage induction. In another aspect of the present application, a compound of the present application of general formula (I) is administered to the cell concurrently with radiation or other cellular DNA damage induction. In yet another aspect of the present application, a compound of the present application of general formula (I) is administered to the cell immediately after the initiation of radiation or other cellular DNA damage induction.

[0437] In another aspect, the cell is in vitro. In another embodiment, the cell is in vivo.

[0438] The compounds of the present application can be administered as the sole agents or in combination with one or more other pharmaceutically active ingredients, where the combination causes no unacceptable adverse effects. Pharmaceutical combinations are also encompassed by the present application. For example, the compounds of the present application can be combined with 131I-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, aminolevulinic acid hexylester, amrubicin, amsacrine, anastrozole, anecortave, anethole dithiolethione, anetumab ravtansine, angiotensin II, antithrombin III, arginovare, aselizumab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecan, bendamustine, bendoitumomab, belinostat, bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonin, calcium folinate, calcium levofolinate, capecitabine, capromab, carmofur, carmustine, catumaxomab, celecoxib, celmoleukin, ceritinib, cetuximab, chlorambucil, chlormadinone, chlormethine, cidofovir, cinacalcet, cisplatin, cladribine, clodronic acid, clofarabine, copanlisib, crisantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, depodeotide, deslorelin, diflucortolone, dienestriol, dienol, diclofenac, dinutuximab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, eculizumab, edrecolomab, edrophonium, elotuzumab, eltrombopag,Endostatin, enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alpha, epoetin beta, epoetin zeta, erbitux, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, filgrastim, fluoxymesterone, floxuridine, fludarabine, fluorouracil, flutamide, folinic acid, formestane, fosaprepitant, fotemustine, fulvestrant, gadobutrol, gadodiamide, gadofosveset, gadopentetic acid, gadoxetate, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, carboxypeptidase, glutoxim, GM-CSF, goserelin, granisetron, granulocyte colony-stimulating factor, histamine dihydrochloride, histrelin, hydroxycarbamide, I-125 seed, lansoprazole, ibandronic acid, ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisuban, incadronic acid, ingenol mebutate, interferon alpha, interferon beta, interferon gamma, iobitridol, iobenguane (123I), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lasocholine, lenalidomide, lenvatinib, leograstim, lentinan, letrozole, leuprolide, levamisole, levonorgestrel, levothyroxine sodium, lysuride, meplatin, lomustine, masoprocol, medroxyprogesterone, megestrol, melarsoprol, melarsone, mercaptopurine, mesna, methadone, methotrexate, methoxsalen, methyl aminolevulinate, methylprednisolone, methyltestosterone, metirosine, mifamurtide, mitoguazone, miriplatin, mitobronitol, mitobronito, mitomycin, mitotane, mitoxantrone, mogamulizumab, movelthromb, morphine hydrochloride, morphine sulfate, nabiximols, nafarelin, naloxone + azoxystrobin, naltrexone, nagrestip, nacolomab tafenatox, nedaplatin, nelarabine, neridronic acid, nelfintrantel / palonosetron, nivolumab, neovastat, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustine, nintedanib, nitraerine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaratumab,homoharringtonine, omeprazole, octreotide, oprelvekin, oragen, orilotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicin, p53 gene therapy, paclitaxel, palbociclib, pallifermin, palladium-103 seeds, palonosetron, pamidronic acid, panitumumab, pariprostil, pantoprazole, pazopanib, pegaspargase, PEG-betaheraperitn (methoxy PEG-betaheraperitn), pembrolizumab, pegfilgrastim, peginterferon alfa-2b, pembrolizumab, letrozole, pentoxyverine, pentostatin, perlomycin, perfluorobutane, perfosfamide, pertuzumab, picibanil, pilocarpine, pirarubicin, picibanil, plerixafor, plicamycin, poliglusam, polyestradiol phosphate, polvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, ramucirumab, ramucirumab, ranimustine, rasburicase, refametinib, regorafenib, risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romosozumab, roniciclib, samarium-153 lexidronate, sargramostim, satumomab, secretin, siltuximab, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole, sonidegib, sorafenib, stanozolol, streptozocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol, tasonermin, teceleukin, technetium [99mTc] meridulant, technetium-99m-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone,Tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alfa, tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trabectedin, trametinib, tramadol, trastuzumab, trastuzumab-emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinib, triplatin, thrombopoietin, tryptophan, ubenimex, vatalanib, valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vindesine, vindesine, vinorelbine, vismodegib, vorinostat, vorozole, yttrium-90 microspheres, zinostatin, zinecard, zoledronic acid, zorubicin.

[0439] The compounds of the present application can further be combined with other agents targeting the immune system, such as immune checkpoint inhibitors, e.g. PD-1 / -L1 axis antagonists.

[0440] PD-1 and its ligands PD-L1 and PD-L2 act as negative regulators of T cell activation. AHR inhibits immune cell function while increasing cancer cell proliferation and motility. PD-L1 is overexpressed in many cancers and overexpression of PD-1 often accompanies tumor-infiltrating T cells. This leads to a weakening of T cell activation and evasion of immune surveillance, which results in an impaired anti-tumor immune response (Keir M E et al. (2008) Annu. Rev. Immunol. 26:677).

[0441] Simultaneous targeting of the PD-1 / -L1 axis and AHR enhances the anti-tumor immune response more than in an additive manner, leading to an unexpected reduction of tumor growth.

[0442] Thus, compositions comprising a PD-1 / -L1 axis antagonist and an AHR antagonist are surprisingly effective in enhancing the immune response and in the treatment of cancer.

[0443] Furthermore, the compounds of the present application can also be used as therapeutic agents for various other disorders in which AHR is involved, such as cardiovascular and pulmonary diseases.

[0444] Thus, the compounds according to the present application are suitable for the treatment and / or prophylaxis of, in particular, cardiovascular, inflammatory and fibrotic disorders, and renal disorders, in particular acute and chronic renal insufficiency, and acute and chronic renal failure.

[0445] Therefore, the compounds according to the application can be used in a medicament for the treatment and / or prevention of cardiovascular, inflammatory and fibrotic disorders, renal disorders, in particular acute and chronic renal insufficiency, and acute and chronic renal failure.

[0446] For the purposes of the present application, the term renal insufficiency includes both acute and chronic manifestations of renal insufficiency, as well as underlying or associated renal disorders, such as diabetic and non-diabetic nephropathies, hypertensive nephropathy, ischemic nephropathy, renal hypoperfusion, intradialytic hypotension, obstructive uropathy, renal stenosis, glomerulopathy, glomerulonephritis, for example, primary glomerulonephritis; minimal change glomerulonephritis (lipoid nephrosis); membranous glomerulonephritis; focal segmental glomerulosclerosis (FSGS); membranoproliferative glomerulonephritis; crescentic glomerulonephritis; mesangial proliferative glomerulonephritis (IgA nephritis, Berger's disease); post-infectious glomerulonephritis; secondary glomerulonephritis: diabetes mellitus, lupus erythematosus, amyloidosis, Goodpasture's syndrome, Wegener's granulomatosis, purpura, microscopic polyangiitis, acute glomerulonephritis, pyelonephritis (for example due to: urolithiasis, benign prostatic hypertrophy, diabetes mellitus, malformations, misuse of analgesics, Crohn's disease), glomerulosclerosis, arteriolonephrosclerosis, tubulointerstitial disease, nephropathies such as primary and congenital or acquired nephropathies, Alport's syndrome, nephritis, immune renal disorders such as renal transplant rejection and immune complex-induced renal disorders, nephropathies induced by toxic substances, nephropathies induced by contrast agents, diabetic and non-diabetic nephropathies, renal cysts, renal fibrosis, hypertensive renal fibrosis and nephrotic syndrome, which is characterized, for example at the diagnostic level, by an abnormal decrease in the excretion of creatine and / or water, an abnormal increase in the blood concentration of urea, nitrogen, potassium and / or creatine, a change in the activity of renal enzymes such as glutamyl synthetase, a change in the osmolarity of the urine or in the urine volume, an increase in microalbuminuria, massive proteinuria, lesions on the glomeruli and small arteries, tubular dilation, hyperphosphatemia and / or the need for dialysis. The present application also includes the use of the compounds according to the application for the treatment and / or prevention of the sequelae of renal insufficiency, such as pulmonary edema, heart failure, uremia, anemia, electrolyte disorders (for example hypercalcemia, hyponatremia) and disorders of bone and carbohydrate metabolism.

[0447] The compounds according to the application are also suitable for use in the treatment and / or prevention of polycystic kidney disease (PCKD) and the syndrome of inappropriate ADH secretion (SIADH).

[0448] Furthermore, the compounds according to the application are also suitable for the treatment and / or prophylaxis of metabolic syndrome, hypertension, resistant hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiovascular disorders, cardiac arrhythmias, atrial and ventricular arrhythmias and impaired conduction, such as I-III degree atrioventricular block (AB block I-III), supraventricular tachyarrhythmias, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmias, torsade de pointes, atrial and ventricular extrasystoles, AV-nodal extrasystoles, sick sinus syndrome, syncope, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune heart disorders (pericarditis, endocarditis, valvulitis, aortitis, cardiomyopathy), shock such as cardiogenic shock, septic shock and anaphylactic shock, aneurysm, boxer dog cardiomyopathy (ventricular premature contractions (PVC)), for the treatment and / or prophylaxis of thromboembolic disorders and ischemias such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular disorders, coronary and peripheral arterial spasm, edema formation such as pulmonary edema, cerebral edema, renal edema or edema due to heart failure, peripheral circulation disorders, reperfusion injury, arterial and venous thrombosis, myocardial insufficiency, endothelial dysfunction, to prevent restenosis, for example after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), heart transplantation and bypass surgery, as well as micro- and macrovascular damage (angitis), elevated fibrinogen and low-density lipoprotein (LDL) levels and increased concentrations of plasminogen activator inhibitor 1 (PAI-1), also for the treatment and / or prophylaxis of erectile dysfunction and female sexual dysfunction.

[0449] Furthermore, the compounds according to the application are also suitable for the treatment and / or prophylaxis of asthma disorders, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including pulmonary hypertension associated with left heart disease, HIV, sickle cell anemia, thromboembolic pulmonary hypertension (CTEPH), sarcoidosis, COPD or pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), alpha-1-antitrypsin deficiency (AATD), pulmonary fibrosis, emphysema (e.g. emphysema caused by cigarette smoke) and cystic fibrosis (CF).

[0450] The compounds described in the present application are also active compounds for the control of central nervous system disorders characterized by disorders of the NO / cGMP system. They are particularly suitable for improving perception, concentration, learning or memory after cognitive impairment, for example particularly those which occur in connection with conditions / diseases / syndromes such as mild cognitive impairment, age-related impairment of learning and memory, age-related memory loss, vascular dementia, craniocerebral trauma, stroke, dementia occurring after stroke (post-stroke dementia), post-traumatic craniocerebral trauma, general impairment of concentration, impairment of concentration in children with learning and memory problems, Alzheimer's disease, Lewy body dementia, dementia with frontotemporal degeneration including Pick's syndrome, Parkinson's disease, progressive dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, demyelination, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia or Korsakoff's psychosis. They are also suitable for the treatment and / or prevention of central nervous system disorders such as states of anxiety, tension and depression, CNS-related sexual dysfunction and sleep disorders, and for the control of pathological disorders of the intake of food, stimulants and addictive substances.

[0451] Furthermore, the compounds according to the application are also suitable for the control of cerebral blood flow and thus represent effective agents for the control of migraine. They are also suitable for the prevention and control of the sequelae of cerebral infarction (stroke), such as stroke, cerebral ischaemia and craniocerebral trauma. The compounds according to the application can likewise be used for the control of states of pain and tinnitus.

[0452] Furthermore, the compounds according to the application have anti-inflammatory effects and can thus be used as anti-inflammatory agents for the treatment and / or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory disorders of the kidney, chronic intestinal inflammation (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatic disorders, inflammatory skin disorders and inflammatory eye disorders.

[0453] Furthermore, the compounds according to the application can also be used for the treatment and / or prevention of autoimmune diseases.

[0454] The compounds according to the application are also suitable for the treatment and / or prevention of fibrotic disorders of internal organs such as the lung, heart, kidney, bone marrow and in particular the liver, and dermatological fibroplasia and fibrotic eye disorders. In the context of the present application, the term fibrotic disorders includes in particular the following terms: liver fibrosis, cirrhosis of the liver, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage caused by diabetes, myelofibrosis and similar fibrotic disorders, scleroderma, sclerodermia, keloids, hypertrophic scars (also after surgical interventions), nevi, diabetic retinopathy, proliferative vitreoretinopathy and connective tissue disorders (for example sarcoidosis).

[0455] The compounds according to the application are also suitable for the control of postoperative scar formation, for example as a result of glaucoma surgery.

[0456] The compounds according to the application can also be used cosmetically for aged and keratinized skin.

[0457] Furthermore, the compounds according to the application are suitable for the treatment and / or prevention of hepatitis, neoplasms, osteoporosis, glaucoma and gastroparesis.

[0458] The present application further provides the use of a compound according to the application for the treatment and / or prevention of a disorder, in particular of the disorders mentioned above.

[0459] The present application further provides the use of a compound according to the application for the treatment and / or prevention of chronic kidney disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive renal disease, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemia, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anaemia, erectile dysfunction, benign prostatic hyperplasia, dysuria associated with benign prostatic hyperplasia, Huntington's disease, dementia, Alzheimer's disease and Creutzfeldt-Jakob disease.

[0460] The present application further provides a method for the treatment and / or prevention of a disorder, in particular of the disorders mentioned above, using an effective amount of at least one compound according to the application.

[0461] The present application further provides a method for the treatment and / or prevention of chronic kidney disorders, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive renal disease, fibrotic disorders, cardiac insufficiency, angina pectoris, hypertension, pulmonary hypertension, ischaemia, vascular disorders, thromboembolic disorders, arteriosclerosis, sickle cell anaemia, erectile dysfunction, benign prostatic hyperplasia, dysuria associated with benign prostatic hyperplasia, Huntington's disease, dementia, Alzheimer's disease and Creutzfeldt-Jakob disease.

[0462] In another embodiment, the compounds according to the application can also be used for the treatment or prevention of uterine fibroids (uterine leiomyoma or uterine myoma) in women.

[0463] Uterine fibroids are benign tumors of the myometrium, the smooth muscle layer of the uterus. Uterine fibroids grow slowly in a woman's life, their growth is dependent on the female sex hormones estradiol and progesterone [Kawaguchi K et al. Immunohistochemical analysis of oestrogen receptors, progesterone receptors and Ki-67 in leiomyoma and myometrium during the menstrual cycle and pregnancy Virchows Arch A Pathol Anat Histopathol. 1991; 419(4): 309-15.], thus the prevalence of uterine fibroids is highest from the age of 35 to menopause (uterine fibroids shrink due to decreasing hormone levels), with about 70% and >80% of white and US black women, respectively [Baird DD et al. High cumulative incidence of uterine leiomyoma in black and white women: Ultrasound evidence Am J Obstet Gynecol. 2003 Jan; 188(1): 100-7.]. About 30% and 45% of white and US black women, respectively, develop clinically relevant symptoms from their fibroids, these symptoms are menorrhagia and menstrual cycle-related pain [David M et al. Myoma-associated pain frequency and intensity: a retrospective evaluation of 1548 myoma patients. Eur J Obstet Gynecol Reprod Biol. 2016 Apr; 199: 137-40]. In this regard, the definition of menorrhagia is a loss of blood of more than 80 mL during menstrual bleeding [Fraser IS et al. The FIGO Recommendations on Terminologies and Definitions for Normal and Abnormal Uterine Bleeding, Semin Reprod Med 2011; 29(5): 383-390].Submucosal location of uterine fibroids, such as those located just beneath the endometrium, seem to have a more severe impact on uterine bleeding, which can lead to anemia in affected women [Yang JH et al. Impact of submucous myoma on the severity of anemia. Fertil Steril. 2011 Apr;95(5): 1769-72]. Furthermore, uterine fibroids severely impact the quality of life of affected women due to their symptoms [Downes E et al. The burden of uterine fibroids in five European countries. Eur J Obstet Gynecol Reprod Biol. 2010 Sep;152(1):96-102].

[0464] So far, it is not clear how uterine fibroids cause heavy menstrual bleeding. Dysregulated genes in uterine fibroids compared to normal myometrium can provide hints to understand the underlying mechanisms. In published and in-house studies, we found that TDO2 tryptophan 2,3-dioxygenase is highly upregulated [Tsibris JC et al. Insights from gene arrays on the development and growth regulation of uterine leiomyomata. Fertil Steril. 2002 Jul;78(1): 114-21.]. TDO2 metabolizes the substrate L-tryptophan to L-kynurenine, which can be further metabolized to kynurenic acid. Both L-kynurenine and kynurenic acid are physiological ligands and activators of the aryl hydrocarbon receptor AHR [Opitz CA et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor Nature. 2011 Oct 5;478(7368): 197-203].

[0465] L-kynurenine controls at least two physiological processes that are dysregulated in uterine fibroids. By upregulating L-kynurenine, which is synthesized by IDO (indoleamine-2,3-dioxygenase) or TDO2 and acts through the AHR receptor, the immune system is suppressed, preventing immune cells from recognizing and clearing tumor cells [Munn DH Blocking IDO activity to enhance anti-tumor immunity. Front Biosci (Elite Ed). 2012 Jan 1 ;4:734-45]. In addition, upregulation of L-kynurenine leads to vasodilation of blood vessels, thus can directly increase blood loss and hemorrhage [Wang Y et al. Kynurenine is an endothelium-derived relaxing factor produced during inflammation Nature Medicine 16, 279-285 (2010)].

[0466] In summary, upregulation of L-kynurenine by activation of its physiological receptor AHR appears to support uterine fibroid growth by locally suppressing the immune system, and can cause menorrhagia by vasodilation of endometrial blood vessels near the tumor.

[0467] Therefore, systemic or local application of the compounds of the present invention inhibits the activation of AHR and thus blocks the effects of L-kynurenine derived from uterine fibroids provides a new and effective treatment option for uterine fibroids.

[0468] The compounds of the present invention can be used to inhibit, block, reduce or decrease the activation of AHR by exogenous and / or endogenous ligands to reduce tumor growth and modulate dysregulated immune responses, for example to block immune suppression and increase immune cell activation and infiltration in the context of cancer and cancer immunotherapy. The method comprises administering to a mammal, including a human in need thereof, an amount of a compound of the present invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof; which is effective in treating such a condition.

[0469] The present invention also provides methods of treating a variety of other conditions in which AHR is involved, for example but not limited to inflammation, infection and vaccination against cancer, viral infection, obesity and diet-induced obesity, lipomatosis, metabolic disorders, liver steatosis and uterine fibroids.

[0470] These conditions have been well characterized in humans, but similar etiologies exist in other mammals and can be treated by administration of a pharmaceutical composition of the present invention.

[0471] The term "treating" or "treatment" as used herein is used in the conventional sense, e.g., to manage or care for a subject in an effort to combat, reduce, decrease, alleviate, relieve, improve, or slow the progression of a disease or condition, such as a liquid and solid tumor.

[0472] According to a further aspect, the present application covers the use of a compound of general formula (I) as described above or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate and a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the treatment or prophylaxis of a disease, particularly a cancer or a condition with a dysregulated immune response associated with aberrant AHR signaling or other disorders, particularly liquid and solid tumors.

[0473] The pharmaceutical activity of the compounds according to the present application can be explained by their activity as AHR inhibitors.

[0474] According to a further aspect, the present application covers the use of a compound of general formula (I) as described above or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate and a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the treatment or prophylaxis of a disease, particularly a cancer or a condition with a dysregulated immune response associated with aberrant AHR signaling or other disorders, particularly liquid and solid tumors.

[0475] According to a further aspect, the present application covers the use of a compound of general formula (I) as described above or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate and a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the treatment or prophylaxis of a disease, particularly a cancer or a condition with a dysregulated immune response associated with aberrant AHR signaling or other disorders, particularly liquid and solid tumors.

[0476] According to a further aspect, the present application covers the use of a compound of general formula (I) as described above or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate and a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the treatment or prophylaxis of a disease, particularly a cancer or a condition with a dysregulated immune response associated with aberrant AHR signaling or other disorders, particularly liquid and solid tumors.

[0477] According to a further aspect, the present application covers the use of a compound of general formula (I) as described above or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate and a salt thereof, particularly a pharmaceutically acceptable salt thereof, or a mixture of same, for the treatment or prophylaxis of a disease, particularly a cancer or a condition with a dysregulated immune response associated with aberrant AHR signaling or other disorders, particularly liquid and solid tumors.

[0478] According to a further aspect, the present application covers the use of an effective amount of a compound of general formula (I) as described above, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, and a salt, particularly a pharmaceutically acceptable salt, thereof, or a mixture of thereof, for the treatment or prophylaxis of a disease, particularly a cancer associated with aberrant AHR signaling or a condition with dysregulated immune response or other disorders, particularly liquid and solid tumors.

[0479] According to a further aspect, the present application covers a pharmaceutical composition, particularly a medicament, comprising a compound of general formula (I) as described above, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt, particularly a pharmaceutically acceptable salt, thereof, or a mixture of thereof, and one or more excipients, particularly one or more pharmaceutically acceptable excipients. The conventional procedures for the preparation of such pharmaceutical compositions in suitable dosage forms can be used.

[0480] The present application also covers pharmaceutical compositions, particularly medicaments, comprising at least one compound according to the present application, usually together with one or more pharmaceutically suitable excipients, and their use for the above-mentioned purposes.

[0481] The compounds according to the present application can have systemic and / or local activity. For this purpose, they can be administered in a suitable manner, for example, by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, aural route or as an implant or stent.

[0482] For these administration routes, the compounds according to the present application can be administered in suitable administration forms.

[0483] For oral administration, the compounds according to the present application can be formulated in dosage forms known in the art for rapid and / or modified delivery of the compounds of the present application, such as tablets (uncoated or coated tablets, e.g., with enteric or controlled release coatings for delayed or sustained dissolution), orodispersible tablets, films / sheets, films / lyophylisates, capsules (e.g., hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. The compounds according to the present application can be incorporated into the dosage forms in crystalline and / or amorphous and / or dissolved form.

[0484] Parenteral administration can bypass the absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal or intralumbar) or include absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal) to take effect. Administration forms suitable for parenteral administration are, in particular, injection or infusion preparations in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.

[0485] Examples of other routes of administration include drug forms for inhalation [especially powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets / films / sheets / capsules for tongue, sublingual or sublingual administration; suppositories; eye drops, eye ointments, eye baths, eye inserts, ear drops, ear sprays, ear powders, ear washes, earplugs; vaginal capsules, aqueous suspensions (washes, shaken mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapy systems (e.g., patches), emulsions, pastes, foams, powders, implants or stents.

[0486] The compounds according to the invention can be incorporated into the described formulation. This can be achieved in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients particularly include

[0487] • Fillers and carriers (e.g., cellulose, microcrystalline cellulose, e.g., ... ), lactose, mannitol, starch, calcium phosphate (e.g., for example, )),

[0488] • Ointment base (e.g., petrolatum, paraffin, triglycerides, wax, lanolin, lanolin alcohol, hydrophilic ointments, polyethylene glycol),

[0489] • Suppository base (e.g., polyethylene glycol, cocoa butter, stearate),

[0490] Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycol, paraffin),

[0491] Surfactants, emulsifiers, dispersants or wetting agents (e.g., sodium lauryl sulfate), lecithin, phospholipids, fatty alcohols (e.g., ... ), dehydrated sorbitan fatty acid esters (e.g., for example, ), polyoxyethylene dehydrated sorbitan fatty acid esters (e.g., for example, ), polyoxyethylene fatty acid glycerides (e.g., for example, ), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamer (e.g., for example, ),

[0492] • Buffers, acids and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, tromethamine, triethanolamine),

[0493] • Isotonic agents (e.g., glucose, sodium chloride),

[0494] • Adsorbent (e.g., highly dispersed silica),

[0495] • viscosity-increasing agents, gel formers, thickening agents and / or binding agents (e.g. polyvinylpyrrolidone, methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, starch, carbomer, polyacrylic acid (e.g. eudragit®), ); alginate, gelatin),

[0496] • disintegrants (e.g. modified starch, sodium carboxymethyl cellulose, sodium starch glycolate (e.g. explotab®, ), cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose (e.g. crospovidone®, )),

[0497] • flow regulators, lubricants, glidants and release agents (e.g. magnesium stearate, stearic acid, talc, highly dispersed silicon dioxide (e.g. aerosil®, )),

[0498] • coating materials (e.g. sugar, shellac) and film formers for rapidly or modified dissolution or diffusion membranes (e.g. polyvinylpyrrolidone (e.g. povidone®, ), polyvinyl alcohol, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylate, polymethacrylate (e.g. eudragit®, )),

[0499] • capsule materials (e.g. gelatin, hydroxypropyl methyl cellulose),

[0500] • synthetic polymers (e.g. polylactide, polyglycolide, polyacrylate, polymethacrylate (e.g. eudragit®, ), polyvinylpyrrolidone (e.g. povidone®, ), polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, polyethylene glycol and copolymers and block copolymers thereof),

[0501] • plasticizers (e.g. polyethylene glycol, propylene glycol, glycerol, triacetin, triacetyl citrate, dibutyl phthalate),

[0502] • penetration enhancers,

[0503] • stabilizers (e.g. antioxidants, e.g. ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),

[0504] • preservatives (e.g. parabens, sorbic acid, thiomerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

[0505] • colorants (e.g. inorganic pigments, such as iron oxides, titanium dioxide),

[0506] • flavoring agents, sweeteners, taste- and / or odor-masking agents.

[0507] The present application also relates to pharmaceutical compositions comprising at least one compound according to the present application, usually together with one or more pharmaceutically suitable excipients, and their use according to the present application.

[0508] According to another aspect, the present application encompasses a pharmaceutical combination, in particular a medicament, comprising at least one compound of general formula (I) of the present application and at least one or more further active ingredients, in particular for the treatment and / or prevention of cancer or conditions with dysregulated immune responses or other disorders generally associated with aberrant AHR signaling, in particular liquid and solid tumors.

[0509] The term "combination" in the present application can be a fixed combination, a non- fixed combination or a kit-of-parts, as known to the person skilled in the art.

[0510] A "fixed combination" in the present application is defined as a combination, wherein, e.g., the first active ingredient, such as one or more compounds of general formula (I) of the present application, and the further active ingredient(s) are present together in one unit dosage or one single entity, as known to the person skilled in the art. One example of a "fixed combination" is a pharmaceutical composition, wherein the first active ingredient and the further active ingredient are present in admixture for simultaneous administration, e.g. in a formulation. Another example of a "fixed combination" is a pharmaceutical combination, wherein the first active ingredient and the further active ingredient are present in one unit, but not in admixture.

[0511] A non-fixed combination or "kit-of-parts" in the present application is defined as a combination, wherein the first active ingredient and the further active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination, wherein the first active ingredient and the further active ingredient are present separately. The components of a non-fixed combination or kit-of-parts can be administered separately, sequentially, simultaneously, jointly or chronologically staggered.

[0512] Based upon the known assays available to evaluate compounds useful in treating cancers or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, treatment of the above-identified conditions in mammals is determined by standard toxicity tests and by standard pharmacological assays, and by comparing these results with those of known active ingredients or drugs used to treat these conditions, the effective dosage of a compound of this application for treatment of each of the desired indications can be readily determined. The amount of active ingredient administered will vary depending upon such factors as the particular compound employed and the dose unit employed, the mode of administration, the period of treatment, the age and sex of the patient, and the nature and severity of the condition being treated, among others.

[0513] The total quantity of active ingredient to be administered will generally range from about 0.001 mg / kg to about 200 mg / kg body weight per day, preferably from about 0.01 mg / kg to about 20 mg / kg body weight per day. Clinically useful dosing schedules range from one to three doses per day to one dose per week, with the exception of eye and ear drops, which are typically used more frequently. In addition, "drug holidays" are possible, where the patient does not take the drug for a certain period of time, to facilitate the overall balance between pharmacological effect and tolerability. Unit dosages can contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. Average daily doses administered by injection (including intravenous, intramuscular, subcutaneous, and parenteral injections) and using infusion techniques will preferably be from 0.01 to 200 mg / kg of total body weight. Average daily rectal dosage regimens will preferably be from 0.01 to 200 mg / kg of total body weight. Average daily vaginal dosage regimens will preferably be from 0.01 to 200 mg / kg of total body weight. Average daily topical dosage regimens will preferably be from 0.1 to 200 mg applied one to four times per day. Transdermal concentrations will preferably be those required to sustain a daily dose of 0.01 to 200 mg / kg. Average daily inhalation dosage regimens will preferably be from 0.01 to 100 mg / kg of total body weight.

[0514] Of course, the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition, as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, the dosing history of the patient, and drug combinations, among other factors. The skilled artisan will be able to determine needed treatment regimens and the number of doses of a compound of this application or a pharmaceutically acceptable salt or ester thereof or composition using routine treatment.

[0515] Examples

[0516] Experimental Section

[0517] NMR peak forms are stated as they appear in the spectrum, without consideration of possible higher order effects. The multiplicity is stated according to the signal form appearing in the spectrum, without consideration of higher order NMR spectral effects. Multiplicity of NMR signals: s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, br = broad signal, m = multiplet. NMR signals: displacement in [ppm]. Combinations of multiplicities can be, for example, dd = doublet of doublets.

[0518] Chemical names were generated using ACD / Labs' ACD / Name software. In some cases, commonly accepted names of commercially available reagents were used instead of the names generated by ACD / Name.

[0519] Table 1 lists the abbreviations used in this paragraph and in the example section, as far as they are not explained in the text. Other abbreviations have their meaning as it is customary for the person skilled in the art.

[0520] Table 1 : Abbreviations

[0521] ACN acetonitrile

[0522] AcOH acetic acid

[0523] CDCl3 deuterated chloroform

[0524] DAD diode array detector

[0525] DEA diethylamine

[0526] DMF N,N-dimethylformamide

[0527] DMSO-d6 deuterated dimethyl sulfoxide

[0528] DMSO dimethyl sulfoxide

[0529] ELSD evaporative light scattering detector

[0530] ESIpos positive ion electrospray ionization

[0531] Expl. example

[0532] HATU (7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate

[0533] HBTU O-benzotriazol-N,N,N',N'-tetramethyluronium hexafluorophosphate

[0534] HPLC high pressure liquid chromatography

[0535] KA kynurenic acid

[0536] LCMS liquid chromatography mass spectrometry

[0537] LPS lipopolysaccharide

[0538] mL milliliter

[0539] min. minute

[0540] MTBE methyl tert-butyl ether

[0541] PBMC peripheral blood mononuclear cell

[0542] PyBOB (benzotriazol-1-yl)oxytripyrrolidinophosphonium hexafluorophosphate

[0543] RP-HPLC reverse phase high pressure liquid chromatography

[0544] Rt retention time

[0545] rt room temperature

[0546] sat. saturated

[0547] T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide

[0548] THF tetrahydrofuran

[0549] TFA trifluoroacetic acid

[0550] TLC thin layer chromatography

[0551] TNFα tumor necrosis factor alpha

[0552] pM micromole

[0553] UPLC ultra performance liquid chromatography.

[0554] The various aspects of the application described in this application are illustrated by the following examples, which are not meant to limit the application in any way.

[0555] The experimental examples described herein were used to illustrate the application, and the application is not limited to the examples given.

[0556] Experimental Section - General

[0557] All reagents not described in the experimental section were either commercially available or known compounds or could be formed from known compounds by known methods by one skilled in the art.

[0558] Compounds and intermediates prepared according to the methods of the present application can require purification. Purification of organic compounds is well known to those skilled in the art and there can be several methods of purifying the same compound. In some cases, purification can not be required. In some cases, compounds can be purified by crystallization. In some cases, impurities can be stirred out using a suitable solvent. In some cases, compounds can be purified by chromatography, particularly flash column chromatography, using, for example, pre-packed silica gel cartridges, such as Biotage SNAP cartridges or and Biotage automated purification systems or Isolera and eluents such as gradient hexanes / ethyl acetate or DCM / methanol. In some cases, compounds can be purified by preparative HPLC using, for example, a Waters autopurifier equipped with a diode array detector and / or an online electrospray ionization mass spectrometer, and suitable pre-packed reverse phase columns and eluents such as gradient water and acetonitrile, possibly containing additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

[0559] In some cases, the purification methods as described above can provide those compounds of the present application having sufficiently basic or acidic functional groups in salt form, for example trifluoroacetate or formate salts in the case of sufficiently basic compounds of the present application, or, for example, ammonium salts in the case of sufficiently acidic compounds of the present application. Salts of this type are readily converted into their free base or free acid forms, respectively, by the techniques known to those skilled in the art, or used in the salt form in subsequent biological assays. It is understood that the specific forms (e.g., salts, free bases, etc.) of the compounds of the present application as isolated and described herein are not necessarily the only forms in which the compounds described therein can be used in biological assays to quantify a particular biological activity.

[0560] Experimental Section - Intermediates

[0561] Intermediate 1

[0562] 1-(1-Methyl-1H-pyrazol-4-yl)hydrazine-1,2-dicarboxylic acid di-tert-butyl ester

[0563]

[0564] To a solution of 1.5 g of 4-bromo-1-methyl-1H-pyrazole in 30 mL of tetrahydrofuran (30 mL) cooled to -78°C was added 1.7 mL of n-butyllithium (2 M in THF). After stirring at -78°C for 30 minutes, a solution of 2.1 g of di-tert-butyl azodicarboxylate in 10 mL of tetrahydrofuran was added dropwise. After 1 hour, the reaction mixture was warmed to -20°C and quenched with ice. After warming to ambient temperature, the mixture was filtered and rinsed with tetrahydrofuran. The resulting solid was dissolved in a mixture of dichloromethane and water, and the mixture was phase separated. After evaporation in vacuo, the residue was subjected to column chromatography (petroleum ether / ethyl acetate 2:1) to give 800 mg of di-tert-butyl 1-(1-methyl-1H-pyrazol-4-yl)hydrazine-1,2-dicarboxylate.

[0565] 1 H-NMR: (300 MHz, 25°C, methanol-d4): δ [ppm] = 1.44 (s, 18H); 3.77 (s, 3H); 7.17-7.28 (m, 1H); 7.61-7.67 (m, 1H); 9.60 (s, 1H).

[0566] Intermediate 2

[0567] 4-hydrazinyl-1-methyl-1H-pyrazole trifluoroacetate salt (1:1)

[0568]

[0569] A mixture of 800 mg of intermediate 1 in 15 mL of dichloromethane and 1 mL of trifluoroacetic acid was stirred at room temperature for 3 hours. The mixture was evaporated to dryness to give 750 mg (crude) of product which was used directly in the next step without further purification.

[0570] 1 H-NMR: (300 MHz, 25°C, DMSO-d6): δ [ppm] = 3.79 (s, 3H); 7.33 (s, 1H); 7.57 (s, 1H); 9.49 (br s, 3H).

[0571] Intermediate 3

[0572] [2-(4-methylphenyl)-2-oxoethyl]propanedioic acid dimethyl ester

[0573]

[0574] A solution of 49.6 g of 2-bromo-1-(4-methylphenyl)ethanone in 300 mL of acetone was added dropwise to a solution of 10 g of dimethyl malonate in 120 mL of acetone at room temperature. The reaction mixture was stirred at room temperature for 4 hours. Then, the solvent was removed in vacuo. The residue was purified by column chromatography (petroleum ether / ethyl acetate 10:1) to give 10.3 g of [2-(4-methylphenyl)-2-oxoethyl]dimethyl malonate.

[0575] 1 H-NMR: (400 MHz, 25 °C, DMSO-d6): δ [ppm] = 2.38 (s, 3H); 3.60 (d, 2H); 3.68 (s, 6H); 3.97 (t, 1H); 7.34 (d, 2H); 7.89 (d, 2H).

[0576] Intermediate 4

[0577] 6-(4-Methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4- carboxylic acid methyl ester

[0578] A mixture of 818 mg of intermediate 3 and 700 mg of intermediate 2 in 20 mL of ethanol was stirred at 80 °C for 2 hours. Then, the solvent was removed in vacuo. The residue was purified by column chromatography (petroleum ether / ethyl acetate 3:2) to give 500 mg of 6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester.

[0579] 1 H-NMR: (400 MHz, 25 °C, CDCl3): δ [ppm] = 2.41 (s, 3H); 3.14 (dd, 1H); 3.51 (dd, 1H); 3.76 (dd, 1H); 3.79 (s, 3H); 3.91 (s, 3H); 7.27 (d, 2H, signal partially below the CDCl3 signal); 7.74 (d, 2H); 7.87 (s, 1H); 8.00 (s, 1H).

[0580] Intermediate 5

[0581] 6-(4-Methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0582]

[0583] A mixture of 450 mg of intermediate 4 and 371 mg of copper (II) chloride in 20 mL of acetonitrile was stirred at 90 °C for 2 hours. After evaporation in vacuo, the residue was purified by column chromatography (dichloromethane / methanol 20:1) to give 380 mg of methyl 6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate.

[0584] 1 H-NMR: (400 MHz, 25 °C, DMSO-d6): δ [ppm] = 2.37 (s, 3H); 3.88 (s, 3H); 3.91 (s, 3H); 7.34 (d, 2H); 7.93 (d, 2H); 8.08 (s, 1H); 8.40 (s, 1H); 8.49 (s, 1H).

[0585] Intermediate 6

[0586] 6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0587]

[0588] A mixture of 380 mg of intermediate 5 in 30 mL of acetonitrile was treated with 147 mg of lithium hydroxide and dissolved in 2 mL of water. The reaction mixture was stirred at room temperature for 3 hours. The pH value was then adjusted to 5-6 with hydrochloric acid (10%). The solid was collected by filtration, washed with water three times and dried in an oven to give 310 mg of 6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid.

[0589] 1 H-NMR: (400 MHz, 25 °C, DMSO-d6): δ [ppm] = 2.37 (s, 3H); 3.91 (s, 3H); 7.32 (d, 2H); 7.89 (d, 2H); 7.95 (s, 1H); 8.04 (s, 1H); 8.40 (s, 1H).

[0590] Intermediate 7

[0591] 6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid chloride

[0592]

[0593] To a solution of 180 mg of intermediate 6 in 10 mL of dichloromethane and 0.1 mL of N,N-dimethylformamide was added slowly 110 mg of oxalyl chloride. The reaction mixture was stirred at 0°C for 1 hour. The mixture was evaporated to dryness to give 260 mg of crude 6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carbonyl chloride which was used directly in the next step without further purification.

[0594] Intermediate 8

[0595] [2-(4-chlorophenyl)-2-oxoethyl]dimethyl propanedioate

[0596]

[0597] Dissolve 2-chloro-1-(4-chlorophenyl)ethanone (25 g, 107.1 mmol) in acetone (500 mL). Then, add dimethyl propanedioate (31.1 g, 235.4 mmol) and potassium carbonate (22.2 g, 160.6 mmol) at room temperature. Stir it overnight at room temperature. Reduce the reaction mixture under vacuum to half its volume. Then, pour the residue into water. Separate the layers and extract the aqueous phase twice with ethyl acetate. Wash the combined organic layers with water and concentrated aqueous sodium chloride solution, dry over sodium sulfate and concentrate. Purify the crude product by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to give 12.21 g (36%) of the title product.

[0598] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.63 (d, 2H), 3.68 (s, 6H), 3.97 (t, 1H), 7.59-7.64 (m, 2H), 7.99-8.03 (m, 2H).

[0599] Intermediate 9

[0600] 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4- carboxylic acid methyl ester

[0601]

[0602] Dissolve [2-(4-chlorophenyl)-2-oxoethyl] dimethyl malonate (1360 mg, 4.78 mmol) and sodium acetate (1037 mg, 12.65 mmol) in acetic acid (40 mL). Then, add 4-hydrazinyl-l-methyl-lH-pyrazole dihydrochloride (780 mg, 4.22 mmol) portionwise. Stir at room temperature for 1 hour and at 50 °C for 20 hours. Cool the reaction mixture and concentrate on a rotary evaporator under reduced pressure. Add ethyl acetate and water to dissolve the residue. Add concentrated aqueous sodium bicarbonate solution, separate the phases, and extract the aqueous layer with ethyl acetate (four times, 80 mL). Dry the combined organic layers over magnesium sulfate and concentrate. Purify the residue by flash chromatography (silica gel, hexanes / ethyl acetate, gradient) to give 530 mg (36%) of the title product.

[0603] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.35-3.46 (m, 2H), 3.68 (s, 3H), 3.85 (s, 3H), 4.03 (dd, 1H), 7.52-7.57 (m, 2H), 7.75 (d, 1H), 7.92-7.96 (m, 2H), 8.08 (s, 1H).

[0604] Intermediate 10

[0605] 6-(4-Chlorophenyl)-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4- carboxylic acid methyl ester

[0606]

[0607] Dissolve 6-(4-chlorophenyl)-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-2,3,4,5- tetrahydropyridazine-4-carboxylic acid methyl ester (600 mg, 1.730 mmol) in acetonitrile (40 mL). Add copper dichloride (698 mg, 5.191 mmol). Stir at 90 °C for 4 hours. Cool and concentrate on a rotary evaporator. Add water, suction filter the remaining solid, wash with water five times, and dry under vacuum at 50 °C to give 741 mg of the title compound, which is used without further purification in the next step.

[0608] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.35-3.46 (m, 2H), 3.68 (s, 3H), 3.85 (s, 3H), 4.03 (dd, 1H), 7.52-7.57 (m, 2H), 7.75 (d, 1H), 7.92-7.96 (m, 2H), 8.08 (s, 1H).

[0609] Intermediate 11

[0610] 6-(4-chlorophenyl)-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4- carboxylic acid

[0611]

[0612] Methyl 6-(4-chlorophenyl)-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylate (600 mg, 1.74 mmol) was dissolved in acetonitrile (60 mL). A solution of lithium hydroxide (125 mg, 5.221 mmol) in water (1.90 mL) was added at room temperature. It was stirred at 40 °C for 10 hours. Water was added and the pH was adjusted to 4 with 2N HC1. The precipitate was suction filtered, washed with water three times and dried under vacuum at 50 °C to give 520 mg (90%) of the title compound which was used in the next step without further purification.

[0613] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.91 (s, 3H), 7.54 (br d, 2H), 7.78 (s, 1H), 8.00-8.07 (m, 3H), 8.41 (s, 1H).

[0614] Intermediate 12

[0615] Methyl 6-(4-chlorophenyl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

[0616]

[0617] Methyl 6-(4-chlorophenyl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

[0618] 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.16 (dd, 1 H), 3.26 (dd, 1 H), 3.67 (s, 3H), 3.75 (dd, 1 H), 7.47-7.52 (m, 2H), 7.75-7.79 (m, 2H), 11.31 (s, 1 H).

[0619] Intermediate 13

[0620] 6-(4-Chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0621]

[0622] Methyl 6-(4-chlorophenyl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate (4.97 g, 18.64 mmol) was dissolved in acetonitrile (350 mL). Copper dichloride (6.26 g, 46.59 mmol) was added and stirred at 70 °C for 5.5 hours. Then, additional copper dichloride (0.626 g, 4.66 mmol) was added and stirring was continued at 70 °C for 1 hour. The reaction mixture was cooled and concentrated on a rotary evaporator to half its volume. Water (300 mL) was added and the reaction mixture was stirred for 10 minutes. The precipitate was suction filtered, washed with water three times, and dried under vacuum at 50 °C to yield 4.793 g (97%) of the title compound.

[0623] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.85 (s, 3H), 7.53-7.58 (m, 2H), 7.89-7.93 (m, 2H), 8.38 (s, 1 H), 13.70 (s, 1 H).

[0624] Intermediate 14

[0625] {2-Oxo-2-[4-(trifluoromethyl)phenyl]ethyl}propanedioic acid dimethyl ester

[0626]

[0627] Dimethyl malonate (9.894 g, 74.89 mmol) and potassium carbonate (7.763 g, 56.17 mmol) were added to acetone (140 mL). A solution of 2-bromo-l-[4-(trifluoromethyl)phenyl]ethanone (10 g, 37.4 mmol) in acetone (60 mL) was added dropwise with cooling (0-5 °C). It was stirred for 2 hours at 0-5 °C and overnight at room temperature. The volatile compounds were removed on a rotary evaporator. Water and ethyl acetate were added, the layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with concentrated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to give 8.03 g (67%) of the title product.

[0628] 1 H-NMR (400 MHz, chloroform-d3): δ [ppm] = 3.65 (d, 2H), 3.79 (s, 6H), 4.10 (t, 1H), 7.73-7.77 (m, 2H), 8.07-8.11 (m, 2H).

[0629] Intermediate 15

[0630] 3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[0631]

[0632] Dimethyl {2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl}malonate (5.68 g, 17.55 mmol) was dissolved in acetic acid (64 mL). Hydrazine in THF (35 mL, 1.0 M, 35 mmol) was added at room temperature. It was stirred for 3.5 hours at 75 °C. Then, hydrazine in THF (3.5 mL, 1.0 M, 3.5 mmol) was added and stirring was continued for 1 hour at 75 °C. The reaction mixture was cooled and water (0.6 L) was added. The precipitate was suction filtered, washed with water and dried in vacuum at 50 °C to give 4.06 g (76%) of the title compound which was used without further purification in the next step.

[0633] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.23 (dd, 1H), 3.28-3.36 (m, 1H and water signal), 3.68 (s, 3H), 3.79 (dd, 1H), 7.80 (d, 2H), 7.96 (d, 2H), 11.43 (s, 1H).

[0634] Intermediate 16

[0635] 3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0636]

[0637] Methyl 3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3,4,5-tetrahydropyridazine-4-carboxylate (4.06 g, 13.52 mmol) was dissolved in acetonitrile (180 mL). Copper dichloride (4.55 g, 33.81 mmol) was added and stirred at 90 °C for 2.5 hours. The reaction mixture was cooled and concentrated on a rotary evaporator to half its volume. Water (350 mL) was added and the reaction mixture was stirred for 10 minutes. The precipitate was suction filtered, washed with water three times, and dried under vacuum at 50 °C to yield 3.67 g (91%) of the title compound.

[0638] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.86 (s, 3H), 7.86 (d, 2H), 8.11 (d, 2H), 8.45 (s, 1H), 13.83 (s, 1H).

[0639] Intermediate 17

[0640] Methyl 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3- dihydropyridazine-4-carboxylate

[0641]

[0642] Methyl 3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylate (0.5 g, 1.68 mmol) was dissolved in DMF (26.6 mL). 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (698 mg, 3.53 mmol), 2,2'-bipyridine (655 mg, 4.19 mmol), cesium bicarbonate (390 mg, 2.01 mmol), and anhydrous copper diacetate (380.7 mg, 2.10 mmol) were added. This was stirred at room temperature for 21 hours. 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (349 mg, 1.68 mmol) was added and stirring was continued overnight at room temperature. Water (5 mL) was added and the pH was adjusted to 3 with 2N HCl (3.5 mL). The precipitate was filtered, washed with water three times, and dried under vacuum at 50 °C to yield 594 mg (63%) of the title compound.

[0643] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.89 (s, 3H), 3.92 (s, 3H), 7.88 (br d, 2H), 8.11 (s, 1H), 8.28 (br d, 2H), 8.52 (s, 1H), 8.52 (s, 1H).

[0644] Intermediate 18

[0645] 2-(1 -Methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3- dihydropyridazine-4-carboxylic acid

[0646]

[0647] Methyl 2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3- dihydropyridazine-4-carboxylate (590 mg, 1.56 mmol) was dissolved in acetonitrile (54 mL). A solution of lithium hydroxide (112 mg, 4.70 mmol) in water (1.7 mL) was added at room temperature. This was stirred at room temperature for 3 hours. Water (100 mL) was added and the pH was adjusted to 6 with 2N HCI. The precipitate was suction filtered, washed with water and dried under vacuum at 50 °C to give 345 mg (45%) of the title compound which was used in the next step without further purification.

[0648] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.89 (s, 3H), 3.92 (s, 3H), 7.88 (br d, 2H), 8.11 (s, 1H), 8.28 (br d, 2H), 8.52 (s, 1H), 8.52 (s, 1H).

[0649] Intermediate 19

[0650] 6-(4-Chlorophenyl)-2-(1 -cyclobutyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4- carboxylic acid

[0651]

[0652] Step 1 : 6-(4-Chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester (0.5 g, 1.89 mmol) was dissolved in DMF (15 mL). 1 -Cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H- pyrazole (1406 mg, 5.67 mmol), 2,2'-bipyridine (737.7 mg, 4.72 mmol), sodium bicarbonate (318 mg, 3.78 mmol) and anhydrous copper diacetate (429 mg, 3.79 mmol) were added. It was stirred at room temperature for 96 h. Water was added and the pH was adjusted to 3 with 2N HCI. The precipitate was filtered, washed with water three times and dried under vacuum at 50 °C to give 370 mg (36%) of the methyl ester which was used in the next step without further purification.

[0653] Step 2: The ester (293 mg, 0.76 mmol) was dissolved in acetonitrile (16.7 mL). A solution of lithium hydroxide (55 mg, 2.28 mmol) in water (0.65 mL) was added at room temperature. It was stirred at room temperature overnight. Water was added and the pH was adjusted to 6 with 2N HCI. The precipitate was filtered off, washed with water and dried under vacuum at 50 °C to give 93 mg (33%) of the title compound which was used in the next step without further purification.

[0654] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.750 x 2.1 mm; Eluent A: water + 0.2 vol% ammonia water (32%), Eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t = 0.64 min; MS (ESI pos): m / z = 371.3 [M+H] + .

[0655] Intermediate 20

[0656] {2-Oxo-2-[4-(trifluoromethoxy)phenyl]ethyl} dimethyl propanedioate

[0657]

[0658] To a solution of 4.1 g dimethyl malonate and 3.2 g potassium carbonate in 110 mL acetone was added 4.4 g 2-bromo-1-[4-(trifluoromethoxy)phenyl]ethan-1-one. The reaction mixture was stirred at room temperature overnight, then quenched with water. The acetone was evaporated and the remaining aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (hexane / ethyl acetate, gradient up to 30% ethyl acetate) to give 4.9 g {2-oxo-2-[4-(trifluoromethoxy)phenyl]ethyl}dimethyl malonate.

[0659] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: water + 0.1 vol-% formic acid (99%) Eluent B: acetonitrile; Gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t = 1.22 min; MS (ESI pos): m / z = 335 [M+H] + .

[0660] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.33 (s, 6H), 3.62-3.67 (m, 2H), 3.99 (t, 1 H), 7.52 (dd, 2H), 8.1 1 -8.16 (m, 2H).

[0661] Intermediate 21

[0662] 2-(1 -Methyl-1 H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3,4,5- tetrahydropyridazine-4-carboxylic acid methyl ester

[0663] A mixture of 954 mg {2-[4-(difluoromethoxy)phenyl]-2-oxoethyl} dimethyl propanedioate, 1111 mg 4-hydrazinyl-1-methyl-1H-pyrazole dihydrochloride and 1053 mg sodium acetate in 27 mL AcOH was stirred at room temperature for 14 hours and at 50 °C for 6 hours. The reaction mixture was concentrated, the residue was dissolved in water and ethyl acetate and then saturated aqueous sodium bicarbonate solution was added. The phases were separated, the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography (hexane / ethyl acetate, gradient up to 80% ethyl acetate) to give 559 mg methyl 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3,4,5-tetrahydropyridazine-4-carboxylate.

[0664] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.40-3.43 (m, 2H), 3.69 (s, 3H), 3.85 (s, 3H), 4.04 (t, 1H), 7.48 (d, 2H), 7.75 (s, 1H), 8.04 (d, 2H), 8.08 (s, 1H).

[0665] Intermediate 22

[0666] 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0667] A mixture of 686 mg methyl 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3,4,5-tetrahydropyridazine-4-carboxylate and 698 mg copper(II) chloride in 23 mL acetonitrile was stirred at 50 °C for 2 hours and at 90 °C for 3 hours. After evaporation in vacuo, the residue was suspended in water and the precipitate was filtered off to give 528 mg methyl 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylate.

[0668] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.89 (s, 3H), 3.92 (s, 3H), 7.52 (d, 2H), 8.09 (s, 1H), 8.15-8.20 (m, 2H), 8.46 (s, 1H), 8.51 (s, 1H).

[0669] Intermediate 23

[0670] 2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3- dihydropyridazine-4-carboxylic acid

[0671] A mixture of 528 mg of 2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid methyl ester and 1.7 mL of 2N sodium hydroxide in water in 7 mL of tetrahydrofuran was stirred at room temperature for 14 hours. The pH was then adjusted to 3 with 1 M hydrochloric acid, the precipitate was filtered off, washed with water and dried under vacuum to give 458 mg of 2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid.

[0672] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.92 (s, 3H), 7.51 (d, 2H), 8.11 (s, 1H), 8.17-8.24 (m, 2H), 8.42 (s, 1H), 8.52 (s, 1H).

[0673] Intermediate 24

[0674] {2-[4-(Difluoromethyl)phenyl]-2-oxoethyl}dimethyl propanedioate

[0675]

[0676] A mixture of 2.5 g of 2-bromo-1-[4-(difluoromethyl)phenyl]ethanone (CAS 1227004-73-0), 4.6 mL of dimethyl propanedioate and 2.1 g of potassium carbonate in 70 mL of acetone was stirred at room temperature for 14 hours. After complete conversion (TLC), the reaction mixture was poured into water and the acetone was evaporated under reduced pressure. The resulting solution was extracted three times with ethyl acetate and the combined organic phases were washed with water and brine and the solvent was evaporated under vacuum. The residue was purified by column chromatography (hexane / ethyl acetate gradient to 40% ethyl acetate) to give 1.45 g of {2-[4-(difluoromethyl)phenyl]-2-oxoethyl}dimethyl propanedioate.

[0677] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm] = 3.64-3.70 (m, 8H); 4.00 (t, 1H); 7.15 (t, 1H); 7.74 (d, 2H); 8.12 (d, 2H).

[0678] Intermediate 25

[0679] 6-[4-(difluoromethyl)phenyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[0680]

[0681] A mixture of 75 mg {2-[4-(difluoromethyl)phenyl]-2-oxoethyl}dimethyl propanedioate, 44 mg 4-hydrazinyl-l-methyl-lH-pyrazole dihydrochloride and 53 mg sodium acetate in 2.5 mL AcOH was stirred at room temperature for 1 h and at 50 °C for 24 h. Another 88 mg 4-hydrazinyl-l-methyl-lH-pyrazole dihydrochloride was added and the reaction mixture was stirred at 50 °C for 6 h. The reaction mixture was concentrated, the residue was dissolved in water and ethyl acetate and then saturated aqueous sodium bicarbonate solution was added. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by HPLC (Instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm x 30 mm, eluent A: 0.1 vol% formic acid / water, eluent B: acetonitrile; gradient: A 85% / B 15% -> A 45% / B 55%; flow rate: 150 mL / min; UV-detection: 254 nm) to give 24 mg 6-[4-(difluoromethyl)phenyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester.

[0682] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.43 (dd, 2H), 3.69 (s, 3H), 3.85 (s, 3H), 4.02-4.08 (m, 1H), 7.11 (t, 1H), 7.68 (d, 2H), 7.76 (s, 1H), 8.06 (d, 2H), 8.09 (s, 1H).

[0683] Intermediate 26

[0684] 6-[4-(difluoromethyl)phenyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylic acid methyl ester

[0685]

[0686] A mixture of 495 mg of 6-[4-(difluoromethyl)phenyl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester and 551 mg of copper (II) chloride in 15 mL of acetonitrile was stirred at 90 °C for 2 hours. After evaporation in vacuo, the residue was suspended in water, the precipitate was filtered off to give 451 mg of 6-[4-(difluoromethyl)phenyl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester.

[0687] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.89 (s, 3H), 3.92 (s, 3H), 7.13 (t, 1 H), 7.72 (d, 2H), 8.11 (s, 1 H), 8.20 (d, 2H), 8.48 (s, 1 H), 8.52 (s, 1 H).

[0688] Intermediate 27

[0689] 6-[4-(Difluoromethyl)phenyl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylic acid

[0690]

[0691] A mixture of 451 mg of 6-[4-(difluoromethyl)phenyl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester and 6 mL of 1 N sodium hydroxide solution in water in 19 mL of tetrahydrofuran was stirred at room temperature for 48 hours. The pH value was then adjusted to 3 with 1 M hydrochloric acid, the precipitate was filtered off, washed with water and dried in vacuo to give 190 mg of 6-[4-(difluoromethyl)phenyl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid.

[0692] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.93 (s, 3H), 7.13 (t, 1 H), 7.72 (d, 2H), 8.13 (s, 1 H), 8.23 (d, 2H), 8.49 (s, 1 H), 8.54 (s, 1 H).

[0693] Intermediate 28

[0694] {2-[6-(Difluoromethyl)pyridin-3-yl]-2-oxoethyl}dimethyl propanedioate

[0695]

[0696] A mixture of 5 g of 2-bromo-1-[6-(difluoromethyl)pyridin-3-yl]ethanone, 4.5 mL of dimethyl malonate and 4.1 g of potassium carbonate in 140 mL of acetone was stirred at room temperature for 14 hours. After complete conversion (TLC), the reaction mixture was poured into water and the acetone was evaporated under reduced pressure. The resulting solution was extracted three times with ethyl acetate and the combined organic phases were washed with water and brine and the solvent was evaporated under vacuum. The residue was purified by column chromatography (dichloromethane / methanol gradient to 20% methanol) to give 1.1 g of {2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl}dimethyl malonate.

[0697] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.69 (s, 6H), 3.74 (d, 2H), 4.01 (t, 1H), 7.07 (t, 1H), 7.87 (d, 1H), 8.53 (dd, 1H), 9.24 (d, 1H).

[0698] Intermediate 29

[0699] 6-[6-(Difluoromethyl)pyridin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[0700] A mixture of 424 mg of {2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl}dimethyl malonate, 549 mg of 4-hydrazinyl-1-methyl-1H-pyrazole dihydrochloride and 520 mg of sodium acetate in 13 mL of AcOH was stirred at room temperature for 1 hour and at 50°C for 2 hours. The reaction mixture was concentrated, the residue was dissolved in water and ethyl acetate and then a saturated aqueous solution of sodium bicarbonate was added. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by column chromatography (dichloromethane / methanol gradient to 8% methanol) to give 240 mg of 6-[6-(difluoromethyl)pyridin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester.

[0701] 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.39 - 3.56 (m, 2H), 3.70 (s, 3H), 3.85 (s, 3H), 4.05 - 4.12 (m, 1H), 7.04 (t, 1H), 7.77 - 7.83 (m, 2H), 8.12 (s, 1H), 8.49 (dd, 1H), 9.19 (d, 1H).

[0702] Intermediate 30

[0703] 6-[6-(difluoromethyl)pyridin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylic acid

[0704] A mixture of 240 mg of 6-[6-(difluoromethyl)pyridin-3-yl]-2-(1-methyl-1H-pyrazol-4- yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester and 266 mg of copper (II) chloride in 9 mL of acetonitrile was stirred at 90 °C for 2 hours. After evaporation in vacuo, the residue was suspended in water, the precipitate was filtered off and dried to give 184 mg of 6-[6-(difluoromethyl)pyridin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylic acid methyl ester.

[0705] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.89 (s, 3H), 3.91 (s, 3H), 7.05 (t, 1H), 7.83 (d, 1H), 8.13 (s, 1H), 8.54 (d, 2H), 8.63 (dd, 1H), 9.33 (d, 1H).

[0706] Intermediate 31

[0707] 6-[6-(difluoromethyl)pyridin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylic acid

[0708] A mixture of 133 mg of 6-[6-(difluoromethyl)pyridin-3-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester and 0.46 mL of 2N aqueous sodium hydroxide solution in 2 mL of tetrahydrofuran was stirred at room temperature for 14 hours. The pH was then adjusted to 3 with 1 M hydrochloric acid, the precipitate was filtered off, washed with water and dried in vacuo to give 103 mg of 6-[6-(difluoromethyl)pyridin-3-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid.

[0709] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.93 (s, 3H), 6.91 - 7.21 (m, 1H), 7.84 (d, 1H), 8.16 (s, 1H), 8.55 (d, 2H), 8.66 (dd, 1H), 9.36 (d, 1H).

[0710] Intermediate 32

[0711] 5-bromo-2-(difluoromethyl)pyridine

[0712]

[0713] Into a 2000 mL 4-necked round bottom flask was placed a solution of 5-bromopyridine-2-carboxaldehyde (30 g, 161.29 mmol, 1.00 equiv) in dichloromethane (800 mL). Then DAST (diethylaminosulfur trifluoride) (40 g, 1.08 mol, 6.69 equiv) was added dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 12 hours. Then the reaction was quenched by the addition of water. The pH of the solution was adjusted to 8 with sodium carbonate (2 mol / L). The resulting solution was extracted with 3 x 500 mL dichloromethane and the organic layers were combined. The resulting mixture was washed with 1 x 300 mL H20. The resulting mixture was washed with 1 x 300 mL brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1 :10). This resulted in 18 g (54%) of 5-bromo-2-(difluoromethyl)pyridine as a yellow oil.

[0714] Intermediate 33

[0715] 1-[6-(difluoromethyl)pyridin-3-yl]ethanone

[0716]

[0717] Into a 500 mL 4-necked round bottom flask was placed a solution of 5-bromo-2- (difluoromethyl)pyridine (18 g, 86.54 mmol, 1.00 equiv) in dioxane (180 mL), tributyl(1- ethoxyvinyl)tin (35 g, 96.91 mmol, 1.12 equiv), tetrakis(triphenylphosphine)palladium (3 g, 2.60 mmol, 0.03 equiv). The resulting solution was stirred at 100 °C for 2 h. The reaction mixture was cooled with a water bath. The reaction was then quenched by the addition of 250 mL of 2N HC1. The pH of the solution was adjusted to 8 with sodium carbonate (2 mol / L). The resulting solution was extracted with 3 x 500 mL of ethyl acetate and the organic layers were combined. The resulting mixture was washed with 1 x 200 mL of H2O. The resulting mixture was washed with 1 x 200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:10). This resulted in 10 g (68%) of 1-[6-(difluoromethyl)pyridin-3-yl]ethan-1-one as a yellow oil.

[0718] Intermediate 34

[0719] {2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl}(hydroxy)propanedioic acid diethyl ester

[0720]

[0721] Into a 100 mL round bottom flask was placed 1-[6-(difluoromethyl)pyridin-3-yl]ethan-1-one (10 g, 58.43 mmol, 1.00 equiv) and 1,3-diethyl 2-oxopropanedioate (15 g, 86.13 mmol, 1.47 equiv). The resulting solution was stirred at 130 °C for 24 h. The resulting mixture was concentrated under vacuum. This resulted in 24 g (crude) of 2-[2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl]-2-hydroxypropanedioic acid 1,3-diethyl ester as a red oil, which was used without further purification.

[0722] Intermediate 35

[0723] 6-[6-(difluoromethyl)pyridin-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0724]

[0725] Into a 500 mL round bottom flask was placed a solution of 2-[2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl]-2-hydroxypropanedioic acid 1,3-diethyl ester (24 g, 69.51 mmol, 1.00 equiv) in ethanol (200 mL) and hydrazine (15 mL). The resulting solution was stirred at 80 °C for 12 hours. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3 x 300 mL ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x 100 mL water. The resulting mixture was washed with 1 x 100 mL brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (2:1). This resulted in 2.8 g (14%) of 6-[6-(difluoromethyl)pyridin-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid ethyl ester as a yellow solid.

[0726] 1 H-NMR (300 MHz, DMSO-d6) δ [ppm] = 13.84 (s, 1H), 9.17 (s, 1H), 8.46 (m, 2H), 7.83 (m, 1H), 7.03 (t, 1H), 4.35 (m, 2H), 1.33 (t, 3H).

[0727] Intermediate 36

[0728] 6-(4-Chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[0729]

[0730] [2-(4-chlorophenyl)-2-oxoethyl] dimethyl malonate (1.88 g, 6.60 mmol) and sodium acetate (3.25 g, 39.62 mmol) were dissolved in acetic acid (50 mL). Then, 3-hydrazinylpyridine hydrochloride (1 :1) (0.961 g, 6.60 mmol) was added portionwise. This was stirred at room temperature for 24 hours. Further 3-hydrazinylpyridine hydrochloride (1 :1) (0.961 g, 6.60 mmol) was added and stirring was continued at room temperature for 24 hours. Then, again 3-hydrazinylpyridine hydrochloride (1 :1) (0.961 g, 6.60 mmol) was added and this was stirred at room temperature for 24 hours. Finally, this was stirred at 80 °C for 7 hours. The reaction mixture was cooled and concentrated on a rotary evaporator under reduced pressure. Ethyl acetate and water were added to dissolve the residue. Concentrated aqueous sodium bicarbonate solution was added, the phases were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed three times with water, dried over magnesium sulfate and concentrated. The residue was purified by RP-HPLC (column: YMC-Triart CI 5 pm 100 x 50 mm, mobile phase: (water + 0.1 vol% formic acid (99%)) / acetonitrile, gradient) to give 398 mg (18%) of the title product.

[0731] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.43 (dd, 1 H), 3.50 (dd, 1 H), 3.71 (s, 3H), 4.11 (dd, 1 H), 7.51 (ddd, 1 H), 7.51 - 7.56 (m, 2H), 7.86 - 7.90 (m, 2H), 7.97 (ddd, 1 H), 8.50 (dd, 1 H), 8.77 (d, 1 H).

[0732] Intermediate 37

[0733] 6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0734]

[0735] Step 1 : 6-(4-Chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3,4,5-tetrahydropyridazine-4- carboxylic acid methyl ester (1.0 g, 2.909 mmol) was dissolved in acetonitrile (60 mL). Copper dichloride (1.173 g, 8.727 mmol) was added. It was stirred at 90 °C for 4 hours. It was cooled and concentrated on a rotary evaporator. Water was added and the remaining solid was suction filtered, washed with water five times, and dried under vacuum at 50 °C for 24 hours to give 1.262 g of 6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid methyl ester which was used in the next step without further purification.

[0736] Step 2: 6-(4-Chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid methyl ester (1.00 g, 2.93 mmol) was dissolved in acetonitrile (100 mL). A solution of lithium hydroxide (210 mg, 8.778 mmol) in water (3.2 mL) was added at room temperature. It was stirred at 40 °C for 10 hours. Water was added and the pH was adjusted to 6-7 with 0.5 N HC1. The precipitate was suction filtered, washed with water three times, and dried under vacuum at 50 °C to give 910 mg (95%) of the title compound which was used in the next step without further purification.

[0737] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.54 (br d, 2H), 7.59 (dd, 1H), 7.90-7.99 (m, 3H), 8.11 (br d, 1H), 8.63 (br d, 1H), 8.88 (br d, 1H).

[0738] Intermediate 38

[0739] 2-(2-(4-Chlorophenyl)-2-oxoethyl)-2-hydroxypropanedioic acid diethyl ester

[0740]

[0741] A mixture of 4-chloroacetophenone (30 g, 194.8 mmol) and diethyl ketomalonate (45 mL, 292.2 mmol) was heated at 130 °C for 48 hours. The reaction was monitored by TLC and upon completion, the reaction mixture was cooled and triturated with pentane to give 2-(2-(4-chlorophenyl)-2-oxoethyl)-2-hydroxypropanedioic acid diethyl ester (50 g, 79%, LC-MS 98%) as a light yellow liquid.

[0742] Intermediate 39

[0743] 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0744]

[0745] A mixture of 2-(2-(4-chlorophenyl)-2-oxoethyl)-2-hydroxypropanedioic acid diethyl ester (50 g, 152.43 mmol) and hydrazine dihydrochloride (19.2 g, 182.9 mmol) in ethanol (500 mL) was heated at reflux for 16 h. The reaction was monitored by TLC. Upon completion, the reaction mixture was cooled and concentrated under reduced pressure. The reaction mixture was poured into saturated sodium bicarbonate solution (500 mL) and extracted with ethyl acetate (3 x 600 mL). The combined organic layers were washed with water, brine, dried over Na2S04, filtered and concentrated under reduced pressure to get the crude product. The crude product was purified by column chromatography (silica gel, eluent EtOAc / hexane 30:70) to get 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid ethyl ester (21 g, 42%, LC-MS 95%) as a light yellow solid.

[0746] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 1.31 (t, 3H), 4.31 (q, 2H), 7.53-7.60 (m, 2H), 7.87-7.95 (m, 2H), 8.34 (s, 1H), 13.68 (br s, 1H).

[0747] Intermediate 40

[0748] 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0749]

[0750] Methyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (682.3 mg, 2.578 mmol) was dissolved in DMF (27 mL). 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1150 mg, 5.156 mmol), 2,2'-bipyridine (1007 mg, 6.445 mmol), sodium carbonate (328 mg, 3.093 mmol) and anhydrous copper diacetate (585 mg, 3.222 mmol) were added. It was stirred at 40 °C for 5 hours. The reaction mixture was cooled, water was added and the pH was adjusted to 3 with 2N HCI. The precipitate was filtered, washed with water and dried under vacuum at 50 °C. The crude material was purified by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to give 174 mg (13%) of the title compound.

[0751] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.89 (s, 3H), 7.57-7.61 (m, 2H), 7.99-8.04 (m, 2H), 8.23 (ddd, 1 H), 8.54 (s, 1 H), 8.72 (dd, 1 H), 8.86 (br t, 1 H).

[0752] Intermediate 41

[0753] 6-(4-Chlorophenyl)-2-(5-fluoropyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0754]

[0755] Methyl 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4- carboxylate (170 mg, 0.473 mmol) was dissolved in THF (8 mL). A solution of lithium hydroxide (34 mg, 1.418 mmol) in water (0.40 mL) was added at room temperature. It was stirred at room temperature for 24 hours. Water was added, the pH was adjusted to 6 with 2N HCI. The precipitate was filtered off, washed with water and dried under vacuum at 50 °C to give 157 mg (96%) of the title compound which was used without further purification in the next step.

[0756] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.56-7.60 (m, 2H), 8.01-8.06 (m, 2H), 8.24 (dt, 1 H), 8.51 (s, 1 H), 8.73 (d, 1 H), 8.87 (s, 1 H).

[0757] Intermediate 42

[0758] 3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0759]

[0760] Methyl 3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylate (2 g, 6.71 mmol) was dissolved in DMF (90 mL). 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (2.75 g, 13.41 mmol), 2,2'-bipyridine (2.62 g, 16.77 mmol), sodium carbonate (0.85 g, 8.02 mmol) and anhydrous copper diacetate (1.52 g, 8.37 mmol) were added. This was stirred at 60 °C for 3 hours. The reaction mixture was cooled with an ice bath, water (240 mL) was added and the pH was adjusted to 3 with 2N HCI (20 mL). The precipitate was filtered, washed with water and dried under vacuum at 50 °C to give 1.8 g (72%) of the title compound.

[0761] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.89 (s, 3H), 7.62 (dd, 1 H), 7.88 (d, 2H), 8.15-8.21 (m, 3H), 8.60 (s, 1 H), 8.68 (br d, 1 H), 8.93 (br s, 1 H).

[0762] Intermediate 43

[0763] 3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylic acid

[0764]

[0765] Methyl 3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4- carboxylate (1.80 g, 4.80 mmol) was dissolved in THF (28 mL). Lithium hydroxide (345 mg, 23.95 mmol) in water (5 mL) was added at room temperature. It was stirred at room temperature overnight. Water (100 mL) was added and pH was adjusted to 6 with 2N HC1 (4.5 mL). Dichloromethane (50 mL) and chloroform (50 mL) were added to the reaction mixture. The organic layer was separated and discarded. The precipitate was suction filtered, washed with water and dried under vacuum at 50 °C to get 1036 mg (60%) of the title compound which was used for the next step without further purification.

[0766] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.60 (dd, 1 H), 7.84 (d, 2H), 8.02 (s, 1 H), 8.10-8.18 (m, 3H), 8.64 (d, 1 H), 8.89 (d, 1 H).

[0767] Intermediate 44

[0768] Hydroxy {2-oxo-2-[4-(trifluoromethoxy)phenyl]ethyl}propanedioic acid diethyl ester

[0769]

[0770] A mixture of 1-(4-(trifluoromethoxy)phenyl)ethanone (20 g, 98.03 mmol) and diethyl ketomalonate (23 mL, 147.02 mmol) was heated at 130 °C for 48 h, the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0-5 °C and triturated with petroleum ether to get diethyl 2-hydroxy-2-(2-oxo-2-(4-(trifluoromethoxy)phenyl)ethyl)propanedioate 3 (35 g, 94%, LC-MS 98%) as a pale yellow liquid.

[0771] Intermediate 45

[0772] 3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0773]

[0774] A mixture of 2-hydroxy-2-(2-oxo-2-(4-(trifluoromethoxy)phenyl)ethyl)malonic acid diethyl ester (35 g, 92.5 mmol) and hydrazine dihydrochloride (10.6 g, 101.31 mmol) in ethanol (350 mL) was heated to reflux for 16 h and the reaction was monitored by TLC. On completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure, pH was adjusted to 7 using saturated aqueous sodium bicarbonate solution (150 mL) and extracted into ethyl acetate (3 x 350 mL). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to get the crude product. The crude product was purified by column chromatography (silica gel, eluent EtOAc / hexane 30:70) to get 3-oxo-6-(4-(trifluoromethoxy)phenyl)-2,3-dihydropyridazine-4-carboxylic acid ethyl ester (12 g, 40%, LC-MS 97%) as off-white solid.

[0775] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 1.31 (t, 3H), 4.31 (q, 2H), 7.49 (d, 2H), 7.97-8.04 (m, 2H), 8.35 (s, 1H), 13.70 (br s, 1H).

[0776] Intermediate 46

[0777] 3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4- carboxylic acid

[0778]

[0779] Ethyl 3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylate (2 g, 6.1 mmol) was dissolved in DMF (80 mL). Pyridin-3-ylboronic acid (1.5 g, 12.2 mmol), 2,2'-bipyridine (4.76 g, 30.46 mmol), sodium carbonate (0.775 g, 7.3 mmol) and anhydrous copper diacetate (2.76 g, 15.23 mmol) were added. The reaction mixture was stirred at 80 °C for 4 h, cooled and then 6 mL of 2N aqueous sodium hydroxide solution was added. Water was added, the precipitate was filtered off and dried under vacuum to get 2.5 g of the title compound.

[0780] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 50 x 2.1 mm; Eluent A: water + 0.1 vol-% formic acid (99%) Eluent B: acetonitrile; Gradient: 0 - 1.6 min 1 - 99% B, 1.6 - 2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210 - 400 nm; ELSD): R t = 1.14 min; MS (ESIpos): m / z = 378.4 [M+H] + .

[0781] Intermediate 47

[0782] 6-[4-(Difluoromethyl)phenyl]-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[0783]

[0784] A mixture of 2.9 g {2-[4-(difluoromethyl)phenyl]-2-oxoethyl}dimethyl propanedioate and 13.5 mL hydrazine / THF (1 M) in acetic acid was stirred at 70 °C for 4 h. Another 10 mL hydrazine / THF (1 M) was added and the reaction mixture was stirred at 70 °C for 4 h. Water was added and the formed precipitate was filtered off and dried in vacuum to give 2.1 g of the title compound.

[0785] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.15 - 3.32 (m, 2H), 3.65 - 3.69 (m, 3H), 3.77 (dd, 1 H), 7.08 (t, 1 H), 7.63 (d, 2H), 7.89 (d, 2H), 11.36 (s, 1 H).

[0786] Intermediate 48

[0787] 6-[4-(Difluoromethyl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0788]

[0789] A mixture of 2089 mg of 6-[4-(difluoromethyl)phenyl]-3-oxo-2,3,4,5-tetrahydropyridazine-4- carboxylic acid methyl ester and 2487 mg of copper (II) chloride in 215 mL of acetonitrile was stirred at 50°C for 1 hour. After evaporation in vacuo, the residue was suspended in water, the precipitate was filtered off to give 1420 mg of 6-[4-(difluoromethyl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester.

[0790] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.85 (s, 3H), 7.12 (t, 1H), 7.69 (d, 2H), 8.03 (d, 2H), 8.42 (s, 1H), 13.76 (s, 1H).

[0791] Intermediate 49

[0792] 6-[4-(Difluoromethyl)phenyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0793]

[0794] Methyl 6-[4-(difluoromethyl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate (700 mg, 2.5 mmol) was dissolved in DMF (32 mL). Pyridin-3-ylboronic acid (614 mg, 5 mmol), 2,2'-bipyridine (1.95 g, 12.5 mmol), sodium carbonate (318 mg, 3 mmol) and anhydrous copper diacetate (1.13 g, 6.24 mmol) were added. The reaction mixture was stirred at 80°C for 5 hours, cooled and then water was added. The pH was adjusted to 9 by the addition of 1 M aqueous sodium hydroxide solution, the precipitate was filtered off and dried in vacuo to give 481 mg of the title compound.

[0795] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 7.10 (t, 1H), 7.59 (br s, 1H), 7.66 (d, 2H), 7.76 (s, 1H), 8.06 (d, 2H), 8.13 (br d, 1H), 8.63 (br s, 1H), 8.91 (br s, 1H).

[0796] Intermediate 50

[0797] 6-(4-Methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0798]

[0799] A solution of 500 mg of 6-chloro-3-hydroxypyridazine-4-carboxylic acid ethyl ester and 436 mg of 4-methylphenylboronic acid in 20 mL of dioxane was treated with tripotassium phosphate (15 mL of a 0.5 M solution in water) and second generation RuPhos Pd precatalyst (CAS number [1375325-68-0]; 383 mg), heated to 100 °C and stirred for 4 hours. The reaction mixture was cooled to room temperature, the precipitate formed was filtered off, washed with 1,4-dioxane (2 mL) and dried. The resulting material was dissolved in water and freeze-dried to give the title compound (406 mg) which was used in the next step without further purification.

[0800] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 2.35 (s, 3H), 7.29 (d, 2H), 7.89 (d, 2H), 8.06 (s, 1H).

[0801] Intermediate 51

[0802] 6-(4-Methylphenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0803]

[0804] 6-(4-Methylphenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0805] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: water + 0.2 vol% ammonia (32%), Eluent B: acetonitrile; Gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t = 0.58 min; MS (ESI pos): m / z = 308.5 [M+H] + .

[0806] Intermediate 52

[0807] [2-(4-Chloro-2-fluorophenyl)-2-oxoethyl](hydroxy)propanedioic acid diethyl ester

[0808]

[0809] Into a 100 mL round bottom flask was placed 1 -(4-chloro-2-fluorophenyl)ethan-1 -one (10 g, 57.94 mmol, 1.00 equiv) and 2-oxopropanedioic acid 1,3-diethyl ester (15 mL). The resulting solution was stirred at 130 °C for 24 h. The resulting mixture was concentrated in vacuo. This resulted in 24 g (crude) 2-[2-(4-chloro-2-fluorophenyl)-2-oxoethyl]-2-hydroxypropanedioic acid 1,3-diethyl ester as a black oil, which was used without further purification.

[0810] Intermediate 53

[0811] 6-(4-Chloro-2-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0812]

[0813] Into a 500 mL round bottom flask was placed a solution of 2-[2-(4-chloro-2- fluorophenyl)-2-oxoethyl]-2-hydroxypropanedioic acid 1,3-diethyl ester (24 g, 69.22 mmol, 1.00 equiv) in ethanol (250 mL) and hydrazine (15 mL). The resulting solution was stirred at 80 °C for 12 hours. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 2 x 200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x 100 mL of water. The resulting mixture was washed with 1 x 100 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (2:1). This resulted in 2.9 g (14%) of 6-(4-chloro-2-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid ethyl ester as a pink solid.

[0814] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 1.29 (t, 3H), 4.30 (q, 2H), 7.44 (dd, 1H), 7.63 (dd, 1H), 7.74 (t, 1H), 8.10 (d, 1H), 13.84 (s, 1H).

[0815] Intermediate 54

[0816] 6-(4-Chloro-2-fluorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0817]

[0818] Ethyl 6-(4-chloro-2-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (500 mg) was dissolved in DMF (22 mL). 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (691 mg), 2,2'-bipyridine (1.31 g), sodium carbonate (214 mg) and anhydrous copper diacetate (765 mg) were added. The reaction mixture was stirred at 80 °C for 5 hours. After cooling, 1 M aqueous NaOH (1.7 mL) was added and the reaction mixture was stirred at room temperature for 48 hours. 1 M aqueous hydrochloric acid was added until the product precipitated. The precipitate was filtered off and dried in vacuo to give 418 mg of 6-(4-chloro-2-fluorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid which was used without further purification.

[0819] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: water + 0.1 vol-% formic acid (99%) Eluent B: acetonitrile; Gradient: 0 - 1.6 min 1 - 99% B, 1.6 - 2.0 min 99% B; Flow 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210 - 400 nm; ELSD): R t = 1.04 min; MS (ESIpos): m / z = 346.3 [M+H] + .

[0820] Intermediate 55

[0821] 3-(4-Chlorophenyl)-6-oxo-6H-1,4'-bipyridazine-5-carboxylic acid

[0822]

[0823] Ethyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (500 mg) was dissolved in DMF (23 mL). 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridazine (739 mg), 2,2'-bipyridine (1.12 g), sodium carbonate (228 mg) and anhydrous copper diacetate (815 mg) were added. The reaction mixture was stirred at room temperature for 14 hours, then 1.8 mL of a 2N aqueous sodium hydroxide solution was added. Water was added, the precipitate was filtered off and dried under vacuum to yield 438 mg of the title compound.

[0824] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: water + 0.1 vol-% formic acid (99%) Eluent B: acetonitrile; Gradient: 0 - 1.6 min 1 - 99% B, 1.6 - 2.0 min 99% B; Flow 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210 - 400 nm; ELSD): R t = 0.90 min; MS (ESIpos): m / z = 329.2 [M+H] + .

[0825] Intermediate 56

[0826] 3-Oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylic acid

[0827]

[0828] A solution of 6-chloro-3-hydroxypyridazine-4-carboxylic acid ethyl ester (CAS No. [61404-41-9]; 450 mg, 2.22 mmol) and [6-(trifluoromethyl)pyridin-3-yl]boronic acid (CAS No. [868662-36-6]; 1.30 eq, 551 mg, 2.89 mmol) in 1,4-dioxane (17 mL) was treated with tripotassium phosphate (3.00 eq, 6.7 mmol, 13.3 mL of a 0.5 M aqueous solution) and second generation RuPhos Pd precatalyst (CAS No. [1375325-68-0]; 0.20 eq, 345 mg, 444 pmol) heated to 100 °C and stirred for 4.5 h. The reaction mixture was cooled to room temperature, the precipitate that formed was filtered off, washed with 1,4-dioxane (2 mL) and dried. The resulting material was dissolved in water and freeze-dried to give the title compound (555 mg) which was used in the next step without further purification.

[0829] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 7.98 (d, 1 H), 8.30 (s, 1 H), 8.68 (br d, 1 H), 9.39 (s, 1 H).

[0830] Intermediate 57

[0831] N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3- dihydropyridazine-4-carboxamide

[0832] A suspension of crude 3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4- carboxylic acid (486 mg, 0.852 mmol) in DMF (6 mL) was treated with a solution of (2S)-2-aminopropan-1-ol (CAS No. [2749-11-3]; 2.00 eq, 128 mg, 1.70 mmol) in DMF (6 mL), N,N-diisopropylethylamine (4.50 eq, 670 pL, 3.80 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide (CAS No. [68957-94-8]; 1.50 eq, 1.28 mmol, 750 pL of a 50 wt% solution in DMF) and stirred at room temperature for one week. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative reverse phase HPLC followed by lyophilisation to give the title compound (150 mg).

[0833] 1 H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.17 (d, 3H), 3.41-3.49 (m, 2H), 3.98-4.08 (m, 1H), 4.94 (br s, 1H), 8.03 (d, 1H), 8.59 (dd, 1H), 8.65 (s, 1H), 9.28 (d, 1H), 9.62 (br d, 1H), 13.82 (br s, 1H).

[0834] Intermediate 58

[0835] [2-(4-cyanophenyl)-2-oxoethyl](hydroxy)propanedioic acid diethyl ester

[0836]

[0837] Into a 100 mL round bottom flask, was placed 4-acetylbenzonitrile (10 g, 68.89 mmol, 1.00 equiv) and 2-oxopropanedioic acid 1,3-diethyl ester (15 g, 86.13 mmol, 1.25 equiv). The resulting solution was stirred at 130 °C for 24 h. The resulting mixture was concentrated under vacuum. This resulted in 25 g (114%) of 2-[2-(4-cyanophenyl)-2-oxoethyl]-2-hydroxypropanedioic acid 1,3-diethyl ester as a black oil, which was used without further purification.

[0838] Intermediate 59

[0839] 6-(4-cyanophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0840]

[0841] Into a 500 mL round bottom flask, was placed a solution of 2-[2-(4-cyanophenyl)-2-oxoethyl]-2-hydroxypropanedioic acid 1,3-diethyl ester (25 g, 78.29 mmol, 1.00 equiv) in ethanol (200 mL) and hydrazine (15 mL). The resulting solution was stirred at 80 °C for 12 h. The reaction was then quenched by the addition of 200 mL of water. The resulting solution was extracted with 2 x 200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1 x 100 mL of water. The resulting mixture was washed with 1 x 100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (2:1). This resulted in 6 g (28%) of 6-(4-cyanophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid ethyl ester as a yellow solid.

[0842] 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 1.31 (t, 3H), 4.31 (q, 2H), 7.92-8.00 (m, 2H), 8.08 (d, 2H), 8.42 (s, 1H), 13.84 (s, 1H).

[0843] Intermediate 60

[0844] 6-(4-cyanophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0845]

[0846] Ethyl 6-(4-cyanophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (500 mg) was dissolved in DMF (24 mL). 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (762 mg), 2,2'-bipyridine (1.45 g), sodium carbonate (236 mg) and anhydrous copper diacetate (843 mg) were added. The reaction mixture was stirred at 80 °C for 5 h, then 1.8 mL of 2N aqueous sodium hydroxide solution was added. Water was added, the precipitate was filtered off and dried under vacuum to give 632 mg of the title compound.

[0847] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.750 x 2.1 mm; Eluent A: water + 0.1 vol-% formic acid (99%) Eluent B: acetonitrile; Gradient: 0 - 1.6 min 1 - 99% B, 1.6 - 2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210 - 400 nm; ELSD): R t = 0.81 min; MS (ESI pos): m / z = 319.3 [M+H] + .

[0848] Intermediate 61

[0849] 6-(4-chlorophenyl)-3-oxo-2-(pyrimidin-5-yl)-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0850]

[0851] Methyl 6-(4-chlorophenyl)-3-oxo-2-(pyrimidin-5-yl)-2,3-dihydropyridazine-4- carboxylate (275 mg, 0.802 mmol) was dissolved in acetonitrile (13.6 mL). A solution of lithium hydroxide (57.6 mg, 2.41 mmol) in water (0.45 mL) was added at room temperature. It was stirred at 40 °C for 24 h.

[0852] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.89 (s, 3H), 7.59 (br d, 2H), 8.04 (br d, 2H), 8.57 (s, 1H), 9.20-9.33 (m, 3H).

[0853] Intermediate 62

[0854] 6-(4-Chlorophenyl)-3-oxo-2-(pyrimidin-5-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0855]

[0856] Methyl 6-(4-chlorophenyl)-3-oxo-2-(pyrimidin-5-yl)-2,3-dihydropyridazine-4- carboxylate (275 mg, 0.802 mmol) was dissolved in acetonitrile (13.6 mL). A solution of lithium hydroxide (57.6 mg, 2.41 mmol) in water (0.45 mL) was added at room temperature. It was stirred at 40 °C for 24 h.

[0857] Water was added and the pH was adjusted to 6-7 with 0.5 N HCI. The precipitate was suction filtered, washed three times with water and dried under vacuum at 50 °C to yield 251 mg (95%) of the title compound which was used without further purification in the next step.

[0858] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.89 (s, 3H), 7.59 (br d, 2H), 8.04 (br d, 2H), 8.57 (s, 1H), 9.20-9.33 (m, 3H).

[0859] Intermediate 63

[0860] 6-(4-chlorophenyl)-3-oxo-2-(l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0861]

[0862] Batch 1 : 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester (200 mg) was dissolved in DMF (12 mL). 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole (490 mg), 2,2'-bipyridine (295 mg), cesium carbonate (295 mg) and anhydrous copper diacetate (172 mg) were added. It was stirred at room temperature for 5 hours. Water was added and the pH was adjusted to 3 with 2N HCI. The volatiles were removed in vacuo on a rotary evaporator. Water was added and the aqueous phase was extracted three times with chloroform. The combined organic layers were dried over magnesium sulfate and concentrated to give 265 mg of crude product which was purified together with the second batch.

[0863] Batch 2: 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester (544 mg) was dissolved in acetonitrile (5.4 mL). 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- 1-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazole (1 g), pyridine (333 μL), N,N- diethylethanamine (573 μL), anhydrous copper diacetate (747 mg) and molecular sieves (544 mg, 0.4 nm, particle size: < 50 μm) were added. It was stirred at room temperature for one day. 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l-{[2- (trimethylsilyl)ethoxy]methyl}-lH-pyrazole (320 mg) was added and stirring was continued at room temperature for another day. Kieselgel was added and the volatiles were removed in vacuo. It was pre-purified by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to give 427 mg of product which was combined with the first batch and purified by flash chromatography (silica gel, hexane / ethyl acetate 7:3) to give 220 mg of the title compound.

[0864] 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = -0.04 (s, 9H), 0.83-0.88 (m, 2H), 3.55-3.61 (m, 2H), 3.88 (s, 3H), 5.49 (s, 2H), 7.57-7.61 (m, 2H), 8.07-8.12 (m, 2H), 8.21 (s, 1H), 8.46 (s, 1H), 8.69 (s, 1H).

[0865] Intermediate 64

[0866] 6-(4-Chlorophenyl)-3-oxo-2-(l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxylic acid

[0867]

[0868] Methyl 6-(4-chlorophenyl)-3-oxo-2-(l-{[2-(trimethylsilyl)ethoxy]methyl}-lH-pyrazol- 4-yl)-2,3-dihydropyridazine-4-carboxylate (50 mg) was dissolved in acetonitrile (1 mL) and THF (1 mL). Lithium hydroxide (7.8 mg) and water (0.118 mL) were added and stirred at room temperature overnight. The reaction mixture was concentrated to half of its volume and water (150 mL) was added. The pH was adjusted to 3 with 2N HCI (7.5 mL). The precipitate was suction filtered, washed with water and dried under vacuum at 50 °C to give 36 mg of the title compound which was used in the next step without further purification.

[0869] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = -0.04 (s, 9H), 0.83-0.89 (m, 2H), 3.56-3.61 (m, 2H), 5.50 (s, 2H), 7.57-7.61 (m, 2H), 8.10-8.15 (m, 2H), 8.23 (s, 1H), 8.46 (s, 1H), 8.70 (s, 1H), 13.86 (br s, 1H).

[0870] Intermediate 65

[0871] 6-(4-Chlorophenyl)-3-oxo-2-(lH-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0872]

[0873] Method 1, Step 1 : Dissolve 6-(4-chlorophenyl)-3-oxo-2-(l-{[2- (trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid methyl ester (220 mg) in ethanol (1.85 mL). Add hydrogen chloride / dioxane (1.85 mL, 4 M in dioxane) and stir at 70 °C for 2 hours. Allow the reaction mixture to reach room temperature and concentrate to dryness to give 169 mg of 6-(4-chlorophenyl)-3-oxo-2-(lH-pyrazol-4-yl)-2,3- dihydropyridazine-4-carboxylic acid methyl ester. This material is used in the next step without further purification.

[0874] Method 2, Step 1 : Dissolve 6-(4-chlorophenyl)-3-oxo-2-(l-{[2- (trimethylsilyl)ethoxy]methyl}-lH-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid (34 mg) in ethanol (0.29 mL). Add hydrogen chloride / dioxane (0.29 mL, 4 M in dioxane) and stir at 70 °C for 2 hours. Allow the reaction mixture to reach room temperature and continue stirring at room temperature overnight. Concentrate the reaction mixture to dryness to give 27 mg of a mixture of 6-(4-chlorophenyl)-3-oxo-2-(lH-pyrazol-4-yl)-2,3- dihydropyridazine-4-carboxylic acid ethyl ester and 6-(4-chlorophenyl)-3-oxo-2-(lH-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid. This material is used in the next step without further purification.

[0875] Step 2: Combine the crude material from Method 1 and Method 2 in acetonitrile (5 mL). Add lithium hydroxide (80 mg) and water (0.6 mL) and stir at room temperature for 1 hour. Add water (5 mL) and adjust the pH to 3 with 2N HC1 (1.2 mL). Filter off the precipitate, wash with water and dry under vacuum at 50 °C to give 186 mg of the title compound which is used in the next step without further purification.

[0876] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.56-7.61 (m, 2H), 8.09-8.14 (m, 2H), 8.34 (br s, 2H), 8.44 (s, 1H), 13.45 (br s, 2H).

[0877] Intermediate 66

[0878] 6-[4-(dimethylamino)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0879]

[0880] A solution of 6-chloro-3-hydroxypyridazine-4-carboxylic acid ethyl ester (200 mg) and 4-(dimethylamino)-benzolboronsure (212 mg) in 1,4-dioxane (8 mL) was treated with potassium phosphate tribasic (6 mL of a 0.5 M solution in water) and second generation RuPhos Pd pre-catalyst (153 mg), heated to 75 °C and stirred for 6 h. The reaction mixture was cooled to room temperature, treated with water and the pH adjusted to 3 by the addition of 1 M HCI. The precipitate which formed was filtered off and washed with water. The precipitate was dissolved in ethyl acetate and the filtrate was extracted three times with ethyl acetate. The combined organic phases were washed with brine, separated, dried over sodium sulfate, filtered and the ethyl acetate evaporated. The residue was subjected to RP-HPLC (Instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm x 30 mm, eluent A: 0.1 % formic acid in water, eluent B: acetonitrile; gradient: A 85 % / B 15 % -> A 45 % / B 55 %; flow rate: 150 mL / min; UV-detection: 254 nm) to give 59 mg of 6-[4-(dimethylamino)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid.

[0881] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 2.98 (s, 6H), 6.79 (d, 2H), 7.77 (d, 2H), 8.44 (s, 1H).

[0882] Intermediate 67

[0883] 6-[4-(dimethylamino)phenyl]-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2,3- dihydropyridazine-4-carboxamide

[0884] A solution of 59 mg of intermediate 6-[4-(dimethylamino)phenyl]-3-oxo-2,3- dihydropyridazine-4-carboxylic acid, 34 mg of (2S)-2-amino-1-propanol, 174 mg of HATU, 0.16 mL of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 3 mL of DMF was stirred at room temperature for 14 hours. The reaction mixture was then filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm x 30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% -> A 45% / B 55%; flow rate: 150 mL / min; UV-detection: 254 nm) to give 11 mg of 6-[4-(dimethylamino)phenyl]-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2,3- dihydropyridazine-4-carboxamide.

[0885] LC-MS (instrument: Waters Acquity UPLC-MS SQD 3001 ; column: Acquity UPLC BEH C18 1.7 50 x 2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0 - 1.6 min 1 - 99% B, 1.6 - 2.0 min 99% B; flow rate 0.8 mL / min; temperature: 60 °C; injection: 2 μL; DAD scan: 210 - 400 nm; ELSD): R t = 0.84 min; MS (ESI pos): m / z = 317.3 [M+H] + .

[0886] Intermediate 68

[0887] 6-(4-Chlorophenyl)-2-(1 -methyl-1 H-pyrazol-3-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4- carboxylic acid methyl ester

[0888]

[0889] [2-(4-Chlorophenyl)-2-oxoethyl]dimethyl propanedioate (200 mg) and sodium acetate (259 mg) were dissolved in acetic acid (7 mL). Then 3-hydrazino-1-methyl-1H-pyrazole trihydrochloride (327 mg) was added portionwise. This was stirred at room temperature overnight and at 50 °C for 1 hour. The reaction mixture was cooled, treated with water and lyophilized. The residue was subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm x 30 mm, eluent A: 0.1% formic acid / water, eluent B: acetonitrile; gradient: A 85% / B 15% -> A 45% / B 55%; flow rate: 150 mL / min; UV-detection: 254 nm) to give 119 mg of methyl 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-3-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate.

[0890] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.37 - 3.46 (m, 2H), 3.69 (s, 3H), 3.83 (s, 3H), 3.99 - 4.06 (m, 1H), 6.30 (d, 1H), 7.49 - 7.56 (m, 2H), 7.71 (d, 1H), 7.78 - 7.83 (m, 2H).

[0891] Intermediate 69

[0892] 6-(4-Chlorophenyl)-2-(1-methyl-1H-pyrazol-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0893]

[0894] Methyl 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-3-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate (119 mg) was dissolved in acetonitrile (5 mL). Copper dichloride (138 mg) was added. This was stirred at 90 °C for 1 hour. The reaction mixture was cooled, dissolved in water and extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness to give 112 mg of the title compound which was used in the next step without further purification.

[0895] 1H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.87 (s, 3H), 3.90 (s, 3H), 6.56 (d, 1H), 7.55-7.60 (m, 2H), 7.83 (d, 1H), 7.92-7.96 (m, 2H), 8.48 (s, 1H)

[0896] Intermediate 70

[0897] 6-(4-Chlorophenyl)-2-(l-methyl-lH-pyrazol-3-yl)-3-oxo-2,3-dihydropyridazine-4- carboxylic acid

[0898]

[0899] Methyl 6-(4-chlorophenyl)-2-(l-methyl-lH-pyrazol-3-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylate (112 mg) was dissolved in tetrahydrofuran (5 mL). A solution of sodium hydroxide (65 mg) in water (0.8 mL) was added and the reaction mixture was stirred at room temperature for 14 hours. Water was added and the pH was adjusted to 3 with 2N HCl. The precipitate was suction filtered, washed with water three times and dried under lyophilization to give 94 mg of the title compound which was used in the next step without further purification.

[0900] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] 3.91 (s, 3H), 6.57 (d, 1H), 7.57 (d, 2H), 7.84 (d, 1H), 7.96 (d, 2H), 8.48 (s, 1H).

[0901] Intermediate 71

[0902] Methyl 6-(4-chlorophenyl)-2-(l-methyl-lH-pyrazol-3-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylate (112 mg) was dissolved in tetrahydrofuran (5 mL). A solution of sodium hydroxide (65 mg) in water (0.8 mL) was added and the reaction mixture was stirred at room temperature for 14 hours. Water was added and the pH was adjusted to 3 with 2N HCl. The precipitate was suction filtered, washed with water three times and dried under lyophilization to give 94 mg of the title compound which was used in the next step without further purification.

[0903]

[0904] [2-(4-chlorophenyl)-2-oxoethyl]dimethyl propanedioate (200 mg) and sodium acetate (259 mg) were dissolved in acetic acid (7 mL). Then, 5-hydrazinyl-3-methyl-1 H-pyrazole hydrochloride (220 mg) was added portionwise. It was stirred at room temperature overnight and at 50 °C for 1 h. The reaction mixture was cooled, treated with water and lyophilized. The residue was subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125 mm x 30 mm, eluent A: 0.1 % formic acid / water, eluent B: acetonitrile; gradient: A 85 % / B 15 % -> A 45 % / B 55 %; flow rate: 150 mL / min; UV-detection: 254 nm) to give 126 mg of methyl 6-(4-chlorophenyl)-2-(3-methyl-1 H-pyrazol-5-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate.

[0905] LC-MS (instrument: Waters Acquity UPLC-MS SQD 3001 ; column: Acquity UPLC BEH C18 1.7 50 x 2.1 mm; eluent A: water + 0.1 vol-% formic acid (99 %) eluent B: acetonitrile; gradient: 0 - 1.6 min 1 - 99 % B, 1.6 - 2.0 min 99 % B; flow rate 0.8 mL / min; temperature: 60 °C; injection: 2 μL; DAD scan: 210 - 400 nm; ELSD): R t = 1.07 min; MS (ESI pos): m / z = 347.3 [M+H] + .

[0906] Intermediate 72

[0907] 6-(4-chlorophenyl)-2-(3-methyl-1 H-pyrazol-5-yl)-3-oxo-2,3-dihydropyridazine-4- carboxylic acid methyl ester

[0908]

[0909] Methyl 6-(4-chlorophenyl)-2-(3-methyl-1 H-pyrazol-5-yl)-3-oxo-2,3,4,5- tetrahydropyridazine-4-carboxylate (126 mg) was dissolved in acetonitrile (5 mL). Copper dichloride (146 mg) was added. It was stirred at 90 °C for 1 h. The reaction mixture was cooled, treated with water, the formed precipitate was filtered off, washed with water, dried by lyophilization to give 132 mg of the title compound which was used without further purification in the next step.

[0910] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: water + 0.1 vol-% formic acid (99%) Eluent B: acetonitrile; Gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60°C; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t = 1.08 min; MS (ESIpos): m / z = 345.3 [M+H] + .

[0911] Intermediate 73

[0912] 6-(4-Chlorophenyl)-2-(3-methyl-1 H-pyrazol-5-yl)-3-oxo-2,3-dihydropyridazine-4- carboxylic acid

[0913]

[0914] Methyl 6-(4-chlorophenyl)-2-(3-methyl-1 H-pyrazol-5-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylate (132 mg) was dissolved in tetrahydrofuran (6 mL). A solution of sodium hydroxide (76 mg) in water (0.96 mL) was added and the reaction mixture was stirred at room temperature for 14 hours. Water was added and the pH was adjusted to 3 with 2N HCI. The precipitate was suction filtered, washed with water three times and dried under cold drying to give 80 mg of the title compound which was used in the next step without further purification.

[0915] 1 H NMR (400 MHz, DMSO-d6) δ [ppm] = 2.30 (s, 3H), 6.35 (br s, 1 H), 7.57 (d, 2H), 7.97 (br d, 2H), 8.48 (br s, 1 H)

[0916] Intermediate 74

[0917] Methyl 6-(4-chlorophenyl)-3-oxo-2-(1,2-thiazol-4-yl)-2,3-dihydropyridazine-4- carboxylate

[0918]

[0919] Methyl 6-(4-chlorophenyl)-3-oxo-2-(1,2-thiazol-4-yl)-2,3-dihydropyridazine-4- carboxylate (423 mg) was suspended in acetonitrile (1 1 mL). Lithium hydroxide (87 mg) dissolved in water (1.31 mL) was added. The pH was measured (pH = 4) and lithium hydroxide (87 mg) was added again. It was stirred at room temperature for 1 h. Water (5 mL) was added and the pH was adjusted to 3 with 2N HCI (1.2 mL). The precipitate was suction filtered, washed with water and dried at 50 °C under vacuum to yield 340 mg of the title compound which was used without further purification in the next step.

[0920] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.89 (s, 3H), 7.57-7.62 (m, 2H), 8.05-8.10 (m, 2H), 8.52 (s, 1 H), 9.14 (s, 1 H), 9.58 (s, 1 H).

[0921] Intermediate 75

[0922] 6-(4-Chlorophenyl)-3-oxo-2-(1,2-thiazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0923]

[0924] Methyl 6-(4-chlorophenyl)-3-oxo-2-(1,2-thiazol-4-yl)-2,3-dihydropyridazine-4- carboxylate (423 mg) was suspended in acetonitrile (1 1 mL). Lithium hydroxide (87 mg) dissolved in water (1.31 mL) was added. The pH was measured (pH = 4) and lithium hydroxide (87 mg) was added again. It was stirred at room temperature for 1 h. Water (5 mL) was added and the pH was adjusted to 3 with 2N HCI (1.2 mL). The precipitate was suction filtered, washed with water and dried at 50 °C under vacuum to yield 340 mg of the title compound which was used without further purification in the next step.

[0925] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.89 (s, 3H), 7.57-7.62 (m, 2H), 8.05-8.10 (m, 2H), 8.52 (s, 1 H), 9.14 (s, 1 H), 9.58 (s, 1 H).

[0926] Intermediate 76

[0927] Hydroxy{2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl}malonic acid diethyl ester

[0928]

[0929] Hydroxy{2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl}malonic acid diethyl ester (70 g, 0.193 mol) and hydrazine dihydrochloride (22.3 g, 0.212 mol) in ethanol (600 mL) were heated at 70 °C for 24 h. Upon completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate 50%) to give 35.0 g (58%) of the title compound.

[0930] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.19 (t, 6H), 3.76 (s, 2H), 4.18 (q, 4H), 6.47 (s, 1H), 7.91 (d, 2H), 8.15 (d, 2H).

[0931] Intermediate 77

[0932] 3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0933]

[0934] Hydroxy{2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl}malonic acid diethyl ester (70 g, 0.193 mol) and hydrazine dihydrochloride (22.3 g, 0.212 mol) in ethanol (600 mL) were heated at 70 °C for 24 h. Upon completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, hexane / ethyl acetate 50%) to give 35.0 g (58%) of the title compound.

[0935] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.19 (t, 6H), 3.76 (s, 2H), 4.18 (q, 4H), 6.47 (s, 1H), 7.91 (d, 2H), 8.15 (d, 2H).

[0936] Intermediate 78

[0937] 3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0938]

[0939] Ethyl 3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylate (1.20 g, 3.84 mmol) was suspended in acetonitrile (24 mL). 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-thiazole (1.05 g, 5.00 mmol), pyridine (622 μί, 7.69 mmol), N,N-diethylethanamine (1.07 mL, 7.69 mmol) and anhydrous copper diacetate (907 mg, 5.00 mmol) were added. It was stirred at room temperature for 28 hours. Water was added and the pH was adjusted to 3 with 2N HCI. The precipitate was filtered, washed three times with water and dried under vacuum at 50°C to give 1.915 g of the title compound which was used in the next step without further purification.

[0940] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.34 (t, 3H), 4.37 (q, 2H), 7.90 (d, 2H), 8.27 (d, 2H), 8.56 (s, 1 H), 9.15 (s, 1 H), 9.60 (s, 1 H).

[0941] Intermediate 79 3-oxo-2-(1,2-thiazol-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4- carboxylic acid

[0942]

[0943] To ethyl 3-oxo-2-(1,2-thiazol-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3- dihydropyridazine-4-carboxylate (1.91 g, 3.88 mmol) in acetonitrile (35 mL) was added lithium hydroxide (278 mg, 11.63 mmol) in water (4.2 mL). It was stirred at room temperature for 2 hours. Water (5 mL) was added and the pH was adjusted to 3 with hydrochloric acid (3 mL, 2N). The precipitate was filtered, washed with water and dried under vacuum at 50°C to give 1.3 g of the title compound and starting material.

[0944] The precipitate (465 mg) was stirred in aqueous sodium hydroxide at 60°C. The solid material was warmed and filtered and washed with water. The residue was dried, suspended in water (20 mL) and the pH was adjusted to 3 with 2M hydrochloric acid. The solid material was collected, washed with water and dried under vacuum at 50°C to give 195 mg (1 1 %) of the title compound. The first filtrate was acidified with 2M hydrochloric acid to pH 4, the precipitate was collected, washed with water and dried under vacuum at 50°C to give 180 mg (10%) of the title compound.

[0945] The remaining impurities (720 mg) were stirred in aqueous sodium hydroxide solution at room temperature for 1 hour. The pH was adjusted to 3 with hydrochloric acid (2 mL, 2M) and stirred at room temperature for 0.5 hours. The solids were filtered, washed with water three times and dried under vacuum at 50 °C to give 660 mg (37%) of the title compound.

[0946] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.88 (br d, 2H), 8.28 (br d, 2H), 8.59 (br s, 1H), 9.16 (br s, 1H), 9.62 (br s, 1H), 13.94 (br s, 1H).

[0947] Intermediate 80

[0948] 3-oxo-6-[4-(trifluoromethyl)phenyl]-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0949]

[0950] 3-oxo-6-[4-(trifluoromethyl)phenyl]-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H- pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0951] 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.83-0.89 (m, 2H), 1.34 (t, 3H), 3.55-3.63 (m, 2H), 4.36 (q, 2H), 5.50 (s, 2H), 7.89 (d, 2H), 8.23 (s, 1H), 8.29 (d, 2H), 8.51 (s, 1H), 8.72 (s, 1H).

[0952] Intermediate 81

[0953] 3-oxo-2-(1H-pyrazol-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4- carboxylic acid

[0954]

[0955] Step 1 : 3-oxo-6-[4-(trifluoromethyl)phenyl]-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}- 1H-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid ethyl ester (1.38 g, 3.20 mmol) was suspended in ethanol (11.3 mL). Hydrogen chloride / dioxane (11.3 mL, 4M) was added and stirred at 70 °C for 5 hours. It was stirred at room temperature overnight and then at 70 °C for 5 hours. The reaction mixture was cooled and concentrated to dryness to give 1.01 g which was used in the next step without further purification.

[0956] Step 2: The intermediate from Step 1 (1.01 g) was suspended in acetonitrile (24 mL). Lithium hydroxide (192 mg, 8.01 mmol) in water (6 mL) was added and it was stirred at room temperature for 3 hours. Water (5 mL) was added and the pH was adjusted to 3 with hydrochloric acid (1.2 mL, 2N). The precipitate was filtered, washed with water and dried under vacuum at 50 °C to give 695 mg (73%) of the title compound which was used in the next step without further purification.

[0957] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.87 (d, 2H), 8.27-8.43 (m, 5H), 13.38 (br s, 2H).

[0958] Intermediate 82

[0959] 2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3- dihydropyridazine-4-carboxylic acid

[0960] Step 1 : 3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylic acid methyl ester (0.40 g, 1.34 mmol) was suspended in acetonitrile (7 mL). Molecular sieves (400 mg, 0.4 nm, particle size: < 50 pm), 1 -(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H- pyrazole (491 mg, 2.01 mmol), pyridine (0.217 mL, 2.68 mmol), N,N- diethylethanamine (0.374 mL, 2.68 mmol) and anhydrous copper diacetate (487 mg, 2.68 mmol) were added. This was stirred at room temperature for 24 hours. 1 -(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole (300 mg, 1.23 mmol) was added and stirred at room temperature for 3 days. This was diluted with water and acidified with hydrochloric acid (2N). The solid material was filtered off and dried under vacuum at 50 °C to give 1.21 g of intermediate 1 with molecular sieves which was used in the next step without further purification.

[0961] Step 2: Intermediate from step 1 (1.01 g) was suspended in acetonitrile (30 mL). Lithium hydroxide (96.2 mg, 4.02 mmol) in water (2 mL) was added and this was stirred at 40 °C for 20 hours. The reaction mixture was diluted with water (30 mL) and filtered over celite. The filtrate was adjusted to pH 4 with hydrochloric acid (2N). The precipitate was filtered off, washed three times with water and dried under vacuum at 50 °C to give 380 mg (71 %) of the title compound.

[0962] 1 H-NMR (400 MHz, DMSO-d6): d [ppm] = 7.89 (d, 2H), 7.93 (t, 1 H), 8.34 (d, 2H), 8.48-8.57 (m, 2H), 9.01 (s, 1 H), 13.88 (br s, 1 H).

[0963] Intermediate 83

[0964] 6-(4-Chlorophenyl)-2-(5-fluoro-2-thienyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0965]

[0966] Step 1 : 6-(4-Chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester (0.20 g, 0.756 mmol) was suspended in acetonitrile (8 mL). 2-(5-Fluoro-2-thienyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (569 mg, 2.49 mmol), pyridine (0.122 mL, 1.51 mmol), N,N-diethylethanamine (0.211 mL, 1.51 mmol) and anhydrous copper diacetate (275 mg, 1.51 mmol) were added. It was stirred at room temperature for 5 hours and at 50 °C for 120 hours. The reaction mixture was diluted with buffer solution (15 mL, pH 7), stirred, the precipitate was filtered, washed with water three times and dried under vacuum at 50 °C to give 446 mg of crude material which was used in the next step without further purification.

[0967] Step 2: The intermediate from step 1 (446 mg) was suspended in acetonitrile (13 mL). Lithium hydroxide (146 mg, 6.11 mmol) in water (2.5 mL) was added and it was stirred at room temperature for 24 hours. The reaction mixture was diluted with water (30 mL), the pH was adjusted to 3 with hydrochloric acid (2N), the precipitate was filtered, washed with water three times and dried under vacuum at 50 °C to give 335 mg which was used in the next step without further purification.

[0968] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.750 x 2.1 mm; Eluent A: water + 0.2 vol% ammonia water (32%), Eluent B: acetonitrile; Gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t = 0.73 min; MS (ESI pos): m / z = 351.2 [M+H] + .

[0969] Intermediate 84

[0970] 6-(4-Chlorophenyl)-2-(5-methyl-3-thienyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0971]

[0972] Methyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (0.10 g, 0.378 mmol) was suspended in acetonitrile (2 mL). 4,4,5,5-Tetramethyl-2-(5-methyl-3-thienyl)-1,3,2-dioxaborolane (127 mg, 0.567 mmol), pyridine (0.061 mL, 0.756 mmol), N,N-diethylethanamine (0.105 mL, 0.756 mmol) and anhydrous copper diacetate (137 mg, 0.756 mmol) were added. This was stirred at room temperature for 5 hours and at 50 °C for 23 hours. A second batch, synthesised under similar conditions but stirred at 50 °C for 24 hours, was combined with this batch and poured into a pH 7 buffer solution. This was stirred for a short period, the precipitate was filtered, washed twice with water and dried under vacuum at 50 °C to give 460 mg of the title compound which was used in the next step without further purification.

[0973] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.88 (s, 3H), 7.37 (s, 1H), 7.59 (d, 2H), 7.71 (d, 1H), 8.03 (d, 2H), 8.45 (s, 1H).

[0974] Intermediate 85

[0975] 6-(4-Chlorophenyl)-2-(5-methyl-3-thienyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0976]

[0977] Methyl 6-(4-chlorophenyl)-2-(5-methyl-3-thienyl)-3-oxo-2,3-dihydropyridazine-4- carboxylate (272 mg, 0.754 mmol) was dissolved in acetonitrile (6.8 mL). Lithium hydroxide (54.2 mg, 2.262 mmol) in water (1.36 mL) was added and this was stirred at 50 °C for 24 hours. The reaction mixture was cooled, diluted with water (15 mL), the pH was adjusted to 3 with hydrochloric acid (2N), the precipitate was filtered, washed twice with water and dried under vacuum at 50 °C to give 225 mg (86%) which was used in the next step without further purification.

[0978] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: water + 0.2 vol% ammonia (32%), Eluent B: acetonitrile; Gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t = 0.78 min; MS (ESI pos): m / z = 347.2 [M+H] + .

[0979] Intermediate 86

[0980] 6-(4-Chlorophenyl)-2-(5-chloro-3-thienyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0981]

[0982] Methyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (0.20 g, 0.756 mmol) was suspended in acetonitrile (6 mL). 2-(5-Chloro-3-thienyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (277 mg, 1.133 mmol), pyridine (0.122 mL, 1.511 mmol), N,N-diethylethanamine (0.211 mL, 1.511 mmol) and anhydrous copper diacetate (275 mg, 1.511 mmol) were added. This was stirred at 50 °C for 24 h. The reaction mixture was cooled and a pH 7 buffer solution (10 mL) was added. This was stirred for a short while, the precipitate was filtered, washed twice with water and dried under vacuum at 50 °C to give 520 mg of the title compound which was used in the next step without further purification. 70 mg of this batch was purified by HPLC to give 25 mg of the title compound.

[0983] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.88 (s, 3H), 7.57-7.61 (m, 2H), 7.69 (d, 1 H), 8.03-8.07 (m, 2H), 8.10 (d, 1 H), 8.47 (s, 1 H).

[0984] Intermediate 87

[0985] 6-(4-Chlorophenyl)-2-(5-chloro-3-thienyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0986]

[0987] Methyl 6-(4-chlorophenyl)-2-(5-chloro-3-thienyl)-3-oxo-2,3-dihydropyridazine-4- carboxylate (288 mg, 0.755 mmol) was dissolved in acetonitrile (8.3 mL). Lithium hydroxide (54.3 mg, 2.266 mmol) in water (1.60 mL) was added and stirred at 50 °C for 4 h. The reaction mixture was cooled, diluted with water (15 mL), the pH was adjusted to 3 with hydrochloric acid (2 N), the precipitate was filtered off, washed twice with water and dried under vacuum at 45 °C to yield 300 mg, which was used in the next step without further purification.

[0988] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.750 x 2.1 mm; Eluent A: water + 0.2 vol-% ammonia (32%), Eluent B: acetonitrile; Gradient: 0 - 1.6 min 1 - 99% B, 1.6 - 2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210 - 400 nm; ELSD): R t = 0.75 min; MS (ESI pos): m / z = 367.2 [M+H] + .

[0989] Intermediate 88

[0990] Methyl 6-(4-chlorophenyl)-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-oxo-2,3- dihydropyridazine-4-carboxylate

[0991] Methyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (0.10 g, 0.378 mmol) was suspended in acetonitrile (1 mL). Molecular sieves (100 mg, 0.4 nm, particle size: <50 pm), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H- pyrazole (138 mg, 0.567 mmol), pyridine (0.061 mL, 0.756 mmol), N,N- diethylethanamine (0.105 mL, 0.756 mmol) and anhydrous copper diacetate (137 mg, 0.756 mmol) were added. This was stirred at room temperature for 48 hours, 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole (100 mg, 0.410 mmol) was added and stirred at room temperature for 72 hours. This was diluted with water and slightly acidified. The precipitate was filtered and dried under vacuum at 50 °C to give 315 mg of the title compound which was used in the next step without further purification.

[0992] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.89 (s, 3H), 7.58-7.62 (m, 2H), 7.91 (t, 1 H), 8.11-8.15 (m, 2H), 8.50 (s, 1 H), 8.50 (s, 1 H), 8.98 (s, 1 H).

[0993] Intermediate 89

[0994] 6-(4-Chlorophenyl)-2-[1-(difluoromethyl)-1 H-pyrazol-4-yl]-3-oxo-2,3- dihydropyridazine-4-carboxylic acid

[0995]

[0996] Methyl 6-(4-chlorophenyl)-2-[1-(difluoromethyl)-1 H-pyrazol-4-yl]-3-oxo-2,3- dihydropyridazine-4-carboxylate (646 mg, 1.697 mmol) was suspended in acetonitrile (35 mL). Lithium hydroxide (122 mg, 5.09 mmol) in water (2 mL) was added and this was stirred at 40 °C for 20 hours. The reaction mixture was cooled, diluted with water (30 mL) and filtered through celite. The filtrate was adjusted to pH 4 with hydrochloric acid (2N), the precipitate was filtered, washed three times with water and dried under vacuum at 50 °C to give 360 mg which was used in the next step without further purification.

[0997] 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.57-7.62 (m, 2H), 7.92 (t, 1 H), 8.12-8.17 (m, 2H), 8.47 (s, 1 H), 8.51 (s, 1 H), 8.99 (s, 1 H), 13.86 (br s, 1 H).

[0998] Intermediate 90

[0999] 1-(1,2-oxazol-4-yl)hydrazine-1,2-dicarboxylic acid di-tert-butyl ester

[1000]

[1001] To a solution of ethyl ether (30 mL) was added dropwise n-butyllithium (2.5 M in hexanes, 21.6 mL, 54 mmol) at -78 °C. 4-Bromo-1,2-oxazole (4.00 g, 27.0 mmol) was added and the mixture was stirred for 30 min. A solution of (E)-diazen-1,2-dicarboxylic acid di-tert-butyl ester (9.33 g, 40.6 mmol) in ethyl ether (30 mL) was added dropwise and the mixture was stirred for 1 h at -78 °C. The reaction mixture was added to water (200 mL) and extracted with dichloromethane (twice 200 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (silica gel, heptane / ethyl acetate 4:1 to 11:9) to give 1.99 g (16%) of the title product.

[1002] 1 H NMR (400 MHz, CDCl3): δ [ppm] = 1.40-1.60 (m, 18H), 6.68 (s, 1 H), 8.40 (s, 1 H), 8.63 (s, 1 H).

[1003] Intermediate 91

[1004] 4-hydrazinyl-1,2-oxazole hydrochloride

[1005]

[1006] Hydrochloric acid (4 M in 1,4-dioxane, 10.0 mL, 40.0 mmol) was added to a solution of 1-(1,2-oxazol-4-yl)hydrazine-1,2-dicarboxylic acid di-tert-butyl ester (2.64 g, 8.82 mmol) in 1,4-dioxane (10 mL) and the mixture was heated at 50 °C for 5 h. The mixture was concentrated in vacuo to give 863 mg (76%) of the title compound.

[1007] 1H NMR (400 MHz, MeOD-d3): δ [ppm] = 8.42 (s, 1 H), 8.63 (s, 1 H).

[1008] Intermediate 92

[1009] 6-(4-Chlorophenyl)-2-(1,2-oxazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4- carboxylic acid methyl ester

[1010]

[1011] A mixture of [2-(4-chlorophenyl)-2-oxoethyl]dimethyl propanedioate (494 mg, 1.74 mmol), 4-hydrazinyl-1,2-oxazole hydrochloride (588 mg, 3.47 mmol) and sodium acetate (641 mg, 7.81 mmol) in acetic acid (1 1.8 mL) was stirred at room temperature for 96 h. The reaction mixture was concentrated and taken up in water (200 mL). The solid was collected by filtration and dried under vacuum to give 567 mg (98%) of the title compound.

[1012] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.34-3.49 (m, 2H), 3.67 (s, 3H), 4.06-4.13 (m, 1 H), 7.53 (d, 2H), 7.99 (d, 2H), 9.07 (s, 1 H), 9.32 (s, 1 H).

[1013] Intermediate 93

[1014] 6-(4-Chlorophenyl)-2-(1,2-oxazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[1015]

[1016] To a solution of 6-(4-chlorophenyl)-2-(1,2-oxazol-4-yl)-3-oxo-2,3,4,5- tetrahydropyridazine-4-carboxylic acid methyl ester (586 mg, 1.76 mmol) in acetonitrile (10.5 mL) was added copper (II) chloride (1.18 g, 8.78 mmol) and the mixture was heated at 50 °C for 2 h. The mixture was cooled to room temperature and allowed to stand for 16 h. The mixture was heated at 50 °C for 16 h. The mixture was concentrated and taken up in water. The solid was collected by filtration and dried to give 563 mg (97%) of the title compound.

[1017] 1H NMR (400 MHz, DMSO-d6): δ [ppm] = 3.61 (s, 3H), 7.56 (d, 2H), 8.12 (d, 2H), 8.50 (s, 1H), 9.39 (s, 1H), 9.72 (s, 1H).

[1018] Intermediate 94

[1019] 6-(4-Chlorophenyl)-2-(l,2-oxazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[1020]

[1021] To a solution of methyl 6-(4-chlorophenyl)-2-(l,2-oxazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylate (383 mg, 1.16 mmol) in 1,4-dioxane (10 mL) was added hydrochloric acid (2 M in water, 10.0 mL, 20.0 mmol) and the mixture was heated at 100 °C for 48 h. The mixture was cooled to room temperature, the solid was collected by filtration and dried under vacuum to give 246 mg (67%) of the title compound which was used in the next step without further purification.

[1022] 1 H NMR (400 MHz, DMSO-d6): δ [ppm] = 7.56 (d, 2H), 8.14 (d, 2H), 8.46 (br s, 1H), 9.38 (s, 1H), 9.72 (br s, 1H).

[1023] Intermediate 95

[1024] 3-Oxo-2-(l,2-thiazol-4-yl)-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3- dihydropyridazine-4-carboxylic acid ethyl ester

[1025]

[1026] Ethyl 3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylate (475 mg, 1.52 mmol) was suspended in acetonitrile (10 mL). 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-thiazole (480 mg, 2.28 mmol), pyridine (0.245 mL, 3.03 mmol), N,N-diethylethanamine (0.423 mL, 3.03 mmol) and anhydrous copper diacetate (358 mg, 1.97 mmol) were added. It was stirred at room temperature for 24 hours. 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-thiazole (100 mg, 0.474 mmol) was added and stirred at room temperature for 24 hours. Buffer solution pH 7 (50 mL) was added and stirred for a short while. The precipitate was filtered, washed twice with water and dried under vacuum at 45 °C to give 630 mg of the title compound which was used in the next step without further purification.

[1027] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.34 (t, 3H), 4.38 (q, 2H), 8.07 (d, 1 H), 8.63 (s, 1 H), 8.73 (dd, 1 H), 9.19 (s, 1 H), 9.42 (d, 1 H), 9.64 (s, 1 H).

[1028] Intermediate 96

[1029] 3-oxo-2-(1,2-thiazol-4-yl)-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4- carboxylic acid

[1030]

[1031] Ethyl 3-oxo-2-(1,2-thiazol-4-yl)-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4- carboxylate (625 mg, 1.58 mmol) was suspended in THF (19 mL). Lithium hydroxide in water (113 mg, 4.73 mmol) was added and stirred at room temperature for 24 hours. Water (100 mL) was added and the pH was adjusted to 4 with hydrochloric acid (0.5 N). It was stirred for a short while, the precipitate was filtered, washed three times with water and dried under vacuum at 45 °C to give 585 mg of the title compound which was used in the next step without further purification.

[1032] 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 7.99 (br s, 1 H), 8.47 (br s, 1 H), 9.14 (br s, 1 H).

[1033] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 50 x 2.1 mm; Eluent A: water + 0.2 vol% ammonia (32%), Eluent B: acetonitrile; Gradient: 0 - 1.6 min 1 - 99% B, 1.6 - 2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210 - 400 nm; ELSD): R t = 0.59 min; MS (ESIpos): m / z = 369.1 [M+H] + .

[1034] Intermediate 97

[1035] {2-[4-(fluoromethyl)phenyl]-2-oxoethyl} dimethyl propanedioate

[1036]

[1037] Dissolve 2-bromo-1-[4-(fluoromethyl)phenyl]ethanone (5.5 g, 23.80 mmol) in acetone (120 mL). Add dimethyl propanedioate (6.94 g, 52.50 mmol) and potassium carbonate (5.0 g, 36.18 mmol). Stir at room temperature overnight. Reduce the volume by half on a rotary evaporator under vacuum. Then pour into water (550 mL) containing some brine. Separate the layers, extract the aqueous phase with ethyl acetate (200 mL) three times. Dry the combined organic layers over magnesium sulfate and concentrate. Add a second batch prepared under similar conditions (0.5 g of starting bromoketone) and remove the volatiles under high vacuum at 70 °C. Purify the crude product by flash chromatography (hexane / ethyl acetate) to obtain 5.59 g (76%) of the title product.

[1038] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.65 (d, 2H), 3.68 (s, 6H), 3.99 (t, 1 H), 5.54 (d, 2H), 7.56 (d, 2H), 8.04 (d, 2H).

[1039] Intermediate 98

[1040] 6-[4-(fluoromethyl)phenyl]-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[1041]

[1042] Dimethyl {2-[4-(fluoromethyl)phenyl]-2-oxoethyl}propanedioate (2.50 g, 8.86 mmol) was dissolved in acetic acid (31.4 mL). Hydrazine in THF (14 mL, 1.0 M, 14 mmol) was added at room temperature. It was then stirred at 85 °C overnight. The reaction mixture was cooled, hydrazine in THF (2.1 mL, 1.0 M, 2.1 mmol) was added. It was stirred at 75 °C for 3 hours and at room temperature for 120 hours. Water (150 mL) was added and stirred for a while. The precipitate was suction filtered, washed with water three times, and dried under vacuum at 50 °C to give 1.781 g (76%) of the title compound which was used in the next step without further purification.

[1043] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.19 (dd, 1H), 3.29 (dd, 1H), 3.67 (s, 3H), 3.75 (dd, 1H), 5.45 (d, 2H), 7.47 (dd, 2H), 7.78-7.82 (m, 2H), 11.29 (s, 1H).

[1044] Intermediate 99

[1045] 6-[4-(fluoromethyl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[1046]

[1047] Methyl 6-[4-(fluoromethyl)phenyl]-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate (1.00 g, 3.78 mmol) was dissolved in acetonitrile (20 mL). Copper dichloride (1.60 g, 11.90 mmol) was added and it was stirred at 90 °C for 1 hour. The reaction mixture was cooled and poured into water (150 mL). It was stirred for 10 minutes. The precipitate was suction filtered, washed with water three times, and dried under vacuum at 50 °C to give 1.02 g of the title compound which was used in the next step without further purification.

[1048] 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.85 (s, 3H), 5.48 (d, 2H), 7.53 (br d, 2H), 7.93 (br d, 2H), 8.39 (s, 1H), 13.69 (br s, 1H).

[1049] Intermediate 100

[1050] 6-[4-(fluoromethyl)phenyl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4- carboxylic acid methyl ester

[1051]

[1052] Methyl 6-[4-(fluoromethyl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate (0.940 g, 3.58 mmol) was suspended in acetonitrile (10 mL). Anhydrous sodium sulfate (0.950 g, 6.68 mmol), 1 -methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole (1.2 g, 5.77 mmol), pyridine (0.58 mL, 7.17 mmol), N,N-diethylethanamine (1 mL, 7.17 mmol) and anhydrous copper diacetate (1.3 g, 7.17 mmol) were added. It was stirred at room temperature for 2 days. 1 -Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H-pyrazole (0.522 g, 2.51 mmol) and anhydrous copper diacetate (651 mg, 3.58 mmol) were added and stirred at room temperature for 4 days. It was diluted with dichloromethane and silica gel was added. The volatiles were removed under vacuum. The residue was purified by flash chromatography (silica gel, dichloromethane / ethanol 95:5) to give 1.05 g (85%) of the title compound.

[1053] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.89 (s, 3H), 3.92 (s, 3H), 5.51 (d, 2H), 7.54-7.59 (m, 2H), 8.07-8.12 (m, 3H), 8.45 (s, 1 H), 8.51 (s, 1 H).

[1054] Intermediate 101

[1055] 6-[4-(fluoromethyl)phenyl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4 carboxylic acid

[1056]

[1057] Methyl 6-[4-(fluoromethyl)phenyl]-2-(1 -methyl-1 H-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylate (1.05 g, 3.07 mmol) was suspended in THF (50.5 mL). Lithium hydroxide (221 mg, 9.20 mmol) in water (2.5 mL) was added and stirred at room temperature for 1 h. The pH was adjusted to 3 with hydrochloric acid (4 mL, 2N). The precipitate was filtered, washed with water three times and dried under vacuum at 50 °C to yield 352 mg (35%) of the title compound which was used in the next step without further purification.

[1058] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.93 (s, 3H), 5.51 (d, 2H), 7.55-7.59 (m, 2H), 8.11-8.15 (m, 3H), 8.46 (s, 1 H), 8.53 (s, 1 H), 13.88 (br s, 1 H).

[1059] Intermediate 102

[1060] Methyl 6-[4-(fluoromethyl)phenyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4- carboxylate

[1061]

[1062] Methyl 6-[4-(fluoromethyl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate (0.725 g, 2.77 mmol) was suspended in acetonitrile (7.4 mL). Anhydrous sodium sulfate (0.725 g, 5.10 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (851 mg, 4.15 mmol), pyridine (448 μί, 5.53 mmol), N,N-diethylethanamine (771 μί, 5.53 mmol) and anhydrous copper diacetate (1.004 g, 5.53 mmol) were added. It was stirred at room temperature overnight. The pH was adjusted to 3 with hydrochloric acid (2N). The precipitate was filtered, washed with water (1 mL) three times and dried under vacuum at 50 °C overnight. The solid was triturated with dichloromethane / methanol 1 :1, filtered and dried under vacuum at 50 °C to yield 942 mg of the title compound which was used in the next step without further purification.

[1063] 1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.88 (s, 3H), 5.50 (d, 2H), 7.56 (br d, 2H), 8.00 (br d, 2H), 8.40-8.69 (m, 1H).

[1064] Intermediate 103

[1065] 6-[4-(fluoromethyl)phenyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid

[1066]

[1067] Methyl 6-[4-(fluoromethyl)phenyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4- carboxylate (915 mg, 2.70 mmol) was suspended in acetonitrile (24 mL). Lithium hydroxide (194 mg, 8.09 mmol) in water (2.91 mL) was added. An additional amount of water (3 mL) was added. This was stirred at room temperature overnight. The reaction mixture was diluted with water (30 mL), stirred for 30 minutes and then the pH was adjusted to 3 with hydrochloric acid (4 mL, 2N). The precipitate was filtered, washed with water and dried under vacuum at 50 °C to give 728 mg (78%) of the title compound which was used in the next step without further purification.

[1068] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.750 x 2.1 mm; Eluent A: water + 0.2 vol% ammonia water (32%), Eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t = 0.53 min; MS (ESI pos): m / z = 326.4 [M+H] + .

[1069] Intermediate 104

[1070] 6-(4-Chlorophenyl)-3-oxo-2-(pyridin-3-yl)-N-(4,4,4-trifluoro-3-hydroxybutan-2-yl)- 2,3-dihydropyridazine-4-carboxamide

[1071] Dissolve 6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4- carboxylic acid (245 mg, 0.75 mmol) in dry DMF (10 mL). Add 3-amino-1,1,1 - trifluorobutan-2-ol hydrochloride 1 :1 (174.5 mg, 0.97 mmol), N-ethyl-N- isopropylpropan-2-amine (0.59 mL, 3.36 mmol) and propane phosphonic anhydride (T3P, 0.71 g, 50% in DMF, 1.12 mmol) successively. Stir it at room temperature overnight. Purify the crude reaction mixture by RP-HPLC (column: X-Bridge C18 5 pm 100 x 30 mm, mobile phase: (water + 0.1 vol% formic acid (99%)) / acetonitrile, gradient) to give 52.8 mg (16%) of the title compound.

[1072] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 x 50 mm; Eluent A: water + 0.1 vol% formic acid (99%), Eluent B: acetonitrile; Gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 pL; DAD scan: 210-400 nm; ELSD): R t = 1.22 min; MS (ESI pos): m / z = 454.3 [M+H] + .

[1073] Intermediate 105

[1074] 6-(4-chlorophenyl)-2-(5-chloropyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4- carboxylic acid

[1075]

[1076] Dissolve 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid ethyl ester (250 mg, 0.9 mmol) in DMF (12 mL). Add (5-chloropyridin-3-yl)boronic acid (282 mg, 1.79 mmol), 2,2'-bipyridine (700.5 mg, 4.48 mmol), sodium carbonate (0.114 g, 1.076 mmol) and anhydrous copper diacetate (407 mg, 2.24 mmol). Stir the reaction mixture at 80 °C for 4 hours, cool down and then add 2.7 mL of 2N sodium hydroxide aqueous solution. Stir it overnight, add water, filter off the precipitate and dry under vacuum to give 402 mg of the title compound.

[1077] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: water + 0.1 vol-% formic acid (99%), Eluent B: acetonitrile; Gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t = 1.25 min; MS (ESIpos): m / z = 364.0 [M+H] + .

[1078] Intermediate 106

[1079] 6-(4-Chlorophenyl)-2-(5-methylpyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4- carboxylic acid

[1080]

[1081] Ethyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (250 mg, 0.9 mmol) was dissolved in DMF (12 mL). 5-Methylpyridine-3-boronic acid (245.7 mg, 1.79 mmol), 2,2'-bipyridine (700.5 mg, 4.48 mmol), sodium carbonate (0.114 g, 1.076 mmol) and anhydrous copper diacetate (407 mg, 2.24 mmol) were added. The reaction mixture was stirred at 80 °C for 4 hours, cooled down and then 2.7 mL of a 2 N aqueous sodium hydroxide solution was added. It was stirred overnight, water was added, the precipitate was filtered off and dried under vacuum to yield 317 mg of the title compound.

[1082] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: water + 0.1 vol-% formic acid (99%), Eluent B: acetonitrile; Gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t = 1.12 min; MS (ESIpos): m / z = 342.2 [M+H] + .

[1083] Intermediate 107

[1084] {2-[4-(difluoromethoxy)phenyl]-2-oxoethyl} dimethyl malonate

[1085]

[1086] A mixture of {2-[4-(difluoromethoxy)phenyl]-2-oxoethyl} dimethyl malonate (1 g, 3.16 mmol), 4-hydrazinyl-l-methyl-lH-pyrazole dihydrochloride (1.23 g, 6.32 mmol) and sodium acetate (1.17 g, 14.23 mmol) in 30 mL of acetic acid was stirred at 45 °C for 3 hours and at room temperature overnight. Additional 4-hydrazinyl-l-methyl-lH-pyrazole dihydrochloride (1 g, 3.16 mmol) was added and the reaction mixture was stirred at 45 °C for 2 hours. The reaction mixture was then dissolved in water, the precipitate was filtered off and dried under vacuum to yield 1.05 g (88%) of the title compound.

[1087] 1 H NMR (400 MHz, DMSO-d6) δ ppm = 3.60-3.65 (m, 2H), 3.68 (s, 6H), 3.98 (t, 1H), 7.22-7.66 (m, 3H), 8.05-8.11 (m, 2H).

[1088] Intermediate 108

[1089] 6-[4-(difluoromethoxy)phenyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-2,3,4,5- tetrahydropyridazine-4-carboxylic acid methyl ester

[1090]

[1091] A mixture of {2-[4-(difluoromethoxy)phenyl]-2-oxoethyl} dimethyl malonate (1 g, 3.16 mmol), 4-hydrazinyl-l-methyl-lH-pyrazole dihydrochloride (1.23 g, 6.32 mmol) and sodium acetate (1.17 g, 14.23 mmol) in 30 mL of acetic acid was stirred at 45 °C for 3 hours and at room temperature overnight. Additional 4-hydrazinyl-l-methyl-lH-pyrazole dihydrochloride (1 g, 3.16 mmol) was added and the reaction mixture was stirred at 45 °C for 2 hours. The reaction mixture was then dissolved in water, the precipitate was filtered off and dried under vacuum to yield 1.05 g (88%) of the title compound.

[1092] 1H NMR (400 MHz, DMSO-d6) δ ppm = 3.35-3.45 (m, 2H), 3.68 (s, 3H), 3.85 (s, 3H), 3.99-4.05 (m, IH), 7.24-7.30 (m, 2H), 7.36 (t, IH), 7.75 (d, IH), 7.94-8.03 (m, 2H), 8.08 (s, IH).

[1093] Intermediate 109

[1094] 6-[4-(Difluoromethoxy)phenyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylic acid

[1095] A mixture of 6-[4-(difluoromethoxy)phenyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo- 2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester (1.05 g, 2.77 mmol) and copper (II) chloride (1.12 g, 8.3 mmol) in 37.5 mL of acetonitrile was stirred at 90 °C for 3 hours. The reaction mixture was dissolved in water and the precipitate was filtered off to give 1.08 g (quantitative) of the title compound.

[1096] 1 H NMR (400 MHz, DMSO-d6) δ ppm = 3.35-3.45 (m, 2H), 3.68 (s, 3H), 3.85 (s, 3H), 3.99-4.05 (m, IH), 7.24-7.30 (m, 2H), 7.36 (t, IH), 7.75 (d, IH), 7.94-8.03 (m, 2H), 8.08 (s, IH).

[1097] Intermediate 110

[1098] 6-[4-(Difluoromethoxy)phenyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylic acid

[1099] Methyl 6-[4-(difluoromethoxy)phenyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylate (3.8 g, 10.1 mmol) was dissolved in THF (50 mL). A 2 M sodium hydroxide solution (12.6 mL, 25.2 mmol) was added at room temperature and the mixture was stirred overnight, diluted with water and treated with 1 M HCl. The pH was adjusted to 3 and the precipitate was suction filtered, washed with water three times and dried under vacuum to give 276 mg (50%) of the title compound.

[1100] 1 H NMR (400 MHz, DMSO-d6) δ ppm = 3.92 (s, 3H), 7.38 (t, 1H), 7.29-7.34 (m, 2H), 8.09-8.18 (m, 3H), 8.43-8.48 (m, 1H), 8.50-8.55 (m, 1H).

[1101] Intermediate 111

[1102] 6-(4-Chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[1103]

[1104] Ethyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (2.0 g, 7.2 mmol) was dissolved in THF (37 mL). 2M sodium hydroxide solution (9 mL, 18 mmol) was added at room temperature and the mixture was stirred overnight, diluted with water and treated with 2M HCI. The pH was adjusted to 3 and the precipitate was suction filtered, washed with water three times and dried under vacuum to give 1.79 g (99%) of the title compound.

[1105] 1 H NMR (400 MHz, DMSO-d6) δ ppm = 7.55-7.59 (d, 2H), 7.95-7.99 (d, 2H), 8.50 (s, 1H), 14.1 (br s, 2H).

[1106] Intermediate 112

[1107] 6-(4-Chlorophenyl)-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2,3- dihydropyridazine-4-carboxamide

[1108]

[1109] Ethyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (2.0 g, 7.2 mmol) was dissolved in THF (37 mL). 2M sodium hydroxide solution (9 mL, 18 mmol) was added at room temperature and the mixture was stirred overnight, diluted with water and treated with 2M HCI. The pH was adjusted to 3 and the precipitate was suction filtered, washed with water three times and dried under vacuum to give 1.79 g (99%) of the title compound.

[1110] 1 H NMR (400 MHz, DMSO-d6) δ ppm = 1.09-1.11 (m, 3H), 1.13 (d, 3H), 1.15 (s, 3H), 3.85-3.97 (m, 1H), 4.65 (br s, 1H), 7.57 (d, 2H), 7.93 (d, 2H), 8.53 (s, 1H), 9.73 (s, 1H), 13.86 (br s, 1H).

[1111] Intermediate 113

[1112] 3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid

[1113]

[1114] was synthesized in an analogous manner to Intermediate 111 from 3-oxo-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester.

[1115] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.750 x 2.1 mm; Eluent A: water + 0.1 vol% formic acid (99%) Eluent B: acetonitrile; Gradient: 0 - 1.6 min 1 - 99% B, 1.6 - 2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210 - 400 nm; ELSD): R t = 1.07 min; MS (ESI pos): m / z = 301.2 [M+H] + .

[1116] Intermediate 114

[1117] N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-6-[4-(trifluoromethoxy)phenyl]- 2,3-dihydropyridazine-4-carboxamide

[1118] was synthesized in an analogous manner to Intermediate 112 from 3-oxo-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid.

[1119] 1H NMR (400 MHz, DMSO-d6) δ ppm = 1.10 (s, 3H), 1.13 (d, 3H), 1.15 (s, 3H), 3.85-3.97 (m, 1H), 4.64 (s, 1H), 7.42-7.56 (m, 2H), 7.97-8.09 (m, 2H), 8.55 (s, 1H), 9.75 (br d, 1H), 14.02 (br s, 1H).

[1120] Intermediate 115

[1121] {2-[4-(dimethylamino)phenyl]-2-oxoethyl} dimethylmalonate

[1122]

[1123] Dimethyl malonate (5.45 g, 41.3 mmol) and potassium carbonate (4.3 g, 31 mmol) were added to a solution of 4-(dimethylamino)benzoylmethyl bromide (5.0 g, 20.6 mmol) in 145 mL of acetone. The reaction mixture was stirred at room temperature overnight, then quenched with water. The precipitate was filtered off, washed with water and dried under vacuum to give 4.66 g (77%) of the title compound.

[1124] 1 H NMR (400 MHz, DMSO-d6) δ ppm = 3.02 (s, 6H), 3.48 (d, 2H), 3.67 (s, 6H), 3.93 (t, 1H), 6.72 (d, 2H), 7.81 (d, 2H).

[1125] Intermediate 116

[1126] 6-[4-(dimethylamino)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[1127]

[1128] A mixture of {2-[4-(dimethylamino)phenyl]-2-oxoethyl} dimethyl propanedioate (500 mg, 1.7 mmol), 4-hydrazinyl-l-methyl-lH-pyrazole dihydrochloride (336 mg, 2.2 mmol) and sodium acetate (629 mg, 7.6 mmol) in 14 mL of AcOH was stirred at room temperature overnight and then at 50 °C for 1 h. Further 4-hydrazinyl-l-methyl-lH-pyrazole dihydrochloride (258 mg, 1.7 mmol) was added and the reaction mixture was stirred at room temperature overnight and then at 50 °C for 5 h. The reaction mixture was then dissolved in water and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered (MN 617WA filter paper) and concentrated in vacuo to yield 516 mg (85%) of the title compound.

[1129] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.750 x 2.1 mm; Eluent A: water + 0.1 vol-% formic acid (99%) Eluent B: acetonitrile; Gradient: 0 - 1.6 min 1 - 99% B, 1.6 - 2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210 - 400 nm; ELSD): R t = 1.05 min; MS (ESI pos): m / z = 356.5 [M+H] + .

[1130] Intermediate 117

[1131] 6-[4-(dimethylamino)phenyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylic acid methyl ester

[1132] A mixture of 6-[4-(dimethylamino)phenyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-2,3,4,5- tetrahydropyridazine-4-carboxylic acid methyl ester (516 mg, 1.45 mmol) and iodine (737 mg, 2.9 mmol) in 11 mL of acetic acid was stirred at room temperature for 48 h. Further iodine (368.5 mg, 1.45 mmol) was added and the mixture was stirred at room temperature for 24 h. The reaction mixture was dissolved in saturated sodium thiosulfate solution and ethyl acetate. The phases were separated, the organic phase was washed with saturated sodium thiosulfate solution and brine, filtered (MN 617WA filter paper) and concentrated in vacuo to yield 936 mg (55% purity) of the title compound.

[1133] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: water + 0.1 vol% formic acid (99%) Eluent B: acetonitrile; Gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t = 1.7 min; MS (ESIpos): m / z = 354.4 [M+H] + .

[1134] Intermediate 118

[1135] 6-[4-(dimethylamino)phenyl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4- carboxylic acid

[1136] Methyl 6-[4-(dimethylamino)phenyl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4- carboxylate (936 mg, 1.45 mmol, 55%) was dissolved in THF (5 mL). 2M sodium hydroxide solution (1.5 mL, 3.0 mmol) was added at room temperature and the mixture was stirred overnight, diluted with water and treated with 1 M HCI. The pH was adjusted to 3 and ethyl acetate was added. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered (MN 617WA filter paper) and concentrated in vacuo to give 99 mg (20%) of the title compound.

[1137] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: water + 0.1 vol% formic acid (99%) Eluent B: acetonitrile; Gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t = 1.7 min; MS (ESIpos): m / z = 354.4 [M+H] + .

[1138] Intermediate 119

[1139] 3-Oxo-2-(1,2-thiazo-4-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[1140]

[1141] Ethyl 3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylate (207 mg, 0.63 mmol) was dissolved in acetonitrile (6 mL), and then molecular sieves were added. The following compounds were used: powder (0.176 g), 4-(tetramethyl-1,3,2-dioxaborpine-2-yl)-1,2-thiazole (200 mg, 0.95 mmol), triethylamine (0.18 mL, 1.26 mmol), pyridine (0.10 mL, 1.26 mmol), and anhydrous copper diacetate (229.5 mg, 1.26 mmol). The reaction mixture was stirred at 80 °C for 4 hours, filtered through diatomaceous earth, concentrated, and purified by column chromatography (hexane / ethyl acetate, gradient of up to 50% ethyl acetate) to give 95 mg (36%) of the title compound.

[1142] 1 H NMR (400MHz, DMSO-d6) δppm=1.34(t,3H),4.36(q,2H),7.53(dd,2H),8.18(d,2H),8.51(s,1H),9.14(s,1H),9.59(s,1H).

[1143] Intermediate 120

[1144] 3-Oxo-2-(1,2-thiazo-4-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid

[1145]

[1146] Ethyl 3-oxo-2-(1,2-thiazo-4-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylate (90 mg, 0.22 mmol) was dissolved in THF (2 mL). 2 M sodium hydroxide solution (0.33 mL, 0.66 mmol) was added at room temperature, and the mixture was stirred overnight. It was then diluted with water and treated with 1 M HCl. The pH was adjusted to 3, and the precipitate was filtered off, washed with water, and dried under vacuum to give 74 mg (88%) of the title compound.

[1147] 1H NMR (400 MHz, DMSO-d6) δ ppm = 7.48-7.55 (m, 2H), 8.20 (d, 2H), 8.50 (s, 1H), 9.15 (s, 1H), 9.60 (s, 1H).

[1148] Intermediate 121

[1149] 6-[4-(Difluoromethoxy)phenyl]-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[1150]

[1151] A mixture of {2-[4-(difluoromethoxy)phenyl]-2-oxoethyl}dimethyl propanedioate (709 mg, 2.24 mmol), hydrazine / THF (1 M, 4.5 mL, 4.5 mmol) and sodium acetate (828 mg, 10.1 mmol) in 21 mL of AcOH was stirred at room temperature overnight and then at 50 °C for 6 hours. Additional hydrazine / THF (1 M, 6.7 mL, 6.7 mmol) was added and the reaction mixture was stirred at 80 °C for 3 hours. The reaction mixture was then dissolved in water, the precipitate was filtered off and dried under vacuum to give 334 mg (50%) of the title compound.

[1152] 1 H NMR (400 MHz, DMSO-d6) δ ppm = 3.13-3.30 (m, 2H), 3.67 (s, 3H), 3.71-3.77 (m, 1H), 7.20-7.25 (m, 2H), 7.31 (t, 1H), 7.81 (d, 2H), 11.27 (s, 1H).

[1153] Intermediate 122

[1154] 6-[4-(Difluoromethoxy)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[1155]

[1156] A mixture of 6-[4-(difluoromethoxy)phenyl]-3-oxo-2,3,4,5-tetrahydropyridazine-4- carboxylic acid methyl ester (1.3 g, 4.4 mmol) and copper (II) chloride (1.77 g, 13.2 mmol) in 60 mL of acetonitrile was stirred at 90 °C for 4 hours. The reaction mixture was dissolved in water and the precipitate was filtered off to give 1.13 g (87%) of the title compound.

[1157] 1H NMR (400 MHz, DMSO-d6) δ ppm = 3.85 (s, 3H), 7.29 (br d, 2H), 7.34 (t, 1H), 7.94 (d, 2H), 8.37 (s, 1H), 13.66 (s, 1H).

[1158] Intermediate 123

[1159] 6-[4-(Difluoromethoxy)phenyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4- carboxylic acid

[1160]

[1161] Methyl 6-[4-(difluoromethoxy)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate (550 mg, 1.86 mmol) was dissolved in DMF (12 mL) and then pyridin-3-ylboronic acid (456 mg, 3.7 mmol), 2,2'-bipyridine (1.45 g, 9.3 mmol), sodium carbonate (236 mg, 2.23 mmol) and anhydrous copper diacetate (843.1 mg, 4.6 mmol) were added. The reaction mixture was stirred at 80 °C for 4 hours and then at room temperature for 48 hours. Then 2M sodium hydroxide solution (1.86, 3.7 mmol) was added and the mixture was stirred at room temperature for 3 hours and then water was added. The precipitate formed was filtered off, washed with water and dried under vacuum to give 610 mg (91%) of the title compound.

[1162] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.750 x 2.1 mm; Eluent A: water + 0.1 vol% formic acid (99%) Eluent B: acetonitrile; Gradient: 0 - 1.6 min 1 - 99% B, 1.6 - 2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210 - 400 nm; ELSD): R t = 1.07 min; MS (ESI pos): m / z = 360.2 [M+H] + .

[1163] Intermediate 124

[1164] Hydroxy {2-oxo-2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}propanedioic acid diethyl ester

[1165]

[1166] Into a 100 mL round bottom flask was placed 1-[6-(trifluoromethyl)pyridin-3- yl]ethanone (10 g, 52.87 mmol) and 1,3-dimethyl 2-oxopropandioate (15.65 g, 89.9 mmol). The resulting solution was stirred at 130 °C for 24 hours, then more 1,3-dimethyl 2- oxopropandioate (13.81 g, 79.30 mmol) was added and heated at 130 °C for an additional 13 hours. The resulting mixture was cooled to room temperature and poured into pentane. The precipitate was filtered off, washed with pentane and water to give 22.6 g (crude) of hydroxy{2-oxo-2-[6-(trifluoromethyl)pyridin-3-yl]ethyl} propanedioate which was used without further purification.

[1167] Intermediate 125

[1168] 3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[1169]

[1170] To a solution of hydroxy{2-oxo-2-[6-(trifluoromethyl)pyridin-3-yl]ethyl} propanedioate (22.6 g, 62.2 mmol) in ethanol (255 mL) was added hydrazine hydrochloride (7.2 g, 68.5 mmol). The resulting solution was stirred at 80 °C for 24 hours. The reaction was then quenched by the addition of water. The resulting precipitate was filtered off and dried under vacuum to give 13.26 g (68%) of 3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester.

[1171] 1 H NMR (400 MHz, DMSO-d6) δ ppm = 1.32 (t, 3H), 4.33 (q, 2H), 8.01-8.06 (m, 1H), 8.47-8.51 (m, 1H), 8.52-8.57 (m, 1H), 9.23-9.26 (m, 1H), 13.92 (s, 1H).

[1172] Intermediate 126

[1173] 2-(5-fluoropyridin-3-yl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[1174]

[1175] Ethyl 3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylate (5 g, 15.96 mmol) was dissolved in acetonitrile (141 mL) followed by the addition of (5-fluoropyridin-3-yl)boronic acid (3.37 g, 23.94 mmol), triethylamine (4.45 mL, 31.9 mmol), pyridine (2.58 mL, 31.9 mmol) and anhydrous copper diacetate (7.25 g, 39.9 mmol). The reaction mixture was stirred at 80 °C for 3 hours, then water was added. The solution was adjusted to pH 3 by the addition of 1 M aqueous hydrochloric acid solution, then extracted three times with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 5.6 g (86%) of the title compound.

[1176] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.750 x 2.1 mm; Eluent A: water + 0.1 vol% formic acid (99%) Eluent B: acetonitrile; Gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t = 1.15 min; MS (ESI pos): m / z = 409.2 [M+H] + .

[1177] Intermediate 127

[1178] 2-(5-Fluoropyridin-3-yl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3- dihydropyridazine-4-carboxylic acid

[1179]

[1180] Ethyl 2-(5-fluoropyridin-3-yl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3- dihydropyridazine-4-carboxylate (5.6 g, 13.7 mmol) was dissolved in tetrahydrofuran (100 mL) followed by the addition of 20.5 mL (41.1 mmol) of 2N aqueous sodium hydroxide solution. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the pH was adjusted to pH 3 with 1 M aqueous hydrochloric acid solution. The precipitate was filtered off and dried under vacuum to give 3.19 g (70%) of the title compound.

[1181] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.7 50x2.1 mm; Eluent A: water + 0.1 vol% formic acid (99%) Eluent B: acetonitrile; Gradient: 0-1.6 min 1 -99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60°C; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t = 1.00 min; MS (ESIpos): m / z = 381.6 [M+H] + .

[1182] Intermediate 128

[1183] Hydroxy{2-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}propanedioic acid diethyl ester

[1184]

[1185] A mixture of 1 -[5-(trifluoromethyl)pyridin-2-yl]ethanone (3.8 g, 20.1 mmol) and ketomalonate diethyl ester (7.0 g, 40.2 mmol) was stirred at 130 °C for 24 h. After cooling to room temperature, the mixture was dissolved in ethyl acetate and water. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered (MN 617WA filter paper) and concentrated. The crude product was purified by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to give 4.64 g (64%) of the title compound.

[1186] 1 H NMR (400 MHz, DMSO-d6) δ ppm = 1.18 (t, 6H), 3.91 (q, 2H), 4.17 (q, 4H), 6.50 (s, 1 H), 8.12 (d, 1 H), 8.42-8.47 (m, 1 H), 9.17 (dd, 1 H).

[1187] Intermediate 129

[1188] 3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[1189]

[1190] Hydroxy {2-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}propanedioic acid diethyl ester (4.6 g, 12.66 mmol) and hydrazine dihydrochloride (1.79, 17.1 mmol) were dissolved in ethanol (52 mL) and stirred at reflux for 9 hours. After addition of water, a precipitate formed and was filtered off, washed with water and dried in vacuo to give 3.19 g (81 %) of the title compound.

[1191] 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.31 (t, 3 H), 4.32 (q, 2 H), 8.24-8.29 (m, 1 H), 8.35 (dd, 1 H), 8.67 (s, 1 H), 9.07-9.11 (m, 1 H), 13.94 (s, 1 H).

[1192] Intermediate 130

[1193] 3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylic acid

[1194]

[1195] A crude mixture of 3.0 g containing an unknown amount of 3-oxo-6-[5-(trifluoromethyl)- pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester was dissolved in tetrahydrofuran (50 mL) followed by the addition of 9.2 mL (18.4 mmol) of 2 N aqueous sodium hydroxide solution. The reaction mixture was stirred at room temperature overnight. Water was added to the reaction mixture and the pH was adjusted to pH 3 with 1 M aqueous hydrochloric acid solution. The precipitate was filtered off and dried in vacuo to give 1.05 g of a crude mixture containing the title compound.

[1196] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.750 x 2.1 mm; Eluent A: water + 0.1 vol-% formic acid (99%) Eluent B: acetonitrile; Gradient: 0 - 1.6 min 1 - 99% B, 1.6 - 2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210 - 400 nm; ELSD): R t = 1.04 min; MS (ESI pos): m / z = 286.1 [M+H] + .

[1197] Intermediate 131

[1198] N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]- 2,3-dihydropyridazine-4-carboxamide

[1199] A mixture of 1.051 g of a crude mixture containing an unknown amount of 3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylic acid and 312 mg (4.15 mmol) of propanolamine was dissolved in 16 mL of DMF and treated with HATU (2.1 g, 5.54 mmol), N,N-diisopropylethylamine (1.07 g, 8.3 mmol) and 4-dimethylaminopyridine (16.9 mg, 0.14 mmol). The reaction mixture was stirred overnight and dissolved in water and ethyl acetate. The phases were separated, the organic phase was washed with brine, filtered (MN 617WA filter paper) and concentrated. The crude product was purified by flash chromatography (silica gel, hexane / ethyl acetate, gradient) to give 383 mg of the title compound.

[1200] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001 ; Column: Acquity UPLC BEH C18 1.750 x 2.1 mm; Eluent A: water + 0.1 vol-% formic acid (99%) Eluent B: acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL / min; Temperature: 60 °C; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t = 0.93 min; MS (ESI pos): m / z = 343.5 [M+H] + .

[1201] Experimental Part - Example S

[1202] The following examples describe embodiments of the present application, but are not intended to limit the application to only these examples.

[1203] Example 1

[1204] N-(1 -hydroxy-3-methylbutan-2-yl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1205]

[1206] A solution of 100 mg of intermediate 6, 33.2 mg of 2-amino-3-methylbutan-1-ol, 184 mg of HATU and 125 mg of ethyldiisopropylamine in 5 mL of DMF was stirred at room temperature for 2 hours. The reaction was then quenched by water and the mixture was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to dryness. The residue was subjected to RP-HPLC ((column: X-Bridge CI 85 μιη 100 x 30 mm, mobile phase: acetonitrile / water (0.1 vol% formic acid) - gradient) to give 25.3 mg of N-(1-hydroxy-3-methylbutan-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1207] 1 H-NMR: (400 MHz, 25 °C, Methanol-d4): δ [ppm] = 1.00-1.07 (m, 6H); 2.02-2.13 (m, 1H); 2.41 (s, 3H); 3.67-3.75 (m, 2H); 3.95-4.01 (m+s, 4H); 7.34 (d, 2H); 7.88 (d, 2H); 8.15 (s, 1H); 8.49 (s, 1H); 8.64 (s, 1H).

[1208] Example 2

[1209] N-(1-hydroxy-3-methylbutan-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 1

[1210]

[1211] HPLC-separation of 24 mg of N-(1-hydroxy-3-methylbutan-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 1) on a chiral column (Chiralpak IB 5 μιη 250 x 30 mm, eluent: hexane / ethanol, gradient 20-50% ethanol, flow rate 40 mL / min) gave 6 mg of N-(1-hydroxy-3-methylbutan-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 1.

[1212] 1H-NMR (300 MHz, DMSO-d6): δ [ppm] = 0.90-0.96 (m, 6H); 1.95-2.03 (m, 1H); 2.39 (s, 3H); 3.43-3.50 (m, 1H); 3.53-3.60 (m, 1H); 3.81-3.90 (m, 1H); 3.93 (s, 3H); 4.82 (t, 1H); 7.36 (d, 2H); 7.95 (d, 2H); 8.10 (s, 1H); 8.56 (s, 1H); 8.57 (s, 1H); 9.55 (d, 1H).

[1213] Chiral HPLC: Rt = 3.65 min

[1214] Instrument: Agilent HPLC 1260; Column: Chiralpak IB 3 pm 100 x 4.6 mm; Eluent: Hexane / Ethanol 50:50, flow rate 1.4 mL / min; Temperature: 25 °C; DAD scan: 254 nm.

[1215] Example 3

[1216] N-(1 -hydroxy-3-methylbutan-2-yl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 2

[1217]

[1218] According to example 2, 24 mg of example 1 was separated, in addition 6 mg of N-(1 -hydroxy-3-methylbutan-2-yl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 2 were obtained.

[1219] 1 H-NMR (300 MHz, DMSO-d6): δ [ppm] = 0.90-0.96 (m, 6H); 1.95-2.03 (m, 1H); 2.39 (s, 3H); 3.43-3.50 (m, 1H); 3.53-3.60 (m, 1H); 3.81-3.90 (m, 1H); 3.93 (s, 3H); 4.82 (t, 1H); 7.36 (d, 2H); 7.95 (d, 2H); 8.10 (s, 1H); 8.56 (s, 1H); 8.57 (s, 1H); 9.55 (d, 1H).

[1220] Chiral HPLC: Rt = 6.15 min

[1221] Instrument: Agilent HPLC 1260; Column: Chiralpak IB 3 pm 100 x 4.6 mm; Eluent: Hexane / Ethanol 50:50, flow rate 1.4 mL / min; Temperature: 25 °C; DAD scan: 254 nm.

[1222] Example 4

[1223] N-(1 -hydroxybutan-2-yl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide

[1224] A solution of 100 mg of intermediate 7, 40.7 mg of 2-aminobutan-1-ol and 85 pL of triethylamine in 10 mL of dichloromethane was stirred under an ice-water bath for 10 minutes. The reaction was then quenched by water and the mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue was subjected to flash chromatography (ethyl acetate / petroleum ether 1 :2) to give 34 mg of N-(1 -hydroxybutan-2-yl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1225] 1 H-NMR: (400 MHz, 25 °C, Methanol-d4): d [ppm] = 1.02 (t, 3H); 1.59-1.83 (m, 2H); 2.41 (s, 3H); 3.68 (d, 2H); 3.96 (s, 3H); 4.01-4.07 (m, 1H); 7.34 (d, 2H); 7.87 (d, 2H); 8.15 (s, 1H); 8.48 (s, 1H); 8.62 (s, 1H).

[1226] Example 5

[1227] N-(1 -hydroxybutan-2-yl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide, enantiomer 1

[1228]

[1229] HPLC-separation of 33 mg N-(1 -hydroxybutan-2-yl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 4) on a chiral column (Chiralpak IC 5 pm 250x30 mm, eluent: hexane (0.1 % diethylamine) / (ethanol / methanol 50:50), gradient 20-50% (ethanol / methanol 50:50), flow rate 40 mL / min) gave 8 mg N-(1 -hydroxybutan-2-yl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 1.

[1230] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.91 (t, 3H); 1.47-1.56 (m, 1H); 1.64-1.72 (m, 1H); 2.39 (s, 3H); 3.34-3.49 (m, 1H); 3.51-3.56 (m, 1H); 3.87-3.95 (m+s, 4H); 4.89 (t, 1H); 7.36 (d, 2H); 7.95 (d, 2H); 8.11 (s, 1H); 8.56 (s, 2H); 9.51 (d, 1H).

[1231] Chiral HPLC: Rt = 4.68 min

[1232] Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3 pm 100x4.6 mm; eluent: hexane (0.1 % diethylamine) / (ethanol / methanol 50:50), gradient 20-50% (ethanol / methanol 50:50), flow rate 1.4 mL / min; temperature: 25 °C; DAD scan: 254 nm.

[1233] Example 6

[1234] N-(1 -hydroxybutan-2-yl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide, enantiomer 2

[1235]

[1236] According to Example 5, 33 mg Example 4 were separated, additionally 8 mg N-(1 -hydroxybutan-2-yl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide, enantiomer 2 were obtained.

[1237] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.91 (t, 3H); 1.47-1.56 (m, 1H); 1.64-1.72 (m, 1H); 2.39 (s, 3H); 3.34-3.49 (m, 1H); 3.51-3.56 (m, 1H); 3.87-3.95 (m+s, 4H); 4.89 (t, 1H); 7.36 (d, 2H); 7.95 (d, 2H); 8.11 (s, 1H); 8.56 (s, 2H); 9.51 (d, 1H).

[1238] Chiral HPLC: Rt = 6.25 min

[1239] Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3 pm 100 x 4.6 mm; Eluent: Hexane (0.1% diethylamine) / (ethanol / methanol 50:50), gradient from 20-50% (ethanol / methanol 50:50), flow rate 1.4 mL / min; Temperature: 25 °C; DAD scan: 254 nm.

[1240] Example 7

[1241] N-(1-hydroxypropan-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide

[1242] A solution of 100 mg of intermediate 7, 34.3 mg of 2-aminopropan-1-ol and 85 μL of triethylamine in 10 mL of dichloromethane was stirred under ice water bath for 10 minutes. The reaction was then quenched by water and the mixture was extracted with dichloromethane. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The residue was subjected to flash chromatography (ethyl acetate / petroleum ether 1 :2) to give 40.8 mg of N-(1-hydroxypropan-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide.

[1243] 1 H-NMR: (400 MHz, 25 °C, methanol-d4): δ [ppm] = 1.30 (d, 3H); 2.41 (s, 3H); 3.61-3.69 (m, 2H); 3.95 (s, 3H); 4.15-4.23 (m, 1H); 7.33 (d, 2H); 7.85 (d, 2H); 8.13 (s, 1H); 8.46 (s, 1H); 8.60 (s, 1H).

[1244] Example 8

[1245] N-[(2S)-1 -hydroxypropan-2-yl]-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1246]

[1247] A: A solution of 80 mg of intermediate 6, 38 mg of (2S)-2-aminopropan-1 -ol, 147 mg of HATU and 0.135 mL of ethyldiisopropylamine in 5 mL of DMF was stirred at room temperature for 14 hours. The reaction was then quenched by water and the mixture was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was subjected to flash chromatography (dichloromethane / methanol, gradient up to 3% methanol) to give 20 mg of N-[(2S)-1 -hydroxypropan-2-yl]-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1248] B: HPLC-separation of 39 mg of N-(1 -hydroxypropan-2-yl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 7) on a chiral column (Chiralpak IC 5 pm 250x30 mm, eluent: hexane (0.1 % diethylamine) / (ethanol / methanol 50:50), gradient 20-50% (ethanol / methanol 50:50), flow rate 40 mL / min) gave 9 mg of N-[(2S)-1 -hydroxypropan-2-yl]-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1249] 1 H-NMR (400 MHz, CDC13): δ [ppm] = 1.34 (d, 3H); 2.43 (s, 3H); 2.85 (dd, 1 H); 3.70 (ddd, 1 H); 3.80 (ddd, 1 H); 3.98 (s, 3H); 4.26-4.34 (m, 1 H); 7.32 (d, 2H); 7.82 (d, 2H); 8.14 (s, 1 H); 8.33 (s, 1 H); 8.71 (s, 1 H); 9.87 (d, 1 H).

[1250] Chiral HPLC: Rt = 5.28 min

[1251] Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μιη 100x4.6mm; Eluent: Hexane (0.1% diethylamine) / (ethanol / methanol 50:50), gradient from 20-50% (ethanol / methanol 50:50), flow rate 1.4 mL / min; Temperature: 25°C; DAD scan: 254 nm.

[1252] Example 9

[1253] N-[(2R)-1 -hydroxypropan-2-yl]-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1254]

[1255] According to the procedure of Example 8, Part B, 39 mg of Example 7 was isolated, additionally 13 mg of N-[(2R)-1 -hydroxypropan-2-yl]-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide was obtained.

[1256] 1 H-NMR (400 MHz, CDC13): δ [ppm] = 1.34 (d, 3H); 2.43 (s, 3H); 2.85 (dd, 1H); 3.70 (ddd, 1H); 3.80 (ddd, 1H); 3.98 (s, 3H); 4.26-4.34 (m, 1H); 7.32 (d, 2H); 7.82 (d, 2H); 8.14 (s, 1H); 8.33 (s, 1H); 8.71 (s, 1H); 9.87 (d, 1H).

[1257] Chiral HPLC: Rt = 7.07 min

[1258] Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μιη 100x4.6mm; Eluent: Hexane (0.1% diethylamine) / (ethanol / methanol 50:50), gradient from 20-50% (ethanol / methanol 50:50), flow rate 1.4 mL / min; Temperature: 25°C; DAD scan: 254 nm.

[1259] Example 10

[1260] 6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2- hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide

[1261]

[1262] A solution of 100 mg of intermediate 6, 83.2 mg of 3-amino-1,1,1 -trifluoropropan-2-ol, 184 mg of HATU and 0.17 mL of ethyldiisopropylamine in 5 mL of DMF was stirred at room temperature for 14 hours. The reaction was then quenched by water and the mixture was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was subjected to flash chromatography (dichloromethane / methanol, gradient up to 2% methanol) to give 65 mg of 6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4- carboxamide.

[1263] 1 H-NMR (400 MHz, CDC13): δ [ppm] = 2.44 (s, 3H); 3.78 (ddd, 1H); 3.90 (ddd, 1H); 3.99 (s, 3H); 4.18-4.27 (m, 1H); 4.56 (d, 1H); 7.33 (d, 2H); 7.82 (d, 2H); 8.16 (s, 1H); 8.33 (s, 1H); 8.71 (s, 1H); 10.24 (bt, 1H).

[1264] Example 11

[1265] (-)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2- hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide, enantiomer 1

[1266]

[1267] HPLC-separation on a chiral column (Chiralpak IA 5 pm 250x30 mm, eluent: methanol (0.1 % diethylamine) / ethanol 50:50, flow rate 30 mL / min) of 63 mg of 6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3- dihydropyridazine-4-carboxamide (Example 10) gave 29 mg of (-)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3- dihydropyridazine-4-carboxamide, enantiomer 1.

[1268] 1H-NMR (400 MHz, CDC13): δ [ppm] = 2.44 (s, 3H); 3.78 (ddd, 1H); 3.90 (ddd, 1H); 3.99 (s, 3H); 4.18-4.27 (m, 1H); 4.56 (d, 1H); 7.33 (d, 2H); 7.82 (d, 2H); 8.16 (s, 1H); 8.33 (s, 1H); 8.71 (s, 1H); 10.24 (bt, 1H).

[1269] Chiral HPLC: Rt = 2.69 min

[1270] Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3 μm 100 x 4.6 mm; Eluent: methanol (0.1% diethylamine) / ethanol 50:50, flow rate 1.4 mL / min; Temperature: 25 °C; DAD scan: 254 nm

[1271] Optical rotation: [α] D 20 = -6.7° + / - 0.62° (c = 1.00, methanol).

[1272] Example 12

[1273] (+)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2- hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide, enantiomer 2

[1274]

[1275] According to example 11, 63 mg of example 10, in addition 29 mg of (+)-6-(4- methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2- hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide, enantiomer 2, were isolated.

[1276] 1 H-NMR (400 MHz, CDC13): δ [ppm] = 2.44 (s, 3H); 3.78 (ddd, 1H); 3.90 (ddd, 1H); 3.99 (s, 3H); 4.18-4.27 (m, 1H); 4.56 (d, 1H); 7.33 (d, 2H); 7.82 (d, 2H); 8.16 (s, 1H); 8.33 (s, 1H); 8.71 (s, 1H); 10.24 (bt, 1H).

[1277] Chiral HPLC: Rt = 3.11 min

[1278] Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3pm 100x4.6mm; Eluent: methanol (0.1% diethylamine) / ethanol 50:50, flow rate 1.4 mL / min; Temperature: 25°C; DAD scan: 254 nm

[1279] Optical rotation: [a] D 20 = 5.6° + / - 0.47° (c = 1.00, methanol).

[1280] Example 13

[1281] N-(3,3-difluoro-2-hydroxypropyl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide

[1282]

[1283] A solution of 100 mg of intermediate 6, 71.6 mg of 3-amino-1,1 -difluoropropan-2-ol, 184 mg of HATU and 0.17 mL of ethyldiisopropylamine in 5 mL of DMF was stirred at room temperature for 14 hours. The reaction was then quenched by water and the mixture was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was subjected to flash chromatography (dichloromethane / methanol, gradient up to 2% of methanol) to give 55 mg of N-(3,3-difluoro-2-hydroxypropyl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide.

[1284] 1 H-NMR (400 MHz, CDC13): δ [ppm] = 2.43 (s, 3H); 3.67-3.77 (m, 1H); 3.84 (ddd, 1H); 3.95-4.09 (m+s, 4H); 4.11 (d, 1H); 5.79 (dt, 1H); 7.32 (d, 2H); 7.82 (d, 2H); 8.14 (s, 1H); 8.33 (s, 1H); 8.70 (s, 1H); 10.16 (bt, 1H).

[1285] Example 14

[1286] N-(3,3-difluoro-2-hydroxypropyl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide, enantiomer 1

[1287]

[1288] HPLC-separation on a chiral column (Chiralpak IA 5 μm 250x30 mm, eluent: methanol (0.1 % diethylamine) / ethanol 50:50, flow rate 30 mL / min) of 53 mg N-(3,3-difluoro-2-hydroxypropyl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 13) gave 24 mg N-(3,3-difluoro-2-hydroxypropyl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 1.

[1289] 1 H-NMR (400 MHz, CDC13): δ [ppm] = 2.43 (s, 3H); 3.67-3.77 (m, 1H); 3.84 (ddd, 1H); 3.95-4.09 (m+s, 4H); 4.11 (d, 1H); 5.79 (dt, 1H); 7.32 (d, 2H); 7.82 (d, 2H); 8.14 (s, 1H); 8.33 (s, 1H); 8.70 (s, 1H): 10.16 (bt, 1H).

[1290] Chiral HPLC: Rt = 3.92 min

[1291] Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3 μm 100x4.6 mm; eluent: methanol (0.1 % diethylamine) / ethanol 50:50, flow rate 1.4 mL / min; temperature: 25 °C; DAD scan: 254 nm.

[1292] Example 15

[1293] N-(3,3-difluoro-2-hydroxypropyl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 2

[1294]

[1295] According to Example 14 53 mg Example 13 were separated, additionally 24 mg N-(3,3-difluoro-2-hydroxypropyl)-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 2 were obtained.

[1296] 1 H-NMR (400 MHz, CDC13): δ [ppm] = 2.43 (s, 3H); 3.67-3.77 (m, 1H); 3.84 (ddd, 1H); 3.95-4.09 (m+s, 4H); 4.11 (d, 1H); 5.79 (dt, 1H); 7.32 (d, 2H); 7.82 (d, 2H); 8.14 (s, 1H); 8.33 (s, 1H); 8.70 (s, 1H); 10.16 (bt, 1H).

[1297] Chiral HPLC: Rt = 4.78 min

[1298] Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3 pm 100 x 4.6 mm; Eluent: methanol (0.1% diethylamine) / ethanol 50:50, flow rate 1.4 mL / min; Temperature: 25 °C; DAD scan: 254 nm.

[1299] Example 16

[1300] 6-(4-Chlorophenyl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1301]

[1302] A solution of 80 mg of intermediate 11, 49.9 mg of (2S)-2-amino-3-methylbutan-1-ol, 138 mg of HATU and 0.13 mL of ethyldiisopropylamine in 5 mL of DMF was stirred at room temperature for 14 hours. The reaction was then quenched by water and the mixture was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was subjected to RP-HPLC ((column: X-Bridge CI 85 pm 100 x 30 mm, mobile phase: acetonitrile / water (0.1 vol% formic acid) - gradient) to give 45 mg of 6-(4-chlorophenyl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1303] 1H-NMR (400 MHz, CDC13): δ [ppm] = 1.05 (d, 3H), 1.06 (d, 3H), 2.01-2.14 (m, 1H), 2.79 (t, 1H), 3.75-3.82 (m, 1H), 3.83-3.89 (m, 1H), 3.96-4.06 (m, 4H), 7.46-7.51 (m, 2H), 7.85-7.90 (m, 2H), 8.11 (s, 1H), 8.34 (s, 1H), 8.69 (s, 1H), 9.93 (br d, 1H).

[1304] Example 17

[1305] 6-(4-Chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide

[1306] A solution of 80 mg of intermediate 11, 29.1 mg of (2S)-2-aminopropan-1-ol, 110 mg of HATU and 0.1 mL of ethyldiisopropylamine in 5 mL of DMF was stirred at room temperature for 14 hours. The reaction was then quenched by water and the mixture was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was subjected to RP-HPLC ((column: X-Bridge CI 85 μm 100 x 30 mm, mobile phase: acetonitrile / water (0.1 vol% formic acid) - gradient) to give 50 mg of 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide.

[1307] 1 H-NMR (400 MHz, CDC13): δ [ppm] = 1.34 (d, 3H); 2.73-2.82 (m, 1H); 3.66-3.73 (m, 1H); 3.77-3.84 (m, 1H); 3.98 (s, 3H); 4.26-4.36 (m, 1H); 7.49 (d, 2H); 7.87 (d, 2H); 8.12 (s, 1H); 8.33 (s, 1H); 8.69 (s, 1H); 9.82 (bd, 1H).

[1308] Example 18

[1309] 6-(4-Chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2- hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide

[1310]

[1311] A solution of 130 mg of intermediate 11, 101 mg of 3-amino-1,1,1-trifluoropropan-2-ol, 224 mg of HATU and 0.21 mL of ethyldiisopropylamine in 10 mL of DMF was stirred at room temperature for 14 hours. The reaction was then quenched by water and the mixture was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was subjected to flash chromatography (dichloromethane / methanol, gradient up to 2% methanol) to give 160 mg of 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide.

[1312] 1 H-NMR (400 MHz, CDC13): δ [ppm] = 3.70-3.79 (m, 1H); 3.93 (ddd, 1H); 3.98 (s, 3H); 4.21-4.28 (m, 1H); 4.64 (br s, 1H); 7.49 (d, 2H); 7.85 (d, 2H); 8.11 (s, 1H); 8.31 (s, 1H); 8.66 (s, 1H); 10.15 (bt, 1H).

[1313] Example 19

[1314] (-)-6-(4-Chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2- hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide

[1315]

[1316] HPLC-separation on a chiral column (Chiralpak IA 5 pm 250x30 mm, eluent: CO2 / 2-propanol 77:23, flow 100 mL / min, p=150 bar, T=40°C) of 158 mg of 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide (Example 18) gave 50 mg of (-)-6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide.

[1317] 1H-NMR (400 MHz, CDC13): δ [ppm] = 3.70-3.79 (m, 1 H); 3.93 (ddd, 1 H); 3.98 (s, 3 H); 4.21-4.28 (m, 1 H); 4.64 (br s, 1 H); 7.49 (d, 2 H); 7.85 (d, 2 H); 8.11 (s, 1 H); 8.31 (s, 1 H); 8.66 (s, 1 H); 10.15 (bt, 1 H).

[1318] Chiral HPLC: Rt = 2.76 min

[1319] Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3 pm 100 x 4.6 mm; Eluent: C02 / 2-propanol 77:23, flow rate 4 mL / min, p = 100 bar, T = 37.5 °C; DAD scan: 254 nm

[1320] Optical rotation: [a] D 20 = -5.2 ° + / - 0.35 ° (c = 1.00, methanol).

[1321] Example 20

[1322] (+)-6-(4-Chlorophenyl)-2-(1-methyl-1 H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2- hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide

[1323]

[1324] According to example 19, 158 mg of example 18 were isolated, in addition 55 mg of (+)-6-(4-chlorophenyl)-2-(1-methyl-1 H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2- hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide were additionally obtained.

[1325] 1 H-NMR (400 MHz, CDC13): δ [ppm] = 3.70-3.79 (m, 1 H); 3.93 (ddd, 1 H); 3.98 (s, 3 H); 4.21-4.28 (m, 1 H); 4.64 (br s, 1 H); 7.49 (d, 2 H); 7.85 (d, 2 H); 8.11 (s, 1 H); 8.31 (s, 1 H); 8.66 (s, 1 H); 10.15 (bt, 1 H).

[1326] Chiral HPLC: Rt = 3.75 min

[1327] Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3pm 100x4.6mm; Eluent: CO2 / 2-propanol 77:23, flow rate 4 mL / min, p = 100 bar, T = 37.5 °C; DAD scan: 254 nm

[1328] Optical rotation:

[1329] [α] D 20 = 6.9° + / - 0.23° (c = 1.00, methanol).

[1330] Example 21

[1331] 6-(4-Chlorophenyl)-N-(3,3-difluoro-2-hydroxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3- oxo-2,3-dihydropyridazine-4-carboxamide

[1332] A solution of 110 mg of intermediate 11, 59.1 mg of 3-amino-1,1-difluoropropan-2-ol, 152 mg of HATU and 0.14 mL of ethyldiisopropylamine in 5 mL of DMF was stirred at room temperature for 14 hours. The reaction was then quenched by water and the mixture was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was subjected to RP-HPLC ((column: X-Bridge CI 85pm 100x30mm, mobile phase: acetonitrile / water (0.1 vol% formic acid) - gradient) to give 65 mg of 6-(4-chlorophenyl)-N-(3,3-difluoro-2-hydroxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1333] 1 H-NMR (400 MHz, CDC13): δ [ppm] = 3.68-3.77 (m, 1H); 3.85 (ddd, 1H); 3.96-4.08 (m+s, 5H); 5.79 (dt, 1H); 7.49 (d, 2H); 7.86 (d, 2H); 8.12 (s, 1H); 8.32 (s, 1H); 8.67 (s, 1H); 10.10 (bt, 1H).

[1334] Example 22

[1335] (-)-6-(4-Chlorophenyl)-N-(3,3-difluoro-2-hydroxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3- oxo-2,3-dihydropyridazine-4-carboxamide

[1336]

[1337] HPLC-separation on a chiral column (Chiralpak IA 5 pm 250x30mm, eluent: CO2 / 2-propanol 71 :29, flow 100 mL / min, p=150 bar, T=40°C) of 63 mg 6-(4-chlorophenyl)-N-(3,3-difluoro-2-hydroxypropyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 21 ) gave 15 mg (-)-6-(4-chlorophenyl)-N-(3,3-difluoro-2-hydroxypropyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1338] 1 H-NMR (400 MHz, CDC13): δ [ppm] = 3.68-3.77 (m, 1 H); 3.85 (ddd, 1 H); 3.96-4.08 (m+s, 5H); 5.79 (dt, 1 H); 7.49 (d, 2H); 7.86 (d, 2H); 8.12 (s, 1 H); 8.32 (s, 1 H); 8.67 (s, 1 H); 10.10 (bt, 1 H).

[1339] Chiral HPLC: Rt = 2.50 min

[1340] Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3 pm 100x4.6mm; eluent: CO2 / 2-propanol 71 :29, flow 4 mL / min, p=100 bar, T=37.5°C; DAD scan: 254 nm

[1341] Optical rotation: [a] D 20 = -6.6° + / - 0.41 ° (c = 1.00, methanol).

[1342] Example 23

[1343] (+)-6-(4-chlorophenyl)-N-(3,3-difluoro-2-hydroxypropyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1344]

[1345] According to Example 22, 63 mg of Example 21 was isolated, in addition 20 mg of (+)-6-(4-chlorophenyl)-N-(3,3-difluoro-2-hydroxypropyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydro pyridazine-4-carboxamide was additionally obtained.

[1346] 1 H-NMR (400 MHz, CDC13): δ [ppm] = 3.68-3.77 (m, 1H); 3.85 (ddd, 1H); 3.96-4.08 (m+s, 5H); 5.79 (dt, 1H); 7.49 (d, 2H); 7.86 (d, 2H); 8.12 (s, 1H); 8.32 (s, 1H); 8.67 (s, 1H); 10.10 (bt, 1H).

[1347] Chiral HPLC: Rt = 4.12 min

[1348] Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3 pm 100 x 4.6 mm; Eluent: C02 / 2-propanol 71 :29, flow rate 4 mL / min, p = 100 bar, T = 37.5 °C; DAD scan: 254 nm

[1349] Optical rotation: [a] D 20 = 8.4° + / - 0.32° (c = 1.00, methanol).

[1350] Example 24

[1351] 6-(4-chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydro pyridazine-4-carboxamide

[1352]

[1353] A solution of 110 mg of intermediate 11, 55.9 mg of 1-amino-3-methoxypropan-2-ol, 152 mg of HATU and 0.14 mL of ethyldiisopropylamine in 5 mL of DMF was stirred at room temperature for 14 hours. The reaction was then quenched by water and the mixture was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was subjected to RP-HPLC ((column: X-Bridge CI 85 μm 100 x 30 mm, mobile phase: acetonitrile / water (0.1 vol% formic acid) - gradient) to give 40 mg of 6-(4-chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1-methyl-1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1354] 1 H-NMR (400 MHz, CDCI3): δ [ppm] = 3.06 (d, 1 H); 3.40-3.46 (m+s, 4H); 3.47-3.60 (m, 2H); 3.74 (ddd, 1 H); 3.98 (s, 3H); 4.01-4.08 (m, 1 H); 7.49 (d, 2H); 7.88 (d, 2H); 8.13 (s, 1 H); 8.37 (s, 1 H); 8.69 (s, 1 H); 9.97 (bt, 1 H).

[1355] Example 25

[1356] (-)-6-(4-chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1-methyl-1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1357]

[1358] HPLC-separation on a chiral column (Chiralpak AD-H 5 μm 250 x 30 mm, eluent: acetonitrile (0.1 vol% diethylamine) / ethanol 90:10, flow rate 50 mL / min) of 38 mg of 6-(4-chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1-methyl-1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 24) gave 18 mg of (-)-6-(4-chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1-methyl-1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1359] 1H-NMR (400 MHz, CDC13): δ [ppm] = 3.06 (d, 1 H); 3.40-3.46 (m+s, 4H); 3.47-3.60 (m, 2H); 3.74 (ddd, 1 H); 3.98 (s, 3H); 4.01-4.08 (m, 1 H); 7.49 (d, 2H); 7.88 (d, 2H); 8.13 (s, 1 H); 8.37 (s, 1 H); 8.69 (s, 1 H); 9.97 (bt, 1 H).

[1360] Chiral HPLC: Rt = 3.83 min

[1361] Instrument: Agilent HPLC 1260; Column: Chiralpak AD-H 3 μm 100 x 4.6 mm; Eluent: Acetonitrile (0.1 vol% diethylamine) / Ethanol 90:10, flow rate 1.4 mL / min, DAD scan: 254 nm

[1362] Optical rotation: [α] D 20 = -5.2° + / - 0.44° (c = 1.00, methanol).

[1363] Example 26

[1364] (+)-6-(4-Chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1-methyl-1 H-pyrazol-4-yl)-3- oxo-2,3-dihydropyridazine-4-carboxamide

[1365]

[1366] According to example 25, 38 mg of example 24 were isolated, additionally 15 mg of (+)-6-(4-Chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1-methyl-1 H-pyrazol-4-yl)-3- oxo-2,3-dihydropyridazine-4-carboxamide were obtained.

[1367] 1 H-NMR (400 MHz, CDC13): δ [ppm] = 3.06 (d, 1 H); 3.40-3.46 (m+s, 4H); 3.47-3.60 (m, 2H); 3.74 (ddd, 1 H); 3.98 (s, 3H); 4.01-4.08 (m, 1 H); 7.49 (d, 2H); 7.88 (d, 2H); 8.13 (s, 1 H); 8.37 (s, 1 H); 8.69 (s, 1 H); 9.97 (bt, 1 H).

[1368] Chiral HPLC: Rt = 4.88 min

[1369] Instrument: Agilent HPLC 1260; Column: Chiralpak AD-H 3 pm 100 x 4.6 mm; Eluent: Acetonitrile (0.1 vol% diethylamine) / Ethanol 90:10, flow rate 1.4 mL / min, DAD scan: 254 nm

[1370] Optical rotation: [a] D 20 = 6.2° + / - 0.31 ° (c = 1.00, methanol).

[1371] Example 27

[1372] 6-(4-Chlorophenyl)-N-[(2S)-2,3-dihydroxypropyl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1373]

[1374] Dissolve 6-(4-chlorophenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) in dry DMF (1.1 mL). Add successively (2S)-3-aminopropane-1,2-diol (27.5 mg, 0.30 mmol), N- ethyl-N-isopropylpropan-2-amine (0.118 mL, 0.68 mmol) and propane phosphonic anhydride (T3P, 132 μL, 50% in DMF, 227 μmol). Stir at room temperature overnight. Purify the crude reaction mixture by RP-HPLC (column: X-Bridge CI 85 μm 100 x 30 mm, mobile phase: (water + 0.2 vol% ammonia water (32%)) / acetonitrile, gradient) to give 21.5 mg (35%) of the title compound.

[1375] Optical rotation: [a] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.20-3.30 (m, 1 H), 3.30-3.36 (m, 1 H and water signal), 3.38-3.44 (m, 1 H), 3.58-3.67 (m, 2H), 3.93 (s, 3H), 4.70 (t, 1 H), 5.03 (d, 1 H), 7.58-7.62 (m, 2H), 8.08-8.13 (m, 3H), 8.55 (s, 1 H), 8.59 (s, 1 H), 9.63 (t, 1 H).

[1376] Optical rotation: [a] D 20= -5.5 ° (c = 1.00, DMSO).

[1377] Example 28

[1378] 6-(4-Chlorophenyl)-N-[(2R)-2,3-dihydroxypropyl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1379] Dissolve 6-(4-chlorophenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) in dry DMF (1.1 mL). Add successively (2R)-3-aminopropane-1,2-diol (27.5 mg, 0.30 mmol), N- ethyl-N-isopropylpropan-2-amine (0.118 mL, 0.68 mmol) and propane phosphonic anhydride (T3P, 132 μί, 50% in DMF, 227 μιηοΐ). Stir at room temperature overnight. Purify the crude reaction mixture by RP-HPLC (column: X-Bridge CI 85 μιη 100 x 30 mm, mobile phase: (water + 0.2 vol% ammonia water (32%)) / acetonitrile, gradient) to give 17.5 mg (29%) of the title compound.

[1380] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.21 - 3.30 (m, 1 H), 3.30 - 3.36 (m, 1 H and water signal), 3.38 - 3.44 (m, 1 H), 3.58 - 3.67 (m, 2H), 3.93 (s, 3H), 4.70 (t, 1 H), 5.03 (d, 1 H), 7.58 - 7.62 (m, 2H), 8.08 - 8.13 (m, 3H), 8.55 (s, 1 H), 8.59 (s, 1 H), 9.63 (t, 1 H).

[1381] [α] D 20 = +14.3 ° (c = 1.00, DMSO).

[1382] Example 29

[1383] 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxy-3-methoxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1384]

[1385] Dissolve 6-(4-chlorophenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4- carboxylic acid (50 mg, 0.15 mmol) in dry DMF (1.1 mL). Add successively (2S)-2-amino-3- methoxypropan-1 -ol (31.8 mg, 0.30 mmol), N-ethyl-N-isopropylpropan-2-amine (0.118 mL, 0.68 mmol) and propane phosphonic anhydride (T3P, 132 μί, 50% in DMF, 227 μιηοΐ). Stir at room temperature overnight. Purify the crude reaction mixture by RP-HPLC (column: X-Bridge CI 85 μιη 100 x 30 mm, mobile phase: (water + 0.2 vol% ammonia (32%)) / acetonitrile, gradient) to give 33 mg (52%) of the title compound.

[1386] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.30 (s, 3H), 3.44-3.61 (m, 4H), 3.93 (s, 3H), 4.10-4.19 (m, 1 H), 4.99 (t, 1 H), 7.58-7.62 (m, 2H), 8.08-8.12 (m, 3H), 8.56 (s, 1 H), 8.60 (s, 1 H), 9.64 (d, 1 H).

[1387] Example 30

[1388] 6-(4-Chlorophenyl)-N-[(2R)-1 -hydroxy-3-methoxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1389]

[1390] Dissolve 6-(4-chlorophenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4- carboxylic acid (50 mg, 0.15 mmol) in dry DMF (1.1 mL). Add successively (2S)-2-amino-3- methoxypropan-1 -ol (31.8 mg, 0.30 mmol), N-ethyl-N-isopropylpropan-2-amine (0.118 mL, 0.68 mmol) and propane phosphonic anhydride (T3P, 132 μί, 50% in DMF, 227 μιηοΐ). Stir at room temperature overnight. Purify the crude reaction mixture by RP-HPLC (column: X-Bridge CI 85 μιη 100 x 30 mm, mobile phase: (water + 0.2 vol% ammonia (32%)) / acetonitrile, gradient) to give 33 mg (52%) of the title compound.

[1391] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.30 (s, 3H), 3.44-3.61 (m, 4H), 3.93 (s, 3H), 4.10-4.19 (m, 1H), 4.99 (t, 1H), 7.58-7.62 (m, 2H), 8.08-8.12 (m, 3H), 8.56 (s, 1H), 8.60 (s, 1H), 9.64 (d, 1H).

[1392] Example 31

[1393] 6-(4-Chlorophenyl)-N-(1,3-dihydroxypropan-2-yl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1394] Dissolve 6-(4-chlorophenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) in dry DMF (1.1 mL). Add successively (2R)-2-aminopropan-1,3-diol (27.5 mg, 0.30 mmol), N- ethyl-N-isopropylpropan-2-amine (0.118 mL, 0.68 mmol) and propane phosphonic anhydride (T3P, 132 μί, 50% in DMF, 227 μιηοΐ). Stir at room temperature overnight. Purify the crude reaction mixture by RP-HPLC (column: X-Bridge CI 85 μιη 100 x 30 mm, mobile phase: (water + 0.2 vol% ammonia water (32%)) / acetonitrile, gradient) to give 29 mg (48%) of the title compound.

[1395] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.47-3.54 (m, 2H), 3.57-3.63 (m, 2H), 3.93 (s, 3H), 3.94-4.02 (m, 1H), 4.89 (t, 2H), 7.58-7.62 (m, 2H), 8.07-8.13 (m, 3H), 8.57 (s, 1H), 8.60 (s, 1H), 9.63 (d, 1H).

[1396] Example 32

[1397] 6-(4-Chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1398] Dissolve 6-(4-chlorophenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydro- pyridazine-4-carboxylic acid (50 mg, 0.15 mmol) in dry DMF (1.1 mL). Add successively 1 -amino-2-methylpropan-2-ol (27 mg, 0.30 mmol), N-ethyl-N- isopropylpropan-2-amine (0.118 mL, 0.68 mmol) and triphosgene (T3P, 132 μί, 50% in DMF, 227 μιηοΐ). Stir at room temperature overnight. Purify the crude reaction mixture by RP-HPLC (column: X-Bridge CI 8 5 μιη 100 x 30 mm, mobile phase: (water + 0.2 vol% ammonia (32%)) / acetonitrile, gradient) to give 20 mg (33%) of the title compound.

[1399] 1 H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.15 (s, 6H), 3.32-3.35 (m, 2H and water signal), 3.93 (s, 3H), 4.70 (s, 1 H), 7.58-7.62 (m, 2H), 8.07-8.13 (m, 3H), 8.56 (s, 1 H), 8.59 (s, 1 H), 9.65 (t, 1 H).

[1400] Example 33

[1401] 6-(4-Chlorophenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-N-[(2RS)-1, 1, 1 - trifluoro-3-hydroxypropan-2-yl]-2,3-dihydropyridazine-4-carboxamide

[1402]

[1403] Dissolve 6-(4-chlorophenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydro- pyridazine-4-carboxylic acid (100 mg, 0.30 mmol) in dry DMF (2.3 mL). Add successively ...

Claims

1. A pharmaceutical composition, which is a tablet, comprising a compound of general formula (I): Their enantiomers, diastereomers, racemates, tautomers, and their physiologically acceptable salts, R 1 represents C2-C6-hydroxyalkyl, wherein said C2-C6-hydroxyalkyl is optionally substituted one time with cyano, -COOR 10 , -CONR 11 R 12 , C1-C2-alkoxy or cyclopropyl one time and optionally one to three times with halogen, or C4-C6-cycloalkyl, which is substituted one time with hydroxy and optionally one time with C1-C3-alkyl and / or one to three times with halogen, or C3-C6-cycloalkyl-methyl, which is substituted once with a hydroxyl group and optionally substituted once with a C1-C3-alkyl group and / or substituted once to three times with a halogen, or (C3-C6-cycloalkyl)2-methyl, which is substituted once with a hydroxyl group and optionally substituted once with a C1-C3-alkyl group and / or substituted once to three times with a halogen, or 5- or 6-membered heterocyclic alkyl group, which is substituted once with a hydroxyl group and optionally substituted once with a C1-C3-alkyl group and / or substituted once to three times with a halogen; R 2 represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy or trifluoromethoxy; R 3 represents hydrogen or fluorine; R 4 represents hydrogen or fluorine; R 5 represents a monocyclic heteroaryl group, which is optionally substituted one to three times, independently of one another, by R 6 one to three times, independently of one another, by R R 6 represents methyl, difluoromethyl, methoxy, halogen or cyano; X represents CH or N; R 10 represents C1-C4-alkyl; R 11 and R 12 are identical or different and, independently of each other, signify hydrogen or Ci-C3-alkyl, or form together with the nitrogen atom to which they are attached a 4- to 6-membered nitrogen containing heterocyclic ring, which optionally contains one further heteroatom selected from O, S, NH, NR a wherein R a represents CrC4-alkyl; and One or more pharmaceutically acceptable excipients.

2. The pharmaceutical composition according to claim 1, wherein: R 1 represents C2-C5-hydroxyalkyl, wherein said C2-C5-hydroxyalkyl is optionally substituted one time with cyano, -COOCH3, -CONH2, methoxy or cyclopropyl, and optionally one to three times with fluorine, or C4-C6-cycloalkyl, which is substituted once with a hydroxyl group and optionally substituted once with a methyl group and / or substituted once or twice with a fluorine group, or C3-C4-cycloalkyl-methyl, which is substituted once with a hydroxyl group, or 5- or 6-membered heterocyclic alkyl group, which is substituted once with a hydroxyl group, wherein the heterocyclic alkyl group contains one oxygen atom; R 2 represents chlorine, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy; R 3 represents hydrogen; R 4 represents hydrogen or fluorine; R 5 represents a group selected from the following: Where * indicates the connection point between the group and the rest of the molecule; R 6a represents hydrogen, methyl, fluorine or chlorine; X represents CH or N.

3. The pharmaceutical composition according to claim 1 or 2, wherein the compound of general formula (I) is selected from: N-(1-hydroxy-3-methylbut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1-hydroxy-3-methylbut-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxy-3-methylbut-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxybut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1-hydroxybut-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxybut-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxypropyl-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1-hydroxypropyl-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1 -hydroxypropan-2-yl]-6-(4-methylphenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(3,3-difluoro-2-hydroxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-3,3-difluoro-2-hydroxypropyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-3,3-difluoro-2-hydroxypropyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2R)-2-hydroxy-3-methoxypropyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-2-hydroxy-3-methoxypropyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(2,3-dihydroxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-2,3-dihydroxypropyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-2,3-dihydroxypropyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(1-hydroxy-3-methoxypropyl-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2R)-1-hydroxy-3-methoxypropyl-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1-hydroxy-3-methoxypropyl-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(1,3-dihydroxypropyl-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2R)-1,1,1-trifluoro-3- hydroxypropan-2-yl] -2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2R)-1,1,1-trifluoro-3- hydroxypropan-2-yl] -2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2R)-1,1,1-trifluoro-3- hydroxypropan-2-yl] -2,3-dihydropyridazine-4-carboxamide; 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl]-6-[4- (trifluoromethyl)phenyl] -2,3-dihydropyridazine-4-carboxamide; 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl]-6-[4- (trifluoromethyl)phenyl] -2,3-dihydropyridazine-4-carboxamide; 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl]-6-[4- (trifluoromethyl)phenyl] -2,3-dihydropyridazine-4-carboxamide; 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl]-6-[4- (trifluoromethyl)phenyl] -2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxypropan-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxypropan-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxypropan-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2- hydroxypropan-2-yl] -2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2- hydroxypropan-2-yl] -2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2- hydroxypropan-2-yl] -2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(1-cyclobutyl-1H-pyrazol-4-yl)-3-oxo-N-[(2R)-1,1,1-trifluoro-3- hydroxypropan-2-yl] -2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(1-cyclobutyl-1H-pyrazol-4-yl)-N-(1-hydroxypropan-2-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(1-cyclobutyl-1H-pyrazol-4-yl)-N-[(2S)-1-hydroxypropan-2-yl]-3- oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(cis)-4-hydroxytetrahydrofuran-3-yl]-2-(1-methyl-1H-pyrazol-4- yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(3R,4R)-4-hydroxytetrahydrofuran-3-yl]-2-(1-methyl-1H-pyrazol- 4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]-2-(1-methyl-1H-pyrazol- 4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(cis)-2-hydroxycyclohexyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide; N-[(1S,2R)-2-hydroxycyclohexyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethoxy)phenyl] -2,3-dihydropyridazine-4-carboxamide; 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(1,1,1-trifluoro-3-hydroxypropan-2-yl)-6-[4- (trifluoromethoxy)phenyl] -2,3-dihydropyridazine-4-carboxamide; 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl]-6- [4-(trifluoromethoxy)phenyl] -2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(cis)-2-hydroxycyclohexyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(1S,2R)-2-hydroxycyclohexyl]-2-(1-methyl-1H-pyrazol-4-yl)-3- oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(trans)-2-hydroxycyclopentyl]-2-(1-methyl-1H-pyrazol-4-yl)-3- oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(lS,2S)-2-hydroxycyclopentyl]-2-(l-methyl-lH-pyrazol-4-yl)- 3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(lS,2S)-2-hydroxycyclopentyl]-2-(l-methyl-lH-pyrazol-4-yl)- 3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(lS,2S)-2-hydroxycyclopentyl]-2-(l-methyl-lH-pyrazol-4-yl)- 3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethyl)phenyl]-N-[(trans)-2-hydroxycyclopentyl]-2-(l-methyl-lH-pyrazol- 4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-(l-hydroxypropan-2-yl)-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide; N-(l-hydroxypropan-2-yl)-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-[(lS,2R)-2-hydroxycyclohexyl]-2-(l-methyl-lH- pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-[(lS,2R)-2-hydroxycyclohexyl]-2-(l-methyl-lH- pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(3R,4R)-4-hydroxytetrahydrofuran-3-yl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-6- [4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(3R,4R)-4-hydroxytetrahydrofuran-3-yl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-6- [4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(3R,4R)-4-hydroxytetrahydrofuran-3-yl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-6- [4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethyl)phenyl]-N-(l-hydroxypropan-2-yl)-2-(l-methyl-lH-pyrazol-4-yl)- 3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethyl)phenyl]-N-(l-hydroxypropan-2-yl)-2-(l-methyl-lH-pyrazol-4-yl)- 3-oxo-2,3-dihydropyridazine-4-carboxamide; N-(2-hydroxy-2-methylpropyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethyl)phenyl]-N-[(cis)-4-hydroxytetrahydrofuran-3-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 1,5-Anhydro-2-({[6-(4-chlorophenyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3- dihydropyridazin-4-yl]carbonyl}amino)-2,4-dideoxy-D-erythro-pentitol; 6-[4-(difluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)-2-(1 -methyl- 1 H-pyrazol- 4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(trans)-4-hydroxytetrahydrofuran-3-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-(1 -hydroxypropan-2-yl)-2-(1 -methyl- 1 H-pyrazol-4- yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-[(2S)-1 -hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol- 4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-(2-hydroxy-2-methylpropyl)-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(1 -hydroxypropan-2-yl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine- 4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-1 -hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(1,3-dihydroxypropan-2-yl)-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(2,3-dihydroxypropyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-2,3-dihydroxypropyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-2,3-dihydroxypropyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(1-hydroxy-3-methoxypropyl-2-yl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2R)-1-hydroxy-3-methoxypropyl-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1-hydroxy-3-methoxypropyl-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-N-(1,1,1-trifluoro-3-hydroxypropyl-2-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-N-[(2R)-1,1,1-trifluoro-3-hydroxypropyl-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-N-[(2S)-1,1,1-trifluoro-3-hydroxypropyl-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(1-cyclopropyl-2-hydroxyethyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(1R)-1-cyclopropyl-2-hydroxyethyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(1S)-1-cyclopropyl-2-hydroxyethyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-3-oxo-2-(pyridin-3-yl)-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(3,3-difluoro-2-hydroxypropyl)-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-3,3-difluoro-2-hydroxypropyl]-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-3,3-difluoro-2-hydroxypropyl]-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-(1-hydroxypropan-2-yl)-3-oxo-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(2R)-1-hydroxypropan-2-yl]-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-(2-hydroxy-2-methylpropyl)-3-oxo-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-(1-hydroxy-3-methylbutan-2-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(2S)-1-hydroxy-3-methylbutan-2-yl]- 3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(1,3-dihydroxypropan-2-yl)-2-(5-fluoropyridin-3-yl)-3-oxo-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-(1-hydroxy-3-methoxypropan-2-yl)-3- oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(2R)-1-hydroxy-3-methoxypropan-2- yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(2S)-1-hydroxy-3-methoxypropan-2- yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(1-fluoro-3-hydroxypropan-2-yl)-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-1-fluoro-3-hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; N-(1-cyclopropyl-2-hydroxyethyl)-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; N-[(1S)-1-cyclopropyl-2-hydroxyethyl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(1-cyclopropyl-2-hydroxyethyl)-2-(5-fluoropyridin-3-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(2,3-dihydroxypropyl)-2-(5-fluoropyridin-3-yl)-3-oxo-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-2,3-dihydroxypropyl]-2-(5-fluoropyridin-3-yl)-3-oxo-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-2,3-dihydroxypropyl]-2-(5-fluoropyridin-3-yl)-3-oxo-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-3-oxo-N-(1,1,1-trifluoro-3-hydroxypropan- 2-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-3-oxo-N-[(2R)-1,1,1-trifluoro-3- hydroxypropan-2-yl]-2,3-dihydropyridazine-4-carboxamide; N-(3,3-difluoro-2-hydroxypropyl)-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; N-(2-hydroxycyclopentyl)-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3- dihydropyridazine-4-carboxamide; N-[(1S,2S)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; N-[(1R,2R)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; N-[(1R,2S)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; N-[(1S,2R)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; N-[(cis)-2-hydroxycyclohexyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; N-[(lS,2R)-2-hydroxycyclohexyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; N-[(cis)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-oxo-2-(pyridin-3-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-oxo-2-(pyridin-3-yl)-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-oxo-2-(pyridin-3-yl)-N-(l,l,l-trifluoro-3-hydroxypropan-2-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-oxo-2-(pyridin-3-yl)-N-[(2R)-l,l,l-trifluoro-3-hydroxypropan-2-yl]-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-(l-hydroxy-3-methoxypropan-2-yl)-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-l-hydroxy-3-methoxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-(2,3-dihydroxypropyl)-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; N-[(2R)-2,3-dihydroxypropyl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-2,3-dihydroxypropyl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-(2-hydroxy-2-methylpropyl)-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-(l,3-dihydroxypropan-2-yl)-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-(l-hydroxypropan-2-yl)-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1 -hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(1 -hydroxypropan-2-yl)-3-oxo-2-(pyrimidin-5-yl)-2,3- dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(pyrimidin-5-yl)-2,3- dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-3-oxo-2-(pyridin-3-yl)-N-(1,1,1 -trifluoro-3-hydroxy-3- methylbutan-2-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-3-oxo-2-(pyridin-3-yl)-N-[(2R)-1,1,1 -trifluoro-3-hydroxy-3- methylbutan-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-3-oxo-2-(pyridin-3-yl)-N-[(2S)-1,1,1 -trifluoro-3-hydroxy-3- methylbutan-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(cis)-2-hydroxycyclohexyl]-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(1 S,2R)-2-hydroxycyclohexyl]-3- oxo-2,3-dihydropyridazine-4-carboxamide; N-[(Cis)-2-hydroxycyclohexyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]- 2,3-dihydropyridazine-4-carboxamide; N-[(1 S,2R)-2-hydroxycyclohexyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]- 2,3-dihydropyridazine-4-carboxamide; 6-[4-(Difluoromethyl)phenyl]-3-oxo-2-(pyridin-3-yl)-N-(1,1,1 -trifluoro-3- hydroxypropan-2-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[4-(Difluoromethyl)phenyl]-3-oxo-2-(pyridin-3-yl)-N-[(2R)-1,1,1 -trifluoro-3- hydroxypropan-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(5-fluoropyridin-3-yl)-3-oxo-N-(3,3,3-trifluoro-2- hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(5-fluoropyridin-3-yl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(cis)-2-hydroxycyclopentyl]-3-oxo- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(1S,2R)-2-hydroxycyclopentyl]-3- oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(trans)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(1S,2S)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 3-oxo-2-(pyridin-3-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-oxo-2-(pyridin-3-yl)-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(trans)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(1S,2S)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(cis)-2-hydroxycyclohexyl]-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 3-oxo-2-(pyridin-3-yl)-N-(1,1,1-trifluoro-3-hydroxypropan-2-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-oxo-2-(pyridin-3-yl)-N-[(2R)-1,1,1-trifluoro-3-hydroxypropan-2-yl]-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-oxo-2-(pyridin-3-yl)-N-(1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-oxo-2-(pyridin-3-yl)-N-[(2R)-1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl]-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-oxo-2-(pyridin-3-yl)-N-[(2S)-1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl]-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(cis)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(1R,2S)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethyl)phenyl]-N-[(trans)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide 6-[4-(difluoromethyl)phenyl]-N-[(1S,2S)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; N-[(trans)-3,3-difluoro-2-hydroxycyclohexyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(1S,2R)-3,3-difluoro-2-hydroxycyclohexyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(1R,2S)-3,3-difluoro-2-hydroxycyclohexyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(trans)-3,3-difluoro-2-hydroxycyclohexyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(1S,2R)-3,3-difluoro-2-hydroxycyclohexyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(1R,2S)-3,3-difluoro-2-hydroxycyclohexyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; N-[(cis)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(1S,2R)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-(1-Cyclopropyl-2-hydroxyethyl)-6-[4-(difluoromethyl)phenyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; N-[(1S)-1-cyclopropyl-2-hydroxyethyl]-6-[4-(difluoromethyl)phenyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethyl)phenyl]-N-(1-hydroxypropyl-2-yl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethyl)phenyl]-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxypropan-2-yl)-6-(4-methylphenyl)-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxypropan-2-yl]-6-(4-methylphenyl)-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; N-(1-hydroxypropan-2-yl)-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]- 2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(trans)-4-hydroxytetrahydrofuran-3-yl]- 3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]- 3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]- 3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(cis)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(3R,4R)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(trans)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chloro-2-fluorophenyl)-N-(1-hydroxypropan-2-yl)-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 6-(4-chloro-2-fluorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 3-(4-chlorophenyl)-N-[(cis)-2-hydroxycyclopentyl]-6-oxo-6H-1,4'-bipyridazine-5- carboxamide; 3-(4-chlorophenyl)-N-[(1S,2R)-2-hydroxycyclopentyl]-6-oxo-6H-1,4'-bipyridazine-5- carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-[(trans)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3- yl)-2,3-dihydropyridazine-4-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-[(1S,2S)-2-hydroxycyclopentyl]-3-oxo-2-(pyridin-3- yl)-2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxypropan-2-yl)-3-oxo-2-(pyridin-3-yl)-6-[6-(trifluoromethyl)pyridin-3-yl]- 2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[6-(trifluoromethyl)pyridin-3- yl]-2,3-dihydropyridazine-4-carboxamide; 3-(4-chlorophenyl)-N-[(cis)-2-hydroxycyclopentyl]-6-oxo-6H-1,4'-bipyridazine-5- carboxamide; 3-(4-chlorophenyl)-N-[(1S,2R)-2-hydroxycyclopentyl]-6-oxo-6H-1,4'-bipyridazine-5- carboxamide; 6-(4-chlorophenyl)-N-[(trans)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(cis)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(3R,4R)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 3-(4-chlorophenyl)-N-[(trans)-2-hydroxycyclopentyl]-6-oxo-6H-1,4'-bipyridazine-5- carboxamide; 3-(4-chlorophenyl)-N-[(1S,2S)-2-hydroxycyclopentyl]-6-oxo-6H-1,4'-bipyridazine-5- carboxamide; 1,5-Anhydro-2-({[6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazin-4- yl]carbonyl}amino)-2,4-dideoxy-cis-pentitol; 1,5-Anhydro-2-({[6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazin-4- yl]carbonyl}amino)-2,4-dideoxy-D-erythro-pentitol; 1,5-Anhydro-2,4-dideoxy-2-[({3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]- 2,3-dihydropyridazin-4-yl}carbonyl)amino]-cis-pentitol; 1,5-Anhydro-2,4-dideoxy-2-[({3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]- 2,3-dihydropyridazin-4-yl}carbonyl)amino]-D-erythro-pentitol; 3-(4-chlorophenyl)-N-(1-hydroxypropan-2-yl)-6-oxo-6H-1,4'-bipyridazine-5-carboxamide; 3-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-6-oxo-6H-1,4'-bipyridazine-5- carboxamide; 3-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-6-oxo-6H-1,4'-bipyridazine-5- carboxamide; 6-(4-cyanophenyl)-N-(1-hydroxypropan-2-yl)-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 6-(4-cyanophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-(1-hydroxypropan-2-yl)-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2-(pyridin- 3-yl)-2,3-dihydropyridazine-4-carboxamide; 3-(4-chlorophenyl)-N-[(cis)-4-hydroxytetrahydrofuran-3-yl]-6-oxo-6H-1,4'-bipyridazine- 5-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-[(cis)-4-methyltetrahydrofuran-3-yl]-3-oxo-2- (pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-[(3R,4S)-4-methyltetrahydrofuran-3-yl]-3-oxo- 2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(1 H-pyrazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2-(1,2-thiazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; N-[(1-hydroxycyclobutyl)methyl]-3-oxo-2-(1,2-thiazol-4-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(1,2-thiazol-4-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; (+)-3-oxo-2-(pyridin-3-yl)-N-(1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-3-oxo-2-(1,2-thiazol-4-yl)-N-[(2R)-1,1,1-trifluoro-3- hydroxypropan-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-3-oxo-2-(1,2-thiazol-4-yl)-N-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(1-hydroxycyclobutyl)methyl]-3-oxo-2-(1,2-thiazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-1-fluoro-3-hydroxypropan-2-yl]-3-oxo-2-(1,2- thiazol-4-yl)-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1-fluoro-3-hydroxypropan-2-yl]-3-oxo-2-(1,2-thiazol-4-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(1S,2R)-2-hydroxycyclopentyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2-(1,2-thiazol-4-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(1S)-1-cyclopropyl-2-hydroxyethyl]-3-oxo-2-(1,2-thiazol-4-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-(2-hydroxy-2-methylpropyl)-3-oxo-2-(1,2-thiazol-4-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(1,2-thiazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; N-[(1 S,2S)-2-hydroxycyclopentyl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1 -fluoro-3-hydroxypropan-2-yl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-oxo-2-(1 H-pyrazol-4-yl)-N-[(2R)-1,1,1 -trifluoro-3-hydroxypropan-2-yl]-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-oxo-2-(pyridin-3-yl)-N-(1,1,1 -trifluoro-3-hydroxy-3-methylbutan-2-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 2-[1 -(difluoromethyl)- 1 H-pyrazol-4-yl]-3-oxo-N-[(2R)-1,1,1 -trifluoro-3- hydroxypropan-2-yl]-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-cis-4-hydroxytetrahydrofuran-3-yl-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-oxo-2-(1 H-pyrazol-4-yl)-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; (+)-N-cis-2-hydroxycyclobutyl-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; (+)-N-cis-4-hydroxytetrahydrofuran-3-yl-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3,3-difluoro-2-hydroxypropyl]-2-(1 -methyl- 1 H-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(5-fluoro-2-thienyl)-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2,3- dihydropyridazine-4-carboxamide; N-[(2R)-1 -fluoro-3-hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl] -2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-3-oxo-2-(1,2-thiazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 2-[1 -(difluoromethyl)-1 H-pyrazol-4-yl]-3-oxo-N-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4- carboxamide; N-cis-2-Hydroxycyclobutyl-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(5-methyl-3-thienyl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3-Hydroxy-3-methylbutan-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(1 S)-1 -cyano-2-hydroxyethyl]-2-(1 -methyl-1 H-pyrazol-4- yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 2-[1 -(difluoromethyl)-1 H-pyrazol-4-yl]-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]- 3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; (+)-N-cis-4-Hydroxytetrahydrofuran-3-yl-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; (-)-N-(3,3-Difluoro-2-hydroxypropyl)-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; (-)-N-cis-4-Hydroxytetrahydrofuran-3-yl-2-(1 -methyl-1 H-pyrazol-4-yl)-3- oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(5-chloro-3-thienyl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3-Hydroxy-3-methylbutan-2-yl]-3-oxo-2-(1,2-thiazol-4-yl)-6-[6- (trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-3-Hydroxy-3-methylbutan-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(l,2-oxazol-4-yl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2- hydroxypropyl] -2,3-dihydropyridazine-4-carboxamide; 2-[l-(difluoromethyl)-lH-pyrazol-4-yl]-3-oxo-N-[(2S)-3,3,3-trifluoro-2- hydroxypropyl] -6-[4-(trifluoromethyl)phenyl] -2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-3-oxo-2-(pyrimidin-5-yl)-N-[(2S)-3,3,3-trifluoro-2- hydroxypropyl] -2,3-dihydropyridazine-4-carboxamide; N-[(lS)-l-cyclopropyl-2-hydroxyethyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethyl)phenyl] -2,3-dihydropyridazine-4-carboxamide; N-[(lR,2S)-2-hydroxycyclopentyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethyl)phenyl] -2,3-dihydropyridazine-4-carboxamide; N-(2-hydroxy-2-methylpropyl)-3-oxo-2-(l,2-thiazol-4-yl)-6-[6- (trifluoromethyl)pyridin-3-yl] -2,3-dihydropyridazine-4-carboxamide; (-)-3-oxo-2-(pyridin-3-yl)-N-(l,l,l-trifluoro-3-hydroxy-3-methylbutan-2-yl)-6-[4- (trifluoromethyl)phenyl] -2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-l-hydroxypropan-2-yl]-2-(5-methyl-3-thienyl)-3- oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-chloro-3-thienyl)-N-[(2S)-l-hydroxypropan-2-yl]-3- oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-l-hydroxypropan-2-yl]-3-oxo-2-(lH-pyrazol-4-yl)-6-[4- (trifluoromethyl)phenyl] -2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3-fluoro-2-hydroxypropyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethyl)phenyl] -2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-2-(5-methyl-3-thienyl)-3- oxo-2,3-dihydropyridazine-4-carboxamide; (+)-N-(3,3-difluoro-2-hydroxypropyl)-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl] -2,3-dihydropyridazine-4-carboxamide; N-[(lR,2R)-2-hydroxycyclopentyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-6-[4- (trifluoromethyl)phenyl] -2,3-dihydropyridazine-4-carboxamide; (+)-6-(4-chlorophenyl)-N-cis-2-hydroxycyclobutyl-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-chloro-3-thienyl)-N-(2-hydroxy-2-methylpropyl)-3-oxo-2,3- dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2-(1,2-thiazol-4-yl)-6-[6-(trifluoromethyl)pyridin-3-yl]- 2,3-dihydropyridazine-4-carboxamide; (-)-N-cis-4-hydroxytetrahydrofuran-3-yl-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-(1,2-oxazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(1S)-1-cyano-2-hydroxyethyl]-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; N-[(2S)-3-fluoro-2-hydroxypropyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-oxo-N-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1-hydroxy-3-methoxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-cis-2-hydroxycyclobutyl-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(1S)-1-cyclopropyl-2-hydroxyethyl]-2-(5-fluoropyridin-3-yl)-3-oxo- 2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(1H-pyrazol-4-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; 2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N-(2-hydroxy-2-methylpropyl)-3-oxo-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(1-hydroxycyclopropyl)methyl]-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N-[(2S)-3-hydroxy-3- methylbutan-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(pyrimidin-5- yl)-2,3-dihydropyridazine-4-carboxamide; N-(2-Hydroxy-2-methylpropyl)-3-oxo-2-(1H-pyrazol-4-yl)-6-[4-(trifluoromethyl) phenyl]-2,3-dihydropyridazine-4-carboxamide; N-{[6-(4-Chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazin-4- yl]carbonyl}-D-serine methyl ester; (-)-N-cis-2-Hydroxycyclobutyl-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]- 2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-2-(1,2-oxazol-4-yl)-3-oxo-2,3- dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-3-fluoro-2-hydroxypropyl]-2-(1-methyl-1H-pyrazol-4- yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-3-oxo-2-(pyrimidin-5-yl)-N-[(2R)-1,1,1-trifluoro-3-hydroxypropan- 2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N-[(2S)-1-hydroxypropan- 2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(1S)-1-cyclopropyl-2-hydroxyethyl]-3-oxo-2-(pyrimidin-5-yl)- 2,3-dihydropyridazine-4-carboxamide; N-{[6-(4-Chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazin-4-yl]carbonyl}- D-serine methyl ester; 6-[4-(Fluoromethyl)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2R)-1,1,1- trifluoro-3-hydroxypropan-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(1H-pyrazol-4- yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(2-hydroxy-2-methylpropyl)-3-oxo-2-(pyrimidin-5-yl)-2,3- dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-[l-(difluoromethyl)-lH-pyrazol-4-yl]-N-(2-hydroxy-2- methylpropyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-l-hydroxypropan-2-yl]-3-oxo-2-(pyridin-5-yl)-2,3- dihydropyridazine-4-carboxamide; 6-[4-(fluoromethyl)phenyl]-3-oxo-2-(pyridin-3-yl)-N-[(2S)-3,3,3-trifluoro-2- hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; (-)-6-(4-chlorophenyl)-N-cis-2-hydroxycyclobutyl-3-oxo-2-(pyridin-3-yl)-2,3- dihydropyridazine-4-carboxamide; 6-[4-(fluoromethyl)phenyl]-3-oxo-2-(pyridin-3-yl)-N-[(2R)-l,l,l-trifluoro-3- hydroxypropan-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-[4-(fluoromethyl)phenyl]-2-(l-methyl-lH-pyrazol-4-yl)-3-oxo-N-[(2S)-3,3,3- trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; 6-[4-(fluoromethyl)phenyl]-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-2-(l-methyl- lH-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(fluoromethyl)phenyl]-N-[(2S)-l-hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-[4-(fluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-[4-(fluoromethyl)phenyl]-N-[(2S)-l-hydroxypropan-2-yl]-2-(l-methyl-lH-pyrazol- 4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(fluoromethyl)phenyl]-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(pyridin- 3-yl)-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-l-amino-3-hydroxy-l-oxopropan-2-yl]-6-(4-chlorophenyl)-2-(l-methyl- lH-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-cis-4-hydroxytetrahydrothiophen-3-yl-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; (-)-N-cis-4-hydroxytetrahydrothiophen-3-yl-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3,3-difluoro-2-hydroxypropyl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3-fluoro-2-hydroxypropyl]-3-oxo-2-(pyridin-3-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-N-(4,4,4-trifluoro-3- hydroxybutan-2-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(cis)-4-hydroxytetrahydrofuran-3- yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(pyridin-3- yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-chloropyridin-3-yl)-N-[(2S)-1-hydroxypropan-2-yl]-3- oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-(5-methylpyridin-3-yl)-3- oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(1,1,1- trifluoro-3-hydroxy-3-methylbutan-2-yl)-2,3-dihydropyridazine-4-carboxamide; (+) 6-[4-(difluoromethoxy)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(1,1,1- trifluoro-3-hydroxy-3-methylbutan-2-yl)-2,3-dihydropyridazine-4-carboxamide; (-) 6-[4-(difluoromethoxy)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(1,1,1- trifluoro-3-hydroxy-3-methylbutan-2-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S)-1-hydroxypropan-2-yl]-2-(1-methyl-1H- pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-2-(1-methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-2-(1-methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-2-(1-methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(1,2-thiazol-4-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-2-(1-methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-2-(1-methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-2-(1-methyl-1 H-pyrazol- 4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-2-(1-methyl-1 H-pyrazol- 4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-2-(1-methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-2-(1-methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 3-(4-chlorophenyl)-6-oxo-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-6H-1,4'- bipyridazine-5-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-2-(1-methyl- 1 H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-2-(1-methyl-1 H-pyrazol- 4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-2-(1-methyl-1 H-pyrazol- 4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(1,2-thiazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(1,2-thiazol-4-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(1,2-thiazol-4-yl)-6-[4- (trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-(2-hydroxy-2-methylpropyl)-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S)-1 -hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)- 2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(pyridin- 3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(pyridin- 3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-2-(1,2-thiazol-4-yl)- 2,3-dihydropyridazine-4-carboxamide; 2-(5-fluoropyridin-3-yl)-N-[(2S)-1 -hydroxy-3-methylbutan-2-yl]-3-oxo-6-[6- (trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; 2-(5-fluoropyridin-3-yl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-6-[6- (trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; N-[(1 S)-1 -cyano-2-hydroxyethyl]-2-(5-fluoropyridin-3-yl)-3-oxo-6-[6- (trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; 2-(5-fluoropyridin-3-yl)-N-[(2S)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-6-[6- (trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; N-[(1 S)-1 -cyano-2-hydroxyethyl]-2-(5-fluoropyridin-3-yl)-3-oxo-6-[6- (trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; 2-(5-fluoropyridin-3-yl)-N-[(2R)-3-hydroxy-3-methylbutan-2-yl]-3-oxo-6-[6- (trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; 1,5-Anhydro-2,4-dideoxy-2-[({2-(5-fluoropyridin-3-yl)-3-oxo-6-[6- (trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazin-4-yl}carbonyl)amino]-D- erythro-pentitol; 2-(5-fluoropyridin-3-yl)-N-(2-hydroxy-2-methylpropyl)-3-oxo-6-[6- (trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxypropan-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[5- (trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxamide.

4. The pharmaceutical composition of claim 1, wherein the compound of general formula (I) is 6-(4-chlorophenyl)-N-(1-hydroxypropan-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3- oxo-2,3-dihydropyridazine-4-carboxamide.

5. The pharmaceutical composition of claim 1, wherein the compound of general formula (I) is 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropan-2-yl]-2-(1-methyl-1H-pyrazol-4- yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

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