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 patent application No. 201880024008.8 entitled "2-Heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamide for treating cancer". The original application corresponds to international application PCT / EP2018 / 052627, with a filing date of February 2, 2018, and a priority date of February 9, 2017. Technical Field

[0002] This invention includes 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamide compounds of general formula (I) as described and defined herein, methods for preparing said compounds, intermediate compounds that can be used to prepare said compounds, pharmaceutical compositions and combinations comprising said compounds, and use of said compounds in the preparation of pharmaceutical compositions, said pharmaceutical compositions as a sole agent or in combination with other active ingredients for the treatment or prevention of diseases, particularly cancer or conditions of immune dysregulation. Background Technology

[0003] AHR (aryl hydrocarbon receptor) is a ligand-activated transcription factor belonging to the basic helical-loop-helical / Per-Arnt-Sim (bHLH / PAS) family and located in the cytosol. Upon ligand binding, AHR translocates to the nucleus, where it forms a heterodimer with ARNT (AHR nuclear translocase), and then interacts with DREs (dioxin-responsive elements) of AHR-responsive genes to regulate their transcription. AHR is best known for binding to environmental toxins and inducing metabolic mechanisms required for their elimination, such as cytochrome P450 enzymes (e.g., CYP1A1, CYP1A2, and CYP1B1) (Reyes et al., Science, 1992, 256(5060):1193-5). Activation of AHR by biological heterologs 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 deep immunosuppression, 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 immunosuppression, AHR activation promotes the production of regulatory T cells, directly and indirectly inhibits Th1 and Th17 differentiation, and reduces DC activation and maturation (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 regulates innate immune responses, and constitutive AHR expression has shown negative regulation of type I interferon responses to viral infections (Yamada et al., Nat Immunol, 2016). In addition, mice with constitutively active AHR spontaneously develop tumors (Andersson et al., PNAS, 2002, 99(15):9990-5).

[0005] In addition to biological heterologous substances, AHR can also bind to metabolites of tryptophan degradation. Tryptophan metabolites, such as kynurenine and kynuric 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 to AHR, although their physiological effects 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 (IDO1 / IDO2) and tryptophan-2,3-dioxygenase 2 (TDO2) are responsible for catalyzing the first rate-limiting step of tryptophan metabolism. IDO1 / 2-mediated degradation of tryptophan in tumors and tumor-draining lymph nodes reduces antitumor immune responses, and inhibition of IDO inhibits 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-activated AHR can enhance tumor growth, resulting from the suppression of antitumor immune responses and the direct promotion of tumor cell survival and motility (Opitz et al., Nature, 2011, 478(7368):197-203). Therefore, AHR ligands produced by tumor cells act on tumor cells and lymphocytes in both autocrine and paracrine modes 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 especially to heterocyclic compounds capable of downregulating 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 especially to heterocyclic compounds for modulating AHR activity in therapeutic compositions.

[0011] WO 2007 / 058392 relates to novel heterocyclic compounds and their pharmaceutical uses. In particular, WO 2007 / 058392 relates especially to heterocyclic compounds with inhibitory activity against hepatitis C virus cell infection.

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

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

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

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

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

[0017] The compounds of the present invention have been found to have surprising and advantageous properties, and these form the basis of the present invention.

[0018] In particular, it has been surprisingly found that the compounds of the present invention effectively inhibit AHR (data on AHR inhibition are given in the Biological Experiments section), and therefore can be used to treat or prevent cancer or other conditions in which exogenous and endogenous AHR ligands induce dysregulated immune responses, uncontrolled cell growth, tumor cell proliferation and / or survival, immunosuppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, or diseases accompanied by uncontrolled cell growth, tumor cell proliferation and / or survival, immunosuppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses. In particular, diseases mediated by AHR, such as uncontrolled cell growth, tumor cell proliferation and / or survival, immunosuppression in the context of cancer, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, such as fluid and solid tumors, and / or their metastases, for example, 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 their metastases.

[0019] According to the first aspect, the present invention covers compounds of general formula (I):

[0020]

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

[0022] 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.

[0023] 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

[0024] 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

[0025] (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

[0026] 4- to 6-membered heterocyclic alkyl groups, which are 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;

[0027] R 2 It represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

[0028] R 3 Indicates hydrogen, fluorine, chlorine, or methyl;

[0029] R 4 Indicates hydrogen or fluorine;

[0030] R 5 This indicates a monocyclic heteroaryl group, whose optional R 6 Each can replace the other one to three times independently;

[0031] R 6 It can represent C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen, or cyano;

[0032] X represents CH or N;

[0033] R 10 Indicates C1-C4-alkyl;

[0034] R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or

[0035] 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.

[0036] 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. Detailed Implementation

[0037] definition

[0038] 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.

[0039] 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.

[0040] When used in the specification, the term "comprising" includes "consisting of".

[0041] If any item is referred to as “as mentioned in this article”, it means that it can be mentioned anywhere in this article.

[0042] The terms used in this article have the following meanings:

[0043] The term "halogen" refers to fluorine, chlorine, bromine, or iodine, especially fluorine, chlorine, or bromine atoms.

[0044] The term "C1-C6-alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl, or 1,3-dimethylbutyl, or isomers thereof. In particular, the group has 1, 2, 3 or 4 carbon atoms (“C1-C4-alkyl”), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl, and more particularly 1, 2 or 3 carbon atoms (“C1-C3-alkyl”), such as methyl, ethyl, n-propyl or isopropyl.

[0045] The term "C1-C6-haloalkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group, wherein the term "C1-C6-alkyl" is as defined above, and one or more hydrogen atoms are replaced by halogen atoms, either identically or differently. Specifically, the halogen atom is a fluorine atom. The C1-C6-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, or 1,3-difluoropropyl-2-yl. In particular, 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.

[0046] 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 above, and wherein one or two hydrogen atoms are replaced by hydroxyl groups, for example, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropyl-2-yl, 2-hydroxypropyl-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropyl-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl-propyl, 1-hydroxy-2-methyl-propyl.

[0047] The term “C1-C4-alkoxy” refers to a straight-chain or branched saturated monovalent group of the formula (C1-C4-alkyl)-O-, which represents methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, or tert-butoxy.

[0048] 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, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0049] 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 above, and wherein two hydrogen atoms are removed from different carbon atoms to form a dialkyl group.

[0050] The term “4- to 6-membered heterocyclic alkyl” refers to a monocyclic saturated heterocycle having a total of 4, 5 or 6 ring atoms, containing one or two identical or different cyclic heteroatoms from a series of N and O, wherein the heterocyclic alkyl can be attached to the rest of the molecule by any one of the carbon atoms or (if present) a nitrogen atom.

[0051] The heterocyclic alkyl group is not limited to this and can be a 4-membered ring, such as a nitrogen-containing heterocyclic butyl or oxocyclic butyl; or a 5-membered ring, such as tetrahydrofuranyl, 1,3-dioxacyclopentyl, pyrrolidinyl, imidazoalkyl, pyrazolyl, 1,2-oxazolyl or 1,3-oxazolyl; or a 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, piperazineyl, 1,3-dioxyl, 1,4-dioxyl or 1,2-oxazineyl.

[0052] Specifically, "4- to 6-membered heterocyclic alkyl" refers to a 4- to 6-membered heterocyclic alkyl as defined above, containing an epoxy atom and optionally one additional cyclic heteroatom from the series N or O. More specifically, "5- or 6-membered heterocyclic alkyl" refers to a monocyclic saturated heterocycle having a total of 5 or 6 ring atoms and containing an epoxy atom.

[0053] The term “monocyclic heteroaryl” refers to a monovalent aromatic ring having 5 or 6 ring atoms (“5 or 6-membered heteroaryl”), containing at least one cyclic heteroatom and optionally one or two other cyclic heteroatoms from the series N, O and / or S, and which are bonded by a cyclic carbon atom or optionally by a cyclic nitrogen atom (if the valence allows).

[0054] The heteroaryl group can be a 5-membered heteroaryl group, such as thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, or tetrazolyl; or a 6-membered heteroaryl group, such as pyridinyl, pyridinyl, pyrazinyl, or triazinyl.

[0055] Generally, unless otherwise stated, heteroaryl or hypoaryl includes all its possible isomers, such as tautomers and positional isomers relating to the connection points with the rest of the molecule. Thus, for some illustrative, non-limiting examples, the term pyridyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; or the term thiophenyl includes thiophenin-2-yl and thiophenin-3-yl.

[0056] Specifically, the heteroaryl group is isothiazolyl, pyrazolyl, pyridinyl, pyridazinyl, or pyrimidinyl.

[0057] When this article uses the plural forms of terms such as compound, salt, polymorph, hydrate, solvate, etc., it also means single compound, salt, polymorph, isomer, hydrate, solvate, etc.

[0058] A "stable compound" or "stable structure" is a compound that is robust enough to withstand separation from the reaction mixture to a useful purity and formulation into an effective therapeutic agent.

[0059] The compounds of the present invention optionally contain one or more asymmetric centers, depending on the position and nature of the various substituents desired. One or more asymmetric carbon atoms may be present in (R) or (S) configurations, which can produce racemic mixtures in the case of a single asymmetric center, and diastereomeric mixtures in the case of multiple asymmetric centers. In some cases, asymmetry may also exist due to restricted rotation around a given bond, for example, a central bond between two substituted aromatic rings adjacent to the specified compound.

[0060] Preferred compounds are those that produce more desirable biological activity. Isolated, purified, or partially purified isomers and stereoisomers, or mixtures of racemic or diastereomers of the compounds of this invention are also included within the scope of this invention. The purification and isolation of these substances can be accomplished using standard techniques known in the art.

[0061] Preferred isomers are those that produce more desirable biological activity. These isolated, purified, or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of this invention. The purification and isolation of these substances can be accomplished using standard techniques known in the art.

[0062] Optical isomers can be obtained by resolving racemic mixtures using conventional methods, for example, by forming diastereomer salts or covalent diastereomers using optically active acids or bases. Examples of suitable acids are tartaric acid, diacetyltartaric acid, benzoyltartaric acid, and camphorsulfonic acid. Mixtures of diastereomers can be separated into their respective diastereomers based on their physical and / or chemical differences using methods known in the art, such as chromatography or fractional crystallization. An optically active base or acid is then released from the separated diastereomer salts. Different methods for separating optical isomers include using chiral chromatography (e.g., using a chiral HPLC column) optimally selected to maximize the separation of enantiomers, with or without conventional derivatization. Suitable HPLC columns using chiral phases are commercially available, such as those manufactured by Daicel, such as Chiracel OD and Chiracel OJ, etc., which are routinely chosen. Enzymatic separation, with or without derivatization, is also useful. The optically active compounds of this invention can also be obtained by chiral synthesis using optically active raw materials.

[0063] To distinguish between different types of isomers, refer to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

[0064] This invention includes all possible stereoisomers of the compounds of this invention, either as a single stereoisomer or as any mixture of said stereoisomers (e.g., (R)- or (S)- isomers) in any proportion. Separation of a single stereoisomer of the compounds of this invention (e.g., a single enantiomer or a single diastereomer) can be achieved by any suitable prior art method, such as chromatography, especially chiral chromatography.

[0065] Furthermore, the compounds of the present invention can exist as N-oxides, defined as compounds in which at least one nitrogen atom is oxidized. The present invention includes all such possible N-oxides.

[0066] The present invention also includes useful forms of the compounds of the invention, such as metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts, and / or coprecipitates.

[0067] The compounds of the present invention can exist as hydrates or solvates, wherein the compounds contain a polar solvent, particularly water, methanol, or ethanol, for example, as a structural element of the compound lattice. The amount of the polar solvent, particularly water, can be stoichiometric or non-stoichiometric. In the case of stoichiometric solvates, for example, hydrates, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc., solvates or hydrates are possible. The present invention includes all such hydrates or solvates.

[0068] Furthermore, the compounds of the present invention can exist in free form, for example, as a free base, or as a free acid, or as a zwitterion, or as a salt. The salt can be any salt, organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt commonly used in pharmaceutical applications, or for, for example, the isolation or purification of the compounds of the present invention.

[0069] The term "pharmaceutical-acceptable salt" refers to an inorganic or organic acid addition salt of the compounds of the present invention. See, for example, SMBerge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19.

[0070] Suitable pharmaceutically acceptable salts of the compounds of the present invention may be, for example, acid addition salts of the compounds of the present invention having sufficient basicity, such as those containing a nitrogen atom in the chain or ring, for example, acid addition salts with inorganic acids or "mineral acids" such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, bisulfuric acid, phosphoric acid, or nitric acid; or, for example, acid addition salts with organic acids 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-hydroxy) Benzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphtholic acid, nicotinic acid, dihydroxynaphtholic acid, pectinic acid, 3-phenylpropionic acid, tervaline, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecyl sulfate, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic 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, glucoheponic acid, glycerophosphate, aspartic acid, sulfosalicylic acid, or thiocyanate.

[0071] In addition, another suitable pharmaceutically acceptable salt of the compounds of the present invention 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 1-20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, procaine, dibenzylamine, N-methylmorpholine, arginine, etc. Salts of lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methylglucosamine, N,N-dimethylglucosamine, N-ethylglucosamine, 1,6-hexanediamine, glucosamine, sarcosine, serine, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or salts of quaternary ammonium ions 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 benzylalkylammonium.

[0072] Those skilled in the art will further recognize that the acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid using any of many known methods. Alternatively, the alkali metal and alkaline earth metal salts of the acidic compounds of the present invention can be prepared by reacting the compounds of the present invention with a suitable base using various known methods.

[0073] This invention includes all possible salts of the compounds of this invention, either as a single salt or any mixture of the salts in any proportion.

[0074] In this document, particularly in the experimental section, when referring to compounds in the form of salts obtained by their respective preparation and / or purification methods, the precise stoichiometric composition of the salts obtained by the respective preparation and / or purification methods is, in most cases, unknown for the synthesis of intermediates and embodiments of the present invention.

[0075] Unless otherwise specified, suffixes in chemical names or structural formulas related to salts, such as "hydrochloride", "trifluoroacetate", "sodium salt", or "x HCl", "x CF3COOH", "x Na", etc. + ", for example, refers to the salt form, without specifying the stoichiometry of the salt form."

[0076] This similarly applies to cases where synthetic intermediates or example compounds or their salts with unknown stoichiometric composition (if defined) are obtained as solvates such as hydrates through the aforementioned preparation and / or purification methods.

[0077] Furthermore, the present invention includes all possible crystalline forms or polymorphs of the compounds of the present invention, which are single polymorphs or mixtures of more than one polymorph in any proportion.

[0078] Furthermore, the present invention also includes prodrugs of compounds according to the invention. The term "prodrug" herein refers to compounds that may be biologically active or inactive on their own, but which are converted (e.g., metabolized or hydrolyzed) into compounds according to the invention during their residence time in the body.

[0079] The present invention further includes all possible crystalline and polymorphic forms of the compounds of the present invention, wherein the polymorphs exist in a single polymorphic form or as a mixture of several polymorphs at all concentrations.

[0080] According to a second 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:

[0081] 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.

[0082] C3-C6-cycloalkyl, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen, or

[0083] 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

[0084] (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

[0085] 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;

[0086] R 2 It represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

[0087] R 3 Indicates hydrogen, fluorine, chlorine, or methyl;

[0088] R4 Indicates hydrogen or fluorine;

[0089] R 5 This indicates a monocyclic heteroaryl group, whose optional R 6 Each can replace the other one to three times independently;

[0090] R 6 It can represent C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen, or cyano;

[0091] X represents CH or N;

[0092] R 10 Indicates C1-C4-alkyl;

[0093] R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or

[0094] 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.

[0095] 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:

[0096] 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.

[0097] 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

[0098] 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

[0099] (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

[0100] 4- to 6-membered heterocyclic alkyl groups, which are 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;

[0101] R 2 It represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

[0102] R 3 Indicates hydrogen, fluorine, chlorine, or methyl;

[0103] R 4 Indicates hydrogen or fluorine;

[0104] R 5 This indicates a monocyclic heteroaryl group, whose optional R 6 Each can replace the other one to three times independently;

[0105] R 6 It can represent C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen, or cyano;

[0106] X represents CH or N.

[0107] According to a fourth 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:

[0108] R 1 This refers to a C2-C5-hydroxyalkyl group, wherein the C2-C5-hydroxyalkyl group is optionally substituted once with cyano, -COOCH3, -CONH2, methoxy, or cyclopropyl and optionally substituted once to three times with fluorine.

[0109] 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

[0110] C3-C4-cycloalkyl-methyl, which is substituted once by a hydroxyl group, or

[0111] 5- or 6-membered heterocyclic alkyl group, which is substituted once with a hydroxyl group, wherein the heterocyclic alkyl group contains one oxygen atom;

[0112] R 2It represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

[0113] R 3 Indicates hydrogen or fluorine;

[0114] R 4 Indicates hydrogen or fluorine;

[0115] R 5 This indicates a monocyclic heteroaryl group, whose optional R 6 Each can replace the other one to three times independently;

[0116] R 6 It indicates methyl, difluoromethyl, methoxy, halogen, or cyano;

[0117] X represents CH or N;

[0118] R 10 Indicates C1-C4-alkyl;

[0119] R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or

[0120] 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.

[0121] 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:

[0122] 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.

[0123] 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

[0124] C3-C4-cycloalkyl-methyl, which is substituted once by a hydroxyl group, or

[0125] 5- or 6-membered heterocyclic alkyl group, which is substituted once with a hydroxyl group, wherein the heterocyclic alkyl group contains one oxygen atom;

[0126] R 2 It represents chlorine, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy;

[0127] R 3 It represents hydrogen;

[0128] R 4 Indicates hydrogen or fluorine;

[0129] R 5 It indicates that the group is selected from the following:

[0130]

[0131] Where * indicates the connection point between the group and the rest of the molecule;

[0132] R 6a Indicates hydrogen, methyl, fluorine, or chlorine;

[0133] X represents CH or N.

[0134] According to a sixth embodiment of the first aspect, the present invention covers compounds of general formula (Ia):

[0135]

[0136] Their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates, and solvates, as well as their physiologically acceptable salts and solvates of these salts, and mixtures thereof,

[0137] in

[0138] R 2 It represents chlorine, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy;

[0139] R 7 It represents hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethyl, isopropyl, cyclopropyl, cyano, -COOCH3 or -CONH2;

[0140] R 8 This indicates hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, or methoxymethyl.

[0141] Where R 7 and R 8 One of them is different from hydrogen, or

[0142] R 7 and R 8Together they form a cyclopentyl or cyclohexyl ring, optionally substituted with fluorine once or twice, or a heterocyclic alkyl ring containing one oxygen atom;

[0143] R 9 Indicates hydrogen or methyl, or

[0144] R 8 and R 9 Together they form cyclopropyl or cyclobutyl rings.

[0145] According to the seventh embodiment of the first aspect, the present invention covers compounds of general formula (Ib):

[0146]

[0147] Their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates, and solvates, as well as their physiologically acceptable salts and solvates of these salts, and mixtures thereof,

[0148] in

[0149] R 2 It represents chlorine, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy;

[0150] R 5 It indicates that the group is selected from the following:

[0151]

[0152] Where * indicates the connection point between the group and the rest of the molecule;

[0153] R 6a Indicates hydrogen, methyl, fluorine, or chlorine;

[0154] R 7 It represents hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethyl, isopropyl, or cyclopropyl;

[0155] R 8 This indicates hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, or methoxymethyl.

[0156] Where R 7 and R 8 One of them is different from hydrogen, or

[0157] R 7 and R 8 Together they form a cyclopentyl or cyclohexyl ring, optionally substituted with fluorine once or twice, or a heterocyclic alkyl ring containing one oxygen or sulfur atom;

[0158] R9 Indicates hydrogen or methyl, or

[0159] R 8 and R 9 Together they form cyclopropyl or cyclobutyl rings.

[0160] 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:

[0161] 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.

[0162] 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

[0163] 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

[0164] (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

[0165] 4- to 6-membered heterocyclic alkyl groups, which are 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.

[0166] 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:

[0167] 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.

[0168] 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

[0169] C3-C4-cycloalkyl-methyl groups that are substituted with a hydroxyl group once, or

[0170] A 5- or 6-membered heterocyclic alkyl group that has been substituted with a hydroxyl group once, wherein the heterocyclic alkyl group contains an oxygen atom.

[0171] 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:

[0172] 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.

[0173] C3-C6-cycloalkyl, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen, or

[0174] 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

[0175] (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

[0176] 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.

[0177] 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:

[0178] R 1 The term represents a C2-C6-hydroxyalkyl group, wherein the C2-C6-hydroxyalkyl group is optionally substituted once with a C1-C4-alkoxy or C3-C6-cycloalkyl group and optionally substituted once to three times with a halogen.

[0179] C3-C6-cycloalkyl, which is substituted once with a hydroxyl group and optionally substituted once with a methyl group and / or substituted once to three times with a halogen, or

[0180] 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

[0181] (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

[0182] 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.

[0183] 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:

[0184] R 1 The term represents a C2-C6-hydroxyalkyl group, wherein the C2-C6-hydroxyalkyl group is optionally substituted once with a C1-C2-alkoxy or cyclopropyl group and optionally substituted once to three times with a halogen.

[0185] C4-C6-cycloalkyl groups, which are substituted once with a hydroxyl group and optionally once with a methyl group and / or substituted once to three times with a halogen, or

[0186] C3-C6-cycloalkyl-methyl, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen, or

[0187] (C3-C6-cycloalkyl)2-methyl, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen, or

[0188] 5- or 6-membered heterocyclic alkyl group, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen.

[0189] 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:

[0190] R 1 The C2-C5-hydroxyalkyl group is optionally substituted once with a methoxy or cyclopropyl group and optionally substituted once to three times with a fluorine group.

[0191] 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

[0192] C3-C4-cycloalkyl-methyl groups that are substituted with a hydroxyl group once, or

[0193] A 5- or 6-membered heterocyclic alkyl group that has been substituted with a hydroxyl group once, wherein the heterocyclic alkyl group contains an oxygen atom.

[0194] 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:

[0195] R 1 The C2-C5-hydroxyalkyl group is optionally substituted once with a methoxy or cyclopropyl group and optionally substituted once to three times with a fluorine group.

[0196] C4-C6-cycloalkyl, which is substituted once with a hydroxyl group and optionally substituted once with a methyl group or substituted once or twice with a fluorine group, or

[0197] C3-C4-cycloalkyl-methyl groups that are substituted with a hydroxyl group once, or

[0198] A 5- or 6-membered heterocyclic alkyl group that has been substituted with a hydroxyl group once, wherein the heterocyclic alkyl group contains an oxygen atom.

[0199] 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:

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

[0201] 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:

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

[0203] 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:

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

[0205] 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:

[0206] R 3 It indicates hydrogen or fluorine.

[0207] 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:

[0208] R 3 It represents hydrogen.

[0209] 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:

[0210] R 4 It indicates hydrogen or fluorine.

[0211] 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:

[0212] R 4 It represents hydrogen.

[0213] 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:

[0214] R 5 This indicates a monocyclic heteroaryl group, whose optional R 6 They can replace each other one to three times independently.

[0215] 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:

[0216] R 5 It indicates that the group is selected from the following:

[0217]

[0218] Where * indicates the connection point between the group and the rest of the molecule.

[0219] 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:

[0220] R 5 It indicates that the group is selected from the following:

[0221]

[0222] Where * indicates the connection point between the group and the rest of the molecule.

[0223] 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:

[0224] R 5 It indicates that the group is selected from the following:

[0225]

[0226] Where * indicates the connection point between the group and the rest of the molecule.

[0227] 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:

[0228] R 5 It indicates that the group is selected from the following:

[0229]

[0230] Where * indicates the connection point between the group and the rest of the molecule.

[0231] 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:

[0232] R 6 It can represent C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen, or cyano.

[0233] 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:

[0234] R 6 It can represent C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen, or cyano.

[0235] 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:

[0236] R 6 It indicates 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 a methyl group.

[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 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:

[0247] R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or

[0248] Together with the nitrogen atoms they are attached to, they form 4- to 6-membered nitrogen-containing heterocycles.

[0249] 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:

[0250] R 11 and R 12 The same or different and independent of each other represent hydrogen or C1-C3-alkyl.

[0251] 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:

[0252] R 11 and R 12 The same or different and independent of each other represent hydrogen or methyl.

[0253] 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: X represents CH or N.

[0254] 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:

[0255] X represents CH.

[0256] In a particularly further embodiment of the first aspect, the invention, under the heading “Further Embodiments of the First Aspect of the Invention”, covers a combination of two or more of the above embodiments.

[0257] This invention includes any embodiment or sub-combination within any aspect of the compounds of general formula (I) of the present invention described above.

[0258] This invention includes any embodiment or sub-combination within any aspect of the intermediate compound of general formula (VII) of this invention. This invention includes compounds of general formula (I) disclosed in the Examples section below.

[0259] Compounds of general formula (I) according to the present invention can be prepared according to Scheme 1 below. The schemes and procedures described below illustrate the synthetic route of compounds of general formula (I) of the present invention and are not intended to be limiting. It will be apparent to those skilled in the art that the transformation sequence illustrated in Scheme 1 can be modified in various ways. Therefore, the transformation sequence illustrated in this scheme is not intended to be limiting. Furthermore, any substituent R 1 R 2 R 3 R 4 R 5 or R 6 The tautomerism can be achieved before and / or after the illustrative transformations. 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, metallization, metal-catalyzed coupling, substitution, or other reactions known to those skilled in the art. These transformations include the introduction of functional groups that allow for further tautomerism of the substituents. Suitable protecting groups and their introduction and cleavage are well known to those skilled in the art. Specific examples are described in subsequent paragraphs.

[0260] Scheme 1 shows a route for preparing compounds of general formula (I), wherein X, R 1 R 2 R 3 R 4 R 5 and R 6The meaning of general formula (I) is as given above. Ketomalonates, representing intermediates according to formula (III), are commercially available in some cases, or can be synthesized from α-haloacetophenone (II) according to procedures known to those skilled in the art. The relevant α-haloacetophenone is generally commercially available. In a suitable solvent, in the presence of a suitable base, the conversion of this α-haloacetophenone with the malonate results in the formation of a non-commercial ketomalonate according to formula (III). R in formulas (III), (V), and (VI) represents a suitable alkyl group, such as methyl, ethyl, propyl, or other homologue. Suitable solvents may be, but should not be limited to, acetonitrile, DMF, DMA, DMSO, or THF, or even mixtures of these or other solvents. Suitable bases may be, but should not be limited to, potassium carbonate, sodium hydride, cesium carbonate, or potassium hexamethyldisilazane.

[0261] The formation of dihydropyridazinones according to formula (V) from intermediate (III) and a suitable arylhydrazine (IV) (which is commercially available in many cases) can be accomplished by reacting these components in a suitable solvent at elevated temperatures. Suitable solvents may be, but should not be limited to, ethanol or acetic acid.

[0262]

[0263] Scheme 1: A route for preparing compounds of general formula (I), wherein X, R 1 R 2 R 3 R 4 and R 5 With the meaning given above for general formula (I), Hal represents halogen and R represents C1-C4-alkyl.

[0264] The dihydropyridazinone according to formula (V) can be converted to the pyridazinone according to formula (VI). This can be accomplished by using a suitable reagent such as copper dichloride at an elevated temperature.

[0265] The resulting pyridazinone with ester functional groups according to formula (VI) can be converted into pyridazinone carboxylic acid (VII) by methods known to those skilled in the art, such as alkaline hydrolysis with an aqueous solution of an alkali metal hydroxide, or acidic hydrolysis with hydrogen chloride / dioxane or trifluoroacetic acid.

[0266] These acids can be reacted with formula (VIII) (where R) 1 The conversion is achieved by amine coupling, as defined for general formula (I). Coupling agents and methods used for this synthesis of carboxylamides from carboxylic acids and amines are known to those skilled in the art. Examples that may 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 the references.

[0267]

[0268] Scheme 2: A route for preparing compounds of general formula (I), wherein X, R 1 R 2 R 3 R 4 and R 5 With the meanings given above for general formula (I), Hal represents halogen, R represents C1-C4-alkyl and R' and R” simultaneously represent H or C1-C4-alkyl or together forming C2-C7-alkylene as part of 1,2- or 1,3-diol borate esters or -CO-CH2-(NCH3)-CH2-CO- groups.

[0269] The ketomalonate, represented as an intermediate according to formula (III), is commercially available in some cases, or can be synthesized from α-haloacetophenone (II) according to procedures known to those skilled in the art. The relevant α-haloacetophenone is generally commercially available. In a suitable solvent and in the presence of a suitable base, the conversion of this α-haloacetophenone with the malonate results in the formation of a non-commercial ketomalonate according to formula (III). R in formulas (III), (IX), (X), and (VI) represents a suitable alkyl group, such as methyl, ethyl, propyl, or other homologue. Suitable solvents may be, but should not be limited to, acetonitrile, DMF, DMA, DMSO, or THF, or even mixtures of these or other solvents. Suitable bases may be, but should not be limited to, potassium carbonate, sodium hydride, cesium carbonate, or potassium hexamethyldisilazane.

[0270] The formation of dihydropyridazinones according to formula (IX) from intermediate (III) and hydrazine can be accomplished by reacting these components in a suitable solvent at an elevated temperature. Suitable solvents may be, but should not be limited to, ethanol or acetic acid.

[0271] The dihydropyridazinone according to formula (IX) can be converted to the pyridazinone according to formula (X). This can be accomplished by using a suitable reagent. A suitable reagent can be, but should not be limited to, copper dichloride at elevated temperatures.

[0272] The substituted pyridazinones according to formula (VI) can be prepared by a Chan-Lam coupling reaction of the pyridazinones according to formula (X) with a suitable solvent at room temperature or elevated temperatures using boron derivatives such as boric acid, pinacol borate, and tetrafluoroborate. Suitable solvents may be, but are not limited to, acetonitrile, dichloromethane, pyridine, or DMF. Suitable catalysts may be, but are not limited to, copper(II) acetate. Suitable basic additives may be, but are not limited to, trimethylamine, 2,2-bipyridine, sodium carbonate, or cesium carbonate.

[0273] The resulting substituted pyridazinones of formula (VI) having ester functional groups can be converted into pyridazinone carboxylic acid (VII) by methods known to those skilled in the art, such as alkaline hydrolysis with an aqueous solution of an alkali metal hydroxide, or acidic hydrolysis using, for example, hydrogen chloride / dioxane or trifluoroacetic acid.

[0274] These can be obtained by relating them to equation (VIII) (where R) 1 The conversion is achieved by amine coupling, as defined for general formula (I). Coupling agents and methods used for this synthesis of carboxylamides from carboxylic acids and amines are known to those skilled in the art. Examples that may 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 the references.

[0275]

[0276] Scheme 2a: A route for preparing intermediates of general formula (X), wherein X, R 1 R 2 R 3 and R 4 It has the meanings given above for general formula (I) and R represents C1-C4-alkyl.

[0277] Compounds of general formula (IIa) are commercially available and can be reacted with dialkyl ketomalonate, where R represents C1-C4-alkyl. Diethyl ketomalonate as a reagent is commercially available. Dialkyl ketomalonate can be prepared by reacting the corresponding dialkyl malonate with p-toluenesulfonyl azide and diethylene oxide (see, for example: Synth. Commun. 1994, 24, 695) or bromine and potassium acetate (see, for example: J. Org. Chem. 1981, 46, 2598). Acetophenone of general formula (IIa) and dialkyl ketomalonate are heated at 95-100 °C under solvent-free conditions (neat), or under reflux at 120 °C with a solvent such as pyridine. The intermediate of formula (IIIa) is then reacted with hydrazine hydrate / acetic acid under reflux or with hydrazine dihydrochloride / ethanol under reflux to give intermediate (X).

[0278]

[0279] Option 3: Other routes for preparing compounds of general formula (I), wherein X, R 1 R 2 R 3 R 4 and R 5With 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 C2-C7-alkylene as part of 1,2- or 1,3-diol borate esters or –CO-CH2-(NCH3)-CH2-CO- groups.

[0280] Methyl 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylate [CAS 89581-64-6] is commercially available. The conversion of methyl 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylate with an organoboron derivative (boric acid, pinacol borate, MIDA borate, organotrifluoroborate) at room temperature or elevated temperatures in the presence of a suitable palladium(O) catalyst, a suitable base, and a suitable solvent results in the formation of a 6-aryl-substituted 3-oxo-2,3-dihydropyridazine-4-carboxylic acid of formula (XI). The organoboron derivatives used are commercially available or can be synthesized from organohalides. Methods used for such synthesis are known to those skilled in the art. Suitable catalysts may be, but should not be limited to, palladium-phosphine complexes, such as Pd(PPh3)4, PdCl2(PPh3)2, or palladium catalysts that can be prepared in situ from precursors such as Pd(OAc)2 or Pd2(dba)3·CHCl3 with an appropriate amount of phosphine, or cyclic palladium complex catalysts such as, for example, 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 may be, but should not be limited to, potassium phosphate, potassium carbonate, potassium tert-butoxide, cesium carbonate, and triethylamine. Suitable solvents may be, but should not be limited to, dioxane, toluene, THF, and dimethylformamide, or even mixtures of these or other solvents.

[0281] 3-O-2,3-dihydropyridazine-4-carboxylic acid (XI) can be converted to an amide (XII) by coupling with an amine of formula (VIII). Coupling agents and methods used for this synthesis of carboxamides from carboxylic acids and amines are known to those skilled in the art. Examples that may 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 the references.

[0282] The substituted pyridazinones of formula (I) can be prepared by Chan-Lam coupling reaction of boric acid derivatives (boric acid, pinacol borate, MIDA borate, and organofluoroborate) in a suitable solvent at room temperature or elevated temperatures. Suitable solvents may include, but are not limited to, acetonitrile, dichloromethane, pyridine, and DMF. Suitable catalysts may include, but are not limited to, copper acetate (II). Suitable basic additives may include, but are not limited to, trimethylamine, 2,2-bipyridine, sodium carbonate, or cesium carbonate.

[0283]

[0284] Option 4: Other routes for preparing compounds of general formula (I), wherein X, R 1 R 2 R 3 R 4 and R 5 With 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 C2-C7-alkylene as part of 1,2- or 1,3-diol borate esters or –CO-CH2-(NCH3)-CH2-CO- groups.

[0285] 6-Chloro-3-oxo-2,3-dihydropyridazine-4-carboxylic acid [CAS 50681-26-0] is commercially available and can be converted to an amide of formula (XIII) by coupling with an amine of formula (VIII). Coupling agents and methods used for this synthesis of carboxamides from carboxylic acids and amines are known to those skilled in the art. Examples that may be mentioned herein include the use of HATU, HBTU, PyBOB, or T3P with the addition of a suitable base.

[0286] 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxamide (XIII) is converted to a 6-aryl-substituted 3-oxo-2,3-dihydropyridazine-4-carboxamide of formula (XII) in the presence of a suitable palladium(O) catalyst, a suitable base, and a suitable solvent at room temperature or elevated temperatures, using organoboronic acid, pinacol borate, MIDA borate, or organotrifluoroborate. The organoboronic derivatives used are commercially available or can be synthesized from organohalides. Methods for such synthesis are known to those skilled in the art. Suitable catalysts may be, but should not be limited to, palladium-phosphine complexes, such as Pd(PPh3)4, PdCl2(PPh3)2, or palladium catalysts that can be prepared in situ from precursors such as Pd(OAc)2 or Pd2(dba)3·CHCl3 with an appropriate amount of phosphine, or cyclic palladium complex catalysts such as, for example, 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 may be, but should not be limited to, potassium phosphate, potassium carbonate, potassium tert-butoxide, cesium carbonate, and triethylamine. Suitable solvents may be, but should not be limited to, dioxane, toluene, THF, and dimethylformamide, or even mixtures of these or other solvents.

[0287] The substituted pyridazinone according to formula (I) can be prepared by Chan-Lam coupling of a 6-aryl-substituted 3-oxo-2,3-dihydropyridazin-4-carboxamide according to formula (XII) with a suitable solvent at room temperature or elevated temperatures using a boric acid derivative (boric acid, pinacol borate, MIDA borate, and organotrifluoroborate) and a suitable solvent. Suitable solvents may be, but are not limited to, acetonitrile, dichloromethane, pyridine, and DMF. Suitable catalysts may be, but are not limited to, copper acetate (II). Suitable basic additives may be, but are not limited to, trimethylamine, 2,2-bipyridine, sodium carbonate, or cesium carbonate.

[0288] As will be understood by those skilled in the art, the compounds are commercially available or can be prepared according to procedures available from the public domain. Specific examples are described in the Experimental section.

[0289] According to a second aspect, the present invention covers a method for preparing compounds of general formula (I) as defined above, the method comprising the steps of: preparing an intermediate compound of general formula (VII)

[0290]

[0291] in

[0292] R 2 It represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

[0293] R 3 Indicates hydrogen, fluorine, chlorine, or methyl;

[0294] R 4 Indicates hydrogen or fluorine;

[0295] R 5 This indicates a monocyclic heteroaryl group, whose optional R 6 Each can replace the other one to three times independently;

[0296] R 6 It can represent C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen, or cyano;

[0297] X represents CH or N;

[0298] Reaction with compounds of general formula (VIII):

[0299] H 2 NR 1

[0300] (VIII),

[0301] in

[0302] 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.

[0303] C3-C6-cycloalkyl, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen, or

[0304] 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

[0305] (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

[0306] 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;

[0307] R 10 Indicates C1-C4-alkyl;

[0308] R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or

[0309] 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;

[0310] This yields compounds of general formula (I):

[0311]

[0312] Where X and R 1 R 2 R 3 R 4 and R 5 As defined above.

[0313] This invention covers a method for preparing compounds of general formula (I), the method comprising the steps described in the experimental section herein.

[0314] According to a third aspect, the present invention covers intermediate compounds that can be used to prepare compounds of the above general formula (I).

[0315] In particular, this invention covers intermediate compounds of general formula (VII):

[0316]

[0317] in

[0318] R 2 It represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

[0319] R 3 Indicates hydrogen, fluorine, chlorine, or methyl;

[0320] R 4 Indicates hydrogen or fluorine;

[0321] R 5 This indicates a monocyclic heteroaryl group, whose optional R 6 Each can replace the other one to three times independently;

[0322] R 6 It represents C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen or cyano; X represents CH or N.

[0323] 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.

[0324] 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:

[0325]

[0326] in

[0327] R 2 It represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

[0328] R 3 Indicates hydrogen, fluorine, chlorine, or methyl;

[0329] R 4 Indicates hydrogen or fluorine;

[0330] R 5 This indicates a monocyclic heteroaryl group, whose optional R 6 Each can replace the other one to three times independently;

[0331] R 6It represents C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen or cyano; X represents CH or N.

[0332] According to a fifth aspect, the present invention covers a method for preparing compounds of general formula (I) as defined above, the method comprising the step of: preparing an intermediate compound of general formula (XII):

[0333]

[0334] in

[0335] 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.

[0336] C3-C6-cycloalkyl, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen, or

[0337] 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

[0338] (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

[0339] 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;

[0340] R 2 It represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

[0341] R 3 Indicates hydrogen, fluorine, chlorine, or methyl;

[0342] R 4 Indicates hydrogen or fluorine;

[0343] X represents CH or N;

[0344] R 10 Indicates C1-C4-alkyl;

[0345] R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or

[0346] 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;

[0347] Reaction with compounds of general formula (XIV):

[0348]

[0349] in

[0350] R 5 This indicates a monocyclic heteroaryl group, whose optional R 6 Each can replace the other one to three times independently;

[0351] R 6 It can represent C1-C4-alkyl, C1-C4-haloalkyl, C3-C6-cycloalkyl, C1-C4-alkoxy, halogen, or cyano;

[0352] R' and R” both represent H or C1-C4-alkyl or together form C2-C7-alkylene as part of 1,2- or 1,3-diol boronic acid esters or –CO-CH2-(NCH3)-CH2-CO- groups;

[0353] This yields compounds of general formula (I):

[0354]

[0355] Where X and R 1 R 2 R 3 R 4 and R 5 As defined above.

[0356] This invention covers a method for preparing compounds of general formula (I), the method comprising the steps described in the experimental section herein.

[0357] According to a sixth aspect, the present invention covers intermediate compounds that can be used to prepare compounds of the above general formula (I).

[0358] In particular, this invention covers intermediate compounds of general formula (XII):

[0359]

[0360] in

[0361] 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.

[0362] C3-C6-cycloalkyl, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen, or

[0363] 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

[0364] (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

[0365] 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;

[0366] R 2 It represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

[0367] R 3 Indicates hydrogen, fluorine, chlorine, or methyl;

[0368] R 4 Indicates hydrogen or fluorine;

[0369] X represents CH or N;

[0370] R 10 Indicates C1-C4-alkyl;

[0371] R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or

[0372] 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.

[0373] 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.

[0374] 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:

[0375]

[0376] in

[0377] 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.

[0378] C3-C6-cycloalkyl, which is substituted once with a hydroxyl group and optionally substituted once to three times with a halogen, or

[0379] 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

[0380] (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

[0381] 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;

[0382] R 2 It represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

[0383] R 3 Indicates hydrogen, fluorine, chlorine, or methyl;

[0384] R 4 Indicates hydrogen or fluorine;

[0385] X represents CH or N;

[0386] R 10 Indicates C1-C4-alkyl;

[0387] R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or

[0388] 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.

[0389] This invention includes the intermediate compounds disclosed in the Examples section below.

[0390] This invention includes any embodiment or sub-combination within any aspect of the intermediate compound of general formula (VII) of the invention described above.

[0391] Compounds of general formula (I) of the present invention can be converted into any salt as described herein by any method known to those skilled in the art, preferably a pharmaceutically acceptable salt. Similarly, any salt of compounds of general formula (I) of the present invention can be converted into the free compound by any method known to those skilled in the art.

[0392] The compounds of general formula (I) of the present invention exhibit a valuable and unexpected pharmacological spectrum. Surprisingly, the compounds of the present invention have been found to effectively inhibit AHR, and therefore, these compounds can be used to treat or prevent diseases in humans and animals, preferably cancers or conditions or other illnesses associated with abnormal AHR signaling.

[0393] Conditions and diseases particularly suitable for treatment with the AHR inhibitors of this invention are liquid and solid tumors, such as breast cancer, respiratory cancer, brain cancer, reproductive organ cancer, digestive tract cancer, urinary tract cancer, eye cancer, liver cancer, skin cancer, head and neck cancer, thyroid cancer, parathyroid cancer, and their distant metastases. These conditions also include lymphoma, sarcoma, and leukemia.

[0394] 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.

[0395] Examples of respiratory tract cancers include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenoma and pleural pulmonary blastoma.

[0396] Examples of brain cancer include, but are not limited to, brainstem and hypothalamic gliomas, cerebellar and cerebral astrocytomas, glioblastomas, medulloblastomas, ependymomas, and neuroectodermal and pineal tumors.

[0397] Tumors of the male reproductive organs include, but are not limited to, prostate cancer and testicular cancer.

[0398] Tumors of the female reproductive organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, and uterine sarcoma.

[0399] Examples of ovarian cancer include, but are not limited to, serous tumors, endometrioid tumors, mucinous cystadenocarcinomas, granulosa cell tumors, Sertoli-Leydig cell tumors, and androgenetic tumors.

[0400] Examples of cervical cancer include, but are not limited to, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, small cell carcinoma, neuroendocrine tumors, ground-glass cell carcinoma, and choriocarcinoma.

[0401] Digestive tract tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, stomach cancer, pancreatic cancer, rectal cancer, small bowel cancer, and salivary gland cancer.

[0402] 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.

[0403] Examples of gastric cancer include, but are not limited to, intestinal and diffuse gastric adenocarcinoma.

[0404] Examples of pancreatic cancer include, but are not limited to, ductal adenocarcinoma, adenosquamous carcinoma, and pancreatic endocrine tumors.

[0405] Urinary tract tumors include, but are not limited to, bladder, penis, kidney, renal pelvis, ureter, urethra, and human papillary renal cell carcinoma.

[0406] Examples of renal cell carcinoma include, but are not limited to, renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal eosinophilic cell tumor, Bellini duct carcinoma, clear cell sarcoma of the kidney, mesodermal nephroma, and nephroblastoma.

[0407] Examples of bladder cancer include, but are not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, sarcoma, and small cell carcinoma.

[0408] Eye cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

[0409] Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (with or without the fibrolamellar variant), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.

[0410] Skin cancer includes, but is not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

[0411] Head and neck cancers include, but are not limited to, squamous cell carcinoma of the head and neck, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, salivary gland cancer, lip and oral cavity cancer, and squamous cell carcinoma.

[0412] Lymphomas include, but are not limited to, AIDS-related lymphomas, non-Hodgkin's lymphomas, cutaneous T-cell lymphomas, Burkitt lymphomas, Hodgkin's disease, and central nervous system lymphomas.

[0413] Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.

[0414] Leukemia includes, but is not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, and hairy cell leukemia.

[0415] The term "treating" or "treatment" as used throughout this article is used in the conventional sense, for example, to manage or care for a person for the purpose of combating, alleviating, reducing, relieving, or improving the condition of a disease or symptom (such as cancer).

[0416] The compounds of the present invention are particularly useful for the treatment and prevention, i.e., prevention of tumor growth and metastasis, especially in solid tumors of all indications and stages with or without tumor growth pretreatment.

[0417] Typically, the combined use of chemotherapeutic agents and / or anticancer agents with the compounds or pharmaceutical compositions of the present invention will be beneficial:

[0418] 1. Compared to applying any single drug alone, it produces a better effect in reducing tumor growth or even eliminating tumors.

[0419] 2. Provide administration of smaller doses of chemotherapy agents.

[0420] 3. Provides chemotherapy that is well tolerated in patients and has fewer harmful pharmacological complications compared to those observed with single-agent chemotherapy and certain other combination therapies.

[0421] 4. To provide treatment for a wider range of different cancer types in mammals, especially humans.

[0422] 5. Provides a higher response rate in treated patients.

[0423] 6. Compared with standard chemotherapy, it provides longer survival time in treated patients.

[0424] 7. Provides longer time to tumor progression, and / or

[0425] 8. Achieve at least the same efficacy and tolerability results as the drugs used alone, compared to known cases of antagonistic effects when combined with other cancer drugs.

[0426] Furthermore, the compounds of general formula (I) of the present invention can also be used in combination with radiotherapy and / or surgery.

[0427] In another embodiment of the invention, the compounds of general formula (I) of the invention can be used to sensitize cells to radiation, i.e., to treat cells with the compounds of the invention prior to radiation treatment, such that the cells are more sensitive to DNA damage and cell death compared to cells that have not been treated with the compounds of the invention. In one aspect, cells are treated with at least one compound of general formula (I) of the invention.

[0428] Therefore, the present invention also provides a method for killing cells, wherein one or more of the compounds of the present invention are administered to the cells in combination with conventional radiotherapy.

[0429] The present invention also provides a method for making cells more sensitive to cell death, wherein the cells are treated with one or more compounds of general formula (I) of the present invention prior to treatment to induce or cause cell death. In one aspect, after treating the cells with one or more compounds of general formula (I) of the present invention, the cells are treated with at least one compound, or at least one method, or a combination thereof, to induce DNA damage, with the aim of inhibiting the function of normal cells or killing the cells.

[0430] In other embodiments of the invention, cells are killed by treating them with at least one DNA-damaging agent; that is, after treating cells with one or more compounds of general formula (I) of the invention to make them sensitive to cell death, the cells are then treated with at least one DNA-damaging agent to kill them. DNA-damaging agents that can be used in the invention include, but are not limited to, chemotherapeutic agents (e.g., cisplatin), ionizing radiation (X-rays, ultraviolet radiation), carcinogens, and mutagens.

[0431] In other embodiments, cells are killed by treating them with at least one method to induce or cause DNA damage. Such methods include, but are not limited to, activating cell signaling pathways (which lead to DNA damage when activated), inhibiting cell signaling pathways (which lead to DNA damage when inhibited), and inducing biochemical changes in the cell that result in DNA damage. As a non-limiting example, DNA repair pathways in the cell can be inhibited, thereby preventing the repair of DNA damage and leading to an abnormal accumulation of DNA damage in the cell.

[0432] In one aspect of the invention, the compound of general formula (I) of the invention is applied to cells prior to radiation or other cellular DNA damage induction. In another aspect of the invention, the compound of general formula (I) of the invention is applied to cells simultaneously with radiation or other cellular DNA damage induction. In yet another aspect of the invention, the compound of general formula (I) of the invention is applied to cells immediately after the induction of radiation or other cellular DNA damage begins.

[0433] On the other hand, the cells are outside the body. In another embodiment, the cells are inside the body.

[0434] The compounds of this invention can be administered as a single pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients, wherein such combination does not cause unacceptable side effects. This invention also covers such pharmaceutical combinations. For example, the compounds of this invention can be combined with the following substances: 131I-chTNT, abarelix, abiraterone, arubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, interleukin, alectinib, alemtuzumab, alendronate, alitretinoin, hexamethylmelamine, amifostine, aminoglutethimide, hexylaminolevulinate, arubicin, acridine, anastrozole, anisodoxime, anetholedimethylamine, anetumab ravtansine, angiotensin II, antithrombin III, aprepitant, acimomumab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacitidine, basiliximab, belotecone, bendamustine, besoxumab, belistat, bevacizumab, bexarotene, bicalutamide, bisentan, bleomycin, bortezomib, busherin, bosutinib, brentuximab Vedotin, Busulfan, Cabazitaxel, Cabozantinib, Calcitonin, Leucovorin, Leucovorin, Capecitabine, Carolomumab, Carbamipine, Carboplatin, Carpoquinone, Carfilzomib, Carmoflu, Carmustine, Catumaxomab, Celecoxib, Cimointerleukin, Ceritinib, Cetuximab, Chlorpheniramine, Chlormadinone, Nitrogen Mustard, Sidofovir, Cinacalcet, Cisplatin, Cladribine, Clodronate, Clofarabine, Cobitinib, Copanlisib, Crizotinib, Crizotinib, Cyclophosphamide, Cyproterone Acid, Cytarabine, Dacarbazine, Actinomycin D, Darabium, Darbeetin Alfa), dabrafenib, dasatinib, daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab, diprotein, dilorelin, vesicosanol, dextromethorphan, dibromospiramycin, didehydroeugenol, diclofenac, dinutuximab, docetaxel, dolasetron, deoxyfluorouridine, doxorubicin, doxorubicin + estrone, eculizumab, ezolizumab, ellotuzumab, erlotuzumab, eltrombopagEndostatin, Enoxaline, Enzalutamide, Epirubicin, Cyclothothermide, Epoetin Alpha, Epoetin Beta, Epoetin Zeta, Eribulin, Elotinib, Esomeprazole, Estradiol, Estrogenitourin, Etoxin Estradiol, Etoposide, Everolimus, Exemestane, Faldroxazole, Fentanyl, Filgraxazone, Fluorouracil, Fludarabine, Fluorouracil, Flutamide, Leucovorin, Formestane, Fosapiram, Formostane, Fulvestrant, Gadolinol, Gadolinol Gadolinium meglumine, gadofosamide, gadoxetine, gallium nitrate, ganiriplastic, gefitinib, gemcitabine, gemtuzumab, carboxypeptidase, oxidized glutathione, GM-CSF, goserelin, granisetron, granulocyte colony-stimulating factor, histamine dihydrochloride, histamine resveratrol, hydroxyurea, I-125 particles, lansoprazole, ibandronic acid, ibritumomab Tiuxetan), ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisesetron, incardonic acid, phoryl alcohol methylbutenoate, interferon α, interferon β, interferon γ, iodide, iodobenzylguanidine (123I), iodomeprazole, ipilimumab, irinotecan, itraconazole, ixabepilone, ixazomib, lanreotide, nansoprazole Lapatinib, Iasocholine, Lenalidomide, Lenvatinib, Levofloxacin, Mushroom Polysaccharide, Letrozole, Leuprorelin, Levotetramazole, Levonorgestrel, Levothyroxine Sodium, Ergotethamide, Lobaplatin, Cyclohexidine Nitrourea, Clonidamine, Masrophenone, Medroxyprogesterone, Melarsone, Melphalan, Meandrazol, Mercaptopurine, Mesna, Methadone, Methotrexate, Methoxam, Methoxaline, Methylaminolevulinic Acid Salt, methylprednisolone, methyltestosterone, methyltyrosine, mifamurtide, mitefosine, miriplatin, dibromomannitol, propaminazone, dibromoceramide, mitomycin, mitotane, mitoxantrone, mogamulizumab, morasilidine, mopiperazine, morphine hydrochloride, morphine sulfate, nabiximols, nafarelin, naloxone + tebuconazole, naltrexone, natosine, nexituzumab, nedaplatin, nerabine (nelarabine), neridonic acid, netupirant / palonosetron, nivolumab, pentrotide, nilotinib, nilumet, nimozol, nimotuzumab, pyrimidine nitrosourea, nintedanib, nitraerine, nivolumab, obinutuzumab, octreotide, ofatumumab, olaparib, olaparibHomoharringtonine, Omeprazole, Oxytran, Oprelvekin, Oreoprotein, Orilotimod, Osimertinib, Oxaliplatin, Oxycodone, Oxymethylphenidate, Ozogamicine, p53 gene therapy, Paclitaxel, Palbociclib, Palivmin, Palladium-103 particles, Palonosetron, Pamidronate, Panitumumab, Pabbilstat, Pantoprazole, Pazopanib, Pergapasmin, PEG-Betaepotine (Methoxy-PEG-Beta-Epofotin), Pembrolizumab, Pegfilgrastim, Peglin-Interferon Alpha-2b, Pembrolizumab, Pemetrexed, Pentostatin, Pelomycin, Perfluorobutane, Pephosphonamide, Pertuzumab, Picibanil, Pilocarpine, Pirarubicin, Pilosin, Plexafor, Pucomomycin, Polyglucosamine, Polyestradiol Phosphate, Polyvinylpyrrolidone +Sodium hyaluronate, polysaccharide-K, pomalidomide, panatinib, porphyrin sodium, pralatrexate, bismuth subcitrate, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, latotinib, ranoxifene, raltitrexed, ramusetron, ramucirumab, ranimustine, raburicase, ref ametinib, regorafenib, risedronate, rhenium-186 etidronate, rituximab, lorapipant, romidepsin, romiplostim, romotide, roniciclib, samarium 153Sm, samotide, satumomab, secretin, sutuximab, sipuleucel-T, cizonan, sobuzosen, sodium glycyrrhizinate glycididazole), sorafenib, sanne, streptozotocin, sunitinib, talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentathon, tasonermin, tecoleukin, technetium [99mTc]-mercaptomosum, 99mTc-HYNIC-[Tyr3]-octreotide, tegafur, tegafur + gimeracil + oteracil, temoporphyrin, temozolomide, temsirolimus, teniposide, testosteroneTetrofosmin, Thalidomide, Thiotepa, Thymalfasin, Thyrotropin Alpha, Tioguanine, Tocilizumab, Topotecan, Toremifene, Tositumomab, Trabectedin, Trametinib, Tramadol, Trastuzumab, Trastuzumab-Mestane conjugate, Treosulfan, Retinoic acid, Trifluridine + Tipi Racil, Tralostan, Triptorelin, Trametinib, Trafotiam, Thrombopoietin, Tryptophan, Ubenimex, Vatalanib, Valrubicin, Vandetanib, Vaportide, Vemurafenib, Vincristine, Vincristine, Vindesine, Vinflunine, Vinorelbine, Vismodegib, Vorinostat, Vorticoids, Yttrium-90 Glass Microspheres, Neocarcinogen, Netostatin, Zoledronic Acid, Zorubicin.

[0435] The compounds of the present invention can be further combined with other agents that target the immune system, such as immune checkpoint inhibitors, such as PD-1 / -L1 axis antagonists.

[0436] PD-1 and its ligands PD-L1 and PD-L2 act as negative regulators of T cell activation. AHR suppresses immune cell function while increasing cancer cell proliferation and motility. PD-L1 is overexpressed in many cancers, and PD-1 overexpression is often accompanied by the development of tumor-infiltrating T cells. This leads to weakened T cell activation and evasion of immune surveillance, resulting in impaired antitumor immune responses (Keir ME et al. (2008) Annu. Rev. Immunol. 26:677).

[0437] Simultaneous targeting of the PD-1 / -L1 axis and AHR enhances the anti-tumor immune response more than the additive approach, leading to an unexpected reduction in tumor growth.

[0438] Therefore, compositions containing PD-1 / -L1 axis antagonists and AHR antagonists are surprisingly effective in enhancing immune responses and treating cancer.

[0439] Furthermore, the compounds of the present invention can also be used as therapeutic agents for various other conditions involving AHR, such as cardiovascular and pulmonary diseases.

[0440] Therefore, the compounds according to the invention are suitable for the treatment and / or prevention of, in particular, cardiovascular, inflammatory and fibrotic conditions, and kidney conditions, particularly acute and chronic renal insufficiency, as well as acute and chronic renal failure.

[0441] Therefore, the compounds according to the present invention can be used as medicines for the treatment and / or prevention of cardiovascular, inflammatory and fibrotic conditions, kidney diseases, especially acute and chronic renal insufficiency, and acute and chronic renal failure.

[0442] For the purposes of this invention, the term renal insufficiency includes acute and chronic manifestations of renal insufficiency, as well as underlying or related kidney conditions such as diabetic and non-diabetic nephropathy, hypertensive nephropathy, ischemic nephropathy, renal hypoperfusion, hypotension during dialysis, obstructive urinary tract disease, renal stenosis, glomerulonephritis, and glomerulonephritis, such as primary glomerulonephritis; minimal change disease glomerulonephritis (lipoid nephropathy); membranous glomerulonephritis; focal segmental glomerulosclerosis (FSGS); membranoproliferative glomerulonephritis; crescentic glomerulonephritis; mesangial proliferative glomerulonephritis (IgA nephritis, Berger's disease); post-infectious glomerulonephritis; and secondary glomerulonephritis: diabetes mellitus, lupus erythematosus, amyloidosis, Goodpasture syndrome, Wegener's granulomatosis, etc. Purpura, microscopic polyangiitis, acute glomerulonephritis, pyelonephritis (e.g., due to urolithiasis, benign prostatic hyperplasia, diabetes, malformation, analgesic abuse, Crohn's disease), glomerulosclerosis, renal arteriolar sclerosis, tubulointerstitial disease, nephropathy such as primary and congenital or acquired nephropathy, Alport syndrome, nephritis, immune nephropathy such as renal transplant rejection and nephropathy caused by immune complexes, nephropathy caused by toxic substances, nephropathy caused by contrast agents, diabetic and non-diabetic nephropathy, renal cysts, nephrosclerosis, hypertensive nephrosclerosis, and nephrotic syndrome, characterized by abnormally reduced creatinine and / or water excretion, abnormally elevated blood concentrations of urea, nitrogen, potassium, and / or creatinine, altered renal enzyme activity such as gamma-glutamyl synthase, changes in urine osmolality or urine volume, elevated microalbuminuria, massive proteinuria, lesions on the glomeruli and arterioles, renal tubular dilatation, hyperphosphatemia, and / or the need for dialysis. The present invention also includes the use of the compounds according to the invention for the treatment and / or prevention of sequelae of renal insufficiency, such sequelae as pulmonary edema, heart failure, uremia, anemia, electrolyte disturbances (e.g., hypercalcemia, hyponatremia) and bone and carbohydrate metabolism disorders.

[0443] The compounds according to the invention are also suitable for the treatment and / or prevention of polycystic kidney disease (PCKD) and inappropriate ADH secretion syndrome (SIADH).

[0444] Furthermore, the compounds according to the invention are also suitable for the treatment and / or prevention of metabolic syndrome, hypertension, refractory hypertension, acute and chronic heart failure, coronary artery disease, stable and unstable angina, peripheral and cardiovascular diseases, arrhythmias, atrial and ventricular arrhythmias and conduction impairments such as first- to third-degree atrioventricular block (AB block I-III), supraventricular tachyarrhythmias, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmias, torsades de pointes, atrial and ventricular premature contractions, AV junctional premature contractions, sick sinus syndrome, syncope, AV nodal reentrant tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune cardiopathy (pericarditis, endocarditis, valvulitis, aortitis, cardiomyopathy), and shock such as cardiogenic shock, septic shock, and anaphylactic shock. Aneurysm, Boxer cardiomyopathy (ventricular premature beats (PVC)), used for the treatment and / or prevention of thromboembolic conditions and ischemia such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular conditions, coronary and peripheral artery spasm, edema formation such as pulmonary edema, cerebral edema, renal edema or edema due to heart failure, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, myocardial dysfunction, endothelial dysfunction, to prevent restenosis, such as after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), percutaneous transluminal coronary angioplasty (PTCA), heart transplantation and bypass surgery, and microvascular and large vessel injury (vasculitis), elevated fibrinogen and low-density lipoprotein (LDL) levels and increased plasminogen activator inhibitor 1 (PAI-1) concentrations, also used for the treatment and / or prevention of erectile dysfunction and female sexual dysfunction.

[0445] Furthermore, the compounds according to the invention are also suitable for the treatment and / or prevention of asthma symptoms, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including pulmonary hypertension associated with left ventricular disease, HIV, sickle cell anemia, thromboembolism (CTEPH), sarcoidosis, COPD or pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), α-1-antitrypsin deficiency (AATD), pulmonary fibrosis, emphysema (e.g., emphysema caused by cigarette smoke), and cystic fibrosis (CF).

[0446] The compounds described in this invention are also active compounds for controlling central nervous system disorders characterized by NO / cGMP system dysfunction. They are particularly suitable for improving perception, focus, learning, or memory following cognitive impairment, such as those associated with conditions / diseases / syndromes such as: mild cognitive impairment, age-related learning and memory impairment, age-related memory loss, vascular dementia, traumatic brain injury, stroke, post-stroke dementia (post-stroke dementia), post-traumatic brain injury, general attention impairment, attention impairment in children with learning and memory problems, Alzheimer's disease, Lewy body dementia, dementia with frontal lobe degeneration including Pick syndrome, Parkinson's disease, progressive dementia with corticobasal degeneration, amyotrophic lateral sclerosis (ALS), Huntington's disease, demyelinating diseases, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, schizophrenia with dementia, or Korsakoff psychosis. They are also applicable for the treatment and / or prevention of central nervous system disorders, such as anxiety, tension and depression, CNS-related sexual dysfunction and sleep disorders, as well as for the control of pathological disorders caused by food, stimulants and addictive substances.

[0447] Furthermore, the compounds according to the invention are also suitable for controlling cerebral blood flow, thus representing effective agents for controlling migraines. They are also suitable for preventing and controlling the sequelae of cerebral infarction (stroke), such as stroke, cerebral ischemia, and traumatic brain injury. The compounds according to the invention can also be used to control pain and tinnitus.

[0448] Furthermore, the compounds according to the invention have anti-inflammatory effects and can therefore be used as anti-inflammatory agents for the treatment and / or prevention of sepsis (SIRS), multiple organ failure (MODS, MOF), inflammatory conditions of the kidneys, chronic intestinal inflammation (IBD, Crohn's disease, UC), pancreatitis, peritonitis, rheumatoid arthritis, inflammatory skin conditions, and inflammatory eye conditions.

[0449] Furthermore, the compounds according to the present invention can also be used to treat and / or prevent autoimmune diseases.

[0450] The compounds according to the invention are also suitable for treating and / or preventing fibrotic conditions of visceral organs such as the lungs, heart, kidneys, bone marrow, and especially the liver, as well as dermatological fibrosis and fibrotic ocular conditions. In the context of this invention, the term fibrotic condition specifically includes the following terms: liver fibrosis, cirrhosis, pulmonary fibrosis, endocardial myocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic damage caused by diabetes, myelofibrosis and similar fibrotic conditions, scleroderma, morphine, keloids, hypertrophic scars (also post-surgical), nevi, diabetic retinopathy, proliferative vitreoretinopathy, and connective tissue conditions (e.g., sarcoidosis).

[0451] The compounds according to the invention are also suitable for controlling postoperative scar formation, for example, due to glaucoma surgery.

[0452] The compounds according to the present invention can also be used cosmetically for aging and keratinized skin.

[0453] Furthermore, the compounds according to the present invention are suitable for the treatment and / or prevention of hepatitis, tumors, osteoporosis, glaucoma and gastroparesis.

[0454] The present invention further provides the use of the compounds according to the invention for treating and / or preventing diseases, especially the aforementioned diseases.

[0455] The present invention further provides the use of the compounds of the present invention for the treatment and / or prevention of chronic kidney disease, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropathy, fibrotic disease, heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disease, thromboembolic disease, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostatic hyperplasia, dysuria associated with benign prostatic hyperplasia, Huntington's disease, dementia, Alzheimer's disease and Creutzfeldt-Jakob disease.

[0456] The present invention further provides a method for treating and / or preventing diseases, particularly the aforementioned diseases, using an effective amount of at least one compound according to the present invention.

[0457] The present invention further provides methods for treating and / or preventing chronic kidney disease, acute and chronic renal insufficiency, diabetic, inflammatory or hypertensive nephropathy, fibrotic disease, heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disease, thromboembolic disease, arteriosclerosis, sickle cell anemia, erectile dysfunction, benign prostatic hyperplasia, dysuria associated with benign prostatic hyperplasia, Huntington's disease, dementia, Alzheimer's disease and Creutzfeldt-Jakob disease.

[0458] In another embodiment, the compounds of the present invention can also be used to treat or prevent uterine fibroids (uterine leiomyoma or uterine myoma) in women.

[0459] Uterine fibroids are benign tumors of the myometrium, which is the smooth muscle layer of the uterus. Uterine fibroids grow slowly in a woman's life, and their growth depends 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.]. Therefore, it has been found that the incidence of uterine fibroids is highest from age 35 to menopause (when uterine fibroids shrink due to decreased hormone levels), with approximately 70% and >80% in white women and African American 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.]. Approximately 30% and 45% of white and African American women, respectively, experience clinically relevant symptoms due to their fibroids, including heavy menstrual bleeding 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, heavy menstrual bleeding is defined as blood loss exceeding 80 mL during menstruation [Fraser IS et al. The FIGORecommendations on Terminologies and Definitions for Normal and Abnormal Uterine Bleeding, Semin Reprod Med 2011; 29(5):383-390].Submucosal locations of uterine fibroids, such as those located directly beneath the endometrium, appear 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. FertilSteril. 2011 Apr; 95(5):1769-72]. Furthermore, uterine fibroids significantly 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].

[0460] To date, it remains unclear how uterine fibroids cause heavy menstrual bleeding. Dysregulated genes in uterine fibroids, compared to normal myometrium, can provide clues to understanding the underlying mechanisms. In published and internal studies, we found that TDO2 tryptophan 2,3-dioxygenase is highly upregulated [Tsibris JC et al. Insights from gene arrayson the development and growth regulation of uterine leiomyomata. FertilSteril. 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 tumor-promoting ligand of the human aryl hydrocarbon receptor Nature. 2011 Oct 5; 478(7368):197-203].

[0461] L-kynurenine controls at least two dysregulated physiological processes in uterine fibroids. By upregulating IDO (indoleamine-2,3-dioxygenase) or TDO2 synthesis and acting via AHR receptors, L-kynurenine suppresses the immune system, thereby 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]. Furthermore, upregulation of L-kynurenine leads to vasodilation, which can directly increase blood loss and bleeding [Wang Y et al. Kynurenine is anendothelium-derived relaxing factor produced during inflammation Nature Medicine 16, 279–285 (2010)].

[0462] In summary, upregulating L-kynurenine by activating its physiological receptor AHR appears to support uterine fibroid growth by locally suppressing the immune system and may induce heavy menstrual bleeding through vasodilation of endometrial blood vessels near the tumor.

[0463] Therefore, systemic or local application of the compounds of the present invention to inhibit the activation of AHR and thus block the action of L-kynurenine derived from uterine fibroids provides a new and effective treatment option for uterine fibroids.

[0464] The compounds of this 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 dysregulated immune responses, thereby, for example, blocking immunosuppression and increasing immune cell activation and infiltration in the context of cancer and cancer immunotherapy. The method comprises administering a measured amount of the compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate, or ester thereof, to a mammal, including a human, in which such treatment is effective.

[0465] The present invention also provides methods for treating a variety of other conditions involving AHR, such as, but not limited to, inflammation, infection and cancer vaccination, viral infection, obesity and diet-induced obesity, excess fat, metabolic disorders, hepatic steatosis and uterine fibroids.

[0466] These conditions are well characterized in humans, but similar causes exist in other mammals and can be treated by applying the pharmaceutical compositions of the present invention.

[0467] The terms “treating” or “treatment” as used in this article are used in a conventional sense, for example, to manage or care for a subject in order to combat, alleviate, reduce, relieve, or improve the condition of a disease or symptom such as fluid and solid tumors.

[0468] According to another aspect, the present invention covers compounds of general formula (I) as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, especially pharmaceutically acceptable salts thereof, or mixtures thereof, for the treatment or prevention of diseases, particularly cancers or conditions or other ailments associated with abnormal AHR signaling or with dysregulated immune responses.

[0469] The pharmaceutical activity of the compounds according to the invention can be explained by their activity as AHR inhibitors.

[0470] According to another aspect, the present invention covers the use of compounds of general formula (I) as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, especially pharmaceutically acceptable salts thereof, or mixtures thereof, for the treatment or prevention of diseases, particularly cancers or conditions or other illnesses with dysregulated immune responses associated with abnormal AHR signaling, especially fluid and solid tumors.

[0471] According to another aspect, the present invention covers the use of compounds of formula (I) as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, especially pharmaceutically acceptable salts thereof, or mixtures thereof, for the prevention or treatment of diseases, particularly cancers or conditions or other ailments with dysregulated immune responses associated with abnormal AHR signaling, particularly fluid and solid tumors.

[0472] According to another aspect, the present invention covers the use of compounds of general formula (I) as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, especially pharmaceutically acceptable salts thereof, or mixtures thereof, in methods of treating or preventing diseases, particularly cancers or conditions or other ailments with dysregulated immune responses associated with abnormal AHR signaling, especially fluid and solid tumors.

[0473] According to another aspect, the present invention covers the use of compounds of general formula (I) as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts thereof, especially pharmaceutically acceptable salts thereof, or mixtures thereof, in the preparation of pharmaceutical compositions, particularly pharmaceuticals, for the prevention or treatment of diseases, particularly cancers or conditions or other ailments with dysregulated immune responses associated with abnormal AHR signaling, particularly liquid and solid tumors.

[0474] According to another aspect, the present invention covers methods for treating or preventing diseases, particularly cancers or conditions or other conditions with dysregulated immune responses, particularly fluid and solid tumors, using effective amounts of compounds of general formula (I) as described above, or stereoisomers, tautomers, N-oxides, hydrates, solvates and salts thereof, especially pharmaceutically acceptable salts thereof, or mixtures thereof.

[0475] According to another aspect, the present invention covers pharmaceutical compositions, particularly pharmaceuticals, comprising a compound of general formula (I) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, salt, particularly a pharmaceutically acceptable salt, or a mixture thereof, and one or more excipients, particularly one or more pharmaceutically acceptable excipients. Conventional procedures for preparing such pharmaceutical compositions in suitable dosage forms can be used.

[0476] The present invention also covers pharmaceutical compositions, particularly pharmaceuticals, comprising at least one compound according to the invention, usually together with one or more pharmaceutically suitable excipients, and their use for the purposes described above.

[0477] The compounds according to the invention may have systemic and / or local activity. For this purpose, they can be administered in suitable manner, such as by oral, parenteral, pulmonary, nasal, sublingual, tongue, sublingual, rectal, vaginal, skin, transdermal, conjunctival, ear canal routes, or as implants or scaffolds.

[0478] For these routes of administration, the compounds according to the invention can be administered in suitable forms.

[0479] For oral administration, the compounds according to the invention can be formulated into dosage forms known in the art for rapid and / or modified delivery of the compounds, such as tablets (uncoated or coated tablets, e.g., enteric or controlled-release coatings with delayed or non-dissolving properties), orally disintegrating tablets, films / tablets, 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 invention can be incorporated into said dosage forms in crystalline and / or amorphous and / or dissolved forms.

[0480] Parenteral administration can bypass absorption steps (e.g., intravenous, intra-arterial, intracardiac, intraspinal, or lumbar) or involve absorption (e.g., intramuscular, subcutaneous, intradermal, percutaneous, or intraperitoneal) to achieve its effect. Suitable forms of administration for parenteral administration are especially injectable or infusion formulations in the form of solutions, suspensions, emulsions, lyophilized products, or sterile powders.

[0481] 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.

[0482] 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

[0483] • Fillers and carriers (e.g., cellulose, microcrystalline cellulose, e.g., ... ), lactose, mannitol, starch, calcium phosphate (e.g., for example, )),

[0484] • Ointment base (e.g., petrolatum, paraffin, triglycerides, wax, lanolin, lanolin alcohol, hydrophilic ointments, polyethylene glycol),

[0485] • Suppository base (e.g., polyethylene glycol, cocoa butter, stearate),

[0486] Solvents (e.g., water, ethanol, isopropanol, glycerol, propylene glycol, medium-chain triglyceride fatty oils, liquid polyethylene glycol, paraffin),

[0487] 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, ),

[0488] • Buffers, acids and bases (e.g., phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, tromethamine, triethanolamine),

[0489] • Isotonic agents (e.g., glucose, sodium chloride),

[0490] • Adsorbent (e.g., highly dispersed silica),

[0491] • Tackifiers, gelling agents, thickeners and / or adhesives (e.g., polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, starch, carbomer, polyacrylic acid (e.g., for example, (); alginate, gelatin),

[0492] • Disintegrants (e.g., modified starch, sodium carboxymethyl cellulose, sodium starch glycolate (e.g., ...) ), cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose (e.g., for example, )),

[0493] • Flow conditioners, lubricants, flow aids, and release agents (e.g., magnesium stearate, stearic acid, talc, highly dispersed silica (e.g., ...). )),

[0494] • Coating materials (e.g., sugar, shellac) and film-forming agents for rapidly dissolving or in an improved manner dissolving film or diffusion film (e.g., polyvinylpyrrolidone, for example, ...). Polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylate, polymethacrylate, for example, )),

[0495] • Capsule materials (e.g., gelatin, hydroxypropyl methylcellulose),

[0496] • Synthetic polymers (e.g., polylactide, polyglycolic acid ester, polymethacrylate, etc.) ), polyvinylpyrrolidone (e.g., for example, Polyvinyl alcohol, polyvinyl acetate, polyethylene oxide, polyethylene glycol and their copolymers and block copolymers),

[0497] Plasticizers (such as polyethylene glycol, propylene glycol, glycerin, triacetyl triacetate, triacetyl citrate, dibutyl phthalate),

[0498] • Penetration enhancer

[0499] • Stabilizers (e.g., antioxidants, such as ascorbic acid, ascorbate palmitate, sodium ascorbate, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate),

[0500] • Preservatives (e.g., parabens, sorbic acid, thimerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), • Colorants (e.g., inorganic pigments, such as iron oxide, titanium dioxide),

[0501] • Flavoring agents, sweeteners, flavor- and / or odor-masking agents.

[0502] The present invention also relates to pharmaceutical compositions comprising at least one compound according to the invention, typically together with one or more pharmaceutically suitable excipients, and their uses according to the invention.

[0503] According to another aspect, the present invention covers pharmaceutical combinations comprising at least one compound of the general formula (I) of the present invention and at least one or more other active ingredients, particularly pharmaceuticals, which are specifically used to treat and / or prevent cancers or conditions or other conditions with dysregulated immune responses associated with abnormal AHR signaling, commonly known as disorders, particularly fluid and solid tumors.

[0504] As those skilled in the art will know, the term "combination" used in this invention can refer to a fixed combination, a non-fixed combination, or a set of components.

[0505] As is known to those skilled in the art, the term "fixed combination" in this invention is defined as a combination in which, for example, a first active ingredient, such as one or more compounds of general formula (I) of this invention, and other active ingredients are present together in a single unit dose or a single entity. An example of a "fixed combination" is a pharmaceutical composition in which the first active ingredient and other active ingredients are present in a mixture for simultaneous administration, such as simultaneous administration in a formulation. Another example of a "fixed combination" is a pharmaceutical combination in which the first active ingredient and other active ingredients are present in a single unit rather than a mixture.

[0506] As those skilled in the art will recognize, a non-fixed combination or "kit" in this invention is defined as a combination in which a first active ingredient and other active ingredients are present in more than one unit. An example of a non-fixed combination or kit is a combination in which the first active ingredient and other active ingredients are present separately. The components of a non-fixed combination or kit may be applied separately, sequentially, simultaneously, jointly, or sequentially.

[0507] Based on standard laboratory techniques known to have been evaluated for use in treating cancers or conditions with dysregulated immune responses or other illnesses associated with abnormal AHR signaling, the treatment of the above-identified conditions in mammals is determined by standard toxicity tests and standard pharmacological assays. The effective dose of the compounds of the present invention for each desired indication can be readily determined by comparing these results with those of known active ingredients or drugs used to treat these conditions. The amount of active ingredient administered in the treatment of one of these conditions can vary widely depending on considerations such as the specific compound and dosage unit used, the route of administration, the duration of treatment, the age and sex of the patient being treated, and the nature and severity of the condition being treated.

[0508] The total amount of active ingredient to be administered typically ranges 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 regimens range from once to three times daily to once every four weeks. Additionally, a "withdrawal period" is possible, in which the patient does not take the drug for a period of time, which is beneficial for the overall balance between pharmacological effects and tolerability. A unit dose may contain from about 0.5 mg to about 1500 mg of active ingredient and may be administered once or more daily or less than once daily. The average daily dose administered by injection (including intravenous, intramuscular, subcutaneous, and parenteral injection) and using infusion techniques is preferably 0.01 to 200 mg / kg body weight. The average daily rectal dosing regimen is preferably 0.01 to 200 mg / kg body weight. The average daily vaginal dosing regimen is preferably 0.01 to 200 mg / kg body weight. The average daily local dosing regimen is preferably 0.1 to 200 mg administered one to four times daily. The preferred transdermal concentration is one required to maintain a daily dose of 0.01 to 200 mg / kg. The preferred average daily inhalation dose regimen is 0.01 to 100 mg / kg total body weight.

[0509] Of course, the specific initial and continuous dosage regimen for each patient will vary depending on the nature and severity of the condition as determined by the attending physician, the activity of the specific compound used, the patient's age and general condition, the timing of administration, the route of administration, the rate of drug excretion, and the combination of drugs. Those skilled in the art can determine the required mode of treatment and the dosage of the compound of the present invention or its pharmaceutically acceptable salts, esters, or combinations using conventional treatment trials.

[0510] Example

[0511] Experimental Section

[0512] NMR peak forms are described by the form in which they appear in the spectrum, without considering possible higher-order effects. Multiplicity is described by the form of the signal appearing in the spectrum, without considering higher-order NMR spectral effects. NMR signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, quintet, br = broad signal, m = multiply. NMR signal: shift expressed in [ppm]. Combinations of multiplicity can be, for example, dd = doublet from doublet.

[0513] Use ACD / Labs' ACD / Name software to generate chemical names. In some cases, use the generally accepted name of a commercially available reagent instead of the name generated by ACD / Name.

[0514] Table 1 lists the abbreviations used in this paragraph and the Examples section, unless they are explained in the main text. Other abbreviations have their own meanings as commonly understood by those skilled in the art.

[0515] Table 1: Abbreviations

[0516] ACN Acetonitrile

[0517] AcOH (acetic acid)

[0518] CDCl3 (deuterated chloroform)

[0519] DAD Diode Array Detector

[0520] DEA diethylamine

[0521] DMF N,N-dimethylformamide

[0522] DMSO-d6 Deuterated dimethyl sulfoxide

[0523] DMSO (dimethyl sulfoxide)

[0524] ELSD Evaporative Light Scattering Detector

[0525] ESIpos Positive Ion Electrospray Ionization

[0526] Example 1.

[0527] HATU (7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureonium hexafluorophosphate

[0528] HBTU O-benzotriazole-N,N,N',N'-tetramethylureonium hexafluorophosphate

[0529] HPLC (High-Performance Liquid Chromatography)

[0530] KA kynurenic acid

[0531] LCMS (Liquid Chromatography-Mass Spectrometry)

[0532] LPS (lipopolysaccharide)

[0533] mL

[0534] min. minutes

[0535] MTBE (methyl tert-butyl ether)

[0536] PBMCs (peripheral blood mononuclear cells)

[0537] PyBOB (benzotriazol-1-yl)oxytripyrrolidine phosphonium hexafluorophosphate

[0538] RP-HPLC (Reversed-Phase High-Performance Liquid Chromatography)

[0539] Rt retention time

[0540] rt room temperature

[0541] sat. saturated

[0542] T3P 2,4,6-Tripropyl-1,3,5,2,4,6-Trioxatriphosphacyclohexane 2,4,6-trioxide

[0543] THF Tetrahydrofuran

[0544] TFA (trifluoroacetic acid)

[0545] TLC (Thin Layer Chromatography)

[0546] TNFα (tumor necrosis factor α)

[0547] μM micromolar

[0548] UPLC (Ultra-High Performance Chromatography)

[0549] The various aspects of the invention described in this application are illustrated by the following embodiments, which are not intended to limit the invention in any way.

[0550] The embodiments and test experiments described herein are for illustrative purposes only, and the invention is not limited to the given embodiments.

[0551] Experimental Section - General Section

[0552] All reagents not described in the experimental section are commercially available, or are known compounds or can be formed by those skilled in the art from known compounds using known methods.

[0553] Compounds and intermediates prepared according to the method of the present invention may require purification. Purification of organic compounds is well known to those skilled in the art, and several methods exist for purifying the same compound. In some cases, purification may not be necessary. In some cases, the compound can be purified by crystallization. In some cases, impurities can be removed by stirring with a suitable solvent. In some cases, the compound can be purified by chromatography, particularly rapid column chromatography, using, for example, pre-packed silica gel cartridges, such as Biotage SNAP cartridges. or And Biotage automated purification system ( or Isolera Purification can be achieved using eluents such as gradients of hexane / ethyl acetate or DCM / methanol. In some cases, compounds can be purified by preparative HPLC using, for example, a Waters automated purifier equipped with a diode array detector and / or an online electrospray ionization mass spectrometer, along with a suitable pre-packed reversed-phase column and eluents such as gradients of water and acetonitrile (possibly containing additives such as trifluoroacetic acid, formic acid, or ammonia).

[0554] In some cases, the purification methods described above can provide those of the present invention in salt form having sufficiently basic or acidic functional groups, such as trifluoroacetate or formate salts in the case of sufficiently basic compounds of the present invention, or, for example, ammonium salts in the case of sufficiently acidic compounds of the present invention. Salts of this type can be converted to their free base or free acid forms, respectively, by various methods known to those skilled in the art, or used in subsequent bioassays as salts. It should be understood that the specific forms (e.g., salts, free bases, etc.) of the compounds of the present invention isolated and described herein are not necessarily the only forms in which said compounds can be used in bioassays to quantify specific biological activities.

[0555] Experimental Section - Intermediates

[0556] Intermediate 1

[0557] Di-tert-butyl 1-(1-methyl-1H-pyrazol-4-yl)hydrazine-1,2-dicarboxylate

[0558]

[0559] 1.7 mL of n-butyllithium (2 M, in THF) was added 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. After stirring at -78 °C for 30 min, a solution of 2.1 g of di-tert-butyl azodicarbonate 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 washed with tetrahydrofuran. The resulting solid was dissolved in a mixture of dichloromethane and water, and the mixture was subjected to phase separation. After vacuum evaporation, 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-pyrazole-4-yl)hydrazide-1,2-dicarboxylate.

[0560] 1 ¹H-NMR: (300MHz, 25℃, 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).

[0561] Intermediate 2

[0562] 4-Hydroxy-1-methyl-1H-pyrazole trifluoroacetate (1:1)

[0563]

[0564] 800 mg of intermediate 1 was stirred in a mixture of 15 mL of dichloromethane and 1 mL of trifluoroacetic acid at room temperature for 3 hours. The mixture was evaporated to dryness to give 750 mg of (crude) product, which could be used directly in the next step without further purification.

[0565] 1 H-NMR: (300MHz, 25℃, DMSO-d6): δ [ppm] = 3.79 (s, 3H); 7.33 (s, 1H); 7.57 (s, 1H); 9.49 (br s, 3H).

[0566] Intermediate 3

[0567] Dimethyl [2-(4-methylphenyl)-2-oxoethyl]malonate

[0568]

[0569] At room temperature, a solution of 49.6 g of 2-bromo-1-(4-methylphenyl)ethyl ketone in 300 mL of acetone was added dropwise to a solution of 10 g of dimethyl malonate in 120 mL of acetone. The reaction mixture was stirred at room temperature for 4 hours. Then, the solvent was removed under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate 10:1) to give 10.3 g of dimethyl [2-(4-methylphenyl)-2-oxoethyl]malonate.

[0570] 1 H-NMR: (400MHz, 25℃, 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).

[0571] Intermediate 4

[0572] methyl 6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

[0573]

[0574] A mixture of 818 mg intermediate 3 and 700 mg intermediate 2 in 20 mL of ethanol was stirred at 80 °C for 2 hours. The solvent was then removed under vacuum. The residue was purified by column chromatography (petroleum ether / ethyl acetate 3:2) to give 500 mg of methyl 6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate.

[0575] 1 ¹H-NMR: (400MHz, 25℃, 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, some signals below the CDCl₃ signal); 7.74 (d, 2H); 7.87 (s, 1H); 8.00 (s, 1H).

[0576] Intermediate 5

[0577] Methyl 6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

[0578]

[0579] A mixture of 450 mg intermediate 4 and 371 mg copper(II) in 20 mL acetonitrile was stirred at 90 °C for 2 hours. After vacuum evaporation, the residue was purified by column chromatography (dichloromethane / methanol 20:1) to give 380 mg methyl 6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate.

[0580] 1 H-NMR: (400MHz, 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).

[0581] Intermediate 6

[0582] 6-(4-Methylphenyl)-2-(1-Methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0583]

[0584] 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 was then adjusted to 5-6 with 10% hydrochloric acid. The solid was collected by filtration, washed three times with water, 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.

[0585] 1 H-NMR: (400MHz, 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).

[0586] Intermediate 7

[0587] 6-(4-Methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-formyl chloride

[0588]

[0589] 110 mg of oxalyl chloride was slowly added to a solution of 180 mg of intermediate 6 in 10 mL of dichloromethane and 0.1 mL of N,N-dimethylformamide. 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-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-formyl chloride, which was used directly in the next step without further purification.

[0590] Intermediate 8

[0591] Dimethyl [2-(4-chlorophenyl)-2-oxoethyl]malonate

[0592]

[0593] 2-Chloro-1-(4-chlorophenyl)ethyl ketone (25 g, 107.1 mmol) was dissolved in acetone (500 mL). Then, dimethyl malonate (31.1 g, 235.4 mmol) and potassium carbonate (22.2 g, 160.6 mmol) were added at room temperature. The mixture was stirred overnight at room temperature. The reaction mixture was reduced to half its volume under vacuum. The residue was then poured into water. The layers were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water and an aqueous solution of concentrated sodium chloride, dried over sodium sulfate, and concentrated. The crude product was purified by rapid chromatography (silica gel, hexane / ethyl acetate, gradient) to give 12.21 g (36%) of the title product.

[0594] 1 H-NMR (400MHz, 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).

[0595] Intermediate 9

[0596] methyl 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

[0597]

[0598] Dimethyl [2-(4-chlorophenyl)-2-oxoethyl]malonate (1360 mg, 4.78 mmol) and sodium acetate (1037 mg, 12.65 mmol) were dissolved in acetic acid (40 mL). Then, 4-hydrazino-1-methyl-1H-pyrazole dihydrochloride (780 mg, 4.22 mmol) was added in portions. The mixture was stirred at room temperature for 1 hour and then at 50 °C for 20 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. A concentrated aqueous solution of sodium bicarbonate was added, and the phases were separated. The aqueous layer was extracted with ethyl acetate (four times, 80 mL). The combined organic layers were washed twice with water, dried over magnesium sulfate, and concentrated. The residue was purified by rapid chromatography (silica gel, hexane / ethyl acetate, gradient) to give 530 mg (36%) of the title product.

[0599] 1H-NMR (400MHz, 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), 775 (d, 1H), 7.92-7.96 (m, 2H), 8.08 (s, 1H).

[0600] Intermediate 10

[0601] Methyl 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

[0602]

[0603] Methyl 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate (600 mg, 1.730 mmol) was dissolved in acetonitrile (40 mL). Copper dichloride (698 mg, 5.191 mmol) was added. The mixture was stirred at 90 °C for 4 hours. It was cooled and concentrated using a rotary evaporator. Water was added, the remaining solid was filtered off, washed five times with water, and dried under vacuum at 50 °C to give 741 mg of the title compound, which was used for the next step without further purification.

[0604] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.88 (s, 3H), 3.91 (s, 3H), 7.59 (d, 2H), 8.05-8.13 (m, 3H), 8.44 (s, 1H), 8.52 (br s, 1H).

[0605] Intermediate 11

[0606] 6-(4-Chlorophenyl)-2-(1-Methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0607]

[0608] Methyl 6-(4-chlorophenyl)-2-(1-methyl-1H-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. The mixture was stirred at 40 °C for 10 hours. Water was added, and the pH was adjusted to 4 with 2N HCl. The precipitate was filtered off, washed three times with water, and dried under vacuum at 50 °C to give 520 mg (90%) of the title compound, which was used for the next step without further purification.

[0609] 1 H-NMR (400MHz, 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).

[0610] Intermediate 12

[0611] Methyl 6-(4-chlorophenyl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

[0612]

[0613] Dimethyl [2-(4-chlorophenyl)-2-oxoethyl]malonate (16.30 g, 57.25 mmol) was dissolved in acetic acid (203 mL). A THF solution of hydrazine (80 mL, 1.0 M, 80 mmol) was added at room temperature. The mixture was stirred at 75 °C for 5.5 h and then overnight at room temperature. The mixture was then stirred at 75 °C. After 2.5 h, a THF solution of hydrazine (24 mL, 1.0 M, 24 mmol) was added, and stirring was continued at 75 °C for 1.5 h. The reaction mixture was cooled and water (1 L) was added. The precipitate was filtered off, washed with water, and dried under vacuum at 50 °C to give 12.14 g (80%) of the title compound, which was used for the next step without further purification.

[0614] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 3, 16 (dd, 1H), 3.26 (dd, 1H), 3.67 (s, 3H), 3.75 (dd, 1H), 7.47-7.52 (m, 2H), 7.75-7.79 (m, 2H), 11.31 (s, 1H).

[0615] Intermediate 13

[0616] Methyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

[0617]

[0618] 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 the mixture was stirred at 70 °C for 5.5 h. Then, additional copper dichloride (0.626 g, 4.66 mmol) was added and stirring continued at 70 °C for 1 h. The reaction mixture was cooled and concentrated to half its volume using a rotary evaporator. Water (300 mL) was added and the reaction mixture was stirred for 10 min. The precipitate was filtered, washed three times with water, and dried under vacuum at 50 °C to give 4.793 g (97%) of the title compound.

[0619] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.85 (s, 3H), 7.53-7.58 (m, 2H), 7.89-7.93 (m, 2H), 8.38 (s, 1H), 13.70 (s, 1H).

[0620] Intermediate 14

[0621] Dimethyl 2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl malonate

[0622]

[0623] 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-1-[4-(trifluoromethyl)phenyl]ethyl ketone (10 g, 37.4 mmol) in acetone (60 mL) was added dropwise while cooling (0–5 °C). The mixture was stirred at 0–5 °C for 2 hours and then overnight at room temperature. Volatile compounds were removed by rotary evaporation. Water and ethyl acetate were added, and the layers were separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with concentrated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated. The crude product was purified by rapid chromatography (silica gel, hexane / ethyl acetate, gradient) to give 8.03 g (67%) of the title product.

[0624] 1¹H-NMR (400MHz, chloroform-d³): δ [ppm] = 3.65 (d, 2H), 3.79 (s, 6H), 410 (t, 1H), 7.73–7.77 (m, 2H), 8.07–8.11 (m, 2H).

[0625] Intermediate 15

[0626] 3-Oxo-6-[4-(trifluoromethyl)phenyl]-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[0627]

[0628] Dimethyl 2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl malonate (5.68 g, 17.55 mmol) was dissolved in acetic acid (64 mL). A THF solution of hydrazine (35 mL, 1.0 M, 35 mmol) was added at room temperature. The mixture was stirred at 75 °C for 3.5 h. Then, a THF solution of hydrazine (3.5 mL, 1.0 M, 3.5 mmol) was added, and stirring was continued at 75 °C for 1 h. The reaction mixture was cooled, and water (0.6 L) was added. The precipitate was filtered off, washed with water, and dried under vacuum at 50 °C to give 4.06 g (76%) of the title compound, which was used for the next step without further purification.

[0629] 1 ¹H-NMR (400MHz, 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).

[0630] Intermediate 16

[0631] methyl 3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylate

[0632]

[0633] 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 the mixture was stirred at 90 °C for 2.5 h. The reaction mixture was cooled and concentrated to half its volume using a rotary evaporator. Water (350 mL) was added and the reaction mixture was stirred for 10 min. The precipitate was filtered, washed three times with water, and dried under vacuum at 50 °C to give 3.67 g (91%) of the title compound.

[0634] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.86 (s, 3H), 7, 86 (d, 2H), 8.11 (d, 2H), 845 (s, 1H), 13.83 (s, 1H).

[0635] Intermediate 17

[0636] 2-(1-Methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0637] 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-dioxaborhecyclopentan-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. The mixture was stirred at room temperature for 21 hours. 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (349 mg, 1.68 mmol) was added, and stirring continued overnight at room temperature. Add water (5 mL) and adjust the pH to 3 with 2N HCl (3.5 mL). Filter the precipitate, wash three times with water, and dry under vacuum at 50 °C to give 594 mg (63%) of the title compound.

[0638] 1 H-NMR (400MHz, 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).

[0639] Intermediate 18

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

[0641]

[0642] Methyl 2-(1-methyl-1H-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. The mixture was stirred at room temperature for 3 hours. Water (100 mL) was added and the pH was adjusted to 6 with 2N HCl. The precipitate was filtered off, washed with water, and dried under vacuum at 50 °C to give 345 mg (45%) of the title compound, which was used for the next step without further purification.

[0643] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.93 (br s, 3H), 7.47-8.39 (m, 7H).

[0644] Intermediate 19

[0645] 6-(4-Chlorophenyl)-2-(1-Cyclobutyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0646]

[0647] Step 1: Methyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (0.5 g, 1.89 mmol) was dissolved in DMF (15 mL). 1-Cyclobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-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. The mixture was stirred at room temperature for 96 hours. Water was added, and the pH was adjusted to 3 with 2N HCl. The precipitate was filtered, washed three times with water, and dried under vacuum at 50 °C to give 370 mg (36%) of methyl ester, which was used in subsequent steps without further purification.

[0648] 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. The mixture was stirred overnight at room temperature. Water was added, and the pH was adjusted to 6 with 2N HCl. 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 for the next step without further purification.

[0649] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.750x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =0.64min; MS(ESIpos): m / z=371.3[M+H] + .

[0650] Intermediate 20

[0651] Dimethyl 2-oxo-2-[4-(trifluoromethoxy)phenyl]ethyl malonate

[0652]

[0653] 4.1 g of dimethyl malonate and 3.2 g of potassium carbonate were added to a solution of 4.4 g of 2-bromo-1-[4-(trifluoromethoxy)phenyl]ethyl-1-one in 110 mL of acetone. The reaction mixture was stirred overnight at room temperature and 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 of up to 30% ethyl acetate) to give 4.9 g of dimethyl 2-oxo-2-[4-(trifluoromethoxy)phenyl]ethyl}malonate.

[0654] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.750x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.22min; MS (ESIpos): m / z=335[M+H] + .

[0655] 1 H NMR (400MHz, DMSO-d6) δ [ppm] = 3.33 (s, 6H), 3.62-3.67 (m, 2H), 3.99 (t, 1H), 7.52 (dd, 2H), 8.11-8.16 (m, 2H).

[0656] Intermediate 21

[0657] 2-(1-Methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[0658]

[0659] A mixture of 954 mg {2-[4-(difluoromethoxy)phenyl]-2-oxoethyl} dimethyl malonate, 1111 mg 4-hydrazino-1-methyl-1H-pyrazole dihydrochloride, and 1053 mg sodium acetate in 27 mL of AcOH was stirred at room temperature for 14 hours and then at 50 °C for 6 hours. The reaction mixture was concentrated, and the residue was dissolved in water and ethyl acetate, followed by the addition of a saturated aqueous solution of sodium bicarbonate. 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 (hexane / ethyl acetate, gradient up to 80% ethyl acetate) to give 559 mg methyl 2-(1-methyl-1H-pyrazole-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3,4,5-tetrahydropyridazine-4-carboxylate.

[0660] 1H NMR (400MHz, 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)

[0661] Intermediate 22

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

[0663]

[0664] A mixture of 686 mg of methyl 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3,4,5-tetrahydropyridazine-4-carboxylate and 698 mg of copper(II) chloride in 23 mL of acetonitrile was stirred at 50 °C for 2 hours and then at 90 °C for 3 hours. After vacuum evaporation, the residue was suspended in water, and the precipitate was filtered off to give 528 mg of methyl 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylate.

[0665] 1 H NMR (400MHz, 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).

[0666] Intermediate 23

[0667] 2-(1-Methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid

[0668]

[0669] A mixture of 528 mg of methyl 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid and 1.7 mL of 2N sodium hydroxide aqueous solution in 7 mL of tetrahydrofuran was stirred at room temperature for 14 hours. The pH was then adjusted to 3 with 1M hydrochloric acid, the precipitate was filtered off, washed with water, and dried under vacuum to give 458 mg of 2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid.

[0670] 1 H NMR (400MHz, 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).

[0671] Intermediate 24

[0672] Dimethyl {2-[4-(difluoromethyl)phenyl]-2-oxoethyl}malonate

[0673]

[0674] A mixture of 2.5 g of 2-bromo-1-[4-(difluoromethyl)phenyl]ethyl ketone (CAS 1227004-73-0), 4.6 mL of dimethyl malonate, 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 dimethyl {2-[4-(difluoromethyl)phenyl]-2-oxoethyl}malonate.

[0675] 1 H-NMR (400MHz, 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).

[0676] Intermediate 25

[0677] 6-[4-(difluoromethyl)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[0678]

[0679] A mixture of 75 mg {2-[4-(difluoromethyl)phenyl]-2-oxoethyl} dimethyl malonate, 44 mg 4-hydrazino-1-methyl-1H-pyrazole dihydrochloride, and 53 mg sodium acetate in 2.5 mL of AcOH was stirred at room temperature for 1 hour and then at 50 °C for 24 hours. 88 mg of 4-hydrazino-1-methyl-1H-pyrazole dihydrochloride was then added, and the reaction mixture was stirred at 50 °C for 6 hours. The reaction mixture was concentrated, and the residue was dissolved in water and ethyl acetate, followed by the addition of a saturated aqueous solution of sodium bicarbonate. 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 125mm x 30mm; 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 obtain 24 mg of methyl 6-[4-(difluoromethyl)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate).

[0680] 1 H NMR (400MHz, 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).

[0681] Intermediate 26

[0682] 6-[4-(difluoromethyl)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0683]

[0684] A mixture of 495 mg of methyl 6-[4-(difluoromethyl)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate and 551 mg of copper(II) in 15 mL of acetonitrile was stirred at 90 °C for 2 hours. After vacuum evaporation, the residue was suspended in water, and the precipitate was filtered off to give 451 mg of methyl 6-[4-(difluoromethyl)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate.

[0685] 1 H NMR (400MHz, DMSO-d6) δ [ppm] = 3.89 (s, 3H), 3.92 (s, 3H), 7.13 (t, 1H), 7.72 (d, 2H), 8.11 (s, 1H), 8.20 (d, 2H), 8.48 (s, 1H), 8.52 (s, 1H).

[0686] Intermediate 27

[0687] 6-[4-(difluoromethyl)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0688]

[0689] A mixture of 451 mg of methyl 6-[4-(difluoromethyl)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid and 6 mL of 1N sodium hydroxide aqueous solution in 19 mL of tetrahydrofuran was stirred at room temperature for 48 hours. The pH was then adjusted to 3 with 1M hydrochloric acid, the precipitate was filtered off, washed with water, and dried under vacuum to give 190 mg of 6-[4-(difluoromethyl)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid.

[0690] 1 H NMR (400MHz, DMSO-d6) δ [ppm] = 3.93 (s, 3H), 7.13 (t, 1H), 7.72 (d, 2H), 8.13 (s, 1H), 8.23 ​​(d, 2H), 8.49 (s, 1H), 8.54 (s, 1H).

[0691] Intermediate 28

[0692] Dimethyl {2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl}malonate

[0693]

[0694] A mixture of 5 g of 2-bromo-1-[6-(difluoromethyl)pyridin-3-yl]acetone, 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 dimethyl 2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl}malonate.

[0695] 1 H NMR (400MHz, 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).

[0696] Intermediate 29

[0697] methyl 6-[6-(difluoromethyl)pyridin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

[0698]

[0699] A mixture of 424 mg {2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl} dimethyl malonate, 549 mg 4-hydrazino-1-methyl-1H-pyrazole dihydrochloride, and 520 mg sodium acetate in 13 mL of AcOH was stirred at room temperature for 1 hour and then at 50 °C for 2 hours. The reaction mixture was concentrated, and the residue was dissolved in water and ethyl acetate, followed by the addition of a saturated aqueous solution of sodium bicarbonate. 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 methyl 6-[6-(difluoromethyl)pyridin-3-yl]-2-(1-methyl-1H-pyrazole-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate.

[0700] 1H NMR (400MHz, 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).

[0701] Intermediate 30

[0702] methyl 6-[6-(difluoromethyl)pyridin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

[0703]

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

[0705] 1 H NMR (400MHz, 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]

[0709] A mixture of 133 mg of methyl 6-[6-(difluoromethyl)pyridin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazin-4-carboxylic acid and 0.46 mL of 2N sodium hydroxide aqueous solution in 2 mL of tetrahydrofuran was stirred at room temperature for 14 hours. The pH was then adjusted to 3 with 1M hydrochloric acid, the precipitate was filtered off, washed with water, and dried under vacuum to give 103 mg of 6-[6-(difluoromethyl)pyridin-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazin-4-carboxylic acid.

[0710] 1 H NMR (400MHz, 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).

[0711] Intermediate 32

[0712] 5-Bromo-2-(difluoromethyl)pyridine

[0713]

[0714] A solution of 5-bromopyridin-2-carboxaldehyde (30 g, 161.29 mmol, 1.00 equivalent) in dichloromethane (800 mL) was placed in a 2000 mL four-necked round-bottom flask. Then, DAST (diethylaminosulfur trifluoride) (40 g, 1.08 mol, 6.69 equivalent) was added dropwise with stirring at 0 °C. The resulting solution was stirred at room temperature for 12 hours. The reaction was then quenched by adding water. The pH of the solution was adjusted to 8 with sodium carbonate (2 mol / L). The resulting solution was extracted with 3 × 500 mL of dichloromethane, and the organic layers were combined. The mixture was washed with 1 × 300 mL of H₂O. The resulting mixture was washed with 1 × 300 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 yielded 18 g (54%) of 5-bromo-2-(difluoromethyl)pyridine as a yellow oil.

[0715] Intermediate 33

[0716] 1-[6-(difluoromethyl)pyridin-3-yl]acetone

[0717]

[0718] A solution of 5-bromo-2-(difluoromethyl)pyridine (18 g, 86.54 mmol, 1.00 equivalent) in dioxane (180 mL), tributyl(1-ethoxyethylene)tin (35 g, 96.91 mmol, 1.12 equivalent), and tetrakis(triphenylphosphine)palladium (3 g, 2.60 mmol, 0.03 equivalent) were added to a 500 mL four-necked round-bottom flask. The resulting solution was stirred at 100 °C for 2 hours. The reaction mixture was cooled in a water bath. The reaction was then quenched by adding 250 mL of (2N) HCl. The pH of the solution was adjusted to 8 with sodium carbonate (2 mol / L). The resulting solution was extracted with 3 × 500 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 × 200 mL of H₂O. The resulting mixture was washed with 1 × 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 yields 10g (68%) of 1-[6-(difluoromethyl)pyridin-3-yl]ethyl-1-one, which is a yellow oily substance.

[0719] Intermediate 34

[0720] Diethyl {2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl}(hydroxy)malonate

[0721]

[0722] Add 10 g (58.43 mmol, 1.00 equivalent) of 1-[6-(difluoromethyl)pyridin-3-yl]ethyl-1-one and 15 g (86.13 mmol, 1.47 equivalent) of 2-oxomalonic acid 1,3-diethyl ester to a 100 mL round-bottom flask. Stir the resulting solution at 130 °C for 24 hours. Concentrate the mixture under vacuum. This yields 24 g (crude) 1,3-diethyl 2-[2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl]-2-hydroxymalonic acid, a red oil, which is used without further purification.

[0723] Intermediate 35

[0724] Ethyl 6-[6-(difluoromethyl)pyridin-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxylate

[0725]

[0726] A solution of 2,3-diethyl 2-[2-[6-(difluoromethyl)pyridin-3-yl]-2-oxoethyl]-2-hydroxymalonic acid in ethanol (200 mL) and hydrazine (15 mL) was placed in a 500 mL round-bottom flask. The resulting solution was stirred at 80 °C for 12 hours. The reaction was then quenched by adding water. The resulting solution was extracted with 3 × 300 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 × 100 mL of water. The resulting mixture was washed with 1 × 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 yielded 2.8 g (14%) of ethyl 6-[6-(difluoromethyl)pyridin-3-yl]-3-oxo-2,3-dihydropyridazine-4-carboxylate as a yellow solid.

[0727] 1 H-NMR (300MHz, DMSO-d6) δ [ppm] = 13.84 (s, 1H), 9.17 (s, 1H), 8.46 (m, 2H), 7.83 (m, 1H), 7.03 (1, 1H), 4.35 (m, 2H), 1.33 (t, 3H).

[0728] Intermediate 36

[0729] methyl 6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3,4,5-tetrahydropyridazine-4-carboxylate

[0730]

[0731] Dimethyl [2-(4-chlorophenyl)-2-oxoethyl]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-hydrazinopyridine hydrochloride (1:1) (0.961 g, 6.60 mmol) was added in portions. The mixture was stirred at room temperature for 24 hours. Another 3-hydrazinopyridine hydrochloride (1:1) (0.961 g, 6.60 mmol) was added, and stirring continued at room temperature for 24 hours. Then, 3-hydrazinopyridine hydrochloride (1:1) (0.961 g, 6.60 mmol) was added again, and the mixture was stirred at room temperature for 24 hours. Finally, the mixture 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. A concentrated aqueous solution of sodium bicarbonate was added, and the phases were separated. 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 residues were purified by RP-HPLC (column: YMC-Triart C18 5μm 100x50mm, mobile phase: (water + 0.1 vol% formic acid (99%)) / acetonitrile, gradient) to give 398 mg (18%) of the title product.

[0732] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.43 (dd, 1H), 3.50 (dd, 1H), 3.71 (s, 3H), 4.11 (dd, 1H), 7. 51(ddd, 1H), 7.51-7.56(m, 2H), 7.86-7.90(m, 2H), 7.97(ddd, 1H), 8.50(dd, 1H), 8.77(d, 1H).

[0733] Intermediate 37

[0734] 6-(4-Chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0735]

[0736] Step 1: Methyl 6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3,4,5-tetrahydropyridazine-4-carboxylate (1.0 g, 2.909 mmol) was dissolved in acetonitrile (60 mL). Copper dichloride (1.173 g, 8.727 mmol) was added. The mixture was stirred at 90 °C for 4 hours. It was cooled and concentrated on a rotary evaporator. Water was added, the remaining solid was filtered off, washed five times with water, and dried under vacuum at 50 °C for 24 hours to give 1.262 g of methyl 6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylate, which was used in the next step without further purification.

[0737] Step 2: Methyl 6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylate (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. The mixture was stirred at 40 °C for 10 hours. Water was added, and the pH was adjusted to 6-7 with 0.5 N HCl. The precipitate was filtered off, washed three times with water, and dried under vacuum at 50 °C to give 910 mg (95%) of the title compound, which was used for the next step without further purification.

[0738] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 7.54 (br d, 2H), 7.59 (dd, 1H), 790-7.99 (m, 3H), 8.11 (br d, 1H), 8.63 (br d, 1H), 8.88 (br d, 1H).

[0739] Intermediate 38

[0740] Diethyl 2-(2-(4-chlorophenyl)-2-oxoethyl)-2-hydroxymalonic acid

[0741]

[0742] 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 ground with pentane to give diethyl 2-(2-(4-chlorophenyl)-2-oxoethyl)-2-hydroxymalonate (50 g, 79%, LC-MS 98%) as a pale yellow liquid.

[0743] Intermediate 39

[0744] 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0745]

[0746] A mixture of diethyl 2-(2-(4-chlorophenyl)-2-oxoethyl)-2-hydroxymalonate (50 g, 152.43 mmol) and hydrazine dihydrochloride (19.2 g, 182.9 mmol) in ethanol (500 mL) was heated under reflux for 16 hours. The reaction was monitored by TLC. After completion, the reaction mixture was cooled and concentrated under reduced pressure. The reaction mixture was poured into a saturated sodium bicarbonate solution (500 mL) and extracted with ethyl acetate (3 × 600 mL). The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, eluent EtOAc / hexane 30:70) to give ethyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (21 g, 42%, LC-MS 95%) as a pale yellow solid.

[0747] 1 H NMR (400MHz, 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).

[0748] Intermediate 40

[0749] Methyl 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

[0750]

[0751] 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-dioxaborhexacyclopentan-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. The mixture 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 HCl. The precipitate was filtered, washed with water, and dried under vacuum at 50 °C. The crude compound was purified by rapid chromatography (silica gel, hexane / ethyl acetate, gradient) to give 174 mg (13%) of the title compound.

[0752] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.89 (s, 3H), 7.57-7.61 (m, 2H), 7.99-8.04 (m, 2H), 8.23 ​​(ddd, 1H), 8.54 (s, 1H), 8.72 (dd, 1H), 8.86 (br t, 1H).

[0753] Intermediate 41

[0754] 6-(4-Chlorophenyl)-2-(5-Fluoropyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0755]

[0756] 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. The mixture was stirred at room temperature for 24 hours. Water was added, and the pH was adjusted to 6 with 2N HCl. 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 for the next step without further purification.

[0757] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 7.56-7.60 (m, 2H), 8.01-8.06 (m, 2H), 8.24 (dt, 1H), 8.51 (s, 1H), 8.73 (d, 1H), 8.87 (s, 1H).

[0758] Intermediate 42

[0759] methyl 3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylate

[0760]

[0761] 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-dioxaborhecyclopentan-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. The mixture was stirred at 60 °C for 3 hours. The reaction mixture was cooled in an ice bath, water (240 mL) was added, and the pH was adjusted to 3 with 2N HCl (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.

[0762] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.89 (s, 3H), 7.62 (dd, 1H), 7.88 (d, 2H), 8.15-8.21 (m, 3H), 8.60 (s, 1H), 8.68 (br d, 1H), 8.93 (br s, 1H).

[0763] Intermediate 43

[0764] 3-O-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylic acid

[0765]

[0766] 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). A solution of lithium hydroxide (345 mg, 23.95 mmol) in water (5 mL) was added at room temperature. The mixture was stirred overnight at room temperature. Water (100 mL) was added and the pH was adjusted to 6 with 2N HCl (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 filtered off, washed with water, and dried under vacuum at 50 °C to give 1036 mg (60%) of the title compound, which was used for the next step without further purification.

[0767] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 7.60 (dd, 1H), 7.84 (d, 2H), 8.02 (s, 1H), 8.10-8.18 (m, 3H), 8.64 (d, 1H), 8.89 (d, 1H).

[0768] Intermediate 44

[0769] Diethyl hydroxy{2-oxo-2-[4-(trifluoromethoxy)phenyl]ethyl}malonate

[0770]

[0771] A mixture of 1-(4-(trifluoromethoxy)phenyl)ethyl ketone (20 g, 98.03 mmol) and diethyl ketomalonate (23 mL, 147.02 mmol) was heated at 130 °C for 48 hours, and the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0–5 °C and ground with petroleum ether to give diethyl 2-hydroxy-2-(2-oxo-2-(4-(trifluoromethoxy)phenyl)ethyl)malonate 3 (35 g, 94%, LC-MS 98%), as a pale yellow liquid.

[0772] Intermediate 45

[0773] 3-Oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0774]

[0775] Diethyl 2-hydroxy-2-(2-oxo-2-(4-(trifluoromethoxy)phenyl)ethyl)malonate (35 g, 92.5 mmol) and hydrazine dihydrochloride (10.6 g, 101.31 mmol) in ethanol (350 mL) were heated under reflux for 16 hours, and the reaction was monitored by TLC. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The pH was adjusted to 7 using a saturated aqueous sodium bicarbonate solution (150 mL), and the mixture was extracted into ethyl acetate (3 × 350 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product. The crude product was purified by column chromatography (silica gel, eluent EtOAc / hexane 30:70) to give ethyl 3-oxo-6-(4-(trifluoromethoxy)phenyl)-2,3-dihydropyridazine-4-carboxylate (12 g, 40%, LC-MS 97%) as a grayish-white solid.

[0776] 1 H NMR (400MHz, 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).

[0777] Intermediate 46

[0778] 3-O-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid

[0779]

[0780] 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 hours, cooled, and then 6 mL of 2N sodium hydroxide aqueous solution was added. Water was added, the precipitate was filtered off, and dried under vacuum to give 2.5 g of the title compound.

[0781] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.750x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.14min; MS(ESIpos): m / z=378.4[M+H] + .

[0782] Intermediate 47

[0783] methyl 6-[4-(difluoromethyl)phenyl]-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

[0784]

[0785] A mixture of 2.9 g of dimethyl 2-[4-(difluoromethyl)phenyl]-2-oxoethyl}malonate and 13.5 mL of hydrazine / THF (1 M) in acetic acid was stirred at 70 °C for 4 hours. Another 10 mL of hydrazine / THF (1 M) was added, and the reaction mixture was stirred at 70 °C for 4 hours. Water was added, the precipitate formed was filtered off, and the mixture was dried under vacuum to give 2.1 g of the title compound.

[0786] 1 H NMR (400MHz, DMSO-d6) δ [ppm] = 3.15-3.32 (m, 2H), 3.65-3.69 (m, 3H), 3.77 (dd, 1

[0787] H), 7.08(t, 1H), 7.63(d, 2H), 7.89(d, 2H), 11.36(s, 1H).

[0788] Intermediate 48

[0789] Methyl 6-[4-(difluoromethyl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate

[0790]

[0791] A mixture of 2089 mg of methyl 6-[4-(difluoromethyl)phenyl]-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate and 2487 mg of copper(II) chloride in 215 mL of acetonitrile was stirred at 50 °C for 1 hour. After vacuum evaporation, the residue was suspended in water, and the precipitate was filtered off to give 1420 mg of methyl 6-[4-(difluoromethyl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate.

[0792] 1 H NMR (400MHz, 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).

[0793] Intermediate 49

[0794] 6-[4-(difluoromethyl)phenyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0795]

[0796] 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 adding 1 M sodium hydroxide aqueous solution. The precipitate was filtered off and dried under vacuum to give 481 mg of the title compound.

[0797] 1 H NMR (400MHz, 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).

[0798] Intermediate 50

[0799] 6-(4-Methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0800]

[0801] A solution of 500 mg ethyl 6-chloro-3-hydroxypyridazine-4-carboxylate and 436 mg 4-tolylboronic acid in 20 mL of dioxane was treated with tripotassium phosphate (15 mL of 0.5 M aqueous solution) and a second-generation RuPhos Pd precatalyst (CAS No. [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 substance was dissolved in water and freeze-dried to give the title compound (406 mg), which was used for the next step without further purification.

[0802] 1 H NMR (400MHz, DMSO-d6) δ [ppm] = 2.35 (s, 3H), 7.29 (d, 2H), 7.89 (d, 2H), 8.06 (s, 1H).

[0803] Intermediate 51

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

[0805]

[0806] 6-(4-methylphenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg) was dissolved in DMF (3 mL). 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)pyridine (89 mg), 2,2′-bipyridine (170 mg), sodium carbonate (28 mg), and anhydrous copper diacetate (99 mg) were added. The reaction mixture was stirred at 70 °C for 4 hours. The reaction mixture was filtered and purified by RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125mm x 30mm, eluent A: water + 0.2 vol% ammonia (32%), eluent B: acetonitrile; gradient: A 85% / B 15% → A 45% / B 55%; flow rate: 150 mL / min; UV detection: 254 nm) to obtain 17 mg of 6-(4-methylphenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid.

[0807] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.750x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =0.58min; MS(ESIpos): m / z=308.5[M+H] + .

[0808] Intermediate 52

[0809] Diethyl [2-(4-chloro-2-fluorophenyl)-2-oxoethyl](hydroxy)malonate

[0810]

[0811] Add 10 g (57.94 mmol, 1.00 equivalent) of 1-(4-chloro-2-fluorophenyl)ethyl-1-one and 15 mL of 2-oxomalonic acid 1,3-diethyl ester to a 100 mL round-bottom flask. Stir the resulting solution at 130 °C for 24 hours. Concentrate the mixture under vacuum. This yields 24 g (crude) 1,3-diethyl 2-[2-(4-chloro-2-fluorophenyl)-2-oxoethyl]-2-hydroxymalonic acid, which is a black oil and is used without further purification.

[0812] Intermediate 53

[0813] ethyl 6-(4-chloro-2-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

[0814]

[0815] A solution of 2,3-diethyl 2-[2-(4-chloro-2-fluorophenyl)-2-oxoethyl]-2-hydroxymalonic acid in ethanol (250 mL) and hydrazine (15 mL) (24 g, 69.22 mmol, 1.00 equivalent) was placed in a 500 mL round-bottom flask. The resulting solution was stirred at 80 °C for 12 hours. The reaction was then quenched by adding 200 mL of water. The resulting solution was extracted with 2 × 200 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 × 100 mL of water. The resulting mixture was washed with 1 × 100 mL of brine. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (2:1). This yielded 2.9 g (14%) of ethyl 6-(4-chloro-2-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate as a pink solid.

[0816] 1 H NMR (400MHz, 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).

[0817] Intermediate 54

[0818] 6-(4-chloro-2-fluorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0819]

[0820] Ethyl 6-(4-chloro-2-fluorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (500 mg) was dissolved in DMF (22 mL). 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-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 NaOH (1.7 mL) was added, and the reaction mixture was stirred at room temperature for 48 hours. 1 M hydrochloric acid aqueous solution was added until the product precipitated. The precipitate was filtered off and dried under vacuum 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.

[0821] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.750x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.04min; MS(ESIpos): m / z=346.3[M+H] + .

[0822] Intermediate 55

[0823] 3-(4-Chlorophenyl)-6-oxo-6H-1,4′-Bipyridazine-5-carboxylic acid

[0824]

[0825] 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-dioxaborhecyclopentan-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, and then 1.8 mL of 2N sodium hydroxide aqueous solution was added. Water was added, the precipitate was filtered off, and the solution was dried under vacuum to give 438 mg of the title compound.

[0826] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.750x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =0.90min; MS(ESIpos): m / z=329.2[M+H] + .

[0827] Intermediate 56

[0828] 3-O-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylic acid

[0829]

[0830] A solution of ethyl 6-chloro-3-hydroxypyridazine-4-carboxylate (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 equivalent, 551 mg, 2.89 mmol) in 1,4-dioxane (17 mL) was treated with tripotassium phosphate (3.00 equivalent, 6.7 mmol, 13.3 mL in 0.5 M aqueous solution) and a second-generation RuPhos Pd precatalyst (CAS No. [1375325-68-0]; 0.20 equivalent, 345 mg, 444 μmol) to 17 mL of 1,4-dioxane. The mixture was heated to 100 °C and stirred for 4.5 h. 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 substance was dissolved in water and freeze-dried to give the title compound (555 mg), which was used in the next step without further purification.

[0831] 1 H NMR (400MHz, DMSO-d6) δ [ppm] = 7.98 (d, 1H), 8.30 (s, 1H), 8.68 (br d, 1H), 9.39 (s, 1H).

[0832] Intermediate 57

[0833] N-[(2S)-1-hydroxypropyl-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide

[0834] 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-aminoprop-1-ol (CAS No. [2749-11-3]; 2.00 equivalent, 128 mg, 1.70 mmol) in DMF, N,N-diisopropylethylamine (4.50 equivalent, 670 μL, 3.80 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphacyclohexane-2,4,6-trioxide (CAS No. [68957-94-8]; 1.50 equivalent, 1.28 mmol, 750 μL in 50 wt% DMF) and stirred at room temperature for one week. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative reversed-phase HPLC and then lyophilized to give the title compound (150 mg).

[0835] 1 H-NMR (400MHz, 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).

[0836] Intermediate 58

[0837] Diethyl [2-(4-cyanophenyl)-2-oxoethyl](hydroxy)malonate

[0838]

[0839] Add 10 g of 4-acetylbenzyl nitrile (68.89 mmol, 1.00 equivalent) and 1,3-diethyl 2-oxomalaconic acid (15 g, 86.13 mmol, 1.25 equivalent) to a 100 mL round-bottom flask. Stir the resulting solution at 130 °C for 24 hours. Concentrate the mixture under vacuum. This yields 25 g (114%) of 1,3-diethyl 2-[2-(4-cyanophenyl)-2-oxoethyl]-2-hydroxymalonic acid, which is a black oil and is used without further purification.

[0840] Intermediate 59

[0841] 6-(4-cyanophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0842]

[0843] A solution of 1,3-diethyl 2-[2-(4-cyanophenyl)-2-oxoethyl]-2-hydroxymalonic acid (25 g, 78.29 mmol, 1.00 equivalent) in ethanol (200 mL) and hydrazine (15 mL) was placed in a 500 mL round-bottom flask. The resulting solution was stirred at 80 °C for 12 hours. The reaction was then quenched by adding 200 mL of water. The resulting solution was extracted with 2 × 200 mL of ethyl acetate, and the organic layers were combined. The resulting mixture was washed with 1 × 100 mL of water. The resulting mixture was washed with 1 × 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 yielded 6 g (28%) of ethyl 6-(4-cyanophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate as a yellow solid.

[0844] 1H NMR (400MHz, 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).

[0845] Intermediate 60

[0846] 6-(4-cyanophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0847]

[0848] 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-dioxaborhecyclopentan-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 hours, and then 1.8 mL of 2N sodium hydroxide aqueous solution was added. Water was added, the precipitate was filtered off, and the solution was dried under vacuum to give 632 mg of the title compound.

[0849] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.750x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =0.81min; MS(ESIpos): m / z=319.3[M+H] + .

[0850] Intermediate 61

[0851] Methyl 6-(4-chlorophenyl)-3-oxo-2-(pyrimidin-5-yl)-2,3-dihydropyridazine-4-carboxylate

[0852]

[0853] Methyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (50 mg, 0.189 mmol) was dissolved in DMF (3 mL). 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)pyrimidine (77.9 mg, 0.378 mmol), 2,2′-bipyridine (73.8 mg, 0.472 mmol), sodium bicarbonate (31.7 mg, 0.378 mmol), and anhydrous copper diacetate (42.9 mg, 0.236 mmol) were added. The mixture was stirred overnight at room temperature. Water was added, and the pH was adjusted to 3 with 2N HCl. The precipitate was filtered, washed with water, and dried under vacuum at 50 °C to give 39.7 mg (61%) of the title compound.

[0854] 1 H-NMR (400MHz, 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).

[0855] Intermediate 62

[0856] 6-(4-Chlorophenyl)-3-oxo-2-(pyrimidin-5-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0857]

[0858] 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. The mixture was stirred at 40 °C for 24 hours.

[0859] Water was added, and the pH was adjusted to 6-7 with 0.5N HCl. The precipitate was filtered off, washed three times with water, and dried under vacuum at 50°C to give 251 mg (95%) of the title compound, which was used for the next step without further purification.

[0860] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 7.54 (d, 2H), 7.87 (s, 1H), 7.99 (d, 2H), 9.23 (s, 2H), 9.29 (s, 1H).

[0861] Intermediate 63

[0862] 6-(4-chlorophenyl)-3-oxo-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[0863]

[0864] Batch 1: Methyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (200 mg) was dissolved in DMF (12 mL). 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole (490 mg), 2,2′-bipyridine (295 mg), cesium carbonate (295 mg), and anhydrous copper diacetate (172 mg) were added. The mixture was stirred at room temperature for 5 hours. Water was added, and the pH was adjusted to 3 with 2N HCl. Volatiles were removed under vacuum using 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 batch 2.

[0865] Batch 2: Methyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (544 mg) was dissolved in acetonitrile (5.4 mL). 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole (1 g), pyridine (333 μL), N,N-diethylethylamine (573 μL), anhydrous copper diacetate (747 mg), and molecular sieve (544 mg, 0.4 nm, particle size: <50 μm) were added. The mixture was stirred at room temperature for one day. Add 320 mg of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole and continue stirring at room temperature for another day. Add Kieselgel and remove volatiles under vacuum. Pre-purify by rapid chromatography (silica gel, hexane / ethyl acetate, gradient) to give 427 mg of product, which was combined with the first batch and purified by rapid chromatography (silica gel, hexane / ethyl acetate 7:3) to give 220 mg of the title compound.

[0866] 1H-NMR (400MHz, 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).

[0867] Intermediate 64

[0868] 6-(4-Chlorophenyl)-3-oxo-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0869]

[0870] Methyl 6-(4-chlorophenyl)-3-oxo-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-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 the mixture was stirred overnight at room temperature. The reaction mixture was concentrated to half its volume and water (150 mL) was added. The pH was adjusted to 3 with 2N HCl (7.5 mL). The precipitate was filtered off, washed with water, and dried under vacuum at 50 °C to give 36 mg of the title compound, which was used for the next step without further purification.

[0871] 1 H-NMR (400MHz, 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).

[0872] Intermediate 65

[0873] 6-(4-Chlorophenyl)-3-oxo-2-(1H-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0874]

[0875] Method 1, Step 1: Methyl 6-(4-chlorophenyl)-3-oxo-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylate (220 mg) was dissolved in ethanol (1.85 mL). Hydrogen chloride / dioxane (1.85 mL, 4 M, in dioxane) was added and the mixture was stirred at 70 °C for 2 hours. The reaction mixture was allowed to reach room temperature and concentrated to dryness to give 169 mg of methyl 6-(4-chlorophenyl)-3-oxo-2-(1H-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylate. This substance was used in the next step without further purification.

[0876] Method 2, Step 1: 34 mg of 6-(4-chlorophenyl)-3-oxo-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid was dissolved in 0.29 mL of ethanol. Hydrogen chloride / dioxane (0.29 mL, 4 M, in dioxane) was added and stirred at 70 °C for 2 hours. The reaction mixture was allowed to reach room temperature and stirred overnight at room temperature. The reaction mixture was concentrated to dryness to give 27 mg of a mixture of ethyl 6-(4-chlorophenyl)-3-oxo-2-(1H-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid and 6-(4-chlorophenyl)-3-oxo-2-(1H-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid. This substance was used in the next step without further purification.

[0877] Step 2: Combine the crude substances 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 HCl (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 was used for the next step without further purification.

[0878] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 7.56-7.61 (m, 2H), 8.09-8.14 (m, 2H), 8.34 (brs, 2H), 8.44 (s, 1H), 13.45 (br s, 2H).

[0879] Intermediate 66

[0880] 6-[4-(dimethylamino)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0881]

[0882] 6-Chloro-3-hydroxypyridazine-4-carboxylic acid ethyl ester (200 mg) and 4-(dimethylamino)-phenylboronic acid were treated with tripotassium phosphate (6 mL of 0.5 M aqueous solution) and a second-generation RuPhos Pd precatalyst (153 mg). A solution of (212 mg) in 1,4-dioxane (8 mL) was heated to 75 °C and stirred for 6 hours. The reaction mixture was cooled to room temperature, treated with water, and the pH was adjusted to 3 by adding 1 M HCl. The precipitate 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 was evaporated. The residue was subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, LabomaticLabocol Vario-2000 fraction collector; column: Chromatorex C-18 125mm x 30mm, eluent A: 0.1% formic acid / water, eluent B: acetonitrile; gradient: A 85% / B 15% → A 45% / B 55%; flow rate: 150mL / min; UV detection: 254nm) to obtain 59mg of 6-[4-(dimethylamino)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid.

[0883] 1 H NMR (400MHz, DMSO-d6) δ [ppm] = 2.98 (s, 6H), 6.79 (d, 2H), 7.77 (d, 2H), 8.44 (s, 1H).

[0884] Intermediate 67

[0885] 6-[4-(dimethylamino)phenyl]-N-[(2S)-1-hydroxypropyl-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide

[0886]

[0887] A solution of 59 mg intermediate 6-[4-(dimethylamino)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 34 mg (2S)-2-amino-1-propanol, 174 mg HATU, 0.16 mL ethyl diisopropylamine and 1 mg 4-dimethylaminopyridine in 3 mL LDMF 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 125mm x 30mm, eluent A: 0.1% formic acid / water, eluent B: acetonitrile; gradient: A 85% / B 15% → A 45% / B 55%; flow rate: 150mL / min; UV detection: 254nm) to obtain 11 mg of 6-[4-(dimethylamino)phenyl]-N-[(2S)-1-hydroxypropyl-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide).

[0888] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =0.84min; MS(ESIpos): m / z=317.3[M+H] + .

[0889] Intermediate 68

[0890] 6-(4-Chlorophenyl)-2-(1-methyl-1H-pyrazol-3-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[0891]

[0892] Dimethyl [2-(4-chlorophenyl)-2-oxoethyl]malonate (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 in portions. The mixture was stirred overnight at room temperature and then stirred 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 125mm x 30mm, eluent A: 0.1% formic acid / water, eluent B: acetonitrile; gradient: A 85% / B 15% → A 45% / B 55%; flow rate: 150mL / min; UV detection: 254nm) to obtain 119 mg of methyl 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-3-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate.

[0893] 1 H NMR (400MHz, DMSO-d6) δ [ppm] = 3.37-3.46 (m, 2H), 3.69 (s, 3H), 3.83 (s, 3H), 3.9 9-4.06 (m, 1H), 6.30 (d, 1H), 7.49-7.56 (m, 2H), 7.71 (d, 1H), 7.78-7.83 (m, 2H).

[0894] Intermediate 69

[0895] methyl 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

[0896]

[0897] 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. The mixture 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.

[0898] 1H NMR (400MHz, 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)

[0899] Intermediate 70

[0900] 6-(4-Chlorophenyl)-2-(1-Methyl-1H-pyrazol-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0901]

[0902] Methyl 6-(4-chlorophenyl)-2-(1-methyl-1H-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 filtered off, washed three times with water, and dried under lyophilization to give 94 mg of the title compound, which was used for the next step without further purification.

[0903] 1 H NMR (400MHz, 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).

[0904] Intermediate 71

[0905] 6-(4-Chlorophenyl)-2-(3-methyl-1H-pyrazol-5-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[0906]

[0907] Dimethyl [2-(4-chlorophenyl)-2-oxoethyl]malonate (200 mg) and sodium acetate (259 mg) were dissolved in acetic acid (7 mL). Then, 5-hydrazino-3-methyl-1H-pyrazole hydrochloride (220 mg) was added in portions. The mixture was stirred overnight at room temperature and then stirred 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 125mm x 30mm, eluent A: 0.1% formic acid / water, eluent B: acetonitrile; gradient: A 85% / B 15% → A 45% / B 55%; flow rate: 150mL / min; UV detection: 254nm) to obtain 126 mg of methyl 6-(4-chlorophenyl)-2-(3-methyl-1H-pyrazol-5-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate.

[0908] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.750x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.07min; MS(ESIpos): m / z=347.3[M+H] + .

[0909] Intermediate 72

[0910] methyl 6-(4-chlorophenyl)-2-(3-methyl-1H-pyrazol-5-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

[0911]

[0912] 126 mg of methyl 6-(4-chlorophenyl)-2-(3-methyl-1H-pyrazol-5-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate was dissolved in acetonitrile (5 mL). 146 mg of copper chloride was added. The mixture was stirred at 90 °C for 1 hour. The reaction mixture was cooled, treated with water, and the precipitate was filtered off, washed with water, and dried by lyophilization to give 132 mg of the title compound, which was used in the next step without further purification.

[0913] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.750x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.08min; MS(ESIpos): m / z=345.3[M+H] + .

[0914] Intermediate 73

[0915] 6-(4-Chlorophenyl)-2-(3-methyl-1H-pyrazol-5-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0916]

[0917] Methyl 6-(4-chlorophenyl)-2-(3-methyl-1H-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 HCl. The precipitate was filtered off, washed three times with water, and dried under air to give 80 mg of the title compound, which was used for the next step without further purification.

[0918] 1 H NMR (400MHz, DMSO-d6) δ [ppm] = 2.30 (s, 3H), 6.35 (br s, 1H), 7.57 (d, 2H), 7.97 (br d, 2H), 8.48 (br s, 1H)

[0919] Intermediate 74

[0920] Methyl 6-(4-chlorophenyl)-3-oxo-2-(1,2-thiazo-4-yl)-2,3-dihydropyridazine-4-carboxylate

[0921]

[0922] Methyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (500 mg) was provided in acetonitrile (5 mL). Powdered molecular sieve (500 mg, 4A, 50 μm), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2-thiazole (483 mg), pyridine (153 μL), triethylamine (263 μL), and anhydrous copper diacetate (343 mg) were added. The mixture was stirred at room temperature for 3 hours. Then, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2-thiazole (211.1 mg), pyridine (104 μL), triethylamine (179 μL), and anhydrous copper diacetate (343 mg) were added. The mixture was stirred at room temperature for 16 hours. Silica gel was added, and volatiles were removed under vacuum. The mixture was then purified by rapid chromatography (silica gel, hexane / ethyl acetate, gradient) to give 317 mg of the title compound.

[0923] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.89 (s, 3H), 7.57-7.62 (m, 2H), 8.05-8.10 (m, 2H), 8.52 (s, 1H), 9.14 (s, 1H), 9.58 (s, 1H).

[0924] Intermediate 75

[0925] 6-(4-Chlorophenyl)-3-oxo-2-(1,2-thiazo-4-yl)-2,3-dihydropyridazine-4-carboxylic acid

[0926]

[0927] Methyl 6-(4-chlorophenyl)-3-oxo-2-(1,2-thiazo-4-yl)-2,3-dihydropyridazine-4-carboxylate (423 mg) was suspended in acetonitrile (11 mL). Lithium hydroxide (87 mg) dissolved in water (1.31 mL) was added. The pH was determined (pH = 4), and lithium hydroxide (87 mg) was added again. The mixture was stirred at room temperature for 1 hour. Water (5 mL) was added, and the pH was adjusted to 3 with 2N HCl (1.2 mL). The precipitate was filtered off, washed with water, and dried under vacuum at 50 °C to give 340 mg of the title compound, which was used for the next step without further purification.

[0928] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 7.58 (d, 2H), 8.08 (d, 2H), 8.41 (br s, 1H), 9.15 (br s, 1H), 9.59 (br s, 1H).

[0929] Intermediate 76

[0930] Diethyl hydroxy{2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl}malonate

[0931]

[0932] 1-[4-(trifluoromethyl)phenyl]ethyl ketone (50 g, 0.266 mol) and diethyl oxomalonate (66.0 g, 0.379 mol) were stirred at 120 °C for 48 hours. The reaction mixture was cooled to room temperature, the solid was filtered off, and washed with petroleum ether (300 mL) to give 70 g (73%) of the title compound.

[0933] 1 H-NMR (400MHz, 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).

[0934] Intermediate 77

[0935] 3-Oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0936]

[0937] Diethyl hydroxy{2-oxo-2-[4-(trifluoromethyl)phenyl]ethyl}malonate (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. After 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.

[0938] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.31 (t, 3H), 4.32 (q, 2H), 7.86 (d, 2H), 8.11 (d, 2H), 8.42 (s, 1H), 13.81 (s, 1H).

[0939] Intermediate 78

[0940] 3-Oxo-2-(1,2-thiazo-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0941]

[0942] 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-dioxaborhecyclopentan-2-yl)-1,2-thiazole (1.05 g, 5.00 mmol), pyridine (622 μL, 7.69 mmol), N,N-diethylethylamine (1.07 mL, 7.69 mmol), and anhydrous copper diacetate (907 mg, 5.00 mmol) were added. The mixture was stirred at room temperature for 28 hours. Water was added, and the pH was adjusted to 3 with 2N HCl. 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 for the next step without further purification.

[0943] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.34 (t, 3H), 4.37 (q, 2H), 7.90 (d, 2H), 8.27 (d, 2H), 8.56 (s, 1H), 9.15 (s, 1H), 9.60 (s, 1H).

[0944] Intermediate 79 3-O-2-(1,2-thiazo-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylic acid

[0945]

[0946] Ethyl 3-oxo-2-(1,2-thiazo-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylate (1.91 g, 3.88 mmol) in acetonitrile (35 mL) was added to lithium hydroxide (278 mg, 11.63 mmol) in water (4.2 mL). The mixture 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 the starting material.

[0947] The precipitate (465 mg) was stirred in an aqueous sodium hydroxide solution at 60 °C. The solid was warm-filtered and washed with water. The residue was dried, suspended in water (20 mL), and the pH was adjusted to 3 with 2 M hydrochloric acid. The solid was collected, washed with water, and dried under vacuum at 50 °C to give 195 mg (11%) of the title compound. The first filtrate was acidified to pH 4 with 2 M hydrochloric acid, the precipitate was collected, washed with water, and dried under vacuum at 50 °C to give 180 mg (10%) of the title compound.

[0948] The remaining impurities (720 mg) were stirred in an aqueous sodium hydroxide solution at room temperature for 1 hour. The pH was adjusted to 3 with hydrochloric acid (2 mL, 2 M) and stirred at room temperature for 0.5 hours. The solid was filtered, washed three times with water, and dried under vacuum at 50 °C to give 660 mg (37%) of the title compound.

[0949] 1 H-NMR (400MHz, 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).

[0950] Intermediate 80

[0951] 3-Oxo-6-[4-(trifluoromethyl)phenyl]-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[0952]

[0953] Ethyl 3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylate (1.00 g, 3.20 mmol) was suspended in acetonitrile (10 mL). 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole (1.35 g, 4.16 mmol), pyridine (0.52 mL, 6.41 mmol), N,N-diethylethylamine (0.893 mL, 6.41 mmol), and anhydrous copper diacetate (756 mg, 4.16 mmol) were added. The mixture was stirred at room temperature for 4 days. Add 1 equivalent of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole. Stir at room temperature for 1 day, at 50°C for 1 day, at 60°C for 8 hours, and at 50°C overnight. Cool the reaction mixture and purify by column chromatography (silica gel, hexane / ethyl acetate 75:25) to give 1.44 g (88%) of the title compound.

[0954] 1H-NMR (400MHz, DMSO-d6): δ [ppm] = -0.04 (s, 9H), 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).

[0955] Intermediate 81

[0956] 3-O-2-(1H-pyrazol-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylic acid

[0957]

[0958] Step 1: Ethyl 3-oxo-6-[4-(trifluoromethyl)phenyl]-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxylate (1.38 g, 3.20 mmol) was suspended in ethanol (11.3 mL). Hydrogen chloride / dioxane (11.3 mL, 4 M) was added and the mixture was stirred at 70 °C for 5 hours. The mixture was stirred overnight at room temperature, and then stirred at 70 °C for 5 hours. The reaction mixture was cooled and concentrated to dryness to give 1.01 g, which was used for the next step without further purification.

[0959] 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 the mixture 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 for the next step without further purification.

[0960] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 7.87 (d, 2H), 8.27-8.43 (m, 5H), 13.38 (br s, 2H).

[0961] Intermediate 82

[0962] 2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylic acid

[0963]

[0964] Step 1: Methyl 3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxylate (0.40 g, 1.34 mmol) was suspended in acetonitrile (7 mL). Molecular sieve (400 mg, 0.4 nm, particle size: <50 μm), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (491 mg, 2.01 mmol), pyridine (0.217 mL, 2.68 mmol), N,N-diethylethylamine (0.374 mL, 2.68 mmol), and anhydrous copper diacetate (487 mg, 2.68 mmol) were added. The mixture was stirred at room temperature for 24 hours. 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (300 mg, 1.23 mmol) was added and stirred at room temperature for 3 days. The mixture was diluted with water and acidified with hydrochloric acid (2N). The solid was filtered off and dried under vacuum at 50 °C to give 1.21 g of intermediate 1 with a molecular sieve, which was used for the next step without further purification.

[0965] Step 2: The 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 the mixture was stirred at 40 °C for 20 hours. The reaction mixture was diluted with water (30 mL) and filtered through diatomaceous earth. The filtrate was adjusted to pH 4 with hydrochloric acid (2 N). The precipitate was filtered, washed three times with water, and dried under vacuum at 50 °C to give 380 mg (71%) of the title compound.

[0966] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 7.89 (d, 2H), 7.93 (t, 1H), 8.34 (d, 2H), 8.48-8.57 (m, 2H), 9.01 (s, 1H), 13.88 (br s, 1H).

[0967] Intermediate 83

[0968] 6-(4-Chlorophenyl)-2-(5-Fluoro-2-thienyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0969]

[0970] Step 1: Methyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (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-dioxabortiacyclopentane (569 mg, 2.49 mmol), pyridine (0.122 mL, 1.51 mmol), N,N-diethylethylamine (0.211 mL, 1.51 mmol), and anhydrous copper diacetate (275 mg, 1.51 mmol) were added. The mixture was stirred at room temperature for 5 hours, then at 50 °C for 120 hours. The reaction mixture was diluted with a buffer solution (15 mL, pH 7), stirred, the precipitate was filtered, washed three times with water, and dried under vacuum at 50 °C to give 446 mg of crude material, which was used for the next step without further purification.

[0971] 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 the mixture 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 three times with water, and dried under vacuum at 50 °C to give 335 mg, which was used for the next step without further purification.

[0972] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =0.73min; MS(ESIpos): m / z=351.2[M+H] + .

[0973] Intermediate 84

[0974] methyl 6-(4-chlorophenyl)-2-(5-methyl-3-thienyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

[0975]

[0976] 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-dioxabortiacyclopentane (127 mg, 0.567 mmol), pyridine (0.061 mL, 0.756 mmol), N,N-diethylethylamine (0.105 mL, 0.756 mmol), and anhydrous copper diacetate (137 mg, 0.756 mmol) were added. The mixture was stirred at room temperature for 5 hours and then at 50 °C for 23 hours. A second batch synthesized under similar conditions (but stirred at 50 °C for 24 hours) was combined with this batch and then poured into a buffer solution at pH 7. Stir the mixture for a short period of time, filter the precipitate, wash it twice with water and dry it under vacuum at 50°C to obtain 460 mg of the title compound, which was used in the next step without further purification.

[0977] 1 H-NMR (400MHz, 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).

[0978] Intermediate 85

[0979] 6-(4-Chlorophenyl)-2-(5-methyl-3-thienyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0980]

[0981] 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 the mixture was stirred at 50 °C for 24 hours. The reaction mixture was cooled, diluted with water (15 mL), and 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.

[0982] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =0.78min; MS(ESIpos): m / z=347.2[M+H] + .

[0983] Intermediate 86

[0984] Methyl 6-(4-chlorophenyl)-2-(5-chloro-3-thienyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

[0985]

[0986] 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-dioxabortiacyclopentane (277 mg, 1.133 mmol), pyridine (0.122 mL, 1.511 mmol), N,N-diethylethylamine (0.211 mL, 1.511 mmol), and anhydrous copper diacetate (275 mg, 1.511 mmol) were added. The mixture was stirred at 50 °C for 24 hours. The reaction mixture was cooled and a pH 7 buffer solution (10 mL) was added. The mixture was stirred briefly, 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 for the next step without further purification. 70 mg of this batch was purified by HPLC to obtain 25 mg of the title compound.

[0987] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.88 (s, 3H), 7.57-7.61 (m, 2H), 7.69 (d, 1H), 8.03-8.07 (m, 2H), 8.10 (d, 1H), 8.47 (s, 1H)

[0988] Intermediate 87

[0989] 6-(4-Chlorophenyl)-2-(5-Chloro-3-thienyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[0990]

[0991] 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 the mixture was stirred at 50 °C for 4 hours. The reaction mixture was cooled, diluted with water (15 mL), and the pH was adjusted to 3 with hydrochloric acid (2N). The precipitate was filtered, washed twice with water, and dried under vacuum at 45 °C to give 300 mg, which was used in the next step without further purification.

[0992] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =0.75min; MS(ESIpos): m / z=367.2[M+H] + .

[0993] Intermediate 88

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

[0995]

[0996] Methyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (0.10 g, 0.378 mmol) was suspended in acetonitrile (1 mL). Molecular sieve (100 mg, 0.4 nm, particle size: <50 μm), 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (138 mg, 0.567 mmol), pyridine (0.061 mL, 0.756 mmol), N,N-diethylethylamine (0.105 mL, 0.756 mmol), and anhydrous copper diacetate (137 mg, 0.756 mmol) were added. The mixture was stirred at room temperature for 48 hours, then 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-pyrazole (100 mg, 0.410 mmol) was added, and the mixture was stirred at room temperature for 72 hours. The mixture 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 for the next step without further purification.

[0997] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.89 (s, 3H), 7.58-7.62 (m, 2H), 7.91 (t, 1H), 8.11-8.15 (m, 2H), 8.50 (s, 1H), 8.50 (s, 1H), 8.98 (s, 1H).

[0998] Intermediate 89

[0999] 6-(4-Chlorophenyl)-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[1000]

[1001] Methyl 6-(4-chlorophenyl)-2-[1-(difluoromethyl)-1H-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 the mixture was stirred at 40 °C for 20 hours. The reaction mixture was cooled, diluted with water (30 mL), and filtered through diatomaceous earth. 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.

[1002] 1H-NMR (400MHz, DMSO-d6): δ [ppm] = 7.57-7.62 (m, 2H), 7.92 (t, 1H), 8.12-8.17 (m, 2H), 8.47 (s, 1H), 8.51 (s, 1H), 8.99 (s, 1H), 13.86 (br s, 1H).

[1003] Intermediate 90

[1004] Di-tert-butyl 1-(1,2-oxazol-4-yl)hydrazine-1,2-dicarboxylate

[1005]

[1006] To a solution of n-butyllithium (2.5 M, in hexane, 21.6 mL, 54 mmol) in diethyl ether (30 mL) at -78 °C, add dropwise. Add 4-bromo-1,2-oxazole (4.00 g, 27.0 mmol) and stir the mixture for 30 min. Add dropwise a solution of (E)-diazepine-1,2-dicarboxylic acid di-tert-butyl ester (9.33 g, 40.6 mmol) in diethyl ether (30 mL) and stir the mixture at -78 °C for 1 h. Add the reaction mixture to water (200 mL) and extract with dichloromethane (200 mL twice). Dry the combined organic phases with sodium sulfate, filter, and concentrate. Purify the crude residue by column chromatography (silica gel, heptane / ethyl acetate 4:1 to 11:9) to give 1.99 g (16%) of the title product.

[1007] 1 H NMR (400MHz, CDCl3): δ [ppm] = 1.40-1.60 (m, 18H), 6.68 (s, 1H), 8.40 (s, 1H), 8.63 (s, 1H).

[1008] Intermediate 91

[1009] 4-Hydroxy-1,2-oxazole hydrochloride

[1010]

[1011] Hydrochloric acid (4 M, in 1,4-dioxane, 10.0 mL, 40.0 mmol) was added to a solution of di-tert-butyl 1-(1,2-oxazol-4-yl)hydrazine-1,2-dicarboxylate (2.64 g, 8.82 mmol) in 1,4-dioxane (10 mL), and the mixture was heated at 50 °C for 5 hours. The mixture was concentrated under vacuum to give 863 mg (76%) of the title compound.

[1012] 1H NMR (400MHz, MeOD-d3): δ [ppm] = 8.42 (s, 1H), 8.63 (s, 1H).

[1013] Intermediate 92

[1014] Methyl 6-(4-chlorophenyl)-2-(1,2-oxazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

[1015]

[1016] A mixture of dimethyl [2-(4-chlorophenyl)-2-oxoethyl]malonate (494 mg, 1.74 mmol), 4-hydrazino-1,2-oxazole hydrochloride (588 mg, 3.47 mmol), and sodium acetate (641 mg, 7.81 mmol) in acetic acid (11.8 mL) was stirred at room temperature for 96 hours. The reaction mixture was concentrated and added to water (200 mL). The solid was collected by filtration and dried under vacuum to give 567 mg (98%) of the title compound.

[1017] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 334-3.49 (m, 2H), 3.67 (s, 3H), 4.06-4.13 (m, 1H), 7.53 (d, 2H), 7.99 (d, 2H), 9.07 (s, 1H), 9.32 (s, 1H).

[1018] Intermediate 93

[1019] Methyl 6-(4-chlorophenyl)-2-(1,2-oxazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

[1020]

[1021] To a solution of methyl 6-(4-chlorophenyl)-2-(1,2-oxazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate (586 mg, 1.76 mmol) in acetonitrile (10.5 mL), copper(II) chloride (1.18 g, 8.78 mmol) was added, and the mixture was heated at 50 °C for 2 hours. The mixture was cooled to room temperature and allowed to stand for 16 hours. The mixture was then heated at 50 °C for 16 hours. The mixture was concentrated and added to water. The solid was collected by filtration and dried to give 563 mg (97%) of the title compound.

[1022] 1H NMR (400MHz, DMSO-d6): δ [ppm] = 3.61 (s, 3H), 756 (d, 2H), 8.12 (d, 2H), 8.50 (s, 1H), 9.39 (s, 1H), 9.72 (s, 1H).

[1023] Intermediate 94

[1024] 6-(4-Chlorophenyl)-2-(1,2-oxazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[1025]

[1026] Hydrochloric acid (2 M, in water, 10.0 mL, 20.0 mmol) was added to a solution of methyl 6-(4-chlorophenyl)-2-(1,2-oxazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (383 mg, 1.16 mmol) in 1,4-dioxane (10 mL), and the mixture was heated at 100 °C for 48 hours. 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 for the next step without further purification.

[1027] 1 H NMR (400MHz, 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).

[1028] Intermediate 95

[1029] 3-Oxo-2-(1,2-thiazo-4-yl)-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[1030]

[1031] 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-dioxaborhecyclopentan-2-yl)-1,2-thiazole (480 mg, 2.28 mmol), pyridine (0.245 mL, 3.03 mmol), N,N-diethylethylamine (0.423 mL, 3.03 mmol), and anhydrous copper diacetate (358 mg, 1.97 mmol) were added. The mixture was stirred at room temperature for 24 hours. 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1,2-thiazole (100 mg, 0.474 mmol) was then added, and the mixture was stirred at room temperature for 24 hours. Add a buffer solution at pH 7 (50 mL) and stir for a short time. Filter the precipitate, wash twice with water, and dry under vacuum at 45 °C to give 630 mg of the title compound, which was used for the next step without further purification.

[1032] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 1.34 (t, 3H), 4.38 (q, 2H), 8.07 (d, 1H), 8.63 (s, 1H), 8.73 (dd, 1H), 9.19 (s, 1H), 9.42 (d, 1H), 9.64 (s, 1H).

[1033] Intermediate 96

[1034] 3-O-2-(1,2-thiazo-4-yl)-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylic acid

[1035]

[1036] Ethyl 3-oxo-2-(1,2-thiazo-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 (113 mg, 4.73 mmol) in water (2.3 mL) was added, and the mixture was 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). The mixture was stirred for a short time, 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 for the next step without further purification.

[1037] 1H-NMR (400MHz, DMSO-d6): δ [ppm] = 7.99 (br s, 1H), 8.47 (br s, 1H), 9.14 (br s, 1H).

[1038] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =0.59min; MS(ESIpos): m / z=369.1[M+H] + .

[1039] Intermediate 97

[1040] Dimethyl {2-[4-(fluoromethyl)phenyl]-2-oxoethyl}malonate

[1041]

[1042] 2-Bromo-1-[4-(fluoromethyl)phenyl]ethyl ketone (5.5 g, 23.80 mmol) was dissolved in acetone (120 mL). Dimethyl malonate (6.94 g, 52.50 mmol) and potassium carbonate (5.0 g, 36.18 mmol) were added. The mixture was stirred overnight at room temperature. The volume was reduced by half under vacuum using a rotary evaporator. The volume was then poured into water (550 mL) containing some brine. The layers were separated, and the aqueous phase was extracted three times with ethyl acetate (200 mL). The combined organic layers were washed with water and a concentrated sodium chloride aqueous solution, dried over magnesium sulfate, and concentrated. A second batch prepared under similar conditions (0.5 g of the starting bromoketone) was added, and volatiles were removed under high vacuum at 70 °C. The crude product was purified by rapid chromatography (hexane / ethyl acetate) to give 5.59 g (76%) of the title product.

[1043] 1 H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.65 (d, 2H), 3.68 (s, 6H), 3.99 (t, 1H), 5.54 (d, 2H), 7.56 (d, 2H), 8.04 (d, 2H).

[1044] Intermediate 9 8

[1045] methyl 6-[4-(fluoromethyl)phenyl]-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

[1046]

[1047] Dimethyl 2-[4-(fluoromethyl)phenyl]-2-oxoethyl}malonate (2.50 g, 8.86 mmol) was dissolved in acetic acid (31.4 mL). A THF solution of hydrazine (14 mL, 1.0 M, 14 mmol) was added at room temperature. The mixture was then stirred overnight at 85 °C. The reaction mixture was cooled, and a THF solution of hydrazine (2.1 mL, 1.0 M, 2.1 mmol) was added. The mixture was stirred at 75 °C for 3 h and then at room temperature for 120 h. Water (150 mL) was added and stirred briefly. The precipitate was filtered off, washed three times with water, and dried under vacuum at 50 °C to give 1.781 g (76%) of the title compound, which was used for the next step without further purification.

[1048] 1 H-NMR (400MHz, 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).

[1049] Intermediate 99

[1050] Methyl 6-[4-(fluoromethyl)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate

[1051]

[1052] 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 the mixture 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 filtered, washed three times with water, and dried under vacuum at 50 °C to give 1.02 g of the title compound, which was used for the next step without further purification.

[1053] 1H-NMR (400MHz, 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).

[1054] Intermediate 100

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

[1056]

[1057] 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-dioxaborhecyclopentan-2-yl)-1H-pyrazole (1.2 g, 5.77 mmol), pyridine (0.58 mL, 7.17 mmol), N,N-diethylethylamine (1 mL, 7.17 mmol), and anhydrous copper diacetate (1.3 g, 7.17 mmol) were added. The mixture was stirred at room temperature for 2 days. 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H-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. The mixture was diluted with dichloromethane and silica gel was added. Volatile substances were removed under vacuum. The residue was purified by rapid chromatography (silica gel, dichloromethane / ethanol 95:5) to give 1.05 g (85%) of the title compound.

[1058] 1 H-NMR (400MHz, 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, 1H), 8.51 (s, 1H).

[1059] Intermediate 101

[1060] 6-[4-(fluoromethyl)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[1061]

[1062] Methyl 6-[4-(fluoromethyl)phenyl]-2-(1-methyl-1H-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 the mixture was stirred at room temperature for 1 hour. The pH was adjusted to 3 with hydrochloric acid (4 mL, 2N). The precipitate was filtered, washed three times with water, and dried under vacuum at 50 °C to give 352 mg (35%) of the title compound, which was used for the next step without further purification.

[1063] 1 H-NMR (400MHz, 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, 1H), 8.53 (s, 1H), 13.88 (br s, 1H).

[1064] Intermediate 102

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

[1066]

[1067] 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-dioxaborhecyclopentan-2-yl)pyridine (851 mg, 4.15 mmol), pyridine (448 μL, 5.53 mmol), N,N-diethylethylamine (771 μL, 5.53 mmol), and anhydrous copper diacetate (1.004 g, 5.53 mmol) were added. The mixture was stirred overnight at room temperature. The pH was adjusted to 3 with hydrochloric acid (2N). The precipitate was filtered, washed three times with water (1 mL), and dried under vacuum at 50 °C overnight. The solid was ground with dichloromethane / methanol in a 1:1 ratio, filtered, and dried under vacuum at 50°C to give 942 mg of the title compound, which was used in the next step without further purification.

[1068] 1H-NMR (400MHz, 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).

[1069] Intermediate 103

[1070] 6-[4-(fluoromethyl)phenyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid

[1071]

[1072] 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) was added in water (2.91 mL). An additional amount of water (3 mL) was added. The mixture was stirred overnight at room temperature. 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 for the next step without further purification.

[1073] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =0.53min; MS(ESIpos): m / z=326.4[M+H] + .

[1074] Intermediate 104

[1075] 6-(4-Chlorophenyl)-3-oxo-2-(pyridin-3-yl)-N-(4,4,4-trifluoro-3-hydroxybut-2-yl)-2,3-dihydropyridazine-4-carboxamide

[1076]

[1077] 6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid (245 mg, 0.75 mmol) was dissolved in anhydrous DMF (10 mL). 3-amino-1,1,1-trifluorobut-2-ol hydrochloride 1:1 (174.5 mg, 0.97 mmol), N-ethyl-N-isopropylprop-2-amine (0.59 mL, 3.36 mmol), and propanephosphonic anhydride (T3P, 0.71 g, 50% in DMF, 1.12 mmol) were added sequentially. The mixture was stirred overnight at room temperature. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C185 μm 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.

[1078] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.22min; MS(ESIpos): m / z=454.3[M+H] + .

[1079] Intermediate 105

[1080] 6-(4-Chlorophenyl)-2-(5-chloropyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[1081]

[1082] Ethyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (250 mg, 0.9 mmol) was dissolved in DMF (12 mL). (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) were added. The reaction mixture was stirred at 80 °C for 4 hours, cooled, and then 2.7 mL of 2N sodium hydroxide aqueous solution was added. The mixture was stirred overnight, water was added, the precipitate was filtered off, and the solution was dried under vacuum to give 402 mg of the title compound.

[1083] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.25min; MS(ESIpos): m / z=364.0[M+H] + .

[1084] Intermediate 106

[1085] 6-(4-Chlorophenyl)-2-(5-methylpyridin-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[1086]

[1087] 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, and then 2.7 mL of 2N sodium hydroxide aqueous solution was added. The mixture was stirred overnight, water was added, the precipitate was filtered off, and the solution was dried under vacuum to give 317 mg of the title compound.

[1088] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.12min; MS(ESIpos): m / z=342.2[M+H] + .

[1089] Intermediate 107

[1090] Dimethyl {2-[4-(difluoromethoxy)phenyl]-2-oxoethyl}malonate

[1091]

[1092] 4.5 g of dimethyl malonate and 3.6 g of potassium carbonate were added to 120 mL of acetone solution containing 4.8 g of 2-bromo-1-[4-(difluoromethoxy)phenyl]ethyl-1-one. The reaction mixture was stirred overnight at room temperature and 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 40% ethyl acetate) to give 4.3 g of dimethyl 2-[4-(difluoromethoxy)phenyl]-2-oxoethyl}malonate.

[1093] 1 H NMR (400MHz, DMSO-d6) δppm=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).

[1094] Intermediate 108

[1095] 6-[4-(difluoromethoxy)phenyl]-2-(1-methyl-1H-pyrazole-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[1096]

[1097] A mixture of dimethyl 2-[4-(difluoromethoxy)phenyl]-2-oxoethyl}malonate (1 g, 3.16 mmol), 4-hydrazino-1-methyl-1H-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 then stirred overnight at room temperature. 4-hydrazino-1-methyl-1H-pyrazole dihydrochloride (1 g, 3.16 mmol) was then 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 give 1.05 g (88%) of the title compound.

[1098] 1H NMR (400MHz, DMSO-d6) δppm=3.35-3.45 (m, 2H), 3.68 (s, 3H), 3.85 (s, 3H), 3.99-4.05 (m, 1H), 7.24-7.30 (m, 2H), 736 (t, 1H), 7.75 (d, 1H), 7.94-8.03 (m, 2H), 8.08 (s, 1H).

[1099] Intermediate 109

[1100] 6-[4-(difluoromethoxy)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid methyl ester

[1101]

[1102] A mixture of methyl 6-[4-(difluoromethoxy)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate (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.

[1103] 1 H NMR (400MHz, DMSO-d6) δppm=3.88 (s, 3H), 3.92 (s, 3H), 7.29-7.34 (m, 2H), 7 .38(t, 1H), 8.08-8.10(m, 1H), 8.10-8.14(m, 2H), 8.44(s, 1H), 8.50(s, 1H).

[1104] Intermediate 110

[1105] 6-[4-(difluoromethoxy)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[1106]

[1107] Methyl 6-[4-(difluoromethoxy)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (3.8 g, 10.1 mmol) was dissolved in THF (50 mL). 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 filtered off, washed three times with water, and dried under vacuum to give 276 mg (50%) of the title compound.

[1108] 1 H NMR (400MHz, DMSO-d6) δppm=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).

[1109] Intermediate 111

[1110] 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[1111]

[1112] Ethyl 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (2.0 g, 7.2 mmol) was dissolved in THF (37 mL). 2 M sodium hydroxide solution (9 mL, 18 mmol) was added at room temperature, and the mixture was stirred overnight. The solution was diluted with water and treated with 2 M HCl. The pH was adjusted to 3, and the precipitate was filtered off, washed three times with water, and dried under vacuum to give 1.79 g (99%) of the title compound.

[1113] 1 H NMR (400MHz, DMSO-d6) δppm=7.55-7.59 (d, 2H), 7.95-7.99 (d, 2H), 8.50 (s, 1H), 14.1 (br s, 2H).

[1114] Intermediate 112

[1115] 6-(4-Chlorophenyl)-N-[(2R)-3-hydroxy-3-methylbut-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1116]

[1117] 6-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid (1425 mg, 5.68 mmol) was dissolved in anhydrous DMF (30 mL). (3R)-3-amino-2-methyl-but-2-ol hydrochloride 1:1 (1191 mg, 8.53 mmol), N-ethyl-N-isopropylpropyl-2-amine (4.46 mL, 25.6 mmol), and propanephosphonic anhydride (T3P, 5.43 g, 50% in DMF, 8.53 mmol) were added sequentially. The mixture was stirred overnight at room temperature, and then water and a saturated ammonium chloride solution were added. The freshly formed precipitate was filtered off, washed with water, and dried under vacuum to give 626 mg (33%) of the title compound.

[1118] 1 H NMR (400MHz, DMSO-d6) δppm=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).

[1119] Intermediate 113

[1120] 3-Oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid

[1121]

[1122] The synthesis was carried out in a manner similar to that of intermediate 111 from ethyl 3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylate.

[1123] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.07min; MS(ESIpos): m / z=301.2[M+H] + .

[1124] Intermediate 114

[1125] N-[(2R)-3-hydroxy-3-methylbut-2-yl]-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide

[1126]

[1127] The synthesis was carried out in a manner similar to that of intermediate 112 from 3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid.

[1128] 1 H NMR (400MHz, DMSO-d6) δppm=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).

[1129] Intermediate 115

[1130] Dimethyl {2-[4-(dimethylamino)phenyl]-2-oxoethyl}malonate

[1131]

[1132] 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 overnight at room temperature and 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.

[1133] 1 H NMR (400MHz, DMSO-d6) δppm=3.02 (s, 6H), 3.48 (d, 2H), 3.67 (s, 6H), 3.93 (t, 1H), 6.72 (d, 2H), 7.81 (d, 2H).

[1134] Intermediate 116

[1135] 6-[4-(dimethylamino)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid methyl ester

[1136]

[1137] A mixture of dimethyl 2-[4-(dimethylamino)phenyl]-2-oxoethyl}malonate (500 mg, 1.7 mmol), 4-hydrazino-1-methyl-1H-pyrazole dihydrochloride (336 mg, 2.2 mmol), and sodium acetate (629 mg, 7.6 mmol) in 14 mL of AcOH was stirred overnight at room temperature, followed by stirring at 50 °C for 1 hour. Then, 4-hydrazino-1-methyl-1H-pyrazole dihydrochloride (258 mg, 1.7 mmol) was added, and the reaction mixture was stirred overnight at room temperature, followed by stirring at 50 °C for 5 hours. 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 under vacuum to give 516 mg (85%) of the title compound.

[1138] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.05min; MS(ESIpos): m / z=356.5[M+H] + .

[1139] Intermediate 117

[1140] methyl 6-[4-(dimethylamino)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate

[1141]

[1142] A mixture of methyl 6-[4-(dimethylamino)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate (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 hours. Additional iodine (368.5 mg, 1.45 mmol) was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was dissolved in a saturated sodium thiosulfate solution and ethyl acetate. The phases were separated; the organic phase was washed with a saturated sodium thiosulfate solution and brine, filtered (MN 617 WA filter paper), and concentrated under vacuum to give 936 mg (55% purity) of the title compound.

[1143] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.7min; MS(ESIpos): m / z=354.4[M+H] + .

[1144] Intermediate 118

[1145] 6-[4-(dimethylamino)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylic acid

[1146]

[1147] Methyl 6-[4-(dimethylamino)phenyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxylate (936 mg, 1.45 mmol, 55%) was dissolved in THF (5 mL). 2 M 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 HCl. The pH was adjusted to 3, and then 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 617 WA filter paper), and concentrated under vacuum to give 99 mg (20%) of the title compound.

[1148] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.11min; MS(ESIpos): m / z=340.3[M+H] + .

[1149] Intermediate 119

[1150] 3-Oxo-2-(1,2-thiazo-4-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[1151]

[1152] 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-dioxaboron-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.

[1153] 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).

[1154] Intermediate 120

[1155] 3-O-2-(1,2-thiazo-4-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxylic acid

[1156]

[1157] 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, 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.

[1158] 1H NMR (400MHz, DMSO-d6) δppm=7.48-7.55 (m, 2H), 8.20 (d, 2H), 8.50 (s, 1H), 9.15 (s, 1H), 9.60 (s, 1H).

[1159] Intermediate 121

[1160] methyl 6-[4-(difluoromethoxy)phenyl]-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

[1161]

[1162] A mixture of dimethyl 2-[4-(difluoromethoxy)phenyl]-2-oxoethyl}malonate (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 overnight at room temperature, followed by stirring at 50 °C for 6 hours. Then, 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.

[1163] 1 H NMR (400MHz, DMSO-d6) δppm=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).

[1164] Intermediate 122

[1165] Methyl 6-[4-(difluoromethoxy)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate

[1166]

[1167] A mixture of methyl 6-[4-(difluoromethoxy)phenyl]-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate (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.

[1168] 1H NMR (400MHz, DMSO-d6) δppm=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).

[1169] Intermediate 123

[1170] 6-[4-(difluoromethoxy)phenyl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxylic acid

[1171]

[1172] Methyl 6-[4-(difluoromethoxy)phenyl]-3-oxo-2,3-dihydropyridazine-4-carboxylate (550 mg, 1.86 mmol) was dissolved in DMF (12 mL), followed by the addition of 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). The reaction mixture was stirred at 80 °C for 4 h, followed by stirring at room temperature for 48 h. Then, 2 M sodium hydroxide solution (1.86 g, 3.7 mmol) was added, and the mixture was stirred at room temperature for 3 h, followed by the addition of water. The precipitate formed was filtered off, washed with water, and dried under vacuum to give 610 mg (91%) of the title compound.

[1173] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.07min; MS(ESIpos): m / z=360.2[M+H] + .

[1174] Intermediate 124

[1175] Diethyl hydroxy{2-oxo-2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}malonate

[1176]

[1177] To a 100 mL round-bottom flask, add 10 g (52.87 mmol) of 1-[6-(trifluoromethyl)pyridin-3-yl]acetone and 1,3-diethyl 2-oxomalactone (15.65 g, 89.9 mmol). Stir the resulting solution at 130 °C for 24 hours, then add more 1,3-diethyl 2-oxomalactone (13.81 g, 79.30 mmol) and heat at 130 °C for another 13 hours. Cool the resulting mixture to room temperature and pour it into pentane. Filter out the precipitate, wash with pentane and water to give 22.6 g (crude) diethyl hydroxy{2-oxo-2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}malonate, which is used without further purification.

[1178] Intermediate 125

[1179] 3-Oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[1180]

[1181] Hydrazine hydrochloride (7.2 g, 68.5 mmol) was added to an ethanol (255 mL) solution of diethyl hydroxy{2-oxo-2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}malonate (22.6 g, 62.2 mmol). The resulting solution was stirred at 80 °C for 24 hours. The reaction was then quenched by adding water. The resulting precipitate was filtered off and dried under vacuum to give 13.26 g (68%) of ethyl 3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylate.

[1182] 1 H NMR (400MHz, DMSO-d6) δppm=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).

[1183] Intermediate 126

[1184] 2-(5-Fluoropyridin-3-yl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[1185]

[1186] 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, followed by the addition of water. The solution was adjusted to pH 3 by adding 1 M hydrochloric acid aqueous solution, and then extracted three times with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 5.6 g (86%) of the title compound.

[1187] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.15min; MS(ESIpos): m / z=409.2[M+H] + .

[1188] Intermediate 127

[1189] 2-(5-Fluoropyridin-3-yl)-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxylic acid

[1190]

[1191] 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 sodium hydroxide aqueous solution. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the pH was adjusted to 3 using 1M hydrochloric acid aqueous solution. The precipitate was filtered off and dried under vacuum to give 3.19 g (70%) of the title compound.

[1192] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.00min; MS(ESIpos): m / z=381.6[M+H] + .

[1193] Intermediate 128

[1194] Diethyl hydroxy{2-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}malonate

[1195]

[1196] 1-[5-(trifluoromethyl)pyridin-2-yl]acetone (3.8 g, 20.1 mmol) and diethyl ketomalonate (7.0 g, 40.2 mmol) were mixed and 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 617 WA filter paper), and concentrated. The crude product was purified by rapid chromatography (silica gel, hexane / ethyl acetate, gradient) to give 4.64 g (64%) of the title compound.

[1197] 1 H NMR (400MHz, DMSO-d6) δppm=1.18 (t, 6H), 3.91 (q, 2H), 4.17 (q, 4H), 6.50 (s, 1H), 8.12 (d, 1H), 8.42-8.47 (m, 1H), 9.17 (dd, 1H).

[1198] Intermediate 129

[1199] 3-Oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylic acid ethyl ester

[1200]

[1201] Diethyl hydroxy{2-oxo-2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}malonate (4.6 g, 12.66 mmol) and hydrazine dihydrochloride (1.79 g, 17.1 mmol) were dissolved in ethanol (52 mL) and stirred under reflux for 9 hours. Upon addition of water, a precipitate formed and was filtered off. The precipitate was washed with water and dried under vacuum to give 3.19 g (81%) of the title compound.

[1202] 1 H NMR (400MHz, DMSO-d6) δppm 1.31 (t, 3H), 4.32 (q, 2H), 8.24-8.29 (m, 1H), 8.35 (dd, 1H), 8.67 (s, 1H), 9.07-9.11 (m, 1H), 13.94 (s, 1H).

[1203] Intermediate 130

[1204] 3-O-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylic acid

[1205]

[1206] 3.0 g of a crude mixture containing an unknown amount of ethyl 3-oxo-6-[5-(trifluoromethyl)-pyridin-2-yl]-2,3-dihydropyridazine-4-carboxylate was dissolved in tetrahydrofuran (50 mL), followed by the addition of 9.2 mL (18.4 mmol) of 2N sodium hydroxide aqueous solution. The reaction mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the pH was adjusted to pH 3 using 1M hydrochloric acid aqueous solution. The precipitate was filtered off and dried under vacuum to give 1.05 g of a crude mixture containing the title compound.

[1207] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =1.04min; MS(ESIpos): m / z=286.1[M+H] + .

[1208] Intermediate 131

[1209] N-[(2S)-1-hydroxypropyl-2-yl]-3-oxo-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxamide

[1210]

[1211] 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 propanol 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 617 WA filter paper), and concentrated. The crude product was purified by rapid chromatography (silica gel, hexane / ethyl acetate, gradient) to give 383 mg of the title compound.

[1212] LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C181.7 50x2.1mm; 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℃; Injection: 2 μL; DAD scan: 210-400 nm; ELSD): R t =0.93min; MS(ESIpos): m / z=343.5[M+H] + .

[1213] Experimental Section - Example S

[1214] The following examples describe embodiments of the present invention, but do not limit the invention to these examples.

[1215] Example 1

[1216] N-(1-hydroxy-3-methylbut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1217]

[1218] A solution of 100 mg intermediate 6, 33.2 mg 2-amino-3-methylbut-1-ol, 184 mg HATU, and 125 mg ethyl diisopropylamine in 5 mL DMF was stirred at room temperature for 2 hours. The reaction was then quenched with 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 C18 5 μm 100 x 30 mm, mobile phase: acetonitrile / water (0.1 vol% formic acid)-gradient) to give 25.3 mg N-(1-hydroxy-3-methylbut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide).

[1219] 1 ¹H-NMR: (400MHz, 25℃, 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).

[1220] Example 2

[1221] N-(1-hydroxy-3-methylbut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 1

[1222]

[1223] 24 mg of N-(1-hydroxy-3-methylbut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 1) was separated by HPLC on a chiral column (Chiralpak IB 5 μm 250x30 mm, eluent: hexane / ethanol, gradient of 20-50% ethanol, flow rate 40 mL / min) to obtain 6 mg of N-(1-hydroxy-3-methylbut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 1.

[1224] 1H-NMR (400MHz, 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).

[1225] Chiral HPLC: Rt = 3.65 min

[1226] Instrument: Agilent HPLC 1260; Column: Chiralpak IB 3μm 100x4.6mm; Eluent: Hexane / ethanol 50:50, Flow rate 1.4mL / min; Temperature: 25℃; DAD scan: 254nm.

[1227] Example 3

[1228] N-(1-hydroxy-3-methylbut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 2

[1229]

[1230] According to Example 2, 24 mg of Example 1 was separated, and an additional 6 mg of N-(1-hydroxy-3-methylbut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 2, was obtained.

[1231] 1 H-NMR (300MHz, 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).

[1232] Chiral HPLC: Rt = 6.15 min

[1233] Instrument: Agilent HPLC 1260; Column: Chiralpak IB 3μm 100x4.6mm; Eluent: Hexane / ethanol 50:50, Flow rate 1.4mL / min; Temperature: 25℃; DAD scan: 254nm.

[1234] Example 4

[1235] N-(1-hydroxybut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1236]

[1237] A solution of 100 mg intermediate 7, 40.7 mg 2-aminobut-1-ol, and 85 μL triethylamine in 10 mL dichloromethane was stirred in an ice-water bath for 10 min. The reaction was then quenched with 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 rapid chromatography (ethyl acetate / petroleum ether 1:2) to give 34 mg N-(1-hydroxybut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1238] 1 ¹H-NMR: (400MHz, 25℃, methanol-d⁴): δ [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).

[1239] Example 5

[1240] N-(1-hydroxybut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 1

[1241]

[1242] 33 mg of N-(1-hydroxybut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 4) was separated by HPLC on a chiral column (Chiralpak IC 5 μm 250x30 mm, eluent: hexane (0.1% diethylamine) / (ethanol / methanol 50:50), gradient 20-50% (ethanol / methanol 50:50), flow rate 40 mL / min) to obtain 8 mg of N-(1-hydroxybut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 1.

[1243] 1 H-NMR (400MHz, 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).

[1244] Chiral HPLC: Rt = 4.68 min

[1245] Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μm 100x4.6mm; Eluent: Hexane (0.1% diethylamine) / (ethanol / methanol 50:50), gradient 20-50% (ethanol / methanol 50:50), flow rate 1.4mL / min; Temperature: 25℃; DAD scan: 254nm.

[1246] Example 6

[1247] N-(1-hydroxybut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 2

[1248]

[1249] According to Example 5, 33 mg of Example 4 was separated, and an additional 8 mg of N-(1-hydroxybut-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 2, was obtained.

[1250] 1 H-NMR (400MHz, 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); 795 (d, 2H); 8.11 (s, 1H); 8.56 (s, 2H); 9.51 (d, 1H).

[1251] Chiral HPLC: Rt = 6.25 min

[1252] Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μm 100x4.6mm; Eluent: Hexane (0.1% diethylamine) / (ethanol / methanol 50:50), gradient 20-50% (ethanol / methanol 50:50), flow rate 1.4mL / min; Temperature: 25℃; DAD scan: 254nm.

[1253] Example 7

[1254] N-(1-hydroxypropyl-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1255]

[1256] A solution of 100 mg intermediate 7, 34.3 mg 2-aminoprop-1-ol, and 85 μL triethylamine in 10 mL dichloromethane was stirred in an ice-water bath for 10 min. The reaction was then quenched with 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 rapid chromatography (ethyl acetate / petroleum ether 1:2) to give 40.8 mg N-(1-hydroxypropyl-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1257] 1¹H-NMR: (400MHz, 25℃, 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).

[1258] Example 8

[1259] N-[(2S)-1-hydroxypropyl-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1260]

[1261] A: A solution of 80 mg intermediate 6, 38 mg (2S)-2-aminoprop-1-ol, 147 mg HATU, and 0.135 mL ethyl diisopropylamine in 5 mL DMF was stirred at room temperature for 14 hours. The reaction was then quenched with 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 rapid chromatography (dichloromethane / methanol, gradient up to 3% methanol) to give 20 mg N-[(2S)-1-hydroxyprop-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1262] B: 39 mg of N-(1-hydroxypropyl-2-yl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 7) was separated by HPLC on a chiral column (Chiralpak IC 5 μm 250x30 mm, eluent: hexane (0.1% diethylamine) / (ethanol / methanol 50:50), gradient 20-50% (ethanol / methanol 50:50), flow rate 40 mL / min) to obtain 9 mg of N-[(2S)-1-hydroxypropyl-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide).

[1263] 1H-NMR (400MHz, CDCl3): δ [ppm] = 1.34 (d, 3H); 2.43 (s, 3H); 285 (dd, 1H); 3.70 (ddd, 1H); 3.80 (ddd, 1H); 3.9 8 (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).

[1264] Chiral HPLC: Rt = 5.28 min

[1265] Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μm 100x4.6mm; Eluent: Hexane (0.1% diethylamine) / (ethanol / methanol 50:50), gradient 20-50% (ethanol / methanol 50:50), flow rate 1.4mL / min; Temperature: 25℃; DAD scan: 254nm.

[1266] Example 9

[1267] N-[(2R)-1-hydroxypropyl-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1268]

[1269] According to Procedure B of Example 8, 39 mg of Example 7 was separated, and an additional 13 mg of N-[(2R)-1-hydroxypropyl-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide was obtained.

[1270] 1 H-NMR (400MHz, CDCl3): δ [ppm] = 1.34 (d, 3H); 2.43 (s, 3H); 2.85 (dd, 1H); 3.70 (ddd, 1H); 3.80 (ddd, 1H); 3.9 8 (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).

[1271] Chiral HPLC: Rt = 7.07 min

[1272] Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μm 100x4.6mm; Eluent: Hexane (0.1% diethylamine) / (ethanol / methanol 50:50), gradient 20-50% (ethanol / methanol 50:50), flow rate 1.4mL / min; Temperature: 25℃; DAD scan: 254nm.

[1273] Example 10

[1274] 6-(4-Methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide

[1275]

[1276] A solution of 100 mg intermediate 6, 83.2 mg 3-amino-1,1,1-trifluoroprop-2-ol, 184 mg HATU, and 0.17 mL ethyl diisopropylamine in 5 mL DMF was stirred at room temperature for 14 hours. The reaction was then quenched with 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 rapid chromatography (dichloromethane / methanol, gradient up to 2% methanol) to give 65 mg 6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide.

[1277] 1 H-NMR (400MHz, CDCl3): δ [ppm] = 2.44 (s, 3H); 3.78 (ddd, 1H); 390 (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).

[1278] Example 11

[1279] (-)-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 1

[1280]

[1281] 63 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 (Example 10) was separated by HPLC on a chiral column (Chiralpak IA 5 μm 250 x 30 mm, eluent: methanol (0.1% diethylamine) / ethanol 50:50, flow rate 30 mL / min) to obtain 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 1.

[1282] 1 H-NMR (400MHz, CDCl3): 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).

[1283] Chiral HPLC: Rt = 2.69 min

[1284] Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μm 100x4.6mm; Eluent: Methanol (0.1% diethylamine) / ethanol 50:50, Flow rate 1.4mL / min; Temperature: 25℃; DAD scan: 254nm

[1285] Optical rotation: [α] D 20 = -6.7° + / -0.62° (c = 1.00, methanol).

[1286] Example 12

[1287] (+)-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

[1288]

[1289] According to Example 11, 63 mg of Example 10 was separated, and an additional 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, was obtained.

[1290] 1 H-NMR (400MHz, CDCl3): 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).

[1291] Chiral HPLC: Rt = 3.11 min

[1292] Instrument: Agilent HPLC 1260; Column: Chiralpak IC 3μm 100x4.6mm; Eluent: Methanol (0.1% diethylamine) / ethanol 50:50, Flow rate 1.4mL / min; Temperature: 25℃; DAD scan: 254nm

[1293] Optical rotation: [α] D 20 =5.6°+ / -0.47° (c=1.00, methanol).

[1294] Example 13

[1295] N-(3,3-difluoro-2-hydroxypropyl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1296]

[1297] A solution of 100 mg intermediate 6, 71.6 mg 3-amino-1,1-difluoroprop-2-ol, 184 mg HATU, and 0.17 mL ethyl diisopropylamine in 5 mL DMF was stirred at room temperature for 14 hours. The reaction was then quenched with 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 rapid chromatography (dichloromethane / methanol, gradient up to 2% methanol) to give 55 mg N-(3,3-difluoro-2-hydroxypropyl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1298] 1 H-NMR (400MHz, CDCl3): δ [ppm] = 2.43 (s, 3H); 3.67-3.77 (m, 1H); 3.84 (ddd, 1H); 3.95-4.09 (m+s, 4H); 4.1 1(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).

[1299] Example 14

[1300] 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

[1301]

[1302] 53 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 (Example 13) was separated by HPLC on a chiral column (Chiralpak IA 5 μm 250 x 30 mm, eluent: methanol (0.1% diethylamine) / ethanol 50:50, flow rate 30 mL / min) to obtain 24 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, enantiomer 1.

[1303] 1H-NMR (400MHz, CDCl3): δ [ppm] = 2.43 (s, 3H); 3.67-3.77 (m, 1H); 3.84 (ddd, 1H); 3.95-4.09 (m+s, 4H); 4.1 1(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).

[1304] Chiral HPLC: Rt = 3.92 min

[1305] Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3μm 100x4.6mm; Eluent: Methanol (0.1% diethylamine) / ethanol 50:50, Flow rate 1.4mL / min; Temperature: 25℃; DAD scan: 254nm.

[1306] Example 15

[1307] N-(3,3-difluoro-2-hydroxypropyl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 2

[1308]

[1309] According to Example 14, 53 mg of Example 13 was separated, and an additional 24 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, enantiomer 2, was obtained.

[1310] 1 H-NMR (400MHz, CDCl3): δ [ppm] = 2.43 (s, 3H); 3.67-3.77 (m, 1H); 3.84 (ddd, 1H); 3.95-4.09 (m+s, 4H); 4.1 1(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).

[1311] Chiral HPLC: Rt = 4.78 min

[1312] Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3pm 100x4.6mm; Eluent: Methanol (0.1% diethylamine) / ethanol 50:50, flow rate 1.4mL / min; Temperature: 25℃; DAD scan: 254nm.

[1313] Example 16

[1314] 6-(4-Chlorophenyl)-N-[(2S)-1-hydroxy-3-methylbut-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1315]

[1316] A solution of 80 mg intermediate 11, 49.9 mg (2S)-2-amino-3-methylbut-1-ol, 138 mg HATU, and 0.13 mL ethyl diisopropylamine in 5 mL DMF was stirred at room temperature for 14 hours. The reaction was then quenched with 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 C18 5 μm 100 x 30 mm, mobile phase: acetonitrile / water (0.1 vol% formic acid) gradient) to give 45 mg 6-(4-chlorophenyl)-N-[(2S)-1-hydroxy-3-methylbut-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide).

[1317] 1 H-NMR (400MHz, CDCl3): 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).

[1318] Example 17

[1319] 6-(4-Chlorophenyl)-N-[(2S)-1-hydroxypropyl-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1320] A solution of 80 mg intermediate 11, 29.1 mg (2S)-2-aminoprop-1-ol, 110 mg HATU, and 0.1 mL ethyl diisopropylamine in 5 mL DMF was stirred at room temperature for 14 hours. The reaction was then quenched with 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 C18 5 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-hydroxyprop-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide).

[1321] 1 H-NMR (400MHz, CDCl3): 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).

[1322] Example 18

[1323] 6-(4-Chlorophenyl)-2-(1-Methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide

[1324]

[1325] A solution of 130 mg intermediate 11, 101 mg 3-amino-1,1,1-trifluoroprop-2-ol, 224 mg HATU, and 0.21 mL ethyl diisopropylamine in 10 mL DMF was stirred at room temperature for 14 hours. The reaction was then quenched with 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 rapid chromatography (dichloromethane / methanol, gradient up to 2% methanol) to give 160 mg 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide.

[1326] 1H-NMR (400MHz, CDCl3): 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).

[1327] Example 19

[1328] (-)-6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazole-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide

[1329]

[1330] 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) was separated by HPLC on a chiral column (Chiralpak IA 5 μm 250x30 mm, eluent: CO2 / 2-propanol 77:23, flow rate 100 mL / min, p = 150 bar, T = 40 °C) to obtain 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.

[1331] 1 H-NMR (400MHz, CDCl3): 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).

[1332] Chiral HPLC: Rt = 2.76 min

[1333] Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3μm 100x4.6mm; Eluent: CO2 / 2-propanol 77:23, Flow rate 4mL / min, p=100 bar, T=37.5℃; DAD scan: 254nm

[1334] Optical rotation: [α] D 20 = -5.2° + / -0.35° (c = 1.00, methanol).

[1335] Example 20

[1336] (+)-6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide

[1337]

[1338] According to Example 19, 158 mg of Example 18 was isolated, and an additional 55 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 was obtained.

[1339] 1 H-NMR (400MHz, CDCl3): 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).

[1340] Chiral HPLC: Rt = 3.75 min

[1341] Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3μm 100x4.6mm; Eluent: CO2 / 2-propanol 77:23, Flow rate 4mL / min, p=100 bar, T=37.5℃; DAD scan: 254nm

[1342] Optical rotation:

[1343] [α] D 20 =6.9°+ / -0.23° (c=1.00, methanol).

[1344] Example 21

[1345] 6-(4-Chlorophenyl)-N-(3,3-difluoro-2-hydroxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1346]

[1347] A solution of 110 mg intermediate 11, 59.1 mg 3-amino-1,1-difluoroprop-2-ol, 152 mg HATU, and 0.14 mL ethyl diisopropylamine in 5 mL DMF was stirred at room temperature for 14 hours. The reaction was then quenched with 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 C18 5 μm 100 x 30 mm, mobile phase: acetonitrile / water (0.1 vol% formic acid) gradient) to give 65 mg 6-(4-chlorophenyl)-N-(3,3-difluoro-2-hydroxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1348] 1 H-NMR (400MHz, CDCl3); δ [ppm] = 3.68-3.77 (m, 1H); 3.85 (ddd, 1H); 3.96-4.08 (m+s, 5H); 5.7 9(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).

[1349] Example 22

[1350] (-)-6-(4-chlorophenyl)-N-(3,3-difluoro-2-hydroxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1351]

[1352] 63 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 (Example 21) was separated by HPLC on a chiral column (Chiralpak IA 5 μm 250x30 mm, eluent: CO2 / 2-propanol 71:29, flow rate 100 mL / min, p = 150 bar, T = 40 °C) to obtain 15 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.

[1353] 1 H-NMR (400MHz, CDCl3): δ [ppm] = 3.68-3.77 (m, 1H); 3.85 (ddd, 1H); 3.96-4.08 (m+s, 5H); 5.7 9(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).

[1354] Chiral HPLC: Rt = 2.50 min

[1355] Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3μm 100x4.6mm; Eluent: CO2 / 2-propanol 71:29, Flow rate 4mL / min, p=100 bar, T=37.5℃; DAD scan: 254nm

[1356] Optical rotation: [α] D 20 = -6.6° + / -0.41° (c = 1.00, methanol).

[1357] Example 23

[1358] (+)-6-(4-chlorophenyl)-N-(3,3-difluoro-2-hydroxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1359]

[1360] According to Example 22, 63 mg of Example 21 was separated, and an additional 20 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 was obtained.

[1361] 1 H-NMR (400MHz, CDCl3): δ [ppm] = 3.68-3.77 (m, 1H); 3.85 (ddd, 1H); 3.96-4.08 (m+s, 5H); 5.7 9(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).

[1362] Chiral HPLC: Rt = 4.12 min

[1363] Instrument: Agilent HPLC 1260; Column: Chiralpak IA 3μm 100x4.6mm; Eluent: CO2 / 2-propanol 71:29, Flow rate 4mL / min, p=100 bar, T=37.5℃; DAD scan: 254nm

[1364] Optical rotation: [α] D 20 =8.4°+ / -0.32° (c=1.00, methanol).

[1365] Example 24

[1366] 6-(4-Chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1367]

[1368] A solution of 110 mg intermediate 11, 55.9 mg 1-amino-3-methoxyprop-2-ol, 152 mg HATU, and 0.14 mL ethyl diisopropylamine in 5 mL DMF was stirred at room temperature for 14 hours. The reaction was then quenched with 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 C18 5 μm 100 x 30 mm, mobile phase: acetonitrile / water (0.1 vol% formic acid) gradient) to give 40 mg 6-(4-chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1369] 1H-NMR (400MHz, CDCl3): δ [ppm] = 3.06 (d, 1H); 3.40-3.46 (m+s, 4H); 3.47-3.60 (m, 2H); 3.74 (ddd, 1H); 3.98 (s, 3H); 4.01-4.08 (m, 1H); 7.49 (d, 2H); 7.88 (d, 2H); 8.13 (s, 1H); 8.37 (s, 1H); 8.69 (s, 1H); 9.97 (bt, 1H).

[1370] Example 25

[1371] (-)-6-(4-chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1372]

[1373] 38 mg of 6-(4-chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 24) was separated by HPLC 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) to obtain 18 mg of (-)-6-(4-chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

[1374] 1 H-NMR (400MHz, CDCl3): δ [ppm] = 3.06 (d, 1H); 3.40-3.46 (m+s, 4H); 3.47-3.60 (m, 2H); 3.74 (ddd, 1H); 3.98 (s, 3H); 4.01-4.08 (m, 1H); 7.49 (d, 2H); 7.88 (d, 2H); 8.13 (s, 1H); 8.37 (s, 1H); 8.69 (s, 1H); 9.97 (bt, 1H).

[1375] Chiral HPLC: Rt = 3.83 min

[1376] Instrument: Agilent HPLC 1260; Column: Chiralpak AD-H 3μm 100x4.6mm; Eluent: Acetonitrile (0.1 vol% diethylamine) / ethanol 90:10, Flow rate 1.4 mL / min, DAD scan: 254 nm

[1377] Optical rotation: [α] D 20 = -5.2° + / -0.44° (c = 1.00, methanol).

[1378] Example 26

[1379] (+)-6-(4-chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1380]

[1381] According to Example 25, 38 mg of Example 24 was isolated, and an additional 15 mg of (+)-6-(4-chlorophenyl)-N-(2-hydroxy-3-methoxypropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide was obtained.

[1382] 1 H-NMR (400MHz, CDCl3): δ [ppm] = 3.06 (d, 1H); 3.40-3.46 (m+s, 4H); 3.47-3.60 (m, 2H); 3.74 (ddd, 1H); 3.98 (s, 3H); 4.01-4.08 (m, 1H); 7.49 (d, 2H); 7.88 (d, 2H); 8.13 (s, 1H); 8.37 (s, 1H); 8.69 (s, 1H); 9.97 (bt, 1H).

[1383] Chiral HPLC: Rt = 4.88 min

[1384] Instrument: Agilent HPLC 1260; Column: Chiralpak AD-H 3μm 100x4.6mm; Eluent: Acetonitrile (0.1 vol% diethylamine) / ethanol 90:10, Flow rate 1.4 mL / min, DAD scan: 254 nm

[1385] Optical rotation: [α] D 20 =6.2°+ / -0.31° (c=1.00, methanol).

[1386] Example 27

[1387] 6-(4-Chlorophenyl)-N-[(2S)-2,3-dihydroxypropyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1388]

[1389] 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazin-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF (1.1 mL). (2S)-3-aminopropane-1,2-diol (27.5 mg, 0.30 mmol), N-ethyl-N-isopropylpropane-2-amine (0.118 mL, 0.68 mmol), and propanephosphonic anhydride (T3P, 132 μL, 50%, in DMF, 227 μmol) were added sequentially. The mixture was stirred overnight at room temperature. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100 x 30 mm, mobile phase: (water + 0.2 vol% ammonia (32%)) / acetonitrile, gradient) to give 21.5 mg (35%) of the title compound.

[1390] 1 ¹H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.20–3.30 (m, 1H), 3.30–3.36 (m, 1H and water signal), 3.38–3.44 (m, 1H), 3.58–3.67 (m, 2H), 3.93 (s, 3H), 4.70 (t, 1H), 5.03 (d, 1H), 7.58–7.62 (m, 2H), 8.08–8.13 (m, 3H), 8.55 (s, 1H), 8.59 (s, 1H), 9.63 (t, 1H).

[1391] [α] D 20 = -5.5° (c = 1.00, DMSO).

[1392] Example 28

[1393] 6-(4-Chlorophenyl)-N-[(2R)-2,3-dihydroxypropyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide

[1394]

[1395] 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazin-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF (1.1 mL). (2R)-3-aminopropane-1,2-diol (27.5 mg, 0.30 mmol), N-ethyl-N-isopropylpropane-2-amine (0.118 mL, 0.68 mmol), and propanephosphonic anhydride (T3P, 132 μL, 50%, in DMF, 227 μmol) were added sequentially. The mixture was stirred overnight at room temperature. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100 x 30 mm, mobile phase: (water + 0.2 vol% ammonia (32%)) / acetonitrile, gradient) to give 17.5 mg (29%) of the title compound.

[1396] 1 ¹H-NMR (400MHz, DMSO-d6): δ [ppm] = 3.21–3.30 (m, 1H), 3.30–3.36 (m, 1H and water signal), 3.38–3.44 (m, 1H), 3.58–3.67 (m, 2H), 3.93 (s, 3H), 4.70 (t, 1H), 5.03 (d, 1H), 7.58–7.62 (m, 2H), 8.08–8.13 (m, 3H), 8.55 (s, 1H), 8.59 (s, 1H), 9.63 (1, 1H).

[1397] [α] D 20 = +14.3° (c = 1.00, DMSO).

[1398] Example 29

[1399] 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

[1400]

[1401] 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazin-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF (1.1 mL). (2S)-2-amino-3-methoxyprop-1-ol (31.8 mg, 0.30 mmol), N-ethyl-N-isopropylprop-2-amine (0.118 mL, 0.68 mmol), and propanephospho...

Claims

1. Compounds of general formula (I): Their enantiomers, diastereomers, racemates, tautomers, and their physiologically acceptable salts, 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 C1C2 alkoxy or cyclopropyl group is substituted once, and optionally substituted with halogens one to three times, or C4-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 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 C1C3 alkyl group and / or substituted once to three times with a halogen; R 2 It represents chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy; R 3 Indicates hydrogen or fluorine; R 4 Indicates hydrogen or fluorine; R 5 This indicates a monocyclic heteroaryl group, whose optional R 6 Each can replace the other one to three times independently; R 6 It indicates methyl, difluoromethyl, methoxy, halogen, or cyano; X represents CH or N; R 10 Indicates C1-C4-alkyl; R 11 and R 12 The same or different and independently representing hydrogen or C1-C3-alkyl, or 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, Used for the preparation of a medicament for the treatment or prevention of a disease, wherein the medicament is a tablet, and wherein the disease is glioblastoma, melanoma, lymphoma, or leukemia associated with abnormal AHR signaling.

2. The use according to claim 1, wherein: 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. 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 by 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 It represents chlorine, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy; R 3 It represents hydrogen; R 4 Indicates hydrogen or fluorine; R 5 It indicates that the group is selected from the following: Where * indicates the connection point between the group and the rest of the molecule; R 6a Indicates hydrogen, methyl, fluorine, or chlorine; X represents CH or N.

3. The use according to claim 1, 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-hydroxypropyl-2-yl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; N-(3,3-difluoro-2-hydroxypropyl)-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-3,3-difluoro-2-hydroxypropyl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3,3-difluoro-2-hydroxypropyl]-6-(4-methylphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(1-hydroxy-3-methylbut-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1-hydroxy-3-methylbut-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(1-hydroxypropyl-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropyl-2-yl]-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-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-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-(1,1,1-trifluoro-3-hydroxypropyl-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-hydroxypropyl-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2S)-1,1,1-trifluoro-3-hydroxypropyl-2-yl]-2,3-dihydropyridazine-4-carboxamide; 2-(1-Methyl-1H-pyrazol-4-yl)-3-oxo-N-(1,1,1-trifluoro-3-hydroxypropyl-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-hydroxypropyl-2-yl]-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 2-(1-Methyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 2-(1-Methyl-1H-pyrazol-4-yl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxypropyl-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1-hydroxypropyl-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxypropyl-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-Cyclobutyl-1H-pyrazol-4-yl)-3-oxo-N-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(1-Cyclobutyl-1H-pyrazol-4-yl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(1-Cyclobutyl-1H-pyrazol-4-yl)-3-oxo-N-(1,1,1-trifluoro-3-hydroxypropyl-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-hydroxypropyl-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(1-Cyclobutyl-1H-pyrazol-4-yl)-N-(1-hydroxypropyl-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(1-Cyclobutyl-1H-pyrazol-4-yl)-N-[(2S)-1-hydroxypropyl-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-hydroxypropyl-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-hydroxypropyl-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-[(1S,2S)-2-hydroxycyclopentyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(cis)-2-hydroxycyclopentyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(1S,2R)-2-hydroxycyclopentyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethyl)phenyl]-N-[(trans)-2-hydroxycyclopentyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxypropyl-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxypropyl-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-[(cis)-2-hydroxycyclohexyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-[(1S,2R)-2-hydroxycyclohexyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(cis)-4-hydroxytetrahydrofuran-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(3R,4R)-4-hydroxytetrahydrofuran-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(3S,4S)-4-hydroxytetrahydrofuran-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethyl)phenyl]-N-(1-hydroxypropyl-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethyl)phenyl]-N-[(2S)-1-hydroxypropyl-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-(2-hydroxy-2-methylpropyl)-2-(1-methyl-1H-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-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 1,5-Dehydr-2-({[6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazin-4-yl]carbonyl}amino)-2,4-dideoxy-D-erythritol; 6-[4-(difluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(trans)-4-hydroxytetrahydrofuran-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-(1-hydroxypropyl-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-[(2S)-1-hydroxypropyl-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-(2-hydroxy-2-methylpropyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(1-hydroxypropyl-2-yl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2R)-1-hydroxypropyl-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropyl-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(1,3-dihydroxypropyl-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)-3-oxo-2-(pyridin-3-yl)-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-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-hydroxypropyl-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(2R)-1-hydroxypropyl-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(2S)-1-hydroxypropyl-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-methylbut-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(2S)-1-hydroxy-3-methylbut-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(1,3-dihydroxypropyl-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-methoxypropyl-2-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(2R)-1-hydroxy-3-methoxypropyl-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-N-[(2S)-1-hydroxy-3-methoxypropyl-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(1-fluoro-3-hydroxypropyl-2-yl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2R)-1-fluoro-3-hydroxypropyl-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-hydroxypropyl-2-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-fluoropyridin-3-yl)-3-oxo-N-[(2R)-1,1,1-trifluoro-3-hydroxypropyl-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-[(1S,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-O-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-(1,1,1-trifluoro-3-hydroxypropyl-2-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-Oxo-2-(pyridin-3-yl)-N-[(2R)-1,1,1-trifluoro-3-hydroxypropyl-2-yl]-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxy-3-methoxypropyl-2-yl)-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxy-3-methoxypropyl-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-(1,3-dihydroxypropyl-2-yl)-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxypropyl-2-yl)-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1-hydroxypropyl-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxypropyl-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(1-hydroxypropyl-2-yl)-3-oxo-2-(pyrimidin-5-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropyl-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-methylbut-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-methylbut-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-methylbut-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-[(1S,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-[(1S,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-hydroxypropyl-2-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethyl)phenyl]-3-oxo-2-(pyridin-3-yl)-N-[(2R)-1,1,1-trifluoro-3-hydroxypropyl-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-hydroxypropyl-2-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-Oxo-2-(pyridin-3-yl)-N-[(2R)-1,1,1-trifluoro-3-hydroxypropyl-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-methylbut-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-methylbut-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-methylbut-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-hydroxypropyl-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxypropyl-2-yl)-6-(4-methylphenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxypropyl-2-yl]-6-(4-methylphenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; N-(1-hydroxypropyl-2-yl)-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxypropyl-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-hydroxypropyl-2-yl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chloro-2-fluorophenyl)-N-[(2S)-1-hydroxypropyl-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 3-(4-Chlorophenyl)-N-[(cis)-2-hydroxycyclohexyl]-6-oxo-6H-1,4'-bipyridazine-5-carboxamide; 3-(4-Chlorophenyl)-N-[(1S,2R)-2-hydroxycyclohexyl]-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-hydroxypropyl-2-yl)-3-oxo-2-(pyridin-3-yl)-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxypropyl-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-Dehydr-2-({[6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazin-4-yl]carbonyl}amino)-2,4-dideoxy-cis-pentitol; 1,5-Dehydr-2-({[6-(4-chlorophenyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazin-4-yl]carbonyl}amino)-2,4-dideoxy-D-erythritol; 1,5-Dehydr-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-Dehydr-2,4-Dideoxy-2-[({3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazin-4-yl}carbonyl)amino]-D-erythritol; 3-(4-Chlorophenyl)-N-(1-hydroxypropyl-2-yl)-6-oxo-6H-1,4'-bipyridazine-5-carboxamide; 3-(4-chlorophenyl)-N-[(2S)-1-hydroxypropyl-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-hydroxypropyl-2-yl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-cyanophenyl)-N-[(2S)-1-hydroxypropyl-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-(1-hydroxypropyl-2-yl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[6-(difluoromethyl)pyridin-3-yl]-N-[(2S)-1-hydroxypropyl-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-[6-(difluoromethyl)pyridin-3-yl]-N-[(3S,4R)-4-methyltetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-3-oxo-2-(pyrimidin-5-yl)-N-(1,1,1-trifluoro-3-hydroxy-3-methylbut-2-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-3-oxo-2-(pyrimidin-5-yl)-N-[(2R)-1,1,1-trifluoro-3-hydroxy-3-methylbut-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-3-oxo-2-(pyrimidin-5-yl)-N-[(2S)-1,1,1-trifluoro-3-hydroxy-3-methylbut-2-yl]-2,3-dihydropyridazine-4-carboxamide; N-[(1-hydroxycyclopropyl)methyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(1-hydroxycyclobutyl)methyl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(1-hydroxypropyl-2-yl)-3-oxo-2-(1H-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-1-hydroxypropyl-2-yl]-3-oxo-2-(1H-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[4-(dimethylamino)phenyl]-N-(1-hydroxypropyl-2-yl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[4-(dimethylamino)phenyl]-N-[(2S)-1-hydroxypropyl-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(1-hydroxypropyl-2-yl)-2-(1-methyl-1H-pyrazol-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropyl-2-yl]-2-(1-methyl-1H-pyrazol-3-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(1-hydroxypropyl-2-yl)-2-(3-methyl-1H-pyrazol-5-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropyl-2-yl]-2-(3-methyl-1H-pyrazol-5-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-(1-hydroxypropyl-2-yl)-3-oxo-2-(1,2-thiazo-4-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropyl-2-yl]-3-oxo-2-(1,2-thiazo-4-yl)-2,3-dihydropyridazine-4-carboxamide; N-[(1-hydroxycyclobutyl)methyl]-3-oxo-2-(1,2-thiazo-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3-hydroxy-3-methylbut-2-yl]-3-oxo-2-(1,2-thiazo-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-methylbut-2-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-3-oxo-2-(1,2-thiazolyl-4-yl)-N-[(2R)-1,1,1-trifluoro-3-hydroxypropyl-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-3-oxo-2-(1,2-thiazolyl-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-thiazolyl-4-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-1-fluoro-3-hydroxypropyl-2-yl]-3-oxo-2-(1,2-thiazolyl-4-yl)-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-3-hydroxy-3-methylbut-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-hydroxypropyl-2-yl]-3-oxo-2-(1,2-thiazo-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-hydroxypropyl-2-yl]-3-oxo-2-(1,2-thiazo-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide N-[(2S)-3-hydroxy-3-methylbut-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-thiazo-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-(2-hydroxy-2-methylpropyl)-3-oxo-2-(1,2-thiazo-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-3-hydroxy-3-methylbut-2-yl]-3-oxo-2-(1,2-thiazo-4-yl)-2,3-dihydropyridazine-4-carboxamide; N-[(1S,2S)-2-hydroxycyclopentyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1-fluoro-3-hydroxypropyl-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-Oxo-2-(1H-pyrazol-4-yl)-N-[(2R)-1,1,1-trifluoro-3-hydroxypropyl-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-methylbut-2-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-3-oxo-N-[(2R)-1,1,1-trifluoro-3-hydroxypropyl-2-yl]-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-cis-4-hydroxytetrahydrofuran-3-yl-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 3-Oxo-2-(1H-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-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3,3-difluoro-2-hydroxypropyl]-2-(1-methyl-1H-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-hydroxypropyl-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1-fluoro-3-hydroxypropyl-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-thiazo-4-yl)-2,3-dihydropyridazine-4-carboxamide; 2-[1-(difluoromethyl)-1H-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-methylbut-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(1S)-1-cyano-2-hydroxyethyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N-[(2S)-3-hydroxy-3-methylbut-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-1H-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-methylbut-2-yl]-3-oxo-2-(1,2-thiazo-4-yl)-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-3-hydroxy-3-methylbut-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(1,2-oxazol-4-yl)-3-oxo-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-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-[(1S)-1-cyclopropyl-2-hydroxyethyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(1R,2S)-2-hydroxycyclopentyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-(2-hydroxy-2-methylpropyl)-3-oxo-2-(1,2-thiazo-4-yl)-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; (-)-3-oxo-2-(pyridin-3-yl)-N-(1,1,1-trifluoro-3-hydroxy-3-methylbut-2-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropyl-2-yl]-2-(5-methyl-3-thienyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-(5-chloro-3-thienyl)-N-[(2S)-1-hydroxypropyl-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-1-hydroxypropyl-2-yl]-3-oxo-2-(1H-pyrazol-4-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3-fluoro-2-hydroxypropyl]-2-(1-methyl-1H-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-[(1R,2R)-2-hydroxycyclopentyl]-2-(1-methyl-1H-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-hydroxypropyl-2-yl]-3-oxo-2-(1,2-thiazo-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-hydroxypropyl-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-methoxypropyl-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-methylbut-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-hydroxypropyl-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-methylbut-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-3-hydroxy-3-methylbut-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-hydroxypropyl-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-2-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N-[(2S)-1-hydroxypropyl-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-hydroxypropyl-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-3-hydroxy-3-methylbut-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-[1-(difluoromethyl)-1H-pyrazol-4-yl]-N-(2-hydroxy-2-methylpropyl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2R)-1-hydroxypropyl-2-yl]-3-oxo-2-(pyrimidin-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)-1,1,1-trifluoro-3-hydroxypropyl-2-yl]-2,3-dihydropyridazine-4-carboxamide; 6-[4-(fluoromethyl)phenyl]-2-(1-methyl-1H-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-methylbut-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(fluoromethyl)phenyl]-N-[(2S)-1-hydroxypropyl-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)-1-hydroxypropyl-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(fluoromethyl)phenyl]-N-[(2S)-3-hydroxy-3-methylbut-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-1-amino-3-hydroxy-1-oxopropyl-2-yl]-6-(4-chlorophenyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-cis-4-hydroxytetrahydrothiophene-3-yl-3-oxo-2-(pyridin-3-yl)-6-[4-(trifluoromethyl)phenyl]-2,3-dihydropyridazine-4-carboxamide; (-)-N-cis-4-hydroxytetrahydrothiophene-3-yl-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-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide 3-Oxo-2-(pyridin-3-yl)-N-[(2R)-3,3,3-trifluoro-2-hydroxypropyl]-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-3-hydroxy-3-methylbut-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-hydroxybut-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-methylbut-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-2-(5-chloropyridin-3-yl)-N-[(2S)-1-hydroxypropyl-2-yl]-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropyl-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-methylbut-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-methylbut-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-methylbut-2-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S)-1-hydroxypropyl-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-methylbut-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(dimethylamino)phenyl]-N-[(2S)-3-hydroxy-3-methylbut-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(dimethylamino)phenyl]-N-[(2S)-1-hydroxypropyl-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; N-[(2S)-3-hydroxy-3-methylbut-2-yl]-3-oxo-2-(1,2-thiazo-4-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethyl)phenyl]-3-oxo-2-(pyridin-3-yl)-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-3-oxo-2-(pyridin-3-yl)-N-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2S)-3-hydroxy-3-methylbut-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-(2-hydroxy-2-methylcyclopentyl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethyl)phenyl]-N-[(cis)-4-hydroxytetrahydrofuran-3-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethyl)phenyl]-N-[(2S)-3-hydroxy-3-methylbut-2-yl]-3-oxo-2-(pyridin-3-yl)-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-(difluoromethyl)phenyl]-N-(2-hydroxy-2-methylpropyl)-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2R)-1-hydroxypropyl-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(2R)-3-hydroxy-3-methylbut-2-yl]-3-oxo-2-(1H-pyrazol-4-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-chlorophenyl)-N-[(2R)-3-hydroxy-3-methylbut-2-yl]-3-oxo-2-(1,2-thiazolyl-4-yl)-2,3-dihydropyridazine-4-carboxamide; N-[(2R)-3-hydroxy-3-methylbut-2-yl]-3-oxo-2-(1,2-thiazo-4-yl)-6-[4-(trifluoromethoxy)phenyl]-2,3-dihydropyridazine-4-carboxamide; N-[(cis)-2-hydroxy-2-methylcyclopentyl]-3-oxo-2-(pyridin-3-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-hydroxypropyl-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S)-3-hydroxy-3-methylbut-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-[4-(difluoromethoxy)phenyl]-N-[(2S,3S)-3-hydroxybut-2-yl]-3-oxo-2-(pyridin-3-yl)-2,3-dihydropyridazine-4-carboxamide; 6-(4-Chlorophenyl)-N-[(cis)-2-hydroxy-2-methylcyclopentyl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide; 2-(5-Fluoropyridin-3-yl)-N-[(2S)-1-hydroxy-3-methylbut-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; 2-(5-Fluoropyridin-3-yl)-N-[(1S,2R)-2-hydroxycyclopentyl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; N-[(1S)-1-cyclopropyl-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-methylbut-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; N-[(1S)-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-methylbut-2-yl]-3-oxo-6-[6-(trifluoromethyl)pyridin-3-yl]-2,3-dihydropyridazine-4-carboxamide; 1,5-Dehydr-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-erythritol; 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-hydroxypropyl-2-yl]-3-oxo-2-(pyridin-3-yl)-6-[5-(trifluoromethyl)pyridin-2-yl]-2,3-dihydropyridazine-4-carboxamide.

4. The use according to claim 1, wherein the compound of general formula (I) is 6-(4-chlorophenyl)-N-(1-hydroxypropyl-2-yl)-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

5. The use according to claim 1, wherein the compound of general formula (I) is 6-(4-chlorophenyl)-N-[(2S)-1-hydroxypropyl-2-yl]-2-(1-methyl-1H-pyrazol-4-yl)-3-oxo-2,3-dihydropyridazine-4-carboxamide.

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