EA037978B1 - 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamides for the treatment of cancer - Google Patents

Abstract

The invention covers 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamide compounds of general formula (I)in which X, R1, R2, R3, R4 and R5 are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of cancer or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, as a sole agent or in combination with other active ingredients.

Description

The invention encompasses 2-heteroaryl-3-oxo-2,3-dihydropyridazine-4-carboxamide compounds of general formula (I) as described and defined in this application, methods for the preparation of these compounds, intermediates suitable for the preparation of these compounds, pharmaceutical compositions and combinations containing said compounds and the use of said compounds for the production of pharmaceutical compositions for the treatment or prevention of diseases, in particular cancer or conditions with dysregulated immune responses, alone or in combination with other active ingredients.

Background of the invention

AHR (Aryl Hydrocarbon Receptor) is a ligand-activated transcription factor belonging to the main helix-loop-helix / Per-Arnt-Sim (bHLH / PAS) family and is present in the cytosol. After ligand binding, AHR is translocated into the nucleus, where it heterodimerizes with ARNT (AHR nuclear translocator), after which it interacts with DRE (dioxin response elements) of AHR-sensitive genes to regulate their transcription. AHR is the most well-known receptor responsible for binding to environmental toxins and inducing metabolic mechanisms such as cytochrome P 450 enzymes (e.g. CYP1A1, CYP1A2 and CYP1B1) required for their elimination (Reyes et al., Science, 1992, 256 (5060): 1193-5). The activation of AHR by xenobiotics has demonstrated its role in numerous cellular processes such as embryogenesis, tumorigenesis, and inflammation.

AHR is expressed in many cells of the immune system, including dendritic cells (DC), macrophages, T cells, and NK cells, and plays an important role in immunoregulation (Nguyen et al., Front Immunol., 2014, 5: 551). Classic exogenous AHR ligands such as TCDD and 3-methylcholanthrene are known to induce profound 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 generation of regulatory T cells, inhibits Th1 and Th17 differentiation, directly and indirectly, and decreases 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 modulates the innate immune response and constitutive expression of AHR has been shown to negatively regulate the type-I interferon response to viral infection (Yamada et al., Nat. Immunol., 2016). In addition, tumors spontaneously develop in mice with constitutively active AHR (Andersson et al., PNAS, 2002, 99 (15): 9990-5).

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

The immunosuppressive properties of kynurenine and the pathways for the degradation of tryptophan are well described, and their relationship with immunosuppression associated with malignant neoplasms has been established. The enzymes indolamine 2,3-dioxygenase 1 and 2 (IDO1 / IDO2), as well as tryptophan-2,3-dioxygenase 2 (TDO2), are responsible for catalysis of the first and rate-limiting step of tryptophan metabolism. IDO1 / 2-mediated tryptophan degradation in tumors and tumor-draining lymph nodes reduces antitumor immune responses, and inhibition of IDO may suppress 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).

TDO2 is also highly expressed in cancer and may lead to the production of the immunosuppressive kynurenine. In glioma, the process of AHR activation by kynurenin, downstream of TDO-mediated tryptophan degradation, enhances tumor growth by inhibiting antitumor immune responses, and also directly promotes survival and motility of tumor cells (Opitz et al., Nature, 2011, 478 (7368): 197 -203). Therefore, the AHR ligands generated by tumor cells act on tumor cells and lymphocytes in both an autocrine and paracrine manner, respectively, stimulating tumor growth.

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

State of the art

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

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

WO 2007/058392 relates to novel heterocyclic compounds and their pharmaceutical

- 1 037978 applications. In particular, WO 2007/058392 relates, inter alia, to heterocyclic compounds having hepatitis C virus infection inhibitory activity in cells.

WO 2002/022587 relates to novel compounds showing inhibitory activity against the AMPA receptor and / or the kainate receptor. In particular, WO 2002/022587 relates, inter alia, to pyridazinone and triazinone compounds.

US 5418233 relates to heterobiaryl derivatives that inhibit cell aggregation and cell-matrix interactions. In particular, US Pat. No. 5,418,233 relates to heterobiarl derivatives that are histamine receptor antagonists.

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

WO 2009/142732 relates to substituted pyridazinone derivatives and their use as H ₃ antagonists / inverse agonists.

However, the current state of the art does not describe the 2-heteroaryl-3-oxo-2,3-dihydropyridazine 4-carboxamide compounds of the general formula (I) of the present invention as described and defined in this application.

It has been found, and this forms the basis of the present invention, that the compounds of the present invention have unexpected and beneficial properties.

In particular, it has surprisingly been found that the compounds of the present invention effectively inhibit AHR, as reported in the Biological Experimental Section, and therefore can be used to treat or prevent cancer or other conditions where exogenous and endogenous AHR ligands induce dysregulated immune responses, uncontrolled cell growth, proliferation and / or survival of tumor cells, immunosuppression in the context of cancer, inappropriate cellular immune responses or inappropriate cellular inflammatory responses, or diseases that are accompanied by uncontrolled cell growth, proliferation and / or survival of tumor cells, immunosuppression in the context malignant neoplasm, inadequate cellular immune responses or inappropriate cellular inflammatory responses, in particular, where uncontrolled cell growth, proliferation and / or survival of tumor cells, and mmunosuppression in the context of malignant neoplasm, inappropriate cellular immune responses or inappropriate cellular inflammatory responses mediated by AHR, such as tumors of fluid tissues and solid tumors, and / or their metastases, such as head and neck tumors, including brain tumors and brain metastases , chest tumors, including non-small 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, urological tumors, including kidney tumors, bladder and prostate, skin tumors and sarcomas and / or their metastases.

Description of the invention

According to a first aspect, the invention encompasses compounds of general formula (I)

R ⁵

I

in which R ¹ is C2-C6 hydroxyalkyl, wherein said C2-C6 hydroxyalkyl groups are optionally substituted once with cyano, —COOR ¹⁰ , —CONR ¹¹ R ¹² , C1-C4 alkoxy or C ₃ -C ₆ cycloalkyl, and optionally 1-3 times with halogen, or

C ₃ -C ₆ cycloalkyl substituted once with hydroxy and optionally once with C ₁ -C ₃ alkyl and / or 13 times with halogen, or

C ₃ -C ₆ -cycloalkyl-C ₁ -C ₃ -alkyl substituted once with hydroxy and optionally once with C1-C3 alkyl and / or 1-3 times with halogen, or (C ₃ -C ₆ -cycloalkyl) ₂ -C ₁ -C ₃ -alkyl substituted once with hydroxy and optionally once with C1-C3 alkyl and / or 1-3 times with halogen, or

4-6 membered heterocycloalkyl substituted once with hydroxy and optionally once with C1-C3 alkyl and / or 1-3 times with halogen;

R ² is chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R ³ is hydrogen, fluorine, chlorine or methyl;

R ⁴ is hydrogen or fluorine;

R ⁵ is monocyclic heteroaryl, which is optionally substituted 1 to 3 times, independently of one another, with R ⁶ ;

- 2 037978

R ⁶ represents a _C1-C4 alkyl, _C1-C4 haloalkyl, _C3-C6 cycloalkyl, _C1-C4 alkoxy, halo or cyano;

X is CH or N;

R ¹⁰ represents a _C1-C4 alkyl;

R ¹¹ and R ¹² are the same or different and are, independently of one another, hydrogen or C1-C3 alkyl, or together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic ring, wherein said ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C1-C4 alkyl group;

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.

In addition, the invention encompasses their use in combination with other anti-cancer drugs such as immunotherapeutic agents, targeted anti-cancer agents or chemotherapeutic agents.

Definitions.

The term “substituted” means that one or more hydrogen atoms on the indicated atom or group are replaced by substituents selected from the indicated group, provided that the normal valence of the indicated atom is not exceeded under existing circumstances. Combinations of substituents and / or variables are allowed.

The term optionally substituted means that the number of substituents may be zero or different. Unless otherwise indicated, it is possible for the optionally substituted groups to be substituted with a number of optional substituents that can be substituted by replacing each hydrogen with a non-hydrogen substituent on any available carbon atom. Typically, the number of optional substituents, when present, may be 1, 2, or 3.

The term containing, when used in the description, includes consisting of.

If within the framework of this application in any part is indicated as mentioned in this application, this means that the specified can be mentioned anywhere in this application.

The terms mentioned in this text have the following meanings.

The term halogen means fluorine, chlorine, bromine or iodine, in particular a fluorine, chlorine or bromine atom.

The term C ₁ -C ₆ -alkyl means a linear or branched, saturated, monovalent hydrocarbon group containing 2, 3, 4, 5 or 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert -butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neo-pentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3methylpentyl, 4-methylpentyl , 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl or 1,3dimethylbutyl group or its isomer. In particular, said group comprises 1, 2, 3 or 4 carbon atoms _(C1-C4 alkyl), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl group, especially 1, 2 or 3 carbon atoms (C ₁ -C ₃ -alkyl), such as a methyl, ethyl, n-propyl or isopropyl group.

The term C ₁ -C ₆ -halogenoalkyl means a linear or branched, saturated, monovalent hydrocarbon group, where the term C ₁ -C ₆ -alkyl has the meaning indicated above, and where one or more hydrogen atoms are replaced, equally or differently, with a halogen atom ... In particular, said halogen atom is a fluorine atom. Said C ₁ -C ₆ -halogenoalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl or 1,3 -difluoropropan-2-yl. In particular, said group contains 1, 2, 3 or 4 carbon atoms (C ₁ -C ₄ -haloalkyl), in particular 1, 2 or 3 carbon atoms (C ₁ -C ₃ haloalkyl), for example a fluoromethyl, difluoromethyl or trifluoromethyl group ...

The term C ₂ -C ₆ -hydroxyalkyl means a linear or branched, saturated, monovalent hydrocarbon group, where the term C ₂ -C ₆ -alkyl has the meaning indicated above, and where 1 or 2 hydrogen atoms are replaced by a hydroxy group, for example 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl, 1-hydroxypropan-2-yl, 2-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropyl-2-yl, 3-hydroxy-2-methylpropyl, 2-hydroxy-2-methylpropyl, 1-hydroxy-2-methylpropyl group.

The term C1-C4-alkoxy means a linear or branched, saturated, monovalent group of the formula (C1-C4-alkyl) -O-, which means methoxy, ethoxy, n-propoxy, isopropoxy, nbutoxy, sec-butoxy, isobutoxy or tert-butoxy ...

The term C ₃ -C ₆ -cycloalkyl means a saturated, monovalent, monocyclic hydrocarbon ring that contains 3, 4, 5 or 6 carbon atoms (C ₃ -C ₆ -cycloalkyl). Said C ₃ -C ₆ cycloalkyl group is a monocyclic hydrocarbon ring such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

- 3 037978

The term C ₂ -C ₇ -alkylene means a linear or branched, saturated, divalent hydrocarbon group, where the term C ₂ -C ₇ -alkyl is as defined above, and where 2 hydrogen atoms from different carbon atoms are removed to form a diradical group.

The term 4-6 membered heterocycloalkyl means a monocyclic, saturated heterocycle with a total of 4, 5 or 6 ring atoms, which contains one or two identical or different ring heteroatoms from the series N and O, and the specified heterocycloalkyl group can be attached to the rest of the molecule through any of the carbon atoms or, if present, a nitrogen atom.

Said heterocycloalkyl group, without limitation listed, may be a 4-membered ring such as azetidinyl or oxetanyl; or a 5-membered ring such as, for example, tetrahydrofuranyl, 1,3-dioxolanyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, 1,2-oxazolidinyl, or 1,3-oxazolidinyl; or a 6-membered ring such as, for example, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, 1,3-dioxanyl, 1,4-dioxanyl, or 1,2-oxazinanyl.

In particular, 4-6 membered heterocycloalkyl means 4-6 membered heterocycloalkyl, as defined above, containing one ring oxygen atom and optionally one additional ring heteroatom from the series: N, O. In particular, 5- or 6-membered heterocycloalkyl means monocyclic, saturated heterocycle with a total of 5 or 6 ring atoms, containing one ring oxygen atom.

The term monocyclic heteroaryl means a monovalent, aromatic ring that contains 5 or 6 ring atoms (5- or 6-membered heteroaryl group), and which contains at least one ring heteroatom and optionally one or two additional ring heteroatoms from the series: N , O and / or S, and which is attached via a ring carbon atom or optionally via a ring nitrogen atom (if valency allows).

Said heteroaryl group may be a 5-membered heteroaryl group such as, for example, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, or tetrazolyl; or a 6-membered heteroaryl group such as, for example, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

In general, and unless otherwise indicated, heteroaryl or heteroarylene groups include all their possible isomeric forms, for example tautomers and positional isomers relative to the site of attachment to the rest of the molecule. Thus, for purposes of separate illustrative, non-limiting examples, the term pyridinyl includes pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl; or the term thienyl includes thien-2-yl and thien-3-yl.

Where the plural form is used in the present application for a compound, salt, polymorph, hydrate, solvate, and the like, this also includes a single compound, salt, polymorph, isomer, hydrate, solvate, or the like.

By a stable compound or a stable structure is meant a compound that is stable enough to withstand isolation to a suitable degree of purity from the reaction mixture and the preparation of an effective therapeutic agent therefrom.

The compounds of the present invention optionally contain one or more asymmetric centers, depending on the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) - or (S) configuration, which can lead to racemic mixtures in the case of one asymmetric center and diastereomeric mixtures in the case of several asymmetric centers. In some cases, it is possible that asymmetry is also present due to limited rotation about a given bond, for example a central bond adjacent to two substituted aromatic rings of the specified compounds.

Preferred compounds are those that produce the more desirable biological activity. Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention. Purification and separation of such materials can be accomplished using standard techniques known in the art.

Preferred isomers are those that produce the more desirable biological activity. These isolated, pure or partially purified isomers or racemic mixtures of the compounds of this invention are also included within the scope of the present invention. Purification and separation of such materials can be accomplished using standard techniques known in the art.

Optical isomers can be obtained by resolving racemic mixtures according to conventional methods, for example, by forming diastereoisomeric salts using an optically active acid or base, or by forming covalent diastereomers. Examples of suitable acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acids. Mixtures of diastereoisomers can be separated into their individual diastereomers based on their physical and / or chemical differences using methods known in the art, for example, by chromatography or fractional crystallization. The optically active bases or acids are then liberated from the separated diastereomeric salts. Another way to separate optical isomers

- 4 037978 includes the use of chiral chromatography (eg HPLC columns using a chiral phase), with or without conventional derivatization optimally selected for maximum separation of enantiomers. Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, for example Chiracel OD and Chiracel OJ, among many others generally chosen. Enzymatic separation methods, with or without derivatization, are also suitable. The optically active compounds of the invention can also be prepared by chiral synthesis using optically active starting materials.

In order to differentiate the different types of isomers from each other, reference is made to the IUPAC rules, section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of the compounds of the present invention as individual stereoisomers, or as any mixture of said stereoisomers, for example (R) - or (S) -isomers, in any ratio. Isolation of a single stereoisomer, for example a single enantiomer or a single diastereomer, of the compounds of the present invention is achieved by any suitable method of the prior art, such as, for example, chromatography, in particular chiral chromatography.

In addition, the compounds of the present invention may exist as N-oxides, which are determined by the fact that at least one nitrogen atom of the compounds of the present invention is oxidized. The present invention includes all such possible N-oxides.

The present invention also encompasses suitable forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and / or co-precipitation products.

The compounds of the present invention can exist as a hydrate or as a solvate, where the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol, for example, as a structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to be in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, for example hydrates, hemi- (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc. are possible. solvates or hydrates, respectively. The present invention includes all such hydrates or solvates.

In addition, it is possible for the compounds of the present invention to exist in free form, for example as a free base or as a free acid, or as a zwitterion, or exist in the form of a salt. Said salt can be any salt, either an organic or inorganic addition salt, in particular any pharmaceutically acceptable organic or inorganic addition salt, which is commonly used in the pharmaceutical industry, or which is used, for example, for the isolation or purification of the compounds of the present invention.

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

A suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid addition salt of a compound of the present invention bearing a nitrogen atom, for example, in a chain or in a ring, which is sufficiently basic, such as an inorganic acid addition salt or a mineral acid, such as, for example, hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bead, phosphoric or nitric acid, or with an organic acid such as, for example, formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic undecane, lauric, benzoic, salicylic, 2- (4-hydroxybenzoyl) benzoic, camphor, cinnamic, cyclopentane propionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic, pamoic, pectin, 3-phenylpropionic, itanes, 2-pivalylpropionic , trifluoromethanesulfonic, dodecyl sulfuric, ethanesulfonic, benzenesulfonic, steam a-toluenesulfonic, methanesulfonic, 2-naphthalenesulfonic, naphthalenedisulfonic, camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, alginic, maleic, fumaricorbic, mindelucone , aspartic, sulfosalicylic or thiocyanic acid.

In addition, another suitable pharmaceutically acceptable salt of a compound of the present invention that is sufficiently acidic is an alkali metal salt such as sodium or potassium salt, an alkaline earth metal salt such as calcium, magnesium or strontium salt, or aluminum or zinc salt , or an ammonium salt derived from ammonia or from an organic primary, secondary or tertiary amine containing from 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanolamine hydroxymethyl) aminomethane, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methylglucamine, N, N-dimethylglucamine, N-ethylglucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or the even-5 037978 salt of a vertical ammonium ion containing about t 1 to 20 carbon atoms, such as tetramethylammonium, tetraethylammonium, tetra (n-propyl) ammonium, tetra (n-butyl) ammonium, N-benzyl-N, N, N-trimethylammonium, choline or benzalkonium.

Those of skill in the art will also recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with a suitable inorganic or organic acid using any of a number of known methods. Alternatively, the acidic alkali and alkaline earth metal salts of the present invention are prepared by reacting the compounds of the invention with a suitable base using a variety of known methods.

The present invention includes all possible salts of the compounds of the present invention as separate salts or as any mixture of these salts in any ratio.

In the present text, in particular in the experimental section, in the case of describing the synthesis of intermediates and compounds - examples of the present invention, when the compound is mentioned in the form of a salt with the corresponding base (s) or acid, the exact stoichiometric composition of said salt form obtained using the corresponding method obtaining and / or purifying, in most cases not disclosed, i. e. is unknown.

Unless otherwise indicated, suffixes (or prefixes) in chemical names or structural formulas referring to salts, such as, for example, hydrochloride, trifluoroacetate, sodium salt, or x HCl, x CF3COOH, x Na ⁺ , denote a salt form whose stoichiometry not installed.

This applies analogously to cases in which the synthesis intermediates or the examples compounds or their salts were obtained using the described preparation and / or purification methods, in the form of solvates such as hydrates, with (if of a certain type) an unknown stoichiometric composition.

In addition, the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as a single polymorph or as a mixture of more than one polymorph, in any ratio.

Moreover, the present invention also includes prodrugs of the compounds according to the invention. The term prodrug in this application refers to compounds that may themselves be biologically active or inactive, but are converted (eg, metabolically or hydrolytically) into compounds in accordance with the invention during their stay in the body.

In addition, the present invention includes all possible crystalline and polymorphic forms of the compounds of the present invention, and the polymorphs exist either as a single polymorphic form or as a mixture of several polymorphs at any concentration.

According to a second embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ¹ is C2-C6 hydroxyalkyl, wherein said C2-C6 hydroxyalkyl groups are optionally substituted once with cyano, —COOR ¹⁰ , —CONR11R ¹² , C1-C4 alkoxy or C ₃ -C ₆ cycloalkyl and optionally 1-3 times with halogen, or

C ₃ -C ₆ -cycloalkyl substituted once with hydroxy and optionally 1 to 3 times with halogen, or

C ₃ -C ₆ -cycloalkyl-C ₁ -C ₃ -alkyl substituted once with hydroxy and optionally 1 to 3 times with halogen, or (C ₃ -C ₆ -cycloalkyl) ₂ -C ₁ -C ₃ -alkyl substituted with one times hydroxy and optionally 1-3 times halogen, or

4-6 membered heterocycloalkyl substituted once with hydroxy and optionally 1-3 times with halogen;

R ² is chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R ³ is hydrogen, fluorine, chlorine or methyl;

R ⁴ is hydrogen or fluorine;

R ⁵ is monocyclic heteroaryl, which is optionally substituted 1 to 3 times, independently of one another, with R ⁶ ;

R ⁶ represents a C ₁ -C ₄ -alkyl, C 1 C ₄ haloalkyl, C ₃ -C ₆ -cycloalkyl, C 1 C ₄ -alkoxy, halogen or cyano;

X is CH or N;

R ¹⁰ represents a _C1-C4 alkyl;

R ¹¹ and R ¹² are the same or different and are, independently of one another, hydrogen or C1-C3 alkyl, or together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic ring, wherein said ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C1-C4 alkyl group;

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.

According to a third embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which:

R ¹ is C2-C6 hydroxyalkyl, wherein said C2-C6 hydroxyalkyl groups are optionally substituted once with cyano, —COOR ¹⁰ , —CONR ¹¹ R ¹² , C1-C4 alkoxy or C ₃ -C ₆ cycloalkyl and optionally 1 -3 times halogen, or

C ₃ -C ₆ cycloalkyl substituted once with hydroxy and optionally once with C ₁ -C ₃ alkyl and / or 13 times with halogen, or

C ₃ -C ₆ -cycloalkyl-C ₁ -C ₃ -alkyl substituted once with hydroxy and optionally once with C1-C3 alkyl and / or 1-3 times with halogen, or (C ₃ -C ₆ -cycloalkyl) ₂ -C ₁ -C ₃ -alkyl substituted once with hydroxy and optionally once with C1-C3 alkyl and / or 1-3 times with halogen, or

4-6 membered heterocycloalkyl substituted once with hydroxy and optionally once with C1-C3 alkyl and / or 1-3 times with halogen;

R ² is chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R ³ is hydrogen, fluorine, chlorine or methyl;

R ⁴ is hydrogen or fluorine;

R ⁵ is monocyclic heteroaryl, which is optionally substituted 1 to 3 times, independently of one another, with R ⁶ ;

R ⁶ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloalkyl, _{C 1 -C 4} alkoxy, halogen or cyano;

X is CH or N;

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.

According to a fourth embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ¹ is C ₂ -C ₅ hydroxyalkyl, wherein said C ₂ -C ₅ hydroxyalkyl groups are optionally substituted once with cyano, —COOCH3, —CONH2, methoxy or cyclopropyl and optionally 1-3 times with fluorine, or

C ₄ -C ₆ -cycloalkyl substituted once with hydroxy and optionally once with methyl and / or 1-2 times with fluorine, or

C ₃ -C ₄ -cycloalkylmethyl substituted once with hydroxy, or 5- or 6-membered heterocycloalkyl substituted once with hydroxy, wherein said heterocycloalkyl contains one oxygen atom;

R ² is chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R ³ is hydrogen or fluorine;

R ⁴ is hydrogen or fluorine;

R ⁵ is monocyclic heteroaryl, which is optionally substituted 1 to 3 times, independently of one another, with R ⁶ ;

R ⁶ is methyl, difluoromethyl, methoxy, halogen, or cyano;

X is CH or N;

R ¹⁰ represents a _C1-C4 alkyl;

R ¹¹ and R ¹² are the same or different and are, independently of one another, hydrogen or C1-C3 alkyl, or together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic ring, wherein said ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C1-C4 alkyl group;

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.

According to a fifth embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ¹ is C ₂ -C ₅ hydroxyalkyl, wherein said C ₂ -C ₅ hydroxyalkyl groups are optionally substituted once with cyano, —COOCH ₃ , —CONH ₂ , methoxy or cyclopropyl and optionally 1-3 times with fluorine, or

C ₄ -C ₆ -cycloalkyl substituted once with hydroxy and optionally once with methyl and / or 1-2 times with fluorine, or

C ₃ -C ₄ -cycloalkylmethyl substituted once with hydroxy, or 5- or 6-membered heterocycloalkyl substituted once with hydroxy, wherein said heterocycloalkyl contains one oxygen atom;

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

R ³ is hydrogen;

R ⁴ is hydrogen or fluorine;

R ⁵ represents a group selected from

- 7 037978

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ^6a represents hydrogen, methyl, fluorine or chlorine;

X is CH or N;

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.

According to a sixth embodiment of the first aspect, the present invention encompasses compounds of the general formula (Ia)

CH ₃

R

R

... ₉ R ⁸

R (b) in which R ² is chlorine, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy;

R ⁷ is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethyl, isopropyl, cyclopropyl, cyano, —COOCH3, or —CONH2;

R ⁸ is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, or methoxymethyl, where one of R ⁷ and R ^{8 is} not hydrogen, or

R ⁷ and R ⁸ together form a cyclopentyl or cyclohexyl ring, which is optionally substituted 1-2 times with fluorine, or a heterocycloalkyl ring which contains one oxygen atom;

R ⁹ is hydrogen or methyl, or

R ⁸ and R ⁹ together form a cyclopropyl or cyclobutyl ring;

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.

According to a seventh embodiment of the first aspect, the present invention encompasses compounds of general formula (Ib)

in which R ² represents chlorine, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluorome-8 037978 thyl, difluoromethoxy or trifluoromethoxy;

R ⁵ represents a group selected from

where * denotes the point of attachment of the specified group to the rest of the molecule;

R ^6a represents hydrogen, methyl, fluorine or chlorine;

R ⁷ is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, methoxymethyl, ethyl, isopropyl, or cyclopropyl;

R ⁸ is hydrogen, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, hydroxymethyl, or methoxymethyl, where one of R ⁷ and R ^{8 is} not hydrogen, or

R ⁷ and R ⁸ together form a cyclopentyl or cyclohexyl ring which is optionally substituted 1-2 times with fluorine, or a heterocycloalkyl ring which contains one oxygen or sulfur atom;

R ⁹ is hydrogen or methyl, or

R ⁸ and R ⁹ together form a cyclopropyl or cyclobutyl ring;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ¹ is C2-C6 hydroxyalkyl, wherein said C2-C6 hydroxyalkyl groups are optionally substituted once with cyano, —COOR ¹⁰ , —CONR ¹¹ R ¹² , C1-C4 alkoxy or C3-C ₆ cycloalkyl and optionally 1- 3 times with halogen, or

C ₃ -C ₆ cycloalkyl substituted once with hydroxy and optionally once with C ₁ -C ₃ alkyl and / or 13 times with halogen, or

C ₃ -C ₆ -cycloalkyl-C ₁ -C ₃ -alkyl substituted once with hydroxy and optionally once with C ₁ -C ₃ alkyl and / or 1-3 times with halogen, or (C ₃ -C ₆ -cycloalkyl) ₂ -C ₁ -C ₃ -alkyl substituted once with hydroxy and optionally once with C1-C3 alkyl and / or 1-3 times with halogen, or

4-6 membered heterocycloalkyl substituted once with hydroxy and optionally once with C1-C3 alkyl and / or 1-3 times with halogen;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ¹ is C ₂ -C ₅ hydroxyalkyl, wherein said C ₂ -C ₅ hydroxyalkyl groups are optionally substituted once with cyano, —COOCH3, —CONH2, methoxy or cyclopropyl and optionally 1-3 times with fluorine, or

C ₄ -C ₆ -cycloalkyl substituted once with hydroxy and optionally once with methyl and / or 1-2 times with fluorine, or

C ₃ -C ₄ -cycloalkylmethyl substituted once with hydroxy, or 5- or 6-membered heterocycloalkyl substituted once with hydroxy, wherein said heterocycloalkyl contains one oxygen atom;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ¹ is C2-C6 hydroxyalkyl, wherein said C2-C6 hydroxyalkyl groups are optionally substituted once with cyano, —COOR ¹⁰ , —CONR11R ¹² , C1-C4 alkoxy or C ₃ -C ₆ cycloalkyl and optionally 1-3 times with halogen, or

C ₃ -C ₆ -cycloalkyl substituted once with hydroxy and optionally 1 to 3 times with halogen, or

C ₃ -C ₆ -cycloalkyl-C ₁ -C ₃ -alkyl substituted once with hydroxy and optionally 1 to 3 times with halogen, or (C ₃ -C ₆ -cycloalkyl) ₂ -C ₁ -C ₃ -alkyl substituted with one times hydroxy and optionally 1-3 times halogen, or

4-6 membered heterocycloalkyl substituted once with hydroxy and optionally 1-3 times with halogen;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

- 9 037978

R ¹ represents a _C2-C6 hydroxyalkyl, wherein said _C2-C6 -gidroksialkilnye group optionally substituted once C1-C ₄ -alkoxy or C ₃ -C ₆ -cycloalkyl and optionally 1-3 times with halogen, or

C ₃ -C ₆ -cycloalkyl substituted once with hydroxy and optionally once with methyl and / or 1-3 times with halogen, or

C ₃ -C ₆ -cycloalkyl-C ₁ -C ₃ -alkyl substituted once with hydroxy and optionally 1 to 3 times with halogen, or (C ₃ -C ₆ -cycloalkyl) ₂ -C ₁ -C ₃ -alkyl substituted with one times hydroxy and optionally 1-3 times halogen, or

4-6 membered heterocycloalkyl substituted once with hydroxy and optionally 1-3 times with halogen;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ¹ is C ₂ -C ₆ hydroxyalkyl, wherein said C ₂ -C ₆ hydroxyalkyl groups are optionally substituted once with C ₁ -C ₂ alkoxy or cyclopropyl and optionally 1 to 3 times with halogen, or

C ₄ -C ₆ -cycloalkyl substituted once with hydroxy and optionally once with methyl and / or 1-3 times with halogen, or

C ₃ -C ₆ -cycloalkylmethyl substituted once with hydroxy and optionally 1-3 times with halogen, or (C ₃ -C ₆ -cycloalkyl) ₂ -methyl substituted once with hydroxy and optionally 1-3 times with halogen, or

5- or 6-membered heterocycloalkyl substituted once with hydroxy and optionally 1 to 3 times with halogen;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ¹ is C ₂ -C ₅ hydroxyalkyl, wherein said C ₂ -C ₅ hydroxyalkyl groups are optionally substituted once with methoxy or cyclopropyl and optionally 1-3 times with fluorine, or

C ₄ -C ₆ -cycloalkyl substituted once with hydroxy and optionally once with methyl and / or 1-2 times with fluorine, or

C ₃ -C ₄ -cycloalkylmethyl substituted once with hydroxy, or 5- or 6-membered heterocycloalkyl substituted once with hydroxy, wherein said heterocycloalkyl contains one oxygen atom;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ¹ is C ₂ -C ₅ hydroxyalkyl, wherein said C ₂ -C ₅ hydroxyalkyl groups are optionally substituted once with methoxy or cyclopropyl and optionally 1-3 times with fluorine, or

C ₄ -C ₆ -cycloalkyl substituted once with hydroxy and optionally once with methyl or 1-2 times with fluorine, or

C ₃ -C ₄ -cycloalkylmethyl substituted once with hydroxy, or 5- or 6-membered heterocycloalkyl substituted once with hydroxy, wherein said heterocycloalkyl contains one oxygen atom;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ² is chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

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

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ³ is hydrogen, fluorine, chlorine or methyl;

their polymorphs, enantiomers, diastereomers, racemates, tautomers, N-oxides, hydrates and solvates,

- 10 037978 as well as their physiologically acceptable salts and solvates of these salts, as well as their mixtures.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ³ is hydrogen or fluorine;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ³ is hydrogen;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ⁴ is hydrogen or fluorine;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ⁴ is hydrogen;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ⁵ is monocyclic heteroaryl, which is optionally substituted 1 to 3 times, independently of one another, with R ⁶ ;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ⁵ represents a group selected from

where * denotes the point of attachment of the specified group to the rest of the molecule;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ⁵ represents a group selected from

CH ₃ CH ₃

where * denotes the point of attachment of the specified group to the rest of the molecule;

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.

- 11 037978

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ⁵ represents a group selected from

CH ₃ Ν-ΝΗ Ν — NS — N

where * denotes the point of attachment of the specified group to the rest of the molecule;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ⁵ represents a group selected from

where * denotes the point of attachment of the specified group to the rest of the molecule;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ⁶ represents a C ₁ -C ₄ -αlkil, C 1 C ₄ haloalkyl, C ₃ -C ₆ -cycloalkyl, C 1 C ₄ -alkoxy, halogen or cyano;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ⁶ is C ₁ -C ₄ alkyl, C ₃ -C ₆ cycloαalkyl, C1-C ₄ alkoxy, halogen or cyano;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ⁶ is methyl, methoxy, halogen or cyano;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ^6a represents hydrogen, methyl, fluorine or chlorine;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ¹⁰ represents a _C1-C4 alkyl;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ¹⁰ is methyl;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ¹¹ and R ¹² are the same or different and are, independently of one another, hydrogen or C1-C3-α-alkyl, or together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic ring, wherein said ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C1-C4 alkyl group;

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.

In accordance with yet another embodiment of the first aspect, the present invention coats compounds of general formula (I) as defined above, in which

R ¹¹ and R ¹² are the same or different and represent, independently of one another, hydrogen or C ₁ -C ₃ -alkyl, or together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic ring;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ¹¹ and R ¹² are the same or different and represent, independently of one another, hydrogen or C ₁ -C ₃ -alkyl;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

R ¹¹ and R ¹² are the same or different and represent, independently of one another, hydrogen or methyl;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

X is CH or N;

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.

In accordance with another embodiment of the first aspect, the present invention encompasses compounds of general formula (I) as defined above, in which

X is CH;

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.

In a separate additional embodiment of the first aspect, the present invention encompasses combinations of two or more of the aforementioned embodiments under the heading additional embodiments of the first aspect of the present invention.

The present invention encompasses any subcombination within any embodiment or aspect of the present invention, the compounds of general formula (I) as defined above.

The present invention encompasses any subcombination within any embodiment or aspect of the present invention of intermediates of general formula (VII). The present invention covers compounds of general formula (I), which are disclosed in the Examples section of this text below.

Compounds according to the invention of general formula (I) can be prepared according to the following Scheme 1. The scheme and procedures described below illustrate routes for synthesizing compounds of general formula (I) of the invention and are not intended to limit their scope. The person skilled in the art will understand that the order of transformations illustrated in Scheme 1 can be modified in various ways. Thus, the order of transformations illustrated in this diagram is not intended to limit the scope of the invention. In addition, the interconversion of any substituents R ¹ , R ² , R ³ , R ⁴ , R ⁵ or R ⁶ can be performed before and / or after the illustrated transformations. These modifications may be such as the introduction of protective groups, removal of protective groups, reduction or oxidation of functional groups, halogenation, metallation, metal catalyzed coupling reactions, substitution, or other reactions known to the person skilled in the art. Such transformations include those that introduce a functional group that allows further interconversion of substituents. Suitable protecting groups and methods for their introduction and cleavage are well known to the person skilled in the art. Specific examples are described in the following sections.

Scheme 1 shows a route for the preparation of compounds of general formula (I), in which R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ have the meanings given for general formula (I) above. Ketomalonates provided as intermediates according to formula (III) are rarely commercially available or can be synthesized from alpha-haloacetophenones (II) according to methods known to those skilled in the art. The related alpha-haloacetophenones are generally commercially available. The reaction of such alpha-haloacetophenones with malonic acid esters in the presence of a suitable base in a suitable solvent leads to the formation of non-commercial ketomalonates according to formula (III). R in formula (III), (V) and (VI) is a suitable alkyl group such as methyl, ethyl, propyl or other homologous groups. A suitable solvent can be, but are not limited to, acetonitrile, DMF, DMA, DMSO, or THF, or even mixtures of these or other solvents.

- 13 037978

A suitable base may be, but are not limited to, potassium carbonate, sodium hydride, cesium carbonate, or potassium hexamethylenedisilazane.

The preparation of dihydropyrazinones according to formula (V) from intermediates (III) and suitable aryl hydrazines (IV), which in many cases are commercially available, can be accomplished by reacting these components in a suitable solvent at elevated temperature. A suitable solvent can be, without ethanol or acetic acid.

Scheme 1 restrictions listed,

A route for the preparation of compounds of general formula (I), in which X, R ¹ , R ² , R ³ , R ⁴ , and

R ⁵ have the meanings given for the general formula ^) above and Hal represents halogen, and R represents a _C1-C4 alkyl.

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

The resulting pyridazinones according to formula (VI) with an ester functional group can be converted by methods known to a person skilled in the art, for example, by alkaline hydrolysis using, for example, aqueous solutions of alkali metal hydroxides, or by acid hydrolysis using, for example , hydrogen chloride in dioxane or trifluoroacetic acid, in pyridazinone carboxylic acids (VII).

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

- 14 037978

Scheme 2

A process for the preparation of compounds of general formula (I), where X, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings indicated for general formula (I), as indicated above, and Hal is halogen, R is is _C1-C4 alkyl and R 'and R''both represent H or _C1-C4 alkyl or together form a C ₂ -C ₇ alkylene group as part of the ester 1,2- or 1,3- diolboronic acid or a -CO-CH2- (NCH3) -CH2-CO- group.

Ketomalonates provided as intermediates according to formula (III) are rarely commercially available or can be synthesized from alphahalo-acetophenones (II) according to methods known to those skilled in the art. The related alpha-haloacetophenones are generally commercially available. The reaction of such alpha-haloacetophenones with malonic acid esters in the presence of a suitable base in a suitable solvent leads to the formation of non-commercial ketomalonates according to formula (III). R in formula (III), (IX), (X) and (VI) is a suitable alkyl group such as methyl, ethyl, propyl or other homologous groups. A suitable solvent can be, but are not limited to, acetonitrile, DMF, DMA, DMSO, or THF, or even mixtures of these or other solvents. A suitable base may be, but are not limited to, potassium carbonate, sodium hydride, cesium carbonate, or potassium hexamethylenedisilazane.

The preparation of dihydropyridazinones according to formula (IX) from intermediates (III) and hydrazine can be accomplished by reacting these components in a suitable solvent at elevated temperature. A suitable solvent can be, but are not limited to, ethanol or acetic acid.

Dihydropyridazinones according to formula (IX) can be converted to pyridazinones according to formula (X). This conversion can be accomplished by using suitable reagents. A suitable reagent can be, but is not limited to, copper dichloride at an elevated temperature.

Substituted pyridazinones according to formula (VI) can be prepared by Chan-Lam coupling reactions of pyridazinones according to formula (X) using boron derivatives such as boronic acids, pinacolates and boronic acid tetrafluoroborates with suitable solvents at room temperature or elevated temperatures. A suitable solvent can be, but are not limited to, acetonitrile, dichloromethane, pyridine, or DMF. A suitable catalyst can be, but is not limited to, copper (II) acetate. Suitable basic additives can be, but are not limited to, trimethylamine, 2,2-bipyridine, sodium carbonate or cesium carbonate.

The resulting pyridazinones according to formula (VI) with an ester functional group can be converted by methods known to a person skilled in the art, for example, by alkaline hydrolysis using, for example, aqueous solutions of alkaline hydroxides.

- 15 037978 metals, or by acid hydrolysis using, for example, hydrogen chloride in dioxane or trifluoroacetic acid, to pyridazinone carboxylic acids (VII).

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

Scheme 2 a

(Na) (Sha) (X)

A route for the preparation of intermediates of general formula (X), where X, R ¹ , R ² , R ³ and R ⁴ have the meanings indicated for general formula (I), as indicated above, and R is C ₁ -C ₄ -alkyl ...

Compounds of general formula (IIa) are commercially available and can be reacted with dialkyl ketomalonate, where R is C ₁ -C ₄ alkyl. Diethyl ketomalonate reagent is commercially available. Dialkyl ketomalonates can be prepared from the corresponding dialkyl malonates with tosylazide and dioxirane (see, for example, Synth. Commun. 1994, 24, 695) or bromine and potassium acetate (see, for example: J. Org. Chem. 1981, 46, 2598) ... Acetophenones of general formula (IIa) and dialkyl ketomalonates are heated in pure form at 95-100 ° C or with a solvent, for example pyridine, under reflux at 120 ° C. The intermediates of formula (IIIa) are then reacted with hydrazine hydrate in acetic acid under reflux or with hydrazinium dihydrochloride in ethanol under reflux to provide intermediates (X).

Scheme 3

(Xi)

(XII) (I)

An additional method for preparing compounds of general formula (I), where X, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings indicated for general formula (I), as indicated above, and R is C ₁ -C ₄ -alkyl, and R 'and R are simultaneously H or C1-C ₄ -alkyl or together form a C ₂ -C ₇ alkylene group as part of a 1,2- or 1,3-diolboronic acid ester or a -CO group -CH ₂ - (NCH ₃ ) -CH ₂ CO-.

Methyl 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylate [CAS 89581-64-6] is commercially available. Reaction of methyl 6-chloro-3-oxo-2,3-dihydropyridazine-4-carboxylate with organoboronic derivatives (boronic acids, boronic acid pinacolates, MIDA-boronates, organotrifluoroborate salts) in the presence of a suitable palladium (0) catalyst, a suitable base and in a suitable solvent at room temperature or at elevated temperatures leads to the formation of 6-aryl-substituted 3-oxo-2,3-dihydropyridazine-4-carboxylic acids of formula (XI). Suitable organoboron derivatives are commercially available or can be synthesized from organohalides. Methods for such syntheses are known to those skilled in the art. A suitable catalyst can be, but are not limited to, palladium phosphine complexes such as Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , or palladium catalysts, which

- 16 037978 can be obtained in situ from precursors such as Pd (OAc) 2 or Pd ₂ (dba) ₃ -CHCl ₃ , with appropriate amounts of phosphines or palladacyclic catalysts, such as the 2nd generation RuPhos pre-catalyst, chlorine (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1,1'-biphenyl) [2 (2'-amino-1,1'-biphenyl)] palladium (II), RuPhos-Pd-G2. A suitable base can be, but are not limited to, potassium phosphate, potassium carbonate, potassium t-butoxide, cesium carbonate, and triethylamine. A suitable solvent can be, but are not limited to, dioxane, toluene, TG F and dimethylformamide, or even mixtures of these or other solvents.

3-Oxo-2,3-dihydropyridazine-4-carboxylic acids (XI) can be converted to amides (XII) by coupling with amines of formula (VIII). Coupling agents and methods for such syntheses of carboxamides from carboxylic acids and amines are known to the person skilled in the art. Examples that may be mentioned in this case include the use of HATU, HBTU, PyBOB or T3P with the addition of a suitable base. The conversion of carboxylic acids to their amides is described in general terms in reference books.

Substituted pyridazinones according to formula (I) can be prepared by Chan-Lam coupling reactions using boronic acid derivatives (boronic acids, boronic acid pinacolates, MIDA-boronates and organotrifluoroborate salts) in suitable solvents at room temperature or at elevated temperatures. A suitable solvent can be, but are not limited to, acetonitrile, dichloromethane, pyridine, and DMF. A suitable catalyst can be, but is not limited to, copper (II) acetate. Suitable basic additives can be, but are not limited to, trimethylamine, 2,2-bipyridine, sodium carbonate or cesium carbonate.

Scheme 4

An additional method for the preparation of compounds of general formula (I) where X, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings indicated for general formula (I), as indicated above, and R is C1-C ₄ - alkyl, and R 'and R simultaneously represent H or _C1-C4 alkyl or together form a C ₂ -C ₇ alkylene group as part of the ester 1,2- or 1,3-diolboronovoy acid group or -CO-CH2 - (NCH ₃ ) -CH2CO-.

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

6-Chloro-3-oxo-2,3-dihydropyridazine-4-carboxamides (XIII) can be converted using organoboron derivatives (boronic acids, boronic acid pinacolates, MIDA-boronates, organotrifluoroborate salts) in the presence of a suitable palladium (0) catalyst, a suitable base and in a suitable solvent at room temperature or at elevated temperatures, into the 6aryl-substituted 3-oxo-2,3-dihydropyridazine-4-carboxamides of formula (XII). Suitable organoboron derivatives are commercially available or can be synthesized from organohalides. Methods for such syntheses are known to those skilled in the art. A suitable catalyst can be, but are not limited to, palladium-phosphine complexes such as Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ or palladium catalysts, which can be prepared in situ from precursors such as Pd (OAc) ₂ or Pd ₂ (dba) ₃ -CHCl ₃ , with appropriate amounts of phosphines or palladacyclic catalysts such as the 2nd generation RuPhos precatalyst, chlorine (2-dicyclohexylphosphino-2 ', 6'-diisopropoxy-1, 1'-biphenyl) [2- (2'-amino-1,1'-bife-17 037978 nyl)] palladium (II), RuPhos-Pd-G2. A suitable base can be, but are not limited to, potassium phosphate, potassium carbonate, potassium t-butoxide, cesium carbonate, and triethylamine. A suitable solvent can be, but are not limited to, dioxane, toluene, THF and dimethylformamide, or even mixtures of these or other solvents.

Substituted pyridazinones according to formula (I) can be obtained by the Chan-Lam coupling reactions of 6-aryl-substituted 3-oxo-2,3-dihydropyridazine-4-carboxamides according to formula (XII) using boronic acid derivatives ( boronic acids, boronic acid pinacolates, MIDA-boronates and organotrifluoroborate salts) with suitable solvents at room temperature or at elevated temperatures. A suitable solvent can be, but are not limited to, acetonitrile, dichloromethane, pyridine, and DMF. A suitable catalyst can be, but is not limited to, copper (II) acetate. Suitable basic additives can be, but are not limited to, trimethylamine, 2,2-bipyridine, sodium carbonate or cesium carbonate.

These compounds are either commercially available or can be prepared according to open source techniques as understood by one of ordinary skill in the art. Typical examples are described in the experimental section.

According to a second aspect, the present invention encompasses processes for the preparation of compounds of general formula (I) as defined above, which comprise the step of reacting an intermediate of general formula (VII)

R ⁵ I

in which R ² is chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R ³ is hydrogen, fluorine, chlorine or methyl;

R ⁴ is hydrogen or fluorine;

R ⁵ is monocyclic heteroaryl, which is optionally substituted 1 to 3 times, independently of one another, with R ⁶ ;

R ⁶ is _{C 1} -C ₄ alkyl, C _{1 -C 4} haloalkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₄ alkoxy, halogen or cyano;

X is CH or N;

with a compound of general formula (VIII)

H2N-R ¹ (VIII) in which R ¹ is C2-C6 hydroxyalkyl, wherein said C2-C6 hydroxyalkyl groups are optionally substituted once with cyano, —COOR ¹⁰ , —CONR ¹¹ R ¹² , C1-C4 alkoxy or C ₃ -C ₆ cycloalkyl and optionally 1 to 3 times halogen, or

C ₃ -C ₆ -cycloalkyl substituted once with hydroxy and optionally 1 to 3 times with halogen, or

C ₃ -C ₆ -cycloalkyl-C ₁ -C ₃ -alkyl substituted once with hydroxy and optionally 1 to 3 times with halogen, or (C ₃ -C ₆ -cycloalkyl) ₂ -C ₁ -C ₃ -alkyl substituted with one times hydroxy and optionally 1-3 times halogen, or

4-6 membered heterocycloalkyl substituted once with hydroxy and optionally 1-3 times with halogen;

R ¹⁰ represents a _C1-C4 alkyl;

R ¹¹ and R ¹² are the same or different and are, independently of one another, hydrogen or C1-C3 alkyl, or together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic ring, wherein said ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C1-C4 alkyl group;

thus obtaining a compound of general formula (I)

- 18 037978

R ⁵ I (i), in which X, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings indicated above.

The present invention encompasses processes for the preparation of compounds of this invention of general formula (I), which include the steps described in the experimental section of this application.

According to a third aspect, the present invention encompasses intermediates which are useful in the preparation of compounds of general formula (I) as indicated above.

In particular, the invention encompasses intermediates of general formula (VII)

R ⁵ I

(Vii) in which R ² is chloro, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R ³ is hydrogen, fluorine, chlorine or methyl;

R ⁴ is hydrogen or fluorine;

R ⁵ is monocyclic heteroaryl, which is optionally substituted 1 to 3 times, independently of one another, with R ⁶ ;

R ⁶ represents a C ₁ -C ₄ -αlkil, C 1 C ₄ haloalkyl, C ₃ -C ₆ -tsikloalkil, _C1-C4 alkoxy, halo or cyano;

X is CH or N.

According to a fourth aspect, the present invention encompasses the use of said intermediates for the preparation of a compound of general formula (I) as described above.

In particular, the invention covers the use of intermediates of general formula (VII)

R ⁵ I

(Vii) in which R ² is chloro, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R ³ is hydrogen, fluorine, chlorine or methyl;

R ⁴ is hydrogen or fluorine;

R ⁵ is monocyclic heteroaryl, which is optionally substituted 1 to 3 times, independently of one another, with R ⁶ ;

R ⁶ represents a _C1-C4 alkyl, _C1-C4 haloalkyl, C ₃ -C ₆ -tsikloalkil, _C1-C4 alkoxy, halo or cyano;

X is CH or N;

to obtain a compound of general formula (I) as described above.

According to a fifth aspect, the present invention encompasses processes for the preparation of compounds of general formula (I) as described above, wherein said processes comprise the step of reacting an intermediate of general formula (XII)

(HP),

- 19 037978 in which R ¹ is C ₂ -C ₆ -hydroxyalkyl, wherein said C ₂ -C ₆ -hydroxyalkyl groups are optionally substituted once with cyano, —COOR ¹⁰ , —CONR11R ¹² , C1-C ₄ alkoxy or C ₃ -C ₆ -cycloalkyl and optionally 1 to 3 times halogen, or

C ₃ -C ₆ -cycloalkyl substituted once with hydroxy and optionally 1 to 3 times with halogen, or

C ₃ -C ₆ -cycloalkyl-C ₁ -C ₃ -alkyl substituted once with hydroxy and optionally 1 to 3 times with halogen, or (C ₃ -C ₆ -cycloαalkyl) ₂ -C ₁ -C ₃ -alkyl substituted with one times hydroxy and optionally 1-3 times halogen, or

4-6 membered heterocycloalkyl substituted once with hydroxy and optionally 1-3 times with halogen;

R ² is chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R ³ is hydrogen, fluorine, chlorine or methyl;

R ⁴ is hydrogen or fluorine;

X is CH or N;

R ¹⁰ represents a _C1-C4 alkyl;

R ¹¹ and R ¹² are the same or different and are, independently of one another, hydrogen or C1-C3 alkyl, or together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic ring, wherein said ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C1-C4 alkyl group;

with a compound of general formula (XIV) at OP

RO (XIV), in which R ⁵ is monocyclic heteroaryl, which is optionally substituted 1-3 times, independently of each other, R ⁶ ;

R ⁶ represents a _C1-C4 alkyl, _C1-C4 haloalkyl, C ₃ -C ₆ -cycloalkyl, C 1 C ₄ -alkoxy, halogen or cyano;

R ', R''both represent H or _C1-C4 alkyl or together form C2-C7alkilenovuyu group as part of the ester 1,2- or 1,3-diolboronovoy acid group or -SOCH ₂ - (NCH ₃₎ - CH ₂ -CO-;

thus obtaining a compound of general formula (I)

in which X, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the meanings indicated above.

The present invention encompasses processes for the preparation of compounds of this invention of general formula (I), which include the steps described in the experimental section of this application.

According to a sixth aspect, the present invention encompasses intermediates which are useful in the preparation of compounds of general formula (I) as indicated above.

In particular, the invention covers intermediates of general formula (XII)

in which R ¹ is C2-C6 hydroxyalkyl, wherein said C2-C6 hydroxyalkyl groups are optionally substituted once with cyano, —COOR ¹⁰ , —CONR ¹¹ R ¹² , C1-C4 alkoxy or C ₃ -C ₆ cycloalkyl and optionally 1-3 times with halogen, or

C ₃ -C ₆ -cycloalkyl substituted once with hydroxy and optionally 1 to 3 times with halogen, or

C ₃ -C ₆ -cycloalkyl-C ₁ -C ₃ -alkyl substituted once with hydroxy and optionally 1 to 3 times with halogen, or (C ₃ -C ₆ -cycloαalkyl) ₂ -C ₁ -C ₃ -alkyl substituted with one times hydroxy and optionally 1-3 times halogen, or

- 20 037978

4-6 membered heterocycloalkyl substituted once with hydroxy and optionally 1-3 times with halogen;

R ² is chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R ³ is hydrogen, fluorine, chlorine or methyl;

R ⁴ is hydrogen or fluorine;

X is CH or N;

R ¹⁰ is C ₁ -C ₄ -αalkyl;

R ¹¹ and R ¹² are the same or different and are, independently of one another, hydrogen or C1-C3 -alkyl, or together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic ring, wherein said ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C1-C4 alkyl group;

According to a seventh aspect, the present invention encompasses the use of said intermediates for the preparation of a compound of general formula (I) as described above.

In particular, the invention covers the use of intermediates of general formula (XII)

(XII) in which R ¹ is C2-C6 hydroxyalkyl, wherein said C2-C6 hydroxyalkyl groups are optionally substituted once with cyano, —COOR ¹⁰ , —CONR11R ¹² , C1-C4 alkoxy or C ₃ -C ₆ cycloalkyl and optionally 1-3 times with halogen, or

C ₃ -C ₆ -cycloalkyl substituted once with hydroxy and optionally 1 to 3 times with halogen, or

C ₃ -C ₆ -cycloalkyl-C ₁ -C ₃ -alkyl substituted once with hydroxy and optionally 1 to 3 times with halogen, or (C ₃ -C ₆ -cycloalkyl) ₂ -C ₁ -C ₃ -alkyl substituted with one times hydroxy and optionally 1-3 times halogen, or

4-6 membered heterocycloalkyl substituted once with hydroxy and optionally 1-3 times with halogen;

R ² is chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy;

R ³ is hydrogen, fluorine, chlorine or methyl;

R ⁴ is hydrogen or fluorine;

X is CH or N;

R ¹⁰ represents a _C1-C4 alkyl;

R ¹¹ and R ¹² are the same or different and are, independently of one another, hydrogen or C1-C3 alkyl, or together with the nitrogen atom to which they are attached form a 4-6 membered nitrogen-containing heterocyclic ring, wherein said ring optionally contains one additional heteroatom selected from O, S, NH, NR ^a , where R ^a is a C1-C4 alkyl group;

to obtain a compound of general formula (I) as described above.

The present invention covers the intermediates that are disclosed in the Examples section of this text below.

The present invention encompasses any subcombination within any embodiment or aspect of the present invention of intermediates of general formula (VII) as defined above.

The compounds of general formula (I) of the present invention can be converted into any salt, preferably pharmaceutically acceptable salts, as described in this application, using any method known to the person skilled in the art. Likewise, any salt of the compound of general formula (I) of the present invention can be converted to the free compound by any method known to a person skilled in the art.

The compounds of general formula (I) of the present invention exhibit a valuable pharmacological spectrum of action that could not be predicted. Surprisingly, it has been found that the compounds of the present invention effectively inhibit AHR and, therefore, these compounds can be used for the treatment or prevention of diseases, preferably cancer or conditions with dysregulated immune responses, or other disorders associated with aberrant AHR signaling in humans and animals.

- 21 037978

Disorders and conditions particularly suitable for treatment with an AHR inhibitor of the present invention are liquid tissue tumors and solid tumors such as breast, respiratory, brain, reproductive, alimentary, urinary, eye, liver, skin, head cancers. and neck, thyroid gland, parathyroid gland and their distant metastases. Such diseases also include lymphomas, sarcomas, and leukemias.

Examples of types 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.

Examples of types of airway cancer include, but are not limited to, small cell and non-small cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.

Examples of types of brain cancer include, but are not limited to, brainstem glioma and hypothalamic glioma, cerebellar and brain astrocytoma, glioblastoma, medulloblastoma, ependymoma, and neuroectodermal and pineal tumors.

Tumors of the male reproductive organs include, but are not limited to, prostate and testicular cancers.

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

Examples of ovarian cancer include, but are not limited to, serous tumor, endometrioid tumor, mucinous cystadenocarcinoma, granulosa cell tumor, sertolileydig cell tumor, and arrhenoblastoma.

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

Tumors of the digestive tract include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder, stomach, pancreas, rectal cancer, cancer of the small intestine, and salivary gland.

Examples of esophageal cancers include, but are not limited to, cell carcinomas and adenocarcinomas of the esophagus, as well as squamous cell carcinomas, leiomyosarcoma, malignant melanoma, rhabdomyosarcoma, and lymphoma.

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

Examples of pancreatic cancer include, but are not limited to, ductal adenocarcinoma, adenosquamous carcinomas, and pancreatic endocrine tumors.

Tumors of the urinary tract include, but are not limited to, cancer of the bladder, cancer of the penis, cancer of the kidney, renal pelvis, ureter, urethra, and human papillary renal cancer.

Examples of renal cancer include, but are not limited to, renal cell carcinoma, urothelial cell carcinoma, juxtaglomerular cell tumor (reninoma), angiomyolipoma, renal oncocytoma, Bellini's tubule carcinoma, renal clear cell sarcoma, mesoblastic nephroma.

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

Ocular cancers include, but are not limited to, intraocular melanoma and retinoblastoma.

Examples of liver cancer types include, but are not limited to, hepatocellular carcinoma (liver cell carcinomas with or without a fibrolamellar variant), cholangiocarcinoma (intrahepatic carcinoma of the bile duct), and mixed hepatocellular cholangiocarcinoma.

Types of skin cancer include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer.

Types of head and neck cancer include, but are not limited to, squamous cell carcinoma of the head and neck, cancer of the larynx, subpharyngeal, nasopharyngeal, oropharyngeal cancer, cancer of the salivary glands, cancer of the lips and mouth, and squamous cell carcinoma.

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

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

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

The term treat or treat, as defined herein, is used traditionally, for example, to mean the management or care of a patient for the purpose of controlling, alleviating, reducing, relieving, ameliorating a disease or disorder such as carcinoma.

- 22 037978

The compounds of the present invention can be used in particular for therapy and prevention, i. E. prevention, tumor growth and metastases, especially in the case of solid tumors, for all indications and at all stages, with or without preliminary treatment of tumor growth.

Typically, the use of chemotherapeutic agents and / or anticancer agents in combination with a compound or pharmaceutical composition of the present invention will contribute to:

1) obtaining better efficacy in reducing tumor growth or even eliminating a tumor compared to the introduction of any one such agent alone;

2) ensuring the introduction of smaller amounts of administered chemotherapeutic agents;

3) providing chemotherapy treatments that are well tolerated by a patient with fewer harmful pharmacological complications than are seen with single-dose chemotherapy and certain other combination therapies;

4) providing treatment for a wider range of different types of cancer in mammals, especially humans;

5) ensuring a higher response rate among treated patients;

6) ensuring a longer survival time among treated patients compared to standard chemotherapy treatments;

7) providing a longer time to tumor progression; and / or

8) obtaining efficacy and tolerability results that are at least as good as the results for the agents used alone, compared with known cases where combinations of other anticancer agents have antagonistic effects.

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

In a further embodiment of the present invention, the compounds of general formula (I) of the present invention can be used to sensitize cells to radiation, i. E. treating a cell with a compound of the present invention prior to exposing the cell to radiation renders the cell more susceptible to DNA damage and necrosis than if the cell was treated with radiation in the absence of any treatment with the compound of the present invention. In one aspect, the cell is treated with at least one compound of the general formula (I) of the present invention.

Thus, the present invention also provides a method of killing a cell, wherein one or more compounds of the present invention are administered to a cell in combination with conventional radiation therapy.

The present invention also provides a method of rendering a cell more susceptible to necrosis, wherein the cell is treated with one or more compounds of the general formula (I) of the present invention prior to a specific treatment of the cell, the purpose of which is to induce or induce necrosis. In one aspect, after the cell is treated with one or more compounds of general formula (I) of the present invention, the cell is treated with at least one compound, or at least one method, or a combination thereof, in order to cause DNA damage to inhibit the function normal cell or cell killing.

In other embodiments, the cell is sacrificed by treating the cell with at least one DNA damaging agent, i. E. after treating the cell with one or more compounds of general formula (I) of the present invention in order to sensitize the cell to necrosis, the cell is treated with at least one DNA damaging agent in order to kill the cell. DNA damaging agents suitable for the present invention include, but are not limited to, chemotherapeutic agents (eg, cisplatin), ionizing radiation (X-rays, ultraviolet radiation), carcinogenic agents, and mutagenic agents.

In other embodiments, the cell is killed by treating the cell with at least one method for causing or inducing DNA damage. Such methods include, but are not limited to, activation of signaling pathways in cells, which results in DNA damage when the pathway is activated, inhibition of signaling pathways in cells, which leads to DNA damage when a given pathway is inhibited, and inducing a biochemical change in a cell where the change results in DNA damage. By way of non-limiting example, the DNA repair pathway in a cell can be inhibited, thereby preventing the repair of damaged DNA and, as a result, resulting in an abnormal accumulation of DNA damage in the cell.

In one aspect of the invention, the compound of general formula (I) of the present invention is administered to a cell prior to irradiation or other induction of DNA damage in the cell. In another aspect of the invention, the compound of general formula (I) of the present invention is administered to a cell in addition to irradiation or other induction of DNA damage in the cell. In yet another aspect of the present invention, the compound of general formula (I) of the present invention is introduced into the cell immediately after the initiation of irradiation or other induction of DNA damage in the cell.

In another aspect, the cell is an in vitro cell. In another embodiment, the cell is an in vivo cell.

- 23 037978

The compounds of the present invention can be administered as a single pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients, where the combination does not cause unacceptable side effects. The present invention also encompasses such pharmaceutical combinations. For example, the compounds of the present invention can be combined with the following components: 131I-chTNT, abarelix, abiraterone, aclarubicin, adalimumab, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alectinib, alemtuzumab, alendronic acid, alitretinetamine , amrubicin, amsacrine, anastrozole, ancestim, anetol dithioletion, anetumab ravtansin, angiotensin II, antithrombin III, aprepitant, arcytumomab, arglabin, arsenic trioxide, asparaginase, atezolizumab, axitinib, azacimabtidine, basilixumabine, bexarotene, bicalutamide, bisanthrene, bleomycin, blinatumomab, bortezomib, buserelin, bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonin, calcium carbolinate, carbolinate, carboplatinate, capromabazimo, capecitabine , celecoxib, celmoleukin, ceritinib, cetuximab, chlo Rambucil, Chlormadinone, Chlormethine, Cidofovir, Cinacalcet, Cisplatin, Cladribine, Clodronic Acid, Clofarabine, Cobimetinib, Copanlisib, Crisantaspase, Crizotinib, Cyclophosphamide, Cyproterone, Cytarabine, Dacarubinamycin, Dacarubinamycin, Dacarubinamycin degarelix, denileukin diftitoks, denosumab, depreotid, deslorelin diangidrogalaktitol, dexrazoxane, dibrospidiya chloride diangidrogalaktitol, diclofenac, dinutuksimab, docetaxel, dolasetron, doxifluridine, doxorubicin, doxorubicin + estrone, dronabinol, ekulizumab, edrekolomab, elliptinium acetate, elotuzumab, eltrombopag, endostatin , enocitabine, enzalutamide, epirubicin, epitiostanol, epoetin alfa, epoetin beta, epoetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, estramustine, ethinylestradiol, etoposide, epoetinuestanimus, phyllidin fluorouracil, flutamide, folinic acid, formestane, fosaprepita NT, fotemustine, fulvestrant, gadobutrol, gadoteridol, gadoteric acid - meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine, gemtuzumab, glucarpidase, glutoximide, colonytalamide-CSF histrelin, hydroxycarbamide, grain I-125, lansoprazole, ibandronic acid, ibritumomab tuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, indisetron, incadronic acid, ingenol gambutate, interguenonferon 123I), iomeprol, ipilimumab, irinotecan, itraconazole, ixabepilone, ixazomib, lanreotide, lansoprazole, lapatinib, lazocholine, lenalidomide, lenvatinib, lenograstim, lontinan, letrozole, levorimirelatin, levorgestin, levorgestone masoprokol, medroxyprogesterone, megestrol, melarsoprol, melphalan, mepitiostan, mercaptopurine, mesna, meta don, methotrexate, methoxalen, methylaminolevulinate, methylprednisolone, methyltestosterone, methyrosin, mithamurtide, miltefosine, myriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotan, mitoxantrone, mogamulizumab, nabarel, nabarel, naloxone + pentazocine, naltrexone, nartograstim, necytumumab, nedaplatin, nelarabine, neridronic acid, netupitant / palonosetron, nivolumab, pentetraotide, nilotinib, nilutamide, nimorazole, nimotuzumab, nimustin, nitrakubinumabirinum , omacetaxin mepesuccinate, omeprazole, ondansetron, oprelvekin, orgothein, orlotimod, osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamycin, p53 gene therapy, paclitaxel, palbociclib, palifermin, palonosetronum-103, pallifermin, palonositronum-103 grains, palliferin pazopanib, pegaspargase, PEG-epoetin β (methoxy PEG-epoetin β), pembrolisum ab, pegfilgrastim, peginterferon a-2b, pembrolizumab, pemetrexed, pentazocine, pentostatin, peplomycin, perflubutane, perphosphamide, pertuzumab, picibanil, pilocarpine, pyirubicin, picantrone, pliricamidone polyparilamide, polyparidiolate sodium, polyparidiolate-polyparylidiolate , pomalidomide, ponatinib, porfimer sodium, pralatrexate, prednimustin, prednison, procarbazine, procodazole, propranolol, quinagolide, rabeprazole, racotumomab, radium-223 chloride, radotinib, raloxifene, raltitrexed, regbutinimustosetron, rasitrexed, ramusbiosetron , risedronic acid, rhenium-186 etidronate, rituximab, rolapitant, romidepsin, romiplostim, romurtide, ronicyclib, samarium (153Sm) lexidronam, sargramostim, satumomab, secretin, siltuximab, sipuzydioxibranium-T, stanozolol, streptozocin, sunitinib, talaporfin, laherparepvec talimogen, tamibaroten, tamoxifen, tapentadol, tasonermin, tecele ykin, technetium (99mTc) nofetumomab-merpentane, 99mTc-HYNIC- [Tyr3] octreotide, tegafur, tegafur + gimeracil + oteracil, temoporfin, temozolomide, temsirolimus, teniposide, testosterone, tetrofosymalaniph, thiepasin, thalidomide tocilizumab, topotecan, toremifene, tositumomab, trabektedin, trametinib, tramadol, trastuzumab, trastuzumab emtansine, treosulfan, tretinoin, trifluridine + tipiracil, trilostane, triptorelin, trametinidin, trofoposfami

- 24 037978 vemurafenib, vinblastine, vincristine, vindesine, vinflunine, vinorelbine, vismodegib, vorinostat, vorozol, ytrium-90 glass microspheres, zinostatin, zinostatin stimulamer, zoledronic acid, zorubicin.

The compounds of the invention can be further combined with other reagents targeting the immune system, such as immune checkpoint inhibitors, eg aPD-1 / -L1 axis antagonists.

PD-1, as well as its ligands PD-L1 and PD-L2, functions as negative regulators of T cell activation. AHR suppresses the function of immune cells while increasing cancer cell proliferation and motility. PD-L1 is overexpressed in many malignant neoplasms, and concomitantly, PD-1 is often overexpressed in tumor-infiltrating T cells. This leads to depletion of T-cell activation and evasion of immune surveillance, which contributes to the disruption of antitumor immune responses. (Keir M. E. et al. (2008) Annu. Rev. Immunol. 26: 677).

Simultaneous targeting of both the PD-1 / -L1 axis and the AHR enhances antitumor immune responses in a more than additive manner, resulting in an unexpected decrease in tumor growth.

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

In addition, the compounds of the invention can also be used as a therapeutic agent for a variety of other disorders in which AHR is implicated, such as cardiovascular diseases and lung diseases.

Accordingly, the compounds according to the invention are suitable for the treatment and / or prevention, in particular of cardiovascular, inflammatory and fibrotic disorders and renal dysfunctions, in particular acute and chronic renal failure, as well as acute and chronic decompensated renal failure. ...

Accordingly, the compounds according to the invention can be used in medicaments for the treatment and / or prevention of cardiovascular, inflammatory and fibrotic disorders, renal dysfunctions, in particular acute and chronic renal failure, as well as acute and chronic decompensated renal failure.

For the purposes of the present invention, the term renal failure includes both acute and chronic manifestations of renal failure as well as primary or related renal dysfunctions such as diabetic and non-diabetic nephropathy, hypertensive nephropathy, ischemic renal dysfunction, renal hypoperfusion, intradialysis hypotension, obstructive uropathy. , renal stenosis, glomerulopathies, glomerulonephritis (such as, for example, primary glomerulonephritis; glomerulonephritis of minimal changes (lipoid nephrosis); membranous glomerulonephritis; focal segmental glomerulosclerosis (FSGS); membranous serum proliferative glomeruloma Berger); post-infectious glomerulonephritis; secondary glomerulonephritis: diabetes mellitus, erythematous lupus, amyloidosis, Goodpasture's syndrome, Wegener's granulomatosis, Henoch-Schönlein purpura, microscopic polyangiitis, acute glome rulonephritis, pyelonephritis (eg, as a result of: urolithiasis, benign prostatic hyperplasia, diabetes, malformations, analgesic abuse, Crohn's disease), glomerulosclerosis, renal arteriolonecrosis, tubulointerstitial diseases, nephropathic disorders such as primary and congenital renal dysfunction or syndrome Alport, nephritis, immunological renal dysfunctions such as kidney transplant rejection and immunocomplex-induced renal dysfunctions, toxicant-induced nephropathy, contrast-induced nephropathy, diabetic and non-diabetic nephropathy, kidney cysts, nephrosclerosis, hypertensive and nephrosclerosis syndrome can be characterized diagnostically, for example, by abnormally decreased excretion of creatinine and / or water, abnormally increased blood concentrations of urea, nitrogen, potassium and / or creatinine, altered renal fertility drugs such as glutamyl synthetase, altered urine osmolarity or urine volume, increased microalbuminuria, macroalbuminuria, glomerular and arteriole lesions, tubular dilation, hyperphosphatemia, and / or the need for dialysis. The present invention also includes the use of compounds according to the invention for the treatment and / or prevention of the consequences of renal failure, for example pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders of bone and carbohydrate metabolism. The invention also includes the use of compounds according to the invention for the treatment and / or prevention of the consequences of renal failure, for example pulmonary edema, heart failure, uremia, anemia, electrolyte imbalances (eg, hyperkalemia, hyponatremia) and disorders of bone tissue and carbohydrate metabolism.

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).

In addition, the compounds according to the invention are also suitable for the treatment of

- 25 037978 and / or prevention of metabolic syndrome, hypertension, persistent arterial hypertension, acute and chronic heart failure, coronary heart disease, stable and unstable angina pectoris, peripheral and cardiac vascular disorders, arrhythmias, atrial and ventricular arrhythmias and conduction disturbances, for example, grade I-III atrioventricular block (AV block I-III), supraventricular tachyarrhythmias, atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter, ventricular tachyarrhythmias, polymorphic ventricular tachycardia, pirouette-type AV, atrial atrial nodes sinus node weakness, syncope, AV nodal reciprocal tachycardia, Wolff-Parkinson-White syndrome, acute coronary syndrome (ACS), autoimmune cardiac disorders (pericarditis, endocarditis, valvulitis, aortitis, cardiomyopathies), shock such as septic shock, septic shock and anaphylactic shock, aneurysms, boxer's cardiomyopathy (premature ventricular contraction (PVC)), for the treatment and / or prevention of thromboembolic disorders and ischemia, such as myocardial ischemia, myocardial infarction, stroke, cardiac hypertrophy, transient and ischemic attacks, preeclampsia, inflammatory cardiovascular vascular disorders, spasms of the coronary arteries and peripheral arteries, the formation of edema such as pulmonary edema, cerebral edema, renal edema or edema caused by heart failure, peripheral circulatory disorders, reperfusion injury, arterial and venous thrombosis, myocardial insufficiency, endothelial dysfunction, to prevent restenosis, for example after thrombolytic therapy, percutaneous transluminal angioplasty (PTA), transluminal coronary angioplasty (PTCA), heart transplants and cardiac operations with cardiac shutdown, as well as micro- and macrovascular lesions (vasculitis), increased fibrosis rhinogen and low density lipoprotein (LDL) and increased concentrations of plasminogen activator inhibitor 1 (PAI-1), as well as for the treatment and / or prevention of erectile dysfunction and sexual dysfunction in women.

In addition, the compounds according to the invention are also suitable for the treatment and / or prevention of asthmatic disorders, pulmonary arterial hypertension (PAH) and other forms of pulmonary hypertension (PH), including diseases of the left heart, HIV, sickle cell anemia, thromboembolism ( STERN), sarcoidosis associated with COPD or pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute lung injury (ALI), α-1-antitrypsin deficiency (AATD), pulmonary fibrosis, emphysema of the lungs (eg, emphysema of the lungs induced by cigarette smoke) and cystic fibrosis (CF).

The compounds described in the present invention are also active compounds for combating disorders of the central nervous system, which are characterized by a disruption of the NO / cGMP system. They are suitable, in particular, for improving perception, concentration, learning or memory after cognitive impairments such as those observed in particular in connection with situations / diseases / syndromes such as mild cognitive impairments, age-related learning and memory impairments. age-related amnesia, vascular dementia, traumatic brain injury, stroke, post-stroke dementia (post-stroke dementia), post-traumatic brain injury, general concentration disorders, concentration disorders in children with learning and memory problems, Alzheimer's disease, dementia with calves Levy, dementia with degeneration of the frontal lobes including Pick syndrome, Parkinson's disease, progressive dementia with corticobasal degeneration, amyolateral sclerosis (ALS), Huntington's disease, demyelination, multiple sclerosis, thalamic degeneration, dementia due to Creutzfeldt-Jakob dementia, HIV dementia or Korsakov's psychosis. They are also suitable for the treatment and / or prevention of central nervous system disorders such as anxiety, tension and depression, CNS-related sexual dysfunctions and sleep disorders, and for the control of pathological eating disorders, stimulants and addictive substances.

The compounds according to the invention are also suitable for controlling cerebral blood flow and thus are effective agents for the control of migraine pain. They are also suitable for the prevention and control of the consequences of cerebral infarction (cerebral apoplexy) such as stroke, cerebral ischemia and traumatic brain injury. The compounds according to the invention can also be used to control conditions of pain and tinnitus.

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

In addition, the compounds according to the invention can also be used for the treatment and / or prevention of autoimmune diseases.

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The compounds according to the invention are also suitable for the treatment and / or prevention of fibrotic disorders of internal organs, for example the lungs, heart, kidney, bone marrow and in particular the liver, as well as skin fibrosis and ocular fibrosis. In the context of the present invention, the term fibrotic disorders includes, inter alia, the following terms: liver fibrosis, liver cirrhosis, pulmonary fibrosis, endomyocardial fibrosis, nephropathy, glomerulonephritis, interstitial renal fibrosis, fibrotic lesions due to diabetes, bone marrow fibrosis and similar fibrotic disorders, scleroderma , focal scleroderma, keloids, hypertrophic scars (also after surgical procedures), nevi, diabetic retinopathy, proliferative vitreoretinopathy, and connective tissue disorders (eg, sarcoidosis).

The compounds according to the invention are also suitable for the control of postoperative scarring, for example after glaucoma surgery.

The compounds according to the invention can also be used for cosmetic purposes for aging and keratinized skin.

Moreover, the compounds according to the invention are suitable for the treatment and / or prevention of hepatitis, neoplasms, osteoporosis, glaucoma and gastroparesis.

The invention further provides the use of the compounds according to the invention for the treatment and / or prevention of disorders, in particular the above-mentioned disorders.

The present invention further provides the use of compounds according to the invention for the treatment and / or prevention of chronic renal dysfunction, acute and chronic renal failure, diabetic, inflammatory or hypertensive nephropathy, fibrotic disorders, heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, thromboembolic complications, 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.

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

The invention further provides a method for the treatment and / or prevention of chronic renal dysfunction, acute and chronic renal failure, diabetic, inflammatory or hypertensive nephropathy, fibrotic disorders, heart failure, angina pectoris, hypertension, pulmonary hypertension, ischemia, vascular disorders, thromboembolic complications, 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.

In another embodiment, the compounds of the invention can also be used to treat or prevent uterine fibroids (uterine leiomyomas or uterine fibroids) in women.

Fibroids of the uterus are benign tumors of the myometrium, the smooth muscle layer of the uterus. Fibroids of the uterus grow slowly during a woman's life, and their growth depends on the female sex hormones estradiol and progesterone [Kawaguchi K. et al. Immunohistochemical analysis of estrogen 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, the highest prevalence of uterine fibroids with rates of approx. 70% and> 80% in white and African American women, respectively, are observed between the ages of 35 and menopause, when they contract due to decreased hormone levels [Baird D.D. 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, show clinically significant symptoms due to their fibroids, which are heavy menstrual bleeding and pain associated with the menstrual cycle [David M. et al. Myomaassociated pain frequency and intensity : a retrospective evaluation of 1548 myoma patients. Eur. J. Obstet. Gynecol. Reprod. Biol. 2016 Apr; 199: 137-40]. Heavy menstrual bleeding in this regard is determined by the loss of blood volume of more than 80 ml during the period of menstrual bleeding [Fraser I.S. et al. The FIGO Recommendations on Terminologies and Definitions for Normal and Abnormal Uterine Bleeding, Semin. Reprod. Med. 2011; 29 (5): 383-390]. The submucosal location of uterine fibroids, such as fibroids located just below the endometrium, seems to have an even more serious effect on uterine bleeding, which can lead to anemia in women with this disease [Yang J.H. et al. Impact of submucous myoma on the severity of anemia. Fertil. Steril. 2011 Apr; 95 (5): 1769-72]. In addition, uterine fibroids, due to their symptoms, seriously affect the quality of life of women with this disease [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].

It is still unclear how uterine fibroids cause heavy menstrual bleeding. Dysregulated genes of uterine fibroids compared with normal myometrium, can give under

- 27 037978 a tale to understand the basic mechanisms. In published and internal studies we have found that there is a strong upregulation of TDO2, tryptophan 2,3-dioxygenase [Tsibris J.C. et al. Insights from gene arrays on the development and growth regulation of uterine leiomyomata. Fertil Steril. 2002 Jul; 78 (1): 114-21]. TDO2 metabolizes the substrate L-tryptophan to L-kynurenine, which can be further metabolized to kynurenic acid. Both L-kynurenine and kynurenic acid are physiological ligands and activators for the aryl hydrocarbon receptor AHR [Opitz C.A. et al. An endogenous tumor-promoting ligand of the human aryl hydrocarbon receptor Nature. 2011 Oct 5; 478 (7368): 197-203].

L-Cynurenine controls at least two physiological processes that are dysregulated in uterine fibroids. L-Kynurenine, synthesized by up-regulation of IDO (indoleamine-2,3-dioxygenase) or TDO2, and acting through the AHR receptor, suppresses the immune system and thus prevents the recognition and removal of tumor cells by immune cells [Munn D.H. Blocking IDO activity to enhance anti-tumor immunity. Front. Biosci. (Elite Ed.). 2012 Jan 1; 4: 734-45]. In addition, upregulation of L-kynurenine leads to vasodilation, and thus can directly increase blood loss and increase bleeding [Wang Y. et al. Kynurenine is an endothelium-derived relaxing factor produced during inflammation Nature Medicine 16, 279-285 ( 2010)].

Thus, upregulation of L-kynurenine through activation of its physiological receptor AHR appears to support the growth of uterine fibroids by local suppression of the immune system and may cause severe menstrual bleeding due to vasodilation of the endometrium near the tumor.

Therefore, the systemic or topical application of the compounds of the present invention that inhibit the activation of AHR and thus block the action of L-kynurenine produced by uterine fibroids represents a new and effective treatment for uterine fibroids.

The compounds of the present invention can be used to inhibit, block, reduce or reduce AHR activation by exogenous and / or endogenous ligands to reduce tumor growth and modulate dysregulated immune responses, for example, blocking immunosuppression and increasing activation and infiltration of immune cells in the context of cancer and immunotherapy cancer. This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of this invention, or a pharmaceutically acceptable salt, isomer, polymorph, metabolite, hydrate, solvate or ester thereof, that is effective to treat the disorder.

The present invention also provides methods of treating a number of other disorders in which AHR is involved, such as, but not limited to, inflammation, infection & cancer vaccination, viral infections, obesity and alimentary obesity, fat deposition, metabolic disorders, fatty hepatosis and uterine fibroids. ...

These disorders have been well characterized in humans, but also exist with a similar etiology in other mammals and can be treated by administering the pharmaceutical compositions of the present invention.

The term “treat” or “treat” as used herein is used traditionally, for example, to mean the management or care of a patient for the purpose of controlling, alleviating, reducing, relieving, improving the condition of the disease or disorder, such as tumors of liquid tissues and solid tumors.

In a further aspect, the present invention encompasses compounds of general formula (I) as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular their pharmaceutically acceptable salts, or mixtures thereof, for use in treatment or prevention of diseases, in particular malignant neoplasm or conditions with dysregulated immune responses, or other disorders associated with aberrant AHR signaling.

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

In a further aspect, the present invention encompasses the use of compounds of general formula (I) as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular their pharmaceutically acceptable salts, or mixtures thereof, for the treatment or prevention of diseases, in particular malignant neoplasm or conditions with dysregulated immune responses, or other disorders associated with aberrant AHR signaling, in particular of tumors of liquid tissues and solid tumors.

In a further aspect, the present invention encompasses the use of a compound of formula (I) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, in particular a pharmaceutically acceptable salt thereof, or a mixture thereof, for the prevention or treatment of diseases, in particular malignant neoplasm or conditions with dysregulated immune responses, or other disorders associated with aberrant AHR signaling, in particular tumors of liquid tissues and solid tumors.

- 28 037978

According to a further aspect, the present invention encompasses the use of compounds of general formula (I) as described above, or their stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular their pharmaceutically acceptable salts, or mixtures thereof, in a method of treatment or prevention of diseases, in particular malignant neoplasm or conditions with dysregulated immune responses, or other disorders associated with aberrant AHR signaling, in particular tumors of liquid tissues and solid tumors.

In a further aspect, the present invention encompasses the use of a compound of general formula (I) as described above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular its pharmaceutically acceptable salts, or mixtures thereof, for the preparation of a pharmaceutical a composition, preferably a medicament, for the prevention or treatment of diseases, in particular malignant neoplasms or conditions with dysregulated immune responses, or other disorders associated with aberrant AHR signaling, in particular tumors of liquid tissues and solid tumors.

In accordance with a further aspect, the present invention encompasses a method for the treatment or prevention of diseases, in particular cancer or conditions with dysregulated immune responses, or other disorders associated with aberrant AHR signaling, in particular tumors of liquid tissues and solid tumors, using an effective amount of a compound of general formula (I) as described above, or its stereoisomers, tautomers, N-oxides, hydrates, solvates and salts, in particular its pharmaceutically acceptable salts, or mixtures thereof.

According to a further aspect, the present invention encompasses pharmaceutical compositions, in particular medicaments, containing a compound of general formula (I) as described above, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, salt thereof, in particular a pharmaceutically acceptable salt thereof , or a mixture thereof, and one or more excipient (s), in particular one or more pharmaceutically acceptable excipient (s). You can use conventional techniques to obtain such pharmaceutical compositions in suitable dosage forms.

The present invention also encompasses pharmaceutical compositions, in particular medicaments, which contain at least one compound according to the invention, usually together with one or more pharmaceutically acceptable excipients, and their use for the above purposes.

The compounds according to the invention can exhibit systemic and / or local activity. For this purpose, they can be administered in a suitable manner such as oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, aural, or as an implant or stent.

For these routes of administration, the compounds of the invention may be administered in suitable dosage forms.

For oral administration, the compounds of the invention may be formulated as known in the art that deliver the compounds of the invention rapidly and / or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with coatings resistant to gastric juice or controlled release, which dissolves with a delay or insoluble), tablets dissolving in the mouth, films / wafers, films / lyophilisates, capsules (e.g. hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. In these dosage forms, the compounds according to the invention can be incorporated in crystalline and / or amorphous and / or dissolved form.

Parenteral administration can be performed by avoiding the absorption step (eg, intravenous, intra-arterial, intracardiac, intraspinal, or intralumbar) or with absorption included (eg, intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal). Dosage forms that are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

Examples that are suitable for other routes of administration are pharmaceutical forms for inhalation [including, inter alia, the use of powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays, tablets / films / wafers / capsules for lingual, sublingual or buccal administration, suppositories, eye drops, eye ointments, eye baths, eye inserts, ear drops, ear sprays, ear powders, ear washes, ear tampons; vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, powders, implants or stents.

Compounds in accordance with the invention can be included in the indicated dosage forms. This can be done in a manner known per se by mixing with pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients include, but are not limited to

- 29 037978 fillers and carriers (such as, for example, cellulose, microcrystalline cellulose (such as, for example, Avicel®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos®)), ointment bases ( such as, for example, liquid paraffin, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), suppository bases (such as, for example, polyethylene glycols, cocoa butter, tallow), solvents ( such as, for example, water, ethanol, isopropanol, glycerin, propylene glycol, fatty oils - medium chain triglycerides, liquid polyethylene glycols, paraffins), surfactants, emulsifiers, dispersants or wetting agents (such as, for example, sodium dodecyl sulfate, lecithin , phospholipids, fatty alcohols (such as Lanette®), sorbitol fatty acid esters (such as Span®), polyoxyethylene sorbitol fatty acid esters (such as Tween®), polyoxyethyl new fatty acid glycerides (such as Cremophor®), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as Pluronic®)), buffers, acids and bases ( such as, for example, phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine), isotonic agents (such as, for example, glucose, sodium chloride), adsorbents (such as, for example , highly dispersed silica gel), viscosity-increasing agents, gelling agents, thickeners and / or binders (such as, for example, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, starch, carbomers®, for example, Carbopol alginates, gelatin), disintegrants (such as, for example, modified starch, sodium carboxymethyl cellulose, sodium starch alglycollate (such as, for example, Explotab®), cross-linked polyvinylpyrrolidone, croscarmellose sodium (such as, for example, AcDiSol®)), flow regulators, lubricants, glidants and mold release agents (such as, for example, stearate magnesium, stearic acid, talc, highly dispersed silica gel (such as, for example, Aerosil®)), coating agents (such as sugar, shellac) and film formers for films or diffusion membranes that dissolve quickly or in a modified manner (such as polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®), such as substances for capsules , gelatin, hydroxypropyl methylcellulose), synthetic polymers (such as, for example, polylactides, polyglycolides, poly acrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinylacetates, polyethylene oxides, polyethylene glycols and their copolymers and block copolymers), plasticizers (such as, for example, polyethylene glycols) propylene glycol, glycerin, triacetin, triacetyl citrate, dibutyl phthalate), penetration enhancers, stabilizers (such as antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, propyl hydroxygallate, for example , sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), colorants (such as, for example, inorganic pigments such as iron oxides, titanium dioxide), fragrances, sweeteners, flavor and / or odor correctors.

The present invention also relates to a pharmaceutical composition that contains at least one compound in accordance with the invention, usually together with one or more pharmaceutically acceptable excipient (s), and to its use in accordance with the present invention.

In accordance with another aspect, the present invention encompasses pharmaceutical combinations, in particular medicaments, containing at least one compound of general formula (I) of the present invention and at least one or more additional active ingredients, in particular for the treatment and / or prevention of malignant neoplasms or conditions with dysregulated immune responses, or other disorders associated with aberrant AHR signaling, in particular tumors of liquid tissues and solid tumors.

The term combination in the present invention is used as known to those skilled in the art, and said combination may be a fixed combination, an unfixed combination, or a set of components.

The term fixed combination in the present invention is used as known to those skilled in the art and is defined as a combination in which, for example, a first active ingredient such as one or more compounds of general formula (I) of the present invention and an additional active ingredient are present together in one unit dosage form or in the form of a single whole. One example of a fixed combination is a pharmaceutical composition in which the first active ingredient and the additional active ingredient are present in a mixture for simultaneous administration, such as in a formulation. Another example of a fixed combination is a pharmaceutical combination in which the first active ingredient and the additional active ingredient are present in one unit in an unmixed state.

The term "non-fixed combination" or set of components in the present invention is used as known to those skilled in the art and is defined as a combination in which the first active component and the additional active component are present in more than one unit. One example of a non-fixed combination or set of components is a combination in which the first active component and the additional active component are present separately. The components of a non-fixed combination or set of components can be administered separately, sequentially, simultaneously, in parallel, or chronologically displaced.

Based on standard laboratory procedures known for evaluating compounds useful in the treatment of malignant neoplasm or conditions with dysregulated immune responses, or other disorders associated with aberrant AHR signaling, using standard toxicity tests and using standard pharmacological assays to determine treatment parameters for conditions identified above in mammals, and by comparing these results with those of known active ingredients or drugs that are used to treat these conditions, an effective dosage of the compounds of the present invention to treat each target indication can be readily determined. The amount of active ingredient to be administered to treat one of these conditions can vary widely according to factors considered, such as the particular compound and dosage unit used, the route of administration, the period of treatment, the age and sex of the patient being treated, and the nature and severity of the condition. being treated.

The total amount of active ingredient to be administered will generally range from about 0.001 mg / kg to about 200 mg / kg body weight per day, and preferably from about 0.01 mg / kg to about 20 mg / kg body weight per day. Clinically suitable dosing regimens will range from dosing one to three times a day to dosing once every four weeks. In addition, drug interruptions, during which the patient does not take the drug for a certain period of time, can be beneficial for the overall balance between pharmacological effect and tolerance. The dosage unit may contain from about 0.5 mg to about 1500 mg of active ingredient and may be administered one or more times a day, or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and the use of infusion techniques, will preferably be from 0.01 to 200 mg / kg total body weight. The average daily rectal dosing regimen will preferably be from 0.01 to 200 mg / kg total body weight. The average daily vaginal dosing regimen will preferably be from 0.01 to 200 mg / kg total body weight. The average daily topical dosing regimen will preferably be 0.1 to 200 mg administered one to four times a day. The transdermal concentration will preferably be such as is necessary to maintain a daily dose of 0.01 to 200 mg / kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg / kg total body weight.

Undoubtedly, the specific initial and ongoing dosage regimen for each patient will vary depending on the nature and severity of the condition, determined by the attending diagnostician, the activity of the particular compound used, the age and general condition of the patient, the time of administration, the route of administration, the rate of elimination of the drug from the body, combinations medicines, etc. The desired method of treatment and the number of doses of a compound of the present invention, or a pharmaceutically acceptable salt or ester or composition thereof, can be determined by those skilled in the art using routine experimental treatment.

Experimental section

The NMR peak shapes are indicated as they appear in the spectra; possible higher-order effects are not considered. Multiplicities are indicated according to the waveform that appears in the spectrum; higher-order NMR spectroscopic effects were not taken into account. Multiplicity of NMR signals: s - singlet, d - doublet, t - triplet, q - quartet, quin quintet, br - broad signal, m - multiplet. NMR signals: shift indicated in [ppm]. A combination of multiplicity 31 037978 can be, for example, dd is a doublet of a doublet.

Chemical names were generated using software

ACD / Name from ACD / Labs. In some cases, the common names of commercially available reagents have been used in place of the names generated by the ACD / Name.

Table 1 lists the abbreviations used in this section and in the Examples section as they are not explained in the main text. Other abbreviations have the meanings, as such, common to a person skilled in the art.

Table 1. Abbreviations

ACN - acetonitrile;

AcOH - acetic acid;

CDCl ₃ - deuterochloroform;

DAD - diode array detector;

DEA - diethylamine;

DMF - N, N-dimethylformamide;

DMSO-d ₆ - deuterated dimethyl sulfoxide;

DMSO - dimethyl sulfoxide;

ELSD - Evaporative Light Scattering Detector;

ESI will put it down. - positive electrospray ionization;

Approx. - example;

HATU - (7-aza-1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate;

HBTU - O-benzotriazole-N, N, N ', N'-tetramethyluronium hexafluorophosphate;

HPLC - high performance liquid chromatography (high pressure liquid chromatography);

KA - kynurenic acid;

LC-MS - liquid chromatography combined with mass spectrometry;

LPS, lipopolysaccharide;

ml - milliliter;

min - minute (s);

MTBE - methyl tert-butyl ether;

PBMC - peripheral blood mononuclear cells;

PyVOB - hexafluorophosphate (benzotriazol-1-yl) oxytripyrrolidinophosphonium;

RP-HPLC - reverse phase high performance liquid chromatography (reverse phase high pressure liquid chromatography);

Rt is the retention time;

CT - room temperature;

saturate - saturated;

T3P 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide;

THF - tetrahydrofuran;

TFA - trifluoroacetic acid;

TLC - thin layer chromatography;

TNFa - tumor necrosis factor-α;

μM micromolar;

UHPLC stands for Ultra High Performance Chromatography.

Various aspects of the invention described in this application are illustrated by the following examples, which are not intended to limit the invention in any way.

The illustrative test experiments described in this application serve to illustrate the present invention, and the invention is not limited to the examples.

Experimental section - general part.

All reagents for which synthesis is not described in the experimental part are either commercially available, or are known compounds, or can be prepared from known compounds by a person skilled in the art using known methods.

Compounds and intermediates made in accordance with the methods of the invention may require purification. Methods for purifying organic compounds are well known to the person skilled in the art, and there may be several methods for purifying the same compound. In some cases, cleaning may not be necessary. In some cases, the compounds can be purified by crystallization. In some cases, contamination can be removed using a mixing technique in a suitable solvent. In some cases, compounds can be purified by chromatography, in particular flash column chromatography, using, for example, pre-filled silica gel cartridges, such as Biotage SNAP cartridges KP-Sil® or KPNH®, in combination with an automatic Biotage purifier (SP4® or Isolera Four®) and eluents such as hexane / ethyl acetate or DCM / methanol gradients. In some cases, compounds can be purified by preparative HPLC using, for example, a Waters automatic purifier equipped with a diode array detector and / or an online electrospray mass spectrometer in combination with a suitable pre-packed reverse phase column and eluents. such as water and acetonitrile gradients, which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

In some cases, purification methods as described above can provide compounds of the present invention that have a sufficient basic or acidic functionality in the form of a salt, such as in the case of a compound of the present invention that is sufficiently basic, such as trifluoroacetate or formate, or in the case of a compound of the present invention, which is acidic enough, for example, an ammonium salt. A salt of this type can either be converted to its free base form or its free acid form, respectively, by various methods known to the person skilled in the art, or directly used as such in subsequent biological analyzes. It should be understood that a particular form (e.g., salt, free base, etc.) of a compound of the present invention isolated and described in this application is not necessarily the only form in which said compound can be used in a biological assay to quantify a specific biological activity. ...

Experimental Section - Intermediates.

Intermediate 1.di-tert-Butyl 1- (1-methyl-1H-pyrazol-4-yl) hydrazine-1,2-dicarboxylate

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

¹ H-NMR: (300 MHz, 25 ° C, Methanol-d ₄ ): δ [ppm] = 1.44 (s, 18H); 3.77 (s, 3H); 7.17-7.28 (m, 1H); 7.617.67 (m, 1H); 9.60 (s, 1H).

Intermediate 2. 4-hydrazinyl-1-methyl-1H-pyrazole trifluoroacetate (1: 1)

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

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

Intermediate 3. Dimethyl [2- (4-methylphenyl) -2-oxoethyl] propanedioate

A solution of 49.6 g of 2-bromo-1- (4-methylphenyl) ethanone in

300 ml of acetone was added dropwise at RT to a solution of 10 g of dimethylmalonate in 120 ml of acetone. The reaction mixture was stirred at room temperature for 4 hours. Then the solvent was removed in vacuo. The residue was purified by column chromatography (petroleum ether / ethyl acetate 10: 1) to obtain 10.3 g of dimethyl [2- (4methylphenyl) -2-oxoethyl] propanedioate.

¹ H-NMR: (400 MHz, 25 ° C, DMSO-d ₆ ): 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).

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Intermediate 4. Methyl 6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3,4,5-tetrahydropyridazine-4-carboxylate

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

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

Intermediate 5.Dihydropyridazine-4-carboxylate

Methyl 6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-

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

1 H-NMR: (400 MHz, 25 ° C, DMSO-de): 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).

Intermediate 6. 6- (4-Methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

A mixture of 380 mg of intermediate 5 in 30 ml of acetonitrile was treated with 147 mg of lithium hydroxide 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 hydrochloric acid (10%). The solids were collected by filtration, washed three times with water and dried in an oven to give 310 mg of 6- (4methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine -4-carboxylic acid.

1 H-NMR: (400 MHz, 25 ° C, DMSO ^): 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).

Intermediate 7. 6- (4-Methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carbonyl chloride

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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

h. The mixture was evaporated to dryness to obtain 260 mg of crude 6- (4-methylphenyl) -2- (1-methyl-1H-pyrazole-4-

yl) -3-oxo-2,3-dihydropyridazine-4-carbonyl chloride, which was used directly in the next step without further purification.

Intermediate 8. Dimethyl [2- (4-chlorophenyl) -2-oxoethyl] malonate

2-Chloro-1- (4-chlorophenyl) ethanone (25 g, 107.1 mmol) was dissolved in acetone (500 ml). Then dimethylmalonate (31.1 g, 235.4 mmol) and potassium carbonate (22.2 g, 160.6 mmol) were added at RT. The mixture was stirred at RT overnight. The volume of the reaction mixture was reduced by half in vacuo. Then the residue was 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 concentrated aqueous sodium chloride solution, dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, gradient: hexane / ethyl acetate) to give 12.21 g (36%) of the title product.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.63 (d, 2H), 3.68 (s, 6H), 3.97 (t, 1H), 7.59-7.64 (m, 2H ), 7.998.03 (m, 2H).

Intermediate 9. Methyl 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3,4,5tetrahydropyridazine-4-carboxylate

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 4hydrazino-1-methyl-1H-pyrazole dihydrochloride (780 mg, 4.22 mmol) was added in portions. The mixture was stirred for 1 h at RT and 20 h at 50 ° C. The reaction mixture was cooled and concentrated on a rotary evaporator under reduced pressure. Ethyl acetate and water were added to dissolve the residue. Added concentrated aqueous sodium hydrogen carbonate solution, the phases were separated and the aqueous layer was extracted with ethyl acetate (80 ml, four times). The combined organic layers were washed twice with water, dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography (silica gel, gradient: hexane / ethyl acetate) to give 530 mg (36%) of the title product.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.35-3.46 (m, 2H), 3.68 (s, 3H), 3.85 (s, 3H), 4.03 (dd, 1H ), 7.52-7.57 (m, 2H), 7.75 (d, 1H), 7.92-7.96 (m, 2H), 8.08 (s, 1H).

Intermediate 10. Methyl 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylate

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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 for 4 h at 90 ° C. It was cooled and concentrated on a rotary evaporator. Water was added, the remaining solid was suction filtered, washed five times with water and dried in vacuo at 50 ° C to give 741 mg of the title compound, which was used without further purification in the next step.

¹ H-NMR (400 MHz, 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).

Intermediate 11.6- (4-Chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

CH ₃ Ν — NVN ^ °

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). At RT, a solution of lithium hydroxide (125 mg, 5.221 mmol) in water (1.90 ml) was added. The mixture was stirred for 10 h at 40 ° C. Water was added and the pH was adjusted to 4 with 2N. HCl. The precipitate was filtered off with suction, washed three times with water and dried in vacuo at 50 ° C to give 520 mg (90%) of the title compound, which was used without further purification in the next step.

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

Intermediate 12. Methyl 6- (4-chlorophenyl) -3-oxo-2,3,4,5-tetrahydropyridazine-4carboxylate

H N'V ° СГ CH ₃

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

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.16 (dd, 1H), 3.26 (dd, 1H), 3.67 (s, 3H), 3.75 (dd, 1H), 7.477. 52 (m, 2H), 7.75-7.79 (m, 2H), 11.31 (s, 1H).

Intermediate 13. Methyl 6- (4-chlorophenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate

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

1H-NMR (400 MHz, DMSO-d ₆ ): 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).

Intermediate connection 14.

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

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Dimethylmalonate (9.894 g, 74.89 mmol) and potassium carbonate (7.763 g, 56.17 mmol) were added to acetone (140 ml). With cooling, a solution of 2-bromo-1- [4- (trifluoromethyl) phenyl] ethanone (10 g, 37.4 mmol) in acetone (60 ml) was added dropwise (0-5 ° C). The mixture was stirred for 2 h at 0-5 ° C and at RT overnight. The volatiles were removed on a rotary evaporator. Added water and ethyl acetate, the layers were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with concentrated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The crude product was purified using flash chromatography (silica gel, gradient: hexane / ethyl acetate) to give 8.03 g (67%) of the title product.

¹ H-NMR (400 MHz, Chloroform ^): δ [ppm] = 3.65 (d 2H), 3.79 (s, 6H), 4.10 (t, 1H), 7.73-7.77 (m, 2H),

8.07-8.11 (m, 2H).

Intermediate 15.pyridazine-4-carboxylate

Methyl 3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3,4,5-tetrahydro-

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

¹ H-NMR (400 MHz, DMSO-d ₆ ): 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).

Intermediate 16. Methyl 3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4carboxylate

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

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

Intermediate 17. Methyl 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylate

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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). Added 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1Hpyrazole (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). The mixture was stirred for 21 h at RT. 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (349 mg, 1.68 mmol) was added and stirring was continued at RT overnight. Water (5 ml) was added and the pH was adjusted to 3 with 2N. HCl (3.5 ml). The precipitate was filtered, washed three times with water and dried at 50 ° C in vacuo to give 594 mg (63%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 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).

Intermediate 18. 2- (1-Methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) phenyl] 2,3-dihydropyridazine-4-carboxylic acid

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). At RT, a solution of lithium hydroxide (112 mg, 4.70 mmol) in water (1.7 ml) was added. The mixture was stirred for 3 h at RT. Water (100 ml) was added and the pH was adjusted to 6 with 2N. HCl. The precipitate was filtered off with suction, washed with water and dried in vacuo at 50 ° C to give 345 mg (45%) of the title compound, which was used without further purification in the next step.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.93 (br s, 3H), 7.47-8.39 (m, 7H).

Intermediate 19.6- (4-Chlorophenyl) -2- (1-cyclobutyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

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). Added 1-cyclobutyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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). The mixture was stirred for 96 h at RT. Water was added and the pH was adjusted to 3 with 2N. HCl. The precipitate was filtered, washed three times with water and dried at 50 ° C in vacuo to give 370 mg (36%) of methyl ester, which was used in the next step without further purification.

Stage 2. Ester (293 mg, 0.76 mmol) was dissolved in acetonitrile (16.7 ml). At RT, a solution of lithium hydroxide (55 mg, 2.28 mmol) in water (0.65 ml) was added. The mixture was stirred at RT overnight. Water was added and the pH was adjusted to 6 with 2N. HCl. The precipitate was filtered off with suction, washed with water and dried in vacuo at 50 ° C to give 93 mg (33%) of the title compound, which was used without further purification in the next step.

LCMS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.2 vol% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0 -1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): R _t = 0.64 min; MS (ESI positive): m / z = 371.3 [M + H] ⁺ .

Intermediate 20. Dimethyl {2-oxo-2- [4- (trifluoromethoxy) phenyl] ethyl} malonate

4.1 g of dimethylmalonate and 3.2 g of potassium carbonate were added to a solution of 4.4 g of 2-bromo-1- [4- (trifluoromethoxy) phenyl] ethan-1-one in 110 ml of acetone. The reaction mixture was stirred at room temperature overnight 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 (gradient: hexane / ethyl acetate with up to 30% ethyl acetate) to obtain 4.9 g of dimethyl {2-oxo-2- [4- (trifluoromethoxy) phenyl] ethyl} malonate.

LC-MS (instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): R _t = 1.22 min; MS (ESI positive): m / z = 335 [M + H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.33 (s, 6H), 3.62-3.67 (m, 2H), 3.99 (t, 1H), 7.52 (dd, 2H), 8.118 .16 (m, 2H).

Intermediate 21. Methyl 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3,4,5-tetrahydropyridazine-4-carboxylate

CH ₃

N — N

X M CL

О CH ₃ pF

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

¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

Intermediate 22. Methyl 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylate

- 39 037978

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

1H NMR (400 MHz, DMSO-d ₆ ) 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).

Intermediate 23.2- (1-Methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine-4-carboxylic acid

A mixture of 528 mg methyl 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylate and 1.7 ml of 2N. an aqueous solution of sodium hydroxide in 7 ml of tetrahydrofuran was stirred at RT for 14 h. Then the pH value was adjusted to 3 with 1M hydrochloric acid and the precipitate was filtered off, washed with water and dried in vacuo to give 458 mg of 2- (1-methyl-1H- pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylic acid.

¹ H NMR (400 MHz, DMSO-d ₆ ) [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).

Intermediate 24. Dimethyl {2- [4- (difluoromethyl) phenyl] -2-oxoethyl} propanedioate

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

1 H-NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 3.64-3.70 (m, 8H); 4.00 (t, 1H); 7.15 (t, 1H); 7.74 (d, 2H); 8.12 (d, 2H).

Intermediate 25. Methyl 6- [4- (difluoromethyl) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

- 40 037978

A mixture of 75 mg of dimethyl {2- [4- (difluoromethyl) phenyl] -2-oxoethyl} propanedioate, 44 mg of 4-hydrazino-1-methyl-1H-pyrazole dihydrochloride and 53 mg of sodium acetate in 2.5 ml of AcOH was stirred at RT for 1 h and 50 ° C for 24 h. Another 88 mg of 4-hydrazino-1-methyl-1H-pyrazole dihydrochloride was added and the reaction mixture was stirred at 50 ° C for 6 h. The reaction mixture was concentrated and the residue was taken up in water and ethyl acetate followed by the addition of saturated aqueous sodium bicarbonate solution. 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 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) to give 24 mg methyl 6- [4- (difluoromethyl) phenyl] -2- (1-methyl1H-pyrazol-4-yl) -3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate.

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

Intermediate 26. Methyl 6- [4- (difluoromethyl) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3-dihydropyridazine-4-carboxylate

CH ₃ Ν — NV N.. О _F ij IY ^V CH ₃

F

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) chloride in 15 ml of acetonitrile was stirred at 90 ° C for 2 h. After evaporation in a vacuum, the residue was suspended in water and the precipitate was filtered off to obtain 451 mg of methyl 6- [4- (difluoromethyl) phenyl] -2- ( 1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylate.

Ή NMR (400 MHz, 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).

Intermediate 27.6- [4- (Difluoromethyl) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

A mixture of 451 mg methyl 6- [4- (difluoromethyl) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylate and 6 ml of 1N. aqueous sodium hydroxide solution in 19 ml of tetrahydrofuran was stirred at RT for 48 h. Then the pH value was adjusted to 3 with 1M hydrochloric acid and the precipitate was filtered off, washed with water and dried in vacuo to obtain 190 mg of 6- [4- (difluoromethyl) phenyl ] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 3.93 (s, 3H), 7.13 (t, 1H), 7.72 (d, 2H), 8.13 (s, 1H), 8.23 ( d, 2H),

- 41 037978

8.49 (s, 1H), 8.54 (s, 1H).

Intermediate 28. Dimethyl {2- [6- (difluoromethyl) pyridin-3-yl] -2-oxoethyl} malonate

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

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

Intermediate 29. Methyl 6- [6- (difluoromethyl) pyridin-3-yl] -2- (1-methyl-1H-pyrazol-4yl) -3-oxo-2,3,4,5-tetrahydropyridazine-4- carboxylate

A mixture of 424 mg of dimethyl {2- [6- (difluoromethyl) pyridin-3-yl] -2-oxoethyl} malonate, 549 mg of 4-hydrazino-1-methyl-1H-pyrazole dihydrochloride and 520 mg of sodium acetate in 13 ml of AcOH was stirred at RT for 1 h and at 50 ° C for 2 h. The reaction mixture was concentrated and the residue was taken up in water and ethyl acetate, followed by the addition of saturated aqueous sodium bicarbonate solution. 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 (gradient: dichloromethane / methanol to 8% methanol) to give 240 mg of methyl 6- [6- (difluoromethyl) pyridin-3-yl] -2- (1-methyl-1H-pyrazole-4- yl) -3-oxo-2,3,4,5tetrahydropyridazine-4-carboxylate.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

Intermediate 30. Methyl 6- [6- (difluoromethyl) pyridin-3-yl] -2- (1-methyl-1H-pyrazol-4yl) -3-oxo-2,3-dihydropyridazine-4-carboxylate

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

Ή NMR (400 MHz, DMSO-d ₆ ) 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).

Intermediate 31.6- [6- (Difluoromethyl) pyridin-3-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3-dihydropyridazine-4-carboxylic acid

- 42 037978

A mixture of 133 mg methyl 6- [6- (difluoromethyl) pyridin-3-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3 dihydropyridazine-4-carboxylate and 0.46 ml of 2n ... an aqueous solution of sodium hydroxide in 2 ml of tetrahydrofuran was stirred at RT for 14 h. Then the pH value was adjusted to 3 with 1M hydrochloric acid and the precipitate was filtered off, washed with water and dried in vacuo to give 103 mg of 6- [6- (difluoromethyl) pyridine -3-yl] -2- (1-methyl-III-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

Intermediate 32.5-Bromo-2- (difluoromethyl) pyridine

A solution of 5-bromopyridine-2-carbaldehyde (30 g, 161.29 mmol, 1.00 eq.) In dichloromethane (800 ml) was placed in a 2000 ml 4-necked round-bottom flask. Thereafter, DAST (diethylaminosulfur trifluoride) (40 g, 1.08 mol, 6.69 equiv.) Was added dropwise with stirring at 0 ° C. The resulting solution was stirred for 12 hours at room temperature. The reaction mixture was then quenched by the addition of water. The solution was adjusted to pH 8 with sodium carbonate (2 mol / L). The resulting solution was extracted with 3x500 ml dichloromethane and the organic layers were combined. The resulting mixture was washed with 1 x 300 ml of H ₂ O. The resulting mixture was washed with 1 x 300 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:10). This gave 18 g (54%) of 5-bromo-2- (difluoromethyl) pyridine as a yellow oil.

Intermediate 33.1- [6- (Difluoromethyl) pyridin-3-yl] ethanone

O

R J

F

A solution of 5-bromo-2- (difluoromethyl) pyridine (18 g, 86.54 mmol, 1.00 equiv.) In dioxane (180 ml), tributyl (1-ethoxyethenyl) stannane (35 g, 96.91 mmol, 1.12 eq.), Tetrakis (triphenylphosphane) palladium (3 g, 2.60 mmol, 0.03 eq.). The resulting solution was stirred for 2 h at 100 ° C. The reaction mixture was cooled with a water bath. The reaction mixture was then quenched by the addition of 250 ml (2N) HCl. The solution was adjusted to pH 8 with sodium carbonate (2 mol / L). The resulting solution was extracted with 3x500 ml ethyl acetate and the organic layers were combined. The resulting mixture was washed with 1x200 ml H2O. The resulting mixture was washed with 1x200 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (1:10). This gave 10 g (68%) of 1- [6- (difluoromethyl) pyridin-3-yl] ethan-1-one as a yellow oil.

Intermediate 34. Diethyl {2- [6- (difluoromethyl) pyridin-3-yl] -2-oxoethyl} (hydroxy) malonate

- 43 037978

1- [6- (difluoromethyl) pyridin-3-yl] ethan-1-one (10 g, 58.43 mmol, 1.00 eq.) And 1,3-diethyl 2-oxopropanedioate (15 g, 86.13 mmol, 1.47 eq.). The resulting solution was stirred for 24 h at 130 ° C. The resulting mixture was concentrated in vacuo. This gave 24 g (crude) 1,3-diethyl 2- [2- [6- (difluoromethyl) pyridin-3-yl] -2oxoethyl] -2-hydroxypropanedioate as a red oil, which was used without further purification.

Intermediate 35. Ethyl 6- [6- (difluoromethyl) pyridin-3-yl] -3-oxo-2,3-dihydropyridazine-4-carboxylate

A solution of 1,3-diethyl 2- [2- [6- (difluoromethyl) pyridin-3-yl] 2-oxoethyl] -2-hydroxypropanedioate (24 g, 69.51 mmol, 1.00 eq.) In ethanol (200 ml) and hydrazine (15 ml). The resulting solution was stirred for 12 hours at 80 ° C. The reaction mixture was then quenched by the addition of water. The resulting solution was extracted with 3x300 ml ethyl acetate and the organic layers were combined. The resulting mixture was washed with 1 x 100 ml of water. The resulting mixture was washed with 1 x 100 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (2: 1). This gave 2.8 g (14%) ethyl 6- [6- (difluoromethyl) pyridin-3-yl] -3-oxo-2,3-dihydropyridazine-4-carboxylate as a yellow solid.

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

Intermediate 36. Methyl 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3,4,5tetrahydropyridazine-4-carboxylate

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 for 24 h at RT. Once again, 3-hydrazinopyridine hydrochloride (1: 1) (0.961 g, 6.60 mmol) was added and stirring was continued for 24 h at RT. Then 3-hydrazinopyridine hydrochloride (1: 1) (0.961 g, 6.60 mmol) was added again and the mixture was stirred for 24 h at RT. Finally, the mixture was stirred for 7 hours at 80 ° C. The reaction mixture was cooled and concentrated on a rotary evaporator under reduced pressure. Ethyl acetate and water were added to dissolve the residue. Was added concentrated aqueous sodium hydrogen carbonate solution, the phases were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed three times with water, dried over magnesium sulfate and concentrated. The residue was purified by RP-HPLC (column: YMC-Triart C18 5 μm 100x50 mm, mobile phase: (gradient: water + 0.1 vol% formic acid (99%)) / acetonitrile) to give 398 mg (18%) of the indicated in the title of the product.

Ή-NMR (400 MHz, DMSO-d ₆ ): 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).

Intermediate 37.6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4carboxylic acid

- 44 037978

Stage 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 for 4 h at 90 ° C. The mixture was cooled and concentrated on a rotary evaporator. Water was added, the remaining solid was filtered with suction, washed five times with water and dried in vacuo at 50 ° C for 24 h to give 1.262 g of methyl 6- (4-chlorophenyl) 3-oxo-2- (pyridin-3-yl ) -2,3-dihydropyridazine-4-carboxylate, which were used without further purification in the next step.

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 RT. The mixture was stirred for 10 h at 40 ° C. Water was added and the pH was adjusted to 6-7 with 0.5N. HCl. The precipitate was filtered off with suction, washed three times with water and dried in vacuo at 50 ° C to give 910 mg (95%) of the title compound, which was used without further purification in the next step.

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

Intermediate 38. Diethyl 2- (2- (4-chlorophenyl) -2-oxoethyl) -2-hydroxymalonate

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 h. The reaction was monitored by TLC, and after its completion, the reaction mixture was cooled and triturated with pentane to give diethyl 2- (2- (4-chlorophenyl) -2 oxoethyl) -2-hydroxymalonate (50 g, 79%, LCMS 98%) as a pale yellow liquid.

Intermediate 39. Ethyl 6- (4-chlorophenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate

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 h. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled and concentrated under reduced pressure. The reaction mixture was poured into sat. sodium bicarbonate solution (500 ml) and extracted with ethyl acetate (3x600 ml). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the 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.

1H NMR (400 MHz, DMSO-d ₆ ) 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).

Intermediate 40. Methyl 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylate

Methyl 6- (4-chlorophenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate (682.3 mg, 2.578 mmol) was dissolved in DMF (27 ml). Added 3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (1150 mg, 5.156 mmol), 2,2'-bipyridine (1007 mg, 6.445 mmol), sodium carbonate (328 mg, 3.093 mmol) and anhydrous copper diacetate (585 mg, 3.222 mmol). The mixture was stirred for 5 h at 40 ° C. The reaction mixture was cooled, water was added and the pH was adjusted to 3 with 2N. HCl. Sediment

- 45 037978 was filtered, washed with water and dried at 50 ° C under vacuum. The crude material was purified by flash chromatography (silica gel, gradient: hexane / ethyl acetate) to give 174 mg (13%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 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, IH), 8.72 (dd, IH), 8.86 (br t, IH).

Intermediate 41.6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

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). At RT, a solution of lithium hydroxide (34 mg, 1.418 mmol) in water (0.40 ml) was added. The mixture was stirred for 24 h at RT. Water was added and the pH was adjusted to 6 with 2N. HCl. The precipitate was filtered off with suction, washed with water and dried in vacuo at 50 ° C to give 157 mg (96%) of the title compound, which was used without further purification in the next step.

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

Intermediate 42. Methyl 3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3 dihydropyridazine-4-carboxylate

Methyl 3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylate (2 g, 6.71 mmol) was dissolved in DMF (90 ml). Added 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (2.75 g, 13.41 mmol), 2,2'-bipyridine (2.62 g, 16.77 mmol), carbonate sodium (0.85 g, 8.02 mmol) and anhydrous copper diacetate (1.52 g, 8.37 mmol). The mixture was stirred for 3 h at 60 ° C. The reaction mixture was cooled with 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 at 50 ° C in vacuo to give 1.8 g (72%) of the title compound.

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

Intermediate 43.3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid

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). At RT, a solution of lithium hydroxide (345 mg, 23.95 mmol) in water (5 ml) was added. The mixture was stirred at RT overnight. Water (100 ml) was added and the pH was adjusted to 6 with 2N. HCl (4.5 ml). Methylene chloride (50 ml) and chloroform (50 ml) were added to the reaction mixture. The organic layer was separated and discarded. The precipitate was filtered off with suction, washed with water and dried in vacuo at 50 ° C to give 1036 mg (60%) of the title compound, which was used without further purification in the next step.

- 46 037978 ¹ H-NMR (400 MHz, DMSO-de): 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).

Intermediate 44. Diethyl hydroxy {2-oxo-2- [4- (trifluoromethoxy) phenyl] ethyl} malonate

A mixture of 1 - (4- (trifluoromethoxy) phenyl) ethanone

(20 g, 98.03 mmol) and diethyl ketomalonate (23 ml,

147.02 mmol) was heated at 130 ° C for 48 h and the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to 0-5 ° C and triturated with petroleum ether to obtain diethyl 2-hydroxy-2- (2-oxo-2- (4- (trifluoromethoxy) phenyl) ethyl) malonate 3 (35 g , 94%, LCMS 98%) as a pale yellow liquid.

Intermediate 45. Ethyl 3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine 4-carboxylate

A mixture of 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) was heated reflux for 16 h and the reaction was monitored by TLC. Upon completion, the reaction mixture was cooled to RT and concentrated under reduced pressure, the pH was adjusted to 7 using sat. aqueous sodium bicarbonate solution (150 ml) and was extracted in ethyl acetate (3x350 ml). The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to give the 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 %, LCMS 97%) as an off-white solid.

1H NMR (400 MHz, DMSO-de) 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).

Intermediate 46.3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylic acid

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 for 4 h at 80 ° C, cooled, followed by the addition of 6 ml of 2N. an aqueous solution of sodium hydroxide. Water was added and the precipitate was filtered and dried in vacuo to give 2.5 g of the title compound.

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): Rt = 1.14 min; MS (ESI positive): m / z = 378.4 [M + H] ⁺ .

Intermediate 47. Methyl 6- [4- (difluoromethyl) phenyl] -3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

- 47 037978

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

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

Intermediate 48. Methyl 6- [4- (difluoromethyl) phenyl] -3-oxo-2,3-dihydropyridazine-4carboxylate

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 for 1 hour. After evaporation in a vacuum, the residue was suspended in water and the precipitate was filtered off to obtain 1420 mg of methyl 6- [4- (difluoromethyl) phenyl] -3-oxo-2,3-dihydropyridazine-4-carboxylate.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

Intermediate 49.6- [4- (Difluoromethyl) phenyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid

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). The reaction mixture was stirred for 5 h at 80 ° C, cooled, followed by the addition of water. The pH was adjusted to 9 by adding 1M aqueous sodium hydroxide solution, and the precipitate was filtered off and dried in vacuo to give 481 mg of the title compound.

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

Intermediate 50.6- (4-Methylphenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

A solution of 500 mg of ethyl 6-chloro-3-hydroxypyridazine-4-carboxylate and 436 mg of 4-tolylboronic acid in 20 ml of dioxane was treated with tripotassium phosphate (15 ml of a 0.5M solution in water) and Pd with a second generation RuPhos precatalyst (CAS No. [1375325- 68-0]; 383 mg), heated to 100 ° C and stirred for 4 h. The reaction mixture was cooled to room temperature, the formed precipitate was filtered off, washed with 1,4-dioxane (2 ml) and dried. The resulting material was taken up in water and freeze-dried to give the title compound (406 mg), which was used in the next step without further purification.

- 48 037978

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

Intermediate 51.6- (4-Methylphenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine 4-carboxylic acid

6- (4-Methylphenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg) was dissolved in DMF (3 ml). Added 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (89 mg), 2,2'bipyridine (170 mg), sodium carbonate (28 mg) and anhydrous copper diacetate (99 mg). The reaction mixture was stirred for 4 h at 70 ° C. The reaction mixture was filtered and purified using SPHPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: water + 0.2 vol.% Aqueous ammonia (32% ), eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) to give 17 mg of 6- (4-methylphenyl) -3 -oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid.

LCMS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.2 vol% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0 -1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): R _t = 0.58 min; MS (ESI positive): m / z = 308.5 [M + H] ⁺ .

Intermediate 52. Diethyl [2- (4-chloro-2-fluorophenyl) -2-oxoethyl] (hydroxy) malonate

In a 100-ml round-bottom flask were placed 1- (4-chloro-2-fluorophenyl) ethan-1-one (10 g, 57.94 mmol, 1.00 eq.) And 1,3-diethyl 2-oxopropanedioate (15 ml). The resulting solution was stirred for 24 h at 130 ° C. The resulting mixture was concentrated in vacuo. This gave 24 g of (crude) 1,3-diethyl 2- [2- (4-chloro-2-fluorophenyl) -2-oxoethyl] -2-hydroxypropanedioate as a black oil, which was used without further purification.

Intermediate 53. Ethyl 6- (4-chloro-2-fluorophenyl) -3-oxo-2,3-dihydropyridazine-4carboxylate

A solution of 1,3-diethyl 2- [2- (4-chloro-2-fluorophenyl) -2oxoethyl] -2-hydroxypropanedioate (24 g, 69.22 mmol, 1.00 eq.) In ethanol (250 ml ) and hydrazine (15 ml). The resulting solution was stirred for 12 hours at 80 ° C. The reaction mixture was then quenched by the addition of 200 ml of water. The resulting solution was extracted with 2x200 ml ethyl acetate and the organic layers were combined. The resulting mixture was washed with 1 x 100 ml of water. The resulting mixture was washed with 1 x 100 ml of brine. The mixture was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (2: 1). This gave 2.9 g (14%) of ethyl 6- (4-chloro-2-fluorophenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate as a pink solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

Intermediate 54.6- (4-Chloro-2-fluorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid

- 49 037978

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

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): Rt = 1.04 min; MS (ESI positive): m / z = 346.3 [M + H] ⁺ .

Intermediate 55.3- (4-Chlorophenyl) -6-oxo-6H-1,4'-bipyridazine-5-carboxylic acid

Ethyl 6- (4-chlorophenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate (500 mg) was dissolved in DMF (23 ml). 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridazine (739 mg), 2,2'-bipyridine (1.12 g), sodium carbonate (228 mg) and anhydrous copper diacetate (815 mg). The reaction mixture was stirred at RT for 14 h, followed by the addition of 1.8 ml of 2N. an aqueous solution of sodium hydroxide. Water was added and the precipitate was filtered and dried in vacuo to give 438 mg of the title compound.

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): R _t = 0.90 min; MS (ESI positive): m / z = 329.2 [M + H] ⁺ .

Intermediate 56.3-Oxo-6- [6- (trifluoromethyl) pyridin-3-yl] -2,3-dihydropyridazine 4-carboxylic acid

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 equiv., 551 mg, 2.89 mmol) in 1,4-dioxane (17 ml) was treated with tripotassium phosphate (3.00 equiv. 6.7 mmol, 13.3 ml 0.5 M solution in water) and Pd with the second generation RuPhos precatalyst (CAS No. [1375325-68-0]; 0.20 equiv. 345 mg, 444 μmol), heated to 100 ° C and stirred for 4.5 h. The reaction mixture was cooled to room temperature, the formed precipitate was filtered off, washed with 1,4-dioxane (2 ml) and dried. The resulting material was taken up in water and freeze-dried to give the title compound (555 mg), which was used in the next step without further purification.

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

Intermediate 57. N - [(2S) -1-Hydroxypropan-2-yl] -3-oxo-6- [6- (trifluoromethyl) pyridin-3-yl] -2,3-dihydropyridazine-4-carboxamide

- 50 037978

A suspension of crude 3-oxo-6- [6- (trifluoromethyl) pyridin-3-yl] -2,3-dihydropyridazine-4-carboxylic acid (486 mg, 0.852 mmol) in DMF (6 ml) was treated with a solution of (2S) - 2-aminopropan-1-ol (CAS # [2749-11-3]; 2.00 equiv. 128 mg, 1.70 mmol) in DMF (6 ml), N, N-diisopropylethylamine (4.50 equiv. 670 μl, 3.80 mmol) and 2,4,6-trioxide 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane (CAS No. [68957-948]; 1.50 equiv. 1.28 mmol, 750 μl 50 wt.% Solution in DMF) and stirred at room temperature for one week. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative reverse phase HPLC, followed by lyophilization to give the title compound (150 mg).

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

Intermediate 58. Diethyl [2- (4-cyanophenyl) -2-oxoethyl] (hydroxy) malonate

In a 100-ml round-bottom flask were placed 4-acetylbenzonitrile (10 g, 68.89 mmol, 1.00 eq.) And 1,3 diethyl 2-oxopropanedioate (15 g, 86.13 mmol, 1.25 eq.). The resulting solution was stirred for 24 h at 130 ° C. The resulting mixture was concentrated in vacuo. This gave 25 g (114%) 1,3-diethyl 2- [2- (4-cyanophenyl) -2-oxoethyl] -2-hydroxypropanedioate as a black oil, which was used without further purification.

Intermediate 59. Ethyl 6- (4-cyanophenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate

H

BUT

IX X 1 SN ₃

In a 500-ml round-bottom flask, a solution of 1,3-diethyl 2- [2- (4-cyanophenyl) -2-oxoethyl] -2-hydroxypropanedioate (25 g, 78.29 mmol, 1.00 eq.) In ethanol (200 ml) and hydrazine was placed (15 ml). The resulting solution was stirred for 12 hours at 80 ° C. The reaction mixture was then quenched by the addition of 200 ml of water. The resulting solution was extracted with 2x200 ml ethyl acetate and the organic layers were combined. The resulting mixture was washed with 1 x 100 ml of water. The resulting mixture was washed with 1 x 100 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was applied to a silica gel column using ethyl acetate / petroleum ether (2: 1). This gave 6 g (28%) ethyl 6- (4-cyanophenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate as a yellow solid.

1H NMR (400 MHz, DMSO-d ₆ ) 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).

Intermediate 60.6- (4-Cyanophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine 4-carboxylic acid

- 51 037978

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

LCMS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): Rt = 0.81 min; MS (ESI positive): m / z = 319.3 [M + H] ⁺ .

Intermediate 61. Methyl 6- (4-chlorophenyl) -3-oxo-2- (pyrimidin-5-yl) -2,3-dihydropyridazine-4-carboxylate

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

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.89 (s, 3H), 7.59 (br d, 2H), 8.04 (br d, 2H), 8.57 (s, 1H ), 9.209.33 (m, 3H).

Intermediate 62.6- (4-Chlorophenyl) -3-oxo-2- (pyrimidin-5-yl) -2,3-dihydropyridazine-4-carboxylic acid

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). At RT, a solution of lithium hydroxide (57.6 mg, 2.41 mmol) in water (0.45 ml) was added. The mixture was stirred for 24 h at 40 ° C.

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

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.54 (d, 2H), 7.87 (s, 1H), 7.99 (d, 2H), 9.23 (s, 2H), 9.29 (s, 1H).

Intermediate 63. Methyl 6- (4-chlorophenyl) -3-oxo-2- (1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol-4-yl) -2,3-dihydropyridazine-4 -carboxylate

- 52 037978

Batch 1. Methyl 6- (4-chlorophenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate (200 mg) was dissolved in DMF (12 ml). Added 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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). The mixture was stirred for 5 h at RT. Water was added and the pH was adjusted to 3 with 2N. HCl. The volatiles were removed in vacuo on a rotary evaporator. Water was added and the aqueous phase was extracted three times with chloroform. The combined organic layers were dried over magnesium sulfate and concentrated to give 265 mg of crude product, which was purified along with a second batch.

Batch 2. Methyl 6- (4-chlorophenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate (544 mg) was dissolved in acetonitrile (5.4 ml). Added 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazole (1 g), pyridine (333 μl), N, N-diethylethanamine (573 μl), anhydrous copper diacetate (747 mg) and molecular sieves (544 mg, 0.4 nm, particle size: <50 μm). The mixture was stirred for one day at RT. 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 - {[2 (trimethylsilyl) ethoxy] methyl} -1H-pyrazole (320 mg) was added and stirring was continued for another day with CT. Silica gel was added and the volatiles were removed in vacuo. The mixture was pre-purified by flash chromatography (silica gel, gradient: hexane / ethyl acetate) to give 427 mg of product, which was combined with the first batch and purified by flash chromatography (silica gel, hexane / ethyl acetate 7: 3) to give 220 mg of the indicated in the connection header.

¹ H-NMR (400 MHz, DMSO-de): 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).

Intermediate 64.6- (4-Chlorophenyl) -3-oxo-2- (1 - {[2- (trimethylsilyl) ethoxy] methyl} 1H-pyrazol-4-yl) -2,3-dihydropyridazine-4-carboxylic acid

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 at RT overnight. 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 with suction, washed with water and dried in vacuo at 50 ° C. to give 36 mg of the title compound, which was used without further purification in the next step.

1H-NMR (400 MHz, DMSO-de): 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).

Intermediate Ridazine-4-Carboxylic Acid

65.6- (4-Chlorophenyl) -3-oxo-2- (1H-pyrazol-4-yl) -2,3-dihydrop-

Method 1, stage 1. Methyl

6- (4-chlorophenyl) -3-oxo-2- (1- {[2- (trimethylsilyl) ethoxy] methyl} -1H pyrazol-4-yl) -2,3-dihydropyridazine-4-carboxylate (220 mg) dissolved in ethanol (1.85 ml). Hydrochloric acid in dioxane (1.85 ml, 4M in dioxane) was added and the mixture was stirred for 2 h at 70 ° C. The reaction mixture was allowed to reach RT and concentrated to dryness to give 169 mg of methyl

- 53 037978

6- (4-chlorophenyl) -3-oxo-2- (1H-pyrazol-4-yl) -2,3-dihydropyridazine-4-carboxylate. This material was used without further purification in the next step.

Method 2, step 1. 6- (4-Chlorophenyl) -3-oxo-2- (1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazole-4yl) -2,3-dihydropyridazine-4- carboxylic acid (34 mg) was dissolved in ethanol (0.29 ml). Hydrochloric acid in dioxane (0.29 ml, 4M in dioxane) was added and the mixture was stirred for 2 h at 70 ° C. The reaction mixture was allowed to reach RT and stirring was continued at RT overnight. The reaction mixture was concentrated to dryness to give 27 mg of a mixture of ethyl 6- (4-chlorophenyl) -3-oxo-2- (1Hpyrazol-4-yl) -2,3-dihydropyridazine-4-carboxylate and 6- (4-chlorophenyl) - 3-oxo-2- (1H-pyrazol-4-yl) -2,3 dihydropyridazine-4-carboxylic acid. This material was used without further purification in the next step.

Step 2. The crude material obtained in Method 1 and Method 2 was combined in acetonitrile (5 ml). Lithium hydroxide (80 mg) and water (0.6 ml) were added and the mixture was stirred at RT for 1 h. Water (5 ml) was added and the pH was adjusted to 3 with 2N HCl. HCl (1.2 ml). The precipitate was filtered off with suction, washed with water and dried in vacuo at 50 ° C. to give 186 mg of the title compound, which was used without further purification in the next step.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.56-7.61 (m, 2H), 8.09-8.14 (m, 2H), 8.34 (br s, 2H), 8.44 ( s, 1H), 13.45 (br s, 2H).

Intermediate 66.6- [4- (Dimethylamino) phenyl] -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

i ch ₃

A solution of ethyl 6-chloro-3-hydroxypyridazine-4-carboxylate (200 mg) and 4- (dimethylamino) benzene boronic acid (212 mg) in 1,4-dioxane (8 ml) was treated with tripotassium phosphate (6 ml of a 0.5 M solution in water ) and Pd with a second generation RuPhos precatalyst (153 mg), heated to 75 ° C and stirred for 6 h. The reaction mixture was cooled to room temperature, treated with water, and the pH value was adjusted to 3 by adding 1M HCl. The formed precipitate was filtered off, 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: gradient pump Labomatic HD-3000 HPLC, fraction collector: Labomatic Labocol Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; gradient : A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) to obtain 59 mg of 6- [4- (dimethylamino) phenyl] -3-oxo 2,3-dihydropyridazine-4-carboxylic acid.

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

Intermediate 67.6- [4- (Dimethylamino) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -3oxo-2,3-dihydropyridazine-4-carboxamide

A solution of 59 mg of 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 of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 3 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column : Chromatorex C-18 125x30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) to obtain 11 mg of 6- [4- (dimethylamino) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2,3-dihydropyridazine-4-carboxamide.

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 1-99% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): R _t = 0.84 min ; MS (ESI positive): m / z = 317.3 [M + H] ⁺ .

Intermediate 68. Methyl 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) -3-oxo2,3,4,5-tetrahydropyridazine-4-carboxylate

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Dimethyl [2- (4-chlorophenyl) -2-oxoethyl] malonate (200 mg) and sodium acetate (259 mg) were dissolved in acetic acid (7 ml). Then 3-hydrazinyl-1-methyl-1H-pyrazole trihydrochloride (327 mg) was added portionwise. The mixture was stirred at RT overnight and for 1 h at 50 ° C. 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 125x30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) to obtain 119 mg methyl 6- (4-chlorophenyl) -2- (1-methyl- 1H-pyrazol-3-yl) -3-oxo-2,3,4,5-tetrahydropyridazine-4carboxylate.

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

Intermediate 69. Methyl 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylate

H ₃ C

Η .O ^sn z

JI about

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 for 1 hour at 90 ° C. The reaction mixture was cooled, poured into 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 without further purification in the next step.

1H NMR (400 MHz, DMSO-de) 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).

Intermediate 70.6- (4-Chlorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

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 RT for 14 h. Water was added and the pH value was adjusted to 3 with 2N HCl. HCl. The precipitate was filtered off with suction, washed three times with water and dried with lyophilization to give 94 mg of the title compound, which was used without further purification in the next step.

1H NMR (400 MHz, DMSO-de) 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).

Intermediate 71. Methyl 6- (4-chlorophenyl) -2- (3-methyl-1H-pyrazol-5-yl) -3-oxo2,3,4,5-tetrahydropyridazine-4-carboxylate

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Dimethyl [2- (4-chlorophenyl) -2-oxoethyl] malonate (200 mg) and sodium acetate (259 mg) were dissolved in acetic acid (7 ml). Then 5-hydrazinyl-3-methyl-1H-pyrazole hydrochloride (220 mg) was added in portions. The mixture was stirred at RT overnight and for 1 h at 50 ° C. 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 125x30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) yielding 126 mg methyl 6- (4chlorophenyl) -2- (3-methyl-1H- pyrazol-5-yl) -3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate.

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): Rt = 1.07 min; MS (ESI positive): m / z = 347.3 [M + H] ⁺ .

Intermediate 72. Methyl 6- (4-chlorophenyl) -2- (3-methyl-1H-pyrazol-5-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylate

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

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): R _t = 1.08 min; MS (ESI positive): m / z = 345.3 [M + H] ⁺ .

Intermediate 73.6- (4-Chlorophenyl) -2- (3-methyl-1H-pyrazol-5-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

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 RT for 14 h. Water was added and the pH was adjusted to 3 with 2N HCl. HCl. The precipitate was filtered off with suction, washed three times with water and dried by lyophilization to give 80 mg of the title compound, which was used without further purification in the next step.

¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

Intermediate 74. Methyl 6- (4-chlorophenyl) -3-oxo-2- (1,2-thiazol-4-yl) -2,3-dihydropyridazine-4-carboxylate

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Methyl 6- (4-chlorophenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate (500 mg) was added to acetonitrile (5 ml). Powdered molecular sieve (500 mg, 4 A, 50 μm), 4- (4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl) -1,2-thiazole (483 mg), pyridine (153 μl), triethylamine (263 μl) and anhydrous copper diacetate (343 mg). The mixture was stirred for 3 h at RT. Added 4- (4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl) -1,2-thiazole (211.1 mg), pyridine (104 μl), triethylamine (179 μl) and anhydrous copper diacetate (343 mg). The mixture was stirred for 16 h at RT. Silica gel was added and the volatiles were removed in vacuo. The mixture was purified using flash chromatography (silica gel, gradient: hexane / ethyl acetate) to give 317 mg of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 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).

Intermediate 75.6- (4-Chlorophenyl) -3-oxo-2- (1,2-thiazol-4-yl) -2,3-dihydropyridazine 4-carboxylic acid

Methyl 6- (4-chlorophenyl) -3-oxo-2- (1,2-thiazol-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 adjusted (pH 4) and lithium hydroxide (87 mg) was added again. The mixture was stirred for 1 h at RT. Water (5 ml) was added and the pH was adjusted to 3 with 2N. HCl (1.2 ml). The precipitate was filtered off with suction, washed with water and dried in vacuo at 50 ° C to give 340 mg of the title compound, which was used without further purification in the next step.

¹ H-NMR (400 MHz, 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).

Intermediate 76. Diethyl hydroxy {2-oxo-2- [4- (trifluoromethyl) phenyl] ethyl} malonate

1- [4- (Trifluoromethyl) phenyl] ethanone (50 g, 0.266 mol) and diethyloxomalonate (66.0 g, 0.379 mol) were stirred at 120 ° C for 48 h. The reaction mixture was cooled to RT and the solid was filtered and washed with petroleum ether (300 ml) to give 70 g (73%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 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).

Intermediate 77. Ethyl 3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4carboxylate

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 RT and concentrated under reduced pressure. The crude pro 57 037978 duct was purified by column chromatography (silica gel, hexane / ethyl acetate 50%) to give

35.0 g (58%) of the title compound.

¹ H-NMR (400 MHz, 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).

Intermediate dihydropyridazine-4-carboxylate

78. Ethyl 3-oxo-2- (1,2-thiazol-4-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-

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

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

1H), 9.15 (s, 1H), 9.60 (s, 1H).

Intermediate 79. ropyridazine-4-carboxylic acid

3-Oxo-2- (1,2-thiazol-4-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihyd-

To ethyl 3-oxo-2- (1,2-thiazol-4-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylate (1.91 g, 3.88 mmol) in acetonitrile ( 35 ml), lithium hydroxide (278 mg, 11.63 mmol) in water (4.2 ml) was added. The mixture was stirred for 2 h at RT. 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 in vacuo at 50 ° C. to give 1.3 g of the title compound and starting material.

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

The remaining substance with impurities (720 mg) was stirred in an aqueous solution of sodium hydroxide for 1 h at RT. The pH value was adjusted to 3 with hydrochloric acid (2 ml, 2 M), and the mixture was stirred for 0.5 h at RT. The solid was filtered, washed three times with water, dried in vacuo at 50 ° C to give 660 mg (37%) of the title compound.

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

Intermediate 80. Ethyl 3-oxo-6- [4- (trifluoromethyl) phenyl] -2- (1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazol-4-yl) -2,3- dihydropyridazine-4-carboxylate

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Ethyl 3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylate (1.00 g, 3.20 mmol) was suspended in acetonitrile (10 ml). Added 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1 {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazole (1.35 g, 4.16 mmol) , pyridine (0.52 ml, 6.41 mmol), N, N diethylethanamine (0.893 ml, 6.41 mmol) and anhydrous copper diacetate (756 mg, 4.16 mmol). The mixture was stirred for 4 days at RT. 1 equivalent of 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl) -1 - {[2- (trimethylsilyl) ethoxy] methyl} -1H-pyrazole was added. The mixture was stirred for 1 day at RT, 1 day at 50 ° C, 8 h at 60 ° C and overnight at 50 ° C. The reaction mixture was cooled and purified by column chromatography (silica gel, hexane / ethyl acetate 75:25) to provide 1.44 g (88%) of the title compound.

¹ H-NMR (400 MHz, 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).

Intermediate 81. 3-Oxo-2- (1H-pyrazol-4-yl) -6- [4- (trifluoromethyl) phenyl] -2,3 dihydropyridazine-4-carboxylic acid

Stage 1. Ethyl 3-oxo-6- [4- (trifluoromethyl) phenyl] -2- (1 - {[2- (trimethylsilyl) ethoxy] methyl} -1Hpyrazol-4-yl) -2,3-dihydropyridazine-4 β-carboxylate (1.38 g, 3.20 mmol) was suspended in ethanol (11.3 ml). Hydrochloride in dioxane (11.3 ml, 4M) was added and stirred for 5 h at 70 ° C. The mixture was stirred overnight at RT and then for 5 h at 70 ° C. The reaction mixture was cooled and concentrated to dryness to give 1.01 g of compound, which was used without further purification in the next step.

Step 2. The intermediate compound (1.01 g) obtained in step 1 was suspended in acetonitrile (24 ml). Lithium hydroxide (192 mg, 8.01 mmol) in water (6 ml) was added and the mixture was stirred for 3 h at RT. 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 in vacuo at 50 ° C to give 695 mg (73%) of the title compound, which was used without further purification in the next step.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 7.87 (d, 2H), 8.27-8.43 (m, 5H), 13.38 (br s, 2H).

Intermediate 82.2- [1- (Difluoromethyl) -1H-pyrazol-4-yl] -3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid

Stage 1. Methyl 3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylate (0.40 g,

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1.34 mmol) was suspended in acetonitrile (7 ml). Added molecular sieves (400 mg, 0.4 nm, particle size: <50 μm), 1- (difluoromethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - 1H-pyrazole (491 mg, 2.01 mmol), pyridine (0.217 ml, 2.68 mmol), U, U-diethylethanamine (0.374 ml, 2.68 mmol) and anhydrous copper diacetate (487 mg, 2.68 mmol). The mixture was stirred for 24 h at RT. Added 1 (difluoromethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (300 mg, 1.23 mmol) and stirred for 3 days at RT ... The mixture was diluted with water and acidified with hydrochloric acid (2N). The solid was filtered off and dried in vacuo at 50 ° C to give 1.21 g of molecular sieve intermediate 1, which was used without further purification in the next step.

Step 2. The intermediate compound (1.01 g) obtained in step 1 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 for 20 h at 40 ° C. The reaction mixture was 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 with water three times and dried in vacuo at 50 ° C to give 380 mg (71%) of the title compound.

-NMR (400 MHz, DMSO-d ₆ ): 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).

Intermediate 83.6- (4-Chlorophenyl) -2- (5-fluoro-2-thienyl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

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). Added 2- (5-fluoro-2-thienyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (569 mg, 2.49 mmol), pyridine (0.122 ml, 1.51 mmol), U, U-diethylethanamine (0.211 ml, 1.51 mmol) and anhydrous copper diacetate (275 mg, 1.51 mmol). The mixture was stirred for 5 h at RT and 120 h at 50 ° C. The reaction mixture was diluted with buffer solution (15 ml, pH 7), stirred and the precipitate was filtered, washed three times with water and dried in vacuo at 50 ° C to give 446 mg of crude material, which was used without further purification in the next step.

Step 2. The intermediate compound (446 mg) obtained in step 1 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 for 24 h at RT. The reaction mixture was diluted with water (30 ml), the pH was adjusted to 3 with hydrochloric acid (2N) and the precipitate was filtered, washed with water three times and dried in vacuo at 50 ° C to give 335 mg of the compound, which was used without further purification for next stage.

LCMS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.2 vol% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0 -1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): R _t = 0.73 min; MS (ESI positive): m / z = 351.2 [M + H] ⁺ .

Intermediate 84. Methyl 6- (4-chlorophenyl) -2- (5-methyl-3-thienyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate

Methyl 6- (4-chlorophenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate (0.10 g, 0.378 mmol) was suspended in acetonitrile (2 ml). Added 4,4,5,5-tetramethyl-2- (5-methyl-3-thienyl) -1,3,2-dioxaborolane (127 mg, 0.567 mmol), pyridine (0.061 ml, 0.756 mmol), Y, Y β-diethylethanamine (0.105 ml, 0.756 mmol) and anhydrous copper diacetate (137 mg, 0.756 mmol). The mixture was stirred for 5 h at RT and 23 h at 50 ° C. The second batch, which was synthesized under similar conditions, but stirred for 24 h at 50 ° C, was combined with this batch and then poured into a buffer solution with a pH value of 7. The mixture

- 60 037978 was stirred for a short period of time, the precipitate was filtered, washed twice with water and dried in vacuo at 50 ° C to give 460 mg of the title compound, which was used without further purification in the next step.

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

Intermediate 85.6- (4-Chlorophenyl) -2- (5-methyl-3-thienyl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

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 for 24 h at 50 ° C. The reaction mixture was cooled, diluted with water (15 ml), the pH was adjusted to 3 with hydrochloric acid (2N) and the precipitate was filtered, washed with water twice and dried in vacuo at 50 ° C to give 225 mg (86%), which was used without further purification in the next step.

LCMS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.2 vol% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0 -1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): R _t = 0.78 min; MS (ESI positive): m / z = 347.2 [M + H] ⁺ .

Intermediate 86. Methyl 6- (4-chlorophenyl) -2- (5-chloro-3-thienyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate

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

¹ H-NMR (400 MHz, DMSO-d ₆ ): 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).

Intermediate 87.6- (4-Chlorophenyl) -2- (5-chloro-3-thienyl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

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 for 4 h at 50 ° C. The reaction mixture was cooled, diluted

- 61 037978 with water (15 ml), the pH was adjusted to 3 with hydrochloric acid (2N) and the precipitate was filtered, washed with water twice and dried in vacuo at 45 ° C to give 300 mg of the compound, which was used without further purification in the next stages.

LCMS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.2 vol% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0 -1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): R _t = 0.75 min; MS (ESI positive): m / z = 367.2 [M + H] ⁺ .

Intermediate 88. Methyl 6- (4-chlorophenyl) -2- [1- (difluoromethyl) -1H-pyrazol-4-yl] -3oxo-2,3-dihydropyridazine-4-carboxylate

Methyl 6- (4-chlorophenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate (0.10 g, 0.378 mmol) was suspended in acetonitrile (1 ml). Added molecular sieves (100 mg, 0.4 nm, particle size: <50 μm), 1- (difluoromethyl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - 1H-pyrazole (138 mg, 0.567 mmol), pyridine (0.061 ml, 0.756 mmol), N, N-diethylethanamine (0.105 ml, 0.756 mmol) and anhydrous copper diacetate (137 mg, 0.756 mmol). The mixture was stirred for 48 h at RT, 1- (difluoromethyl) -4 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1Н-pyrazole (100 mg, 0.410 mmol ) and stirred for 72 h at RT. The mixture was diluted with water and acidified slightly. The precipitate was filtered and dried in vacuo at 50 ° C to give 315 mg of the title compound, which was used without further purification in the next step.

¹ H-NMR (400 MHz, DMSO-dg): 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).

Intermediate 89.6- (4-Chlorophenyl) -2- [1- (difluoromethyl) -1H-pyrazol-4-yl] -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

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 for 20 h at 40 ° C. 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) and the precipitate was filtered, washed three times with water and dried in vacuo at 50 ° C to give 360 mg of the compound, which was used without further purification in the next step.

¹ H-NMR (400 MHz, DMSO-dg): 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).

Intermediate 90. Di-tert-butyl 1- (1,2-oxazol-4-yl) hydrazine-1,2-dicarboxylate

To a solution of diethyl ether (30 ml) at -78 ° C was added n-butyllithium (2.5 M in hexa

- 62 037978 not, 21.6 ml, 54 mmol). 4-bromo-1,2-oxazole (4.00 g, 27.0 mmol) was added and the mixture was stirred for 30 min. A solution of di-tert-butyl (E) -diazole-1,2-dicarboxylate (9.33 g, 40.6 mmol) in diethyl ether (30 ml) was added dropwise and the mixture was stirred for 1 h at -78 ° C. The reaction mixture was added to water (200 ml) and was extracted with dichloromethane (twice 200 ml). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude residue was purified by column chromatography (silica gel, heptane / ethyl acetate 4: 1-11: 9) to give 1.99 g (16%) of the title product.

Ή NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.40-1.60 (m, 18H), 6.68 (s, 1H), 8.40 (s, 1H), 8.63 (s, 1H).

Intermediate 91. 4-hydrazino-1,2-oxazole hydrochloride

Hydrochloric acid (4M 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 h. The mixture was concentrated in vacuo to give 863 mg (76%) of the title compound.

1H NMR (400 MHz, MeOD-d ₃ ): δ [ppm] = 8.42 (s, 1H), 8.63 (s, 1H).

Intermediate 92. Tetrahydropyridazine-4-carboxylate

Methyl 6- (4-chlorophenyl) -2- (1,2-oxazol-4-yl) -3-oxo-2,3,4,5-

A mixture of dimethyl [2- (4-chlorophenyl) -2-oxoethyl] malonate (494 mg, 1.74 mmol), 4hydrazino-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 h. The reaction mixture was concentrated and added to water (200 ml). The solids were collected by filtration and dried in vacuo to give 567 mg (98%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.34-3.49 (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).

Intermediate 93. Methyl 6- (4-chlorophenyl) -2- (1,2-oxazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylate

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 copper (II) chloride (1.18 g, 8.78 mmol) was added to acetonitrile (10.5 ml) and the mixture was heated at 50 ° C for 2 h. The mixture was cooled to room temperature and cooled for 16 h. The mixture was heated at 50 ° C for 16 h. The mixture was concentrated and added to water. The solids were collected by filtration and dried to give 563 mg (97%) of the title compound.

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

Intermediate 94.6- (4-Chlorophenyl) -2- (1,2-oxazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

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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), hydrochloric acid (2M in water, 10.0 ml, 20.0 mmol) was added and the mixture was heated at 100 ° C for 48 h. The mixture was cooled to RT and the solids were collected by filtration and dried in vacuo to give 246 mg ( 67%) of the title compound, which was used in the next step without further purification.

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

Intermediate 95. Ethyl 3-oxo-2- (1,2-thiazol-4-yl) -6- [6- (trifluoromethyl) pyridin-3-yl] 2,3-dihydropyridazine-4-carboxylate

Ethyl 3-oxo-6- [6- (trifluoromethyl) pyridin-3-yl] -2,3-dihydropyridazine-4-carboxylate (475 mg, 1.52 mmol) was suspended in acetonitrile (10 ml). 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl) -1,2-thiazole (480 mg, 2.28 mmol), pyridine (0.245 ml, 3.03 mmol), N, N β-diethylethanamine (0.423 ml, 3.03 mmol) and anhydrous copper diacetate (358 mg, 1.97 mmol). The mixture was stirred for 24 h at RT. 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,2-thiazole (100 mg, 0.474 mmol) was added and stirred for 24 h at RT. A buffer solution with a pH value of 7 (50 ml) was added and stirred for a short period of time. The precipitate was filtered, washed twice with water and dried in vacuo at 45 ° C to give 630 mg of the title compound, which was used without further purification in the next step.

¹ H-NMR (400 MHz, 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).

Intermediate 96. 3-Oxo-2- (1,2-thiazol-4-yl) -6- [6- (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine-4-carboxylic acid

Ethyl 3-oxo-2- (1,2-thiazol-4-yl) -6- [6- (trifluoromethyl) pyridin-3-yl] -2,3-dihydropyridazine-4-carboxylate (625 mg, 1.58 mmol) suspended in THF (19 ml). Lithium hydroxide (113 mg, 4.73 mmol) in water (2.3 ml) was added and stirred at RT for 24 h. Water (100 ml) was added and the pH was adjusted to 4 with hydrochloric acid (0.5N). The mixture was stirred for a short period of time, the precipitate was filtered, washed three times with water and dried at 45 ° C in vacuo to give 585 mg of the title compound, which was used without further purification in the next step.

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

LCMS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.2 vol% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0 -1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): Rt = 0.59 min; MS (ESI positive): m / z = 369.1 [M + H] +.

Intermediate 97. Dimethyl {2- [4- (fluoromethyl) phenyl] -2-oxoethyl} malonate

- 64 037978

2-Bromo-1- [4- (fluoromethyl) phenyl] ethanone (5.5 g, 23.80 mmol) was dissolved in acetone (120 ml). Dimethylmalonate (6.94 g, 52.50 mmol) and potassium carbonate (5.0 g, 36.18 mmol) were added. The mixture was stirred at RT overnight. The volume of the mixture was reduced by half under vacuum on a rotary evaporator. Then it was poured into water (550 ml) containing a small amount of 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 concentrated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. A second batch prepared under similar conditions (0.5 g of bromidoketone starting material) was added and the volatiles were removed under high vacuum at 70 ° C. The crude product was purified by flash chromatography (hexane / ethyl acetate) to provide 5.59 g (76%) of the title product.

¹ H-NMR (400 MHz, 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).

Intermediate 98. Methyl 6- [4- (fluoromethyl) phenyl] -3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

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

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

Intermediate 99. Methyl 6- [4- (fluoromethyl) phenyl] -3-oxo-2,3-dihydropyridazine-4carboxylate

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 for 1 h at 90 ° C. The reaction mixture was cooled and poured into water (150 ml). The mixture was stirred for 10 minutes. The precipitate was suction filtered, washed three times with water and dried at 50 ° C. in vacuo to give 1.02 g of the title compound, which was used without further purification in the next step.

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

Intermediate 100. Methyl 6- [4- (fluoromethyl) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3-dihydropyridazine-4-carboxylate

- 65 037978

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), 1methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (1.2 g, 5.77 mmol) was added , pyridine (0.58 ml, 7.17 mmol), Ν, Ν-diethylethanamine (1 ml, 7.17 mmol) and anhydrous copper diacetate (1.3 g, 7.17 mmol). The mixture was stirred at RT for 2 days. 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (0.522 g, 2.51 mmol) and anhydrous copper diacetate (651 mg, 3.58 mmol) and stirred at RT for 4 days. The mixture was diluted with dichloromethane and silica gel was added. The volatiles were removed in vacuo. The residue was purified by flash chromatography (silica gel, dichloromethane / ethanol 95: 5) to give 1.05 g (85%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.89 (s, 3H), 3.92 (s, 3H), 5.51 (d, 2H), 7.54-7.59 (m, 2H ), 8.078.12 (m, 3H), 8.45 (s, 1H), 8.51 (s, 1H).

Intermediate 101.6- [4- (Fluoromethyl) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

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 stirred at RT for 1 h. The pH was adjusted to 3 with hydrochloric acid (4 ml, 2N). The precipitate was filtered, washed three times with water and dried in vacuo at 50 ° C to give 352 mg (35%) of the title compound, which was used without further purification in the next step.

¹ H-NMR (400 MHz, DMSO-de): 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).

Intermediate 102. Methyl 6- [4- (fluoromethyl) phenyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxylate

Methyl 6- [4- (fluoromethyl) phenyl] -3-oxo-2,3-dihydropyridazine-4-carboxylate (0.725 g, 2.77 mmol) was suspended in acetonitrile (7.4 ml). Anhydrous sodium sulfate (0.725 g, 5.10 mmol), 3 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (851 mg, 4.15 mmol), pyridine (448 μL, 5.53 mmol), Ν, Ν-diethylethanamine (771 μL, 5.53 mmol) and anhydrous copper diacetate (1.004 g, 5.53 mmol). The mixture was stirred at RT overnight. 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 solids were triturated with dichloromethane / methanol 1: 1, filtered and dried in vacuo at 50 ° C to give 942 mg of the title compound, which was used without further purification in the next step.

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

- 66 037978

8.69 (m, 1H).

Intermediate 103.6- [4- (Fluoromethyl) phenyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid

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

LCMS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.2 vol% aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0 -1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): R _t = 0.53 min; MS (ESI positive): m / z = 326.4 [M + H] ⁺ .

Intermediate 104.6- (4-Chlorophenyl) -3-oxo-2- (pyrugin-3-yl) -N- (4,4,4-trifluoro-3hydroxybutan-2-yl) -2,3-dihydropyridazine- 4-carboxamide

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-amino1,1,1-trifluorobutan-2-ol hydrochloride 1: 1 (174.5 mg, 0.97 mmol), N-ethyl-N-isopropylpropan-2-amine (0.59 ml, 3.36 mmol) and propane phosphonic acid anhydride ( T3P, 0.71 g, 50% in DMF, 1.12 mmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: XBridge C18 5 μm 100x30 mm, mobile phase: (water + 0.1 vol% formic acid (99%)) / acetonitrile, gradient) to give 52.8 mg (16%) of the indicated in the connection header.

LCMS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0 -1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): Rt = 1.22 min; MS (ESI positive): m / z = 454.3 [M + H] ⁺ .

Intermediate pyridazine-4-carboxylic acid

105.6- (4-Chlorophenyl) -2- (5-chloropyridin-3-yl) -3-oxo-2,3-dihydro-

Ethyl 6- (4-chlorophenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylate (250 mg, 0.9 mmol) was dissolved in DMF (12 ml). Added (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). The reaction mixture was stirred for 4 h at 80 ° C, cooled, followed by the addition of 2.7 ml of 2N. an aqueous solution of sodium hydroxide. The mixture was stirred overnight, water was added and the precipitate was filtered off and dried in vacuo to give 402 mg of the title compound.

- 67 037978

LCMS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0 -1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan:

210-400 nm; ELSD): R _t = 1.25 min; MS (ESI positive): m / z = 364.0 [M + H] ⁺ .

Intermediate 106.6- (4-Chlorophenyl) -2- (5-methylpyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

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 ). The reaction mixture was stirred for 4 h at 80 ° C, cooled, followed by the addition of 2.7 ml of 2N. an aqueous solution of sodium hydroxide. The mixture was stirred overnight, water was added and the precipitate was filtered off and dried in vacuo to give 317 mg of the title compound.

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): Rt = 1.12 min; MS (ESI positive): m / z = 342.2 [M + H] ⁺ .

Intermediate 107. Dimethyl {2- [4- (difluoromethoxy) phenyl] -2-oxoethyl} malonate

4.5 g of dimethylmalonate and 3.6 g of potassium carbonate were added to a solution of 4.8 g of 2-bromo-1- [4 (difluoromethoxy) phenyl] ethan-1-one in 120 ml of acetone. The reaction mixture was stirred at room temperature overnight 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 (gradient: hexane / ethyl acetate with up to 40% ethyl acetate) to give 4.3 g of dimethyl {2- [4- (difluoromethoxy) phenyl] -2-oxoethyl} malonate.

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

Intermediate 108. Methyl 6- [4- (difluoromethoxy) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) 3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

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 h and at RT overnight. An additional amount of 4-hydrazino-1-methyl-1H-pyrazole dihydrochloride (1 g, 3.16 mmol) was added and the reaction mixture was stirred at 45 ° C for 2 h. Then the reaction mixture was added to water, the precipitate was filtered off and dried in vacuo to give 1.05 g (88%) of the title compound.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm = 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), 7.36 (t, 1H), 7.75 (d, 1H), 7.94-8.03 (m, 2H), 8.08 (s, 1H).

- 68 037978

Intermediate 109. Methyl 6- [4- (difluoromethoxy) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) 3-oxo-2,3-dihydropyridazine-4-carboxylate

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 h. The reaction mixture was added to water and the precipitate was filtered off to obtain 1.08 g (quantitatively) of the title compound.

Ή NMR (400 MHz, DMSO-d6) δ ppm = 3.88 (s, 3H), 3.92 (s, 3H), 7.29-7.34 (m, 2H), 7.38 (t, 1H), 8.088.10 (m , 1H), 8.10-8.14 (m, 2H), 8.44 (s, 1H), 8.50 (s, 1H).

Intermediate 110.6- [4- (Difluoromethoxy) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4-carboxylic acid

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

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

Intermediate 111.6- (4-Chlorophenyl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid

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

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

Intermediate 112 6- (4-Chlorophenyl) -N - [(2R) -3-hydroxy-3-methylbutan-2-yl] -3-oxo2,3-dihydropyridazine-4-carboxamide

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-methylbutan-2-ol hydrochloride 1: 1 (1191 mg, 8.53 mmol), N-ethyl-N-isopropylpropan-2-amine (4.46 ml, 25.6 mmol) and propane phosphonic anhydride acid (T3P, 5.43 g, 50% in DMF, 8.53 mmol). The mixture was stirred at RT overnight followed by the addition of water and saturated ammonium chloride solution. The newly formed precipitate was filtered off, washed with water and dried in a vacuum to give 626 mg (33%)

- 69 037978 specified in the header of the connection.

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

Intermediate 113. 3-Oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4carboxylic acid

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

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): Rt = 1.07 min; MS (ESI positive): m / z = 301.2 [M + H] ⁺ .

Intermediate 114. N - [(2R) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide

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

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

Intermediate 115. Dimethyl {2- [4- (dimethylamino) phenyl] -2-oxoethyl} malonate

Dimethylmalonate (5.45 g, 41.3 mmol) and potassium carbonate (4.3 g, 31 mmol) were added to a solution of 4 (dimethylamino) phenacyl bromide (5.0 g, 20.6 mmol) in acetone (145 ml). The reaction mixture was stirred at room temperature overnight and then quenched with water. The precipitate was filtered off, washed with water and dried in vacuo to give 4.66 g (77%) of the title compound.

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

Intermediate 116. Methyl 6- [4- (dimethylamino) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) 3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

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 at RT overnight and then at 50 ° C for 1 h.

- 70 037978 the amount of 4-hydrazino-1-methyl-1H-pyrazole dihydrochloride (258 mg, 1.7 mmol) and the reaction mixture was stirred at RT overnight and then at 50 ° C for 5 h. Then the reaction mixture was added to water and the mixture was extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered (MN 617 WA filter paper) and concentrated in vacuo to give 516 mg (85%) of the title compound.

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): Rt = 1.05 min; MS (ESI positive): m / z = 356.5 [M + H] ⁺ .

Intermediate 117. Methyl 6- [4- (dimethylamino) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) 3-oxo-2,3-dihydropyridazine-4-carboxylate

CH ₃ n-n '

N. / O N ^x CH O

II [। ^J n ₃ with Ji L o

CH ₃

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 iodide (737 mg, 2.9 mmol) in 11 ml of acetic acid was stirred at RT for 48 h. An additional amount of iodide (368.5 mg, 1.45 mmol) was added and the mixture was stirred at RT for 24 h. saturated solution of sodium thiosulfate and ethyl acetate. The phases were separated and the organic phase was washed with saturated sodium thiosulfate solution and brine, filtered (filter paper MN 617 WA) and concentrated in vacuo to give 936 mg (55% purity) of the title compound.

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V;

flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): R _t = 1.7 min; MS (ESI positive): m / z = 354.4 [M + H] ⁺ .

Intermediate 118.6- [4- (Dimethylamino) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4-carboxylic acid

Methyl 6- [4- (dimethylamino) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4carboxylate (936 mg, 1.45 mmol, 55%) was dissolved in THF (5 ml). At RT, 2M sodium hydroxide solution (1.5 ml, 3.0 mmol) was added and the mixture was stirred overnight, diluted with water, and treated with 1M HCl. The pH was adjusted to 3 followed by the addition of ethyl acetate. The phases were separated and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with brine, filtered (filter paper MN 617 WA) and concentrated in vacuo to give 99 mg (20%) of the title compound.

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): R _t = 1.11 min; MS (ESI positive): m / z = 340.3 [M + H] +.

Intermediate 119. Ethyl 3-oxo-2- (1,2-thiazol-4-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3 dihydropyridazine-4-carboxylate

- 71 037978

Ethyl 3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylate (207 mg, 0.63 mmol) was dissolved in acetonitrile (6 ml) followed by the addition of molecular sieves (4 A, powder, 0.176 g), 4- (tetramethyl-1,3,2-dioxoborolan-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 for 4 h at 80 ° C, filtered through celite, concentrated and purified by column chromatography (gradient: hexane / ethyl acetate with up to 50% ethyl acetate) to give 95 mg (36%) of the title compound.

1H NMR (400 MHz, DMSO-d6) δ ppm = 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).

Intermediate 120. 3-Oxo-2- (1,2-thiazol-4-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3 dihydropyridazine-4-carboxylic acid

Ethyl 3-oxo-2- (1,2-thiazol-4-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylate (90 mg, 0.22 mmol) was dissolved in THF ( 2 ml). At RT, 2M sodium hydroxide solution (0.33 ml, 0.66 mmol) was added and the mixture was stirred overnight, diluted with water, and treated with 1M HCl. The pH was adjusted to 3 and the precipitate was filtered off, washed with water and dried in vacuo to give 74 mg (88%) of the title compound.

1H NMR (400 MHz, DMSO-d6) δ ppm = 7.48-7.55 (m, 2H), 8.20 (d, 2H), 8.50 (s, 1H), 9.15 (s, 1H), 9.60 (s, 1H ).

Intermediate 121. Methyl 6- [4- (difluoromethoxy) phenyl] -3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylate

A mixture of dimethyl {2- [4- (difluoromethoxy) phenyl] -2-oxoethyl} malonate (709 mg, 2.24 mmol), hydrazine in THF (1M, 4.5 ml, 4.5 mmol) and sodium acetate (828 mg, 10.1 mmol) in 21 ml of AcOH was stirred at RT overnight and then 6 h at 50 ° C. An additional amount of hydrazine in THF (1M, 6.7 ml, 6.7 mmol) was added and the reaction mixture was stirred at 80 ° C for 3 h. Then the reaction mixture was added to water, the precipitate was filtered off and dried in vacuum to obtain 334 mg (50%) of the indicated in the connection header.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm = 3.13-3.30 (m, 2H), 3.67 (s, 3H), 3.71-3.77 (m, 1H), 7.20-7.25 (m, 2H) , 7.31 (t, 1H), 7.81 (d, 2H), 11.27 (s, 1H).

Intermediate 122. Methyl 6- [4- (difluoromethoxy) phenyl] -3-oxo-2,3-dihydropyridazine 4-carboxylate

- 72 037978

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 h. The reaction mixture was added to water and the precipitate was filtered off to give 1.13 g (87%) of the title compound.

1H NMR (400 MHz, DMSO-d6) δ ppm = 3.85 (s, 3H), 7.29 (br d, 2H), 7.34 (t, 1H), 7.94 (d, 2H), 8.37 (s, 1H) , 13.66 (s, 1H).

Intermediate 123.6- [4- (Difluoromethoxy) phenyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid

CH ₃

HE

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 for 4 h at 80 ° C and then 48 h at RT. Then a 2M sodium hydroxide solution (1.86, 3.7 mmol) was added, and the mixture was stirred at RT for 3 h, followed by the addition of water. The resulting precipitate was filtered off, washed with water and dried in vacuo to give 610 mg (91%) of the title compound.

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): Rt = 1.07 min; MS (ESI positive): m / z = 360.2 [M + H] +.

Intermediate 124. Diethyl hydroxy {2-oxo-2- [6- (trifluoromethyl) pyridin-3yl] ethyl} malonate o CH ₃

In a 100 ml round bottom flask were placed 1- [6- (trifluoromethyl) pyridin-3-yl] ethanone (10 g, 52.87 mmol) and 1,3-diethyl 2-oxopropanedioate (15.65 g, 89.9 mmol). The resulting solution was stirred for 24 h at 130 ° C followed by the addition of more 1,3-diethyl 2-oxopropanedioate (13.81 g, 79.30 mmol) and heating for another 13 h at 130 ° C. The resulting mixture was cooled to RT and poured into pentane. The precipitate was filtered off, washed with pentane and water to obtain 22.6 g of (crude) diethyl hydroxy {2-oxo-2- [6- (trifluoromethyl) pyridin-3-yl] ethyl} malonate, which was used without further purification.

Intermediate 125. Ethyl 3-oxo-6- [6- (trifluoromethyl) pyridin-3-yl] -2,3-dihydropyridazine-4-carboxylate

To a solution of diethyl hydroxy {2-oxo-2- [6- (trifluoromethyl) pyridin-3-yl] ethyl} malonate (22.6 g, 62.2

- 73 037978 mmol) in ethanol (255 ml) was added hydrazine hydrochloride (7.2 g, 68.5 mmol). The resulting solution was stirred for 24 h at 80 ° C. The reaction mixture was then quenched by the addition of water. The resulting precipitate was filtered off and dried in vacuo to give 13.26 g (68%) of ethyl 3-oxo-6- [6- (trifluoromethyl) pyridin-3-yl] -2,3-dihydropyridazine-4-carboxylate.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm = 1.32 (t, 3H), 4.33 (q, 2H), 8.01-8.06 (m, 1H), 8.47-8.51 (m, 1H),

8.52-8.57 (m, 1H), 9.23-9.26 (m, 1H), 13.92 (s, 1H).

Intermediate 126. Ethyl 2- (5-fluoropyridin-3-yl) -3-oxo-6- [6- (trifluoromethyl) pyridin-3-yl] -2,3-dihydropyridazine-4-carboxylate

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-fluoropyridine -3yl) 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 for 3 h at 80 ° C followed by the addition of water. The solution was adjusted to pH 3 by adding 1M aqueous hydrochloric acid, followed by extraction with ethyl acetate three times. 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.

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): R _t = 1.15 min; MS (ESI positive): m / z = 409.2 [M + H] ⁺ .

Intermediate 127.2- (5-fluoropyridin-3-yl) -3-oxo-6- [6- (trifluoromethyl) pyridine-3yl] -2,3-dihydropyridazine-4-carboxylic acid

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) 2N. an aqueous solution of sodium hydroxide. The reaction mixture was stirred overnight at RT. Water was added to the reaction mixture and the pH was adjusted to pH 3 with 1M aqueous hydrochloric acid. The precipitate was filtered off and dried in vacuo to give 3.19 g (70%) of the title compound.

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V;

flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD):

Rt = 1.00 min; MS (ESI positive): m / z = 381.6 [M + H] ⁺ .

Intermediate 128. Diethyl yl] ethyl} malonate hydroxy {2-oxo-2- [5- (trifluoromethyl) pyridine-2-

- 74 037978

1- [5- (Trifluoromethyl) pyridin-2-yl] ethanone (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 RT, the mixture was added into 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 using flash chromatography (silica gel, gradient: hexane / ethyl acetate) to give 4.64 g (64%) of the title compound.

Ή NMR (400 MHz, DMSO-d6) δ ppm = 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).

Intermediate 129. Ethyl pyridazine-4-carboxylate

-oxo-6 - [5- (trifluoromethyl) pyridin-2-yl] -2,3-dihydro-

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

Ή NMR (400 MHz, DMSO-d ₆ ) δ ppm 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).

Intermediate 130.3-Oxo-6- [5- (trifluoromethyl) pyridin-2-yl] -2,3-dihydropyridazine 4-carboxylic acid

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

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 199% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan: 210-400 nm; ELSD): Rt = 1.04 min; MS (ESI positive): m / z = 286.1 [M + H] ⁺ .

Intermediate 131. N - [(2S) -1-Hydroxypropan-2-yl] -3-oxo-6- [5- (trifluoromethyl) pyridin-2-yl] -2,3-dihydropyridazine-4-carboxamide

1.051 g of a crude mixture containing an unknown amount of 3-oxo-6- [5- (trifluoromethyl) pyridin-2yl] -2,3-dihydropyridazine-4-carboxylic acid and 312 mg (4.15 mmol) alaninol was dissolved in 16 ml of DMF and treated with HATU (2.1 g, 5.54 mmol), N, N-diisonropylethylamine (1.07 g, 8.3 mmol) and 4-dimethylaminopyridine (16.9 mg, 0.14 mmol). The reaction mixture was stirred overnight and added to water and ethyl acetate. The phases were separated and the organic phase was washed with brine, filtered (MN 617 WA filter paper) and concentrated. The crude product was purified using flash chromatography (silica gel, gradient: hexane / ethyl acetate) to give 383 mg of the title compound.

LC-MS (Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEN C18 1.7 50x2.1 mm; eluent A: water + 0.1 vol% formic acid (99%) eluent B: acetonitrile; gradient: 0- 1.6 min 1- 75 037978

99% V, 1.6-2.0 min 99% V; flow 0.8 ml / min; temperature: 60 ° C; injection: 2 μl; DAD scan:

210-400 nm; ELSD): Rt = 0.93 min; MS (ESI positive): m / z = 343.5 [M + H] +.

Experimental section - examples.

The following examples describe an embodiment of the present invention without limiting the invention to only these examples.

Example 1. N- (1-Hydroxy-3-methylbutan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3 -dihydropyridazine-4-carboxamide

A solution of 100 mg of intermediate 6, 33.2 mg of 2-amino-3-methylbutan-1-ol, 184 mg of HATU and 125 mg of ethyldiisopropylamine in 5 ml of DMF was stirred at room temperature for 2 h. Then the reaction mixture was 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 100x30 mm, mobile phase: acetonitrile / water (0.1 vol% formic acid) gradient)) to obtain 25.3 mg of N- (1-hydroxy-3-methylbutane -2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3 oxo-2,3-dihydropyridazine-4-carboxamide.

¹ H-NMR: (400 MHz, 25 ° C, Methanol ^): 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).

Example 2. N- (1-Hydroxy-3-methylbutan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3-dihydropyridazine -4-carboxamide, enantiomer 1

HPLC separation 24 mg N- (1-hydroxy-3-methylbutan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2 , 3-dihydropyridazine-4-carboxamide (example 1) on a chiral column (Chiralpak IB 5 μm 250x30 mm, eluent: hexanes / ethanol, gradient, with 20-50% ethanol, flow 40 ml / min) gave 6 mg of N - (1-hydroxy-3-methylbutan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4-carboxamide , enantiomer 1.

¹ H-NMR (400 MHz, DMSO-d ₆ ): 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).

Chiral HPLC: _Rt = 3.65 min.

Instrument: Agilent HPLC 1260; column: Chiralpak IB 3 μm 100x4.6 mm; eluent: hexanes / ethanol 50:50, flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm.

Example 3. N- (1-G hydroxy-3-methylbutan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3- dihydropyridazine-4-carboxamide, enantiomer 2

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Separation of 24 mg of Example 1 in accordance with Example 2 further resulted in 6 mg of X- (1-hydroxy-3-methylbutan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazole -4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 2.

¹ H-NMR (300 MHz, DMSO-d ₆ ): 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).

Chiral HPLC: _Rt = 6.15 min.

Instrument: Agilent HPLC 1260; column: Chiralpak IB 3 μm 100x4.6 mm; eluent: hexanes / ethanol 50:50, flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm.

Example 4. X- (1-Hydroxybutan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-III-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4 -carboxamide

A solution of 100 mg of intermediate 7, 40.7 mg of 2-aminobutan-1-ol, and 85 μl of triethylamine in 10 ml of dichloromethane was stirred in an ice water bath for 10 min. Then the reaction mixture was 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 flash chromatography (ethyl acetate / petroleum ether 1: 2) to give 34 mg of X- (1-hydroxybutan-2-yl) -6- (4-methylphenyl) -2- (1-methyl1H-pyrazol-4-yl ) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

¹ H-NMR: (400 MHz, 25 ° C, methanol-d ₄ ): 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).

Example 5. X- (1-Hydroxybutan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3 dihydropyridazine-4-carboxamide , enantiomer 1

HPLC separation 33 mg X- (1-hydroxybutan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) 3-oxo-2,3-dihydropyridazine- 4-carboxamide (example 4) on a chiral column (Chiralpak IC 5 μm 250x30 mm, eluent: hexanes (0.1% diethylamine) / (ethanol / methanol 50:50) gradient with 20-50% (ethanol / methanol 50:50), flow 40 ml / min) yielded 8 mg of X- (1-hydroxybutan-2-yl) -6- (4methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2 , 3-dihydropyridazine-4-carboxamide, enantiomer 1.

1 H-NMR (400 MHz, DMSO-d ₆ ): 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).

Chiral HPLC: _Rt = 4.68 min.

Instrument: Agilent HPLC 1260; column: Chiralpak IC 3 μm 100x4.6 mm; eluent: hexanes (0.1% diethylamine) / (ethanol / methanol 50:50) gradient with 20-50% (ethanol / methanol 50:50), flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm.

Example 6 X- (1-Hydroxybutan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide , enantiomer 2

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Separation of 33 mg of Example 4 according to Example 5 further resulted in 8 mg of N- (1-hydroxybutan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl ) -3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 2.

1 H-NMR (400 MHz, DMSO-de): 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).

Chiral HPLC: _Rt = 6.25 min.

Instrument: Agilent HPLC 1260; column: Chiralpak IC 3 μm 100x4.6 mm; eluent: hexanes (0.1% diethylamine) / (ethanol / methanol 50:50) gradient with 20-50% (ethanol / methanol 50:50), flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm.

Example 7. Ν- (1-Ohydroxypropan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3 dihydropyridazine-4- carboxamide

A solution of 100 mg of intermediate 7, 34.3 mg of 2-aminopropan-1-ol and 85 μl of triethylamine in 10 ml of dichloromethane was stirred in an ice-water bath for 10 min. Then the reaction mixture was 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 flash chromatography (ethyl acetate / petroleum ether 1: 2) to give 40.8 mg of N- (1-hydroxypropan-2-yl) -6- (4-methylphenyl) -2- (1methyl-1H-pyrazol-4-yl ) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

¹ H-NMR: (400 MHz, 25 ° C, Methanol ^): 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).

Example 8. N - [(2S) -1-O-hydroxypropan-2-yl] -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine -4-carboxamide

A: A solution of 80 mg of intermediate 6, 38 mg of (2S) -2-aminopropan-1-ol, 147 mg of HATU and 0.135 ml of ethyldiisopropylamine in 5 ml of DMF was stirred at room temperature for 14 hours. The reaction mixture was then quenched with water and the mixture extracted with dichloromethane twice. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was subjected to flash chromatography (gradient: dichloromethane / methanol with up to 3% methanol) to give 20 mg of N - [(2S) -1 hydroxypropan-2-yl] -6- (4-methylphenyl) -2- (1-methyl-1H -pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

B: HPLC separation of 39 mg N- (1-hydroxypropan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazole-4-

- 78 037978 yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide (example 7) on a chiral column (Chiralpak IC 5 μm

250x30 mm, eluent: hexanes (0.1% diethylamine) / (ethanol / methanol 50:50) gradient with 20-50% (ethanol / methanol 50:50), flow 40 ml / min) yielded 9 mg N - [( 2S) -1-hydroxypropan-2-yl] -6- (4methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.34 (d, 3H); 2.43 (s, 3H); 2.85 (dd, 1H); 3.70 (ddd, 1H); 3.80 (ddd, 1H); 3.98 (s, 3H); 4.26-4.34 (m, IH); 7.32 (d, 2H); 7.82 (d, 2H); 8.14 (s, IH); 8.33 (s, IH); 8.71 (s, IH); 9.87 (d, IH).

Chiral HPLC: Rt = 5.28 min.

Instrument: Agilent HPLC 1260; column: Chiralpak IC 3 μm 100x4.6 mm; eluent: hexanes (0.1% diethylamine) / (ethanol / methanol 50:50) gradient with 20-50% (ethanol / methanol 50:50), flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm.

Example 9 N - [(2R) -1-Hydroxypropan-2-yl] -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine -4-carboxamide

Separation of 39 mg of Example 7, in accordance with Example 8, Procedure B, further resulted in 13 mg of N - [(2R) -1-hydroxypropan-2-yl] -6- (4-methylphenyl) -2- (1- methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 1.34 (d, 3H); 2.43 (s, 3H); 2.85 (dd, IH); 3.70 (ddd, IH); 3.80 (ddd, IH); 3.98 (s, 3H); 4.26-4.34 (m, IH); 7.32 (d, 2H); 7.82 (d, 2H); 8.14 (s, IH); 8.33 (s, IH); 8.71 (s, IH); 9.87 (d, IH).

Chiral HPLC: R _t = 7.07 min.

Instrument: Agilent HPLC 1260; column: Chiralpak IC 3 μm 100x4.6 mm; eluent: hexanes (0.1% diethylamine) / (ethanol / methanol 50:50) gradient with 20-50% (ethanol / methanol 50:50), flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm.

Example 10 6- (4-Methylphenyl) -2- (1-methyl-1H-pyrαzol-4-yl) -3-oxo-N- (3,3,3-trifluoro-2-hydroxypropyl) -2,3 -dihydropyridazine-4-carboxamide

A solution of 100 mg of intermediate 6, 83.2 mg of 3-amino-1,1,1-trifluoropropan-2-ol, 184 mg of HATU, and 0.17 ml of ethyldiisopropylamine in 5 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was quenched with water and the mixture was extracted with dichloromethane twice. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was subjected to flash chromatography (gradient: dichloromethane / methanol with up to 2% methanol) to give 65 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.

1 H-NMR (400 MHz, CDCl3): δ [ppm] = 2.44 (s, 3H); 3.78 (ddd, IH); 3.90 (ddd, 1H); 3.99 (s, 3H); 4.18-4.27 (m, IH); 4.56 (d, IH); 7.33 (d, 2H); 7.82 (d, 2H); 8.16 (s, 1H); 8.33 (s, IH); 8.71 (s, IH); 10.24 (bt, IH).

Example 11 (-) - 6- (4-Methylphenyl) -2- (1-methyl-1H-pyrαzol-4-yl) -3-oxo-N- (3,3,3-trifluoro-2-hydroxypropyl) -2,3-dihydropyridazine-4-carboxamide, enantiomer 1

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HPLC separation 63 mg 6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-N- (3,3,3-trifluoro-2hydroxypropyl) -2,3 -dihydropyridazine-4-carboxamide (example 10) on a chiral column (Chiralpak IA 5 μm 250x30 mm, eluent: methanol (0.1% diethylamine) / ethanol 50:50, flow 30 ml / min) yielded 29 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, enantiomer 1.

¹ H-NMR (400 MHz, CDCl ₃ ): 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).

Chiral HPLC: R _t = 2.69 min.

Instrument: Agilent HPLC 1260; column: Chiralpak IC 3 μm 100x4.6 mm; eluent: methanol (0.1% diethylamine) / ethanol 50:50, flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm.

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

Example 12 (+) - 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

Separation of 63 mg of Example 10 according to Example 11 further resulted in 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.

¹ H-NMR (400 MHz, CDCl ₃ ): 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).

Chiral HPLC: _Rt = 3.11 min.

Instrument: Agilent HPLC 1260; column: Chiralpak IC 3 μm 100x4.6 mm; eluent: methanol (0.1% diethylamine) / ethanol 50:50, flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm.

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

Example 13 N- (3,3-Difluoro-2-hydroxypropyl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3-dihydropyridazine-4 -carboxamide

100 mg solution of intermediate 6, 71.6 mg 3-amino-1,1-difluoropropan-2-ol, 184 mg

HATU and 0.17 ml of ethyldiisopropylamine in 5 ml of DMF were stirred at room temperature for 14 hours. Then the reaction mixture was quenched with water and the mixture was extracted with dichloromethane twice.

The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was subjected to flash chromatography (gradient: dichloromethane / methanol with up to 2% methanol) to give 55 mg

N- (3,3-difluoro-2-hydroxypronyl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrαzol-4-yl) -3-oxo-2,3-dihydrogronyridazine-4- carboxamide.

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 2.43 (s, 3H); 3.67-3.77 (m, 1H); 3.84 (ddd, 1H); 3.95-4.09 (m + s, 4H); 4.11 (d, IH); 5.79 (dt, IH); 7.32 (d, 2H); 7.82 (d, 2H); 8.14 (s, IH); 8.33 (s, IH); 8.70 (s, IH); 10.16 (bt, IH).

Example 14. 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

HPLC separation 53 mg N- (3,3-difluoro-2-hydroxynpropyl) -6- (4-methylphenyl) -2- (1-methyl-1Hpyrazol-4-yl) -3-oxo-2,3-dihydropyridazine -4-carboxamide (example 13) on a chiral column (Chiral pak IA 5 μm 250x30 mm, eluent: methanol (0.1% diethylamine) / ethanol 50:50, flow 30 ml / min) yielded 24 mg of N- (3, 3-difluoro-2-hydroxypropyl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 1.

S-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 2.43 (s, 3H); 3.67-3.77 (m, IH); 3.84 (ddd, IH); 3.95-4.09 (m + s, 4H); 4.11 (d, IH); 5.79 (dt, IH); 7.32 (d, 2H); 7.82 (d, 2H); 8.14 (s, IH); 8.33 (s, IH); 8.70 (s, IH); 10.16 (bt, IH).

Chiral HPLC: _Rt = 3.92 min.

Instrument: Agilent HPLC 1260; column: Chiralpak IA 3 μm 100x4.6 mm; eluent: methanol (0.1% diethylamine) / ethanol 50:50, flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm.

Example 15 N- (3,3-Difluoro-2-hydroxypropyl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrαzol-4-yl) -3oxo-2,3-dihydropyridazine-4 -carboxamide, enantiomer 2

Separation of 53 mg of Example 13, in accordance with Example 14, further gave 24 mg of N- (3,3-difluoro-2-hydroxynpropyl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazole -4-yl) -3-oxo-2,3 dihydropyridazine-4-carboxamide, enantiomer 2.

S-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 2.43 (s, 3H); 3.67-3.77 (m, IH); 3.84 (ddd, IH); 3.95-4.09 (m + s, 4H); 4.11 (d, IH); 5.79 (dt, IH); 7.32 (d, 2H); 7.82 (d, 2H); 8.14 (s, IH); 8.33 (s, IH); 8.70 (s, IH); 10.16 (bt, IH).

Chiral HPLC: R _t = 4.78 min.

Instrument: Agilent HPLC 1260; column: Chiralpak IA 3 μm 100x4.6 mm; eluent: methanol (0.1% diethylamine) / ethanol 50:50, flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm.

Example 16. 6- (4-Chlorophenyl) -N - [(2S) -1-hydroxy-3-methylbutan-2-yl] -2- (1-methyl-1H-pyrαzol-4-yl) 3-oxo 2,3-dihydropyridazine-4-carboxamide

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A solution of 80 mg of intermediate 11, 49.9 mg of (2S) -2-amino-3-methylbutan-1-ol, 138 mg of HATU and 0.13 ml of ethyldiisopropylamine in 5 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was quenched with water and the mixture was extracted with dichloromethane twice. 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 100x30 mm, mobile phase: acetonitrile / water (0.1 vol% formic acid) gradient)) to obtain 45 mg of 6- (4-chlorophenyl) -N- [(2S) -1-hydroxy-3-methylbutan2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

-NMR (400 MHz, CDCl ₃ ): 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).

Example 17 6- (4-Chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -2- (1-methyl-1 H-pyrazol-4-yl) -3-oxo2,3- dihydropyridazine-4-carboxamide

A solution of 80 mg of intermediate 11, 29.1 mg of (2S) -2-aminopropan-1-ol, 110 mg of HATU, and 0.1 ml of ethyldiisopropylamine in 5 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was quenched with water and the mixture was extracted with dichloromethane twice. 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 100x30 mm, mobile phase: acetonitrile / water (0.1 vol% formic acid) gradient)) to obtain 50 mg of 6- (4-chlorophenyl) -N- [(2S) -1-hydroxynropan-2-yl] -2- (1-methyl-1Hpyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

S-NMR (400 MHz, CDCl ₃ ): 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).

Example 18 6- (4-Chlorophenyl) -2- (1-methyl-III-pyrazol-4-yl) -3-oxo-X- (3,3,3-trifluoro-2-hydroxypropyl) -2,3 -dihydropyridazine-4-carboxamide

A solution of 130 mg of intermediate 11, 101 mg of 3-amino-1,1,1-trifluoropropan-2-ol, 224 mg of HATU and 0.21 ml of ethyldiisopropylamine in 10 ml of DMF was stirred at room temperature for 14 hours. Then the reaction mixture was quenched with water and the mixture was extracted with dichloromethane twice. The combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was subjected to flash chromatography (gradient: dichloromethane / methanol with up to 2% methanol) to give 160 mg

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6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-X- (3,3,3-trifluoro-2-hydroxypropyl) -2,3 dihydropyridazine-4- carboxamide.

1 H-NMR (400 MHz, CDCl 3): 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).

Example 19 (-) - 6- (4-Chlorophenyl) -2- (1-methyl-III-pyrazol-4-yl) -3-oxo-X- (3,3,3-trifluoro-2-hydroxypropyl) -2,3-dihydropyridazine-4-carboxamide

CH ₃

N-N .O

N / O

X OH F <F

HPLC separation 158 mg 6- (4-chlorophenyl) -2- (1-methyl-III-pyrazol-4-yl) -3-oxo-X- (3,3,3-trifluoro-2hydroxypropyl) -2,3 -dihydropyridazine-4-carboxamide (example 18) on a chiral column (Chiralpak IA 5 μm 250x30 mm, eluent: CO ₂ /2-propanol 77:23, flow 100 ml / min, p = 150 bar, T = 4O ° C) gave 50 mg of (-) - 6- (4-chlorophenyl) -2- (1-methyl-III-pyrazol-4-yl) -3-oxo-N- (3,3,3-trifluoro-2hydroxypropyl) -2,3-dihydropyridazine-4-carboxamide.

¹ H-NMR (400 MHz, CDCl ₃ ): 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).

Chiral HPLC: _Rt = 2.76 min.

Instrument: Agilent HPLC 1260; column: Chiralpak IA 3 μm 100x4.6 mm; eluent: CO ₂ /2-propanol 77:23, flow 4 ml / min, p = 100 bar, T = 37.5 ° C; DAD scan: 254 nm.

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

Example 20 (+) - 6- (4-Chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-X- (3,3,3-trifluoro-2-hydroxypropyl) -2,3-dihydropyridazine-4-carboxamide

Separation of 158 mg of Example 18 in accordance with Example 19 further resulted in 55 mg of (+) - 6- (4-chlorophenyl) -2- (1-methyl-N-pyrazol-4-yl) -3-oxo-X- (3,3,3-trifluoro-2-hydroxypropyl) -2,3-dihydropyridazine-4-carboxamide.

1 H-NMR (400 MHz, CDCl ₃ ): 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).

Chiral HPLC: _Rt = 3.75 min.

Instrument: Agilent HPLC 1260; column: Chiralpak IA 3 μm 100x4.6 mm; eluent: CO ₂ /2-propanol 77:23, flow 4 ml / min, p = 100 bar, T = 37.5 ° C; DAD scan: 254 nm.

Optical rotation:

[a] _D ²⁰ = 6.9 ° +/- 0.23 ° (c = 1.00, methanol).

Example 21 6- (4-Chlorophenyl) -X- (3,3-difluoro-2-hydroxypropyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine -4-carboxamide

- 83 037978

A solution of 110 mg of intermediate 11, 59.1 mg of 3-amino-1,1-difluoropropan-2-ol, 152 mg of HATU, and 0.14 ml of ethyldiisopropylamine in 5 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was quenched with water and the mixture extracted with dichloromethane twice. 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 100x30 mm, mobile phase: acetonitrile / water (0.1 vol% formic acid) gradient)) to obtain 65 mg of 6- (4-chlorophenyl) -N- (3,3-difluoro-2-hydroxypropyl) 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 3.68-3.77 (m, 1H); 3.85 (ddd, 1H); 3.96-4.08 (m + s, 5H); 5.79 (dt, 1H); 7.49 (d, 2H); 7.86 (d, 2H); 8.12 (s, 1H); 8.32 (s, 1H); 8.67 (s, 1H); 10.10 (bt, 1H).

Example 22. (-) - 6- (4-Chlorophenyl) -N- (3,3-difluoro-2-hydroxynpropyl) -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3 -dihydropyridazine-4-carboxamide

CH ₃

Ν — Ν ¥

Ν ^Ν γ °

L J ΗΝ.

Or%

R Λ γ ^ Ο Η

F

HPLC separation 63 mg 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) on a chiral column (Chiralpak IA 5 μm 250x30 mm, eluent: CO2 / 2-propanol 71:29, flow 100 ml / min, p = 150 bar, T = 4O ° C) gave to obtain 15 mg of (-) - 6- (4-chlorophenyl) -N- (3,3-difluoro-2-hydroxinpropyl) -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2, 3-dihydropyridazine-4-carboxamide.

¹ H-NMR (400 MHz, CDCl ₃ ): δ [ppm] = 3.68-3.77 (m, 1H); 3.85 (ddd, 1H); 3.96-4.08 (m + s, 5H); 5.79 (dt, 1H); 7.49 (d, 2H); 7.86 (d, 2H); 8.12 (s, 1H); 8.32 (s, 1H); 8.67 (s, 1H); 10.10 (bt, 1H).

Chiral HPLC: _Rt = 2.50 min.

Instrument: Agilent HPLC 1260; column: Chiralpak IA 3 μm 100x4.6 mm; eluent: CO2 / 2-propanol 71:29, flow 4 ml / min, p = 100 bar, T = 37.5 ° C; DAD scan: 254 nm.

Optical rotation: [a] _D ²⁰ = -6.6 ° +/- 0.41 ° (c = 1.00, methanol).

Example 23. (+) - 6- (4-Chlorophenyl) -N- (3,3-difluoro-2-hydroxynpropyl) -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3 -dihydropyridazine-4-carboxamide

Separation of 63 mg of Example 21 according to Example 22 further resulted in 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.

- 84 037978

1 H-NMR (400 MHz, CDCl 3): δ [ppm] = 3.68-3.77 (m, 1H); 3.85 (ddd, 1H); 3.96-4.08 (m + s, 5H); 5.79 (dt,

1H); 7.49 (d, 2H); 7.86 (d, 2H); 8.12 (s, 1H); 8.32 (s, 1H); 8.67 (s, 1H); 10.10 (bt, 1H).

Chiral HPLC: _Rt = 4.12 min.

Instrument: Agilent HPLC 1260; column: Chiralpak IA 3 μm 100x4.6 mm; eluent: CO2 / 2-propanol 71:29, flow 4 ml / min, p = 100 bar, T = 37.5 ° C; DAD scan: 254 nm.

Optical rotation: [a] _D ²⁰ = 8.4 ° +/- 0.32 ° (c = 1.00, methanol).

Example 24 6- (4-Chlorophenyl) -N- (2-hydroxy-3-methoxypropyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4-carboxamide

A solution of 110 mg of intermediate 11, 55.9 mg of 1-amino-3-methoxypropan-2-ol, 152 mg of HATU, and 0.14 ml of ethyldiisopropylamine in 5 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was quenched with water and the mixture was extracted with dichloromethane twice. 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 100x30 mm, mobile phase: acetonitrile / water (0.1 vol% formic acid) gradient)) to obtain 40 mg of 6- (4-chlorophenyl) -N- (2-hydroxy-3-methoxypropyl) 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

¹ H-NMR (400 MHz, CDCls): 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).

Example 25. (-) - 6- (4-Chlorophenyl) -N- (2-hydroxy-3-methoxypropyl) -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3-dihydropyridazine -4-carboxamide

HPLC separation 38 mg 6- (4-chlorophenyl) -N- (2-hydroxy-3-methoxypropyl) -2- (1-methyl-1H-pyrazol4-yl) -3-oxo-2,3-dihydropyridazine-4 -carboxamide (example 24) on a chiral column (Chiralpak AD-H 5 μm 250x30 mm, eluent: acetonitrile (0.1 vol% diethylamine) / ethanol 90:10, flow 50 ml / min) yielded 18 mg of (-) - 6- (4-chlorophenyl) -N- (2-hydroxy-3-methoxypropyl) -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3-dihydropyridazine-4-carboxamide.

¹ H-NMR (400 MHz, CDCl ₃ ): 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).

Chiral HPLC: _Rt = 3.83 min.

Instrument: Agilent HPLC 1260; column: Chiralpak AD-H 3 μm 100x4.6 mm; eluent: acetonitrile (0.1 vol% diethylamine) / ethanol 90:10, flow: 1.4 ml / min, DAD scan: 254 nm.

Optical rotation: [a] _D ²⁰ = -5.2 ° +/- 0.44 ° (c = 1.00, methanol).

Example 26. (+) - 6- (4-Chlorophenyl) -N- (2-hydroxy-3-methoxypropyl) -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3-dihydropyridazine -4-carboxamide

- 85 037978

Separation of 38 mg of Example 24 according to Example 25 further resulted in 15 mg of (+) - 6- (4-chlorophenyl) -N- (2-hydroxy-3-methoxypropyl) -2- (1-methyl-1H-pyrazole -4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

1 H-NMR (400 MHz, CDC13): 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).

Chiral HPLC: R _t = 4.88 min.

Instrument: Agilent HPLC 1260; column: Chiralpak AD-H 3 μm 100x4.6 mm; eluent: acetonitrile (0.1 vol% diethylamine) / ethanol 90:10, flow: 1.4 ml / min, DAD scan: 254 nm.

Optical rotation: [a] _D ²⁰ = 6.2 ° +/- 0.31 ° (c = 1.00, methanol).

Example 27 6- (4-Chlorophenyl) -N - [(2S) -2,3-dihydroxypropyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4 -carboxamide

6- (4-Chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF ( 1.1 ml). (2S) -3aminopropane-1,2-diol (27.5 mg, 0.30 mmol), N-ethyl-N-isopropylpropane-2-amine (0.118 mL, 0.68 mmol) and propane phosphonic anhydride (T3P, 132 μL, 50 % in DMF, 227 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 21.5 mg (35% ) specified in the connection header.

Ή-NMR (400 MHz, DMSO-de): 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).

[u] d ²⁰ = -5.5 ° (c = 1.00, DMSO).

Example 28 6- (4-Chlorophenyl) -N - [(2R) -2,3-dihydroxypropyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4 -carboxamide

6- (4-Chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF ( 1.1 ml). (2R) -3aminopropane-1,2-diol (27.5 mg, 0.30 mmol), N-ethyl-N-isopropylpropan-2-amine (0.118 mL, 0.68 mmol) and propane phosphonic anhydride (T3P, 132 μL, 50 % in DMF, 227 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified using RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 17.5 mg (29% ) specified in the connection header.

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 3.21-3.30 (m, 1H), 3.30-3.36 (m, 1H and water signal), 3.38-3.44

- 86 037978 (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).

[a] D ²⁰ = + 14.3 ° (c = 1.00, DMSO).

Example 29 6- (4-Chlorophenyl) -N - [(2S) -1-hydroxy-3-methoxypropan-2-yl] -2- (1-methyl-1H-pyrazol-4yl) -3-oxo-2 , 3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF ( 1.1 ml). (2S) -2-amino-3methoxypropan-1-ol (31.8 mg, 0.30 mmol), X-ethyl-X-isopropylpropan-2-amine (0.118 ml, 0.68 mmol) and propane phosphonic acid anhydride (T3P, 132 μl , 50% in DMF, 227 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 33 mg (52% ) specified in the connection header.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.30 (s, 3H), 3.44-3.61 (m, 4H), 3.93 (s, 3H), 4.10-4.19 (m, 1H), 4.99 (t, 1H), 7.58-7.62 (m, 2H), 8.08-8.12 (m, 3H), 8.56 (s, 1H), 8.60 (s, 1H), 9.64 (d, 1H).

Example 3 0.6- (4-Chlorophenyl) -N - [(2R) -1-hydroxy-3-methoxypropan-2-yl] -2- (1-methyl-1 H-pyrazol-4yl) -3-oxo -2,3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF ( 1.1 ml). (2R) -2-amino-3methoxypropan-1-ol (31.8 mg, 0.30 mmol), X-ethyl-X-isopropylpropan-2-amine (0.118 ml, 0.68 mmol) and propane phosphonic anhydride (T3P, 132 μl , 50% in DMF, 227 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 26 mg (41% ) specified in the connection header.

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.30 (s, 3H), 3.44-3.61 (m, 4H), 3.93 (s, 3H), 4.10-4.19 (m, 1H ), 4.99 (t, 1H), 7.58-7.62 (m, 2H), 8.08-8.12 (m, 3H), 8.56 (s, 1H), 8.60 (s, 1H), 9.64 (d, 1H).

Example 31.6- (4-Chlorophenyl) -N- (1,3-dihydroxypropan-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4 -carboxamide

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

- 87 037978 (50 mg, 0.15 mmol) was dissolved in anhydrous DMF (1.1 ml). 2-aminopropane-1,3-diol (27.5 mg, 0.30 mmol), Y-ethyl-N-isopropylpropan-2-amine (0.118 ml, 0.68 mmol), and propane phosphonic anhydride (T3P, 132 μL, 50% in DMF, 227 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 29 mg (48% ) specified in the connection header.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.47-3.54 (m, 2H), 3.57-3.63 (m, 2H), 3.93 (s, 3H), 3.94-4.02 (m, 1H), 4.89 (t, 2H), 7.58-7.62 (m, 2H), 8.07-8.13 (m, 3H), 8.57 (s, 1H), 8.60 (s, 1H), 9.63 (d, 1H ).

Example 32 6- (4-Chlorophenyl) -N- (2-hydroxy-2-methylpropyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4-carboxamide SN ₃ Ν — Ν V .Ο

6- (4-Chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF ( 1.1 ml). 1-amino-2methylpropan-2-ol (27 mg, 0.30 mmol), Y-ethyl-N-isopropylpropan-2-amine (0.118 mL, 0.68 mmol), and propane phosphonic anhydride (T3P, 132 μL, 50% in DMF, 227 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 20 mg (33% ) specified in the connection header.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.15 (s, 6H), 3.32-3.35 (m, 2H and water signal), 3.93 (s, 3H), 4.70 ( s, 1H), 7.58-7.62 (m, 2H), 8.07-8.13 (m, 3H), 8.56 (s, 1H), 8.59 (s, 1H), 9.65 (t, 1H).

Example 33 6- (4-Chlorophenyl) -2- (1-methyl-1H-nyrazol-4-yl) -3-oxo-N - [(2RS) -1,1,1-trifluoro-3hydroxypropane-2- yl] -2,3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.30 mmol) was dissolved in anhydrous DMF ( 2.3 ml). Hydrochloride (2RS) -2-amino-3,3,3-trifluoropropan-1-ol (1: 1) (100 mg, 0.61 mmol), Y-ethyl-N-isopropylpropan-2-amine (342 μL, 1.97 mmol) and propane phosphonic acid anhydride (T3P, 265 μL, 50% in DMF, 454 μmol). The mixture was stirred for 48 h at RT. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 35 mg (26% ) specified in the connection header.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.68-3.76 (m, 1H), 3.81-3.88 (m, 1H), 3.93 (s, 3H), 4.81-4.93 (m, 1H), 5.45-5.49 (m, 1H), 7.58-7.63 (m, 2H), 8.10-8.14 (m, 3H), 8.59 (s, 1H), 8.65 (s, 1H), 10.12 (d , 1H).

Example 34. (-) - 6- (4-Chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-N - [(2S) -1,1,1-trifluoro- 3-hydroxypropan-2-yl] -2,3-dihydropyridazine-4-carboxamide

- 88 037978

6- (4-Chlorophenyl) -2- (1-methyl-1 H-pyrazol-4-yl) -3-oxo-N - [(2RS) -1,1,1-trifluoro-3-hydroxypropane-2yl] -2,3-dihydropyridazine-4-carboxamide (27.7 mg) was separated by chiral HPLC (column: Chiralpak IB 5 μm 250x30 mm, mobile phase: isocratic mode (82:18) carbon dioxide / 2-propanol, 100 ml / min, temperature 40 ° C, BPR: 150 bar, UV: 254 nm) to give 14 mg (51%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.68-3.76 (m, 1H), 3.81-3.88 (m, 1H), 3.93 (s, 3H), 4.81-4.93 (m, 1H), 5.47 (br s, 1H), 7.57-7.63 (m, 2H), 8.09-8.15 (m, 3H), 8.59 (s, 1H), 8.65 (s, 1H), 10.12 (d, 1H).

Chiral HPLC: _Rt = 2.54 min.

Instrument: Agilent HPLC 1260: Chiralpak IB 5 μm 100x4.6 mm; eluent: carbon dioxide / 2-propanol, isocratic mode: 82:18, flow: 4 ml / min, temperature: 37.5 ° C, BPR: 100 bar, UV: 254 nm.

[a] D ²⁰ = -34.5 ° (c = 1.00, methanol).

Example 35. (+) - 6- (4-Chlorophenyl) -2- (1-methyl-1 H-pyrazol-4-yl) -3-oxo-N - [(2R) -1,1,1-trifluoro -3 hydroxypropan-2-yl] -2,3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -2- (1-methyl-1 H-pyrazol-4-yl) -3-oxo-N - [(2RS) -1,1,1-trifluoro-3-hydroxypropane-2yl] -2,3-dihydropyridazine-4-carboxamide (27.7 mg) was separated by chiral HPLC (column: Chiralpak IB 5 μm 250x30 mm, mobile phase: isocratic mode (82:18) carbon dioxide / 2-propanol, 100 ml / min, temperature 40 ° C, BPR: 150 bar, UV: 254 nm) to give 14 mg (51%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.68-3.76 (m, 1H), 3.84 (dt, 1H), 3.93 (s, 3H), 4.81-4.94 (m, 1H), 5.47 (t, 1H), 7.58-7.63 (m, 2H), 8.10-8.15 (m, 3H), 8.60 (s, 1H), 8.65 (s, 1H), 10.12 (d, 1H).

Chiral HPLC: _Rt = 3.61 min.

Instrument: Agilent HPLC 1260: Chiralpak IB 5 μm 100x4.6 mm; eluent: carbon dioxide / 2-propanol, isocratic mode: 82:18, flow: 4 ml / min, temperature: 37.5 ° C, BPR: 100 bar, UV: 254 nm.

[a] D ²⁰ = + 40.1 ° (c = 1.00, methanol).

Example 36. 2- (1-Methyl-1H-pyrazol-4-yl) -3-oxo-N - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -6 [4 - (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide

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

- 89 037978 Acid (50 mg, 0.137 mmol) was dissolved in anhydrous DMF (1.5 ml). (2R) -2-amino-3,3,3-trifluoropropan-1-ol hydrochloride (1: 1) (35.5 mg, 0.215 mmol), N-3tuh-Nisopropylpropan-2-amine (0.108 ml, 0.62 mmol ) and propane phosphonic anhydride (T3P, 121 μL, 50% in DMF, 207 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuo and purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient, twice) with obtaining 10.9 mg (17%) of the title compound.

¹ H-NMR (400 MHz, DMSO ^): δ [ppm] = 3.69-3.77 (m, 1H), 3.82-3.88 (m, 1H), 3.94 (s, 3H), 4.88 (dt, 1H ), 5.48 (s, 1H), 7.90 (d, 2H), 8.15 (s, 1H), 8.32 (d, 2H), 8.61 (s, 1H), 8.71 (s, 1H), 10.10 (d, 1H) ...

Example 37. 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

2- (1-Methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.137 mmol) was dissolved in anhydrous DMF (1.5 ml). (2S) -3-amino-1,1,1-trifluoropropan-2-ol (35.5 mg, 0.262 mmol), N-ethyl-N-isopropylpropan-2-amine (0.108 ml, 0.62 mmol) and propane phosphonic anhydride acid (T3P, 121 μl, 50% in DMF, 207 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuo and purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient, twice) with obtaining 12.7 mg (19%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d _b ): δ [ppm] = 3.46-3.54 (m, 1H), 3.74-3.82 (m, 1H), 3.94 (s, 3H), 4.19-4.30 (m, 1H), 6.71 (s, 1H), 7.90 (d, 2H), 8.14 (s, 1H), 8.30 (d, 2H), 8.56 (s, 1H), 8.67 (s, 1H), 9.72 ( t, 1H).

[a] D ²⁰ = -4.1 ° (c = 1.00, methanol).

Example 38. (-) - [(2R) -1-Hydroxypropan-2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) phenyl ] -2,3-dihydropyridazine-4-carboxamide

2- (1-Methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.137 mmol) was dissolved in anhydrous DMF (1.5 ml). (2R) -2-aminopropan-1-ol (21 mg, 0.28 mmol), N-ethyl-N-isopropylpropan-2-amine (0.108 mL, 0.62 mmol) and propane phosphonic anhydride (T3P, 121 μL, 50 % in DMF, 207 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuo and purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient, twice) with obtaining 12.5 mg (21%) of the title compound.

¹ H-NMR (400 MHz, DMSO-db): δ [ppm] = 1.19 (d, 3H), 3.43-3.52 (m, 2H), 3.93 (s, 3H), 4.01-4.11 (m, 1H), 4.97 (t, 1H), 7.90 (d, 2H), 8.13 (s, 1H), 8.30 (d, 2H), 8.58 (s, 1H), 8.65 (s, 1H), 9.52 (d, 1H ).

[a] D ²⁰ = -14.0 ° (c = 1.00, methanol).

Example 39. (+) - N - [(2S) -1-Hydroxypropan-2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl ) phenyl] -2,3-dihydropyridazine-4-carboxamide

- 90 037978

2- (1-Methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (45 mg, 0.124 mmol) was dissolved in anhydrous DMF (1.5 ml). (2S) -2-aminopropan-1-ol (18.6 mg, 0.25 mmol), N-ethyl-N-isopropylpropan-2-amine (0.097 mL, 0.56 mmol) and propane phosphonic anhydride (T3P, 108 μL, 50 % in DMF, 185 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuo and purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient, twice) with obtaining 10 mg (19%) of the title compound.

Ή-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.19 (d, 3H), 3.43-3.53 (m, 2H), 4.01-4.11 (m, 1H), 4.97 (t, 1H ), 7.90 (d, 2H), 8.13 (s, 1H), 8.30 (d, 2H), 8.59 (s, 1H), 8.65 (s, 1H), 9.52 (d, 1H).

[a] D ²⁰ = + 30.0 ° (c = 1.00, methanol).

Example 40 6- (4-Chlorophenyl) -2- (1-cyclobutyl-1H-pyrazol-4-yl) -3-oxo-N - [(2S) -3,3,3-trifluoro-2hydroxypropyl] -2 , 3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -2- (1-cyclobutyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.135 mmol) was dissolved in anhydrous DMF ( 1.5 ml). (2S) 3-amino-1,1,1-trifluoropropan-2-ol (35 mg, 0.27 mmol), N-ethyl-N-isopropylpropan-2-amine (0.106 ml, 0.61 mmol) and propane phosphonic anhydride (T3P , 118 μl, 50% in DMF, 202 μmol). The mixture was stirred for 1 h at RT. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient, twice) to give 23 mg ( 35%) specified in the title of the compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.75-1.86 (m, 2H), 2.36-2.46 (m, 2H), 2.46-2.58 (m, 2H and DMSO signal) , 3.49 (ddd, 1H), 3.77 (ddd, 1H), 4.19-4.24 (m, 1H), 4.91-5.01 (m, 1H), 6.69 (s, 1H), 7.58-7.63 (m, 2H), 8.08 -8.13 (m, 2H), 8.18 (s, 1H), 8.59 (s, 1H), 8.61 (s, 1H), 9.73 (t, 1H).

[a] D ²⁰ = -2.7 ° (c = 1.00, methanol).

Example 41 6- (4-Chlorophenyl) -2- (1-cyclobutyl-1 H-pyrazol-4-yl) -3-okco-N - [(2R) -1,1,1-trifluoro-3 hydroxypropane- 2-yl] -2,3-dihydropyridazine-4-carboxamide

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

- 91 037978 acid (45 mg, 0.121 mmol) was dissolved in anhydrous DMF (1.5 ml). (2R) -2-amino-3,3,3-trifluoropropan-1-ol hydrochloride (1: 1) (40 mg, 0.24 mmol), N-ethyl-N-isopropylpropan2-amine (0.137 ml, 0.79 mmol ) and propane phosphonic anhydride (T3P, 106 μL, 50% in DMF, 182 μmol). The mixture was stirred for 1 h at RT. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient, twice) to give 22 mg ( 38%) specified in the title of the compound.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.75-1.88 (m, 2H), 2.36-2.45 (m, 2H), 2.46-2.60 (m, 2H and DMSO signal) , 3.67-3.75 (m, 1H), 3.85 (dt, 1H), 4.81-5.02 (m, 2H), 5.47 (t, 1H), 7.58-7.64 (m, 2H), 8.10-8.15 (m, 2H) , 8.18 (s, 1H), 8.62 (s, 1H), 8.65 (s, 1H), 10.09 (d, 1H).

[a] D ²⁰ = + 36.7 ° (c = 1.00, methanol).

Example 42 6- (4-Chlorophenyl) -2- (1-cyclobutyl-1H-pyrazol-4-yl) -N - [(2S) -1-hydroxypropan-2-yl] -3oxo-2,3-dihydropyridazine -4-carboxamide

6- (4-Chlorophenyl) -2- (1-cyclobutyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (47 mg, 0.127 mmol) was dissolved in anhydrous DMF ( 1.5 ml). (2S) 2-aminopropan-1-ol (19 mg, 0.25 mmol), N-ethyl-N-isopropylpropan-2-amine (99.3 μL, 0.57 mmol) and propane phosphonic anhydride (T3P, 111 μL, 50% in DMF, 190 μmol). The mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo and purified by SPHPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.1 vol% formic acid (99%)) / acetonitrile, gradient, DAD: 210-400 nm ) to give 15.5 mg (29%) of the title compound.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.18 (d, 3H), 1.75-1.89 (m, 2H), 2.36-2.45 (m, 2H), 2.46-2.59 ( m, 2H and DMSO signal), 3.42-3.52 (m, 2H), 4.00-4.11 (m, 1H), 4.90-5.00 (m, 2H), 7.58-7.63 (m, 2H), 8.088.12 (m, 2H), 8.16 (s, 1H), 8.59 (s, 1H), 8.61 (s, 1H), 9.52 (d, 1H).

[a] _D ²⁰ = + 20.5 ° (c = 1.00, methanol).

Example 43 6- (4-Chlorophenyl) -N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-pyrazol-4yl) -3-oxo-2,3-dihydropyridazine -4-carboxamide

A solution of 150 mg of intermediate 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4-carboxylic acid, 126.6 mg of cis-4 hydrochloride α-aminotetrahydro-3-furanol (1: 1), 344.9 mg HATU, 0.32 ml of ethyldiisopropylamine and 4 mg of 4-dimethylaminopyridine in 3.1 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC ( Instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol.% Formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% (A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) to give 127 mg of the title compound.

1H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.47 (t, 1H), 3.64 (dd, 1H), 3.93 (s, 3H), 3.94-3.98 (m, 1H), 4.01 ( dd, 1H), 4.26-4.33 (m, 1H), 4.34-4.44 (m, 1H), 5.70 (d, 1H), 7.57-7.63 (m, 2H), 8.06-8.11 (m, 2H), 8.11 ( s, 1H), 8.55 (s, 1H), 8.61 (s, 1H), 9.90 (d, 1H).

Example 44 6- (4-Chlorophenyl) -N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-pyrazol-4yl) -3-oxo-2,3-dihydropyridazine -4-carboxamide, enantiomer 1

- 92 037978

HPLC separation 127 mg 6- (4-chlorophenyl) -X- (4-hydroxytetrahydrofuran-3-yl) -2- (1-methyl-Spirazol-4-yl) -3-oxo-2,3-dihydropyridazin-4 -carboxamide (example 43) on a chiral column (instrument:

Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IE 5 μm 250x30 mm; eluent A: tert-butyl methyl ether; eluent B: methanol; isocratic mode: 50% A + 50% B; flow 50.0 ml / min; UV: 280 nm) yielded 48 mg of the title compound.

Chiral HPLC: R _t = 2.46 min (instrument: Agilent HPLC 1260; column: Chiralpak IE 3 μm 100x4.6 mm; eluent A: tert-butyl methyl ether + 0.1% v / v diethylamine (99%); eluent B: methanol; isocratic mode: 50% A + 50% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 280 nm).

Example 45 6- (4-Chlorophenyl) -X - [(cis) -4-hydroxytetrahydrofuran-3-yl] -2- (1-methyl-N-pyrazol-4yl) -3-oxo-2,3-dihydropyridazine -4-carboxamide, enantiomer 2

Separation of 127 mg 6- (4-chlorophenyl) -X- (4-hydroxytetrahydrofuran-3-yl) -2- (1-methyl-1H-pyrazol-4yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide (Example 43), in accordance with Example 44, further yielded 46 mg of the title compound.

Chiral HPLC: R _t = 2.02 min (instrument: Agilent HPLC 1260; column: Chiralpak IE 3 μm 100x4.6 mm; eluent A: tert-butyl methyl ether + 0.1% v / v diethylamine (99%); eluent B: methanol; isocratic mode: 50% A + 50% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 280 nm).

Example 46. N - [(1S, 2R) -2-Hydroxycyclohexyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2, 3-dihydropyridazine-4-carboxamide

CH ₃

N— N

Solution of 75 mg of intermediate 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylic acid, 63 mg of hydrochloride (1R, 2S) -2-aminocyclohexanol (1: 1), 150 mg HATU, 0.14 ml of ethyldiisopropylamine, and 1 mg of 4-dimethylaminopyridine in 1.5 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5 μm 100x30 mm; eluent A: water + 0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B ; flow 70 ml / min; temperature: 25 ° C; DAD scan: 210-400 nm) to obtain 42 mg of N - [(1S, 2R) -2-hydroxycyclohexyl] -2- (1-methyl-1H-pyrazole -4-yl) -3-oxo-6- [4 (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.27-1.40 (m, 2H), 1.49-1.76 (m, 6H), 3.76-3.84 (m, 1H), 3.93 (m , 4H), 4.90 (d, 1H), 7.47-7.58 (m, 2H), 8.12 (d, 1H), 8.17-8.22 (m, 2H), 8.56 (s, 1H), 8.61 (s, 1H), 9.72 (d, 1H).

Example 47. 2- (1-Methyl-1H-pyrazol-4-yl) -3-oxo-N - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -6 [4 - (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide

- 93 037978

Solution of 75 mg of intermediate 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylic acid, 65.3 mg of hydrochloride (2R) -2-amino-3,3,3trifluoropropan-1-ol (1: 1), 150 mg HATU, 0.14 ml of ethyldiisopropylamine, and 1 mg of 4-dimethylaminopyridine in 1.5 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument: Waters Autopurification MS SingleQuad; column: Waters XBrigde C18 5 μm 100x30 mm; eluent A: water + 0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0 -5.5 min 5-100% B; flow 70 ml / min; temperature: 25 ° C; DAD scan: 210-400 nm) to obtain 56 mg of 2- (1-methyl-III-pyrazol-4-yl) -3- oxo-N - [(2R) -1,1,1trifluoro-3-hydroxypropan-2-yl] -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 3.65-3.77 (m, 1H), 3.85 (m, 1h), 3.93 (s, 3H), 4.81-4.96 (m, 1H) , 5.47 (t, 1H), 7.36-7.54 (m, 2H), 8.13 (d, 1H), 8.17-8.31 (m, 2H), 8.60 (s, 1H), 8.66 (s, 1H), 10.12 (d , 1H).

Example 48 6- (4-Chlorophenyl) -N - [(1S, 2R) -2-hydroxycyclohexyl] -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3-dihydropyridazine-4 -carboxamide

Solution of 75 mg of intermediate 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4-carboxylic acid, 44 mg of (1R, 2S) hydrochloride -2-aminocyclohexanol (1: 1), 105 mg HATU, 0.14 ml ethyldiisopropylamine and 1 mg 4-dimethylaminopyridine in 1 ml DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument: Waters Autopurification MS SingleQuad; column: Waters XBrigde C18 5 μm 100x30 mm; eluent A: water + 0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5100% B; flow 70 ml / min; temperature: 25 ° C; DAD scan: 210-400 nm) to obtain 43 mg of the title compound.

1H NMR (400 MHz, DMSO-d6) δ [ppm] = 1.28-1.41 (m, 2H), 1.49-1.76 (m, 6H), 3.80 (br s, 1H), 3.93 (s, 4H) , 4.90 (br d, 1H), 7.57-7.63 (m, 2H), 8.06-8.10 (m, 2H), 8.11 (s, 1H), 8.55 (s, 1H), 8.59 (s, 1H), 9.72 ( d, 1H).

Example 49 6- (4-Chlorophenyl) -N - [(1S, 2S) -2-hydroxycyclopentyl] -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3-dihydropyridazine-4 -carboxamide

A solution of 128 mg of intermediate 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4-carboxylic acid (46%), 50 mg of hydrochloride ( 1S, 2S) -2-aminocyclopentanol (1: 1), 135 mg HATU, 0.13 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 1 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC ( instrument: gradient pump Labomatic HD-3000 HPLC, fraction collector Labo-94 037978 matic Labocol Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to give 3 mg of 6- (4-chlorophenyl) -N - [(1S, 2S) -2 -hydroxycyclopentyl] -2- (1methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

Ή NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.38-1.58 (m, 2H), 1.60-1.79 (m, 2H), 1.80-1.89 (m, 1H), 2.032.18 ( m, 1H), 3.93 (s, 3h), 3.94-3.99 (m, 1H), 3.99-4.07 (m, 1H), 4.97 (d, 1H), 7.55-7.65 (m, 2H), 8.07-8.14 ( m, 3H), 8.52-8.60 (m, 2H), 9.44 (d, 1H).

Example 50 6- (4-Chlorophenyl) -N - [(1S, 2R) -2-hydroxycyclopentyl] -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3-dihydropyridazine-4 -carboxamide

A solution of 75 mg of intermediate 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4-carboxylic acid (61%), 38.5 mg of hydrochloride ( 1R, 2S) -2-aminocyclopentanol (1: 1), 105 mg HATU, 0.1 ml ethyldiisopropylamine and 1 mg 4-dimethylaminopyridine in 1 ml DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC ( instrument: Waters Autopurification MS SingleQuad; column: Waters XBrigde C18 5 μm 100x30 mm; eluent A: water + 0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml / min; temperature: 25 ° C; DAD scan: 210-400 nm) to obtain 16 mg of 6- (4-chlorophenyl) -N - [(1S, 2R) -2-hydroxycyclopentyl] -2- ( 1-methyl-1H-pyrazol-4-yl) -3oxo-2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.50-1.67 (m, 3H), 1.71-1.89 (m, 2H), 1.92-2.04 (m, 1H), 3.93 (s , 3H), 4.02-4.15 (m, 2H), 5.05 (br s, 1H), 7.56-7.64 (m, 2H), 8.07-8.13 (m, 3H), 8.55-8.58 (m, 1H), 8.60 ( s, 1H), 9.77 (d, 1H).

Example 51 6- (4-Chlorophenyl) -N - [(trans) -2-hydroxycyclopentyl] -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-2,3-dihydropyridazine-4-carboxamide

A solution of 65 mg of intermediate 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4-carboxylic acid, 56 mg of (trans) -2 hydrochloride α-aminocyclopentanol (1: 1), 149.5 mg HATU, 0.14 ml ethyldiisopropylamine and 1.2 mg 4-dimethylaminopyridine in 2 ml DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Waters Autopurification MS SingleQuad ; column: Waters XBrigde C18 5 μm 100x30 mm; eluent A: water + 0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 05.5 min 5-100% B; flow 70 ml / min; temperature: 25 ° C; DAD scan: 210-400 nm) to obtain 56 mg of 6- (4-chlorophenyl) -N - [(trans) -2-hydroxycyclopentyl] -2- (1-methyl-1H-pyrazole-4- yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.41-1.57 (m, 2H), 1.61-1.78 (m, 2H), 1.80-1.91 (m, 1H), 2.042.16 ( m, 1H), 3.93 (s, 3H), 3.94-3.99 (m, 1H), 4.00-4.08 (m, 1H), 4.97 (d, 1H), 7.56-7.64 (m, 2H), 8.08-8.13 ( m, 3H), 8.53-8.58 (m, 2H), 9.44 (d, 1H).

Example 52 6- [4- (Difluoromethyl) phenyl] -N - [(trans) -2-hydroxycyclopentyl] -2- (1-methyl-1H-pyrazol4-yl) -3-oxo-2,3-dihydropyridazine- 4-carboxamide

- 95 037978

A solution of 47 mg of intermediate 6- [4- (difluoromethyl) phenyl] -2- (1-methyl-1H-pyrazole-4yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 37.4 mg of hydrochloride (trans ) -2-aminocyclopentanol (1: 1), 103 mg HATU, 0.1 ml ethyldiisopropylamine and 1 mg 4-dimethylaminopyridine in 1 ml DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient Labomatic HD-3000 HPLC pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% m A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to obtain 41 mg of 6- [4- (difluoromethyl) phenyl] -N - [(trans) -2-hydroxycyclopentyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

Ή NMR (400 MHz, DMSO-d6) δ [ppm] = 1.42-1.57 (m, 2H), 1.61-1.80 (m, 2H), 1.81-1.92 (m, 1H), 2.052.18 (m , 1H), 3.93 (s, 3H), 3.94-3.99 (m, 1H), 4.00-4.08 (m, 1H), 4.97 (d, 1H), 7.14 (t, 1H), 7.74 (d, 2H), 8.13 (s, 1H), 8.22 (d, 2H), 8.57 (s, 1H), 8.60 (s, 1H), 9.44 (d, 1H).

Example 53 N - [(2S) -1 -Hydroxypropan-2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide

A solution of 75 mg of intermediate 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylic acid, 65.3 mg ( S) - (+) - 2-amino-1-propanol, 150 mg HATU, 0.1 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 1.5 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RPHPLC (Instrument : Waters Autopurification MS SingleQuad; column: Waters XBrigde C18 5 μm 100x30 mm; eluent A: water + 0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5100% B; 70 ml flow / min; temperature: 25 ° C; DAD scan: 210-400 nm) to obtain 53 mg of N [(2S) -1-hydroxypropan-2-yl] -2- (1-methyl-1H-pyrazole-4- yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3 dihydropyridazine-4-carboxamide.

Ή NMR (400 MHz, DMSO-de) δ [ppm] = 1.19 (d, 3H), 3.42-3.51 (m, 2H), 3.93 (s, 3H), 4.00-4.13 (m, 1H), 4.96 (t, 1H), 7.53 (d, 2H), 8.12 (s, 1H), 8.16-8.24 (m, 2H), 8.57 (s, 1H), 8.60 (s, 1H), 9.53 (d, 1H) ...

Example 54 6- [6- (Difluoromethyl) pyridin-3-yl] -N - [(1S, 2R) -2-hydroxycyclohexyl] -2- (1-methyl-1Hpyrazol-4-yl) -3-oxo 2,3-dihydropyridazine-4-carboxamide

A solution of 55 mg of intermediate 6- [6- (difluoromethyl) pyridin-3-yl] -2- (1-methyl-1Hpyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 50.5 mg hydrochloride (1R, 2S) -2

- 96 037978 aminocyclohexanol (1: 1), 120 mg HATU, 0.11 ml ethyldiisopropylamine and 1.5 mg 4dimethylaminopyridine in 1 ml DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument: Labomatic HD3000 gradient pump HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / At 55%; flow: 150 ml / min; UV detection: 254 nm) to obtain 39 mg of 6- [6 (difluoromethyl) pyridin-3-yl] -N - [(1 S, 2R) -2-hydroxycyclohexyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4-carboxamide.

¹ HNMR (400 MHz, DMSO-de) δ [ppm] = 1.35 (br d, 2H), 1.51-1.75 (m, 6H), 3.81 (br s, 1H), 3.93 (m, 4H), 4.92 (d, 1H), 7.07 (t, 1H), 7.85 (d, 1H), 8.17 (s, 1H), 8.59 (s, 1H), 8.66 (dd, 1H), 8.70 (s, 1H), 9.36 (d, 1H), 9.70 (d, 1H).

Example 55. N - [(cis) -4-Hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4 (trifluoromethoxy) phenyl] -2 , 3-dihydropyridazine-4-carboxamide ch ₃

N — N

V? ^H

JI / J HN. JI

I F \ /

X '—o

A solution of 153 mg of intermediate 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylic acid, 112.3 mg of cis-4aminotetrahydro-3-furanol hydrochloride (1: 1), 306 mg of HATU, 0.28 ml of ethyldiisopropylamine and 4 mg of 4dimethylaminopyridine in 3 ml of DMF were stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument : Waters Autopurification MS SingleQuad; column: Waters XBrigde C18 5 μm 100x30 mm; eluent A: water + 0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml / min; temperature: 25 ° C; DAD scan: 210-400 nm) to obtain 120 mg N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -2- (1-methyl1H-pyrazol-4-yl ) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide.

1H NMR (400 MHz, DMSO-de) δ [ppm] = 3.48 (t, 1H), 3.65 (dd, 1H), 3.93 (s, 3H), 3.94-3.98 (m, 1H), 4.01 ( t, 1H), 4.26-4.33 (m, 1H), 4.34-4.44 (m, 1H), 5.70 (d, 1H), 7.53 (d, 2H), 8.12 (s, 1H), 8.17-8.23 (m, 2H), 8.56 (s, 1H), 8.63 (s, 1H), 9.90 (d, 1H).

Example 56 N - [(cis) -4-Hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4 (trifluoromethoxy) phenyl] -2 , 3-dihydropyridazine-4-carboxamide, enantiomer 1

HPLC separation 115 mg rac-N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-pyrazol-4yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl ] -2,3-dihydropyridazine-4-carboxamide (example 55) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IE 5 μm 250x30 mm; eluent A: tert -butyl methyl ether; eluent B: methanol; isocratic mode: 50% A + 50% B; flow 50.0 ml / min; UV: 280 nm) yielded 42 mg N - [(cis) -4 hydroxytetrahydrofuran-3-yl] - 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoro-methoxy) phenyl] -2,3 dihydropyridazine-4-carboxamide, enantiomer 1.

Chiral HPLC: R _t = 1.76 min (instrument: Agilent HPLC 1260; column: Chiralpak IE 3 μm 100x4.6 mm; eluent A: tert-butyl methyl ether + 0.1% v / v diethylamine (99%); eluent B: methanol; isocratic mode: 50% A + 50% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 280 nm).

Example 57 N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4 (trifluoromethoxy) phenyl] -2 , 3-dihydropyridazine-4-carboxamide, enantiomer 2

- 97 037978

HPLC separation 115 mg No. [(cis) -4-hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-pyrazol-4-yl) 3-oxo-6- [4- (trifluoromethoxy) phenyl] - 2,3-dihydropyridazine-4-carboxamide (example 55) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IE 5 μm 250x30 mm; eluent A: tert-butyl methyl ether; eluent B: methanol; isocratic mode: 50% A + 50% B; flow 50.0 ml / min; UV: 280 nm) yielded 42 mg of N - [(cis) -4hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoro-methoxy) phenyl] -2,3 dihydropyridazine-4-carboxamide, enantiomer 2.

Chiral HPLC: R _t = 2.19 min (instrument: Agilent HPLC 1260; column: Chiralpak IE 3 μm 100x4.6 mm; eluent A: tert-butyl methyl ether + 0.1 vol% diethylamine (99%); eluent B: methanol; isocratic mode: 50% A + 50% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 280 nm).

Example 58 6- [4- (Difluoromethyl) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -2- (1-methyl-1H-pyrazol-4yl) -3-oxo-2 , 3-dihydropyridazine-4-carboxamide

Solution of 47 mg of intermediate 6- [4- (difluoromethyl) phenyl] -2- (1-methyl-1H-pyrazole-4yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 20.4 mg (2S) -2-aminopropan-1-ol, 103 mg HATU, 0.1 ml of ethyldiisopropylamine, and 1 mg of 4-dimethylaminopyridine in 1 ml of DMF were stirred at room temperature for 14 h. Another 50 mg of HATU, 0.05 ml of ethyldiisopropylamine, 1 mg of 4-dimethylaminopyridine were added and 10 mg of (2S) -2-aminopropan-1-ol, followed by stirring at 50 ° C for 3 hours. The reaction mixture was then filtered and subjected to RP-HPLC (Instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol fraction collector Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: water + 0.2 vol.% Aqueous ammonia (32%), eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55 %; flow: 150 ml / min; UV detection: 254 nm) to give 41 mg of 6- [4 (difluoromethyl) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -2- (1 -methyl-1H-pyrαzol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm] = 1.19 (d, 3H), 3.42-3.52 (m, 2H), 3.93 (s, 3H), 3.99-4.12 (m, 1H) , 4.96 (t, 1H), 7.14 (t, 1H), 7.74 (d, 2H), 8.13 (s, 1H), 8.22 (d, 2H), 8.58 (s, 1H), 8.63 (s, 1H), 9.53 (d, 1H).

Example 59. N- (2-Hydroxy-2-methylpropyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3- dihydropyridazine-4-carboxamide

Solution of 75 mg of intermediate 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylic acid, 51 mg of hydrochloride 1-amino-2-methylpropan-2-ol (1: 1), 150 mg HATU, 0.14 ml of ethyldiisopropylamine and 1.2 mg of 4-dimethylaminopyridine in

- 98 037978

1.5 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument: Waters Autopurification MS SingleQuad; column: Waters XBrigde C18 5 μm 100x30 mm; eluent A: water + 0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml / min; temperature: 25 ° C; DAD-scan: 210-400 nm) to obtain 56 mg N- ( 2-hydroxy-2-methylpropyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4 (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide.

Ή NMR (400 MHz, DMSO-d6) δ [ppm] = 1.15 (s, 6H), 3.33 (d, 2H), 3.93 (s, 3H), 4.70 (s, 1H), 7.48-7.55 ( m, 2H), 8.12 (d, 1H), 8.16-8.23 (m, 2H), 8.56 (s, 1H), 8.61 (s, 1H), 9.65 (t, 1H).

Example 60 6- [4- (Difluoromethyl) phenyl] -N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1Hpyrazol-4-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxamide

CH ₃

Ν — Ν? Η .Ο? ^Η

F С- θ '

A solution of 47 mg of intermediate 6- [4- (difluoromethyl) phenyl] -2- (1-methyl-1H-pyrazole-4yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 38 mg of cis- hydrochloride 4-aminotetrahydro-3furanol (1: 1), 103 mg HATU, 0.1 ml ethyldiisopropylamine and 1 mg 4-dimethylaminopyridine in 1 ml DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument: gradient Labomatic HD-3000 HPLC pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) yielding 38 mg of 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 H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.48 (t, 1H), 3.65 (dd, 1H), 3.94 (s, 3H), 3.94-3.98 (m, 1H), 4.02 (t, 1H), 4.27-4.33 (m, 1H), 4.34-4.43 (m, 1H), 5.71 (d, 1H), 7.13 (t, 1H), 7.74 (d, 2H), 8.13 (s, 1H ), 8.21 (d, 2H), 8.56 (s, 1H), 8.65 (s, 1H), 9.90 (d, 1H).

Example 61. 1,5-Anhydro-2 - ({[6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4- yl] carbonyl} amino) -2,4-dideoxy-O-erythro-pentitol

A solution of 95 mg of intermediate 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4-carboxylic acid, 56 mg of (3S, 4R) hydrochloride -3-aminooxan-4-ol (1: 1), 133.3 mg HATU, 0.12 ml of ethyldiisopropylamine and 1.6 mg of 4-dimethylaminopyridine in 2 ml of DMF were stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC ( Instrument: Waters Autopurification MS SingleQuad; Column: Waters XBrigde C18 5 μm

100x30 mm; eluent A: water + 0.1 vol.% formic acid (99%), eluent B: acetonitrile; gradient: 05.5 min 5-100% B; flow 70 ml / min; temperature: 25 ° C; DAD scan: 210-400 nm) yielding 30 mg of 1,5-anhydro-2 - ({[6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3 -oxo-2,3-dihydropyridazine-4yl] carbonyl} amino) -2,4-dideoxy-O-erythro-pentitol.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.60-1.71 (m, 1H), 1.73-1.85 (m, 1H), 3.48-3.60 (m, 3H), 3.683.77 ( m, 1H), 3.93 (s, 3H), 3.94-3.98 (m, 1H), 4.05-4.13 (m, 1H), 5.24 (d, 1H), 7.56-7.63 (m, 2H), 8.07-8.13 ( m, 3H), 8.55 (s, 1H), 8.60 (s, 1H), 9.76 (d, 1H).

Example 62 6- [4- (Difluoromethyl) phenyl] -N- (2-hydroxy-2-methylpropyl) -2- (1-methyl-1H-pyrazole-4yl) -3-oxo-2,3-dihydropyridazine- 4-carboxamide

- 99 037978

A solution of 47 mg of intermediate 6- [4- (difluoromethyl) phenyl] -2- (1-methyl-1H-pyrazole-4yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 24 mg of 1-amino -2-methylpropan-2-ol, 103 mg HATU, 0.1 ml ethyldiisopropylamine and 1 mg 4-dimethylaminopyridine in 1 ml DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument: Labomatic gradient pump HD-3000 HPLC, Labomatic Labocol Vario2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: water + 0.2 vol.% Aqueous ammonia (32%), eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to obtain 27 mg of 6- [4- (difluoromethyl) phenyl] -N- (2-hydroxy-2-methylpropyl) - 2- (1-methyl-1Hpyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

Ή NMR (400 MHz, dichloromethane-d2) δ [ppm] = 1.13 (s, 6H), 3.91 (s, 3H), 4.68 (s, 1H), 7.11 (t, 1H), 7.71 (d, 2H), 8.11 (s, 1H), 8.19 (d, 2H), 8.54 (s, 1H), 8.61 (s, 1H), 9.62 (t, 1H).

Example 63. X - [(trans) -4-Hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4 (trifluoromethoxy) phenyl] -2 , 3-dihydropyridazine-4-carboxamide

Solution of 122 mg of intermediate compound methoxy) phenyl] -2,3-dihydropyridazine-4-carboxylic tetrahydro-3-furanol (1: 1), 244 mg HATU, 0.22

2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoroacids, 89.6 mg of trans-4-aminoml ethyldiisopropylamine hydrochloride and 3 mg of 4-dimethylaminopyridine in 3 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument: Waters Autopurification MS SingleQuad; column: Waters XBrigde C18 5 μm 100x30 mm; eluent A: water + 0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml / min; temperature: 25 ° C; DAD scan: 210-400 nm) to obtain 41 mg of X - [(trans) -4-hydroxytetrahydrofuran- 3-yl] -2- (1-methyl1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide.

Ή NMR (400 MHz, DMSO-d6) δ [ppm] = 3.56 (dd, 1H), 3.68 (dd, 1H), 3.90-3.95 (m, 4H), 3.99 (dd, 1H), 4.15- 4.22 (m, 1H), 4.23-4.29 (m, 1H), 5.51 (d, 1H), 7.53 (d, 2H), 8.12 (s, 1H), 8.17-8.23 (m, 2H), 8.56-8.59 ( m, 2H), 9.56 (d, 1H).

Example 64. X - [(trans) -4-Hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4 (trifluoromethoxy) phenyl] -2 , 3-dihydropyridazine-4-carboxamide, enantiomer 1

HPLC separation 39 mg X - [(trans) -4-hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-pyrazol-4yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] - 2,3-dihydropyridazine-4-carboxamide (example 63) on a chiral 100 037978 column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IE 5 μm 250x30 mm; eluent A : tert-butyl methyl ether; eluent B: methanol; isocratic mode: 50% A + 50% B; flow 50.0 ml / min; UV: 280 nm) yielded 16 mg of U - [(trans) -4hydroxytetrahydrofuran-3-yl ] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3 dihydropyridazine-4-carboxamide, enantiomer 1.

Chiral HPLC: R _t = 1.91 min (instrument: Agilent HPLC 1260; column: Chiralpak IE 3 μm 100x4.6 mm; eluent A: tert-butyl methyl ether + 0.1 vol% diethylamine (99%); eluent B: methanol; isocratic mode: 50% A + 50% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 280 nm).

Example 65. U - [(trans) -4-Hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4 (trifluoromethoxy) phenyl] -2 , 3-dihydropyridazine-4-carboxamide, enantiomer 2

Separation of 38 mg U - [(trans) -4-hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3oxo-6- [4- (trifluoromethoxy) phenyl] -2, 3-dihydropyridazine-4-carboxamide (Example 63), in accordance with Example 64, additionally resulted in 15 mg of U - [(trans) -4-hydroxytetrahydrofuran-3yl] -2- (1-methyl-1H-pyrazole-4 -yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4carboxamide, enantiomer 2.

Chiral HPLC: R _t = 2.33 min (instrument: Agilent HPLC 1260; column: Chiralpak IE 3 μm 100x4.6 mm; eluent A: tert-butyl methyl ether + 0.1% v / v diethylamine (99%); eluent B: methanol; isocratic mode: 50% A + 50% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 280 nm).

Example 66 6- [6- (Difluoromethyl) pyridin-3-yl] -N - [(2S) -1-hydroxypropan-2-yl] -2- (1-methyl-1Hpyrazol-4-yl) -3- oxo-2,3-dihydropyridazine-4-carboxamide

A solution of 55 mg of intermediate 6- [6- (difluoromethyl) pyridin-3-yl] -2- (1-methyl-1H pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 23.8 mg of (S) - (+) - 2-amino-1-propanol, 120 mg HATU, 0.11 ml of ethyldiisopropylamine and 1.5 mg of 4-dimethylaminopyridine in 1 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (Instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: water + 0.2 vol% aqueous ammonia (32%), eluent B: acetonitrile; gradient: A 90% / B 10% ^ A 50% / B 50%; flow: 150 ml / min; UV detection: 254 nm) to give 22 mg of 6- [6- (difluoromethyl) pyridine-3- yl] -N - [(2S) -1-hydroxypropan-2-yl] 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO) δ [ppm] = 1.19 (d, 3H), 3.43-3.51 (m, 2 h and water signal), 3.93 (s, 3H), 4.00-4.11 (m, 1H), 5.00 (t, 1H), 7.06 (t, 1H), 7.85 (d, 1H), 8.17 (s, 1H), 8.60 (s, 1H), 8.66 (dd, 1h), 8.69 (s, 1h ), 9.35 (d, 1H), 9.50 (d, 1H).

Example 67. Y- (2-Hydroxy-2-methylpropyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3- dihydropyridazine-4-carboxamide

- 101 037978

2- (1-Methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.137 mmol) was dissolved in anhydrous DMF (1.5 ml). 1-amino-2-methylpropan-2-ol (24.5 mg, 0.28 mmol), X-ethyl-X-isopropylpropan-2-amine (0.108 mL, 0.62 mmol) and propane phosphonic anhydride (T3P, 121 μL, 50 % in DMF, 207 μmol). After stirring for 5.5 h at RT, 1-amino-2-methylpropan-2-ol (12.5 mg, 0.14 mmol), X-ethyl-X-isopropylpropan-2-amine (72 μL, 0.41 mmol) and propane phosphonic anhydride acid (T3P, 80 μl, 50% in DMF, 137 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was concentrated in vacuo and purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient, twice) with obtaining 8 mg (13%) of the title compound.

1H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.15 (s, 6H), 3.31-3.36 (m, 2H and water signal), 3.94 (s, 3H), 4.71 (s, 1H), 7.89 (d, 2H), 8.14 (s, 1H), 8.30 (d, 2H), 8.58 (s, 1H), 8.66 (s, 1H), 9.63 (t, 1H).

Example 68 6- (4-Chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid (70 mg, 0.21 mmol) was dissolved in anhydrous DMF (1.6 ml). (2S) -2-aminopropane-1ol (32.1 mg, 0.43 mmol), X-ethyl-X-isopropylpropan-2-amine (0.167 mL, 0.96 mmol) and propane phosphonic anhydride (T3P, 187 μL, 50% in DMF, 320 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 31 mg (38% ) specified in the connection header.

¹ H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.16 (d, 3H), 3.39-3.49 (m, 2H), 3.98-4.09 (m, 1H), 4.94 (t, 1H), 7.57-7.61 (m, 2H), 7.63 (ddd, 1H), 7.99-8.03 (m, 2H), 8.16 (ddd, 1H), 8.67 (s, 1H), 8.69 (dd, 1H), 8.91 (d, 1h), 9.41 (d, 1H).

[a] D ²⁰ = + 13.8 ° (c = 1.00, DMSO).

Example 69 6- (4-Chlorophenyl) -N - [(2R) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid (70 mg, 0.21 mmol) was dissolved in anhydrous DMF (1.6 ml). (2R) -2-aminopropane-1ol (32.1 mg, 0.43 mmol), X-ethyl-X-isopropylpropan-2-amine (0.167 mL, 0.96 mmol) and propane phosphonic anhydride (T3P, 187 μL, 50% in DMF, 320 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 29

- 102,037978 mg (35%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.16 (d, 3H), 3.40-3.49 (m, 2H), 3.98-4.09 (m, 1H), 4.94 (t, 1H), 7.57-7.61 (m, 2H), 7.63 (dd, 1H), 7.99-8.03 (m, 2H), 8.16 (ddd, 1H), 8.67 (s, 1H), 8.69 (br d, 1H), 8.91 (br s, 1H), 9.41 (d, 1H).

[a] D ²⁰ = -5.5 ° (c = 1.00, DMSO).

Example 70 6- (4-Chlorophenyl) -N- (1,3-dihydroxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid (70 mg, 0.21 mmol) was dissolved in anhydrous DMF (1.6 ml). 2-aminopropane-1,3diol (38.9 mg, 0.43 mmol), N-ethyl-N-isopropylpropan-2-amine (0.167 ml, 0.96 mmol) and propane phosphonic anhydride (T3P, 187 μL, 50% in DMF, 320 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 39 mg (46% ) specified in the connection header.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.44-3.52 (m, 2H), 3.54-3.61 (m, 2H), 3.92-4.00 (m, 1H), 4.87 ( t, 2H), 7.57-7.61 (m, 2H), 7.63 (dd, 1H), 7.99-8.03 (m, 2H), 8.16 (ddd, 1H), 8.66-8.73 (m, 2H), 8.91 (br s , 1H), 9.51 (d, 1H).

Example 71 6- (4-Chlorophenyl) -N- (2-hydroxy-2-methylpropyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid (70 mg, 0.21 mmol) was dissolved in anhydrous DMF (1.6 ml). 1-amino-2methylpropan-2-ol (38.1 mg, 0.43 mmol), N-ethyl-N-isopropylpropan-2-amine (0.167 ml, 0.96 mmol) and propane phosphonic anhydride (T3P, 187 μL, 50% in DMF, 320 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified using RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 27 mg (32% ) specified in the connection header.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.13 (s, 6H), 3.31 (d, 2H), 4.67 (s, 1H), 7.56-7.61 (m, 2H) , 7.63 (ddd, 1H), 7.99-8.03 (m, 2H), 8.17 (ddd, 1H), 8.68 (s, 1H), 8.69 (dd, 1H), 8.92 (d, 1H), 9.52 (t, 1H ).

Example 72. (-) - 6- (4-Chlorophenyl) -N - [(2S) -2,3-dihydroxypropyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazin-4 -carboxamide

6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid (70 mg, 0.21 mmol) was dissolved in anhydrous DMF (1.6 ml). (2S) -3-aminopropane1,2-diol (38.9 mg, 0.43 mmol), N-ethyl-N-isopropylpropan-2-amine (0.167 mL, 0.96 mmol), and propane phosphonic acid anhydride (T3P, 187 μL, 50 % in DMF, 320 μmol). The mixture was stirred at RT for

- 103 037978 during the night. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm

100x30 mm mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile gradient) to give 34 mg (40%) of the title compound.

^ -NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.19-3.32 (m, 2H), 3.36-3.43 (m, 1H), 3.55-3.64 (m, 2H), 4.69 ( t, 1H), 5.00 (d, 1H), 7.56-7.61 (m, 2H), 7.63 (dd, 1H), 8.01 (d, 2H), 8.14-8.19 (m, 1H), 8.67 (s, 1H) , 8.69 (br s, 1H), 8.92 (br s, 1H), 9.51 (t, 1H).

[a] D ²⁰ = -10.0 ° (c = 1.00, DMSO).

Example 73. (+) - 6- (4-Chlorophenyl) -N - [(2R) -2,3-dihydroxypropyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid (70 mg, 0.21 mmol) was dissolved in anhydrous DMF (1.6 ml). (2R) -3-aminopropane1,2-diol (38.9 mg, 0.43 mmol), N-ethyl-N-isopropylpropan-2-amine (0.167 mL, 0.96 mmol) and propane phosphonic anhydride (T3P, 187 μL, 50 % in DMF, 320 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 26 mg (30% ) specified in the connection header.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.19-3.32 (m, 2H), 3.36-3.42 (m, 1H), 3.56-3.64 (m, 2H), 4.69 (t, 1H), 5.00 (d, 1H), 7.57-7.61 (m, 2H), 7.63 (ddd, 1H), 7.99-8.03 (m, 2H), 8.17 (ddd, 1H), 8.67 (s, 1H ), 8.69 (dd, 1H), 8.92 (d, 1H), 9.51 (t, 1H).

[a] D ²⁰ = + 20.2 ° (c = 1.00, DMSO).

Example 74. (+) - 6- (4-Chlorophenyl) -N - [(2S) -1-hydroxy-3-methoxypropan-2-yl] -3-oxo-2- (pyridin-3yl) -2.3 -dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid (70 mg, 0.21 mmol) was dissolved in anhydrous DMF (1.6 ml). (2S) -2-amino-3methoxypropan-1-ol (44.9 mg, 0.43 mmol), N-ethyl-N-isopropylpropan-2-amine (0.167 ml, 0.96 mmol) and propane phosphonic acid anhydride (T3P, 187 μl , 50% in DMF, 320 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 40 mg (30% ) specified in the connection header.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.28 (s, 3H), 3.41-3.58 (m, 4H), 4.08-4.17 (m, 1H), 4.97 (t , 1H), 7.57-7.61 (m, 2H), 7.63 (dd, 1H), 7.99-8.03 (m, 2H), 8.16 (ddd, 1H), 8.66-8.73 (m, 2H), 8.91 (br s, 1H), 9.51 (d, 1H).

[a] D ²⁰ = + 2.2 ° (c = 1.00, DMSO).

Example 75 (-) - 6- (4-Chlorophenyl) -N - [(2R) -1-hydroxy-3-methoxypropan-2-yl] -3-oxo-2- (pyridin-3yl) -2.3 -dihydropyridazine-4-carboxamide

- 104 037978

6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid (70 mg, 0.21 mmol) was dissolved in anhydrous DMF (1.6 ml). (2R) -2-amino-3methoxypropan-1-ol (44.9 mg, 0.43 mmol), X-ethyl-N-isopropylpropan-2-amine (0.167 ml, 0.96 mmol) and propane phosphonic anhydride (T3P, 187 μl , 50% in DMF, 320 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 40 mg (30% ) specified in the connection header.

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.28 (s, 3H), 3.41-3.59 (m, 4H), 4.08-4.17 (m, 1H), 4.97 (t, 1H ), 7.56-7.61 (m, 2H), 7.63 (br dd, 1H), 7.98-8.03 (m, 2H), 8.16 (br d, 1H), 8.66-8.75 (m, 2H), 8.91 (br s, 1H), 9.51 (d, 1H).

[a] D ²⁰ = -6.1 ° (c = 1.00, DMSO).

Example 76 6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -N - [(2RS) -1,1,1-trifluoro-3-hydroxypropane-2yl] -2,3 -dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.31 mmol) was dissolved in anhydrous DMF (2.3 ml). Hydrochloride (2RS) -2amino-3,3,3-trifluoropropan-1-ol (1: 1) (101 mg, 0.61 mmol), X-ethyl-N-isopropylpropan-2-amine (0.345 ml, 1.98 mmol ) and propane phosphonic anhydride (T3P, 267 μL, 50% in DMF, 458 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified using SPHPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 33 mg (25%) of the indicated in the connection header.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.65-3.73 (m, 1H), 3.78-3.86 (m, 1H), 4.79-4.92 (m, 1H), 5.43 (t, 1H), 7.59 (d, 2H), 7.64 (br dd, 1H), 8.03 (d, 2H), 8.18 (br d, 1H), 8.63-8.79 (s, 2H), 8.93 (br s, 1H), 9.97 (d, 1H).

Example 77 6- (4-Chlorophenyl) -N - [(1 RS) -1 -cyclopropyl-2-hydroxyethyl] -3-oxo-2- (pyridin-3-yl) 2,3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.31 mmol) was dissolved in anhydrous DMF (2.3 ml). (2RS) -2-amino-2-cyclopropylethanol hydrochloride (1: 1) (84 mg, 0.61 mmol), X-ethyl-N-isopropylpropan-2-amine (0.345 ml, 1.98 mmol) and propane phosphonic acid anhydride (T3P, 267 μl, 50% in DMF, 458 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified using RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 37.5 mg (30% ) specified in the connection header.

- 105 037978

S-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.26-0.50 (m, 4H), 1.03-1.13 (m, 1H), 3.40-3.47 (m, 1H), 3.523. 62 (m, 2H), 4.92 (t, 1H), 7.56-7.61 (m, 2H), 7.63 (dd, 1H), 7.99-8.03 (m, 2H), 8.17 (ddd, 1H), 8.68 (s, 1H),

8.70 (br d, 1H), 8.92 (br s, 1H), 9.53 (d, 1H).

Example 78 6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -N - [(2RS) -3,3,3-trifluoro-2-hydroxypropyl] 2,3-dihydropyridazine- 4-carboxamide

6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.31 mmol) was dissolved in anhydrous DMF (2.3 ml). (2RS) -3-amino-1,1,1trifluoropropan-2-ol (78.8 mg, 0.61 mmol), N-ethyl-N-isopropylpropan-2-amine (0.239 ml, 1.37 mmol) and propane phosphonic anhydride ( T3P, 267 μL, 50% in DMF, 458 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 23 mg (23% ) specified in the connection header.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.43-3.52 (m, 1H), 3.71-3.79 (m, 1H), 4.17-4.28 (m, 1H), 6.66 ( d, 1H), 7.57-7.61 (m, 2H), 7.64 (dd, 1H), 7.99-8.04 (m, 2H), 8.17 (ddd, 1H), 8.66-8.73 (m, 2H), 8.92 (br s , 1H), 9.61 (t, 1H).

Example 79 6- (4-Chlorophenyl) -N - [(2RS) -3,3-difluoro-2-hydroxypropyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydr opyridazin-4 - car box amide

6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.31 mmol) was dissolved in anhydrous DMF (2.3 ml). (2RS) -3amino-1,1-difluoropropan-2-ol hydrochloride (1: 1) (90 mg, 0.61 mmol), N-ethyl-N-isopropylpropan-2-amine (0.345 ml, 1.98 mmol) and propane phosphonic anhydride (T3P, 267 μl, 50% in DMF, 458 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 28.3 mg (22% ) specified in the connection header.

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.36-3.43 (m, 1H), 3.66 (dt, 1H), 3.78-3.91 (m, 1H), 5.94 (d, 1H ), 5.99 (d, 1H), 7.59 (d, 2H), 7.64 (br dd, 1H), 8.02 (d, 2H), 8.17 (br d, 1H), 8.64-8.75 (m, 2H), 8.93 ( br s, 1H), 9.54 (t, 1H).

Example 80 6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2,3 dihydr opyridazin-4 - car box amide

6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF (1.5 ml). (2S) -2aminopropan-1-ol (18 mg, 0.25 mmol), N-ethyl-N-isopropylpropan-2-amine (0.113 ml, 0.65 mmol) and propane phosphonic anhydride (T3P, 127 μl, 50% in DMF, 217 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5

106 037978 μm 100x30 mm mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile gradient) to give 31 mg (51%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.16 (d, 3H), 3.40-3.50 (m, 2H), 3.99-4.09 (m, 1H), 4.95 (t, 1H),

7.57-7.61 (m, 2H), 8.01-8.05 (m, 2H), 8.25 (dt, 1H), 8.67 (s, 1H), 8.76 (d, 1H), 8.85 (t, 1H), 9.34 (d, 1H).

[a] D ²⁰ = + 9.5 ° (c = 1.00, methanol).

Example 81 6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(2R) -1-hydroxynropan-2-yl] -3-oxo-2,3 dihydropyridazine-4- carboxamide

6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF (1.5 ml). (2R) -2aminopropan-1-ol (18 mg, 0.25 mmol), N-ethyl-N-isopropylpropan-2-amine (0.113 ml, 0.65 mmol) and propane phosphonic anhydride (T3P, 127 μl, 50% in DMF, 217 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified using RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 27 mg (46% ) specified in the connection header.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.17 (d, 3H), 3.40-3.50 (m, 2H), 3.99-4.09 (m, 1H), 4.95 (t, 1H), 7.57-7.61 (m, 2H), 8.01-8.05 (m, 2H), 8.25 (dt, 1H), 8.67 (s, 1H), 8.76 (d, 1H), 8.85 (t, 1H), 9.34 (d, 1H).

[a] D ²⁰ = -8.9 ° (c = 1.00, methanol).

Example 82 6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -N- (2-hydroxy-2-methylpropyl) -3-oxo-2,3-dihydropyridazine-4-carboxamide st

U / O? ^Ns

A ΗΝ. D er ^ Ioh ch ₃

6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF (1.5 ml). 1-amino-2methylpropan-2-ol (22 mg, 0.25 mmol), N ethyl-N-isopronylpropan-2-amine (0.113 ml, 0.65 mmol) and propane phosphonic anhydride (T3P, 127 μl, 50% in DMF , 217 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 35 mg (58% ) specified in the connection header.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.13 (s, 6H), 3.32 (d, 2H), 4.68 (s, 1H), 7.57-7.61 (m, 2H ), 8.018.06 (m, 2H), 8.25 (dt, 1H), 8.68 (s, 1H), 8.76 (d, 1H), 8.87 (t, 1H), 9.45 (t, 1H).

Example 83 6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(2S) -1-hydroxy-3-methylbutan-2-yl] -3oxo-2,3-dihydropyridazine -4-carboxamide

n ₃ gr sn ₃

6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF (1.5 ml). (2S) -2-amino-3-107 037978 methylbutan-1-ol (25 mg, 0.25 mmol), N-ethyl-N-isopropylpropan-2-amine (0.113 ml, 0.65 mmol) and propane phosphonic acid anhydride ( T3P, 127 μl, 50% in DMF, 217 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 33 mg (53% ) specified in the connection header.

1H-NMR (400 MHz, DMSO ^): δ [ppm] = 0.89 (d, 3H), 0.93 (d, 3H), 1.91-2.03 (m, 1H), 3.41-3.48 (m, 1H) , 3.52-3.59 (m, 1H), 3.81-3.89 (m, 1H), 4.82 (t, 1H), 7.57-7.62 (m, 2H), 8.01-8.05 (m, 2H), 8.26 (dt, 1H) , 8.68 (s, 1H), 8.76 (d, 1H), 8.86 (t, 1H), 9.30 (d, 1H).

[a] D ²⁰ = -20.2 ° (c = 1.00, methanol).

Example 84 6- (4-Chlorophenyl) -N- (1,3-dihydroxypropan-2-yl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF (1.5 ml). 2-aminopropane-1,3diol (22 mg, 0.25 mmol), N-ethyl-N-isopropylpropane-2-amine (0.113 ml, 0.65 mmol) and propane phosphonic anhydride (T3P, 127 μl, 50% in DMF, 217 μmol). The mixture was stirred at RT overnight. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 45 mg (74% ) specified in the connection header.

¹ H-NMR (400 MHz, DMSO-d _b ): δ [ppm] = 3.44-3.52 (m, 2H), 3.55-3.62 (m, 2H), 3.92-4.01 (m, 1H), 4.88 (t, 2H), 7.57-7.62 (m, 2H), 8.01-8.05 (m, 2H), 8.25 (br d, 1H), 8.69 (s, 1H), 8.79 (br s, 1H), 8.87 (br s, 1H), 9.45 (d, 1H).

Example 85 6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(2R) -1-hydroxy-3-methoxypropan-2-yl] -3oxo-2,3-dihydropyridazine -4-carboxamide

6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF (1.5 ml). (2R) -2-amino-3methoxypropan-1-ol (26 mg, 0.25 mmol), N-ethyl-N-isopropylpropan-2-amine (0.113 ml, 0.65 mmol) and propane phosphonic acid anhydride (T3P, 127 μl , 50% in DMF, 217 μmol). The mixture was stirred for 2 h at RT. The crude reaction mixture was purified using RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 40 mg (64% ) specified in the connection header.

¹ H-NMR (400 MHz, DMSO-db): δ [ppm] = 3.28 (s, 3H), 3.42-3.58 (m, 4H), 4.09-4.17 (m, 1H), 4.98 (t, 1H), 7.57-7.62 (m, 2H), 8.01-8.05 (m, 2H), 8.25 (ddd, 1H), 8.69 (s, 1H), 8.76 (d, 1H), 8.85 (t, 1H), 9.44 (d, 1H).

[a] D ²⁰ = -0.94 ° (c = 1.00, methanol).

Example 86 6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(2 S) -1-hydroxy-3-methoxypropan-2-yl] -3 oxo-2,3 -dihydropyridazine-4-carboxamide

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6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF (1.5 ml). (2S) -2-amino-3methoxypropan-1-ol (26 mg, 0.25 mmol), X-ethyl-X-isopropylpropan-2-amine (0.113 ml, 0.65 mmol) and propane phosphonic acid anhydride (T3P, 127 μl , 50% in DMF, 217 μmol). The mixture was stirred for 1 h at RT. The crude reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 41 mg (65% ) specified in the connection header.

Ή-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.28 (s, 3H), 3.42-3.59 (m, 4H), 4.09-4.17 (m, 1H), 4.98 (t, 1H ), 7.57-7.62 (m, 2H), 8.01-8.05 (m, 2H), 8.25 (dt, 1H), 8.69 (s, 1H), 8.76 (d, 1H), 8.85 (t, 1H), 9.44 ( d, 1H).

[a] D ²⁰ = + 0.47 ° (c = 1.00, methanol).

Example 87. (-) - 6- (4-Chlorophenyl) -X- (3,3-difluoro-2-hydroxypropyl) -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -N - [(2RS) -3,3-difluoro-2-hydroxypropyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide ( 23.7 mg) was separated by chiral HPLC (column: YMC Amylose SA 5 μm 250x30 mm, mobile phase: isocratic mode (1: 1) methanol / ethanol mixture, 40 ml / min, UV: 254 nm) to give 9.4 mg (40 %) specified in the connection header.

-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.35-3.41 (m, 1H), 3.62-3.69 (m, 1H), 3.78-3.91 (m, 1H), 5.94 ( dt, 1H), 6.00 (d, 1H), 7.57-7.61 (m, 2H), 7.64 (ddd, 1H), 7.99-8.04 (m, 2H), 8.17 (ddd, 1H), 8.68 (s, 1H) , 8.69 (dd, 1H), 8.92 (d, 1H), 9.54 (t, 1H).

Chiral HPLC: _Rt = 3.34 min.

Instrument: Agilent HPLC 1260: YMC Amylose SA 3 μm 100x4.6 mm; eluent: (A: methanol + 0.1 vol% diethylamine (99%)) / B: ethanol, isocratic mode: 1: 1, flow: 1.4 ml / min, temperature: 25 ° C, UV: 254 nm.

[a] D ²⁰ = -11.8 ° (c = 1.00, methanol).

Example 88. (+) - 6- (4-Chlorophenyl) -X- (3,3-difluoro-2-hydroxypropyl) -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -N - [(2RS) -3,3-difluoro-2-hydroxypropyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide ( 23.7 mg) was separated by chiral HPLC (column: YMC Amylose SA 5 μm 250x30 mm, mobile phase: methanol / ethanol, isocratic mode: 1: 1, 40 ml / min, UV: 254 nm) to give 9.4 mg (40% ) specified in the connection header.

-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.35-3.41 (m, 1H), 3.62-3.69 (m, 1H), 3.78-3.91 (m, 1H), 5.94 ( dt, 1H), 6.00 (br d, 1H), 7.57-7.61 (m, 2H), 7.64 (ddd, 1H), 7.99-8.04 (m, 2H), 8.17 (ddd, 1H), 8.68 (s, 1H ),

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8.69 (dd, 1H), 8.92 (d, 1H), 9.54 (t, 1H).

Chiral HPLC: R _t = 4.33 min.

Instrument: Agilent HPLC 1260: YMC Amylose SA 3 μm 100x4.6 mm; eluent: (A: methanol + 0.1 vol% diethylamine (99%)) / B: ethanol, isocratic mode: 1: 1, flow: 1.4 ml / min, temperature: 25 ° C, UV:

254 nm.

[a] D ²⁰ = + 11.0 ° (c = 1.00, methanol).

Example 89. (-) - 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 - [(2RS) -3,3,3-trifluoro-2-hydroxypropyl] -2,3-dihydropyridazine-4- carboxamide (19.3 mg) was separated by chiral HPLC (column: YMC Amylose SA 5 μm 250x30 mm, mobile phase: methanol / ethanol, isocratic mode: 1: 1, 40 ml / min, UV: 254 nm) to give 7.3 mg ( 38%) specified in the title of the compound.

¹ H-NMR (400 MHz, DMSO-de): δ [ppm] = 3.48 (ddd, 1H), 3.75 (ddd, 1H), 4.17-4.28 (m, 1H), 6.67 (br s, 1H ), 7.57-7.61 (m, 2H), 7.64 (ddd, 1H), 7.99-8.04 (m, 2H), 8.17 (ddd, 1H), 8.67-8.71 (m, 2H), 8.92 (d, 1H), 9.61 (t, 1H).

Chiral HPLC: _Rt = 2.23 min.

Instrument: Agilent HPLC 1260: YMC Amylose SA 3 μm 100x4.6 mm; eluent: (A: methanol + 0.1 vol% diethylamine (99%)) / B: ethanol, isocratic mode: 1: 1, flow: 1.4 ml / min, temperature: 25 ° C, UV: 254 nm.

[a] D ²⁰ = -13.2 ° (c = 1.00, methanol).

Example 90. (+) - 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 - [(2RS) -3,3,3-trifluoro-2-hydroxypropyl] -2,3-dihydropyridazine-4- carboxamide (19.3 mg) was separated by chiral HPLC (column: YMC Amylose SA 5 μm 250x30 mm, mobile phase: methanol / ethanol, isocratic mode: 1: 1, 40 ml / min, UV: 254 nm) to give 7.5 mg ( 39%) specified in the title of the compound.

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.48 (ddd, 1H), 3.75 (ddd, 1H), 4.28 4.18 (m, 1H), 6.67 (br d, 1H), 7.57-7.61 (m, 2H), 7.64 (ddd, 1H), 7.99-8.04 (m, 2H), 8.17 (ddd, 1H), 8.67-8.72 (m, 2H), 8.92 (d, 1H), 9.61 ( t, 1H).

Chiral HPLC: _Rt = 3.70 min.

Instrument: Agilent HPLC 1260: YMC Amylose SA 3 μm 100x4.6 mm; eluent: (A: methanol + 0.1 vol% diethylamine (99%)) / B: ethanol, isocratic mode: 1: 1, flow: 1.4 ml / min, temperature: 25 ° C, UV: 254 nm.

[a] D ²⁰ = + 12.7 ° (c = 1.00, methanol).

Example 91 (+) - 6- (4-Chlorophenyl) -N- (1-cyclopropyl-2-hydroxyethyl) -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxamide

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6- (4-Chlorophenyl) -N - [(1RS) -1-cyclopropyl-2-hydroxyethyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide (32 mg ) was separated by chiral HPLC (column: Cellulose SC 5 μm 250x30 mm, mobile phase: methanol / ethanol, isocratic mode: 1: 1, 30 ml / min, UV: 280 nm) to give 14 mg (47%) of the specified connection header.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.25-0.50 (m, 4H), 1.03-1.11 (m, 1H), 3.40-3.48 (m, 1H), 3.63 (ddd, 2H), 4.93 (t, 1H), 7.56-7.61 (m, 2H), 7.61-7.65 (m, 1H), 7.99-8.03 (m, 2H), 8.17 (ddd, 1H), 8.68 (s , 1H), 8.70 (dd, 1H), 8.91 (d, 1H), 9.53 (d, 1H).

Chiral HPLC: _Rt = 1.75 min.

Instrument: Agilent HPLC 1260: Cellulose SC 3 μm 100x4.6 mm; eluent: (A: methanol + 0.1 vol% diethylamine (99%)) / B: ethanol, isocratic mode: 1: 1, flow: 1.4 ml / min, temperature: 25 ° C, UV: 280 nm.

[a] D ²⁰ = + 29.2 ° (c = 1.00, methanol).

Example 92. (-) - 6- (4-Chlorophenyl) -X- (1-cyclopropyl-2-hydroxyethyl) -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -N - [(1RS) -1-cyclopropyl-2-hydroxyethyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide (32 mg ) was separated by chiral HPLC (column: Cellulose SC 5 μm 250x30 mm, mobile phase: methanol / ethanol, isocratic mode: 1: 1, 30 ml / min, UV: 280 nm) to give 13 mg (41%) of the specified connection header.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.26-0.50 (m, 4H), 1.03-1.11 (m, 1H), 3.40-3.48 (m, 1H), 3.523 .62 (m, 2H), 4.93 (t, 1H), 7.56-7.61 (m, 2H), 7.63 (ddd, 1H), 7.99-8.03 (m, 2H), 8.17 (ddd, 1H), 8.68 (s , 1H), 8.70 (dd, 1H), 8.91 (d, 1H), 9.53 (d, 1H).

Chiral HPLC: _Rt = 2.75 min.

Instrument: Agilent HPLC 1260: Cellulose SC 3 μm 100x4.6 mm; eluent: (A: methanol + 0.1 vol% diethylamine (99%)) / B: ethanol, isocratic mode: 1: 1, flow: 1.4 ml / min, temperature: 25 ° C, UV: 280 nm.

[a] D ²⁰ = -26.7 ° (c = 1.00, methanol).

Example 93 (+) - 6- (4-Chlorophenyl) -N - [(2R) -1-fluoro-3-hydroxypropan-2-yl] -3-oxo-2- (nyridin-3-yl) 2, 3-dihydropyridazine-4-car boxamide

6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.15 mmol) was dissolved in anhydrous DMF (1.5 ml). (2R) -2amino-3-fluoropropan-1-ol hydrochloride (1: 1) (36 mg, 0.28 mmol), X-ethyl-X-isopropylpropan-2-amine (167 μL, 0.96 mmol) and propane phosphonic anhydride acid (T3P, 134 μl, 50% in DMF, 229 μmol). The mixture was stirred for 1 h at RT. The crude reaction mixture was purified by RP-HPLC (column:

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X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol.% Aqueous ammonia (32%)) / acetonitrile, gradient) and RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.1 vol% formic acid (99%)) / acetonitrile, gradient) to give 3 mg (5%) of the title compound.

1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.48-3.56 (m, 1H), 3.57-3.64 (m, 1H), 4.18-4.32 (m, 1H), 4.464. 55 (m, 1H), 4.58-4.67 (m, 1H), 5.16 (t, 1H), 7.57-7.61 (m, 2H), 7.63 (ddd, 1H), 7.99-8.04 (m, 2H), 8.16 ( ddd, 1H), 8.67-8.71 (m, 2H), 8.91 (dd, 1H), 9.59 (d, 1H).

[a] D ²⁰ = + 10.0 ° (c = 1.00, methanol).

Example 94. N - [(1S) -1 -cyclopropyl-2-hydroxyethyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine- 4-carboxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (150 mg, 0.42 mmol) was dissolved in anhydrous DMF (3.0 ml) ... (2S) -2-amino-2-cyclopropylethanol hydrochloride (1: 1) (114 mg, 0.83 mmol), N-ethyl-N-isopropylpropan-2-amine (470 μL, 2.70 mmol) and propane phosphonic acid anhydride ( T3P, 364 μL, 50% in DMF, 624 μmol). The mixture was stirred for 2 h at RT. The reaction mixture was concentrated in vacuo and purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give an oil, to which was added tert-butyl methyl ether. The mixture was sonicated for 10 minutes to give a white solid. The solvent was removed in vacuo, the solid was dried in vacuo at 50 ° C overnight to give 84 mg (46%) of the title compound.

1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.26-0.50 (m, 4H), 1.04-1.13 (m, 1H), 3.41-3.49 (m, 1H), 3.533. 62 (m, 2H), 4.93 (t, 1H), 7.64 (ddd, 1H), 7.88 (d, 2H), 8.16-8.24 (m, 3H), 8.71 (dd, 1H), 8.74 (s, 1H) , 8.93 (d, 1H), 9.52 (d, 1H).

[a] D ²⁰ = + 30.4 (c = 1.00, methanol).

Example 95. (-) - 6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -N - [(2S) -1,1,1-trifluoro-3-hydroxypropan2-yl] -2,3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -N - [(2RS) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -2,3 dihydropyridazine- 4-carboxamide (29 mg) was separated by chiral HPLC (column: Chiralpak IB 5 μm 250x30 mm, mobile phase: isocratic mode (80:20) carbon dioxide / 2-propanol mixture, 80 ml / min, temperature 40 ° C, BPR: 150 bar, UV: 254 nm) to give 12.3 mg (42%) of the title compound.

Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 3.66-3.73 (m, 1H), 3.82 (dt, 1H), 4.80-4.91 (m, 1H), 5.43 (t, 1H ), 7.57-7.61 (m, 2H), 7.64 (ddd, 1H), 8.01-8.05 (m, 2H), 8.18 (ddd, 1H), 8.70 (dd, 1H), 8.74 (s, 1H), 8.92 ( dd, 1H), 9.97 (d, 1H).

Chiral HPLC: _Rt = 2.54 min.

Instrument: Agilent HPLC 1260: Chiralpak IB 5 μm 100x4.6 mm; eluent: carbon dioxide / 2-propanol, isocratic mode: 80:20, flow: 4 ml / min, temperature: 37.5 ° C, BPR: 100 bar, UV: 254 nm.

[a] D ²⁰ = -8.5 ° (c = 1.00, methanol).

Example 96 (+) - 6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -N - [(2R) -1,1,1-trifluoro-3-hydroxypropan2-yl] -2,3-dihydropyridazine-4-carboxamide

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6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -N - [(2RS) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -2,3 dihydropyridazine- 4-carboxamide (29 mg) was separated by chiral HPLC (column: Chiralpak IB 5 μm 250x30 mm, mobile phase: isocratic mode (80:20) carbon dioxide / 2-propanol mixture, 80 ml / min, temperature 40 ° C, BPR: 150 bar, UV: 254 nm) to give 11.5 mg (40%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.65-3.73 (m, 1H), 3.82 (dt, 1H), 4.80-4.91 (m, 1H), 5.44 (t, 1H), 7.57-7.62 (m, 2H), 7.64 (ddd, 1H), 8.01-8.06 (m, 2H), 8.18 (ddd, 1H), 8.70 (dd, 1H), 8.74 (s, 1H), 8.92 (dd, 1H), 9.97 (d, 1H).

Chiral HPLC: _Rt = 3.40 min.

Instrument: Agilent HPLC 1260: Chiralpak IB 5 μm 100x4.6 mm; eluent: carbon dioxide / 2-propanol, isocratic mode: 80:20, flow: 4 ml / min, temperature: 37.5 ° C, BPR: 100 bar, UV: 254 nm.

[a] D ²⁰ = + 14.4 ° (c = 1.00, methanol).

Example 97 6- (4-Chlorophenyl) -N - [(1RS) -1-cyclopropyl-2-hydroxyethyl] -2- (5-fluoropyridin-3-yl) -3oxo-2,3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.29 mmol) was dissolved in anhydrous DMF (2.2 ml). Hydrochloride (2RS) of 2-amino-2-cyclopropylethanol (1: 1) (80 mg, 0.58 mmol), N-ethyl-N-isopropylpropan-2-amine (328 μL, 1.88 mmol) and propane phosphonic acid anhydride (T3P , 254 μL, 50% in DMF, 434 μmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with methanol and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.1 vol% formic acid (99%)) / acetonitrile, gradient) to give 43.8 mg (35%) of the indicated in the connection header.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.26-0.50 (m, 4H), 1.03-1.13 (m, 1H), 3.40-3.47 (m, 1H), 3.523. 63 (m, 2H), 4.93 (t, 1H), 7.57-7.61 (m, 2H), 8.01-8.06 (m, 2H), 8.26 (ddd, 1H), 8.68 (s, 1H), 8.77 (d, IH), 8.86 (d, 1H), 9.47 (t, 1H).

Example 98 6- (4-Chlorophenyl) -N - [(2R) -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-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.145 mmol) was dissolved in anhydrous DMF (1.1 ml). (2R) -3aminopropane-1,2-diol (26.4 mg, 0.29 mmol), N-ethyl-N-isopropylpropan-2-amine (164 μL, 0.94 mmol) and propane phosphonic anhydride (T3P, 127 μL, 50 % in DMF, 217 μmol). The mixture was stirred

- 113 037978 at CT during the night. The reaction mixture was diluted with methanol and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water +

0.1 vol% formic acid (99%)) / acetonitrile gradient) to give 19.2 mg (32%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.19-3.43 (m, 3H and water signal), 3.55-3.64 (m, 2H), 4.69 (br s, 1H) , 5.00 (br s, 1H), 7.57-7.62 (m, 2H), 8.01-8.06 (m, 2H), 8.25 (ddd, 1H), 8.68 (s, 1H), 8.76 (d, 1H), 8.86 ( t, 1H), 9.44 (t, 1H).

[a] D ²⁰ = + 13.4 ° (c = 1.00, methanol).

Example 99 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-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.145 mmol) was dissolved in anhydrous DMF (1.1 ml). (2S) -3aminopropane-1,2-diol (26.4 mg, 0.29 mmol), H-ethyl-N-isopropylpropan-2-amine (164 μL, 0.94 mmol), and propane phosphonic anhydride (T3P, 127 μL, 50 % in DMF, 217 μmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with methanol and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.1 vol% formic acid (99%)) / acetonitrile, gradient) to give 9.2 mg (15%) of the indicated in the connection header.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.20-3.43 (m, 3H and water signal), 3.56-3.64 (m, 2H), 4.69 (br t, 1H) , 5.01 (br d, 1H), 7.57-7.62 (m, 2H), 8.02-8.06 (m, 2H), 8.25 (ddd, 1H), 8.68 (s, 1H), 8.76 (d, 1H), 8.86 ( s, 1H), 9.44 (t, 1H).

[a] D ²⁰ = -8.4 ° (c = 1.00, methanol).

Example 100 6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-N - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -2,3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.145 mmol) was dissolved in anhydrous DMF (1.1 ml). Hydrochloride (2R) 2-amino-3,3,3-trifluoropropan-1-ol (1: 1) (47.9 mg, 0.29 mmol), H-ethyl-N-isopropylpropan-2-amine (164 μL, 0.94 mmol) and propane phosphonic anhydride (T3P, 127 μL, 50% in DMF, 217 μmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with methanol and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.1 vol% formic acid (99%)) / acetonitrile gradient) to give 27.9 mg (42%) of the indicated in the connection header.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.66-3.73 (m, 1H), 3.79-3.86 (m, 1H), 4.80-4.92 (m, 1H), 5.45 (br s, 1H), 7.58-7.62 (m, 2H), 8.03-8.07 (m, 2H), 8.26 (ddd, 1H), 8.74 (s, 1H), 8.77 (d, 1H), 8.86 (t, 1H), 9.90 (d, 1H).

[a] D ²⁰ = + 11.0 ° (c = 1.00, methanol).

Example 101 N - [(2RS) -3,3-Difluoro-2-hydroxypropyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3- dihydropyridazine-4-carboxamide

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3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.277 mmol) was dissolved in anhydrous DMF (2.1 ml) ... (2RS) -3-amino-1,1-difluoropropan-2-ol hydrochloride (1: 1) (81.7 mg, 0.55 mmol), N-ethyl-N-isopropylpropan-2-amine (314 μL, 1.80 mmol ) and propane phosphonic acid anhydride (T3P, 243 μL, 50% in DMF, 415 μmol). The mixture was stirred for 2 h at RT. The reaction mixture was diluted with methanol and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile gradient) to give 90.1 mg (72%) of the indicated in the connection header.

Ή-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.36-3.44 (m, 1H), 3.66 (dt, 1H), 3.79-3.91 (m, 1H), 5.94 (dt, 1H ), 6.00 (d, 1H), 7.65 (dd, 1H), 7.89 (d, 2H), 8.16-8.25 (m, 3H), 8.71 (dd, 1H), 8.74 (s, 1H), 8.93 (d, 1H), 9.53 (t, 1H).

Example 102. N - [(1S, 2S) -2-Hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4- carboxamide, 14 / O ίι ίΓ i ^0H fH I /

F kJ

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.138 mmol) was dissolved in anhydrous DMF (1.05 ml) ... (1S, 2S) -2-aminocyclopentanol hydrochloride (1: 1) (38 mg, 0.28 mmol), N-ethyl-N-isopropylpropan-2-amine (157 μL, 0.90 mmol) and propane phosphonic acid anhydride (T3P, 122 μl, 50% in DMF, 208 μmol). The mixture was stirred for 2 h at RT. The reaction mixture was diluted with methanol and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile gradient) to give 22.2 mg (36%) ac connected in the header of the connection.

-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.41-1.56 (m, 2H), 1.57-1.87 (m, 3H), 2.04-2.14 (m, 1H), 3.94 ( quin, 1H), 3.99-4.07 (m, 1H), 4.95 (d, 1H), 7.64 (dd, 1H), 7.89 (d, 2H), 8.17 (ddd, 1H), 8.21 (d, 2H), 8.69 -8.73 (m, 2H), 8.92 (d, 1H), 9.29 (d, 1H).

[a] D ²⁰ = + 40.1 ° (c = 1.00, methanol).

Example 103. N - [(1R, 2S) -2-Hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4- carboxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.138 mmol) was dissolved in anhydrous DMF (1.05 ml) ... (1S, 2R) -2-aminocyclopentanol hydrochloride (1: 1) (38 mg, 0.28 mmol), N-ethyl-N-isopropylpropan-2-amine (157 μL, 0.90 mmol) and propane phosphonic acid anhydride (T3P, 122 μl, 50% in DMF, 208 μmol). The mixture was stirred for 2 h at RT. The reaction mixture was diluted with methanol and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 36.5 mg (59%) ac - 115 037978 associated in the header of the connection.

1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.46-1.65 (m, 3H), 1.70-1.88 (m, 2H), 1.92-2.04 (m, 1H), 3.994. 12 (m, 2H), 5.05 (d, 1H), 7.64 (ddd 1H), 7.89 (d, 2H), 8.18 (ddd 1H), 8.21 (d 2H), 8.70 (dd, 1H), 8.75 (s,

1H), 8.92 (d, 1H), 9.66 (d, 1H).

[a] D ²⁰ = -2.1 ° (c = 1.00, methanol).

Example 104. N - [(1R, 2R) -2-Ghydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-opyridazine dihydr- 4-carboxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.138 mmol) was dissolved in anhydrous DMF (1.05 ml) ... (1R, 2R) -2-aminocyclopentanol hydrochloride (1: 1) (38 mg, 0.28 mmol), N-ethyl-N-isopropylpropan-2-amine (157 μL, 0.90 mmol) and propane phosphonic acid anhydride (T3P, 122 μl, 50% in DMF, 208 μmol). The mixture was stirred for 2 h at RT. The reaction mixture was diluted with methanol and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 19 mg (31%) indicated leg in the header of the connection.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.41-1.56 (m, 2H), 1.57-1.87 (m, 3H), 2.04-2.14 (m, 1H), 3.913 .97 (m, 1H), 3.99-4.06 (m, 1H), 4.95 (d, 1H), 7.64 (ddd, 1H), 7.89 (d, 2H), 8.18 (ddd, 1H), 8.21 (d, 2H ), 8.698.72 (m, 2H), 8.92 (d, 1H), 9.29 (d, 1H).

[a] D ²⁰ = -32.6 ° (c = 1.00, methanol).

Example 105. N - [(1S, 2R) -2-Hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3 - opyridazine-4 dihydr - carboxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.138 mmol) was dissolved in anhydrous DMF (1.05 ml) ... (1R, 2S) -2-aminocyclopentanol hydrochloride (1: 1) (38 mg, 0.28 mmol), N-ethyl-N-isonropylpropan-2-amine (157 μL, 0.90 mmol) and propane phosphonic anhydride (T3P, 122 μl, 50% in DMF, 208 μmol). The mixture was stirred for 2 h at RT. The reaction mixture was diluted with methanol and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 19 mg (31%) indicated leg in the header of the connection.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.47-1.64 (m, 3H), 1.70-1.88 (m, 2H), 1.93-2.03 (m, 1H), 3.994 .12 (m, 2H), 5.05 (d, 1H), 7.64 (ddd, 1H), 7.89 (d, 2H), 8.17 (ddd, 1H), 8.21 (d, 2H), 8.70 (dd, 1H), 8.74 (s, 1H), 8.92 (d, 1H), 9.66 (d, 1H).

[a] D ²⁰ = + 3.7 ° (c = 1.00, methanol).

Example 106. N - [(1S, 2R) -Hydroxycyclohexyl] -3-oxo-2-pyridin-3-yl) -6- [4- (fluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide

- 116 037978

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.138 mmol) was dissolved in anhydrous DMF (1.05 ml) ... (1R, 2S) -2-aminocyclohexanol hydrochloride (1: 1) (44.2 mg, 0.28 mmol), X-ethyl-X-isopropylpropan-2-amine (157 μL, 0.90 mmol) and propane phosphonic acid anhydride (T3P, 122 μl, 50% in DMF, 208 μmol). The mixture was stirred at RT overnight.

The reaction mixture was diluted with dichloromethane and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 30.1 mg (47%) of the indicated in the connection header.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.25-1.38 (m, 2H), 1.48-1.69 (m, 6H), 3.75-3.80 (m, 1H), 3.883 .96 (m, 1H), 4.88 (d, 1H), 7.64 (ddd, 1H), 7.88 (d, 2H), 8.16-8.23 (m, 3H), 8.71 (dd, 1H), 8.74 (s, 1H ), 8.92 (dd, 1H), 9.60 (d, 1H).

[a] D ²⁰ = + 5.0 ° (c = 1.00, methanol).

Example 107 N - [(3RS, 4RS) -4-Hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3- dihydropyridazine-4-carboxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.277 mmol) was dissolved in anhydrous DMF (2.1 ml) ... (3RS, 4RS) -4-aminotetrahydrofuran-3-ol hydrochloride (1: 1) (77.3 mg, 0.55 mmol), X-ethyl-X-isopropylpropan-2-amine (314 μL, 1.80 mmol) and propane phosphonic anhydride acid (T3P, 243 μl, 50% in DMF, 415 μmol). The mixture was stirred at RT overnight.

The reaction mixture was diluted with dichloromethane and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 70.2 mg (57%) of the indicated in the connection header.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.46 (t, 1H), 3.61 (dd, 1H), 3.93 (dd, 1H), 4.01 (dd, 1H), 4.254 .31 (m, 1H), 4.32-4.40 (m, 1H), 5.70 (br s, 1H), 7.65 (ddd, 1H), 7.89 (d, 2H), 8.18 (ddd, 1H), 8.21 (d, 2H), 8.71 (dd, 1H), 8.76 (s, 1H), 8.92 (d, 1H), 9.80 (d, 1H).

Example 108. 3-Oxo-2- (pyridin-3-yl) -N - [(2RS) -3,3,3-trifluoro-2-hydroxypropyl] -6- [4- (trifluoromethyl) phenyl] -2, 3-dihydropyridazine-4-carboxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.277 mmol) was dissolved in anhydrous DMF (2.1 ml) ... (2RS) -3amino-1,1,1-trifluoropropan-2-ol (71.5 mg, 0.55 mmol), X-ethyl-X-isopropylpropan-2-amine (314 μL, 1.80 mmol) and propane phosphonic anhydride ( T3P, 243 μL, 50% in DMF, 415 μmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with dichloromethane and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, movable

117 037978 phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 57.3 mg (44%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.49 (ddd, 1H), 3.76 (ddd, 1H), 4.18-4.29 (m, 1H), 6.68 (br s, 1H ), 7.65 (ddd, 1H), 7.89 (d, 2H), 8.18 (ddd, 1H), 8.22 (d, 2H), 8.71 (dd, 1H), 8.75 (s, 1H), 8.93 (d, 1H) , 9.59 (t, 1H).

Example 109. N - [(1RS) -1-cyclopropyl-2-hydroxyethyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine- 4-carboxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.277 mmol) was dissolved in anhydrous DMF (2.1 ml) ... (2RS) -2-amino-2-cyclopropylethanol hydrochloride (1: 1) (76.2 mg, 0.55 mmol), N-ethyl-N-isopropylpropan-2-amine (314 μL, 1.80 mmol) and propane phosphonic acid anhydride ( T3P, 243 μL, 50% in DMF, 415 μmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with dichloromethane and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 52.5 mg (43%) of the indicated in the connection header.

1 H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 0.26-0.50 (m, 4H), 1.03-1.13 (m, 1H), 3.41-3.49 (m, 1H), 3.523. 68 (m, 2H), 4.94 (t, 1H), 7.64 (ddd, 1H), 7.88 (d, 2H), 8.16-8.24 (m, 3H), 8.71 (dd, 1H), 8.74 (s, 1H) , 8.93 (d, 1H), 9.52 (d, 1H).

Example 110 3-Oxo-2- (pyridin-3-yl) -N - [(2RS) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -6- [4- (trifluoromethyl) phenyl ] -2,3-dihydropyridazine-4-carboxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.277 mmol) was dissolved in anhydrous DMF (2.1 ml) ... (2RS) -2amino-3,3,3-trifluoropropan-1-ol (71.5 mg, 0.55 mmol), N-ethyl-N-isopropylpropan-2-amine (217 μL, 1.25 mmol) and propane phosphonic acid anhydride ( T3P, 243 μL, 50% in DMF, 415 μmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with dichloromethane and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile gradient) to give 64.4 mg (49%) of the indicated in the connection header.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.66-3.75 (m, 1H), 3.83 (dd, 1H), 4.81-4.91 (m, 1H), 5.43 (br s , 1H), 7.65 (ddd, 1H), 7.89 (d, 2H), 8.19 (ddd, 1H), 8.23 (d, 2H), 8.72 (dd, 1H), 8.80 (s, 1H), 8.93 (d, 1H), 9.96 (d, 1H).

Example 111 N - [(2S) -1-Hydroxy-3-methoxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2, 3-dihydropyridazine-4-carboxamide

- 118 037978

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.138 mmol) was dissolved in anhydrous DMF (1.05 ml) ... (28) -2-amino3-methoxypropan-1-ol (29.1 mg, 0.28 mmol), X-ethyl-N-isopropylpropan-2-amine (109 μL, 0.62 mmol) and propane phosphonic acid anhydride (T3P, 122 μL , 50% in DMF, 208 μmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with dichloromethane and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.1 vol% formic acid (99%)) / acetonitrile gradient) to give 26 mg (42%) of the indicated in the connection header.

Ή-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.28 (s, 3H), 3.42-3.59 (m, 4H), 4.09-4.18 (m, 1H), 4.98 (t, 1H), 7.64 (ddd, 1H), 7.89 (d, 2H), 8.18 (ddd, 1H), 8.21 (d, 2H), 8.71 (dd, 1H), 8.75 (s, 1H), 8.92 (dd, 1H ), 9.50 (d, 1H).

[a] D ²⁰ = + 15.1 ° (c = 1.00, methanol).

Example 112. 3-Oxo-2- (pyridin-3-yl) -N - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -6- [4- (trifluoromethyl) phenyl ] -2,3-dihydropyridazine-4-carboxamide

X OH

F। Ϊ ^F f ^ Sf

F

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.138 mmol) was dissolved in anhydrous DMF (1.05 ml) ... (2R) -2-amino-3,3,3-trifluoropropan-1-ol hydrochloride (1: 1) (45.8 mg, 0.28 mmol), X-ethyl-N-isopropylpropan-2-amine (108.5 μL, 0.62 mmol) and propane phosphonic acid anhydride (T3P, 121.2 μL, 50% in DMF, 208 μmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with dichloromethane and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile gradient) to give 17 mg (26%) of the indicated in the connection header.

-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.66-3.74 (m, 1H), 3.79-3.86 (m, 1H), 4.81-4.92 (m, 1H), 5.45 ( br t, 1H), 7.65 (ddd, 1H), 7.89 (d, 2H), 8.19 (ddd, 1H), 8.23 (d, 2H), 8.72 (dd, 1H), 8.80 (s, 1H), 8.93 ( d, 1H), 9.96 (d, 1H).

[a] D ²⁰ = + 13.2 ° (c = 1.00, methanol).

Example 113. N - [(2R) -2,3-Dihydroxypropyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] 2,3-dihydropyridazine-4-carboxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.138 mmol) was dissolved in anhydrous DMF (1.05 ml) ... (2R) -3aminopropane-1,2-diol (25.2 mg, 0.28 mmol), X-ethyl-N-isopropylpropan-2-amine (108.5 μL, 0.62 mmol)

- 119 037978 and propane phosphonic acid anhydride (T3P, 121.2 μl, 50% in DMF, 208 μmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with dichloromethane and concentrated in vacuo.

The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile gradient) to give 24.5 mg (41%) of the indicated in the connection header.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.20-3.32 (m, 2H), 3.37-3.43 (m, 1H), 3.56-3.65 (m, 2H), 4.70 (t, 1H), 5.01 (d, 1H), 7.64 (ddd, 1H), 7.89 (d, 2H), 8.18 (ddd, 1H), 8.21 (d, 2H), 8.70 (dd, 1H), 8.74 ( s, 1H), 8.93 (dd, 1H), 9.50 (t, 1H).

[a] D ²⁰ = + 0.6 ° (c = 1.00, methanol).

Example 114 N - [(2S) -2,3-Dihydroxypropyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] 2,3-dihydropyridazine-4-carboxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.138 mmol) was dissolved in anhydrous DMF (1.05 ml) ... (2S) -3aminopropane-1,2-diol (25.2 mg, 0.28 mmol), X-ethyl-N-isopropylpropan-2-amine (109 μL, 0.62 mmol) and propane phosphonic anhydride (T3P, 122 μL, 50 % in DMF, 208 μmol). The mixture was stirred at RT overnight. The reaction mixture was diluted with dichloromethane and concentrated in vacuo. The residue was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 17.3 mg (29%) of the indicated in the connection header.

1H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.20-3.30 (m, 2H), 3.36-3.43 (m, 1H), 3.56-3.65 (m, 2H), 4.70 ( br t, 1H), 5.01 (br d, 1H), 7.64 (ddd, 1H), 7.89 (d, 2H), 8.18 (ddd, 1H), 8.21 (d, 2H), 8.70 (dd, 1H), 8.74 (s, 1H), 8.93 (dd, 1H), 9.50 (t, 1H).

[a] D ²⁰ = -9.7 ° (c = 1.00, methanol).

Example 115 X- (2-Hydroxy-2-methylpropyl) -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] 2,3-dihydropyridazine-4-carboxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.138 mmol) was dissolved in anhydrous DMF (1.5 ml) ... 1-amino-2methylpropan-2-ol (21 mg, 0.24 mmol), X-ethyl-N-isopropylpropan-2-amine (108 μL, 0.62 mmol), and propane phosphonic anhydride (T3P, 121 μL, 50% in DMF, 208 μmol). The mixture was stirred at RT overnight. The reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient and column: X-Bridge C18 5 μm 100x30 mm mobile phase: (water + 0.1 vol% formic acid (99%)) / acetonitrile gradient) to give 25 mg (42%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.13 (s, 6H), 3.31-3.33 (m, 2H and water signal), 4.68 (s, 1H), 7.65 ( ddd, 1H), 7.88 (d, 2H), 8.17-8.24 (m, 3H), 8.70 (dd, 1H), 8.74 (s, 1H), 8.93 (d, 1H), 9.50 (t, 1H).

Example 116 X- (1,3-Dihydroxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] 2,3-dihydropyridazine-4-carboxamide

- 120 037978

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.138 mmol) was dissolved in anhydrous DMF (1.5 ml) ... 2-aminopropane-1,3-diol (21 mg, 0.24 mmol), X-ethyl-X-isopropylpropan-2-amine (108 μL, 0.62 mmol), and propane phosphonic anhydride (T3P, 121 μL, 50% in DMF, 208 μmol). The mixture was stirred at RT overnight. The reaction mixture was purified using RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 33 mg (55%) specified in the header of the connection.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 3.45-3.52 (m, 2H), 3.55-3.62 (m, 2H), 3.93-4.01 (m, 1H), 4.89 (t, 2H), 7.64 (dd, 1H), 7.89 (d 2H), 8.17 (ddd, 1H), 8.21 (d 2H), 8.70 (dd, 1H), 8.75 (s, 1H), 8.92 (d IH ), 9.50 (d, 1H).

Example 117 3-Oxo-2- (nyridin-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) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.138 mmol) was dissolved in anhydrous DMF (1.5 ml) ... (2S) -3-amino1,1,1-trifluoropropan-2-ol (30 mg, 0.24 mmol), X-ethyl-X-isopropylpropan-2-amine (108 μL, 0.62 mmol) and propane phosphonic anhydride ( T3P, 121 μl, 50% in DMF, 208 μmol). The mixture was stirred at RT overnight. The reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 32 mg (49%) specified in the header of the connection.

¹ H-NMR (400 MHz, DMSO-d6): δ [ppm] = 3.49 (ddd, 1H), 3.72-3.80 (m, 1H), 4.18-4.29 (m, 1H), 6.67 (d, 1H), 7.65 (ddd, 1H), 7.89 (d, 2H), 8.18 (ddd, 1H), 8.22 (d, 2H), 8.71 (dd, 1H), 8.76 (s, 1H), 8.93 (d, 1H ), 9.59 (t, 1H).

[a] D ²⁰ = -12.3 ° (c = 1.00, methanol).

Example 118. N - [(2R) -1-hydroxynropan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] 2,3-dihydropyridazine-4 -carboxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.138 mmol) was dissolved in anhydrous DMF (1.5 ml) ... (2R) -2aminopropan-1-ol (18 mg, 0.24 mmol), X-ethyl-X-isopropylpropan-2-amine (108 μL, 0.62 mmol), and propane phosphonic anhydride (T3P, 121 μL, 50% in DMF, 208 μmol). The mixture was stirred at RT overnight. The reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient and column: X-Bridge C18 5 μm 100x30 mm mobile phase (water + 0.1 vol% formic acid (99%)) / acetonitrile gradient) to give 22 mg (38%) of the title compound.

- 121 037978 ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17 (d, 3H), 3.40-3.50 (m, 2H), 3.99-4.10 (m, 1H), 4.95 (t, 1H),

7.64 (ddd, 1H), 7.89 (d, 2H), 8.18 (ddd, 1H), 8.21 (d, 2H), 8.70 (dd, 1H), 8.73 (s, 1H), 8.92 (d, 1H), 9.39 (d, 1H).

[a] D ²⁰ = -8.9 ° (c = 1.00, methanol).

Example 119. N - [(2S) -1-Hydroxynropan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] 2,3-dihydropyridazine-4 - car boxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (50 mg, 0.138 mmol) was dissolved in anhydrous DMF (1.5 ml) ... (2S) -2aminopropan-1-ol (18 mg, 0.24 mmol), N-ethyl-N-isonronylnropan-2-amine (108 μL, 0.62 mmol), and propane phosphonic anhydride (T3P, 121 μL, 50% in DMF, 208 μmol). The mixture was stirred at RT overnight. The reaction mixture was purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient and column: X-Bridge C18 5 μm 100x30 mm mobile phase: (water + 0.1 vol% formic acid (99%)) / acetonitrile gradient) to give 25 mg (43%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17 (d, 3H), 3.40-3.50 (m, 2H), 4.00-4.09 (m, 1H), 4.95 (t , 1H), 7.64 (ddd, 1H), 7.89 (d, 2H), 8.18 (ddd, 1H), 8.21 (d, 2H), 8.70 (dd, 1H), 8.73 (s, 1H), 8.92 (d, 1H), 9.39 (d, 1H).

[a] D ²⁰ = + 12.1 (c = 1.00, methanol).

Example 120 6- (4-Chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyrimidin-5-yl) -2,3 dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -3-oxo-2- (pyrimidin-5-yl) -2,3-dihydropyridazine-4-carboxylic acid (60 mg, 0.183 mmol) was dissolved in anhydrous DMF (1.4 ml). (2S) -2-amino-propan1-ol (27.4 mg, 0.37 mmol), N-ethyl-N-isopropylpropan-2-amine (143 μL, 0.82 mmol) and propane phosphonic anhydride (T3P, 160 μL, 50% in DMF, 274 μmol). The mixture was stirred for 24 h at 55 ° C. The reaction mixture was purified using RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient and column: X-Bridge C18 5 μm 100x30 mm mobile phase (water + 0.1 vol% formic acid (99%)) / acetonitrile gradient) to give 5.3 mg (8%) of the title compound.

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.17 (d, 3H), 3.40-3.50 (m, 2H), 3.99-4.10 (m, 1H), 4.96 (t , 1H), 7.58-7.62 (m, 2H), 8.03-8.07 (m, 2H), 8.68 (s, 1H), 9.25 (s, 2H), 9.29-9.32 (m, 2H).

[a] D ²⁰ = + 1.1 (c = 1.00, methanol).

Example 121 6- (4-Chlorophenyl) -3-oxo-2 - (pyridine-3 -ηλ) -Ν- (1,1,1-trifluoro-3-hydroxy-3-methylbutan2-yl) -2,3 -dihydropyridazine-4 - carboxamide

A solution of 150 mg of intermediate 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxylic acid, 177 mg of 3-amino-4,4,4-trifluoro hydrochloride -2-methylbutane-2- 122 037978 ol (1: 1), 348 mg HATU, 0.32 ml of ethyldiisopropylamine, and 4 mg of 4-dimethylaminopyridine in 3 ml of DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP- HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70 % / B 30% (A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to obtain 98 mg of the title compound.

Ή NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.19 (s, 3H), 1.34 (s, 3H), 4.66 (quin, 1H), 5.21 (s, 1H), 7.56-7.61 (m, 2H), 7.64 (dd, 1H), 8.00-8.06 (m, 2H), 8.16-8.22 (m, 1H), 8.70 (dd, 1H), 8.74 (s, 1H), 8.93 (d, 1H ), 10.01 (d, 1H).

Example 122 6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -N- (1,1,1-trifluoro-3-hydroxy-3-methylbutan2-yl) -2,3 -dihydropyridazine-4-carboxamide, enantiomer 1

HPLC separation 92 mg 6- (4-chlorophenyl) -3-oxo-2- (pyrigin-3-yl) -N- (1,1,1-trifluoro-3-hydroxy-3methylbutan-2-yl) -2 , 3-dihydropyridazine-4-carboxamide (example 121) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IA 5 μm 250x30 mm; eluent A: methanol; eluent B : ethanol; isocratic mode: 50% A + 50% B; flow 40.0 ml / min; UV: 254 nm) yielded 36 mg of 6- (4-chlorophenyl) -3-oxo-2- (pyrigin-3-yl ) -N- (1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl) -2,3-dihydropyridazine-4-carboxamide, enantiomer 1.

Chiral HPLC: R _t = 1.74 min (instrument: Agilent HPLC 1260; column: Chiralpak IA 3 μm 100x4.6 mm; eluent A: methanol + 0.1% v / v diethylamine (99%); eluent B: ethanol; isocratic mode: 50 % A + 50% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

Example 123 6- (4-Chlorophenyl) -3-oxo-2- (pyridin-3-yl) -N- (1,1,1-trifluoro-3-hydroxy-3-methylbutan2-yl) -2,3 -dihydropyridazine-4-carboxamide, enantiomer 2

HPLC separation 92 mg 6- (4-chlorophenyl) -3-oxo-2- (pyrigin-3-yl) -N- (1,1,1-trifluoro-3-hydroxy-3methylbutan-2-yl) -2 , 3-dihydropyridazine-4-carboxamide (example 121) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IA 5 μm 250x30 mm; eluent A: methanol; eluent B : ethanol; isocratic mode: 50% A + 50% B; flow 40.0 ml / min; UV: 254 nm) yielded 37.5 mg 6- (4-chlorophenyl) -3-oxo-2- (pyrigin-3-yl ) -N- (1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl) -2,3-dihydropyridazine-4-carboxamide, enantiomer 2.

Chiral HPLC: R _t = 2.27 min (instrument: Agilent HPLC 1260; column: Chiralpak IA 3 μm 100x4.6 mm; eluent A: methanol +0.1 vol% diethylamine (99%); eluent B: ethanol; isocratic mode: 50 % A + 50% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

Example 124 6- (4-Chlorophenyl) -2- (5-fluoropyrigin-3-yl) -N - [(1S, 2R) -2-hydroxycyclohexyl] -3-oxo2,3-dihydropyridazine-4-carboxamide

- 123 037978

Solution of 75 mg of intermediate 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 66 mg of (1R, 2S) -2-aminocyclohexanol hydrochloride (1: 1), 165 mg HATU, 0.11 ml of ethyldiisopropylamine and 1.5 mg of 4-dimethylaminopyridine in 2 ml of DMF were stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RPHPLC (instrument: Labomatic HD-3000 HPLC gradient pump, collector of fractions Labomatic Labocol Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70 %; flow: 150 ml / min; UV detection: 254 nm) to give 12 mg of 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(1S, 2R) -2 hydroxycyclohexyl ] -3-oxo-2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.33 (br d, 2H), 1.47-1.70 (m, 6H), 3.77 (br d, 1H), 3.86-3.95 (m , 1H), 4.89 (d, 1H), 7.55-7.62 (m, 2H), 7.99-8.05 (m, 2H), 8.22-8.28 (m, 1H), 8.68 (s, 1H), 8.76 (d, 1H ), 8.85 (t, 1h), 9.55 (d, 1H).

Example 125 6- (4-Chlorophenyl) -N - [(1S, 2R) -2-hydroxycyclohexyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxamide

Solution of 75 mg of intermediate 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid, 69 mg of (1R, 2S) -2-aminocyclohexanol hydrochloride (1: 1), 165 mg HATU, 0.16 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70 %; flow: 150 ml / min; UV detection: 254 nm) to give 31 mg of 6- (4-chlorophenyl) -N - [(1S, 2R) -2-hydroxycyclohexyl] -3-oxo-2- (pyridine -3-yl) -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.24-1.38 (m, 2H), 1.47-1.70 (m, 6H), 3.77 (br s, 1H), 3.87-3.96 ( m, 1H), 4.87 (d, 1H), 7.58 (d, 2H), 7.63 (dd, 1H), 8.00 (d, 2H), 8.13-8.19 (m, 1H), 8.67 (s, 1H), 8.69 (br d, 1H), 8.91 (s, 1H), 9.62 (d, 1H).

Example 126 N - [(1S, 2R) -Hydroxycyclohexyl] -3-oxo-2-pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide

Solution of 75 mg of intermediate 3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine-4-carboxylic acid, 60 mg of (1R, 2S) -2 hydrochloride α-aminocyclohexanol (1: 1), 151 mg HATU, 0.14 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD -3000 HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30 % / V 70%; flow: 150 ml / min; UV detection: 254 nm) to obtain 17 mg N - [(1S, 2R) -2-hydroxycyclohexyl] -3-oxo-2- (pyridin-3-yl ) -6- [4 (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm] = 1.32 (br s, 2H), 1.46-1.69 (m, 6H), 3.77 (br s, 1H), 3.87-3.98 (m, 1H), 4.88 (d, 1H), 7.51 (d, 2H), 7.63 (dd, 1H), 8.08-8.13 (m, 2H), 8.14-8.19 (m, 1H), 8.67-8.72 (m, 2H) , 8.91 (d, 1H), 9.62 (d, 1H).

Example 127 6- [4- (Difluoromethyl) phenyl] -3-oxo-2- (pyridine-3 -πλ) -Ν - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl ] -2,3-dihydropyridazine-4-carboxamide

- 124 037978

A solution of 65 mg of intermediate 6- [4- (difluoromethyl) phenyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxylic acid, 60 mg of (2R) -2-amino hydrochloride 3,3,3-trifluoropropan-1-ol (1: 1), 144 mg of HATU, 0.1 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP -HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) yielding 37 mg of 6- [4- (difluoromethyl) phenyl] -3-oxo-2- (pyridine -3-yl) -N [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -2,3-dihydropyridazine-4-carboxamide.

Ή NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 3.65-3.75 (m, 1H), 3.83 (dt, 1H), 4.81-4.92 (m, 1H), 5.44 (t, 1H) , 7.13 (t, 1H), 7.65 (dd, 1H), 7.73 (d, 2H), 8.15 (d, 2H), 8.17-8.22 (m, 1H), 8.69-8.74 (m, 1H), 8.78 (s , 1H), 8.93 (d, 1H), 9.97 (d, 1H).

Example 128 6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-N - [(2S) -3,3,3-trifluoro-2-hydroxypropyl] -2,3 -dihydropyridazine-4-carboxamide or - X

F ^ l

F

A solution of 75 mg of intermediate 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 56 mg (2S) -3-amino-1, 1,1-trifluoropropan-2-ol, 165 mg HATU, 0.11 ml of ethyldiisopropylamine and 1.5 mg of 4-dimethylaminopyridine in 2 ml of DMF was stirred at room temperature for 14 hours. The reaction mixture was then filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30 % / V 70%; flow: 150 ml / min; UV detection: 254 nm) to obtain 14 mg of 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-N- [(2S) -3,3,3-trifluoro-2-hydroxypropyl] -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 3.48 (ddd, 1H), 3.69-3.80 (m, 1H), 4.23 (br s, 1H), 6.67 (d, 1H) , 7.55-7.63 (m, 2H), 8.00-8.07 (m, 2H), 8.23-8.27 (m, 1H), 8.69 (s, 1H), 8.77 (d, 1H), 8.87 (d, 1H), 9.54 (t, 1H).

Example 129 6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(1S, 2R) -2-hydroxycyclopentyl] -3-oxo2,3-dihydropyridazine-4-carboxamide

Solution of 75 mg of intermediate 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 60 mg of (1R, 2S) -2-aminocyclopentanol hydrochloride (1: 1), 165 mg HATU, 0.11 ml of ethyldiisopropylamine and 1.5 mg of 4-dimethylaminopyridine in 2 ml of DMF were stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RPHPLC (instrument: Labomatic HD-3000 HPLC gradient pump, collector of fractions Labomatic Labocol Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol.% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30 % / V 70%; flow: 150 ml / min; UV detection:

254 nm) to obtain 18 mg of 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(1S, 2R) -2hydroxycyclopentyl] -3-oxo-2,3-dihydropyridazine- 4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.47-1.64 (m, 3H), 1.70-1.89 (m, 2H), 1.93-2.04 (m, 1H), 3.994.12 (m, 2H), 5.06 (d, 1H), 7.56-7.61 (m, 2H), 7.99-8.06 (m, 2H), 8.24 (dt, 1H), 8.68 (s, 1H), 8.76 (d, 1H ), 8.85 (t, 1H), 9.62 (d, 1H).

Example 130 6- (4-Chlorophenyl) -N - [(1S, 2S) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxamide

Solution of 75 mg of intermediate 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid, 62 mg of (1S, 2S) -2-aminocyclopentanol hydrochloride (1: 1), 174 mg HATU, 0.16 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70 %; flow: 150 ml / min; UV detection: 254 nm) to give 31 mg of 6- (4-chlorophenyl) -N - [(1S, 2S) -2-hydroxycyclopentyl] -3-oxo-2- (pyridine -3-yl) -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.39-1.55 (m, 2H), 1.58-1.76 (m, 2H), 1.77-1.88 (m, 1H), 2.032.14 (m, 1H), 3.90-3.96 (m, 1H), 3.98-4.06 (m, 1H), 4.94 (d, 1H), 7.56-7.61 (m, 2H), 7.63 (dd, 1H), 7.98-8.03 (m, 2H), 8.16 (ddd, 1H), 8.65 (s, 1H), 8.69 (dd, 1H), 8.91 (d, 1H), 9.31 (d, 1H).

[a] _D ²⁰ = + 34.5 (c = 1.00, DMSO).

Example 131. 3-Oxo-2- (pyridin-3-yl) -N - [(2S) -3,3,3-trifluoro-2-hydroxypropyl] -6- [4- (trifluoromethoxy) phenyl] -2, 3-dihydropyridazine-4-carboxamide

A solution of 75 mg of intermediate 3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine-4-carboxylic acid, 51 mg (2S) -3-amino 1,1,1-trifluoropropan-2-ol, 151 mg HATU, 0.14 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RPHPLC (instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to obtain 24 mg of 3-oxo-2- (pyridin-3-yl) -N - [(2S) -3.3 , 3-trifluoro-2-hydroxypropyl] -6- [4 (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-de) δ [ppm] = 3.48 (ddd, 1H), 3.72-3.80 (m, 1H), 4.18-4.28 (m, 1H), 6.66 (d, 1H) , 7.52 (d, 2H), 7.64 (dd, 1H), 8.08-8.15 (m, 2H), 8.15-8.20 (m, 1H), 8.67-8.72 (m, 2H), 8.93 (d, 1H), 9.61 (t, 1H).

Chiral HPLC: Rt = 1.74 min (instrument: Agilent HPLC 1260; column: YMC Amylose SA 3 μm 100x4.6 mm; eluent A: methanol + 0.1 vol% diethylamine (99%), eluent B: ethanol; isocratic mode: 50 % A + 50% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm.

[a] D ²⁰ = - 8.4 (c = 1.00, DMSO).

Example 132. N - [(1S, 2S) -2-Hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4- carboxamide

- 126 037978

A solution of 150 mg of intermediate 3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylic acid, 109 mg (1S, 2S) -2 α-aminocyclopentanol, 302 mg HATU, 0.28 ml of ethyldiisopropylamine and 2 mg of 4-dimethylaminopyridine in 3 ml of DMF were stirred at 40 ° C for 3 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC, collector of fractions Labomatic Labocol Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70 %; flow: 150 ml / min; UV detection: 254 nm) to obtain 75 mg of N - [(1S, 2S) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3 dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.39-1.55 (m, 2H), 1.57-1.67 (m, 1H), 1.67-1.76 (m, 1H), 1.771.87 (m, 1H), 2.03-2.14 (m, 1H), 3.90-3.97 (m, 1H), 3.98-4.06 (m, 1H), 4.95 (d, 1H), 7.51 (d, 2H), 7.63 (dd , 1H), 8.09-8.13 (m, 2H), 8.14-8.19 (m, 1H), 8.66 (s, 1H), 8.69 (d, 1H), 8.91 (d, 1H), 9.31 (d, 1H).

Example 133 6- (4-Chlorophenyl) -N - [(cis) -2-hydroxycyclohexyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide

A solution of 75 mg of intermediate 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxylic acid, 69 mg of cis-2-amino-1-cyclohexanol hydrochloride (1 : 1), 174 mg HATU, 0.16 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF were stirred at room temperature for 48 h. Then the reaction mixture was filtered and subjected to RPHPLC (instrument: Labomatic HD-3000 HPLC gradient pump, fraction collector Labomatic Labocol Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to obtain 39 mg of 6- (4-chlorophenyl) -N - [(cis) -2-hydroxycyclohexyl] -3-oxo-2- (pyridin-3-yl ) 2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.26-1.37 (m, 2H), 1.46-1.69 (m, 6H), 3.77 (m, 1H), 3.86-3.97 (m , 1H), 4.88 (d, 1H), 7.55-7.60 (m, 2H), 7.63 (dd, 1H), 7.97-8.03 (m, 2H), 8.13-8.19 (m, 1H), 8.67 (s, 1H ), 8.69 (dd, 1H), 8.91 (d, 1H), 9.62 (d, 1H).

Example 134. 3-Oxo-2- (pyridin-3-yl) -N - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -6- [4- (trifluoromethoxy) phenyl ] -2,3-dihydropyridazine-4-carboxamide

Solution of 52 mg of intermediate 3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine-4-carboxylic acid, 46.6 mg of (2R) -2-amino hydrochloride -3,3,3-trifluoropropan1-ol (1: 1), 105 mg HATU, 0.07 ml ethyldiisopropylamine and 1 mg 4-dimethylaminopyridine in 1 ml DMF

127 037978 was stirred at 40 ° C for 3 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A : water + 0.2 vol.% aqueous ammonia (32%), eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm ) to obtain 24 mg of 3-oxo-2- (pyridin-3-yl) -N - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -6- [4 (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-do) δ [ppm] = 3.65-3.74 (m, 1H), 3.82 (dt, 1H), 4.80-4.91 (m, 1H), 5.44 (t, 1H) , 7.52 (d, 2H), 7.64 (dd, 1H), 8.10-8.16 (m, 2H), 8.16-8.21 (m, 1H), 8.71 (dd, 1H), 8.75 (s, 1H), 8.92 (d , 1H), 9.98 (d, 1H).

[a] D ²⁰ = 10.2 ° (c = 1.00, DMSO).

Example 135. 3-Oxo-2- (pyridin-3-yl) -Y- [1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl] -6- [4- (trifluoromethoxy) phenyl ] -2,3-dihydropyridazine-4-carboxamide

A solution of 150 mg of intermediate 3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylic acid, 154 mg of 3-amino-4 hydrochloride, 4,4-trifluoro-2methylbutan-2-ol (1: 1), 302 mg of HATU, 0.3 ml of ethyldiisopropylamine and 4 mg of 4-dimethylaminopyridine in 3 ml of DMF was stirred at RT for 14 h. Then the reaction mixture was filtered and subjected to RP- HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: water + 0.2 vol.% Aqueous ammonia (32%), eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to give 63 mg of 3-oxo-2- (pyridin-3-yl) -Y- [1,1,1-trifluoro-3-hydroxy-3methylbutan-2-yl] -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm] = 1.20 (s, 3H), 1.34 (s, 3H), 4.67 (quin, 1H), 5.22 (s, 1H), 7.51 (d , 2H), 7.61-7.67 (m, 1H), 8.11-8.15 (m, 2H), 8.19 (ddd, 1H), 8.70 (dd, 1H), 8.75 (s, 1H), 8.93 (d, 1H), 10.02 (d, 1H).

Example 136. 3-Oxo-2- (pyridin-3-yl) -Y- [1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl] -6- [4- (trifluoromethoxy) phenyl ] -2,3-dihydropyridazine-4-carboxamide, enantiomer 1

HPLC separation 58 mg 3-oxo-2- (pyridin-3-yl) -Y- [1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl] 6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide (example 135) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IB 5 μm 250x30 mm; eluent A: methyl tert-butyl ether + 0.1 vol% diethylamine (99%); eluent B: ethanol; isocratic mode: 90% A + 10% B; flow 50.0 ml / min; UV: 254 nm) yielded 23 mg of 3oxo -2- (pyridin-3-yl) -Y- [1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl] -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine -4-carboxamide, enantiomer 1.

Chiral HPLC: Rt = 1.57 min (instrument: Agilent HPLC 1260; column: Chiralpak IB 3 μm 100x4.6 mm; eluent A: methyl tert-butyl ether + 0.1% v / v diethylamine (99%); eluent B: ethanol; isocratic mode: 90% A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

Example 137. 3-Oxo-2- (pyridin-3-yl) -Y- [1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl] -6- [4- (trifluoromethoxy) phenyl ] -2,3-dihydropyridazine-4-carboxamide, enantiomer 2

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HPLC separation 58 mg 3-oxo-2- (pyridin-3-yl) -N- [1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl] 6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide (example 135) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IB 5 μm 250x30 mm; eluent A: methyl tert-butyl ether + 0.1 vol% diethylamine (99%); eluent B: ethanol; isocratic mode: 90% A + 10% B; flow 50.0 ml / min; UV: 254 nm) yielded 20 mg of 3oxo -2- (pyridin-3-yl) -No- [1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl] -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine -4-carboxamide, enantiomer 2.

Chiral HPLC: R _t = 3.29 min (instrument: Agilent HPLC 1260; column: Chiralpak IB 3 μm 100x4.6 mm; eluent A: methyl tert-butyl ether + 0.1 vol% diethylamine (99%); eluent B: ethanol ; isocratic mode: 90% A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

Example 138 6- (4-Chlorophenyl) -N - [(1R, 2S) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxamide

Solution of 75 mg of intermediate 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid, 63 mg of (1S, 2R) -2-aminocyclopentanol hydrochloride (1: 1), 174 mg HATU, 0.16 ml of ethyldiisopropylamine, and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF were stirred at room temperature for 90 min. Then the reaction mixture was filtered and subjected to SPHPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to give 35 mg of 6- (4-chlorophenyl) -N - [( 1R, 2S) -2-hydroxycyclopentyl] -3-oxo-2- (pyridine-3yl) -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.46-1.64 (m, 3H), 1.70-1.88 (m, 2H), 1.92-2.03 (m, 1H), 3.994.12 (m, 2H), 5.04 (d, 1H), 7.56-7.61 (m, 2H), 7.61-7.66 (m, 1H), 7.97-8.03 (m, 2H), 8.16 (ddd, 1H), 8.66-8.70 (m, 2H), 8.91 (d, 1H), 9.67 (d, 1H).

Example 139 6- [4- (Difluoromethyl) phenyl] -N - [(1S, 2S) -2-hydroxycyclopentyl] -3-oxo-2- (pyridine-3yl) -2,3-dihydropyridazine-4-carboxamide

A solution of 65 mg of intermediate 6- [4- (difluoromethyl) phenyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxylic acid, 60 mg of (1S, 2S) -2- hydrochloride aminocyclopentanol (1: 1), 144 mg HATU, 0.1 ml ethyldiisopropylamine and 1 mg 4-dimethylaminopyridine in 2 ml DMF were stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RPHPLC (instrument: gradient pump Labomatic HD-3000 HPLC , fraction collector Labomatic Labocol Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection:

- 129 037978

254 nm) to give 13 mg of 6- [4- (difluoromethyl) phenyl] -N - [(1S, 2S) -2-hydroxycyclopentyl] -3-oxo-2 (pyridin-3-yl) -2,3-dihydropyridazine -4-carboxamide.

1H NMR (400 MHz, DMSO-de) δ [ppm] = 1.39-1.56 (m, 2H), 1.58-1.76 (m, 2H), 1.77-1.87 (m, 1H), 2.042.14 (m , 1H), 3.94 (br d, 1H), 3.98-4.07 (m, 1H), 4.95 (br d, 1H), 7.13 (t, 1H), 7.64 (dd, 1H), 7.72 (d, 2H), 8.13 (d, 2H), 8.15-8.20 (m, 1H), 8.66-8.72 (m, 2H), 8.92 (d, 1H), 9.31 (d, 1H).

Example 140. X - [(trans) -3,3-Difluoro-2-hydroxycyclohexyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3- dihydropyridazine-4-carboxamide

A solution of 150 mg of intermediate 3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylic acid, 149 mg of trans-6-amino hydrochloride 2,2difluorocyclohexan-1-ol (1: 1), 302 mg HATU, 0.3 ml of ethyldiisopropylamine and 4 mg of 4dimethylaminopyridine in 3 ml of DMF was stirred at RT for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: water + 0.2 vol.% Aqueous ammonia (32%), eluent B: acetonitrile; gradient: A 70% / B 30% (A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to obtain 66 mg of X - [(trans) -3,3-difluoro-2-hydroxycyclohexyl] -3-oxo 2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4carboxamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.40-1.54 (m, 2H), 1.66 (br s, 1H), 1.72-1.90 (m, 1H), 1.94-2.11 (m , 2H), 3.69-3.82 (m, 1H), 3.97 (br s, 1H), 5.78 (d, 1H), 7.52 (d, 2H), 7.64 (dd, 1H), 8.08-8.14 (m, 2H) , 8.158.20 (m, 1H), 8.68-8.72 (m, 2H), 8.92 (d, 1H), 9.52 (d, 1H).

Example 141. X - [(trans) -3,3-Difluoro-2-hydroxycyclohexyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3- dihydropyridazine-4-carboxamide, enantiomer 1

HPLC separation 58 mg X - [(trans) -3,3-difluoro-2-hydroxycyclohexyl] -3-oxo-2- (pyridin-3-yl) -6 [4- (trifluoromethoxy) phenyl] -2.3 -dihydropyridazine-4-carboxamide (example 140) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IA 5 μm 250x30 mm; eluent A: ethanol + 0.1 vol.% diethylamine (99%); eluent B: methanol; isocratic mode: 50% A + 50% B; flow 40.0 ml / min; UV: 254 nm) yielded 21 mg of X - [(trans) -3,3 difluoro-2 -hydroxycyclohexyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide, enantiomer 1.

Chiral HPLC: R _t = 1.48 min (instrument: Agilent HPLC 1260; column: Chiralpak IA 3 μm 100x4.6 mm; eluent A: ethanol + 0.1% v / v diethylamine (99%); eluent B: ethanol; isocratic mode: 90 % A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

Example 142. X - [(trans) -3,3-Difluoro-2-hydroxycyclohexyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3- dihydropyridazine-4-carboxamide, enantiomer 2

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HPLC separation 58 mg Y - [(trans) -3,3-difluoro-2-hydroxycyclohexyl] -3-oxo-2- (pyridin-3-yl) -6 [4- (trifluoromethoxy) phenyl] -2.3 -dihydropyridazine-4-carboxamide (example 140) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IA 5 μm 250x30 mm; eluent A: ethanol + 0.1 vol.% diethylamine (99%); eluent B: methanol; isocratic mode: 50% A + 50% B; flow 40.0 ml / min; UV: 254 nm) yielded 23 mg U - [(trans) -3,3 difluoro-2 -hydroxycyclohexyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide, enantiomer 2.

Chiral HPLC: R _t = 1.78 min (instrument: Agilent HPLC 1260; column: Chiralpak IA 3 μm 100x4.6 mm; eluent A: ethanol + 0.1% v / v diethylamine (99%); eluent B: ethanol; isocratic mode: 90 % A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

Example 143 6- (4-Chlorophenyl) -U - [(trans) -3,3-difluoro-2-hydroxycyclohexyl] -3-oxo-2- (pyridine-3yl) -2,3-dihydropyridazine-4-carboxamide

A solution of 150 mg of intermediate 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxylic acid, 172 mg of (trans) -6-amino-2,2 hydrochloride -difluorocyclohexan-1-ol (1: 1), 348 mg HATU, 0.3 ml of ethyldiisopropylamine and 4 mg of 4-dimethylaminopyridine in 3 ml of DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to obtain 66 mg of rac-6- (4-chlorophenyl) -Y - [(trans) -3,3-difluoro-2-hydroxycyclohexyl ] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.40-1.53 (m, 2H), 1.66 (br s, 1H), 1.72-1.89 (m, 1H), 1.92-2.11 ( m, 2H), 3.69-3.80 (m, 1H), 3.96 (br s, 1H), 5.77 (d, 1H), 7.56-7.61 (m, 2H), 7.63 (dd, 1H), 7.98-8.02 (m , 2H), 8.14-8.18 (m, 1H), 8.67 (s, 1H), 8.70 (dd, 1H), 8.91 (d, 1H), 9.51 (d, 1H).

Example 144 6- (4-Chlorophenyl) -U - [(trans) -3,3-difluoro-2-hydroxycyclohexyl] -3-oxo-2- (pyridin-3yl) -2,3-dihydropyridazine-4-carboxamide , enantiomer 1

HPLC separation 58 mg 6- (4-chlorophenyl) -Y - [(trans) -3,3-difluoro-2-hydroxycyclohexyl] -3-oxo-2 (pyridin-3-yl) -2,3-dihydropyridazine- 4-carboxamide (Example 143) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: YMC Cellulose SC 5 μm 250x30 mm; eluent A: methanol; eluent B: ethanol; isocratic mode: 50% A + 10% B; flow 40.0 ml / min; UV: 254 nm) yielded 20 mg of 6- (4-chlorophenyl) -M - [(trans) -3,3-difluoro-2-hydroxy - 131 037978 cyclohexyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide, enantiomer 1.

Chiral HPLC: Rt = 1.74 min (instrument: Agilent HPLC 1260; column: YMC Cellulose SC 3 μm

100x4.6 mm; eluent A: methanol + 0.1% by volume diethylamine (99%); eluent B: ethanol; isocratic mode:

50% A + 50% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

Example 145 6- (4-Chlorophenyl) -X - [(trans) -3,3-difluoro-2-hydroxycyclohexyl] -3-oxo-2- (pyridin-3yl) -2,3-dihydropyridazine-4-carboxamide , enantiomer 2

HPLC separation 58 mg 6- (4-chlorophenyl) -X - [(trans) -3,3-difluoro-2-hydroxycyclohexyl] -3-oxo-2 (pyridin-3-yl) -2,3-dihydropyridazine- 4-carboxamide (Example 143) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: YMC Cellulose SC 5 μm 250x30 mm; eluent A: methanol; eluent B: ethanol; isocratic mode: 50% A + 10% B; flow 40.0 ml / min; UV: 254 nm) yielded 19 mg 6- (4-chlorophenyl) -X - [(trans) -3,3-difluoro-2hydroxycyclohexyl] - 3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide, enantiomer 2.

Chiral HPLC: R _t = 2.29 min (instrument: Agilent HPLC 1260; column: YMC Cellulose SC 3 μm 100x4.6 mm; eluent A: methanol + 0.1 vol% diethylamine (99%); eluent B: ethanol; isocratic mode: 50% A + 50% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

Example 146. 3-Oxo-2- (pyridin-3-yl) -X- [3,3,3-trifluoro-2-hydroxypropyl] -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine- 4-carboxamide

A solution of 50 mg of intermediate 3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine-4-carboxylic acid, 34 mg of 3-amino-1,1, 1-trifluoro-2-propanol, 101 mg HATU, 0.1 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 1 ml of DMF was stirred at RT for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD- 3000 HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: water + 0.2 vol% aqueous ammonia (32%), eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to obtain 8 mg of rac-3oxo-2- (pyridin-3-yl) -X- [3,3,3- trifluoro-2-hydroxypropyl] -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide.

Ή NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 3.48 (ddd, 1H), 3.70-3.79 (m, 1H), 4.16-4.29 (m, 1H), 6.66 (d, 1H) , 7.52 (d, 2H), 7.64 (dd, 1H), 8.09-8.14 (m, 2H), 8.15-8.20 (m, 1H), 8.67-8.72 (m, 2H), 8.93 (d, 1H), 9.61 (t, 1H).

Example 147. N - [(1S, 2R) -2-Hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4- carboxamide

A solution of 75 mg of intermediate 3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] - 132 037978

2,3-dihydropyridazine-4-carboxylic acid, 54 mg of (1R, 2S) -2-aminocyclopentanol hydrochloride (1: 1), 151 mg of HATU, 0.14 ml of ethyldiisopropylamine, and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF were stirred at RT at for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to give 19 mg N - [(1S, 2R) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3 dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.46-1.64 (m, 3H), 1.69-1.88 (m, 2H), 1.92-2.02 (m, 1H), 3.994.09 (m, 2H), 5.04 (d, 1H), 7.51 (d, 2H), 7.60-7.66 (m, 1H), 8.07-8.14 (m, 2H), 8.17 (ddd, 1H), 8.67-8.71 (m , 2H), 8.91 (d, 1H), 9.68 (d, 1H).

Example 148 6- (4-Chlorophenyl) -N - [(trans) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxamide

Solution of 75 mg of intermediate 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid, 63 mg of trans-2-aminocyclopentanol hydrochloride (1: 1 ), 174 mg HATU, 0.16 ml of ethyldiisopropylamine, and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF were stirred at RT for 48 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic fraction collector Labocol Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow : 150 ml / min; UV detection: 254 nm) to give 26 mg of 6- (4-chlorophenyl) -N - [(trans) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.39-1.56 (m, 2H), 1.59-1.67 (m, 1H), 1.67-1.75 (m, 1H), 1.771.86 ( m, 1H), 2.03-2.13 (m, 1H), 3.93 (quin, 1H), 3.98-4.06 (m, 1H), 4.94 (d, 1H), 7.56-7.60 (m, 2H), 7.63 (dd, 1H), 7.98-8.03 (m, 2H), 8.16 (ddd, 1H), 8.65 (s, 1H), 8.69 (dd, 1H), 8.91 (d, 1H), 9.31 (d, 1H).

Example 149. 3-Oxo-2- (pyridin-3-yl) -N- (1,1,1-trifluoro-3-hydroxypropan-2-yl) -6- [4- (trifluoromethoxy) phenyl] -2, 3-dihydropyridazine-4-carboxamide

Solution of 75 mg of intermediate 3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine-4-carboxylic acid, 68 mg of 2-amino-3,3 hydrochloride , 3-trifluoropropan-1-ol (1: 1), 151 mg HATU, 0.14 ml of ethyldiisopropylamine, and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF were stirred at RT for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument : Waters Autopurification MS SingleQuad; column: Waters XBrigde C18 5 μm 100x30 mm; eluent A: water + 0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml / min; temperature: 25 ° C; DAD scan: 210-400 nm) to obtain 46 mg of 3-oxo-2 (pyridin-3-yl) -N- (1,1,1-trifluoro-3- hydroxypropan-2-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide.

1H NMR (400 MHz, DMSO-d6) δ [ppm] 3.66-3.74 (m, 1H), 3.79-3.85 (m, 1H), 4.86 (dt, 1H), 5.44 (t, 1H), 7.52 (d, 2H), 7.64 (dd, 1H), 8.11-8.16 (m, 2H), 8.16-8.21 (m, 1H), 8.68-8.72 (m, 1H), 8.75 (s, 1H), 8.92 (d , 1H), 9.98 (d, 1H).

Example 150. N - [(1S) -1-Cyclopropyl-2-hydroxyethyl] -6- [4- (difluoromethyl) phenyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine- 4-carboxamide

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A solution of 85 mg of intermediate 6- [4- (difluoromethyl) phenyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxylic acid, 69 mg of (2S) -2-aminocyclopropylethane hydrochloride 1-ol (1: 1), 190 mg HATU, 0.17 ml of ethyldiisopropylamine and 1.5 mg of 4-dimethylaminopyridine in 3 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / V 70%; flow: 150 ml / min; UV detection: 254 nm) to obtain 43 mg N - [(1S) -1-cyclopropyl-2-hydroxyethyl] -6- [4- (difluoromethyl) phenyl ] -3-oxo-2 (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide.

Ή NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 0.25-0.32 (m, 1H), 0.32-0.39 (m, 1H), 0.40-0.50 (m, 2H), 1.031.13 ( m, 1H), 3.45 (tt, 1H), 3.58 (tq, 2H), 4.93 (t, 1H), 7.13 (t, 1H), 7.61-7.66 (m, 1H), 7.72 (d, 2H), 8.13 (d, 2H), 8.16-8.21 (m, 1H), 8.70 (dd, 1H), 8.72 (s, 1H), 8.93 (d, 1H), 9.53 (d, 1H).

Example 151 6- [4- (Difluoromethyl) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) 2,3-dihydropyridazin-4 -carboxamide

A solution of 65 mg of intermediate 6- [4- (difluoromethyl) phenyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxylic acid, 28 mg (2S) -2-amino-1 -propanol, 144 mg of HATU, 0.1 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, collector fractions Labomatic Labocol Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55% ; flow: 150 ml / min; UV detection: 254 nm) to obtain 14 mg of 6- [4- (difluoromethyl) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo 2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide.

Ή NMR (400 MHz, DMSO-d6) δ [ppm] = 1.17 (d, 3H), 3.41-3.49 (m, 2H), 3.99-4.09 (m, 1H), 4.94 (t, 1H), 7.13 (t, 1H), 7.61-7.66 (m, 1H), 7.72 (d, 2H), 8.13 (d, 2H), 8.15-8.19 (m, 1H), 8.68-8.72 (m, 2H), 8.92 ( d, 1H), 9.41 (d, 1H).

Example 152 N - [(2S) -1-Hydroxypropan-2-yl] -6- (4-methylphenyl) -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxamide

A solution of 17 mg of intermediate 6- (4-methylphenyl) -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxylic acid, 28 mg of (2S) -2-amino-1-propanol, 43 mg of HATU, 0.03 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 0.5 ml of DMF were stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gram-134 037978 laboratory pump Labomatic HD-3000 HPLC, collector of fractions Labomatic Labocol Vario-2000; column:

Chromatorex C-18 125x30 mm, eluent A: water + 0.2 vol.% Aqueous ammonia (32%), eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) to give 14 mg N - [(2S) -1-hydroxypropan-2-yl] -6- (4-methylphenyl) -3-oxo-2- (pyridin-3-yl) -2 , 3-dihydropyridazine 4-carboxamide.

¹ H NMR (400 MHz, DMSO-de) δ [ppm] = 1.16 (d, 3H), 2.37 (s, 3H), 3.40-3.49 (m, 2H), 3.99-4.08 (m, 1H) , 4.94 (t, 1H), 7.34 (d, 2H), 7.60-7.65 (m, 1H), 7.86 (d, 2H), 8.16 (ddd, 1H), 8.64 (s, 1H), 8.68 (dd, 1H ), 8.90 (d, 1H), 9.44 (d, 1H).

Example 153. N - [(2S) -1-Hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine- 4-carboxamide

A solution of 75 mg of intermediate 3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine-4-carboxylic acid, 30 mg (S) - (+) - 2-amino-1-propanol, 151 mg HATU, 0.14 ml ethyldiisopropylamine and 1 mg 4-dimethylaminopyridine in 2 ml DMF was stirred at RT for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Waters Autopurification MS SingleQuad; column: Waters XBrigde C18 5 μm 100x30 mm; eluent A: water + 0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml / min; temperature : 25 ° C; DAD scan: 210-400 nm) to obtain 54 mg of N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2 (pyridin-3-yl) -6- [ 4- (trifluoromethoxy) phenyl] -2,3-dihydropyridzine-4-carboxamide.

1HNMR (400 MHz, DMSO-d6) δ [ppm] = 1.16 (d, 3H), 3.42-3.50 (m, 2H), 3.99-4.09 (m, 1H), 4.95 (t, 1H), 7.51 (d, 2H), 7.63 (dd, 1H), 8.09-8.14 (m, 2H), 8.17 (ddd, 1H), 8.67-8.71 (m, 2H), 8.91 (d, 1H), 9.41 (d, 1H ).

Example 154 6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(trans) -4-hydroxytetrahydrofuran-3yl] -3-oxo-2,3-dihydropyridazine-4-carboxamide

Solution of 150 mg of intermediate 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxylic acid, 124 mg of trans-4-aminotetrahydro-3-furanol hydrochloride (1: 1), 330 mg HATU, 0.23 ml of ethyldiisopropylamine and 2.6 mg of 4-dimethylaminopyridine in 3 ml of DMF were stirred at room temperature for 48 h. Then water was added and the precipitate was subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / 70%; flow: 150 ml / min; UV detection: 254 nm) to give 55 mg of 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(trans) -4 -hydroxytetrahydrofuran-3-yl] -3-oxo-2,3-dihydropyridazine-4-carboxamide.

1H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.54 (dd, 1H), 3.65 (dd, 1H), 3.90 (dd, 1H), 3.98 (dd, 1H), 4.18 (dt, 1H), 4.25 (td, 1H), 5.49 (d, 1H), 7.58-7.61 (m, 2H), 8.01-8.06 (m, 2H), 8.22-8.27 (m, 1H), 8.65 (s, 1H) , 8.76 (d, 1H), 8.85 (s, 1H), 9.34 (d, 1H).

Example 155 6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(trans) -4-hydroxytetrahydrofuran-3yl] -3-oxo-2,3-dihydropyridazine-4-carboxamide , enantiomer 1

- 135 037978

HPLC separation 49 mg 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -X - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2,3-dihydropyridazine -4-carboxamide (example 154) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IB 5 μm 250x30 mm; eluent A: methyl tert-butyl ether + 0.1 vol% diethylamine (99%); eluent B: ethanol; isocratic mode: 90% A + 10% B; flow 40.0 ml / min; UV: 254 nm) yielded 14 mg 6 (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 1.

Chiral HPLC: R _t = 2.36 min (instrument: Agilent HPLC 1260; column: Chiralpak IB 3 μm 100x4.6 mm; eluent A: methyl tert-butyl ether + 0.1 vol% diethylamine (99%); eluent B: ethanol ; isocratic mode: 90% A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

[a] D ²⁰ = - 21.2 ° (c = 1.00, DMSO).

Example 156 6- (4-Chlorophenyl) -2- (5-fluoropyridin-3-yl) -X - [(trans) -4-hydroxytetrahydrofuran-3yl] -3-oxo-2,3-dihydropyridazine-4-carboxamide , enantiomer 2

HPLC separation 49 mg 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -X - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2,3-dihydropyridazine -4-carboxamide (example 154) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IB 5 μm 250x30 mm; eluent A: methyl tert-butyl ether + 0.1 vol% diethylamine (99%); eluent B: ethanol; isocratic mode: 90% A + 10% B; flow 40.0 ml / min; UV: 254 nm) yielded 11 mg 6 (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -X - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2,3-dihydropyridazine-4-carboxamide, enantiomer 2.

Chiral HPLC: R _t = 2.72 min (instrument: Agilent HPLC 1260; column: Chiralpak IB 3 μm 100x4.6 mm; eluent A: methyl tert-butyl ether + 0.1% v / v diethylamine (99%); eluent B: ethanol ; isocratic mode: 90% A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

[α] π ²⁰ = 27.2 ° (c = 1.00, DMSO).

Example 157. X - [(cis) -4-Hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine- 4-carboxamide

A solution of 200 mg of intermediate 3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylic acid, 148 mg of cis-4-aminotetrahydro- 3-furanol (1: 1), 403 mg HATU, 0.37 ml of ethyldiisopropylamine and 3 mg of 4-dimethylaminopyridine in 4 ml of DMF was stirred at RT for 14 h. The reaction mixture was then filtered and subjected to RP-HPLC (HPLC (Instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 12x30 mm, eluent A: 0.1 vol% formic acid

- 136 037978 in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to give 89 mg of X - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2 (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2 , 3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.45 (dd, 1H), 3.61 (dd, 1H), 3.93 (dd, 1H), 4.01 (dd, 1H), 4.244.31 (m, 1H), 4.31-4.40 (m, 1H), 5.69 (d, 1H), 7.48-7.54 (m, 2H), 7.64 (br dd, 1H), 8.09-8.14 (m, 2H), 8.17 ( br d, 1H), 8.71 (m, 2H), 8.93 (brs, 1H), 9.81 (d, 1H).

Example 158. X - [(cis) -4-Hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine- 4-carboxamide, enantiomer 1

HPLC separation 89 mg X - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4 (trifluoromethoxy) phenyl] -2,3-dihydropyridazine -4-carboxamide (example 157) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak ID 5 μm 250x30 mm; eluent A: tert-butyl methyl ether + 0.1 vol. % diethylamine (99%); eluent B: methanol; isocratic mode: 50% A + 50% B; flow 50.0 ml / min; UV: 254 nm) yielded 18 mg of X - [(cis) -4-hydroxytetrahydrofuran- 3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine-4-carboxamide, enantiomer 1.

Chiral HPLC: Rt = 1.73 min (instrument: Agilent HPLC 1260; column: Chiralpak ID 3 μm 100x4.6 mm; eluent A: tert-butyl methyl ether + 0.1 vol% diethylamine (99%); eluent B: methanol; isocratic mode : 90% A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

Example 159. X - [(cis) -4-Hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine- 4-carboxamide, enantiomer 2

HPLC separation 89 mg X - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4 (trifluoromethoxy) phenyl] -2,3-dihydropyridazine -4-carboxamide (example 157) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak ID 5 μm 250x30 mm; eluent A: tert-butyl methyl ether + 0.1 vol. % diethylamine (99%); eluent B: methanol; isocratic mode: 50% A + 50% B; flow 50.0 ml / min; UV: 254 nm) yielded 18 mg of X - [(cis) -4-hydroxytetrahydrofuran- 3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine-4-carboxamide, enantiomer 2.

Chiral HPLC: R _t = 2.58 min (instrument: Agilent HPLC 1260; column: Chiralpak ID 3 μm 100x4.6 mm; eluent A: tert-butyl methyl ether + 0.1% v / v diethylamine (99%); eluent B: methanol; isocratic mode: 90% A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

Example 160. X - [(trans) -4-Hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine- 4-carboxamide

- 137 037978

A solution of 150 mg of intermediate 3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxylic acid, 113 mg of trans-4-aminotetrahydro- 3furanol (1: 1), 302 mg HATU, 0.2 ml ethyldiisopropylamine and 2.5 mg 4-dimethylaminopyridine in 3 ml DMF was stirred at RT for 48 h. Then the reaction mixture was filtered and subjected to RPHPLC (HPLC (Instrument: Labomatic HD-3000 gradient pump HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / 70%; flow: 150 ml / min; UV detection: 254 nm) to give 56 mg of N - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2 (pyridin-3-yl) -6 - [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.54 (dd, 1H), 3.65 (dd, 1H), 3.89 (dd, 1H), 3.98 (dd, 1H), 4.18 (br s, 1H), 4.25 (td, 1H), 5.50 (d, 1H), 7.51 (d, 2H), 7.63 (dd, 1H), 8.08-8.14 (m, 2H), 8.15-8.19 (m, 1H) , 8.66 (s, 1H), 8.70 (br d, 1H), 8.92 (br s, 1H), 9.42 (d, 1H).

Example 161. N - [(trans) -4-Hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine- 4-carboxamide, enantiomer 1

HPLC separation 49 mg No. [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6 [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine- 4-carboxamide (example 160) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IB 5 μm 250x30 mm; eluent A: methyl tert-butyl ether + 0.1 vol % diethylamine (99%); eluent B: ethanol; isocratic mode: 90% A + 10% B; flow 40.0 ml / min; UV: 254 nm) yielded 20 mg N [(trans) -4-hydroxytetrahydrofuran- 3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3 dihydropyridazine-4-carboxamide, enantiomer 1.

Chiral HPLC: R _t = 2.37 min (instrument: Agilent HPLC 1260; column: Chiralpak IB 3 μm 100x4.6 mm; eluent A: tert-butyl methyl ether + 0.1% v / v diethylamine (99%); eluent B: ethanol; isocratic mode: 90% A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

[a] D ²⁰ = -30.1 ° (c = 1.00, MeOH).

Example 162 N - [(trans) -4-Hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine- 4-carboxamide, enantiomer 2

HPLC separation 49 mg N - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6 [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine -4-carboxamide (example 160) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IB 5 μm 250x30 mm; eluent A: methyl tert-butyl ether + 0.1 vol% diethylamine (99%); eluent B: ethanol; isocratic mode: 90% A + 10% B; flow 40.0 ml / min; UV: 254 nm) yielded 20 mg N [(trans) -4-hydroxytetrahydrofuran -3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3 dihydropyridazine-4-carboxamide, enantiomer 2.

Chiral HPLC: R _t = 2.94 min (instrument: Agilent HPLC 1260; column: Chiralpak IB 3 μm 100x4.6 mm; eluent A: tert-butyl methyl ether + 0.1% v / v diethylamine (99%); eluent B: ethanol; isocratic mode: 90% A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

[a] _D ²⁰ = 30.5 ° (c = 1.00, MeOH).

Example 163 6- (4-Chloro-2-fluorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazin-4 -carboxamide

- 138 037978

A solution of 75 mg of intermediate 6- (4-chloro-2-fluorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxylic acid, 32.5 mg (2S) -2-amino 1-propanol, 164 mg HATU, 0.15 ml of ethyldiisopropylamine and 1.5 mg of 4-dimethylaminopyridine in 3 ml of DMF was stirred at 40 ° C for 4 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC , fraction collector Labomatic Labocol Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to give 43 mg of 6- (4-chloro-2fluorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo -2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide.

Ή NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.15 (d, 3H), 3.44 (br d, 2H), 3.97-4.08 (m, 1H), 7.45 (dd, 1H), 7.63 (dd, 1H), 7.69 (dd, 1H), 7.86 (t, 1H), 8.16 (dt, 1H), 8.51 (d, 1H), 8.69 (dd, 1H), 8.91 (d, 1H), 9.39 (d, 1H).

Example carboxamide

164. 3- (4-Chlorophenyl) -N - [(1S, 2R) -2-hydroxycyclohexyl] -6-oxo-6H-1,4'-bipyridαzine-5-

Solution mg of intermediate 3- (4-chlorophenyl) -6-oxo-6H-1,4'-bipyridazine-5 carboxylic acid, 66 mg (1R, 2S) -2-aminocyclohexanol hydrochloride (1: 1), 185 mg HATU , 0.17 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector ; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to give 12 mg of 3- (4-chlorophenyl) -N - [(1S, 2R) -2-hydroxycyclohexyl] -6-oxo-6H-1,4'-bipyridαzine-5- carboxamide.

Ή NMR (400 MHz, DMSO-de) δ [ppm] = 1.34 (br d, 2H), 1.48-1.73 (m, 6H), 3.78 (br d, 1H), 3.87-3.95 (m, 1H ), 4.91 (d, 1H), 7.59-7.63 (m, 2H), 8.04-8.10 (m, 2H), 8.21 (dd, 1H), 8.67 (s, 1H), 9.45 (d, 1H), 9.48 ( dd, 1H), 9.74 (dd, 1H).

Example 165 6- [6- (Difluoromethyl) pyridin-3-yl] -N - [(1S, 2S) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -2,3- dihydropyridazine-4-carboxamide

A solution of 75 mg of intermediate 6- [6- (difluoromethyl) pyridin-3-yl] -3-oxo-2- (pyridin-3yl) -2,3-dihydropyridazine-4-carboxylic acid, 60 mg of (1S, 2S hydrochloride) ) -2-aminocyclopentanol (1: 1), 166 mg HATU, 0.15 ml ethyldiisopropylamine and 1 mg 4-dimethylaminopyridine in 2 ml DMF was stirred at RT for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45 % / V 55%; flow: 150 ml / min; UV detection: 254 nm)

- 139 037978 to obtain 54 mg of 6- [6- (difluoromethyl) pyridin-3-yl] -N - [(1S, 2S) -2-hydroxycyclopentyl] -3-oxo-2 (pyridin-3-yl) -2 , 3-dihydropyridazine-4-carboxamide.

1H NMR (400 MHz, DMSO-do) δ [ppm] = 1.39-1.56 (m, 2H), 1.58-1.67 (m, 1H), 1.67-1.76 (m, 1H), 1.771.87 (m , 1H), 2.03-2.15 (m, 1H), 3.94 (quin, 1H), 3.98-4.07 (m, 1H), 4.95 (d, 1H), 7.06 (t, 1H), 7.62-7.67 (m, 1H ), 7.84 (d, 1H), 8.19 (ddd, 1H), 8.58 (dd, 1H), 8.70 (dd, 1H), 8.76 (s, 1H), 8.94 (d, 1H), 9.24-9.29 (m, 2H).

Example 166. N - [(2S) -1-Hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [6- (trifluoromethyl) pyridin-3-yl] -2, 3-dihydropyridazine-4-carboxamide

A solution of N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-6- [6- (trifluoromethyl) pyridin-3-yl] -2,3-dihydropyridazine-4-carboxamide (48 mg, 140 μmol) and 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine (CAS No. [329214-79-1]; 2.0 eq. 57 mg, 279 μmol) in DMF (5 ml) in an argon atmosphere was treated with 2,2'bipyridine (CAS No. [366-18-7]; 2.5 equiv. 55 mg, 349 μmol), sodium bicarbonate (2.0 equiv. 30 mg, 279 μmol) and copper acetate (1.3 eq. 32 mg, 175 μmol) and stirred at room temperature for three days. The reaction mixture was diluted with water (2 ml), adjusted to pH 3 with 2M aqueous hydrochloric acid and subjected to preparative reverse phase HPLC followed by lyophilization to give the title compound (7 mg).

1H-NMR (400 MHz, DMSO-d6) δ [ppm] = 1.17 (d, 3H), 3.42-3.49 (m, 2H), 4.00-4.10 (m, 1H), 4.95 (br s, 1H ), 7.65 (dd, 1H), 8.05 (d, 1H), 8.20 (ddd, 1H), 8.67 (dd, 1H), 8.71 (dd, 1H), 8.81 (s, 1H), 8.95 (d, 1H) , 9.359.37 (m, 2H).

Example 167 3- (4-Chlorophenyl) -N - [(1S, 2R) -2-hydroxycyclopentyl] -6-oxo-6H-1,4'-bipyridazine-5carboxamide

A solution of 65 mg of intermediate 3- (4-chlorophenyl) -6-oxo-6H-1,4'-bipyridazine-5carboxylic acid, 54 mg of (1R, 2S) -2-aminocyclopentanol hydrochloride (1: 1), 150 mg of HATU , 0.14 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile;

gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to give 12 mg of 3 - (4-chlorophenyl) -Y - [(18,211) -2-hydroxycyclopentyl] -6-oxo-6H-1,4'-bipyridazine-5-carboxamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.47-1.66 (m, 3H), 1.70-1.89 (m, 2H), 1.94-2.04 (m, 1H), 4.004.12 ( m, 2H), 5.08 (d, 1H), 7.58-7.63 (m, 2H), 8.06-8.10 (m, 2H), 8.21 (dd, 1H), 8.68 (s, 1H), 9.48 (dd, 1H) , 9.53 (d, 1H), 9.74 (dd, 1H).

Example 168 6- (4-Chlorophenyl) -Y - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3yl) -2,3-dihydropyridazine-4-carboxamide

- 140 037978

A solution of 150 mg of intermediate 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxylic acid, 130 mg of trans-4-aminotetrahydro-3-furanol hydrochloride (1 : 1), 348 mg HATU, 0.24 ml of ethyldiisopropylamine and 2.8 mg of 4-dimethylaminopyridine in 3.5 ml of DMF were stirred at room temperature for 48 h. Then water was added and the precipitate was subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC, collector of fractions Labomatic Labocol Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55 %; flow: 150 ml / min; UV detection: 254 nm) to give 68 mg of 6- (4-chlorophenyl) -U - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2 ( pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-de) δ [ppm] = 3.54 (dd, 1H), 3.64 (dd, 1H), 3.89 (dd, 1H), 3.98 (dd, 1H), 4.17 (tt , 1H), 4.25 (tt, 1H), 5.49 (d, 1H), 7.56-7.61 (m, 2H), 7.61-7.65 (m, 1H), 7.99-8.03 (m, 2H), 8.16 (ddd, 1H ), 8.65 (s, 1H), 8.69 (dd, 1H), 8.91 (d, 1H), 9.42 (d, 1H).

Example 169 6- (4-Chlorophenyl) -U - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3yl) -2,3-dihydropyridazine-4-carboxamide, enantiomer one

HPLC separation 61 mg rac-6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -Y - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2,3 β-dihydropyridazine-4-carboxamide (example 168) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IB 5 μm 250x30 mm; eluent A: methyl tert-butyl ether + 0.1 vol% diethylamine (99%); eluent B: ethanol; isocratic mode: 90% A + 10% B; flow 50.0 ml / min; UV: 254 nm) yielded 19 mg 6 (4-chlorophenyl) - Y - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide, enantiomer 1.

Chiral HPLC: R _t = 2.36 min (instrument: Agilent HPLC 1260; column: Chiralpak IB 3 μm 100x4.6 mm; eluent A: methyl tert-butyl ether + 0.1 vol% diethylamine (99%); eluent B: ethanol ; isocratic mode: 90% A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

[a] _D ²⁰ = - 29.4 ° (c = 1.00, MeOH).

Example 170. 6- (4-Chlorophenyl) -Y - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3yl) -2,3-dihydropyridazine-4-carboxamide, enantiomer 2

HPLC separation 49 mg rac-6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -Y - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2,3 β-dihydropyridazine-4-carboxamide (example 168) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IB 5 μm 250x30 mm; eluent A: methyl tert-butyl ether + 0.1 vol% diethylamine (99%); eluent B: ethanol; isocratic mode: 90% A + 10% B; flow 50.0 ml / min; UV: 254 nm) yielded 20 mg 6 (4-chlorophenyl) - Y - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide, enantiomer 2.

Chiral HPLC: R _t = 2.72 min (instrument: Agilent HPLC 1260; column: Chiralpak IB 3 μm 100x4.6 mm; eluent A: methyl tert-butyl ether + 0.1% v / v diethylamine (99%); eluent B: ethanol ; isocratic mode: 90% A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

[α] π ²⁰ = 30.2 ° (c = 1.00, MeOH).

Example 171 6- (4-Chlorophenyl) -U - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) 2,3-dihydropyridazine-4-carboxamide

- 141 037978

Solution of 75 mg of intermediate 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxylic acid, 64 mg of cis-4-aminotetrahydro-3-furanol hydrochloride (1: 1), 174 mg HATU, 0.16 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF was stirred at room temperature for 48 h. Then water was added and the precipitate was subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 70% / B 30% ^ A 30% / 70%; flow: 150 ml / min; UV detection: 254 nm) to give 31 mg of 6- (4-chlorophenyl) -X - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo 2- (pyridin-3-yl) 2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 3.45 (t, 1H), 3.61 (dd, 1H), 3.93 (dd, 1H), 4.01 (dd, 1H), 4.244. 29 (m, 1H), 4.31-4.40 (m, 1H), 5.68 (d, 1H), 7.57-7.61 (m, 2H), 7.61-7.65 (m, 1H), 8.00-8.03 (m, 2H), 8.158.18 (m, 1H), 8.67-8.73 (m, 2H), 8.91 (d, 1H), 9.81 (d, 1H).

Example 172 6- (4-Chlorophenyl) -X - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) 2,3-dihydropyridazine-4-carboxamide, enantiomer 1

HPLC separation 25 mg rac-6- (4-chlorophenyl) -X - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2 (pyridin-3-yl) -2,3-dihydropyridazine- 4-carboxamide (example 171) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IA 5 μm 250x30 mm; eluent A: acetonitrile + 0.1 vol% diethylamine (99 %); eluent B: ethanol; isocratic mode: 90% A + 10% B; flow 50.0 ml / min; UV: 254 nm) yielded 5 mg 6- (4-chlorophenyl) -X - [(cis) - 4hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide, enantiomer 1.

Chiral HPLC: R _t = 2.46 min (instrument: Agilent HPLC 1260; column: Chiralpak IA 3 μm 100x4.6 mm; eluent A: acetonitrile + 0.1% v / v diethylamine (99%); eluent B: ethanol; isocratic mode: 90 % A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

Example 173 6- (4-Chlorophenyl) -X - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) 2,3-dihydropyridazine-4-carboxamide, enantiomer 2

HPLC separation 25 mg 6- (4-chlorophenyl) -X - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2 (pyridin-3-yl) -2,3-dihydropyridazin-4- carboxamide (example 171) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IA 5 μm 250x30 mm; eluent A: acetonitrile + 0.1 vol% diethylamine (99%) ; eluent B: ethanol; isocratic mode: 90% A + 10% B; flow 50.0 ml / min; UV: 254 nm) yielded 5 mg 6- (4-chlorophenyl) -X - [(cis) -4 hydroxytetrahydrofuran- 3-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide, enantiomer 2.

Chiral HPLC: R _t = 3.63 min (instrument: Agilent HPLC 1260; column: Chiralpak IA 3 μm 100x4.6

- 142,037978 mm; eluent A: acetonitrile + 0.1% by volume diethylamine (99%); eluent B: ethanol; isocratic mode:

90% A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

Example carboxamide

174. 3- (4-Chlorophenyl) -N - [(1S, 2S) -2-hydroxycyclopentyl] -6-oxo-6H-1,4'-bipyridazine-5-

Solution mg of intermediate 3- (4-chlorophenyl) -6-oxo-6H-1,4'-bipyridazine-5 carboxylic acid, 54 mg (1S, 2S) -2-aminocyclopentanol hydrochloride (1: 1), 150 mg HATU , 0.14 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF was stirred at room temperature for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector ; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) to give 14 mg of 3- (4-chlorophenyl) -N - [(1S, 2S) -2-hydroxycyclopentyl] -6-oxo-6H-1,4'-bipyridazine-5- carboxamide.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.41-1.57 (m, 2H), 1.60-1.76 (m, 2H), 1.79-1.88 (m, 1H), 2.072.14 ( m, 1H), 3.90-3.98 (m, 1H), 3.98-4.06 (m, 1H), 4.95 (d, 1H), 7.59-7.64 (m, 2H), 8.05-8.11 (m, 2H), 8.22 ( dd, 1H), 8.63 (s, 1H), 9.10 (d, 1H), 9.48 (dd, 1H), 9.75 (dd, 1H).

Example 175. 1,5-Anhydro-2 - ({[6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazin-4yl] carbonyl} amino) -2 , 4-dideoxy-D-erythropentitol

Solution of 75 mg of intermediate 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxylic acid, 73 mg of (3S, 4R) -3-aminooxane-4 hydrochloride α-ol (1: 1), 174 mg HATU, 0.16 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF was stirred at room temperature for 14 hours. Then water was added and the precipitate was subjected to RP-HPLC (instrument: Waters Autopurification MS SingleQuad ; column: Waters XBrigde C18 5 μm 100x30 mm; eluent A: water + 0.1 vol% formic acid (99%), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml / min; temperature: 25 ° C; DAD scan: 210-400 nm) to obtain 43 mg 1,5-anhydro-2 - ({[6 (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazin-4-yl] carbonyl} amino) -2,4-dideoxy-D-erythropentitol.

Ή NMR (400 MHz, DMSO-d6) δ [ppm] = 1.57-1.65 (m, 1H), 1.72-1.81 (m, 1H), 3.47-3.54 (m, 1H), 3.56 (d, 2H ), 3.64-3.73 (m, 1H), 3.88-3.95 (m, 1H), 4.02-4.12 (m, 1H), 5.23 (br s, 1H), 7.56-7.61 (m, 2H), 7.64 (dd, 1H), 7.98-8.03 (m, 2H), 8.14-8.19 (m, 1H), 8.68-8.71 (m, 2H), 8.91 (s, 1H), 9.66 (d, 1H).

[a] _D ²⁰ = 41.9 ° (c = 1.00, DMSO).

Example 176. 1,5-Anhydro-2,4-dideoxy-2 - [({3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine- 4-yl} carbonyl) amino] -D-eriopentitol

A solution of 75 mg of intermediate 3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl]

- 143 037978

2,3-dihydropyridazine-4-carboxylic acid, 64 mg (3S, 4R) -3-aminooxan-4-ol hydrochloride (1: 1), 151 mg HATU, 0.1 ml ethyldiisopropylamine and 2 mg 4-dimethylaminopyridine in 1.5 ml DMF stirred at RT for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (HPLC (Instrument: Waters Autopurification MS SingleQuad; column: Waters XBrigde C18 5 μm 100x30 mm; eluent A: water + 0.1 vol% formic acid (99 %), eluent B: acetonitrile; gradient: 0-5.5 min 5-100% B; flow 70 ml / min; temperature: 25 ° C; DAD-scan: 210-400 nm) to obtain 26 mg of 1,5-anhydro -2,4-dideoxy-2 - [({3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazin-4-yl} carbonyl) amino] - D-erythropentitol.

Ή NMR (400 MHz, DMSO-de) δ [ppm] = 1.57-1.66 (m, 1H), 1.77 (td, 1H), 3.47-3.53 (m, 1H), 3.56 (d, 2H), 3.65-3.73 (m, 1H), 3.92 (dq, 1H), 4.03-4.11 (m, 1H), 5.23 (d, 1H), 7.51 (d, 2H), 7.64 (dd, 1H), 8.08-8.13 ( m, 2H), 8.15-8.19 (m, 1H), 8.67-8.72 (m, 2H), 8.91 (s, 1H), 9.66 (d, 1H).

Example 177 3- (4-Chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -6-oxo-6H-1,4'-bipyridazine-5-carboxamide

ch ₃

A solution of 65 mg of intermediate 3- (4-chlorophenyl) -6-oxo-6H-1,4'-bipyridazine-5carboxylic acid, 30 mg of (2S) -2-aminopropan-1-ol, 150 mg of HATU, 0.14 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF was stirred at room temperature for 14 h and at 50 ° C for 1 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, fraction collector Labomatic Labocol Vario-2000; column:

Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) to give 4 mg of 3- (4-chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -6-oxo-6H-1,4'-bipyridazine-5- carboxamide.

1H NMR (400 MHz, DMSO-de) δ [ppm] = 1.17 (d, 3H), 3.42-3.50 (m, 2H), 3.99-4.09 (m, 1H), 4.96 (t, 1H), 7.58-7.64 (m, 2H), 8.07-8.11 (m, 2H), 8.22 (dd, 1H), 8.66 (s, 1H), 9.23 (d, 1H), 9.48 (dd, 1H), 9.75 (dd, 1H).

Example 178 3- (4-Chlorophenyl) -X- (2-hydroxy-2-methylpropyl) -6-oxo-6H-1,4'-bipyridazine-5-carboxamide

A solution of 80 mg of intermediate 3- (4-chlorophenyl) -6-oxo-6H-1,4'-bipyridazine-5carboxylic acid, 43 mg of 1-amino-2-methylpropan-2-ol, 185 mg of HATU, 0.17 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 2 ml of DMF was stirred at room temperature for 14 h and at 50 ° C for 1 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, fraction collector Labomatic Labocol Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) to obtain 28 mg of 3- (4-chlorophenyl) -X- (2-hydroxy-2-methylpropyl) -6-oxo-6H-1,4'-bipyridazine -5-carboxamide.

1H NMR (400 MHz, DMSO-de) δ [ppm] = 1.14 (s, 6H), 3.32 (s, 2H), 4.70 (s, 1H), 7.58-7.63 (m, 2H), 8.068. 11 (m, 2H), 8.22 (dd, 1H), 8.68 (s, 1H), 9.34 (t, 1H), 9.48 (dd, 1H), 9.75 (dd, 1H).

Example 179 6- (4-Cyanophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide

- 144 037978

A solution of 150 mg of intermediate 6- (4-cyanophenyl) -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxylic acid, 71 mg of (2S) -2-aminopropan-1-ol, 358 mg HATU, 0.33 ml of ethyldiisopropylamine and 3 mg of 4-dimethylaminopyridine in 6 ml of DMF were stirred at 40 ° C for 4 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic fraction collector Labocol Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow : 150 ml / min; UV detection: 254 nm) to obtain 15 mg of 6- (4-cyanophenyl) -N [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyrugin-3 -yl) -2,3-digugropyrugazine-4-carboxamide.

1H NMR (400 MHz, DMSO-d6) δ [ppm] = 1.16 (d, 3H), 3.41-3.50 (m, 2H), 3.99-4.09 (m, 1H), 4.94 (t, 1H), 7.61-7.66 (m, 1H), 7.97-8.01 (m, 2H), 8.16-8.22 (m, 3H), 8.70 (dd, 1H), 8.73 (s, 1H), 8.92 (d, 1H), 9.37 ( d, 1H).

Example 180 6- [6- (Difluoromethyl) pyrugin-3-yl] -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyrugin3-yl) -2,3 - dihydropyridazine-4-carboxamide

A solution of 85 mg of intermediate 6- [6- (difluoromethyl) pyridin-3-yl] -3-oxo-2- (pyridin-3yl) -2,3-dihydropyridazine-4-carboxylic acid, 37 mg (2S) -2 -aminopropan-1-ol, 188 mg HATU, 0.17 ml of ethyldiisopropylamine and 1.5 mg of 4-dimethylaminopyridine in 3 ml of DMF was stirred at RT for 14 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / 55%; flow: 150 ml / min; UV detection: 254 nm) to give 40 mg of 6- [6 (difluoromethyl) pyridin-3-yl] -N - [(2S) -1-hydroxypropan-2-yl ] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm] = 1.17 (d, 3H), 3.40-3.50 (m, 2H), 3.99-4.10 (m, 1H), 4.95 (t, 1H) , 7.06 (t, 1H), 7.61-7.66 (m, 1H), 7.84 (d, 1H), 8.16-8.21 (m, 1H), 8.58 (dd, 1H), 8.70 (dd, 1H), 8.78 (s , 1H), 8.94 (d, 1H), 9.27 (d, 1H), 9.37 (d, 1H).

Example 181 3- (4-Chlorophenyl) -X - [(cis) -4-hydroxytetrahydrofuran-3-yl] -6-oxo-6H-1,4'-bipyridazine-5-carboxamide

A solution of 125 mg of intermediate 3- (4-chlorophenyl) -6-oxo-6H-1,4'-bipyridazine-5carboxylic acid, 106 mg of cis-4-aminotetrahydro-3-furanol hydrochloride, 289 mg of HATU, 0.19 ml of ethyldiisopropylamine and 3 mg of 4-dimethylaminopyridine in 3 ml of DMF was stirred at room temperature for 14 h and at 50 ° C for 1 h. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic fraction collector Labocol Vario-2000; column: Chromatorex C-18 125x30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection - 145 037978 ration: 254 nm) to obtain 17 mg of 3- (4-chlorophenyl) -N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -6oxo-6H-1,4 '-bipyridazine-5-carboxamide.

1H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.47 (dd, 1H), 3.63 (dd, 1H), 3.94 (dd, 1H), 4.02 (dd, 1H), 4.29 (ddt, 1H), 4.32-4.41 (m, 1H), 5.73 (d, 1H), 7.58-7.63 (m, 2H), 8.05-8.10 (m, 2H), 8.22 (dd, 1H), 8.70 (s, 1H) , 9.48 (dd, 1H), 9.66 (d, 1H), 9.74 (dd, 1H).

Example 182 6- [6- (Difluoromethyl) pyridin-3-yl] -N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo2- (pyridin-3-yl) -2,3- dihydropyridazine-4-carboxamide

A solution of 125 mg of intermediate 6- [6- (difluoromethyl) pyridin-3-yl] -3-oxo-2- (pyridin3-yl) -2,3-dihydropyridazine-4-carboxylic acid, 101 mg of cis-4- hydrochloride aminotetrahydro-3furanol (1: 1), 276 mg HATU, 0.25 ml of ethyldiisopropylamine and 2 mg of 4-dimethylaminopyridine in 3 ml of DMF was stirred at RT for 14 h. Then the reaction mixture was filtered and subjected to RPHPLC (instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: water + 0.2 vol% aqueous ammonia (32%), eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) to give 86 mg of 6- [6- (difluoromethyl) pyridin-3-yl] -N - [(cis) -4- hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d6) δ [ppm] = 3.46 (t, 1H), 3.61 (dd, 1H), 3.93 (dd, 1H), 4.02 (dd, 1H), 4.254.31 (m, 1H), 4.32-4.40 (m, 1H), 5.70 (d, 1H), 7.06 (t, 1H), 7.62-7.67 (m, 1H), 7.84 (d, 1H), 8.19 (ddd, 1H ), 8.58 (dd, 1H), 8.71 (dd, 1H), 8.81 (s, 1H), 8.94 (d, 1H), 9.28 (d, 1H), 9.78 (d, 1H).

Example 183 6- [6- (Difluoromethyl) pyridin-3-yl] -N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo2- (pyridin-3-yl) -2,3- dihydropyridazine-4-carboxamide, enantiomer 1

HPLC separation 81 mg 6- [6- (difluoromethyl) pyridin-3-yl] -N - [(cis) -4-hydroxytetrahydrofuran-3yl] -3-oxo-2- (pyridin-3-yl) -2, 3-dihydropyridazine-4-carboxamide (example 182) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Amylose SA 5 μm 250x30 mm; eluent A: acetonitrile + 0.1 vol. % diethylamine (99%); eluent B: methanol + 0.1 vol% diethylamine (99%); isocratic mode: 50% A + 50% B; flow 50.0 ml / min; UV: 254 nm) yielded 35 mg 6 - [6- (difluoromethyl) pyridin-3-yl] -N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2 (pyridin-3-yl) -2,3-dihydropyridazin-4 -carboxamide, enantiomer 1.

Chiral HPLC: R _t = 1.33 min (instrument: Agilent HPLC 1260; column: Amylose SA 3 μm 100x4.6 mm; eluent A: acetonitrile + 0.1 vol% diethylamine (99%); eluent B: methanol; isocratic mode: 50 % A + 50% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

Example 184. 6- [6- (Difluoromethyl) pyridin-3-yl] -N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo2- (pyridin-3-yl) -2,3- dihydropyridazine-4-carboxamide, enantiomer 2

HPLC separation 81 mg 6- [6- (difluoromethyl) pyridin-3-yl] -N - [(cis) -4-hydroxytetrahydrofuran-3

- 146 037978 yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide (example 182) on a chiral column (instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241 , Labcol Vario 4000, column: Amylose SA 5 μm 250x30 mm; eluent A: acetonitrile + 0.1 vol% diethylamine (99%); eluent B: methanol + 0.1 vol% diethylamine (99%); isocratic mode: 50% A + 50% B; flow 50.0 ml / min; UV: 254 nm) yields 35 mg of 6- [6- (difluoromethyl) pyridin-3-yl] -X - [(cis) -4-hydroxytetrahydrofuran-3-yl ] -3-oxo-2 (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide, enantiomer 2.

Chiral HPLC: Rt = 1.74 min (instrument: Agilent HPLC 1260; column: Amylose SA 3 μm 100x4.6 mm; eluent A: acetonitrile + 0.1 vol% diethylamine (99%); eluent B: methanol; isocratic mode: 50% A + 50% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm).

Example 185 6- (4-Chlorophenyl) -3-oxo-2- (pyrimidin-5-yl) -X- (1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl) -2 , 3-dihydropyridazine-4-carboxamide

A solution of 130 mg of intermediate 6- (4-chlorophenyl) -3-oxo-2- (pyrimidin-5-yl) -2,3 dihydropyridazine-4-carboxylic acid, 153 mg of 3-amino-4,4,4-trifluoro hydrochloride -2-methylbutan-2ol, 301 mg of HATU, 0.21 ml of ethyldiisopropylamine and 3.6 mg of 4-dimethylaminopyridine in 3 ml of DMF was stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD- 3000 HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 vol% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) to obtain 20 mg of 6- (4-chlorophenyl) -3-oxo-2- (pyrimidin-5-yl) -X- (1.1, 1trifluoro-3-hydroxy-3-methylbutan-2-yl) -2,3-dihydropyridazine-4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.19 (s, 3H), 1.35 (s, 3H), 4.60-4.73 (m, 1H), 5.23 (s, 1H), 7.577.63 (m, 2H), 8.08 (d, 2H), 8.75 (s, 1H), 9.26 (s, 2H), 9.31 (s, 1H), 9.90 (d, 1H).

Example 186 6- (4-Chlorophenyl) -3-oxo-2- (pyrimidin-5-yl) -X- (1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl) -2 , 3-dihydropyridazine-4-carboxamide, enantiomer 1

HPLC separation 17 mg 6- (4-chlorophenyl) -3-oxo-2- (pyrimidin-5-yl) -X- (1,1,1-trifluoro-3-hydroxy3-methylbutan-2-yl) -2 , 3-dihydropyridazine-4-carboxamide (example 185) on a chiral column (instrument: Sepiatec: Prep SFC100; column: Chiralpak IB 5 μm 250x30 mm; eluent A: CO ₂ , eluent B: isopropanol; isocratic mode: 30% B; flow 100.0 ml / min; temperature: 40 ° C; BPR: 150 bar; MWD @ 254 nm) yielded 4 mg 6- (4-chlorophenyl) -3-oxo-2- (pyrimidin-5-yl) -X - (1,1,1-trifluoro-3-hydroxy3-methylbutan-2-yl) -2,3-dihydropyridazine-4-carboxamide, enantiomer 1.

Chiral HPLC: R _t = 1.62 min (instrument: Agilent HPLC 1260; column: Chiralpak IB 5 μm 100x4.6 mm; eluent A: CO ₂ ; eluent B: ethanol; isocratic mode: 80% A + 20% B; flow 4.0 ml / min; temperature: 37.5 ° C; BPR: 100 bar; MWD @ 254 nm).

Example 187 6- (4-Chlorophenyl) -3-oxo-2- (pyrimidin-5-yl) -X- (1,1,1-trifluoro-3-hydroxy-3methylbutan-2-yl) -2,3 -dihydropyridazine-4-carboxamide, enantiomer 2

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HPLC separation 17 mg 6- (4-chlorophenyl) -3-oxo-2- (pyrimidin-5-yl) -No (1,1,1-trifluoro-3-hydroxy3-methylbutan-2-yl) -2, 3-dihydropyridazine-4-carboxamide (example 185) on a chiral column (instrument: Sepiatec: Prep SFC100; column: Chiralpak IB 5 μm 250x30 mm; eluent A: CO ₂ , eluent B: isopropanol; isocratic mode: 30% B; flow 100.0 ml / min; temperature: 40 ° C; BPR: 150 bar; MWD @ 254 nm) yielded 4 mg 6- (4-chlorophenyl) -3-oxo-2- (pyrimidin-5-yl) -No ( 1,1,1-trifluoro-3-hydroxy3-methylbutan-2-yl) -2,3-dihydropyridazine-4-carboxamide, enantiomer 2.

Chiral HPLC: R _t = 3.68 min (instrument: Agilent HPLC 1260; column: Chiralpak IB 5 μm 100x4.6 mm; eluent A: CO ₂ ; eluent B: ethanol; isocratic mode: 80% A + 20% B; flow 4.0 ml / min; temperature: 37.5 ° C; BPR: 100 bar; MWD @ 254 nm).

Example 188 N - [(1-Hydroxycyclopropyl) methyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.28 mmol) was dissolved in anhydrous DMF (2.0 ml) ... 1 (aminomethyl) cyclopropanol (48.2 mg, 0.55 mmol), Y-ethyl-N-isopropylpropan-2-amine (217 μL, 1.25 mmol), and propane phosphonic anhydride (T3P, 243 μL, 50% in DMF, 416 μmol ). The mixture was stirred for 3 h at RT. The reaction mixture was concentrated in vacuo and purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 67 mg (51%) of the title compound.

Ή-NMR (400 MHz, DMSO-d6): δ [ppm] = 0.52-0.57 (m, 2H), 0.59-0.64 (m, 2H), 3.47 (d, 2H), 5.52 (s, 1H ), 7.65 (ddd, 1H), 7.89 (d, 2H), 8.17-8.24 (m, 3H), 8.71 (dd, 1H), 8.75 (s, 1H), 8.94 (dd, 1H), 9.58 (t, 1H).

Example 189 Ν - [(1-Γ hydroxycyclobutyl) methyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide

3-Oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxylic acid (100 mg, 0.28 mmol) was dissolved in anhydrous DMF (2.0 ml) ... 1 (aminomethyl) cyclobutanol (59.0 mg, 0.55 mmol), N-ethyl-N-isopropylpropan-2-amine (217 μL, 1.25 mmol) and propane phosphonic anhydride (T3P, 243 μL, 50% in DMF, 416 μmol ). The mixture was stirred for 3 h at RT. The reaction mixture was concentrated in vacuo and purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 81 mg (66%) of the title compound.

-NMR (400 MHz, DMSO-d ₆ ): δ [ppm] = 1.44-1.57 (m, 1H), 1.59-1.68 (m, 1H), 1.92-2.00 (m, 4H), 3.49 ( d, 2H), 5.41 (s, 1H), 7.64 (ddd, 1H), 7.89 (d, 2H), 8.16-8.24 (m, 3H), 8.70 (dd, 1H), 8.76 (s, 1H), 8.92 (d, 1H), 9.49 (t, 1H).

Example 190. (+) - 6- (4-Chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (1H-pyrazol-4-yl) -2.3

- 148 037978 dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -3-oxo-2- (1H-pyrazol-4-yl) -2,3-dihydropyridazine-4-carboxylic acid (75 mg) was dissolved in anhydrous DMF (2 ml). (2S) -2-aminopropan-1-ol (36 mg), Nethyl-N-isopropylpropan-2-amine (0.186 ml) and propane phosphonic anhydride (T3P, 207 μl, 50% in DMF) were added sequentially. The mixture was stirred for 1 h at RT.

The crude reaction mixture was concentrated in vacuo and purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 46 mg of the title compound 'I-NMR (400 MHz, DMSO-de): δ [ppm] = 1.19 (d, 3H), 3.42-3.52 (m, 2H), 4.00-4.11 (m, 1H) , 4.96 (br s, 1H), 7.57-7.62 (m, 2H), 8.07-8.13 (m, 2H), 8.14-8.55 (m, 2H), 8.59 (s, 1H), 9.52 (d, 1H), 13.24 (br s, 1H).

[a] D ²⁰ = + 18.4 ° (c = 1.00, methanol).

Example 191 6- [4- (Dimethylamino) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) 2,3-dihydropyridazin-4 -carboxamide

6- [4- (Dimethylamino) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2,3-dihydropyrigazine-4-carboxamide (14 mg) was dissolved in DMF (0.6 ml ). Pyridin-3-ylboronic acid (11 mg), 2,2'bipyridine (35 mg), sodium carbonate (5.6 mg) and anhydrous copper diacetate (20 mg) were added. The reaction mixture was stirred for 14 h at 80 ° C, cooled and subjected to RP-HPLC (instrument: Labomatic HD-3000 HPLC gradient pump, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1 % formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55%; flow: 150 ml / min; UV detection: 254 nm) to give 5 mg 6- [ 4 (dimethylamino) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine4-carboxamide.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] 1.16 (d, 3H), 2.98 (s, 6H), 3.39-3.49 (m, 2H), 3.97-4.09 (m, 1H) , 4.93 (t, 1H), 6.78-6.83 (m, 2H), 7.58-7.64 (m, 1H), 7.75-7.81 (m, 2H), 8.14 (ddd, 1H), 8.59 (s, 1H), 8.67 (dd, 1H), 8.89 (d, 1H), 9.49 (d, 1H).

Example 192 6- (4-Chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -2- (1-methyl-1H-pyrazol-3-yl) -3-oxo2,3- dihydropyridazine-4-carboxamide

A solution of 94 mg of intermediate 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-3-yl) -3-oxo2,3-dihydropyridazine-4-carboxylic acid, 43 mg (2S) -2- amino-1-propanol, 216 mg HATU, 0.20 ml ethyldiisopropylamine and 2 mg 4-dimethylaminopyridine in 4 ml DMF were stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile;

- 149 037978 gradient: A 70% / B 30% ^ A 30% / B 70%; flow: 150 ml / min; UV detection: 254 nm) to give mg 6- (4-chlorophenyl) -N - [(2S) -1-hydroxynropan-2-yl] -2- (1-methyl-1H-pyrazol-3-yl) - 3-oxo-2,3-dihydropyridazine-4-carbox amide.

1H NMR (400 MHz, DMSO-d ₆ ) δ [ppm] = 1.16 (d, 3H), 3.40-3.48 (m, 2H), 3.91 (s, 3H), 3.98-4.08 (m, 1H) , 4.93 (t, 1H), 6.57 (d, 1H), 7.55-7.60 (m, 2H), 7.86 (d, 1H), 7.92-7.98 (m, 2H), 8.62 (s, 1H), 9.41 (d , 1H).

Example 193 6- (4-Chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -2- (3-methyl-1H-pyrazol-5-yl) -3-oxo

2,3-dihydropyridazine-4-carboxamide

A solution of 75 mg of intermediate 6- (4-chlorophenyl) -2- (3-methyl-1H-pyrazol-5-yl) -3-oxo2,3-dihydropyridazine-4-carboxylic acid, 34 mg (2S) -2- amino-1-propanol, 172 mg HATU, 0.16 ml of ethyldiisopropylamine and 1 mg of 4-dimethylaminopyridine in 4 ml of DMF were stirred at room temperature for 14 hours. Then the reaction mixture was filtered and subjected to RP-HPLC (instrument: gradient pump Labomatic HD-3000 HPLC, Labomatic Labocol Vario-2000 fraction collector; column: Chromatorex C-18 125x30 mm, eluent A: 0.1% formic acid in water, eluent B: acetonitrile; gradient: A 85% / B 15% ^ A 45% / B 55 %; flow: 150 ml / min; UV detection: 254 nm) to give 44 mg of 6- (4-chlorophenyl) -N - [(2S) -1-hydroxynropan-2-yl] -2- (3-methyl -1H-pyrazol-5-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide.

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.16 (d, 3H), 2.31 (s, 3H), 3.40-3.49 (m, 2H), 3.97-4.08 (m, 1H ), 4.93 (t, 1H), 6.33 (d, 1H), 7.55-7.60 (m, 2H), 7.95 (d, 2H), 8.61 (s, 1H), 9.45 (d, 1H), 12.85 (s, 1H).

Example 194. (+) - 6- (4-Chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (1,2-thiazol-4-yl) -2 , 3-dihydropyridazine-4-carboxamide

6- (4-Chlorophenyl) -3-oxo-2- (1,2-thiazol-4-yl) -2,3-dihydropyridazine-4-carboxylic acid (70 mg) was dissolved in anhydrous DMF (2 ml). (2S) -2-aminopropan-1-ol (31.5 mg), N-ethyl-N-isonropropan-2-amine (0.164 ml) and propane phosphonic anhydride (T3P, 184 μl, 50% in DMF) were added sequentially. The mixture was stirred for 2 h at RT.

The crude reaction mixture was concentrated in vacuo and purified by RP-HPLC (column: X-Bridge C18 5 μm 100x30 mm, mobile phase: (water + 0.2 vol% aqueous ammonia (32%)) / acetonitrile, gradient) to give 47 mg of the title compound.

1H-NMR (400 MHz, DMSO-d6): δ [ppm] = 1.18 (d, 3H), 3.42-3.52 (m, 2H), 3.99-4.10 (m, 1H), 4.97 (t, 1H ), 7.58-7.63 (m, 2H), 8.07-8.12 (m, 2H), 8.64 (s, 1H), 9.13 (s, 1H), 9.39 (d, 1H), 9.61 (s, 1H).

[a] D ²⁰ = + 9.55 ° (c = 1.00, DMSO).

The following examples were prepared from the starting materials listed in the table using the procedure described in example 107 or 127. Enantiomers were separated from their racemate by chiral HPLC using the specified conditions relative to the column and solvent.

Table 2. Examples 195-345

Approx. Structure Name according to IUPAC Initial substances Analytical data 195 N — S V Ν / \ ΡιΎ ^{οη F} F N - [(l- hydroxycyclobutyl) methyl] -3 oxo-2- (1,2thiazol-4-yl) -6- [4 (trifluoromethyl) phenyl] -2,3- dihydropyridazine 3-oxo-2- (1,2thiazol-4-yl) -6- [4 (trifluoromethyl) phen yl] -2,3-dihydropyridazine-4-carboxylic acid, 1- (aminomethyl) cyclo C-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.44 - 1.57 (br, 1H), 1.59 - 1.70 (m, B), 1.94 2.02 (t, 4H), 3.51 (d , 2H), 5.45 (s, 1H), 7.90 (d, 2H), 8.29 (d, 2H), 8.73 (s, 1H), 9.14 (s, 1H),

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-4-carboxamide butanol 9.49 (t, 1H), 9.62 (s, 1H). 196 N - SV / ^Ν \ Ζ ° Π Γ ^ 3 ° θ ^Η 3 ___ Λ, Χ n χ = ^0Η ° ^СН з fH F N - [(2S) -3hydroxy-3methylbutan-2-yl] 3-oxo-2- (1,2thiazol-4-yl) -6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide , [a] _D ²⁰ = + 29.8 ° (c = 1.00, DMSO) 3-oxo-2- (1,2thiazol-4-yl) -6- [4 (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, (3S) -3amino-2methylbutan-2-ol ^ -NMR (400 MHz, DMSO-a ₆ ): δ [M.D.] = 1.12 (s, ZN), 1.15 (d, ZN), 1.18 (s, ZN), 3.89 3.97 (br, 1H), 4.69 (s, 1H), 7.90 (d, 2H), 8.29 (d, 2H), 8.71 (s, 1H), 9.13 (s, 1H), 9.49 (d, 1H), 9.62 (s, 1H). 197 ο \ = ο LL LL (+) - 3-oxo-2 (pyridin-3-yl) -N (l, l, l-τp and φτop-3hydroxy-3methylbutan-2-yl) 6- [4 (trifluoromethyl) phenyl] -2, 3-dihydropyridazine -4-carboxamide, enantiomer 2, [a] _D ²⁰ = + 35.8 ° (c = 1.00, methanol) 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethyl) phen yl] -2,3-dihydropyridazine 4-carboxylic acid, 3amino-4,4,4trifluoro-2methylbutan-2-ol hydrochloride, Chiralpak IB 5 μm 250x30 mm, eluent A: CO ₂ , eluent B: ethanol, isocratic mode: 22% B, 100 ml / min, 40 ° C, BPR: 150 bar, 254 nm A-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.20 (s, 3N), 1.35 (s, 3N), 4.67 (quin, 1H), 5.22 (s, br), 7.65 (aaa, br), 7.89 (a, 2H), 8.18 - 8.25 (br, 3H), 8.71 (aa, 1H), 8.80 (s, br), 8.94 (aa, 1H), s.oo (a, w ). Rt = 3.69 min, Chiralpak IB 5 μm 100x4.6 mm, eluent A: CO ₂ , eluent B: ethanol, isocratic mode: 22% B, 4 ml / min, 37.5 ° C, BPR: 100 bar, 254 nm 198 Τ ο $ ..... С ΤΖ LL Ο 2 = 0 ^{ζ =} \ ΛΑ δ 6- (4-chlorophenyl) 3-oxo-2- (1,2thiazol-4-yl) -M [(2R) -1,1,1 trifluoro-3hydroxypropan2-yl] -2,3 dihydropyridazine -4-carboxamide, [a ] _D ²⁰ = + 29.8 ° (c = 1.00, methanol) 6- (4-chlorophenyl) -3oxo-2- (1,2-thiazol4-yl) -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2R) 2-amino-3,3,3trifluoropropane-1ol A-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 3.67 - 3.75 (m, 1H), 3.85 (at, 1H), 4.81 - 4.93 (br, 1H), 5.47 (t, 1H), 7.58 7.63 (br, 2H), 8.09 - 8.13 (br, 2H), 8.70 (s, 1H), 9.13 (s, 1H), 9.63 (s, 1H), 9.97 (a, 1H). 199 Ν— S VF Ν. .0 F. I .F Ν ^χ V Al X Υΐ ^ ΊΓ ^0Η A Γ ο СГ 6- (4-chlorophenyl) 3-oxo-2- (1,2thiazol-4-yl) -M [(2S) -3,3,3trifluoro-2hydroxypropyl] 2,3dihydropyridazine -4-carboxamide, [a] _D ²⁰ = -6.9 ° (c = 1.00, methanol) 6- (4-chlorophenyl) -3oxo-2- (1,2-thiazol4-yl) -2,3- dihydropyridazine 4-carboxylic acid, (2S) -3amino-1,1,1 trifluoropropane-2ol A-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 3.49 (aaa, br), h.7b (aaa, br), 4.19 - 4.zo (br, 1H), 6.69 ( bra, 1H), 7.58 - 7.63 (br, 2H), 8.07 8.12 (br, 2H), 8.66 (s, 1H), 9.14 (s, 1H), 9.60 (s, 1H), 9.60 (t, 1H).

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200 N— S V N YY / \ ^ лЛх ^OH Ji л о cr 6- (4-chlorophenyl) - N - [(l- hydroxycyclobut yl) methyl] -3-oxo2- (1,2-thiazol-4yl) -2,3- dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -3oxo-2- (1,2-thiazol4-yl) -2,3- dihydropyridazine 4-carboxylic acid, 1 (aminomethyl) cyclobutanol N-NMR (400 MHz, DMSO-de): δ [ppm] = 1.44 - 1.57 (br, W), 1.59 - 1.69 (br, 1H), 1.93 2.01 (br, 4H), 3.50 (d, 2H), 5.44 (s, 1H), 7.58 7.62 (br, 2H), 8.07 - 8.11 (m, 2H), 8.66 (s, 1H), 9.13 (s, 1H), 9.50 (1, 1H), 9.60 ( s, 1H). 201 O QC ο = ς o ZI / ..... about τ 6- (4-chlorophenyl) Ν - [(2Κ) -1-φτορ-3hydroxypropan2-yl] -3-oxo-2 (1,2-thiazol-4-yl) 2,3-dihydropyridazine -4-carboxamide, [ a] _D ²⁰ = + 10.0 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -3oxo-2- (1,2-thiazol4-yl) -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2R) 2-amino-3 fluoropropane-1-o la N-NMR (400 MHz, DMSO-de): δ [ppm] = 3.50 - 3.58 (br, W), 3.59 - 3.66 (br, 1H), 4.19 4.33 (m, 1H), 4.49 - 4.57 ( br, 1H), 4.60 - 4.69 (br, 1H), 5.18 (1, 1H), 7.58 7.63 (br, 2H), 8.07 - 8.13 (m, 2H), 8.66 (s, 1H), 9.13 (s, 1H ), 9.58 (d, 1H), 9.61 (s, 1H). 202 CH ₃ Ν — Ν V Ν, 0 Ν X _n H ₃ C ch ₃ Ji X. Y iTj ^ fT i ⁴ ° ^H F ^ Jl ^ ^{0 CH} 3 fH F N - [(2R) -3hydroxy-3methylbutan-2-yl] 2- (1-methyl-1Hpyrazol-4-yl) -3oxo-6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide , [a] _D ²⁰ = -32.4 ° (c = 1.00, methanol) 2- (1-Methyl-1Hpyrazol-4-yl) -3oxo-6- [4 (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, (3R) 3-amino-2methylbutan-2-ol hydrochloride N-NMR (400 MHz, DMSO-de): δ [ppm] = 1.13 (s, 3N), 1.15 (d, 3N), 1.18 (s, 3N), 3.90 3.99 (br, 4H), 4.68 (s, 1H), 7.89 (d, 2H), 8.12 (s, 1H), 8.29 (d, 2H), 8.58 (s, 1H), 8.66 (s, 1H), 9.62 (d, 1H). 203 N — S VM, 0 X ^OH F ^ T F Ν - [(2Κ) -1-phτορ-3hydroxypropan2-yl] -3-oxo-2 (1,2-thiazol-4-yl) 6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4- carboxamide, [a] _D ²⁰ = + 6.2 ° (c = 1.00, DMSO) 3-oxo-2- (1,2thiazol-4-yl) -6- [4 (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2R) 2-amino-3 fluoropropane-1-o la N-NMR (400 MHz, DMSO-de): δ [ppm] = 3.51 - 3.58 (br, W), 3.60 - 3.67 (br, 1H), 4.20 4.34 (br, 1H), 4.49 - 4.57 ( br, 1H), 4.61 - 4.69 (br, 1H), 5.19 (1, 1H), 7.90 (d, 2H), 8.30 (d, 2H), 8.73 (s, 1H), 9.14 (s, 1H), 9.57 (d, 1H), 9.63 (s, 1H). 204 CH ₃ Ν — N VN, ° II YH? ^H F ^ U ° ”O ^F F N - [(lS, 2R) -2hydroxycyclopentyl] -2- (1-methyl1H-pyrazol-4-yl) 3-oxo-6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 11.0 ° (c = 1.00, methanol) 2- (1-Methyl-1H- pyrazol-4-yl) -3- oxo-6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (lR, 2S) -2- aminocyclopentane oh la H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.49 - 1.67 (br, 3H), 1.72 - 1.92 (br, 2H), 1.93 2.03 (br, 1H), 3.94 (s, 3H), 4.02 - 4.14 (br, 2H), 5.06 (d, 1H), 7.90 (d, 2H), 8.13 (s, 1H), 8.30 (d, 2H), 8.57 (s, 1H), 8.67 (s , 1H), 9.76 (d, 1H).

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205 N— S V ιι 1 ^{n 0 CH} 3 fH F N - [(2S) -1-hydroxypropan2-yl] -3-oxo-2 (1,2-thiazol-4-yl) - 6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine - 4-carboxamide, [a] _D ²⁰ = + 24.3 ° (c = 1.00, methanol) 3-oxo-2- (1,2thiazol-4-yl) -6- [4 (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, (2S) -2aminopropane-1 -o l ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.19 (d, 3H), 3.43 - 3.52 (m, 2H), 4.00 - 4.11 (br, 1H), 4.97 (t, 1H ), 7.90 (d, 2H), 8.29 (d, 2H), 8.70 (s, B), 9.14 (s, 1H), 9.38 (d, B), 9.62 (s, 1H). 206 SN ₃ Ν — Ν V Ν. / 0 7if _Η н ₃ с СН ₃ i ^0H F./L^ ⁰ CH ₃ ^F F N - [(2S) -3-hydroxy-3methylbutan-2-yl] - 2- (1-methyl-1Hpyrazol-4-yl) -3oxo-6- [4 (trifluoromethyl) phenyl] -2,3- dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 36.7 ° (c = 1.00, methanol) 2- (1-Methyl-1Hpyrazo l-4-yl) -3 oxo-6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, (3S) -3amino-2- methylbutan-2-ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.13 (s, ZN), 1.15 (d, ZN), 1.18 (s, ZN), 3.90 3.99 (br, 4H), 4.68 (s, 1H), 7.89 (d, 2H), 8.12 (s, 1H), 8.29 (d, 2H), 8.58 (s, 1H), 8.66 (s, 1H), 9.62 (d, 1H). 207 O $ ..... <] IZ O \ = O z = / N - [(1S) -1cyclopropyl-2hydroxyethyl] -3 oxo-2- (1,2thiazol-4-yl) -6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 23.3 ° (c = 1.00, DMSO) 3-oxo-2- (1,2thiazol-4-yl) -6- [4 (trifluoromethyl) phen yl] -2,3 dihydropyridazine 4-carboxylic acid, hydrochloride (2S) 2-amino-2- cyclopropylethanol a ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 0.27 - 0.52 (br, 4H), 1.06 - 1.16 (br, 1H), 3.42 3.50 (br, 1H), 3.54 - 3.65 ( br, 2H), 4.96 (t, 1H), 7.90 (d, 2H), 8.29 (d, 2H), 8.71 (s, 1H), 9.14 (s, 1H), 9.51 (d, 1H), 9.63 (s , 1H). 208 N - S V 'll Г z ^CH 3 JL l x Гд ^ тГ ^he F ^ T F M- (2-hydroxy-2methylpropyl) -3oxo-2- (1,2thiazol-4-yl) -6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide 3-oxo-2- (1,2thiazol-4-yl) -6- [4 (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, 1-amino2-methylpropane-2- ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.15 (s, 6H), 3.33 - 3.35 (m, 2H and water signal), 4.71 (s, 1H), 7.90 (d, 2H), 8.29 (d, 2H), 8.72 (s, B), 9.15 (s, 1H), 9.50 (t, 1H), 9.63 (s, 1H). 209 N - S φ, N .0 II 1 n ⁿ L s ⁿ s JL zj \ XX [ί ^ Ι ^ τΓ i ^0H _CI JV ^{0 CH} s 6- (4-chlorophenyl) N - [(2S) -3hydroxy-3methylbutan-2-yl] 3-oxo-2- (1,2thiazol-4-yl) -2,3 dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 38.4 ° (c = 1.00, methanol) 6- (4-chlorophenyl) -3oxo-2- (1,2-thiazol4-yl) -2,3- dihydropyridazine 4-carboxylic acid, (3S) -3amino-2methylbutan-2-ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.12 (s, ЗН), 1.15 (d, ЗН), 1.17 (s, ЗН), 3.89 3.97 (br, 1H), 4.68 (s, 1H), 7.58 - 7.62 (br, 2H), 8.07 - 8.11 (br, 2H), 8.64 (s, B), 9.12 (s, 1H), 9.50 (d, B), 9.61 (s, 1H ).

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210 CH ₃ Ν — Ν V Ν .0 y Ή n F N - [(lS, 2S) -2hydroxycyclopentyl] -2- (1-methyl1H-pyrazol-4-yl) 3-oxo-6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 48.9 ° (c = 1.00, methanol) 2- (1-Methyl-1Hpyrazo l-4-yl) -3 oxo-6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (lS, 2S) -2- aminocyclopentane o la ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.43 - 1.58 (br, 2H), 1.60 - 1.81 (br, 2H), 1.81 1.91 (br, 1H), 2.06 - 2.16 ( m, 1H), 3.93 (s, 3H), 3.94 - 4.07 (br, 2H), 4.97 (d, 1H), 7.89 (d, 2H), 8.13 (s, 1H), 8.30 (d, 2H), 8.57 (s, 1H), 8.63 (s, 1H), 9.42 (d, 1H). 211 ch ₃ Ν — Ν V Λ ^ 0 II 1 ^{Η 0} \ ^F F Ν - [(2Κ) -1-phτορ-3hydroxypropan2-yl] -2- (1 -methyl1H-pyrazol-4-yl) 3-oxo-6- [4 (trifluoromethyl) phenyl] -2,3dihydropyridazine -4 -carboxamide, [a] _D ²⁰ = + 18.0 ° (c = 1.00, methanol) 2- (1-Methyl-1Hpyrazol-4-yl) -3oxo-6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2R) 2-amino-3 fluoropropane-1-o la ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.52 - 3.59 (br, 1H), 3.60 - 3.67 (br, 1H), 3.94 (s, 3H), 4.20 - 4.34 (br , 1H), 4.49 - 4.58 (br, 1H), 4.61 - 4.70 (br, 1H), 5.19 (1, 1H), 7.90 (d, 2H), 8.14 (s, B), 8.31 (d, 2H), 8.59 (s, 1H), 8.68 (s, 1H), 9.71 (d, 1H). 212 Η Ν — Ν V .KL .0 II ^Η F 3-oxo-2- (1Hpyrazol-4-yl) -M [(2R) -1,1,1 trifluoro-3hydroxypropan2-yl] -6- [4 (trifluoromethyl) phenyl] -2,3-dihydropyridazine -4 -carboxamide, [a] _D ²⁰ = + 34.0 ° (c = 1.00, DMSO) 3-oxo-2- (1Hpyrazol-4-yl) -6- [4 (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2R) 2-amino-3,3,3trifluoropropane-1ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.69 - 3.77 (m, IH), 3.85 (dt, IH), 4.83 - 4.93 (m, IH), 5.48 (t, IH ), 7.90 (d, 2H), 8.09 - 8.36 (m, 3H), 8.37 - 8.66 (m, IH), 8.72 (s, IH), 10.09 (d, IH), 13.29 (br s, IH). 213 IZ U. Ο \ = Ο otf ΛΑ U. U. 3-oxo-2- (pyr idin-3-yl) -N (1,1,1-trifluoro-3hydroxy-3methylbutan-2-yl) - 6- [4- (trifluoromethyl) phenyl l] -2,3- dihydropyridazine -4-carboxamide 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, 3amino-4,4,4 trifluoro-2methylbutan-2-ol hydrochloride ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.20 (s, ЗН), 1.35 (s, ЗН), 4.67 (quin, IH), 5.22 (s, IH), 7.65 ( ddd, IH), 7.89 (d, 2H), 8.18 - 8.25 (m, 3H), 8.71 (dd, IH), 8.80 (s, IH), 8.94 (d, IH), 10.00 (d, IH). 214 F Ν — Ν V Ж ιι 1 ^Η r <V ^x ^ \ f ^N ^^ 0H ^F > ^^ ° F ^ F F 2- [1- (difluoromethyl) 1H-pyrazol-4-yl] - 3-okco-N - [(2R) 1,1,1-trifluoro-3 hydroxypropan2-yl] -6- [4- (trifluoromethyl) fe nor l] -2,3-dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 29.9 ° (c = 2- [1- (difluoromethyl) -Spirazo l-4-yl] -3 oxo-6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2R) 2-amino-3,3,3 trifluoropropane-1- ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.70 - 3.76 (m, IH), 3.83 - 3.89 (m, IH), 4.82 4.95 (m, IH), 5.48 (br s , IH), 7.91 (d, 2H), 7.93 (t, IH), 8.36 (d, 2H), 8.55 (s, IH), 8.75 (s, IH), 9.10 (s, IH), 9.99 (d, IH).

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1.00, DMSO) oh la 215 CH ₃ Ν — Ν V Ν .0 II Υ Η, ^0Η ° to / ^F F N-cis-4- hydroxytetrahydride rofuran-3-yl-2 (1-methyl-1Hpyrazol-4-yl) -3oxo-6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide 2- (1-Methyl-1Hpyrazo l-4-yl) -3 oxo-6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, cis-4aminotetrahydro furan-3-ol hydrochloride ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.48 (t, 1H), 3.65 (dd, 1H), 3.94 - 3.98 (m, 4H), 4.02 (1, 1H), 4.27 - 4.33 (t, 1H), 4.35 - 4.43 (t, 1H), 5.71 (d, 1H), 7.90 (d, 2H), 8.14 (s, 1H), 8.30 (d, 2H), 8.58 (s, 1H), 8.68 (s, 1H), 9.89 (d, 1H). 216 Η Ν — Ν V,, Ν. .0 F. 1 Τ Ν Υ ^ Ж Α Λ Α Λ ΥρΎ ^{ΟΗ F} F 3-oxo-2- (1Hpyrazol-4-yl) -M [(2S) -3,3,3trifluoro-2hydroxypropyl] 6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine -4-carboxamide , [a] _D ²⁰ = -2.0 ° (c = 1.00, DMSO) 3-oxo-2- (1Hpyrazol-4-yl) -6- [4 (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, (2S) -3amino-1,1,1 trifluoropropane-2ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.50 (ddd, 1H), 3.78 (ddd, 1H), 4.20 - 4.30 (t, 1H), 6.69 (brd, 1H), 7.90 (d, 2H), 8.10 - 8.60 (t, 4H), 8.68 (s, 1H), 9.73 (1, 1H), 13.27 (br s, 1H). 217 Τ cP ³ OQ Υα LL LL (+) - LH-cis-2hydroxycyclobut yl-3-oxo-2- (pyridin-3-yl) -6 [4- (trifluoromethyl) phenyl] -2,3- dihydropyridazine -4-carboxamide, enantiomer 1 , [a] _D ²⁰ = + 34.0 ° (c = 1.00, DMSO) 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethyl) phen yl] -2,3-dihydropyridazine 4-carboxylic acid, cis-2aminocyclobutanol hydrochloride Chiralpak IB 5 μm 250x30 mm, eluent А: СО ₂ , eluent B: isopropanol, isocratic mode: 24% B, 100 ml / min, 40 ° C, BPR: 150 bar, 220 nm ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.74 - 1.92 (t, 2H), 2.06 - 2.16 (t, 2H), 4.33 4.41 (t, 2H), 5.51 - 5.54 ( t, 1H), 7.65 (dd, 1H), 7.89 (d, 2H), 8.17 - 8.23 (t, 3H), 8.71 (dd, 1H), 8.73 (s, 1H), 8.93 (d, 1H), 9.88 (brd, 1H). R1 = 2.13 min, Chiralpak IB 5 μm 100x4.6 mm, eluent A: CO ₂ , eluent B: isopropanol, isocratic mode: 24% B, 4 ml / min, 37.5 ° C, BPR: 100 bar, 220 nm 218 ch ₃ Ν — Ν? , Ν. , ο Τι Υ Η, ^0Η ° Υ ^{2 F} F (+) - N-cis-4hydroxytetrahydride rofuran-3-yl-2 (1-methyl-1Hpyrazol-4-yl) -3oxo-6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide, enantiomer 2, [a] _D ²⁰ = + 27.8 ° (c = 1.00, methanol) 2- (1-Methyl-1Hpyrazo l-4-yl) -3 oxo-6- [4- (trifluoromethyl) phen yl] -2,3-dihydropyridazine 4-carboxylic acid, cis-4aminotetrahydrofuran-3-ol hydrochloride Chiralpak IC 5 μm 250x30 mm, eluent A: CO ₂ , eluent B: isopropanol, ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.48 (1, 1H), 3.65 (dd, 1H), 3.92 - 3.98 (m, 4H), 4.02 (1, 1H), 4.27 - 4.33 (t, 1H), 4.35 - 4.43 (t, 1H), 5.71 (d, 1H), 7.90 (d, 2H), 8.14 (s, 1H), 8.30 (d, 2H), 8.58 (s, 1H), 8.68 (s, 1H), 9.89 (d, 1H). R1 = 2.55 min, Chiralpak IC 5μm 100x4.6 mm, eluent А: СО ₂ , eluent

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isocratic mode: 36% B, 100 ml / min, 40 ° C, BPR: 150 bar, 254 nm B: isopropanol, isocratic mode: 36% B, 4 ml / min, 37.5 ° C, BPR: 100 bar, 254 nm 219 CH ₃ N — N V .0 F. Τ ^ ЛАлЛ ^{0H 0 F} F N - [(2S) -3,3 difluoro-2hydroxypropyl] 2- (1-methyl-1Hpyrazol-4-yl) -3oxo-6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide, [ a] _D ²⁰ = -0.1 ° + / 0.33 ° (c = 1.00, DMSO) 2- (1-Methyl-1Hpyrazol-4-yl) -3oxo-6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2S) 3-amino-1,1 difluoropropane-2ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.42 (ddd, IH), 3.68 (dt, IH), 3.81 - 3.96 (m, 4H), 5.96 (dt, IH), 6.03 (d, IH), 7.90 (d, 2H), 8.14 (s, IH), 8.30 (d, 2H), 8.56 (s, IH), 8.66 (s, IH), 9.65 (t, IH). 220 T O $ .. 5 IZ о \ = o TH j z - ς H> o 6- (4-chlorophenyl) 2- (5-fluoro-2-thienyl) -M - [(28) -1hydroxypropan2-yl] -3-oxo-2,3 dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 6.4 ° + / 0.33 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -2 (5-fluoro-2-thienyl) 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2S) 3-amino-1,1 difluoropropane-2ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.19 (d, 3H), 3.43 - 3.53 (m, 2H), 4.00 - 4.11 (m, IH), 4.98 (t, IH ), 6.84 (dd, IH), 7.56 (t, IH), 7.62 (d, 2H), 8.11 (d, 2H), 8.60 (s, IH), 9.22 (d, IH). 221 X o O ..... / O y — Z ^Z n> LL LL Ν - [(2Κ) -1-phτορ-3hydroxypropan2-yl] -3-oxo-2 (pyridin-3-yl) -6 [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide, [ a] _D ²⁰ = + 9.4 ° (c = 1.00, methanol) 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2R) 2-amino-3 fluoropropane-1-o la ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.49 - 3.56 (pt, IH), 3.58 - 3.64 (m, IH), 4.19 4.33 (m, IH), 4.47 - 4.55 ( m, IH), 4.59 - 4.67 (m, IH), 5.17 (t, IH), 7.64 (ddd, IH), 7.89 (d, 2H), 8.18 (ddd, IH), 8.22 (d, 2H), 8.71 (dd, IH), 8.76 (s, IH), 8.92 (d, IH), 9.57 (d, IH). 222 N - S VN, 0 II 1 H ^H ' ^C ₄ Z ^CH 3 Πη ^ τΓ ^he I about SG 6- (4-chlorophenyl) N- (2-hydroxy-2methylpropyl) -3oxo-2- (1,2thiazol-4-yl) -2,3 dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -3oxo-2- (1,2-thiazol4-yl) -2,3- dihydropyridazine 4-carboxylic acid, 1-amino2-methylpropane-2ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.15 (s, 6H), 3.31 - 3.35 (m, 2H and water signal), 4.70 (s, 1H), 7.58 - 7.63 ( m, 2H), 8.07 - 8.12 (br, 2H), 8.65 (s, B), 9.14 (s, 1H), 9.51 (t, 1H), 9.61 (s, 1H). 223 F N — N VF K, 0 RI T N Ж ^ aLaa Α | ΐί ^{he F} F 2- [1- (difluoromethyl) 1H-pyrazol-4-yl] 3-okco-N - [(2S) 3,3,3-trifluoro-2hydroxypropyl] 6- [4- (trifluoromethyl) fe 2- [1- (difluoromethyl) -Spyrazol-4-yl] -3 oxo-6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.51 (ddd, 1H), 3.78 (ddd, 1H), 4.20 - 4.32 (br, 1H), 6.70 (br s, 1H) , 7.91 (d, 2H), 7.94 (t, 1H), 8.35 (d, 2H), 8.54 (s, 1H), 8.71 (s, 1H), 9.04 (s, 1H),

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nor l] -2,3 dihydropyridazine -4-carboxamide, [a] _D ²⁰ = -0.7 ° + / 0.39 (c = 1.00, DMSO) acid, (2S) -3- amino-1,1,1- trifluoropropane-2ol 9.62 (t, 1H). 224 About n || | he F ^ AJ HN./ fH \ \ F M-cis-2hydroxycyclobut yl-3-oxo-2 (pyridin-3-yl) -6 [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, cis-2aminocyclobutano la hydrochloride P-NMR (400 MHz, DMSO-s1 ₆ ): δ [ppm] = 1.74 - 1.92 (pt, 2H), 2.06 - 2.16 (br, 2H), 4.33 4.41 (br, 2H), 5.53 (br s, 1H), 7.65 (dd, 1H), 7.89 (d, 2H), 8.16 - 8.23 (m, 3H), 8.71 (dd, 1H), 8.73 (s, 1H), 8.93 (d, 1H), 9.88 (brd, 1H). 225 SN ₃ V. О N ^ V? ⁿ 4ί L HU U., F X F 6- (4-chlorophenyl) 2- (5-methyl-3thienyl) -3-oxo-N [(2S) -3,3,3trifluoro-2hydroxypropyl] 2,3-dihydropyridazine -4-carboxamide, [a] _D ²⁰ = -4.4 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -2 (5-methyl-Zthienyl) -3-oxo-2,3-dihydropyridazine 4-carboxylic acid, (2S) -3amino-1,1,1trifluoropropane-2ol NMR (400 MHz, DMSOC ₆ ): δ [ppm] = 3.48 (ddd, 1Η), 3.76 (ddd, 1H), 4.18 - 4.29 (m, 1H), 6.68 (brd, 1H), 7.37 (t, 1H), 7.58 - 7.63 (m, 2H), 7.94 (d, 1H), 8.02 8.07 (m, 2H), 8.62 (s, 1H), 9.70 (t, 1H). 226 7 X ^ o N ^x V ίι T Γ ^ 3C ch ₃ xXJ n% X ^ X ——X he F CH ₃ N - [(2S) -3hydroxy-3methylbutan-2-yl] 3-oxo-2- (pyridin-3-yl) -6 [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine -4- carboxamide, [a] _D ²⁰ = + 32.6 ° (c = 1.00, DMSO) 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, (3S) -3amino-2methylbutan-2-ol P-NMR (400 MHz, DMSOC ₆ ): δ [ppm] = 1.10 (s, 3N), 1.13 (d, 3N), 1.16 (s, 3N), 3.88 3.96 (m, 1H), 4.66 ( s, 1H), 7.64 (ddd, 1H), 7.88 (d, 2H), 8.17 - 8.23 (m, 3H), 8.70 (dd, 1H), 8.74 (s, 1H), 8.92 (d, 1H), 9.50 (d, 1H). 227 tons of IZ £> O / = ° O. ___ (GUG \ 2 ^ / \ _ / ^Z - \ LA About 6- (4-chlorophenyl) N - [(18) -1-cyano-2hydroxyethyl] -2 (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3-dihydropyridazine -4-carboxamide, [a] _D ²⁰ = -19.8 ° (c ⁼ 1.00, DMSO) 6- (4-chlorophenyl) -2 (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2S) 2-amino-3 - hydroxypropannit ril NMR (400 MHz, DMSOC ₆ ): δ [ppm] = 3.73 - 3.80 (m, 1H), 3.81 - 3.87 (m, 1H), 3.94 (s, 3H), 5.05 - 5.11 (m, 1H), 5.85 (t, 1H), 7.58 - 7.63 (m, 2H), 8.10 - 8.15 (m, 3H), 8.57 (s, 1H), 8.62 (s, 1H), 10.08 (d, 1H).

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228 F Ν — Ν V, Ν. .0 'll Г Η ^Η Λ / ^СНз ; ^{0Η 0 СН} 3 ^F F 2- [1 (difluoromethyl) 1H-pyrazol-4-yl] - N - [(2S) -3hydroxy-3methylbutan-2-yl] 3-oxo-6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 20.3 ° (c = 1.00, DMSO) 2- [1- (difluoromethyl) -Spyrazol-4-yl] -3 oxo-6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, (3S) -3amino-2methylbutan-2-ol P-NMR (400 MHz, DMSO-de): δ [ppm] = 1.13 (s, 3N), 1.16 (d, 3N), 1.19 (s, 3N), 3.90 3.99 (m, 1H), 4.69 (s, 1H), 7.90 (d, 2H), 7.93 (1, 1H), 8.34 (d, 2H), 8.53 (s, 1H), 8.69 (s, 1H), 9.07 (s, 1H), 9.52 ( d, 1H). 229 9 / About ίι ίΓ g ^he HN.J ^F ^ 0 (+) - N-cis-4hydroxytetrahydride rofuran-3-yl-Zoxo-2- (pyridin3-yl) -6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide, enantiomer 1, [a ] _D ²⁰ = + 24.8 ° (c = 1.00, methanol) 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethyl) phen yl] -2,3-dihydropyridazine 4-carboxylic acid, cis-4aminotetrahydrofuran-3-ol hydrochloride Chiralpak ΙΑ 5 μm 250x30 mm , eluent A: CO ₂ , eluent B: methanol, isocratic mode: 27% B, 100 ml / min, 40 ° C, BPR: 150 bar, 254 nm NMR (400 MHz, DMSO-de): δ [ppm] = 3.46 (1, 1H), 3.61 (dd, 1H), 3.93 (dd, 1H), 4.01 (1, 1H), 4.25 - 4.31 (br, 1H), 4.32 - 4.40 (br, 1H), 5.70 (brd, 1H), 7.65 (ddd, 1H), 7.89 (d, 2H), 8.18 (ddd, 1H), 8.21 (d, 2H) , 8.71 (dd, 1H), 8.76 (s, 1H), 8.92 (d, 1H), 9.80 (d, 1H). R1 = 3.36 min, Chiralpak ΙΑ 5 μm 100x4.6 mm, eluent A: CO ₂ , eluent B: methanol, isocratic mode: 27% B, 4.0 ml / min, 37.5 ° C, BPR: 100 bar, 254 nm 230 G O Y — Z oiy LA (-) - N- (3,3-difluoro2hydroxypropyl) 3-oxo-2- (pyridin-3-yl) -6 [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine -4-carboxamide, enantiomer 2, [a] _D ²⁰ = -8.3 ° (c = 1.00, methanol) 3-oxo-2- (pyridin3-yl) -6- [4 (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, 3amino-1,1-difluoropropane-2ol hydrochloride Chiralpak IE 5 μm 250x30 mm, eluent A: 2-methoxy-2methylpropane and 0.1% by volume diethylamine (99%), eluent B: methanol, isocratic mode: 50% B, 40 ml / min, 254 nm NMR (400 MHz, DMSO-de): δ [ppm] = 3.40 (ddd, 1H), 3.66 (ddd, 1H), 3.79 - 3.91 (br, 1H), 5.94 (dt, 1H), 6.00 (d, 1H), 7.65 (ddd, 1H), 7.89 (d, 2H), 8.18 (ddd, 1H), 8.22 (d, 2H), 8.71 (dd, 1H), 8.74 (s, 1H), 8.93 (d, 1H), 9.53 (1, 1H). R1 = 1.76 min, Chiralpak IE Zμm 100x4.6 mm, eluent A: 2-methoxy-2methylpropane and 0.1 vol% diethylamine (99%), eluent B: methanol, isocratic mode: 50% B, 1.4 ml / min, 25 ° С, 254 nm

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231 SN ₃ N — NVZ ^N \ / 0 II 1 H, ^{OH 0} Ή ' ^F F (-) - N-cis-4hydroxytetrahydride rofuran-3-yl-2 (1-methyl-1Hpyrazol-4-yl) -3 oxo-6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide, enantiomer 1, [a] _D ²⁰ = -23.2 ° (c ⁼ 1.00, methanol) 2- (1-Methyl-1Hpyrazol-4-yl) -3oxo-6- [4- (trifluoromethyl) phen yl] -2,3-dihydropyridazine 4-carboxylic acid, cis-4aminotetrahydrofuran-3-ol hydrochloride Chiralpak IC 5 μm 250x30 mm, eluent A: CO ₂ , eluent B: isopropanol, isocratic mode: 36% B, 100 ml / min, 40 ° C, BPR: 150 bar, 254 nm ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.48 (t, 1H), 3.65 (dd, 1H), 3.92 - 3.98 (br, 4H), 4.02 (t, 1H), 4.27 - 4.33 (br, 1H), 4.35 - 4.43 (br, 1H), 5.71 (d, 1H), 7.90 (d, 2H), 8.14 (s, 1H), 8.30 (d, 2H), 8.58 (s, 1H), 8.68 (s, 1H), 9.89 (d, 1H). Rt = 1.67 min, Chiralpak IC 5μm 100x4.6 mm, eluent A: CO ₂ , eluent B: isopropanol, isocratic mode: 36% B, 4 ml / min, 37.5 ° C, BPR: 100 bar, 254 nm 232 About vJ / K? wx x ^Q zX O V °> —o? I Y. 6- (4-chlorophenyl) 2- (5-chloro-3thienyl) -3-oxo-K [(2S) -3,3,3trifluoro-2hydroxypropyl] 2,3-dihydropyridazine -4-carboxamide, [a] _D ²⁰ = -2.9 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -2 (5-chloro-3-thienyl) 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, (2S) -3amino-1,1,1 trifluoropropane-2ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.48 (ddd, 1H), 3.76 (ddd, 1H), 4.18 - 4.29 (br, 1H), 6.68 (d, 1H), 7.58 7.62 (br, 2H), 7.69 (d, 1H), 8.05 - 8.09 (br, 2H), 8.10 (d, 1H), 8.63 (s, 1H), 9.61 (t, 1H). 233 N — S VN, 0 NX _H H ₃ C CH ₃ ί ^ Ι ^ ίΓ ^0H F. JL 0 CH ₃ 4 ^^ F N - [(2S) -3-hydroxy-3methylbutan-2-yl] 3-oxo-2- (1,2thiazol-4-yl) -6- [6 (trifluoromethyl) pyridin-3-yl] -2, 3 dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 25.2 ° (c = 1.00, DMSO) 3-oxo-2- (1,2thiazol-4-yl) -6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine 4-carboxylic acid, hydrochloride (3S) 3-amino-2methylbutane-2 -ola ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.13 (s, ZN), 1.15 (d, ZN), 1.18 (s, ZN), 3.90 3.98 (br, 1H), 4.70 (s, 1H), 8.06 (d, 1H), 8.75 (dd, 1H), 8.79 (s, 1H), 9.18 (s, 1H), 9.44 (d, 1H), 9.46 (d, 1H), 9.66 ( s, 1H). 234 VM .ON ^x V P Ί ΎΉ ^CH 3 F Lx zk HN N pp he F CH ₃ N - [(2R) -3hydroxy-3methylbutan-2-yl] 3-oxo-2 (pyridin-3-yl) -6 [4- (trifluoromethyl) phenyl] -2,3-dihydropyr idazine -4-carboxamide , [a] _D ²⁰ = -29.2 ° (c = 1.00, methanol) 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, (3R) 3-amino-2methylbutan-2-ol hydrochloride ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.10 (s, ЗН), 1.13 (d, ЗН), 1.16 (s, ЗН), 3.88 3.96 (br, 1H), 4.66 (s, 1H), 7.64 (ddd, 1H), 7.88 (d, 2H), 8.17 - 8.23 (br, 3H), 8.70 (dd, 1H), 8.74 (s, 1H), 8.92 (d, 1H), 9.50 (d, 1H).

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235 N — 0 VF .N. .0 F. I _F N ^x Y II H 1 .____ Ji χ A OH JI o cr 6- (4-chlorophenyl) 2- (1,2-oxazol-4yl) -3-oxo-N [(2S) -3,3,3trifluoro-2hydroxypropyl] 2,3-dihydropyridazine -4-carboxamide, [a] _D ²⁰ = -7.5 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -2 (1,2-oxazol-4-yl) 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, (2S) -3amino-1,1,1 trifluoropropane-2ol H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 3.50 (ddd, 1H), 3.77 (ddd, 1H), 4.18 - 4.30 (m, 1H), 6.70 (d, 1H) , 7.59 7.64 (m, 2H), 8.16 - 8.20 (m, 2H), 8.66 (s, 1H), 9.46 (s, 1H), 9.53 (t, 1H), 9.78 (s, 1H). 236 F —F N — N? X .0 N ^x II n pAA ^ xx _OH cr ⁴ ^ ⁰ fH ^ f F 6- (4-chlorophenyl) 2- [1- (difluoromethyl) 1H-pyrazol-4-yl] 3-okco-N - [(2R) 1,1,1-trifluoro-3 hydroxypropan2-yl] -2,3 - dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 26.8 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -2 [1 - (difluoromethyl) 1H-pyrazol-4-yl] 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2R) 2-amino-3,3,3trifluoropropane-1ol H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 3.69 - 3.75 (m, 1H), 3.85 (at, 1H), 4.82 - 4.94 (m, 1H), 5.47 (t, 1H), 7.59 7.64 (m, 2H), 7.92 (t, 1H), 8.14 - 8.19 (m, 2H), 8.54 (s, 1H), 8.69 (s, 1H), 9.08 (s, 1H), 10.01 ( a, 1H). 237 o. y — z otT λα ϋ 6- (4-chlorophenyl) 3-oxo-2 (pyrimidin-5-yl) N - [(2S) -3,3,3 trifluoro-2hydroxypropyl] 2,3 dihydropyridazine -4-carboxamide, [a] _D ²⁰ = -15.8 ° (c = 1.00, methanol) 6- (4-chlorophenyl) -3oxo-2- (pyrimidin-5-yl) 2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2S) 3-amino-1,1,1trifluoropropane-2ol H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 3.49 (aaa, br), 3.75 (aaa, br), 4.is - 4.29 (m, 1H), 6.67 (a, 1H), 7.58 7.63 (m, 2H), 8.04-8.08 (m, 2H), 8.70 (s, 1H), 9.26 (s, 2H), 9.31 (s, 1H), 9.50 (t, 1H). 238 CH ₃ N — N φ N ^x rDm. X 'to F N - [(1S) -1cyclopropyl-2hydroxyethyl] -2 (1-methyl-1Hpyrazol-4-yl) -3oxo-6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 27.3 ° (c = 1.00, methanol) 2- (1-Methyl-1Hpyrazol-4-yl) -3oxo-6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2S) 2-amino-2- cyclopropylethanol a H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] 0.28 - 0.52 (m, 4Η), 1.07 - 1.17 (m, 1H), 3.43 3.49 (m, 1H), 3.55 - 3.65 ( m, 2H), 3.94 (s, 3H), 4.96 (t, 1H), 7.89 (a, 2H), 8.14 (a, iH), 8.30 (a, 2H), 8.60 (s, IH), 8.66 (s , IH), 9.65 (a, IH). 239 CH ₃ N — N? N. .0 NV x. A / X / ° ίΐ [ ^he f ^ JL ^ ^H O fH Τ / F '/ N - [(lR, 2S) -2-hydroxycyclopentyl] -2- (1-methyl1H-pyrazol-4-yl) 3-oxo-6- [4 (trifluoromethyl) phenyl] -2,3-dihydropyridazine - 4-carboxamide, [a] _D ²⁰ = -7.G (c = 1.00, methanol) 2- (1-Methyl-1H- pyrazol-4-yl) -3- oxo-6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (lS, 2R) -2- aminocyclopentane ola N-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.48 - 1.67 (m, 3H), 1.72 - 1.91 (m, 2H), 1.93 2.03 (m, IH), 3.94 (s , 3H), 4.02 - 4.14 (m, 2H), 5.06 (a, iH), 7.90 (a, 2H), 8.13 (a, IH), 8.30 (a, 2H), 8.57 (s, IH), 8.67 ( s, IH), 9.76 (a, IH).

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240 N — S V Ν, 0 'll Г Η ^Η Α / ^СНз А А ^he F. А о ^N F N- (2-hydroxy-2methylpropyl) -3oxo-2- (1,2thiazol-4-yl) -6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine -4-carboxamide 3-oxo-2- (1,2thiazol-4-yl) -6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine 4-carboxylic acid, 1-amino2-methylpropan-2ol Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 1.15 (s, 6H), 3.32 - 3.36 (m, 2H and water signal), 4.72 (s, 1H), 8.06 (d, 1H), 8.76 (dd, 1H), 8.79 (s, 1H), 9.19 (s, 1H), 9.45 (d, 1H), 9.47 (1, 1H), 9.66 (s, 1H). 241 kn Γ ^CH3 A ^ A A A | Ar m ^on f ^ A ^ A ° f ^ Xf ^F F ^F (-) - 3-oxo-2- (pyridin-3-yl) -N (l, l, l-τp and φτop-3hydroxy-3methylbutan-2-yl) 6- [4- (trifluoromethyl) phenyl] - 2,3-dihydropyridazine -4-carboxamide, enantiomer 1, [a] _D ²⁰ = -20.0 ° (c = 1.00, methanol) 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethyl) phen yl] -2,3-dihydropyridazine 4-carboxylic acid, 3amino-4,4,4trifluoro-2methylbutan-2-ol hydrochloride, Chiralpak IB 5 μm 250x30 mm, eluent A: CO ₂ , eluent B: ethanol, isocratic mode: 22% B, 100 ml / min, 40 ° C, BPR: 150 bar, 254 nm Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 1.20 (s, 3H), 1.35 (s, 3H), 4.67 (quin, 1H), 5.22 (s, 1H), 7.65 ( ddd, 1H), 7.89 (d, 2H), 8.18 - 8.25 (t, 3H), 8.71 (dd, 1H), 8.80 (s, 1H), 8.94 (dd, 1H), 10.00 (d, 1H). Rt = 1.10 min, Chiralpak IB 5 μm 100x4.6 mm, eluent A: CO ₂ , eluent B: ethanol, isocratic mode: 22% B, 4 ml / min, 37.5 ° C, BPR: 100 bar, 254 nm 242 ch ₃ V Ν .O N ^x A ^ C | D <D ^HN ^^^ oh ch ₃ 6- (4-chlorophenyl) - N - [(2S) -1-hydroxypropan2-yl] -2- (5-methyl-3-thienyl) -3-oxo 2,3-dihydropyridazine -4-carboxamide, [a ] _D ²⁰ = + 12.0 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -2 (5-methyl-Zthienyl) -3-oxo-2,3-dihydropyridazine 4-carboxylic acid, (2S) -2aminopropan-1-o l Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 1.17 (d, 3H), 3.41 - 3.51 (m, 2H), 3.99 - 4.09 (br, 1H), 4.95 (1, 1H ), 7.36 (1, 1H), 7.58 - 7.62 (m, 2H), 7.93 (d, 1H), 8.01 - 8.07 (m, 2H), 8.60 (s, 1H), 9.48 (d, 1H). 243 Cl V A .0 N ^x A ^ a / ^hn ^ cr OH CH ₃ 6- (4-chlorophenyl) 2- (5-chloro-3thienyl) -N - [(28) -1hydroxypropan2-yl] -3-oxo-2,3dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 13.6 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -2 (5-chloro-3-thienyl) 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, (2S) -2aminopropane-1 -o l Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 1.17 (d, 3H), 3.41 - 3.51 (m, 2H), 3.99 - 4.09 (br, 1H), 4.95 (1, 1H ), 7.58 7.62 (m, 2H), 7.68 (d, 1H), 8.04 - 8.08 (m, 2H), 8.09 (d, 1H), 8.60 (s, 1H), 9.40 (d, 1H). 244 H Ν — NVAN ^x A ^ II ^H F \ JA ^ 0 CH ₃ ^F F N - [(2S) -1-hydroxypropan2-yl] -3-oxo-2 (1H-pyrazol-4yl) -6- [4 (trifluoromethyl) phenyl] -2,3-dihydropyridazine -4-carboxamide, [ a] _D ²⁰ = + 11.8 ° (c = 1.00, DMSO) 3-oxo-2- (1Hpyrazol-4-yl) -6- [4 (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, (2S) -2aminopropane-1 -o l Ή-NMR (400 MHz, DMSO-de): δ [ppm] = 1.19 (d, 3H), 3.43 - 3.53 (m, 2H), 4.01 - 4.12 (br, 1H), 4.97 (1, 1H ), 7.89 (d, 2H), 8.27 - 8.47 (m, 4H), 8.66 (s, 1H), 9.51 (d, 1H), 13.26 (br s, 1H).

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245 Π Π 'Do I / V X Z — A О w TO Ο -π I Ν - [(28) -3-phτορ-2hydroxypropyl] 2- (1-methyl-1Hpyrazol-4-yl) -3oxo-6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide, [ a] _D ²⁰ = + 1.4 + / 0.47 ° (c = 1.00, DMSO) 2- (1-Methyl-1Hpyrazol-4-yl) -3oxo-6- [4 (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, (2S) 1-amino-3 fluoropropan-2-ol hydrochloride ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.34 - 3.41 (m, 1H), 3.56 (dt, 1H), 3.84 - 3.94 (t, 4H), 4.32 (ddd, 1H ), 4.44 (ddd, 1H), 5.50 (d, 1H), 7.89 (d, 2H), 8.14 (d, 1H), 8.30 (d, 2H), 8.56 (s, 1H), 8.65 (s, 1H) , 9.60 (1, 1H). 246 CH, 9 N ί | y% c _СНз AA HN. > C CT ⁴ ^ OH 6- (4-chlorophenyl) N- (2-hydroxy-2methylpropyl) -2 (5-methyl-Zthienyl) -3-oxo2,3 dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -2 (5-methyl-Zthienyl) -3-oxo-2,3-dihydropyridazine 4-carboxylic acid, 1-amino2-methylpropane-2ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.14 (s, 6H), 3.30 - 3.33 (t, 2H and water signal), 4.69 (s, 1H), 7.35 - 7.38 ( t, 1H), 7.57 - 7.62 (t, 2H), 7.93 (d, 1H), 8.02 8.06 (t, 2H), 8.61 (s, 1H), 9.60 (t, 1H). 247 9 o y — z <3 (+) - N- (3,3-difluoro2- hydroxypropyl) 3-oxo-2- (pyridin-3-yl) -6 [4- (trifluoromethyl) phenyl] -2,3- dihydropyridazine -4- carboxamide, enantiomer 1, [a] _D ²⁰ = + 15.8 ° (c = 1.00, methanol) 3-oxo-2- (pyridin3-yl) -6- [4 (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, 3amino-1,1-difluoropropane-2ol hydrochloride Chiralpak IE 5 μm 250x30 mm, eluent A: 2-methoxy-2methylpropane and 0.1% by volume diethylamine (99%), eluent B: methanol, isocratic mode: 50% B, 40 ml / min, 254 nm ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.40 (ddd, 1H), 3.66 (ddd, 1H), 3.79 - 3.91 (t, 1H), 5.94 (dt, 1H), 6.01 (br d, 1H), 7.65 (ddd, 1H), 7.89 (d, 2H), 8.18 (ddd, 1H), 8.22 (d, 2H), 8.71 (dd, 1H), 8.74 (s, 1H), 8.93 (d, 1H), 9.53 (t, 1H). Rt = 1.28 min, Chiralpak IE Zmkm 100x4.6 mm, eluent A: 2-methoxy-2methylpropane and 0.1 vol% diethylamine (99%), eluent B: methanol, isocratic mode: 50% B, 1.4 ml / min, 25 ° С, 254 nm 248 ch ₃ Ν — N? .N. .0 N ^x YA IL 11 / ° fl τ 'θ ^Η a Ha ^hn ^^ \ fH Τ / F YY N - [(lR, 2R) -2-hydroxycyclopentyl] -2- (1-methyl1H-pyrazol-4-yl) 3-oxo-6- [4 (trifluoromethyl) phenyl] -2,3-dihydropyridazine - 4-carboxamide, [a] _D ²⁰ = -32.7 ° (c = 1.00, methanol) 2- (1-Methyl-1H- pyrazol-4-yl) -3- oxo-6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (lR, 2R) -2- aminocyclopentane oh la ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.43 - 1.58 (m, 2H), 1.60 - 1.81 (t, 2H), 1.81 1.91 (t, 1H), 2.06 - 2.16 ( t, 1H), 3.91 - 3.99 (t, 4H), 4.00 - 4.07 (t, 1H), 4.97 (d, 1H), 7.89 (d, 2H), 8.13 (s, 1H), 8.30 (d, 2H) , 8.57 (s, 1H), 8.63 (s, 1H), 9.42 (d, 1H).

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249 9 .N. .O ί | 1 OH Y L HN. / Cl ^{/ X} ^ - \ (+) - 6- (4chlorophenyl) -Ncis-2hydroxycyclobut yl-3-oxo-2 (pyridin-3-yl) 2,3 dihydropyridazine -4-carboxamide, enantiomer 1, [a] _D ²⁰ = + 13.9 ° (c = 1.00, methanol) 6- (4-chlorophenyl) -3oxo-2- (pyridin-3 yl) -2,3-dihydropyridazine 4-carboxylic acid, cis-2aminocyclobutanol hydrochloride Chiralpak IB 5 μm 250x30 mm, eluent A: CO ₂ , eluent B: isopropanol, isocratic mode: 28% B, 100 ml / min, 40 ° C, BPR: 150 bar, 220 nm H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.74 - 1.92 (br, 2H), 2.06 - 2.16 (br, 2H), 4.33 4.41 (br, 2H), 5.52 (d, 1H), 7.57 - 7.61 (br, 2H), 7.64 (ddd, 1H), 7.99 8.03 (br, 2H), 8.17 (ddd, 1H), 8.67 (s, 1H), 8.70 (dd, 1H), 8.91 - 8.92 (br, 1H), 9.89 (brd, 1H). R1 = 2.98 min, Chiralpak IB 5 μm 100x4.6 mm, eluent A: CO ₂ , eluent B: ethanol, isocratic mode: 24% B, 4 ml / min, 37.5 ° C, BPR: 100 bar, 220 nm 250 Cl V .ON JL <ηρ Г ^ ЗС ch ₃ JI Ή HN. Y cr OH 6- (4-chlorophenyl) 2- (5-chloro-3thienyl) -N- (2hydroxy-2methylpropyl) -3oxo-2,3 dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -2 (5-chloro-3-thienyl) 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, 1-amino 2-methylpropane-2- ol NMR (400 MHz, DMSO-de): δ [ppm] = 1.14 (s, 6H), 3.30 - 3.33 (m, 2H and part of the water signal), 4.69 (s, 1H), 7.57 - 7.62 (br, 2H), 7.68 (d, 1H), 8.04 - 8.08 (br, 2H), 8.10 (d, 1H), 8.61 (s, 1H), 9.51 (1, 1H). 251 N — S V Λ ✓ О N F. JL X 0 CH ₃ F N - [(2S) -1-hydroxypropan2-yl] -3-oxo-2 (1,2-thiazol-4-yl) - 6- [6- (trifluoromethyl) pyridin-3-yl] -2.3 dihydropyridazine-4-carboxamide, [a] _D ²⁰ = + 9.3 ° (c = 1.00, DMSO) 3-oxo-2- (1,2thiazol-4-yl) -6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine 4-carboxylic acid, (2S) -2aminopropan-1 -o l NMR (400 MHz, DMSO-de): δ [ppm] = 1.19 (d, 3H), 3.43 - 3.53 (br, 2H), 4.01 - 4.11 (br, 1H), 4.98 (1, 1H ), 8.07 (d, 1H), 8.75 (dd, 1H), 8.78 (s, 1H), 9.19 (s, 1H), 9.35 (d, 1H), 9.44 (d, 1H), 9.66 (s, 1H) ... 252 9 H .0 ίΐ I ^0H f ^ J! ^ ^HN * ^ - X fX I / ^F ^ 0 (-) - N-cis-4hydroxytetrahydride rofuran-3-yl-Zoxo-2- (pyridin3-yl) -6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide, enantiomer 2, [a ] _D ²⁰ = -16.6 ° (c = 1.00, methanol) 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethyl) phen yl] -2,3-dihydropyridazine 4-carboxylic acid, cis-4aminotetrahydrofuran-3-ο la hydrochloride Chiralpak ΙΑ 5 μm 250x30 mm , eluent A: CO ₂ , eluent B: methanol, isocratic mode: 27% B, 100 ml / min, 40 ° C, BPR: 150 bar, 254 nm NMR (400 MHz, DMSO-de): δ [ppm] = 3.46 (1, 1H), 3.61 (dd, 1H), 3.93 (dd, 1H), 4.01 (1, 1H), 4.25 - 4.31 (br, 1H), 4.32 - 4.40 (br, 1H), 5.70 (brd, 1H), 7.64 (ddd, 1H), 7.89 (d, 2H), 8.18 (ddd, 1H), 8.21 (d, 2H) , 8.71 (dd, 1H), 8.76 (s, 1H), 8.92 (d, 1H), 9.80 (d, 1H). R1 = 5.97 min, Chiralpak ΙΑ 5 μm 100x4.6 mm, eluent A: CO ₂ , eluent B: methanol, isocratic mode:

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27% B, 4.0 ml / min, 37.5 ° C, BPR: 100 bar, 254 nm 253 Ν — 0? Ν ^χ II η C.AJ ^{0 cn} ' 6- (4-chlorophenyl) - N - [(2S) -1-hydroxypropan-2-yl] -2- (1,2-oxazol-4-yl) -3-oxo-2,3-dihydropyridazine -4- carboxamide, [a] _D ²⁰ = + 96.8 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -2 (1,2-oxazol-4-yl) 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, (2S) -2aminopropane-1 -o l ^ -NMR (400 MHz, DMSO-s1 ₆ ): δ [ppm] = 1.19 (d, 3H), 3.43 - 3.52 (br, 2H), 4.01 - 4.12 (br, 1H), 4.98 (br s , 1H), 7.58 - 7.63 (br, 2H), 8.15 8.20 (br, 2H), 8.63 (s, 1H), 9.31 (d, 1H), 9.45 (s, 1H), 9.80 (s, 1H). 254 τ Ο Ο o y — ζ ^ζ OQ ΛΑ Ο 6- (4-chlorophenyl) N - [(18) -1-cyano-2hydroxyethyl] -3 oxo-2- (pyridin3-yl) -2,3-dihydropyridazine -4-carboxamide, [a] _D ²⁰ = -16.5 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -3oxo-2- (pyridin-3 yl) -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2S) 2-amino-3 - hydroxypropannit rila ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.71 - 3.78 (br, 1H), 3.78 - 3.84 (br, 1H), 5.06 (dt, 1H), 5.82 (t, 1H ), 7.57 7.61 (br, 2H), 7.64 (ddd, 1H), 8.01 - 8.06 (m, 2H), 8.18 (ddd, 1H), 8.70 (dd, 1H), 8.72 (s, 1H), 8.92 (d , 1H), 9.96 (d, 1H). 255 4 ΙΖ Ο \ = Ο LL LL Ν - [(28) -3-φτορ-2hydroxypropyl] 3-oxo-2- (pyridin-3-yl) -6 [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine -4-carboxamide, [a] _D ²⁰ = -3.9 ° (c = 1.00, DMSO) 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, (2S) 1-amino-3 fluoropropan-2-ol hydrochloride ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.34 - 3.39 (t, 1H), 3.55 (dt, 1H), 3.82 - 3.95 (t, 1H), 4.30 (ddd, 1H ), 4.42 (ddd, 1H), 5.48 (d, 1H), 7.65 (ddd, 1H), 7.89 (d, 2H), 8.16 - 8.24 (t, 3H), 8.70 (dd, 1H), 8.73 (s, 1H), 8.93 (d, 1H), 9.48 (t, 1H). 256 Ο ^{Ο =} \ θ τι ΖΙ A Ο -π I 6- (4-chlorophenyl) 2- [1- (difluoromethyl) 1H-pyrazol-4-yl] 3-okco-N - [(2S) 3,3,3-trifluoro-2hydroxypropyl] 2,3-dihydropyridazine -4 -carboxamide, [a] _D ²⁰ = -2.5 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -2 [1 - (difluoromethyl) 1H-pyrazol-4-yl] 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, (2S) -3amino-1,1,1 trifluoropropane-2ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.50 (ddd, 1H), 3.77 (ddd, 1H), 4.19 - 4.31 (t, 1H), 6.70 (d, 1H), 7.58 7.64 (t, 2H), 7.94 (t, 1H), 8.12 - 8.17 (t, 2H), 8.53 (s, 1H), 8.64 (s, 1H), 9.02 (s, 1H), 9.63 (t, 1H) ). 257 Jo ΖΙ / ...... \ 0-0 2 * ο I N - [(2R) -1-hydroxy-3methoxypropane-2yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine - 4-carboxamide, [a] _D ²⁰ = -0.95 ° +/- 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, (2R) -2amino-3methoxypropan-1 ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.28 (s, 3H), 3.42 - 3.59 (t, 4H), 4.09 - 4.18 (t, 1H), 4.98 (t, 1H ), 7.64 (ddd, 1H), 7.89 (d, 2H), 8.18 (ddd, 1H), 8.21 (d, 2H), 8.71 (dd, 1H), 8.75 (s, 1H), 8.92 (d, 1H) , 9.50 (d, 1H).

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0.33 ° (c = 1.00, MeOH) 258 9 N ^, 0 i | | [OH Λ xJ hn. / cr \\ 6- (4-chlorophenyl) N-cis-2hydroxycyclobut yl-3-oxo-2 (pyridin-3-yl) 2,3 dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -3oxo-2- (pyridin-3 yl) -2,3- dihydropyridazine 4-carboxylic acid, cis-2aminocyclobutano la hydrochloride Ή-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.74 - 1.91 (m, 2H), 2.05 - 2.16 (m, 2H), 4.33 4.41 (m, 2H), 5.49 - 5.54 (m, 1H), 7.57 - 7.61 (m, 2H), 7.64 (ddd, 1H), 7.98 - 8.03 (m, 2H), 8.17 (ddd, 1H), 8.67 (s, 1H), 8.70 (dd, 1H ), 8.92 (d, 1H), 9.89 (brd, 1H). 259 N XX сЛ - πχ ^^ ΟΗ A 6- (4-chlorophenyl) - N - [(1S) -1-cyclopropyl-2hydroxyethyl] -2 (5-fluoropyridin3-yl) -3-oxo-2,3 dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 30.5 ° (c = 1.00, MeOH) 6- (4-chlorophenyl) -2 (5-fluoropyridin-3 yl) -3-oxo-2,3 dihydropyridazine 4-carboxylic acid, hydrochloride (2S) 2-amino-2- cyclopropylethanol a NMR (400 MHz, DMSO-de): δ [ppm] = 0.26 - 0.50 (m, 4H), 1.03 - 1.13 (m, 1H), 3.40 3.48 (m, 1H), 3.52 - 3.63 ( m, 2H), 4.94 (t, 1H), 7.57 - 7.61 (m, 2H), 8.01 - 8.05 (m, 2H), 8.26 (ddd, 1H), 8.68 (s, 1H), 8.77 (d, 1H) , 8.86 (t, 1H), 9.47 (d, 1H). 260 Η N — NVN .0 71 [ _H ^H 3C pH ₃ iTl ^ FT. he ^{0 SNz F} F N - [(2S) -3-hydroxy-3methylbutan-2-yl] 3-oxo-2- (1Hpyrazol-4-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine - 4-carboxamide, [a] _D ²⁰ = + 30.1 ° (c = 1.00, DMSO) 3-oxo-2- (1Hpyrazol-4-yl) -6- [4 (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, (3S) -3amino-2methylbutan-2-ol NMR (400 MHz, DMSO-de): δ [ppm] = 1.13 (s, 3N), 1.16 (d, 3N), 1.18 (s, 3N), 3.90 3.99 (m, 1H), 4.69 (s, 1H), 7.89 (d, 2H), 8.30 (d, 4H), 8.66 (s, 1H), 9.62 (d, 1H), 13.26 (br s, 1H). 261 F —F N — N V Λ N ^ X ^ II 1 ^H Γ <ν ^^ γ ^Ν ^^ θΗ ⁰ CH ₃ fX F 2- [1- (difluoromethyl) 1H-pyrazol-4-yl] - N - [(2S) -1-hydroxypropan2-yl] -3-oxo-6- [4 (trifluoromethyl) phenyl] -2.3 - dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 13.2 ° (c = 1.00, methanol) 2- [1- (difluoromethyl) -Spirazol-4-yl] -3oxo-6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, (2S) -2aminopropane-Gol NMR (400 MHz, DMSO-de): δ [ppm] = 1.19 (d, 3H), 3.43 - 3.53 (m, 2H), 4.01 - 4.12 (m, 1H), 4.98 (t, 1H ), 7.90 (d, 2H), 7.93 (t, 1H), 8.34 (d, 2H), 8.54 (s, 1H), 8.69 (s, 1H), 9.07 (s, 1H), 9.42 (d, 1H) ... 262 F N — N V N. .0 U [H ^N Л / ^СНз x \ JL л X ^{0H 0 F} F 2- [1- (difluoromethyl) 1H-pyrazol-4-yl] N- (2-hydroxy-2methylpropyl) -3oxo-6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide 2- [1- (difluoromethyl) -Spyrazol-4-yl] -3 oxo-6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, 1-amino2-methylpropane-2- NMR (400 MHz, DMSO-de): δ [ppm] = 1.16 (s, 6Η), 3.33 - 3.36 (m, 2H and water signal), 4.71 (s, 1H), 7.90 (d, 2H), 7.94 (t, B), 8.34 (d, 2H), 8.54 (s, 1H), 8.70 (s, 1H), 9.06 (s, 1H), 9.53 (1, 1H).

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ol 263 9 n N ^x X Л HN X 6- (4-chlorophenyl) N - [(l- hydroxycyclopropyl) methyl] -3oxo-2- (pyridin3-yl) -2,3- dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -3oxo-2- (pyridin-3 - yl) -2,3- dihydropyridazine 4-carboxylic acid, 1- (aminomethyl) cyclopropanol A-NMR (400 MHz, DMSO-de): δ [ppm] = 0.52 - 0.57 (m, 2H), 0.58 - 0.64 (m, 2H), 3.46 (d, 2H), 5.52 (s, Sh ), 7.59 (d, 2H), 7.64 (dd, 1H), 8.02 (d, 2H), 8.18 (ddd, 1H), 8.67 - 8.71 (m, 2H), 8.93 (d, 1H), 9.60 (t, 1H). 264 F —F Ν — N? N, 0 Η [Η ^Η Λ / ^СНз .____ JI xX n, U Ξ ^on A A about sn, ³ 6- (4-chlorophenyl) 2- [1 (difluoromethyl) 1H-pyrazol-4-yl] - N - [(2S) -3hydroxy-3methylbutan-2-yl] 3-oxo-2,3 dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 22.8 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -2 [1 - (difluoromethyl) 1H-pyrazol-4-yl] 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, (3S) -3amino-2- methylbutan-2-ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.13 (s, 3N), 1.15 (d, 3N), 1.18 (s, 3N), 3.89 3.98 (m, 1H), 4.68 (s, 1H), 7.57 - 7.64 (m, 2H), 7.92 (t, 1H), 8.11 - 8.17 (br, 2H), 8.52 (s, 1H), 8.63 (s, 1H), 9.05 (s, 1H ), 9.53 (d, 1H). 265 NX ^ N Ψ N ^x ^ aX ° Yl ^ Y 'ксн ₃ X / HN X ³ cr γ CH ₃ CH ₃ 6- (4-chlorophenyl) - N - [(2R) -3hydroxy-3methylbutan-2-yl] 3-oxo-2 (pyrimidin-5-yl) 2,3 dihydropyridazine -4-carboxamide, [a] _D ²⁰ = - 27.7 ° (c = 1.00, methanol) 6- (4-chlorophenyl) -3oxo-2- (pyrimidin-5-yl) 2,3- dihydropyridazine 4-carboxylic acid, (3R) 3-amino-2methylbutan-2-ol hydrochloride ^ -NMR (400 MHz, DMSOC): δ [ppm] = 1.10 (s, 3N), 1.13 (d, 3N), 1.16 (s, 3N), 3.87 3.96 (m, 1H), 4.67 (br s, 1H), 7.57 - 7.62 (m, 2H), 8.03 - 8.07 (m, 2H), 8.69 (s, 1H), 9.25 (s, 2H), 9.30 (S, 1H), 9.41 (d, 1H) ... 266 H Ν — NV 4 Y _H ^N L / ^SNz AA U ^on fAY ° ^F F M- (2-hydroxy-2methylpropyl) -3oxo-2- (1Hpyrazol-4-yl) -6 [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide 3-oxo-2- (1Hpyrazol-4-yl) -6- [4 (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, 1-amino2-methylpropane-2- ol A-NMR (400 MHz, DMSO-de): δ [ppm] = 1.15 (s, 6H), 3.33 - 3.36 (t, 2H and water signal), 4.71 (s, 1H), 7.89 (d, 2H), 8.11 - 8.61 (t, 4H), 8.67 (s, 1H), 9.64 (t, 1H), 13.27 (br s, 1H). 267 CH ₃ Ν — NV N. .0 N ^x ^ aAa ^ AA 0 X CH, cr ⁴ ^ ο ^ ο ^{ζ 3} Methyl N - {[6- (4chlorophenyl) -2- (1methyl-1Hpyrazol-4-yl) -3oxo-2,3dihydropyridazin-4-yl] carbonyl} D-serinate, [a] _D ²⁰ = -6.8 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -2 (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3- dihydropyridazine 4-carboxylic acid, methyl D-serinate hydrochloride A-NMR (400 MHz, DMSO-de): δ [ppm] = 3.70 (s, 3H), 3.75 (ddd, 1H), 3.88 - 3.95 (t, 4H), 4.65 - 4.70 (t, 1H ), 5.34 (t, 1H), 7.58 - 7.62 (t, 2H), 8.09 - 8.13 (t, 2H), 8.14 (d, 1H), 8.59 (s, 1H), 8.62 (s, Sh), 10.11 ( d, 1H).

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268 Π Π d ° ° I (-) - N-cis-2hydroxycyclobut yl-3-oxo-2- (pyridin-3-yl) -6 [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine -4-carboxamide, enantiomer 2 , [a] _D ²⁰ = -26.8 ° (c = 1.00, MeOH) 3-oxo-2- (pyridin3-yl) -6- [4 (trifluoromethyl) phen yl] -2,3-dihydropyridazine 4-carboxylic acid, cis-2aminocyclobutanol hydrochloride Chiralpak IB 5 μm 250x30 mm, eluent А: СО ₂ , eluent B: isopropanol, isocratic mode: 24% B, 100 ml / min, 40 ° C, BPR: 150 bar, 220 nm ^ -NMR (400 MHz, DMSO-s1 ₆ ): δ [ppm] = 1.74 - 1.93 (br, 2H), 2.06 - 2.17 (br, 2H), 4.33 4.41 (br, 2H), 5.53 (d , 1H), 7.65 (dd, 1H), 7.89 (d, 2H), 8.16 - 8.23 (br, 3H), 8.71 (brd, 1H), 8.73 (s, B), 8.93 (br s, 1H), 9.88 (brd, 1H). Rt = 3.98 min, Chiralpak IB 5 μm 100x4.6 mm, eluent A: CO ₂ , eluent B: isopropanol, isocratic mode: 24% B, 4 ml / min, 37.5 ° C, BPR: 100 bar, 220 nm 269 Ν — Ο V Ν, 0 4 Υ _Η ^Η Λ / ^СНз ΓΑι ^he J1 X о с 6- (4-chlorophenyl) N- (2-hydroxy-2methylpropyl) -2 (1,2-oxazol-4yl) -3-oxo-2,3 dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -2 (1,2-oxazol-4-yl) 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, 1-amino2-methylpropane-2ol ^X H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.15 (s, 6H), 3.33 - 3.35 (m, 2H and water signal), 4.71 (s, 1H), 7.58 - 7.63 (br, 2H), 8.15 - 8.21 (br, 2H), 8.65 (s, 1H), 9.41 9.46 (br, 2H), 9.80 (s, 1H). 270 ch ₃ Ν — Ν? Ν. .0 RN А ЛХаа Al ^ A ^he JL X ⁰ СГ 6- (4-chlorophenyl) Ν - [(28) -3-φτορ-2hydroxypropyl] 2- (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3-dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 1.7 ° + / 0.6 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -2 (1-methyl-1Hpyrazo l-4-yl) -3 oxo-2,3- dihydropyridazine 4-carboxylic acid, (2S) 1-amino-3 fluoropropan-2-ol hydrochloride ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.34 - 3.40 (br, 1H), 3.56 (dt, 1H), 3.84 - 3.96 (br, 4H), 4.27 - 4.36 (br , 1H), 4.39 - 4.48 (br, 1H), 5.50 (d, B), 7.58 - 7.62 (br, 2H), 8.08 - 8.13 (br, 3H), 8.55 (s, 1H), 8.58 (s, 1H ), 9.62 (t, 1H). 271 r o O ..... Li- O y - Z ^Z LL <> Q ΛΑ o 6- (4-chlorophenyl) 3-oxo-2 (pyrimidin-5-yl) N - [(2R) -1,1,1 trifluoro-3hydroxypropan2-yl] -2,3 dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 8.9 ° (c = 1.00, methanol) 6- (4-chlorophenyl) -3oxo-2- (pyrimidin-5-yl) 2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2R) 2-amino-3,3,3trifluoropropane-1ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.66 - 3.74 (m, 1H), 3.83 (dt, 1H), 4.80 - 4.93 (br, 1H), 5.45 (t, 1H ), 7.58 7.63 (br, 2H), 8.05 - 8.10 (m, 2H), 8.75 (s, 1H), 9.26 (s, 2H), 9.32 (s, 1H), 9.86 (d, 1H). 272 F —F Ν — Ν V Ж .0 ΑΑ II ^Η JI J о SN ₃ 6- (4-chlorophenyl) - 2- [1- (difluoromethyl) 1H-pyrazol-4-yl] N - [(2S) -1- hydroxypropan2-yl] -3-oxo-2,3 dihydropyridazine 6- (4-chlorophenyl) -2 [1 - (difluoromethyl) 1H-pyrazol-4-yl] 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, (2S) -2aminopropane-1 -o l ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.19 (d, 3H), 3.43 - 3.52 (br, 2H), 4.00 - 4.11 (br, 1H), 4.97 (t, 1H ), 7.59 7.63 (br, 2H), 7.92 (t, 1H), 8.12 - 8.17 (br, 2H), 8.52 (s, 1H), 8.62 (s, 1H),

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-4-carboxamide, [a] _D ²⁰ = + 13.7 ° (c = 1.00, methanol) 9.05 (s, 1H), 9.43 (d, 1H). 273 N ^ N V YY ^HN ^ 0H Δ 6- (4-chlorophenyl) - N - [(1S) -1-cyclopropyl-2hydroxyethyl] -3 oxo-2- (pyrimidin-5-yl) 2,3-dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 24.9 ° (c = 1.00, methanol) 6- (4-chlorophenyl) -3oxo-2- (pyrimidin-5-yl) 2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2S) 2-amino-2- cyclopropylethanol a H-NMR (400 MHz, DMSO-de): δ [ppm] = 0.26 - 0.51 (m, 4H), 1.04 - 1.14 (br, 1H), 3.40 3.48 (br, 1H), 3.52 - 3.64 ( m, 2H), 4.94 (1, 1H), 7.57 - 7.62 (m, 2H), 8.03 - 8.08 (br, 2H), 8.69 (s, 1H), 9.26 (s, 2H), 9.31 (s, 1H) , 9.43 (d, 1H). 274 τ τ ’o o \ °) ..... <\ o y — z o Υίγ St about Methyl N - {[6- (4chlorophenyl) -3oxo-2- (pyridin3-yl) -2,3 dihydropyridazin-4-yl] carbonyl} D-serinate 6- (4-chlorophenyl) -3oxo-2- (pyridin-3 yl) -2,3- dihydropyridazine 4-carboxylic acid, methyl D-serinate hydrochloride H-NMR (400 MHz, DMSO-de): δ [ppm] = 3.68 (s, 3H), 3.73 (ddd, 1H), 3.88 (ddd, 1H), 4.63 - 4.67 (br, 1H), 5.32 (1, 1H), 7.57 - 7.61 (br, 2H), 7.64 (ddd, 1H), 8.00 8.04 (m, 2H), 8.18 (ddd, 1H), 8.69 - 8.71 (br, 2H), 8.93 (d , 1H), 9.96 (d, 1H). 275 SN ₃ Ν — Ν V ΥΥ II ⁿ p / Mu \ / \ n ° F ^ F F 6- [ ₄ - (fluoromethyl) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) -3okco-N - [(2R) 1,1,1-trifluoro-3 hydroxypropan2-yl] -2 , 3- dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 38.6 ° (c = 1.00, DMSO) 6- [ ₄ - (fluoromethyl) phenyl] -2- (1methyl-1H-pyrazol4-yl) -3-oxo-2,3dihydropyridazine 4-carboxylic acid, (2R) -2amino-3,3,3trifluoropropane-1ol H-NMR (400 MHz, DMSO-de): δ [ppm] = 3.68 - 3.76 (m, 1H), 3.85 (br dd, IH), 3.94 (s, 3H), 4.81 - 4.93 (m, IH), 5.46 (s, 2H), 5.58 (s, IH), 7.59 (dd, 2H), 8.11-8.16 (m, 3H), 8.60 (s, IH), 8.67 (s, IH), 10.14 (d , IH). 276 H Ν-NV Η YH and Reese ^ [Γγ ^ ιΓ = ^0H _a YY of ch ₃ 6- (4-chlorophenyl) - N - [(2S) -3-hydroxy-3methylbutan-2-yl] 3-oxo-2- (1H-pyrazol-4-yl) -2,3 dihydropyridazine -4-carboxamide, [ a] _D ²⁰ = + 37.0 ° (c = 1.00, methanol) 6- (4-chlorophenyl) -3oxo-2- (1Hpyrazol-4-yl) -2,3 dihydropyridazine 4-carboxylic acid, (3S) -3amino-2methylbutan-2-ol N-NMR (400 MHz, DMSO-de): δ [ppm] = 1.12 (s, 3N), 1.15 (d, 3N), 1.18 (s, 3N), 3.90 3.98 (m, IH), 4.68 (s, IH), 7.57 - 7.62 (m, 2H), 8.08 - 8.12 (m, 2H), 8.19 (br s, IH), 8.50 (br s, IH), 8.60 (s, IH), 9.63 (d , IH), 13.24 (br s, IH). 277 nY ^ N V .0 N ^x YY jyX ^ ° ί | P ^ ³ JI HN. Do cr OH 6- (4-chlorophenyl) K- (2-hydroxy-2methylpropyl) -3oxo-2- (pyrimidin-5-yl) 2,3-dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 24.9 ° (c = 1.00, methanol) 6- (4-chlorophenyl) -3oxo-2- (pyrimidin-5-yl) - 2,3- dihydropyridazine 4-carboxylic acid, 1-amino2-methylpropane-2ol H-NMR (400 MHz, DMSO-de): δ [ppm] = 1.13 (s, 6H), 3.31 - 3.33 (m, 2H and water signal), 4.69 (s, 1H), 7.57 - 7.62 ( m, 2H), 8.03 - 8.08 (br, 2H), 8.69 (s, 1H), 9.26 (s, 2H), 9.30 (s, 1H), 9.41 (t, 1H).

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278 F —F N — N? N., 0 Η V and ^HsC \ / ^CHs .____ JI N. V [Γ) ^ ιΓ ^0H JI T о cr 6- (4-chlorophenyl) 2- [l- (difluoromethyl) 1H-pyrazol-4-yl] K- (2-hydroxy-2methylpropyl) -3oxo-2,3dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -2 [1 - (difluoromethyl) 1H-pyrazol-4-yl] 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, 1-amino2-methylpropane-2ol ^ -NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.15 (s, 6H), 3.33 - 3.34 (τη, 2H and water signal), 4.71 (s, 1H), 7.58 - 7.63 (br, 2H), 7.93 (t, 1H), 8.12 - 8.17 (br, 2H), 8.53 (S, 1H), 8.63 (s, 1H), 9.05 (S, 1H), 9.54 (t, 1H). 279 I о (£ О У-Q о у-z OQ λα ω 6- (4-chlorophenyl) N - [(2R) -1hydroxypropan2-yl] -3-oxo-2 (pyrimidin-5-yl) 2,3-dihydropyridazine -4-carboxamide, [a] _D ²⁰ = -0.8 ° + / 0.2 ° (c = 1.00, methanol) 6- (4-chlorophenyl) -3oxo-2- (pyrimidin-5-yl) 2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2R) 2-aminopropane-1 o la ^ -NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.17 (a, 3H), 3.40 - 3.51 (br, 2H), 3.99 - 4.10 (br, 1H), 4.96 (t, 1H), 7.58 7.62 (br, 2H), 8.03 - 8.08 (br, 2H), 8.68 (s, 1H), 9.25 (s, 2H), 9.28 - 9.32 (br, 2H). 280 VA To ο = ς about ZI A О -π I 6- [4- (Fluoromethyl) phenyl] -3oxo-2- (pyridin3-yl) -N - [(28) 3,3,3-trifluoro-2hydroxypropyl] 2,3-dihydropyridazine -4-carboxamide, [a] _D ²⁰ = -11.7 ° (c = 1.00, DMSO) 6- [4- (Fluoromethyl) phenyl] -3oxo-2- (pyridin-3 yl) -2,3- dihydropyridazine 4-carboxylic acid, (2S) -3amino-1,1,1 trifluoropropane-2ol ^ -NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 3.48 (aaa, br), h.7b (aaa, br), 4.18 - 4.28 (br, 1H), 5.51 (a, 2H), 6.68 (s, 1H), 7.57 (aa, 2H), 7.64 (aaa, br), 8.oz (a, 2H), 8.17 (aaa, br), 8.68 - 8.71 (br, 2H), 8.93 (a, 1H), 9.62 (t, 1H). 281 nine i | ] OH Λ T hn. / cr \\ (-) - 6- (4chlorophenyl) -Ncis-2hydroxycyclobut yl-3-oxo-2 (pyridin-3-yl) 2,3 dihydropyridazine -4-carboxamide, enantiomer 2, [a] _D ²⁰ = -18.3 ° (s = 1.00, methanol) 6- (4-chlorophenyl) -3oxo-2- (pyridin-3 yl) -2,3-dihydropyridazine 4-carboxylic acid, cis-2aminocyclobutanol hydrochloride Chiralpak IB 5 μm 250x30 mm, eluent A: CO ₂ , eluent B: isopropanol, isocratic mode: 28% B, 100 ml / min, 40 ° C, BPR: 150 bar, 220 nm ^ -NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.73 - 1.91 (m, 2H), 2.06 - 2.15 (t, 2H), 4.34 4.40 (t, 2H), 5.51 (br a, 1H), 7.57 - 7.61 (t, 2H), 7.64 (aaa, br), 7.99 8.03 (t, 2H), 8.17 (aaa, 1H), 8.67 (s, Sh), 8.70 (aa, br), 8.92 (a, b), 9.89 (bra, 1H). Rt = 5.00 min, Chiralpak IB 5 μm 100x4.6 mm, eluent A: CO ₂ , eluent B: ethanol, isocratic mode: 24% B, 4 ml / min, 37.5 ° C, BPR: 100 bar, 220 nm

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282 V N. .0 II n ° F ^ F 1 F F 6- [4- (Fluoromethyl) phenyl] -3oxo-2- (pyridine3-nn) -N - [(2R) 1,1,1-trifluoro-3 hydroxypropan2-yl] -2,3-dihydropyridazine -4-carboxamide , [a] _D ²⁰ = + 11.7 ° (c = 1.00, DMSO) 6- [4- (Fluoromethyl) phenyl] -3oxo-2- (pyridin-3 yl) -2,3- dihydropyridazine 4-carboxylic acid, hydrochloride (2R) 2-amino-3,3,3 trifluoropropane-1 o la ^ -NMR (400 MHz, DMSO-s1 ₆ ): δ [ppm] = 3.66 - 3.74 (m, 1H), 3.83 (dt, 1H), 4.80 - 4.92 (br, 1H), 5.41 - 5.46 ( m, 2H), 5.57 (s, 1H), 7.55 - 7.59 (br, 2H), 7.64 (dd, 1H), 8.05 (d, 2H), 8.18 (ddd, 1H), 8.71 (dd, 1H), 8.75 (s, 1H), 8.93 (d, 1H), 9.99 (d, 1H). 283 CH ₃ N — N V _r N. .0 F. I V Ar aIaI | Af ^OH JJ ^ J 0 F 6- [4- (Fluoromethyl) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) -3okco-N - [(2S) 3,3,3-trifluoro-2hydroxypropyl] 2,3-dihydropyr idazine -4-carboxamide, [a] _D ²⁰ = + 1.2 ° + / 0.5 ° (c = 1.00, DMSO) 6- [4- (Fluoromethyl) phenyl] -2- (1methyl-1H-pyrazol4-yl) -3-oxo-2,3dihydropyridazine 4-carboxylic acid, (2S) -3amino-1,1,1trifluoropropane-2ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 3.49 (ddd, 1H), 3.78 (dt, 1H), 3.94 (s, 3H), 4.19 4.30 (br, 1H), 5.52 (d, 2H), 6.69 (d, 1H), 7.59 (brd, 2H), 8.09 - 8.15 (br, 3H), 8.55 (s, 1H), 8.63 (s, 1H), 9.76 (brt, 1H). 284 CH ₃ N — NV, N \ / O II Τ n ⁿ L CH ₃ JL Λ AL [D] ^ TG Ξ ^OH A \ X O CH ₃ F 6- [4- (Fluoromethyl) phenyl] -K [(28) -3-hydroxy3-methylbutan-2yl] -2- (1-methyl1H-pyrazol-4-yl) 3-oxo-2,3 dihydropyridazine -4-carboxamide , [a] _D ²⁰ = + 26.1 ° (c = 1.00, DMSO) 6- [4- (Fluoromethyl) phenyl] -2- (1methyl-1H-pyrazol4-yl) -3-oxo-2,3dihydropyridazine 4-carboxylic acid, (3S) -3amino-2methylbutan-2-ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.13 (s, ZN), 1.15 (d, ZN), 1.18 (s, ZN), 3.89 3.99 (br, 4H), 4.67 (s, 1H), 5.52 (d, 2H), 7.58 (dd, 2H), 8.09 - 8.13 (br, 3H), 8.57 (s, 1H), 8.61 (s, 1H), 9.65 (d, 1H). 285 I about $ .. δ IZ oh vo aa 6- [4- (Fluoromethyl) phenyl] -K [(2S) -1-hydroxypropan2-yl] -3-oxo-2 (pyridin-3-yl) 2,3-dihydropyridazine -4-carboxamide, [a] _D ²⁰ = + 7.5 ° (c = 1.00, DMSO) 6- [4- (Fluoromethyl) phenyl] -3oxo-2- (pyridin-3 yl) -2,3- dihydropyridazine 4-carboxylic acid, (2S) -2aminopropane-1 -o l ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.17 (d, 3H), 3.40 - 3.49 (m, 2H), 3.99 - 4.09 (br, 1H), 4.94 (t, 1H ), 5.50 (d, 2H), 7.55 - 7.58 (m, 2H), 7.63 (ddd, 1H), 8.03 (d, 2H), 8.17 (ddd, 1H), 8.68 - 8.71 (br, 2H), 8.91 ( d, 1H), 9.42 (d, 1H). 286 m I X О X IZ about Vo Aa 6- [4- (Fluoromethyl) phenyl] -K (2-hydroxy-2methylpropyl) -3oxo-2- (pyridin3-yl) -2,3 dihydropyridazine -4-carboxamide 6- [4- (Fluoromethyl) phenyl] -3oxo-2- (pyridin-3 yl) -2,3- dihydropyridazine 4-carboxylic acid, 1-amino2-methylpropane-2ol ^ -NMR (400 MHz, DMSO-de): δ [ppm] = 1.13 (s, 6H), 3.31 - 3.33 (m, 2H and water signal), 4.67 (s, 1H), 5.50 (d, 2H), 7.55 - 7.58 (t, 2H), 7.64 (dd, 1H), 8.03 (d, 2H), 8.18 (ddd, 1H), 8.70 (s, 2H), 8.93 (d, 1H), 9.53 (t , 1H).

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287 CH ₃ N — NVX .0 II H AJ ^{0 CH} 3 F 6- [4- (Φτορmethyl) phenyl] -N [(2S) -1-hydroxypropan2-yl] -2- (1-methyl1H-pyrazol-4-yl) 3-oxo-2,3-dihydropyridazine -4-carboxamide , [a] _D ²⁰ = + 13.5 ° (c = 1.00, DMSO) 6- [4- (Fluoromethyl) phenyl] -2- (1methyl-1H-pyrazol4-yl) -3-oxo-2,3dihydropyridazine 4-carboxylic acid, (2S) -2aminopropane-Pol N-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.19 (d, 3H), 3.43 - 3.52 (brd, 2H), 3.93 (s, 3N), 4.00 - 4.12 (br, 1H), 4.96 (br s, 1H), 5.52 (d, 2H), 7.56 - 7.60 (br, 2H), 8.09 - 8.14 (br, 3H), 8.57 (s, 1H), 8.61 (s, 1H), 9.55 (d, 1H). 288 m T I about ° X Dool TZ o \ = o otf LA 6- [4- (Fluoromethyl) phenyl] -M [(28) -3-hydroxy3-methylbutane-2yl] -3-oxo-2 (pyridin-3-yl) 2,3-dihydropyridazine -4-carboxamide, [a ] _D ²⁰ = + 20.0 ° (c = 1.00, DMSO) 6- [4- (Fluoromethyl) phenyl] -3oxo-2- (pyridin-3 yl) -2,3- dihydropyridazine 4-carboxylic acid, (3S) -3amino-2methylbutan-2-ol Sh-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 1.Yu (s, zn), 1.13 (a, ZN), 1.15 (s, ZN), 3.87 3.96 (br, 1H ), 4.65 (s, 1H), 5.50 (a, 2H), 7.56 (aa, 2H), 7.63 (aaa, br), 8.00 - 8.04 (br, 2H), 8.18 (aaa, 1H), 8.68 - 8.71 ( t, 2H), 8.92 (a, 1H), 9.53 (a, 1H). 289 O CM $ ..... ξ iz o £> 0 / = ° O. _ __ / Xzfl ζχ \ _ / ^z - \ ΛΑ δ N - [(2R) -1-Amhho3-hydroxy-1oxopropan-2-yl] 6- (4-chlorophenyl) 2- (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3dihydropyridazine -4-carboxamide, [a] _D ²⁰ = -64.5 ° (c = 1.00, DMSO) 6- (4-chlorophenyl) -2 (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3- dihydropyridazine 4-carboxylic acid, D-serinamide hydrochloride H-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 3.64 - 3.71 (t, 1H), 3.76 - 3.82 (t, 1H), 3.94 (s, 3H), 4.45 - 4.50 ( t, 1H), 5.11 (t, 1H), 7.23 (s, 1H), 7.54 (s, 1H), 7.58 - 7.63 (t, 2H), 8.09 - 8.13 (t, 2H), 8.14 (a, 1H) , 8.59 (s, B), 8.60 (s, 1H), 9.96 (a, 1H). 290 Rj Z / V z — Z О ι— \ ° N-cis-4- hydroxytetrahydrothiophene-3-yl-Zoxo-2- (pyridin3-yl) -6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethyl) phen yl] -2,3- dihydropyridazine 4-carboxylic acid, cis-4aminotetrahydroti ofen-3-ol hydrochloride N-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 2.68 - 2.76 (t, 2H), 3.03 (aa, 1H), s.y (aa, br), 4.30 - 4.38 ( t, 2H), 5.67 (a, b), 7.64 (aa, br), 7.89 (a, 2H), 8.18 (aaa, 1H), 8.22 (a, 2H), 8.71 (aa, 1H), 8.76 (s , 1H), 8.92 (a, 1H), 9.76 (a, 1H). 291 9 V z \ / \ RX / ° fl ^ 1 1 * ^0H fH I / ^F (-) - N-cis-4hydroxytetrahydrothiophene-3-yl-Zoxo-2- (pyridin3-yl) -6- [4 (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide, enantiomer 2, [a ] _D ²⁰ = -2.0 ° (c = 1.00, DMSO) 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethyl) phen yl] -2,3-dihydropyridazine 4-carboxylic acid, cis-4aminotetrahydrotiofen-3-ol hydrochloride Chiralpak ID 5 μm 250x30 mm, eluent A: CO ₂ , eluent B: ethanol, N-NMR (400 MHz, DMSO-a ₆ ): δ [ppm] = 2.69 - 2.76 (t, 2H), 2.99 - 3.06 (t, 1H), s.p (aa, 1H), 4.30 - 4.39 (t, 2H), 5.67 (a, 1H), 7.64 (aaa, 1H), 7.89 (a, 2H), 8.18 (aaa, br), 8.22 (a, 2H), 8.71 (aa, 1H), 8.77 (s, 1H), 8.92 (aa, 1H), 9.76 (a, 1H). Rt = 5.53 min, Chiralpak ID 5 μm 100x4.6 mm,

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isocratic mode: 30% B, 100 ml / min, 40 ° C, BPR: 150 bar, 254 nm eluent A: CO ₂ , eluent B: ethanol, isocratic mode: 30% B, 4 ml / min, 37.5 ° C, BPR: 100 bar, 254 nm 292 9 u YH ^H 9 CH _ II J R> ^CH3 PXY ^^ ch ₃ ⁰ F ^ F F N- (2-hydroxy-2methylpropyl) -3oxo-2- (pyridin3-yl) -6- [4 (trifluoromethoxy) phenyl] -2,3 dihydropyridazine -4-carboxamide 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3- dihydropyridazine 4-carboxylic acid, 1-amino2-methylpropane-2ol Ή NMR (400 MHz, DMSO-Λ) δ ppm = 1.13 (S, 6 H), 3.30 - 3.33 (w, 2 H), 4.68 (s, 1 H), 7.51 (br d, 2 Η), 7.63 (dd, 1 Η), 8.12 (d, 2 Η ), 8.18 (br d, 1 H), 8.69 (m, 2 H), 8.90 - 8.95 (m, 1 H), 9.49 9.55 (m, 1 H). 293 I / + · duHC: .. Ά 3-oxo-2- (pir idin-3-yl) -Y- [(2R) -3,3,3- trifluoro-2hydroxypropyl] - 6- [4- (trifluoromethoxy) phenyl] -2,3- dihydropyridazine -4-carboxamide 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3- dihydropyridazine 4-carboxylic acid, (2R) -3amino-1,1,1 trifluoropropane-2ol Ή NMR (400 MHz, DMSO-Λ) δ ppm = 3.43 - 3.53 (m, 1 Η), 3.71 3.79 (m, 1 Η), 4.17 - 4.28 (m, 1 Η), 6.66 (d, 1 Η), 7.52 (d, 2 Η), 7.64 (dd, 1 Η), 8.13 (d, 2 Η), 8.17 (ddd, 1 Η), 8.67 - 8.73 (m, 2 Η), 8.93 (d, 1 Η), 9.60 (t, 1 Η). 294 Ψν A * χχ ο = ς o ζι o * / <? V- o About 1 t I О ω I N - [(2R) -3hydroxy-3methylbutan-2-yl] 3-oxo-2- (pyr idin-3-yl) -6 [4- (trifluoromethoxy) phenyl] -2,3 dihydropyridazine -4-carboxamide 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3- dihydropyridazine 4-carboxylic acid, (3R) -3amino-2methylbutan-2-ol Ή NMR (400 MHz, DMSO-Λ) δ ppm = 1.10 (s, 3 Η), 1.13 (d, 3 Η), 1.15 (s, 3 Η), 3.89 - 3.96 (dd, 1 Η), 4.66 (s, 1 Η), 7.51 (d, 2 Η) , 7.63 (dd, 1 Η), 8.09 - 8.14 (m, 2 Η), 8.15 - 8.20 (m, 1 Η), 8.67 - 8.72 (m, 2 Η), 8.92 (d, 1 Η), 9.52 (t , 1 Η). 295 r ll O ΙΖ o Vo otf ΛΑ ^- ° A N - [(2S) -3.3- difluoro-2hydroxypropyl] 3-oxo-2- (pyr idin-3-yl) -6 [4- (trifluoromethoxy) phenyl] -2,3- dihydropyridazine -4-carboxamide 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3- dihydropyridazine 4-carboxylic acid, (2S) -3amino-1,1 difluoropropan-2-ol Ή NMR (400 MHz, DMSO-Λ) δ ppm = 3.36 - 3.44 (m, 1 Η), 3.62 3.70 (m, 1 Η), 3.78 - 3.91 (m, 1 Η), 5.94 (dt, 1H), 6.00 (d, 1 H), 7.52 (d, 2 H), 7.64 (dd, 1 H), 8.09 8.15 (m, 2 H), 8.15 - 8.19 (m, 1 H), 8.67 - 8.71 (m, 2 H), 8.93 (d, 1 H), 9.55 ( t, 1 H). 296 r U- О ΙΖ о Vo otf ΛΑ ^- ° А Ν - [(28) -3-φτορ-2hydroxypropyl] - 3-oxo-2- (pyr idin-3-yl) -6 [4- (trifluoromethoxy) phenyl] -2,3 dihydropyridazine -4-carboxamide 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3- dihydropyridazine 4-carboxylic acid, (2S) -1 amino-3fluoropropan-2-ol Ή NMR (400 MHz, DMSO-Λ) δ ppm = 3.30 - 3.40 (m, 1H and water signal), 3.50 - 3.59 (m, 1 Η), 3.82 - 3.94 (m, 1 Η), 4.26 - 4.46 (m, 2 Η), 5.48 (brd, 1 Η) , 7.51 (d, 2 Η), 7.63 (dd, 1 Η), 8.09 8.14 (m, 2 Η), 8.15 - 8.19 (m, 1 Η), 8.65 - 8.72 (m, 2 Η), 8.93 (br s , 1 Η),

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9.50 (t, 1 H). 297 ¢ - II Υ Η? ^Η Hl пт> f JI xJ O CH ₃ F 6- (4-chlorophenyl) 3-oxo-2- (pyr idin-3-yl) -N (4,4,4-τp and φτop-3hydroxybutane-2yl) -2,3- dihydropyridazine-4-carboxamide, isomer 1 6- (4-chlorophenyl) -3oxo-2- (pyridin-3 - yl) -N- (4,4,4trifluoro-3hydroxybutane-2yl) -2,3- dihydropyridazine 4-carboxamide Analytical chiral HPLC: Rt = 1.62 min Instrument: Agilent HPLC 1260; column: YMC Amylose SA 3 μm 100x4.6 mm; eluent: tert-butyl methyl ether + 0.1% by volume diethylamine (99%) / ethanol 90:10, flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm. 298 <e ^ hL. О II YH? ^H ^^^ A ^ A ^ x ^ A ^ F C | AJ ° ^CH 3 ^FF 6- (4-chlorophenyl) 3-oxo-2- (pyr idin-3-yl) -N (4,4,4-τp and φτop-3hydroxybutane-2yl) -2,3- dihydropyridazine-4-carboxamide, isomer 2 6- (4-chlorophenyl) -3oxo-2- (pyridin-3 - yl) -N- (4,4,4trifluoro-3hydroxybutane-2yl) -2,3- dihydropyridazine 4-carboxamide Analytical chiral HPLC: Rt = 2.31 min Instrument: Agilent HPLC 1260; column: YMC Amylose SA 3 μm 100x4.6 mm; eluent: tert-butyl methyl ether + 0.1% by volume diethylamine (99%) / ethanol 90:10, flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm. 299 ¢ - .O II YH? ^H ^^ _? ^ A ^ A ^ f < _x A _s T _C , AJ ° ^CH 3 ^FF 6- (4-chlorophenyl) 3-oxo-2- (pyr idin-3-yl) -N (4,4,4-τp and φτop-3hydroxybutane-2yl) -2,3- dihydropyridazine-4-carboxamide, isomer 3 6- (4-chlorophenyl) -3oxo-2- (pyridin-3 - yl) -N- (4,4,4trifluoro-3hydroxybutane-2yl) -2,3- dihydropyridazine 4-carboxamide Analytical chiral HPLC: Rt = 1.38 min Instrument: Agilent HPLC 1260; column: YMC Amylose SA 3 μm 100x4.6 mm; eluent: tert-butyl methyl ether + 0.1% by volume diethylamine (99%) / ethanol 90:10, flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm. 300 Q .0 N _u OH II “1 ίΐ Υ Π T> f _{C |} A ^ ° ^{СНз F} 6- (4-chlorophenyl) 3-oxo-2- (pyr idin-3-yl) -N (4,4,4-τp and φτop-3hydroxybutane-2yl) -2,3- dihydropyridazine -4-carboxamide, isomer 4 6- (4-chlorophenyl) -3oxo-2- (pyridin-3 - yl) -N- (4,4,4trifluoro-3hydroxybutane-2yl) -2,3- dihydropyridazine 4-carboxamide Analytical chiral HPLC: Rt = 2.86 min Instrument: Agilent HPLC 1260; column: YMC Amylose SA 3 μm 100x4.6 mm; eluent: tert-butyl methyl ether + 0.1% by volume diethylamine (99%) / ethanol 90:10, flow: 1.4 ml / min;

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temperature: 25 ° C; DAD scan: 254 nm. 301 o> = Z / = Z I / V \ / ^z V ° ⁴¹ v— \ ° C> / —O I 6- (4-chlorophenyl) 2- (5- fluoropyridin-3 yl) -N - [(cis) -4hydroxytetrahydrofuran-3-yl] -3oxo-2,3 dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -2 (5-fluoropyridin-3 yl) -3-oxo-2,3- dihydropyridazine4-carboxylic acid, cis-4aminotetrahydro3-furanol hydrochloride 1: 1 'H NMR (400 MHz, DMSO- _{6 6} ) δ ppm. = 3.45 (1, 1 H), 3.61 (dd, 1 H), 3.93 (dd, 1 H), 3.98 4.04 (m, 1 H), 4.25 - 4.30 (w, 1 H), 4.31 - 4.40 (w, 1 H), 5.71 (d, 1 H), 7.57 7.62 (m, 2 H), 8.01 - 8.06 (w, 2 H), 8.25 (dt, 1 H), 8.70 (s, 1 H), 8.77 (d , 1 H), 8.85 (d, 1 H), 9.73 9.77 (m, 1 H). 302 Q .O II YH? ^H 3 ^ N. A-CH ₃ [ΓΥΓ ^ τΓ Yoh _{С |} ^ ° ^CH 3 6- (4-chlorophenyl) N - [(2R) -3hydroxy-3methylbutan-2-yl] 3-oxo-2 (pyridin-3-yl) 2,3 dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -3oxo-2- (pyridin-3 yl) -2,3- dihydropyridazine 4-carboxylic acid, (3R) -3amino-2methylbutan-2-ol 'H NMR (400 MHz, DMSO-O δ ppm = 1.10 (S, 3 H), 1.13 (d, 3 H), 1.15 (s, 3 H), 3.91 (dd, 1 H), 4.55 - 4.75 (m, 1H), 7.56 - 7.61 (m, 2 H), 7.61 - 7.66 (m, 1 H), 7.98 8.03 (m, 2 H), 8.17 (br d, 1 Η), 8.67 (s, 1 Η), 8.68 8.75 (m, 1 Η), 8.88 - 8.98 (m, 1 Η), 9.51 (d, 1 Η). 303 ^CI V ^ N Lij N'V ° YY HN, Cl ^^ <^ OH CH ₃ 6- (4-chlorophenyl) 2- (5-chloropyridine3-hh) -N - [(2S) -1hydroxypropan2-yl] -3-oxo-2,3 dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -2 (5-chloropyr-idin-3 yl) -3-oxo-2,3- dihydropyridazine 4-carboxylic acid, (2S) -2aminopropane-1 -o l 'H NMR (400 MHz, DMSO-O δ ppm = 1.16 (d, 3 H), 3.40 - 3.50 (br, 2 H), 3.98 - 4.09 (m, 1 H), 4.95 (1, 1 H ), 7.59 (d, 2 H), 8.03 (d, 2 H), 8.41 (1, 1 H), 8.67 (s, 1 H), 8.79 (d, 1 H), 8.92 (d, 1 H), 9.31 - 9.36 (w, 1 H). 304 I about / " \ r about γ- about o ^ -z * * q about 6- (4-chlorophenyl) N - [(2S) -1hydroxypropan2-yl] -2- (5methylpyridin-3 yl) -3-oxo-2,3- dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -2 (5-methylpyridin3-yl) -3-oxo-2,3-dihydropyridazine 4-carboxylic acid, (2S) -2aminopropan-1-ol 'H NMR (400 MHz, DMSO-O δ ppm = 1.16 (d, 3 H), 2.41 (s, 3 H), 3.39 - 3.50 (m, 2 H), 3.98 - 4.09 (m, 1 H ), 4.94 (1, 1 H), 7.56 - 7.61 (m, 2 H), 7.96 - 8.02 (w, 3 H), 8.54 (d, 1 H), 8.65 (s, 1 H), 8.69 (d, 1 H), 9.41 (d, 1 H). 305 H ₃ C NN 6- [4- (Difluoromethoxy) phenyl] -2- (1-methyl1H-pyrazol-4-yl) 3-okco-N- (1,1,1trifluoro-3hydroxy-3methylbutan-2-yl) 2,3dihydropyridazine -4-carboxamide 6- [4- (Difluoromethoxy) phenyl] -2- (1-methyl1H-pyrazol-4-yl) 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, 3amino-4,4,4trifluoro-2methylbutan-2-ol hydrochloride (1: 1) 'H NMR (400 MHz, DMSO-O δ ppm = 1.21 (S, 3 H), 1.37 (s, 3 H), 3.93 (S, 3 H), 4.63 - 4.74 (m, 1 H), 5.23 (s, 1 H), 7.33 (d, 2 H), 7.38 (1, 1 H), 8.11 - 8.13 (t, 1 H), 8.13 - 8.17 (t, 2 H), 8.58 (S, 1 H) , 8.64 (s, 1 H), 10.18 (d, 1 H).

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306 n ₃ s' nn V xijAcA F 6- [4- (Difluoromethoxy) phenyl] -2- (1-methyl1H-pyrazol-4-yl) 3-okco-N- (1,1,1trifluoro-3hydroxy-3methylbutan-2-yl) 2,3- dihydropyridazine-4-carboxamide, isomer 1 6- [4- (Difluoromethoxy) phenyl] -2- (1-methyl1H-pyrazol-4-yl) 3-okco-N- (1,1,1trifluoro-3hydroxy-3methylbutan-2-yl) 2,3- dihydropyridazine 4-carboxamide; preparative chiral HPLC: instrument: Labomatic HD5000, Labocord5000; Gilson GX241, Labcol Vario 4000, column: YMC Cellulose SB 5 μm 250x30 mm; eluent A: tert-butyl methyl ether + 0.1% by volume of diethylamine (99%); eluent B: methanol; isocratic mode: 50% A + 50% B; flow 40.0 ml / min; UV: 254 nm. Analytical chiral HPLC: Rt = 3.87 min Instrument: Agilent HPLC 1260; column: YMC Amylose SA 3 μm 100x4.6 mm; eluent: tert-butyl methyl ether + 0.1 vol% diethylamine (99%) / methanol 50:50, flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm. [a] _D ²⁰ = 43.2 ° (c = 1.00, MeOH) 307 H ₃ C 'nn V xijAcA F 6- [4- (Difluoromethoxy) phenyl] -2- (1-methyl1H-pyrazol-4-yl) 3-okco-N- (1,1,1trifluoro-3hydroxy-3methylbutan-2-yl) 2,3- dihydropyridazine-4-carboxamide, isomer 2 6- [4- (Difluoromethoxy) phenyl] -2- (1-methyl1H-pyrazol-4-yl) - 3-okco-N- (1,1,1- trifluoro-3hydroxy-3methylbutan-2-yl) 2,3- dihydropyridazine 4-carboxamide; chiral HPLC see example 306 Analytical chiral HPLC: Rt = 2.67 min Instrument: Agilent HPLC 1260; column: YMC Amylose SA 3 μm 100x4.6 mm; eluent: tert-butyl methyl ether + 0.1 vol% diethylamine (99%) / methanol 50:50, flow: 1.4 ml / min; temperature: 25 ° C; DAD scan: 254 nm. [a] _D ²⁰ = -40.4 ° (c = 1.00, MeOH) 308 H ₃ C 'nn TiY ° ^h I a4Voh A o sn ₃ 6- [4- (Difluoromethoxy) phenyl] -N - [(28) -1hydroxypropan2-yl] -2- (1-methyl1H-pyrazol-4-yl) 3-oxo-2,3dihydropyridazine -4-carboxamide 6- [4- (Difluoromethoxy) phenyl] -2- (1-methyl1H-pyrazol-4-yl) 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, (2S) -2aminopropane-1 -o l 'H NMR (400 MHz, DMSO-b / ₆ ) δ ppm. = 1.19 (d, 3 H), 3.40 - 3.53 (w, 2 H), 3.93 (s, 3 H), 3.98 4.13 (m, 1 H), 4.96 (t, 1 H), 7.30 - 7.35 (m, 2 H), 7.38 (t, 1H), 8.11 - 8.16 (w, 3 H), 8.56 (s, 1 H), 8.58 (s, 1 H), 9.55 (d, 1

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H). 309 H ₃ C 'nn VN ΪΓΥ Η? ⁿ z g ^ A / \ / hA ^CH ₃ 1 ίί Ί P = OH AoA * ^{1 0 CH} 3 6- [4- (Difluoromethoxy) phenyl] -N - [(28) -3hydroxy-3methylbutan-2-yl] 2- (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3- dihydropyridazine -4-carboxamide 6- [4- (Difluoromethoxy) phenyl] -2- (1-methyl1H-pyrazol-4-yl) 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, (3S) 3-amino-2methylbutan-2-ol hydrochloride 1: 1 'H NMR (400 MHz, DMSO-Λ) δ ppm. = 1.12 (S, 3 H), 1.15 (d, 3 H), 1.18 (s, 3 H), 3.88 - 3.99 (w, 4 H), 4.68 (s, 1 H), 7.33 (d, 2 H) , 7.38 (1, 1H), 8.09 - 8.17 (br, 3 H), 8.56 (s, 1 H), 8.59 (s, 1 H), 9.62 - 9.68 (d, 1 H). 310 SN ₃ Ν — NV Zh TG Y N? ⁿ s ^ N „Jr-CH, Tone ^H 3% A ^ o ch ₃ ch ₃ 6- [4- (Dimethylamino) phenyl] -N - [(28) -3hydroxy-3methylbutan-2-yl] 2- (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3- dihydropyridazine -4-carboxamide 6- [4- (Dimethylamino) phenyl] -2 - (1-methyl1H-pyrazol-4-yl) 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, (3S) 3-amino-2methylbutan-2-ol hydrochloride 1: 1 'H NMR (400 MHz, DMSO-Λ) δ ppm. = 1.12 (S, 3 H), 1.15 (d, 3 H), 1.17 (s, 3 H), 3.00 (s, 6 H), 3.89 - 3.98 (w, 4 H), 4.65 (s, 1 H) , 6.80 - 6.86 (w, 2 H), 7.85 - 7.91 (w, 2 H), 8.07 (s, 1 H), 8.52 (S, 2 H), 9.69 - 9.75 (w, 1 H). 311 SN ₃ NN 'V NV ιι 1 ^{n Η} 3 n, s L L o L ³ N ^^^ ^x on s ₃ 6- [4- (Dimethylamino) phenyl] -N - [(28) -1hydroxypropan2-yl] -2- (1 -methyl1H-pyrazol-4-yl) 3-oxo-2,3- dihydropyridazine -4-carboxamide 6- [4- (Dimethylamino) phenyl] -2 - (1-methyl1H-pyrazol-4-yl) 3-oxo-2,3- dihydropyridazine 4-carboxylic acid, (2S) -2aminopropane-1 -o l 'H NMR (400 MHz, DMSO-Λ) δ ppm. = 1.18 (d, 3 H), 3.00 (s, 6 H), 3.42 - 3.52 (w, 2 H), 3.92 (S, 3 H), 4.00 - 4.10 (w, 1 H), 4.95 (t, 1 H), 6.82 (d, 2 H), 7.87 (d, 2 H), 8.08 (d, 1 H), 8.51 (s, 1 H), 8.52 (s, 1 H), 9.59 - 9.65 (w, 1 H). 312 SN V nA ° ΑΑγ? ^Hg JiSs J ΗΝ. Д-СН, 9 ^^ Ύ% η ³ _f A _f ^СНз F N - [(2S) -3- hydroxy-3methylbutan-2-yl] 3-oxo-2- (1,2- thiazol-4-yl) -6- [4 (trifluoromethoxy) phenyl] -2,3- dihydropyridazine -4-carboxamide 3-oxo-2- (1,2thiazol-4-yl) -6- [4 (trifluoromethoxy) phenyl] -2,3 dihydropyridazine 4-carboxylic acid, (3S) 3-amino-2methylbutan-2-ol hydrochloride 1: 1 'H NMR (400 MHz, DMSO-Λ) δ ppm. = 1.12 (S, 3 H), 1.15 (d, 3 H), 1.17 (s, 3 H), 3.87 - 3.98 (w, 1 H), 4.68 (s, 1 H), 7.53 (d, 2 H) , 8.17 - 8.21 (w, 2 H), 8.66 (s, 1 H), 9.13 (s, 1 H), 9.51 (d, 1 H), 9.61 (s, 1 H). 313 About La o = ^ o ZI A z 6- [4- (difluoromethyl) phen yl] -3-oxo-2- (pyr idin-3-yl) -N [(28) -3,3,3 trifluoro-2-hydroxypropyl] 2,3- dihydropyridazine -4-carboxamide 6- [4- (difluoromethyl) phenyl] -3-oxo-2 (pyridin-3-yl) 2,3- dihydropyridazine 4-carboxylic acid, (2S) -3amino-1,1,1 trifluoropropane-2ol ^: H NMR (400 MHz, DMSO-Λ) δ ppm = 3.44 - 3.53 (m, 1 H), 3.72 3.80 (w, 1 H), 4.23 (qd, 1 H), 6.67 (d, 1 H), 7.13 (1, 1 H), 7.62 - 7.67 (br, 1 H), 7.73 (d, 2 H), 8.13 (d, 2 H), 8.18 (ddd, 1 H), 8.70 (dd, 1 H), 8.73 (s, 1 H), 8.93 (d, 1 H) ), 9.57 9.64 (m, 1 H).

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314 9 .... .W F ^ F 6- [4- (Difluoromethoxy) phenyl] -3-oxo-2 (pyridin-3 -ππ) -Ν [(2S) -3,3,3 trifluoro-2hydroxypropyl] 2,3- dihydropyridazine -4-carboxamide 6- [4- (Difluoromethoxy) phenyl] -3-oxo-2 (pyridin-3-yl) 2,3- dihydropyridazine 4-carboxylic acid, (2S) -3amino-1,1,1 trifluoropropane-2ol 'H NMR (400 MHz, DMSO-b / b) δ ppm. = 3.42 - 3.52 (w, 1 H), 3.69 3.80 (w, 1 H), 4.17 - 4.29 (w, 1 H), 6.67 (d, 1 H), 7.32 (d, 2 H), 7.36 (t, 1H), 7.65 (brd, 1 H), 8.03 - 8.07 (w, 2 H), 8.15 - 8.19 (br, 1 H), 8.65 8.71 (br, 2 H), 8.92 (d, 1 H), 9.62 ( t, 1 H). 315 H ₃ C NN V II YHP ^H o Co 'F 6- [4- (difluoromethyl) phen yl] -K - [(cis) -4hydroxytetrahydrofuran-3-yl] -2 (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3dihydropyridazine -4-carboxamide, isomer 1 6- [4- (difluoromethyl) phenyl] -K - [(cis) -4hydroxytetrahydrofuran-3-yl] -2- (1methyl-1H-pyrazol4-yl) -3-oxo-2,3 dihydropyridazine 4-carboxamide; preparative chiral HPLC: instrument: Sepiatec: Prep SFC100; column: Chiralpak IC 5μm 250x30mm; eluent A: CO ₂ , eluent B: 2 propanol + 0.4 vol% diethylamine (99%); isocratic mode: 42% B; flow 100.0 ml / min temperature: 40 ° С; BPR: 150 bar; MWD @ 254 nm. Analytical chiral HPLC: Rt = 2.72 min Instrument: Agilent: 1260, Aurora SFC-module; column: Chiralpak IC 5μm 100x4.6 mm; eluent A: CO ₂ , eluent B: 2-propanol + 0.2 vol% diethylamine (99%); isocratic mode: 42% B; flow 4.0 ml / min; temperature: 37.5 ° С; BPR: 100 bar; MWD @ 254 nm. 'H NMR (400 MHz, DMSO-b / ₆ ) δ ppm. = 3.48 (t, 1 N), 3.65 (dd, 1 N), 3.92 - 3.98 (m, 4 N), 4.02 (t, 1 N), 4.26 - 4.33 (t, 1 N), 4.33 - 4.43 (t , 1 H), 5.71 (d, 1 H), 7.14 (t, 1 H), 7.74 (d, 2 H), 8.13 (s, 1 H), 8.21 (d, 2 H), 8.56 8.57 (t, 1 H), 8.65 (s, 1 H), 9.90 (d, 1 H). 316 CH ₃ NN V _X N ^ _O ^Vl H ₃ C CH ₃ 6- (4-chlorophenyl) - N - [(2S) -3- hydroxy-3methylbutan-2-yl] 2- (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3- dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -2 (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3- dihydropyridazine 4-carboxylic acid, (3S) 3-amino-2methylbutan-2-ol hydrochloride 1: 1 'H NMR (400 MHz, DMSO-b / ₆ ) δ ppm. = 1.12 (S, 3 H), 1.15 (d, 3 H), 1.18 (s, 3 H), 3.87 - 3.98 (t, 4 H), 4.67 (s, 1 H), 7.55 - 7.63 (t, 2 H), 8.06 - 8.14 (t, 3 H), 8.56 (s, 1 H), 8.59 (s, 1 H), 9.60 9.66 (t, 1 H). 317 T o / \ 4> —j ZZ x O) = O O ₄ A_ / ^Ζ Λ ' _{z =} / ΛΑ O 6- (4-chlorophenyl) K - [(cis) -2hydroxy-2methylcyclopentyl] -2- (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -2 (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3-dihydropyridazine 4-carboxylic acid; cis-2amino-1methylcyclopentane 'H NMR (400 MHz, DMSO-b / b) δ ppm. = 1.21 (S, 3 H), 1.39 - 1.51 (t, 1 H), 1.57 - 1.78 (t, 4 H), 2.15 - 2.24 (t, 1 H), 3.93 (S, 3 H), 4.10 - 4.18 (t, 1 H), 4.72 (s, 1 H), 7.57 7.63 (t, 2 H), 8.08 - 8.13 (t, 3 H), 8.55 (s, 1 H),

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ol trifluoroacetic acid 1: 1 8.58 (s, 1 Η), 9.50 (d, 1 Η). 318 V7 yo z- ^ ° 1— \ '° tX J— o z 6- [4- (difluoromethyl) phen yl] -M - [(cis) -4hydroxytetrahydrofuran-3-yl] -3oxo-2- (pyridin3-yl) -2,3 dihydropyridazine -4-carboxamide, isomer 1 6- [4- (difluoromethyl) phenyl] -3-oxo-2 (pyridin-3-yl) 2,3- dihydropyridazine-4-carboxylic acid, cis-4-aminotetrahydro-3-furanol hydrochloride 1: 1; preparative chiral HPLC: instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IA 5 μm 250x30 mm; eluent A: acetonitrile + 0.1% by volume diethylamine (99%); eluent B: ethanol; isocratic mode: 92% A + 08% B; flow: 50.0 ml / min; UV: 254 nm. Analytical chiral HPLC: Rt = 1.89 min instrument: Agilent HPLC 1260; column: Chiralpak 3 μm 100x4.6 mm; eluent A: acetonitrile + 0.1% by volume diethylamine (99%); eluent B: ethanol; isocratic mode: 90% A + 10% B; flow: 1.4 ml / min; temperature: 25 ° C; DAD 254 nm. 319 Q n f YH? ^H 3 AA Jr-CH, Yoh fAY o CH ₃ F 6- [4- (difluoromethyl) phen nn] -N - [(2S) -3hydroxy-3methylbutan-2-yl] 3-oxo-2- (pir idin-3-yl) - 2,3- dihydropyridazine -4-carboxamide 6- [4- (difluoromethyl) phenyl] -3-oxo-2 (pyridin-3-yl) 2,3- dihydropyridazine 4-carboxylic acid, (3S) 3-amino-2methylbutan-2-ol hydrochloride 1: 1 'H NMR (400 MHz, DMSOX) δ ppm. = 1.10 (S, 3 H), 1.13 (d, 3 H), 1.15 (s, 3 H), 3.85 - 3.98 (w, 1 H), 4.66 (s, 1 H), 7.13 (t, 1H), 7.63 (ddd, 1 H), 7.72 (d, 2 H), 8.13 (d, 2 H), 8.18 (ddd, 1 H), 8.70 (dd, 1 H), 8.72 (s, 1 H), 8.92 ( d, 1 H), 9.51 (d, 1 H). [a] _D ²⁰ = 34.1 ° (c = 1.00, DMSO) 320 H ₃ C Ν — N Ψ Ϊ Y ^H 7 ^H fACY о Yq F 6- [4- (difluoromethyl) phen yl] -M - [(cis) -4hydroxytetrahydrofuran-3-yl] -2 (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3- dihydropyridazine-4-carboxamide, isomer 2 6- [4- (difluoromethyl) phenyl] -M - [(cis) -4hydroxytetrahydrofuran-3-yl] -2- (1methyl-1H-pyrazol4-yl) -3-oxo-2,3 dihydropyridazine4-carboxamide; preparative chiral HPLC: instrument: Sepiatec: Prep SFC100; Analytical chiral HPLC: Rt = 1.71 min Instrument: Agilent: 1260, Aurora SFC-module; column: Chiralpak IC 5μm 100x4.6 mm; eluent A: CO ₂ , eluent B: 2-propanol + 0.2 vol% diethylamine (99%); isocratic mode: 42% B; flow: 4.0 ml / min;

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column: Chiralpak IC 5μm 250x30mm; eluent A: CO ₂ , eluent B: 2propanol + 0.4 vol% diethylamine (99%); isocratic mode: 42% B; flow 100.0 ml / min temperature: 40 ° С; PR: 150 bar; MWD (a), 254 nm. temperature: 37.5 ° C; BPR: 100 bar; MWD @ 254 nm. 321 Τ ΙΖ ο S = o λα about 3- (4-chlorophenyl) 6-okco-N - [(2S) 3,3,3-trifluoro-2hydroxypropyl] - 6H-1,4'- bipyridazine-5 carboxamide 3- (4-chlorophenyl) -6oxo-6H- [1,4'bipyridazine] -5carboxylic acid, (2S) -3amino-1,1,1trifluoropropane-2ol 'H NMR (400 MHz, DMSO-b / ₆ ) δ ppm. = 3.49 (ddd, 1 Η), 3.70 - 3.79 (m, 1 Η), 4.24 (qd, 1 Η), 6.67 (d, 1 Η), 7.59 - 7.64 (m, 2 Η), 8.06 - 8.12 (m , 2 Η), 8.22 (dd, 1 Η), 8.66 - 8.71 (m, 1 Η), 9.41 9.47 (m, 1 Η), 9.49 (dd, 1 Η), 9.73 - 9.77 (m, 1 Η). 322 I ^s l QIX IZ o Xo otf LA 6- [4- (difluoromethyl) phen yl] -N- (2hydroxy-2methylpropyl) -3oxo-2- (pyridin3-yl) -2,3 dihydropyridazine -4-carboxamide 6- [4- (difluoromethyl) phenyl] -3-oxo-2- (pir idin-3-yl) - 2,3- dihydropyridazine 4-carboxylic acid, 1-amino 2-methylpropane-2ol 'Η NMR (400 MHz, DMSO-О δ ppm = 1.13 (s, 6 H), 3.31 (s, 2H), 4.68 (s, 1 H), 7.13 (t, 1H), 7.61 - 7.67 ( m, 1 H), 7.72 (d, 2 H), 8.13 (d, 2 H), 8.19 (ddd, 1 H), 8.70 (br d, 1 Η), 8.72 (s, 1 Η), 8.93 (d , 1 Η), 9.49 - 9.54 (m, 1 Η). 323 Ao * ^z v ° 1— \ '° o. I 6- [4- (difluoromethyl) phen yl] -K - [(cis) -4hydroxytetrahydrofuran-3-yl] -3oxo-2- (pyridin3-yl) -2,3 dihydropyridazine -4-carboxamide, isomer 2 6- [4- (difluoromethyl) phenyl] -3-oxo-2 (pyridin-3-yl) 2,3- dihydropyridazine 4-carboxylic acid, cis-4 aminotetrahydro 3-furanol hydrochloride 1: 1; preparative chiral HPLC: instrument: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000, column: Chiralpak IA 5 μm 250x30 mm; eluent A: acetonitrile + 0.1% by volume diethylamine (99%); Analytical chiral HPLC: Rt = 2.61 min Instrument: Agilent: 1260, Aurora SFC-module; column: Chiralpak IC 5μm 100x4.6 mm; eluent A: CO ₂ , eluent B: 2-propanol + 0.2 vol% diethylamine (99%); isocratic mode: 42% B; flow: 4.0 ml / min; temperature: 37.5 ° С; BPR: 100 bar; MWD @ 254 nm.

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eluent B: ethanol; isocratic mode: 92% A + 08% B; flow: 50.0 ml / min; UV: 254 nm. 324 ch ₃ Ν — Ν 'V ,,, Ν Ο π Υ ⁿ C | Y ° ^CH 3 6- (4-chlorophenyl) - N - [(2R) -1- hydroxypropan2-yl] -2- (1 -methyl1H-pyrazol-4-yl) 3-oxo-2,3- dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -2 (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3- dihydropyridazine 4-carboxylic acid; (2R) -2aminopropane-1 -o l 'H NMR (400 MHz, DMSO- _{6 6} ) δ ppm. = 1.19 (d, 3 H), 3.42 - 3.52 (w, 2 H), 3.93 (s, 3 H), 3.99 4.12 (br, 1 H), 4.94 (br s, IH), 7.58 - 7.62 (m, 2 Η), 8.08 - 8.12 (m, 3 Η), 8.56 (s, 1 Η), 8.58 (s, 1 Η), 9.49 - 9.56 (m, 1 Η). [a] _D ²⁰ = -10.9 ° (c = 1.00, DMSO) 325 H Ν — N φ _O ν γ _n n ₃ ssn ₃ Г | ^ 1 ° ^H 0 CH ₃ cr ³ 6- (4-chlorophenyl) - N - [(2R) -3- hydroxy-3methylbutan-2-yl] 3-oxo-2- (1H- pyrazol-4-yl) -2,3 dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -3oxo-2- (1Hpyrazol-4-yl) -2,3 dihydropyridazine 4-carboxylic acid, (3R) -3amino-2methylbutan-2-ol 'H NMR (400 MHz, DMSO- _{6 6} ) δ ppm. = 1.13 (S, 3 H), 1.15 (d, 3 H), 1.18 (s, 3 H), 3.86 - 4.00 (w, 1 H), 4.68 (s, 1 H), 7.57 - 7.62 (w, 2 H), 8.07 - 8.12 (w, 2 H), 8.17 (br s, 1 H), 8.51 (br s, 1 H), 8.59 (s, 1 H), 9.58 - 9.68 (br, 1 H), 13.23 (br s, 1 H). [a] _D ²⁰ = -24.7 ° (c = 1.00, DMSO)

The following examples were prepared from the starting materials listed in the table using the procedures described for intermediate 119. The enantiomers were separated from their racemate by chiral HPLC using the specified column and solvent conditions.

326 SN V Ν ' ^Ν γ ° JI HN. D-CH ₃ Ych ₃ CH ₃ ³ 6- (4-chlorophenyl) - N - [(2R) -3- hydroxy-3methylbutan-2-yl] 3-oxo-2- (1,2thiazol-4-yl) -2,3 dihydropyridazine -4-carboxamide 6- (4-chlorophenyl) -N [(2R) -3-hydroxy-3 methylbutan-2-yl] -3 oxo-2,3- dihydropyridazine 4-carboxamide, 4 (4,4,5,5-tetramethyl1,3,2- dioxaborolane-2yl) -1,2-thiazole 'H NMR (400 MHz, DMSO-O δ ppm = 1.12 (S, 3 H), 1.15 (d, 3 H), 1.17 (s, 3 H), 3.85 - 3.98 (br, 1 H), 4.68 (s, 1 H), 7.57 - 7.62 (w, 2 H), 8.06 - 8.11 (t, 2 H), 8.64 (s, 1 H), 9.12 (s, 1 H), 9.50 (d, 1 H) ), 9.61 (s, 1 H). 327 Y-4 Z - / O o— (zo z \ _o “04 Z o I ω N - [(2R) -3- hydroxy-3methylbutan-2-yl] 3-oxo-2- (1,2thiazol-4-yl) -6- [4 (trifluoromethoxy) phenyl] -2,3- dihydropyridazine -4-carboxamide X - [(2K) -3-hydroxy3-methylbutan-2-yl] 3-oxo-6- [4 (trifluoromethoxy) phenyl] -2,3 dihydropyridazine 4-carboxamide, 4 (4,4,5,5 -tetramethyl1, 3.2- dioxaborolane-2- 'H NMR (400 MHz, DMSO-O δ ppm = 1.12 (S, 3 H), 1.15 (d, 3 H), 1.17 (s, 3 H), 3.88 - 3.97 (t, 1 H), 4.69 (s, 1 H), 7.52 (d, 2 H), 8.17 - 8.21 (t, 2 H), 8.66 (s, 1 H), 9.12 (s, 1 H), 9.51 (d, 1 H), 9.61 (s, 1 H).

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yl) -1,2-thiazole 328 to χΑχίΓ fAf N - [(unc) -2hydroxy-2methylcyclopentyl] -3-oxo-2 (pyridin-3-yl) -6 [4 (trifluoromethoxy) phenyl] -2,3dihydropyridazine -4-carboxamide 3-oxo-2- (pyridin3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3- dihydropyridazine 4-carboxylic acid, cis-2- amino-1- methylcyclo pentane l-o l trifluoroacetic acid ^: H NMR (400 MHz, DMSO-O δ ppm = 1.17 (s, 3), 1.37 - 1.47 (m, 1 Η), 1.53 - 1.64 (m, 2 Η), 1.65 - 1.76 (m, 2 Η), 2.13 - 2.23 (m, 1 Η), 4.10 4.17 (m, 1 Η), 4.70 (s, 1 Η), 7.51 (d, 2 Η), 7.61 7.66 (m, 1 Η), 8.09 - 8.14 (m, 2 Η), 8.17 (ddd, 1 Η), 8.68 (s, 1 Η), 8.70 (dd, 1 Η), 8.91 (d, 1 Η), 9.37 (d, 1Η). 329 Αν Α'Χ ο = ς o ΖΙ f I / \ Jo о τ K - [(cis) -2hydroxy-2methylcyclopentyl] -3-oxo-2- (pyr idin-3-yl) -6 [4- (trifluoromethoxy) phenyl] -2,3- dihydropyridazine-4-carboxamide, isomer 1 K - [(cis) -2hydroxy-2methylcyclopentyl] -3-oxo-2- (pyridin3-yl) -6- [4 (trifluoromethoxy) phenyl] -2,3 dihydropyridazine 4-carboxamide; preparative chiral HPLC: instrument: Labomatic HD5000, Labocord5000; Gilson GX241, Labcol Vario 4000, column: Chiralpak IA 5 μm 250x30 mm; eluent A: hexane + 0.1% by volume diethylamine (99%) eluent B: 2propanol; isocratic mode: 60% A + 40% B; flow: 40.0 ml / min; UV: 254 nm. Analytical chiral HPLC: Rt = 2.80 min Instrument: Agilent HPLC 1260; column: Chiralpak 3 μm 100x4.6 mm; eluent: hexane + 0.1% by volume diethylamine (99%) / 2-propanol 60:40, flow: 1.4 ml / min; temperature: 25 ° C; UV: 254 nm. 330 Αν О A'X ο = ς о ZI _f I / \ Jo about I K - [(cis) -2hydroxy-2methylcyclopentyl] -3-oxo-2 (pyridin-3-yl) -6 [4 (trifluoromethoxy) phenyl] -2,3 dihydropyridazine -4-carboxamide, isomer 2 K - [(cis) -2hydroxy-2methylcyclopentyl] -3-oxo-2- (pyridin3-yl) -6- [4 (trifluoromethoxy) phenyl] -2,3 dihydropyridazine 4-carboxamide; preparative chiral HPLC: instrument: Labomatic HD5000, Labocord5000; Gilson GX241, Labcol Vario 4000, column: Chiralpak IA 5 μm 250x30 Analytical chiral HPLC: Rt = 3.50 min Instrument: Agilent HPLC 1260; column: Chiralpak 3 μm 100x4.6 mm; eluent: hexane + 0.1 vol% diethylamine (99%) / 2-propanol 60:40, flow: 1.4 ml / min; temperature: 25 ° C; UV: 254 nm.

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mm; eluent A: hexane + 0.1% by volume diethylamine (99%) eluent B: 2propanol; isocratic mode: 60% A + 40% B; flow: 40.0 ml / min; UV: 254 nm. 331 О ⁴¹ ΛΑ bо ο = (о ΖΙ R ° s ω 6- [4- (Difluoromethoxy) phenyl] -N- (2hydroxy-2methylpropyl) -3oxo-2- (pyridin-3 yl) -2,3 dihydropyridazine 4-carboxamide 6- [4- (Difluoromethoxy) phenyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine 4-carboxylic acid, 1-amino-2 methylpropan-2-ol W NMR (400 MHz, DMSO-O δ ppm = 1.13 (S, 6 H), 3.30 - 3.32 (br, 2 H), 4.68 (s, 1 H), 7.31 (d, 2 H), 7.36 (t, 1 H), 7.60 7.66 (w, 1 H), 8.02 - 8.06 (w, 2 H), 8.15 - 8.20 (w, 1 H), 8.67 (s, 1 H), 8.69 (dd, 1 H ), 8.92 (d, 1 H), 9.53 (t, 1 H). 332 О ο = ς о ζζ About ζ \ "/ ο ζ 6- [4- (Difluoromethoxy) phenyl] -N - [(28) -1hydroxypropane-2yl] -3-oxo-2- (pyr idin-3-yl) -2,3 dihydropyridazine 4-carboxamide 6- [4- (Difluoromethoxy) phenyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine 4-carboxylic acid, (S) - (+) - 2amino-1-propanol W NMR (400 MHz, DMSO-O δ ppm = 1.16 (d, 3 H), 3.41 - 3.51 (br, 2 H), 3.98 - 4.10 (br, 1 H), 4.94 (sbr, 1 H) , 7.29 7.34 (w, 2 H), 7.36 (t, 1 H), 7.60 - 7.65 (w, 1 H), 8.02 - 8.07 (w, 2 H), 8.16 (ddd, 1 H), 8.66 (s, 1 H), 8.69 (dd, 1 H), 8.91 (d, 1 H), 9.42 (d, 1 H). 333 5% Ο ο = ς ο ζζ Ο / J ζ Vn “ch Ζ u 6- [4- (Difluoromethoxy) phenyl] -N - [(28) -3hydroxy-3methylbutan-2-yl] 3-oxo-2- (pyridin3-yl) -2,3- dihydropyridazine 4-carboxamide 6- [4- (Difluoromethoxy) phenyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine 4-carboxylic acid, (S) -3amino-2methylbutan-2-ol W NMR (400 MHz, DMSO-O δ ppm = 1.10 (S, 3 H), 1.13 (d, 3 H), 1.15 (s, 3 H), 3.86 - 3.96 (br, 1 H), 4.65 (s, 1 H), 7.29 - 7.34 (w, 2 H), 7.36 (t, 1 H), 7.60 - 7.65 (w, 1 H), 8.02 - 8.06 (w, 2 H), 8.17 - 8.19 (ddd , 1 H), 8.67 (s, 1 H), 8.69 (dd, 1 H), 8.91 (d, 1 H), 9.53 (d, 1 H). 334 Ο ο = ς ο ζζ Ο / 4? ) Ο ο * ζ 6- [4- (Difluoromethoxy) phenyl] -M - [(28,38) -3hydroxybutane-2yl] -3-oxo-2- (pyr idin-3-yl) -2,3 dihydropyridazine 4-carboxamide 6- [4- (Difluoromethoxy) phenyl] -3-oxo-2- (pyr idin-3-yl) -2,3 dihydropyridazine 4-carboxylic acid, (2S, 3S) -3aminobutan-2-ol hydrochloride (1: 1) W NMR (400 MHz, DMSO- _{6 6} ) δ ppm. = 1.04 (d, 3 H), 1.15 (d, 3 H), 3.67 - 3.75 (w, 1 H), 3.89 3.98 (m, 1 H), 4.95 (d, 1 H), 7.29 - 7.34 (br, 2 H), 7.36 (t, 1 H), 7.60 - 7.65 (w, 1 H), 8.02 - 8.06 (w, 2 H), 8.17 (ddd, 1 H), 8.67 (s, 1 H), 8.69 ( dd, 1 H), 8.91 (d, 1 H), 9.44 (d, 1 H).

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335 SN, NN ¥ xJC n ^H3 % * ^oh cr 6- (4-chlorophenyl) -K [(cis) -2-hydroxy2- methylcyclopentyl] -2- (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3- dihydropyridazine 4-carboxamide; Isomer 1 6- (4-chlorophenyl) -I [(cis) -2-hydroxy-2 methylcyclopentyl] 2- (1-methyl- 1Hpyrazol-4-yl) -3oxo-2,3- dihydropyridazine 4-carboxamide; preparative chiral HPLC: instrument: Labomatic HD5000, Labocord5000; Gilson GX241, Labcol Vario 4000, column: Chiralpak IA 5 μm 250x30 mm; eluent A: hexane + 0.1% by volume diethylamine (99%) eluent B: ethanol; isocratic mode: 50% A + 50% B; flow: 40.0 ml / min; UV: 254 nm. Analytical chiral HPLC: Rt = 2.96 min Instrument: Agilent HPLC 1260; column: Chiralpak 3 μm 100x4.6 mm; eluent: hexane + 0.1% by volume diethylamine (99%) / ethanol 50:50, flow: 1.4 ml / min; temperature: 25 ° C; UV: 254 nm. 336 CH, NN ¥ Z ^N K / 0 H [hH ₃ C OH JXl o ¥ / cr 6- (4-chlorophenyl) -K [(cis) -2-hydroxy2- methylcyclopentyl] -2- (1-methyl-1Hpyrazol-4-yl) -3oxo-2,3- dihydropyridazine 4-carboxamide; Isomer 2 6- (4-chlorophenyl) -N [(cis) -2-hydroxy-2 methylcyclopentyl] 2- (1-methyl- 1Hpyrazol-4-yl) -3oxo-2,3- dihydropyridazine 4-carboxamide; preparative chiral HPLC: instrument: Labomatic HD5000, Labocord5000; Gilson GX241, Labcol Vario 4000, column: Chiralpak IA 5 μm 250x30 mm; eluent A: hexane + 0.1% by volume diethylamine (99%) eluent B: ethanol; isocratic mode: 50% A + 50% B; flow: 40.0 ml / min; UV: 254 nm. Analytical chiral HPLC: Rt = 5.10 min Instrument: Agilent HPLC 1260; column: Chiralpak 3 μm 100x4.6 mm; eluent: hexane + 0.1% by volume diethylamine (99%) / ethanol 50:50, flow: 1.4 ml / min; temperature: 25 ° C; UV: 254 nm.

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337 KL .О Ν № * u ОН F iT О X _F A ^ H ₃ C ^ CH ₃ F 2- (5-fluoropyridine3-nn) -N - [(2S) -lhydroxy-3methylbutan-2-yl] 3-oxo-6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine4-carboxamide 2- (5-fluoropyridin-3 yl) -3-oxo-6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine 4-carboxylic acid, (2S) -2amino-3methylbutane-Nol 'H NMR (400 MHz, DMSO-J,) δ ppm. = 0.90 (d, 3 H), 0.93 (d, 3 H), 1.93 - 2.03 (m, 1 H), 3.41 3.49 (m, 1 H), 3.52 - 3.60 (m, 1 H), 3.82 - 3.90 ( m, 1 H), 4.83 (tbr, 1 H), 8.06 (d, 1 H), 8.27 - 8.32 (m, 1 H), 8.70 (dd, 1 H), 8.78 (d, 1 H), 8.83 ( s, 1 H), 8.89 8.91 (m, 1 H), 9.26 (d, 1 H), 9.39 (d, 1 H). 338 γ Ν. .0 Η Υ Η hJC-X Ο Λ-ν _F > [ ^Ν HO F 2- (5-fluoropyridine3-nn) -N - [(lS, 2R) -2hydroxycyclopent yl] -3-oxo-6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine4-carboxamide 2- (5-fluoropyridin-3 yl) -3-oxo-6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine 4-carboxylic acid, cis (lR, 2S) -2aminocyclopentanol hydrochloride ( 1: 1) 'H NMR (400 MHz, DMSO-J) δ ppm. = 1.47 1.65 (w, 3 H), 1.70 - 1.88 (m, 2 H), 1.93 - 2.04 (m, 1 H), 3.99 - 4.12 (m, 2 H), 5.07 (d, 1 H), 8.05 ( d, 1 H), 8.29 (ddd, 1 H), 8.69 (dd, 1 H), 8.78 (d, 1 H), 8.83 (s, 1 H), 8.89 (1, 1 H), 9.38 (d, 1 H), 9.58 (d, 1 H). 339 Cha KL .0 Ν U A r'hLAAA fY ^ J o J N - [(1S) -1- cyclopropyl-2hydroxyethyl] -2- (5fluoropyridin-3-yl) -3-oxo-6- [6 (trifluoromethyl) pyridin-3-yl] -2.3 - dihydropyridazine 4-carboxamide 2- (5-fluoropyr-idin-3 yl) -3-oxo-6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine 4-carboxylic acid, (2S) -2amino-2cyclopropylethane-1 ol hydrochloride (1: 1) 'H NMR (400 MHz, DMSO-J) δ ppm. = 0.26 0.33 (m, 1 H), 0.33 - 0.40 (m, 1 H), 0.41 - 0.51 (w, 2 H), 1.04 - 1.15 (m, 1 H), 3.41 - 3.49 (m, 1 H), 3.53 3.64 (m, 2 H), 4.95 (1, 1 H), 8.05 (d, 1 H), 8.28 8.32 (w, 1 H), 8.70 (dd, 1 H), 8.78 (d, 1 H), 8.83 (s, 1 H), 8.90 (1.1 H), 9.39 (d, 1 H), 9.44 (d, 1 H). 340 "T IX" Q Ο Z \ _TO IZ 4j u. О) = O ¹ AY θ 2- (5-fluoropyridine3-nn) -N - [(2S) -3hydroxy-3methylbutan-2-yl] 3-oxo-6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine4-carboxamide 2- (5-fluoropyridin-3 yl) -3-oxo-6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine 4-carboxylic acid, (S) -3amino-2methylbutane-2- hydrochloride ola (1: 1) 'H NMR (400 MHz, DMSO-J,) δ ppm. = 1.11 (d, 3 H), 1.14 (d, 3 H), 1.16 (s, 3 H), 3.88 - 3.97 (m, 1 H), 4.68 (s, 1 H), 8.05 (d, 1 H) , 8.29 (ddd, 1 H), 8.68 (dd, 1 H), 8.78 (d, 1 H), 8.82 (s, 1 H), 8.90 (1, 1 H), 9.37 - 9.42 (t, 2 H) ... 341 IZ ^Z о U- О I ° ^Z о M - [(18) -1-Cyano-2hydroxyethyl] -2- (5fluoropyridin-3 yl) -3-oxo-6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine 4-carboxamide 2- (5-fluoropyr-idin-3-yl) -3-oxo-6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine 4-carboxylic acid, (2S) -2amino-3- hydroxypropanenitre sludge 'H NMR (400 MHz, DMSO-J,) δ ppm. = 3.73 3.86 (t, 2 H), 5.03 - 5.10 (t, 1 H), 5.84 (1, 1 H), 8.07 (d, 1 H), 8.27 - 8.32 (t, 1 H), 8.72 (dd, 1 H), 8.79 (d, 1 H), 8.88 (s, 1 H), 8.91 (1, 1 H), 9.41 (d, 1 H), 9.84 (d, 1 H).

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342 XX A Ν ^ ϊ <[| J ΪΓΥ ^{n Η} ₃ ⁰ J ^0H fA ^ν H ₃ c CH ₃ 2- (5-fluoropyridine3-nn) -N - [(2R) -3hydroxy-3methylbutan-2-yl] 3-oxo-6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine 4-carboxamide 2- (5-fluoropyridin-3 yl) -3-oxo-6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine 4-carboxylic acid, (3R) -3amino-2methylbutane-2- hydrochloride ola (1: 1) 'H NMR (400 MHz, DMSO-O δ ppm = 1.11 (S, 3 H), 1.14 (d, 3 H), 1.16 (s, 3 H), 3.88 - 3.97 (br, 1 H), 4.68 (s, 1 H), 8.05 (d, 1 H), 8.27 - 8.32 (w, 1 H), 8.69 (dd, 1 H), 8.78 (d, 1 H), 8.82 (s, 1 H), 8.90 (t, 1 H), 9.37 9.44 (m, 2 H). 343 P IZ о u- О \ = O ^Z AY о 1,5-Anhydro-2,4dideoxy-2 - [({2- (5fluoropyridin-3 yl) -3-oxo-6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazin4yl} carbonyl) amino] -O-erythro-pentitol 2- (5-fluoropyr-idin-3-yl) -3-oxo-6- [6 (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine 4-carboxylic acid, hydrochloride (3S, 4R) -3- aminooxan-4-ol (1: 1) 'H NMR (400 MHz, DMSO-O δ ppm = 1.59 1.68 (m, 1 H), 1.73 - 1.83 (m, 1 H), 3.47 - 3.54 (m, 1 H), 3.57 (d, 2 H), 3.66 3.74 (m, 1 H), 3.91 - 3.97 (m, 1 H), 4.04 - 4.12 (m, 1 H), 5.25 (d, 1 H), 8.03 8.08 (m, 1 H), 8.26 - 8.32 (w, 1 H), 8.70 (dd, 1 H), 8.78 (d, 1 H), 8.85 (s, 1 H), 8.88 - 8.91 (m, 1 H), 9.39 (d, 1 H) , 9.55 (d, 1 H). 344 A 0? L Y ^H g [L CH ₃ 2- (5-fluoropyridin3-yl) -N- (2hydroxy-2methylpropyl) -3OXO-6- [6- (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazine 4-carboxamide 2- (5-fluoropyr-idin-3 yl) -3-oxo-6- [6- (trifluoromethyl) pyri din-3-yl] -2.3 - dihydropyridazine 4-carboxylic acid, 1-amino-2 methylpropan-2-ol 'H NMR (400 MHz, DMSO-O δ ppm = 1.14 (S, 6 H), 4.68 - 4.71 (s, 1 H), 8.04 - 8.07 (m, 1 H), 8.27 - 8.32 (m, 1 H), 8.70 (dd, 1 H), 8.78 (d, 1 H), 8.83 (s, 1 H), 8.89 - 8.92 (m, 1 H), 9.37 - 9.43 (br, 2 H). 345 n XX o o o) - ⁷ O% ZO ^ = Q ^z O N - [(2S) -1- hydroxypropane-2yl] -3-oxo-2- (pir idin-3-yl) -6- [five- (trifluoromethyl) pyridin-2-yl] -2,3- dihydropyridazine 4-carboxamide N - [(2S) -1- hydroxypropane-2yl] -3-oxo-6- [5 (trifluoromethyl) pyridin-2-yl] -2,3- dihydropyridazine 4-carboxamide, pyridine-3 ylboronic acid 'H NMR (400 MHz, DMSO-O δ ppm = 1.16 (d, 3 H), 3.41 - 3.49 (br, 2 H), 4.00 - 4.10 (m, 1 H), 4.96 (t, 1 H ), 7.65 (dd, 1 H), 8.18 - 8.22 (m, 1 H), 8.32 - 8.38 (m, 2 H), 8.72 (dbr, 1 H), 8.92 - 8.95 (br, 1 H), 9.09 ( s, 1 H), 9.17 9.19 (m, 1 H), 9.36 (d, 1 H).

Description of figures

FIG. 1 describes the sequence listing of the light chain of the TPP-3911 antibody (anti-PD-LL · mIgG1K_RG7446 chimera | light_ chain | pTT5-anti-PD-L1-huVH-muIgG1-CH1-CH3-κ chimera);

fig. 2 is a listing of the heavy chain sequences of the TPP-3911 antibody (anti-PD-L1mIgG1K_RG7446 chimera | heavy_chain | pTT5-anti-PD-L1-huVH-muIgG1 -CH1-CH3-κ-chimera.

Experimental section - biological analyzes.

The examples were tested in selected biological assays one or more times. When testing has been performed more than once, the data is reported either as averages or medians, where the mean, also called the arithmetic mean, is the sum of the values obtained divided by the number of tests performed, and the median is the median of the group of values. when ranked in ascending or descending order. If the number of values in the dataset is odd, the median is the median value. If the number of values in the dataset is even, the median is the arithmetic mean of the two median values.

Examples were synthesized one or more times. When synthesis has been performed more than once, data from biological analyzes are mean values or median values calculated using datasets obtained from testing one or more synthesis batches.

The in vitro activity of the compounds of the present invention can be demonstrated in the following assays.

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Assay of transactivation in a human cell line (in vitro assays 1 and 2).

Transactivation assays were performed on U87 glioblastoma cells (ATCC) endogenously expressing AHR. In addition, cells were stably transfected with an AHR-inducible firefly luciferase gene reporter construct, which carried AHR-binding sites (DRE) in its promoter, and a Renilla reporter gene construct with a constitutively active promoter. Kynurenic acid, which is an endogenous AHR-activating ligand, was used to pre-stimulate the test cells before testing the antagonistic properties of the compounds.

In vitro analysis 1. Antagonism in a human cell line.

Cells were grown in medium (tryptophan-free RPMI, 1% FCS, 2 mM glutamine) supplemented with 150 μM kynurenic acid for 20 h in the absence (negative control) or in the presence of increasing concentrations of test compounds (typical dilutions: 72 pmol / L , 0.25, 0.89; 3.1, 11, 38, 130, 470 nmol / L, 1.6, 5.7 and 20 μmol / L in duplicate). As a positive control for inhibition, cells supplemented with 150 μM kynurenic acid were incubated in the presence of 5 μM staurosporin. Normalization was performed using positive and negative controls.

Firefly and Renilla luciferase activities were determined using the DualGlo Luciferase Assay System (Promega, # 2920). Renilla activity was used to assess the toxicity of the compounds.

In vitro analysis 2. Agonism in a human cell line.

Cells were grown in medium (tryptophan-free RPMI, 1% FCS, 2 mM glutamine) for 20 h in the absence (negative control) or in the presence of increasing concentrations of test compounds (typical dilutions: 72 pmol / L, 0.25, 0.89; 3.1, 11, 38, 130, 470 nmol / L, 1.6, 5.7 and 20 μmol / L in duplicate). As a positive control of activation, cells were incubated with 300 μM kynurenic acid. Normalization was performed using positive and negative controls.

Firefly luciferase activity was determined using the SteadyGlo Luciferase Assay System (Promega, # 2520).

In vitro analysis 3. AHR-regulated expression of CYP1A1 in a human cell line.

To assess the AHR inhibitory activity of the substances described herein, their ability to antagonize ligand-induced regulation of the AHR gene was quantified in a dose-dependent manner. For this purpose, quantitative PCR analysis was used to determine the expression of the AHR-regulated CYP1A1 gene in the human monocytic cell line U937 upon stimulation with 200 μM KA in the presence and absence of an AHR inhibitor. U937 cells were plated at a concentration of 2x10 ⁵ cells / well in 100 μl growth medium (RPMI 1640, 20% FCS) in 96 well microtiter plates. CYP1A1 expression was induced with 200 μM KA (positive control) in the presence or absence of substances for 6 h. Human U937 cells were usually incubated with eight different concentrations of substances (1, 3, 10, 30, 100, 300 nM, 1 and 3 μM) and analyzed in duplicate on the same microtiter plate. After stimulation, cells were lysed with Nucleic Acid Lysis Solution (# 4305895, Applied Biosystems) and RNA was isolated using 6100 Nucleic Acid Preparation Station (Applied Biosystems) and back-transcribed into cDNA using Superscript VILO cDNA synthesis kit (# 11754- 250, Invitrogen). Unstimulated cells were used as negative control. Taqman probes for human CYP1A1 (Hs01054797_g1) and human HPRT (Hs02800695_m1) were used to analyze the expression fold of CYP1A1 or HPRT. Quantification was performed on a Taqman SDS7900HT.

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Table 3. IC50 values of examples in in vitro assays 1-3

Example Analysis 1: AHR-Luz. people, antagonism of IC _5O [Ml Analysis 2: AHR-Luz. people, agonism 1C ₅₀ [M] Analysis 3: CYP1A1 people, antagonism 1C ₅₀ [M] one 7.38 E-9 > 2.00 E-5 4.30 E-9 2 2.57 E-9 > 2.00 E-5 3.03 E-9 3 1.05 E-7 > 2.00 E-5 4 9.52 E-9 > 2.00 E-5 five 5.99 E-9 > 2.00 E-5 3.45 E-9 6 1.81 E-7 > 2.00 E-5 7 2.05 E-8 > 2.00 E-5 eight 1.90 E-8 > 2.00 E-5 1.58 E-8 nine 1.64 E-7 > 2.00 E-5 10 4.25 E-9 > 2.00 E-5 1.02 E-8 AND 4.55 E-9 > 2.00 E-5 1.50 E-10 12 2.32 E-8 > 2.00 E-5 1.85 E-8 13 3.25 E-8 > 2.00 E-5 2.00 E-8 fourteen 1.21 E-8 > 2.00 E-5 2.55 E-8 fifteen 2.65 E-8 > 2.00 E-5 1.22 E-7 sixteen 3.69 E-9 > 2.00 E-5 2.49 E-9 17 1.50 E-8 > 2.00 E-5 2.50 E-8 18 1.42 E-8 > 2.00 E-5 1.13 E-8 nineteen 3.92 E-9 > 2.00 E-5 6.43 E-9 twenty 2.67 E-8 > 2.00 E-5 6.31 E-8 21 2.80 E-8 > 2.00 E-5 1.82 E-8 22 2.00 E-8 > 2.00 E-5 1.12 E-8 23 4.57 E-8 > 2.00 E-5 24 8.75 E-8 > 2.00 E-5 25 6.82 E-8 > 2.00 E-5 9.11 E-8 26 8.75 E-8 > 2.00 E-5 27 1.77 E-7 > 2.00 E-5

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28 2.93 E-7 > 2.00 E-5 29 7.61 E-8 > 2.00 E-5 thirty 6.08 E-8 > 2.00 E-5 31 2.44 E-7 > 2.00 E-5 32 3.56 E-8 > 2.00 E-5 2.19 E-8 33 2.66 E-9 > 2.00 E-5 34 1.30 E-7 > 2.00 E-5 35 1.50 E-9 > 2.00 E-5 4.10 E-8 36 > 2.00 E-5 37 2.64 E-9 > 2.00 E-5 4.23 E-10 38 3.43 E-8 > 2.00 E-5 3.62 E-8 39 2.08 E-9 > 2.00 E-5 3.39 E-9 40 1.10 E-6 > 2.00 E-5 41 1.65 E-6 > 2.00 E-5 42 1.57 E-6 > 2.00 E-5 43 2.30 E-8 > 2.00 E-5 44 1.16 E-8 > 2.00 E-5 9.43 E-9 45 4.15 E-8 > 2.00 E-5 8.35 E-8 46 1.48 E-9 > 2.00 E-5 1.36 E-9 47 1.52 E-9 > 2.00 E-5 1.66 E-9 48 2.49 E-9 > 2.00 E-5 49 6.50 E-9 > 2.00 E-5 7.55 E-9 fifty 8.39 E-9 > 2.00 E-5 6.74 E-9 51 9.54 E-9 > 2.00 E-5 52 1.15 E-8 > 2.00 E-5 53 1.16 E-8 > 2.00 E-5 1.11 E-8 54 1.43 E-8 > 2.00 E-5 55 1.79 E-8 > 2.00 E-5 56 2.56 E-8 > 2.00 E-5 57 7.48 E-9 > 2.00 E-5 58 1.86 E-8 > 2.00 E-5 1.08 E-8 59 2.00 E-8 > 2.00 E-5 60 2.18 E-8 > 2.00 E-5 61 2.84 E-8 > 2.00 E-5 3.89 E-8 62 2.95 E-8 > 2.00 E-5 1.91 E-8 63 8.10 E-8 > 2.00 E-5 64 8.16 E-8 > 2.00 E-5 65 2.55 E-8 > 2.00 E-5 66 2.59 E-7 > 2.00 E-5 67 4.30 E-9 > 2.00 E-5 68 2.42 E-8 > 2.00 E-5 2.18 E-8 69 2.14 E-7 > 2.00 E-5 70 1.59 E-7 > 2.00 E-5 71 3.80 E-8 > 2.00 E-5 6.07 E-8

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72 1.82 E-7 > 2.00 E-5 4.95 E-7 73 2.83 E-7 > 2.00 E-5 3.55 E-7 74 1.52 E-7 > 2.00 E-5 75 8.34 E-8 > 2.00 E-5 76 1.19 E-8 > 2.00 E-5 1.38 E-8 77 1.12 E-8 > 2.00 E-5 8.70 E-9 78 6.68 E-9 > 2.00 E-5 4.81 E-9 79 3.95 E-8 > 2.00 E-5 8.04 E-8 80 2.71 E-8 > 2.00 E-5 3.26 E-8 81 1.06 E-7 > 2.00 E-5 82 3.76 E-8 > 2.00 E-5 3.45 E-8 83 4.61 E-9 > 2.00 E-5 84 1.63 E-7 > 2.00 E-5 85 3.60 E-8 > 2.00 E-5 86 5.59 E-8 > 2.00 E-5 87 2.96 E-8 > 2.00 E-5 2.15 E-8 88 7.80 E-8 > 2.00 E-5 89 4.80 E-9 > 2.00 E-5 2.64 E-9 90 2.17 E-8 > 2.00 E-5 4.02 E-8 91 4.81 E-8 > 2.00 E-5 92 1.90 E-8 > 2.00 E-5 2.76 E-9 93 2.48 E-8 > 2.00 E-5 4.32 E-9 94 8.44 E-9 > 2.00 E-5 1.65 E-8 95 6.23 E-8 > 2.00 E-5 96 3.67 E-9 > 2.00 E-5 3.77 E-9 97 7.06 E-9 > 2.00 E-5 98 2.51 E-7 > 2.00 E-5 99 1.29 E-7 > 2.00 E-5 100 1.27 E-8 > 2.00 E-5 101 9.54 E-9 > 2.00 E-5 102 1.88 E-9 > 2.00 E-5 1.69 E-9 103 1.33 E-8 > 2.00 E-5 2.45 E-8 104 2.02 E-8 > 2.00 E-5 1.48 E-8 105 2.37 E-9 > 2.00 E-5 1.86 E-9 106 > 2.00 E-5 107 1.23 E-8 > 2.00 E-5 108 > 2.00 E-5 109 1.63 E-9 > 2.00 E-5 110 3.31 E-9 > 2.00 E-5 111 2.65 E-8 > 2.00 E-5 112 1.15 E-9 > 2.00 E-5 9.05 E-10 FROM 4.83 E-8 > 2.00 E-5 1.05 E-7 114 8.55 E-8 > 2.00 E-5 115 2.63 E-9 > 2.00 E-5 1.09 E-8

- 189 037978

116 1.15 E-7 > 2.00 E-5 117 > 2.00 E-5 118 4.51 E-8 > 2.00 E-5 5.70 E-8 119 3.06 E-9 > 2.00 E-5 5.72 E-9 120 6.79 E-8 > 2.00 E-5 121 2.54 E-9 > 2.00 E-5 122 2.65 E-8 > 2.00 E-5 123 5.70 E-9 > 2.00 E-5 124 3.64 E-9 > 2.00 E-5 125 3.82 E-9 > 2.00 E-5 4.40 E-9 126 4.60 E-9 > 2.00 E-5 5.15 E-9 127 4.17 E-9 > 2.00 E-5 128 5.05 E-9 > 2.00 E-5 129 5.53 E-9 > 2.00 E-5 130 6.54 E-9 > 2.00 E-5 6.42 E-9 131 6.23 E-9 > 2.00 E-5 7.29 E-9 132 6.88 E-9 > 2.00 E-5 133 7.52 E-9 > 2.00 E-5 134 7.68 E-9 > 2.00 E-5 9.89 E-9 135 7.91 E-9 > 2.00 E-5 136 6.04 E-8 > 2.00 E-5 137 4.23 E-9 > 2.00 E-5 138 9.04 E-9 > 2.00 E-5 7.61 E-9 139 9.20 E-9 > 2.00 E-5 9.16 E-9 140 9.55 E-9 > 2.00 E-5 141 1.48 E-7 > 2.00 E-5 142 8.32 E-9 > 2.00 E-5 143 9.61 E-9 > 2.00 E-5 144 3.14 E-8 > 2.00 E-5 145 6.90 E-9 > 2.00 E-5 146 1.03 E-8 > 2.00 E-5 147 1.22 E-8 > 2.00 E-5 1.11 E-8 148 1.53 E-8 > 2.00 E-5 149 1.88 E-8 > 2.00 E-5 1.12 E-8 150 1.99 E-8 > 2.00 E-5 151 2.11 E-8 > 2.00 E-5 152 2.41 E-8 > 2.00 E-5 2.13 E-8 153 2.42 E-8 > 2.00 E-5 2.17 E-8 154 3.68 E-8 > 2.00 E-5 155 9.05 E-8 > 2.00 E-5 156 2.50 E-8 > 2.00 E-5 157 3.93 E-8 > 2.00 E-5 158 2.18 E-8 > 2.00 E-5 2.52 E-8 159 5.70 E-8 > 2.00 E-5 9.79 E-8

- 190 037978

160 7.92 E-8 > 2.00 E-5 161 1.03 E-7 > 2.00 E-5 162 2.73 E-8 > 2.00 E-5 3.73 E-8 163 1.34 E-7 > 2.00 E-5 164 1.57 E-7 > 2.00 E-5 165 2.09 E-7 > 2.00 E-5 166 1.80 E-7 167 2.39 E-7 > 2.00 E-5 168 2.40 E-7 169 3.17 E-8 > 2.00 E-5 170 5.73 E-8 > 2.00 E-5 2.24 E-8 171 5.84 E-8 > 2.00 E-5 172 2.95 E-8 > 2.00 E-5 2.34 E-8 173 5.49 E-8 > 2.00 E-5 1.40 E-7 174 6.15 E-8 > 2.00 E-5 175 6.61 E-8 > 2.00 E-5 1.12 E-7 176 6.61 E-8 > 2.00 E-5 3.88 E-8 177 4.65 E-7 > 2.00 E-5 178 5.94 E-7 > 2.00 E-5 179 7.36 E-7 > 2.00 E-5 180 7.94 E-7 > 2.00 E-5 181 9.11 E-7 > 2.00 E-5 182 6.11 E-6 > 2.00 E-5 183 1.97 E-6 > 2.00 E-5 184 3.81 E-6 > 2.00 E-5 185 3.71 E-8 > 2.00 E-5 186 1.31 E-7 > 2.00 E-5 187 3.35 E-8 > 2.00 E-5 188 1.25 E-8 > 2.00 E-5 189 3.03 E-9 > 2.00 E-5 190 6.56 E-8 > 2.00 E-5 191 3.35 E-9 > 2.00 E-5 192 3.41 E-7 > 2.00 E-5 4.30 E-9 193 3.52 E-7 > 2.00 E-5 3.03 E-9 194 3.09 E-9 > 2.00 E-5 7.60 E-9 195 3.63 E-10 > 2.00 E-5 196 4.18 E-10 > 2.00 E-5 197 5.02 E-10 > 2.00 E-5 198 5.99 E-10 > 2.00 E-5 199 6.94 E-10 > 2.00 E-5 200 7.34 E-10 > 2.00 E-5 201 8.23 E-10 > 2.00 E-5 202 8.25 E-10 > 2.00 E-5 203 8.52 E-10 > 2.00 E-5

- 191 037978

204 1.00 E-9 > 2.00 E-5 1.55 E-9 205 1.06 E-9 > 2.00 E-5 206 1.07 E-9 > 2.00 E-5 207 1.21 E-9 > 2.00 E-5 208 1.22 E-9 > 2.00 E-5 209 1.24 E-9 > 2.00 E-5 210 1.46 E-9 > 2.00 E-5 2.02 E-9 211 1.62 E-9 > 2.00 E-5 2.67 E-9 212 1.69 E-9 > 2.00 E-5 213 1.92 E-9 > 2.00 E-5 214 2.07 E-9 > 2.00 E-5 215 2.21 E-9 > 2.00 E-5 216 2.38 E-9 > 2.00 E-5 217 2.44 E-9 > 2.00 E-5 7.01 E-9 218 2.78 E-9 > 2.00 E-5 4.01 E-9 219 3.21 E-9 > 2.00 E-5 220 3.36 E-9 > 2.00 E-5 1.96 E-9 221 3.63 E-9 > 2.00 E-5 222 4.27 E-9 > 2.00 E-5 223 4.31 E-9 > 2.00 E-5 224 4.37 E-9 > 2.00 E-5 225 5.04 E-9 > 2.00 E-5 226 5.91 E-9 > 2.00 E-5 227 5.99 E-9 > 2.00 E-5 1.16 E-8 228 1.33 E-8 > 2.00 E-5 229 7.09 E-9 > 2.00 E-5 1.22 E-8 230 7.57 E-9 > 2.00 E-5 1.04 E-8 231 7.89 E-9 > 2.00 E-5 9.93 E-9 232 8.16 E-9 > 2.00 E-5 7.38 E-9 233 8.23 E-9 1.72 E-5 234 8.42 E-9 > 2.00 E-5 9.60 E-9 235 8.87 E-9 > 2.00 E-5 236 9.03 E-9 > 2.00 E-5 237 9.38 E-9 > 2.00 E-5 7.86 E-9 238 9.88 E-9 > 2.00 E-5 1.47 E-8 239 1.00 E-8 > 2.00 E-5 240 1.06 E-8 > 2.00 E-5 2.27 E-8 241 1.09 E-8 > 2.00 E-5 3.63 E-8 242 1.11 E-8 > 2.00 E-5 243 1.18 E-8 > 2.00 E-5 244 1.19 E-8 > 2.00 E-5 245 1.28 E-8 > 2.00 E-5 246 1.32 E-8 > 2.00 E-5 247 1.39 E-8 > 2.00 E-5

- 192 037978

248 1.41 E-8 > 2.00 E-5 3.13 E-8 249 1.53 E-8 > 2.00 E-5 250 1.69 E-8 > 2.00 E-5 1.05 E-8 251 1.79 E-8 > 2.00 E-5 252 1.80 E-8 > 2.00 E-5 253 1.94 E-8 > 2.00 E-5 254 2.29 E-8 > 2.00 E-5 255 2.58 E-8 > 2.00 E-5 256 2.60 E-8 > 2.00 E-5 257 2.63 E-8 > 2.00 E-5 258 2.75 E-8 > 2.00 E-5 259 2.81 E-8 > 2.00 E-5 260 2.94 E-8 > 2.00 E-5 1.44 E-8 261 3.30 E-8 > 2.00 E-5 262 4.12 E-8 > 2.00 E-5 263 4.19 E-8 > 2.00 E-5 264 4.44 E-8 > 2.00 E-5 8.56 E-8 265 4.88 E-8 > 2.00 E-5 266 5.68 E-8 > 2.00 E-5 267 5.69 E-8 > 2.00 E-5 268 5.69 E-8 > 2.00 E-5 269 6.17 E-8 > 2.00 E-5 270 6.45 E-8 > 2.00 E-5 271 7.20 E-8 > 2.00 E-5 272 9.11 E-8 > 2.00 E-5 273 1.01 E-7 > 2.00 E-5 274 1.11 E-7 > 2.00 E-5 275 1.30 E-7 > 2.00 E-5 276 1.31 E-7 > 2.00 E-5 277 1.39 E-7 > 2.00 E-5 278 1.40 E-7 > 2.00 E-5 279 1.68 E-7 > 2.00 E-5 280 1.78 E-7 > 2.00 E-5 281 2.61 E-7 > 2.00 E-5 282 3.04 E-7 > 2.00 E-5 283 4.30 E-7 > 2.00 E-5 284 5.71 E-7 > 2.00 E-5 285 6.02 E-7 > 2.00 E-5 286 6.72 E-7 > 2.00 E-5 287 7.21 E-7 > 2.00 E-5 288 8.20 E-7 > 2.00 E-5 289 8.75 E-7 > 2.00 E-5 290 2.82 E-9 > 2.00 E-5 291 4.38 E-9 > 2.00 E-5

- 193 037978

292 4.59 E-8 > 2.00 E-5 4.33 E-8 293 8.22 E-8 > 2.00 E-5 294 4.98 E-8 > 2.00 E-5 295 3.19 E-8 > 2.00 E-5 8.99 E-8 296 1.18 E-7 > 2.00 E-5 297 1.49 E-9 > 2.00 E-5 298 3.69 E-9 > 2.00 E-5 299 1.33 E-8 > 2.00 E-5 300 > 2.00 E-5 301 3.10 E-8 > 2.00 E-5 302 8.15 E-8 > 2.00 E-5 303 1.33 E-7 > 2.00 E-5 304 3.49 E-7 > 2.00 E-5 305 1.64 E-9 > 2.00 E-5 306 1.33 E-9 > 2.00 E-5 307 7.39 E-8 > 2.00 E-5 308 2.19 E-8 > 2.00 E-5 3.37 E-8 309 1.64 E-8 > 2.00 E-5 4.03 E-8 310 1.70 E-9 > 2.00 E-5 1.69 E-9 311 1.82 E-9 > 2.00 E-5 1.03 E-9 312 1.85 E-9 > 2.00 E-5 313 2.63 E-9 > 2.00 E-5 3.81 E-9 314 5.80 E-9 > 2.00 E-5 1.09 E-8 315 1.59 E-8 > 2.00 E-5 1.19 E-8 316 2.06 E-8 > 2.00 E-5 317 3.03 E-8 > 2.00 E-5 3.73 E-8 318 3.20 E-8 > 2.00 E-5 319 3.55 E-8 > 2.00 E-5 2.23 E-8 320 4.41 E-8 > 2.00 E-5 321 5.06 E-8 > 2.00 E-5 322 5.67 E-8 > 2.00 E-5 3.11 E-8 323 6.04 E-8 > 2.00 E-5 324 1.22 E-7 > 2.00 E-5 325 2.42 E-7 > 2.00 E-5 326 5.04 E-10 > 2.00 E-5 327 2.58 E-9 > 2.00 E-5 328 3.06 E-8 > 2.00 E-5 329 2.94 E-8 > 2.00 E-5 330 9.27 E-8 > 2.00 E-5 331 2.34 E-7 > 2.00 E-5 332 9.45 E-8 > 2.00 E-5 333 7.49 E-8 > 2.00 E-5 334 6.02 E-8 > 2.00 E-5 335 1.13 E-8 > 2.00 E-5 336 4.29 E-8 > 2.00 E-5 337 2.08 E-8 > 2.00 E-5 338 2.41 E-8 > 2.00 E-5 339 2.76 E-8 > 2.00 E-5 340 4.97 E-8 > 2.00 E-5 341 1.02 E-7 > 2.00 E-5 342 1.32 E-7 > 2.00 E-5 343 1.71 E-7 > 2.00 E-5 344 1.74 E-7 > 2.00 E-5 345 5.53 E-8 > 2.00 E-5

In vitro assay 4. Rescue of TNFa production from primary human monocytes.

Determined the ability of substances to enhance the activity of immune cells. The substances were tested for their ability to reverse KA-induced inhibition of TNFa production by LPS-stimulated human monocytes. Human monocytes were purified by negative selection from donor PBMCs using Miltenyi beads and plated at 2x105 cells / well in complete growth medium (RPMI 1640, 10% FCS). Monocytes were incubated with 10 ng / ml LPS (O127: B8, # L4516, Sigma) and 200 μM KA (# 3375, Sigma), substances were added at concentrations of 1, 0.3, and 0.1 μM, and culture

- 194 037978 were run for 18 hours. LPS taken separately served as a positive control. The production of TNFa in the supernatant was measured using the Meso Scale Discovery immunoassay and the ability of the substances to rescue TNFa production was calculated as a percentage of LPS stimulation and KA-induced inhibition and normalized to a donor-specific response using the reference AHR antagonist compound GNF-351 (Smith et al., J. Pharmacol Exp Ther 2011, 338 (1): 31827). Table 4 shows the highest percentage of TNFa rescue relative to the highest percentage of rescue with GNF-351 (observed predominantly at concentrations of 0.3 and 0.1 μM) and the concentration at which the greatest rescue was observed with the test compound.

Table 4. Human Monocytes: Efficacy of Selected Compounds - Examples in In Vitro Assay 4

Example Individual donors % TNFa recovery normalized to reference compound Individual Donors Conc, Greatest Salvation five 67 1 μM 99 1 μM 61 1 μM 7 126 0.1 μM 63 1 μM 49 1 μM eight 99 1 μM 55 1 μM 104 1 μM 109 1 μM 36 0.1 μM 12 74 0.1 μM 122 1 μM 213 0.1 μM 109 0.3 μM 13 24 1 μM 85 1 μM sixteen 249 1 μM 165 1 μM 17 438 1 μM 296 1 μM 18 83 1 μM 73 1 μM 76 0.3 μM 105 0.3 μM 21 87 0.3 μM 77 1 μM 22 66 1 μM 71 1 μM 23 274 1 μM 81 1 μM 24 84 0.3 μM 59 1 μM 25 46 1 μM 53 1 μM

- 195 037978

27 87 105 1 μM 0.3 μM 29 66 88 1 μM 1 μM 36 74 65 1 μM 1 μM 47 68 64 1 μM 1 μM 69 88 97 0.1 μM 0.1 μM 79 76 63 0.3 μM 0.1 μM 88 69 35 1 μM 1 μM ON 85 42 0.1 μM 0.3 μM 113 91 51 1 μM 1 μM 138 49 84 0.1 μM 0.3 μM 147 fifty 89 0.1 μM 0.3 μM 184 63 62 0.1 μM 1 μM 186 65 108 0.1 μM 0.3 μM

In vivo analysis: efficacy of formulations containing an example compound and a PD1 / -L1 axis antagonist.

Animals were ordered from Charles River Sulzfeld, Germany, and entered into the study at the age of 7 weeks. Keeping animals, feeding and sanitary conditions corresponded to the established rules for keeping animals. The B16F10-OVA cells were B16F10 murine melanoma cells that were virally transduced to express ovalbumin. B16F10-OVA cells were cultured with RPMI 1640 with 10% FCS + 2.5 μg / ml blasticidin and split at least 3 times prior to inoculation. The antibiotic blasticidin was removed 1 pass before inoculation. Female C57 / BL6N mice were inoculated with 100,000 B16F10OVA tumor cells in 50% medium / 50% Matrigel by subcutaneous injection into the flanks. After 5 days, the animals were randomized and therapeutic treatment started. The AhR antagonist was dissolved in ethanol / solutol / water (10/40/50) and given to animals at a dose of 30 mg / kg, once a day, po. Anti-PD-L1 antibody (TPP-3911) was dosed at 10 mg / kg, once every 3 days, and / p. Isotypic control mIgG1 was given at 10 mg / kg once every 3 days (TPP-3267), and / p.

Anti-PDL1 antibody was a chimera of the variable domain of atezolizumab with murine IgG1 CH1, 2 and 3 domains. TRP-3911. The isotypic antibody was mouse IgG1 (clone MOPC-21, BioXCell BE0083).

The size of the tumor was measured with a caliper, determining the length (a) and width (b). Tumor volume was calculated in accordance with the formula a x b ²

Based on the tumor volume, efficacy was calculated by dividing the tumor volume in the corresponding treatment group by the tumor volume in the control group (T / C)

Control: isotype + vehicle aPDLl + media Example 17 + isotype Example 17 + aPDLl T / C 1.00 0.96 0.92 0.71

In vivo analysis: efficacy of formulations containing an example compound and a CTLA4 axis antagonist.

Animals were ordered from Charles River Sulzfeld, Germany, and entered into the study at the age of 8 weeks. Keeping animals, feeding and sanitary conditions corresponded to the established rules for keeping animals. The B16F10-OVA cells were B16F10 murine melanoma cells that were virally transduced to express ovalbumin. B16F10-OVA cells were cultured with RPMI 1640 with 10% FCS + 2.5 μg / ml blasticidin and split at least 3 times prior to inoculation. The antibiotic blasticidin was removed 1 pass before inoculation. Female C57 / BL6J mice were inoculated with 10,000 B16F10-OVA tumor cells in 50% medium / 50% Matrigel by subcutaneous injection into the flanks. After 7 days, the animals were randomized and treatment started on day 8. The AhR antagonists were dissolved in a mixture of ethanol / solutol / water (10/40/50) and administered to the animals at a dose of 30 mg / kg, once a day, po. Antibody aHTu-CTLA4 was dosed at 1 mg / kg, once every 3 days, and / p. The anti-CTLA4 antibody was mouse-specific with the Syrian hamster IgG1 isotype (Clone: 9H10 (mouse anti-CTLA4), Fa. BioXCell BE0131). The isotypic antibody was Syrian hamster IgG1 (TPP-9833).

The size of the tumor was measured with a caliper, determining the length (a) and width (b). Tumor volume was calculated in accordance with the formula a x b ²

Based on the tumor volume, efficacy was calculated by dividing the tumor volume in the corresponding treatment group by the tumor volume in the control group (T / C).

Control: aCTLA4 Example Example Example Example 131 isotype + (1 mg / kg) 17 131 17 + + aCTLA4 carrier + carrier + isotype + isotype aCTLA4 (1 mg / kg) (1 mg / kg)

T / C 1.00 0.81 0.90 1.05 0.64 0.69

Clones MORS-21 and 9H10 (mouse anti-CTLA4) can be purchased, for example, through Bio X Cell, 10 Technology Dr., Suit 2B, West Lebanon, NH 03784-1671 USA (Catalog #: BE0083 (in vivo Mab quality) # BP0083 (in vivo Plus quality), corresponding to Catalog #: BE0131).

Claims (13)

CLAIM 1. Compound of general formula (I) in which R ¹ is C ₂ -C ₅ hydroxyalkyl, wherein said C ₂ -C ₅ hydroxyalkyl groups are optionally substituted once with cyano, —COOCH ₃ , —CONH2, methoxy or C ₃ -C ₆ cycloalkyl and optionally 1- 3 times fluorine, or C ₄ -C ₆ -cycloalkyl substituted once with hydroxy and optionally once with methyl and / or 1-2 times with fluorine, or C ₃ -C ₄ -cycloalkylmethyl substituted once with hydroxy, or 5- or 6-membered heterocycloalkyl substituted once with hydroxy, wherein said heterocycloalkyl contains one oxygen or sulfur atom; R ² is chlorine, cyano, dimethylamino, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, difluoromethoxy, or trifluoromethoxy; R ³ is hydrogen; R ⁴ is hydrogen or fluorine; R ⁵ represents a group selected from where * denotes the point of attachment of the specified group to the rest of the molecule; R ^6a represents hydrogen, methyl, fluorine or chlorine; X is CH or N; - 197 037978 their physiologically acceptable salts and solvates of these salts, as well as mixtures thereof. 2. A compound according to claim 1, which is selected from the group consisting of the following compounds: N- (1-hydroxy-3-methylbutan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine- 4-carboxamide; N - [(2R) -1-hydroxy-3-methylbutan-2-yl] -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxamide; N - [(2S) -1-hydroxy-3-methylbutan-2-yl] -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxamide; N- (1-hydroxybutan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide; N - [(2R) -1-hydroxybutan-2-yl] -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine- 4-carboxamide; N - [(2S) -1-hydroxybutan-2-yl] -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine- 4-carboxamide; N- (1-hydroxypropan-2-yl) -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide; N - [(2R) -1-hydroxypropαn-2-yl] -6- (4-methylphenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine- 4-carboxamide; N - [(2S) -1-hydroxypropan-2-yl] -6- (4-methylphenyl) -2- (1-methyl-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 β-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 β-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-methylbutan-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -N - [(2S) -1-hydroxy-3-methylbutan-2-yl] -2- (1-methyl-1H-pyrαzol-4-yl) -3-oxo-2, 3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N- (1-hydroxypropan-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(2S) -1-hydroxypropan-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-pyrαzol-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-methoxynropyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(2R) -2-hydroxy-3-methoxynropyl] -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; - 198 037978 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-methoxypropan-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -N - [(2R) -1-hydroxy-3-methoxypropan-2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3- dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(2S) -1-hydroxy-3-methoxypropan-2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3- dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N- (1,3-dihydroxypropan-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-hydroxypropan-2-yl) -2, 3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-N - [(2R) -1,1,1-trifluoro-3-hydroxypropane-2yl] - 2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-N - [(2S) -1,1,1-trifluoro-3-hydroxypropane-2yl] - 2,3-dihydropyridazine-4-carboxamide; 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-N- (1,1,1-trifluoro-3-hydroxypropan-2-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-N - [(2R) -1,1,1-trifluoro-3-hydroxynropan-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-hydroxynropyl) -6- [4- (trifluoromethyl) phenyl] -2,3 β-dihydropyridazine-4-carboxamide; 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-N - [(2S) -3,3,3-trifluoro-2-hydroxynpropyl] -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; N- (1-hydroxypropan-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4 -carboxamide; N - [(2R) -1-hydroxynropan-2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (mfluoromethyl) phenyl] 2,3- dihydropyridazine-4-carboxamide; N - [(2S) -1-hydroxypropan-2-yl] -2- (1 -methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) phenyl] 2,3- dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (1-cyclobutyl-1H-purazol-4-yl) -3-oxo-N- (3,3,3-mrifluoro-2-hydroxynpropyl) 2,3-dihydropyridazine-4 -carboxamide; 6- (4-chlorophenyl) -2- (1-cyclobutyl-1H-purazol-4-yl) -3-oxo-N - [(2S) -3,3,3-trifluoro-2-hydroxynpropyl] -2, 3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (1-cyclobutyl-1H-purazol-4-yl) -3-oxo-N- (1,1,1-mrifluoro-3-hydroxynropane-2yl) -2,3- dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (1-cyclobutyl-1H-purazol-4-yl) -3-oxo-N - [(2R) -1,1,1-mrifluoro-3-hydroxynropan-2-yl ] -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (1-cyclobutyl-1H-purazol-4-yl) -N- (1-hydroxynropan-2-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (1-cyclobutyl-1H-purazol-4-yl) -N - [(2S) -1-hydroxynropan-2-yl] -3-oxo-2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-purazol-4-yl) -3-oxo2,3-dihydropyridazine-4- carboxamide; 6- (4-chlorophenyl) -N - [(3R, 4R) -4-hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-purazol-4-yl) -3-oxo2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -N - [(3S, 4S) -4-hydroxytetrahydrofuran-3-yl] -2- (1-methyl-1H-purazol-4-yl) -3-oxo2,3-dihydropyridazine- 4-carboxamide; N - [(cis) -2-hydroxycyclohexyl] -2- (1-methyl-1H-purazol-4-yl) -3-oxo-6- [4- (mfluoromethoxy) phenyl] -2,3-dihydropyridazine-4 -carboxamide; N - [(1S, 2R) -2-hydroxycyclohexyl] -2- (1-methyl-1H-purazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine -4-carboxamide; 2- (1-methyl-1H-pyrazol-4-yl) -3-okco-N- (1,1,1-trifluoro-3-hydroxypropan-2-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide; 2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-N - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -6- [4- ( trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(cis) -2-hydroxycyclohexyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(1S, 2R) -2-hydroxycyclohexyl] -2- (1-methyl-1H-purazol-4-yl) -3-oxo-2,3-dihydropyridazine-4- carboxamide; - 199 037978 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, 2R) -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-hydroxypropan-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3 dihydropyridazine-4-carboxamide ; N - [(2S) -1-hydroxypropan-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-pyrαzol-4-yl) 3-oxo-2,3- dihydropyridazine-4-carboxamide; 6- [6- (difluoromethyl) pyridin-3-yl] -N - [(1 S, 2R) -2-hydroxycyclohexyl] -2- (1-methyl-1H-pyrazol-4yl) -3-oxo-2, 3-dihydropyridazine-4-carboxamide; N - [(cis) -4-hydroxytetraαhydrofuran-3-yl] -2- (1-methyl-1Н-pyrαzol-4-yl) -3-oxo-6- [4- (trifluoromethoxy) phenyl] -2,3 β-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-hydroxypropan-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4 -carboxamide; 6- [4- (difluoromethyl) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-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-4yl) -3-oxo-2,3-dihydropyridazine -4-carboxamide; 1,5-anhydro-2 - ({[6- (4-chlorophenyl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine-4yl] carbonyl} amino ) -2,4-dideoxy-E-erythro-pentitol; 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 β-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 - [(3 S, 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-hydroxypropan-2-yl) -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine -4-carboxamide; 6- [6- (difluoromethyl) pyridin-3-yl] -N - [(2S) -1-hydroxypropan-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-hydroxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(2R) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine 4-carboxamide; 6- (4-chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4carboxamide; 6- (4-chlorophenyl) -N- (1,3-dihydroxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4carboxamide; 6- (4-chlorophenyl) -N- (2-hydroxy-2-methylpropyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4carboxamide; 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-4carboxamide; - 200 037978 6- (4-chlorophenyl) -N - [(2S) -2,3-dihydroxypropyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4carboxamide; 6- (4-chlorophenyl) -N- (1-hydroxy-3-methoxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(2R) -1-hydroxy-3-methoxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4- carboxamide; 6- (4-chlorophenyl) -N - [(2S) -1-hydroxy-3-methoxypropan-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-hydroxypropan-2-yl) -2,3-dihydropyridazine-4- carboxamide; 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -N - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -2,3- dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -N - [(2S) -1,1,1-trifluoro-3-hydroxypropan-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-hydroxypropan-2-yl) -3-oxo-2,3-dihydropyridazine 4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(2R) -1-hydroxypropan-2-yl] -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N- (2-hydroxy-2-methylpropyl) -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N- (1-hydroxy-3-methylbutan-2-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(2S) -1-hydroxy-3-methylbutan-2-yl] -3-oxo-2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -N- (1,3-dihydroxypropan-2-yl) -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N- (1-hydroxy-3-methoxypropan-2-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(2R) -1-hydroxy-3-methoxypropan-2-yl] -3-oxo-2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(2S) -1-hydroxy-3-methoxypropan-2-yl] -3-oxo-2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -N- (1-fluoro-3-hydroxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(2R) -1-fluoro-3-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazin-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; - 201 037978 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-okco-N- (1,1,1-trifluoro-3-hydroxypropan-2-yl) -2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-okco-N - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] 2,3 β-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 - [(1 S, 2R) -2-hydroxycyclohexyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] 2,3-dihydropyridazine-4-carboxamide; 3-oxo-2- (pyridin-3-yl) -N- (3,3,3-trifluoro-2-hydroxypropyl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide ; 3-oxo-2- (pyridin-3-yl) -N - [(2S) -3,3,3-trifluoro-2-hydroxypropyl] -6- [4- (trifluoromethyl) phenyl] -2,3 dihydropyridazin-4 -carboxamide; 3-oxo-2- (pyridin-3-yl) -N- (1,1,1-trifluoro-3-hydroxypropan-2-yl) -6- [4- (trifluoromethyl) phenyl] -2,3 dihydropyridazine-4 -carboxamide; 3-oxo-2- (pyridin-3-yl) -N- (1,1,1-trifluoro-3-hydroxypropan-2-yl) -6- [4- (trifluoromethyl) phenyl] -2,3 dihydropyridazine-4 -carboxamide; 3-oxo-2- (pyridin-3-yl) -N - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -6- [4- (trifluoromethyl) phenyl] -2 , 3-dihydropyridazine-4-carboxamide; N- (1-hydroxy-3-methoxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide ; N - [(2S) -1 -hydroxy-3-methoxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] 2,3-dihydropyridazine- 4-carboxamide; N- (2,3-dihydroxypropyl) -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; N - [(2R) -2,3-dihydroxypropyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; N - [(2S) -2,3-dihydroxypropyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; N- (2-hydroxy-2-methylpropyl) -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; N- (1,3-dihydroxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; N- (1-hydroxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; N - [(2R) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide ; N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide ; 6- (4-chlorophenyl) -N- (1-hydroxypropan-2-yl) -3-oxo-2- (pyrimidin-5-yl) -2,3-dihydropyridazine-4carboxamide; 6- (4-chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyrimidin-5-yl) -2,3-dihydropyridazine-4-carboxamide; - 202 037978 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -N- (1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl) -2,3- dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -N - [(2R) -1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl] 2 , 3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -N - [(2S) -1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl] 2 , 3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(cis) -2-hydroxycyclohexyl] -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(1S, 2R) -2-hydroxycyclohexyl] -3-oxo-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-hydroxypropan-2-yl) -2,3 dihydropyridazine-4 -carboxamide; 6- [4- (difluoromethyl) phenyl] -3-oxo-2- (pyridin-3-yl) -N - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] 2, 3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-N- (3,3,3-trifluoro-2-hydroxypropyl) -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -3-oxo-N - [(2S) -3,3,3-trifluoro-2-hydroxypropyl] -2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(cis) -2-hydroxycyclopentyl] -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(1S, 2R) -2-hydroxycyclopentyl] -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(trans) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(1S, 2S) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 3-oxo-2- (pyridin-3-yl) -N- (3,3,3-trifluoro-2-hydroxypropyl) -6- [4- (trifluoromethoxy) phenyl] -2,3 dihydropyridazine-4-carboxamide; 3-oxo-2- (puridin-3-yl) -N - [(2S) -3,3,3-trifluoro-2-hydroxypropyl] -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine- 4-carboxamide; N - [(mrans) -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- (puridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(cis) -2-hydroxycyclohexyl] -3-oxo-2- (puridin-3-yl) -2,3-dihydropuridαzine 4-carboxamide; 3-oxo-2- (pyridin-3-yl) -N- (1,1,1-trifluoro-3-hydroxypropan-2-yl) -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine- 4-carboxamide; 3-oxo-2- (pyridin-3-yl) -N - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -6- [4- (trifluoromethoxy) phenyl] -2 , 3-dihydropyridazine-4-carboxamide; 3-oxo-2- (pyridin-3-yl) -N- (1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl) -6- [4- (trifluoromethoxy) phenyl] -2 , 3-dihydropyridazine-4-carboxamide; 3-oxo-2- (pyridin-3-yl) -N - [(2R) -1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl] -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide; 3-oxo-2- (pyridin-3-yl) -N - [(2S) -1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl] -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(cis) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine 4-carboxamide; 6- (4-chlorophenyl) -N - [(1R, 2S) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 6- [4- (difluoromethyl) phenyl] -N - [(trans) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 6- [4- (difluoromethyl) phenyl] -N - [(1S, 2S) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; - 203 037978 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-hydroxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 6- [4- (difluoromethyl) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyrvdin-3-yl) -2,3-dihydropyridazine-4-carboxamide ; N- (1-hydroxypropan-2-yl) -6- (4-methylphenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4carboxamide; N - [(2S) -1-hydroxypropan-2-yl] -6- (4-methylphenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine 4-carboxamide; N- (1-hydroxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide; N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4-carboxamide ; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(trans) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2,3 dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(3S, 4R) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2,3 dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoropyridin-3-yl) -N - [(3R, 4S) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2,3 dihydropyridazine-4-carboxamide; N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine-4-carboxamide; N - [(3S, 4S) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazin-4 -carboxamide; N - [(3R, 4R) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazin-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-dihydropyridazin-4 -carboxamide; N - [(3R, 4S) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazin-4 -carboxamide; 6- (4-chloro-2-fluorophenyl) -N- (1-hydroxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 6- (4-chloro-2-fluorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazin-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 - [(tαns) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxamide; 6- [6- (difluoromethyl) pyridin-3-yl] -N - [(1S, 2S) -2-hydroxycyclopentyl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxamide ; N- (1-hydroxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -6- [6- (trifluoromethyl) pyridin-3-yl] -2,3-dihydropyridazine-4-carboxamide ; - 204 037978 N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [6- (trifluoromethyl) pyridin-3-yl] -2,3 dihydropyridazin-4 -carboxamide; 3- (4-chlorophenyl) -N - [(cis) -2-hydroxycyclopentyl] -6-oxo-6H-1,4'-bipyridazine-5-carboxamide; 3 - (4-chlorophenyl) -N - [(1 S, 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-hydroxytetraαhydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(3R, 4R) -4-hydroxytetraαhydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(3S, 4S) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 3 - (4-chlorophenyl) -N - [(trans) -2-hydroxycyclopentyl] -6-oxo-6H-1,4'-bipyridazine-5-carboxamide; 3- (4-chlorophenyl) -N - [(1S, 2S) -2-hydroxycyclopentyl] -6-oxo-6H-1,4'-bipyridazine-5-carboxamide; 1,5-anhydro-2 - ({[6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazin-4-yl] carbonyl} amino) -2, 4-dideoxy-cis-pentitol; 1,5-anhydro-2 - ({[6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazin-4-yl] carbonyl} amino) -2, 4-dideoxy-O-erythro-pentitol; 1,5-anhydro-2,4-dideoxy-2 - [({3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4- yl} carbonyl) amino] cis-pentitol; 1,5-anhydro-2,4-dideoxy-2 - [({3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3-dihydropyridazine-4- yl} carbonyl) amino] -B-erythro-pentitol; 3- (4-chlorophenyl) -N- (1-hydroxypropan-2-yl) -6-oxo-6H-1,4'-bipyridazine-5-carboxamide; 3- (4-chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -6-oxo-6H-1,4'-bipyridazine-5-carboxyamide; 3- (4-chlorophenyl) -N- (2-hydroxy-2-methylpropyl) -6-oxo-6H-1,4'-bipyridazine-5-carboxamide; 6- (4-cyanophenyl) -N- (1-hydroxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4carboxamide; 6- (4-cyanophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine 4-carboxamide; 6- [6- (difluoromethyl) pyridin-3-yl] -N- (1-hydroxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide ; 6- [6- (difluoromethyl) pyridin-3-yl] -N - [(2S) -1-hydroxypropαn-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-3yl) -2,3-dihydropyridazin-4 -carboxamide; 6- [6- (difluoromethyl) pyridin-3-yl] -N - [(3R, 4S) -4-methyltetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3yl) -2,3-dihydropyridazine -4-carboxamide; 6- [6- (difluoromethyl) pyridin-3-yl] -N - [(3 S, 4R) -4-methyltetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3 yl) -2.3 β-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -3-oxo-2- (pyrimidin-5-yl) -N- (1,1,1-trifluoro-3-hydroxy-3-methylbutan-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-methylbutan-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-methylbutan-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-hydroxypropan-2-yl) -3-oxo-2- (1H-pyrazol-4-yl) -2,3-dihydropyridazine-4carboxamide; 6- (4-chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (1H-pyrazol-4-yl) -2,3-dihydropyridazine-4-carboxamide; 6- [4- (dimethylamino) phenyl] -N- (1-hydroxypropan-2-yl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 6- [4- (dimethylamino) phenyl] -N - [(2S) -1-hydroxypropαn-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydro- 205 037978 pyridazine -4-carboxamide; 6- (4-chlorophenyl) -N- (1-hydroxypropan-2-yl) -2- (1-methyl-1H-pyrazol-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -2- (1-methyl-1H-pyrazol-3-yl) -3-oxo-2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -N- (1-hydroxypropan-2-yl) -2- (3-methyl-1H-pyrazol-5-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -2- (3-methyl-1H-pyrazol-5-yl) -3-oxo-2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -N- (1-hydroxypropan-2-yl) -3-oxo-2- (1,2-thiazol-4-yl) -2,3-dihydropyridazine-4carboxamide; 6- (4-chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (1,2-thiazol-4-yl) -2,3-dihydropyridazine 4-carboxamide; N - [(1-hydroxycyclobutyl) methyl] -3-oxo-2- (1,2-thiazol-4-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; N - [(2S) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-2- (1,2-thiazol-4-yl) -6- [4- (trifluoromethyl) phenyl] -2 , 3-dihydropyridazine-4-carboxamide; (+) - 3-oxo-2- (pyridin-3-yl) -N- (1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide, enantiomer 2; 6- (4-chlorophenyl) -3-oxo-2- (1,2-thiazol-4-yl) -N - [(2R) -1,1,1-mrifluoro-3-hydroxypropan-2-yl] - 2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -3-oxo-2- (1,2-thiazol-4-yl) -N - [(2S) -3,3,3-trifluoro-2-hydroxypropyl] -2,3- dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(1-hydroxycyclobutyl) methyl] -3-oxo-2- (1,2-thiazol-4-yl) -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(2R) -1-fluoro-3-hydroxypropan-2-yl] -3-oxo-2- (1,2-thiazol-4-yl) -2,3- dihydropyridazine-4-carboxamide; N - [(2R) -3-hydroxy-3-methylbutan-2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; N - [(2R) -1-fluoro-3-hydroxypropan-2-yl] -3-oxo-2- (1,2-thiazol-4-yl) -6- [4- (trifluoromethyl) phenyl] -2 , 3-dihydropyridazine-4-carboxamide; N - [(1S, 2R) -2-hydroxycyclopentyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (mfluoromethyl) phenyl] -2,3-dihydropyridazine -4-carboxamide; N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (1,2-thiazol-4-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine -4-carboxamide; N - [(2S) -3-hydroxy-3-methylbutan-2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; N - [(1S) -1 -cyclopropyl-2-hydroxyethyl] -3-oxo-2- (1,2-thiazol-4-yl) -6- [4- (trifluoromethyl) phenyl] -2,3 dihydropyridazine-4 -carboxamide; N- (2-hydroxy-2-methylpropyl) -3-oxo-2- (1,2-thiazol-4-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide ; 6- (4-chlorophenyl) -N - [(2S) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-2- (1,2-thiazol-4-yl) -2,3- dihydropyridazine-4-carboxamide; N - [(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-hydroxypropan-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-hydroxypropan-2-yl] -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; 3-oxo-2- (pyridin-3-yl) -N- (1,1,1-trifluoro-3-hydroxy-3-methylbutan-2-yl) -6- [4- (trifluoromethyl) phenyl] -2 , 3-dihydropyridazine-4-carboxamide; 2- [1 - (difluoromethyl) -1H-pyrazol-4-yl] -3-okco-N - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -6- [4 (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; N-cis-4-hydroxytetrahydrofuran-3 -yl-2- (1-methyl-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, enantiomer 1; (+) - N-cis-4-hydroxytetrahydrofuran-3-yl-2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) phenyl] -2.3 β-dihydropyridazine-4-carboxamide, enantiomer 2; N - [(2S) -3,3-difluoro-2-hydroxypropyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) fe-206 037978 nyl] -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-fluoro-2-thienyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2,3-dihydropyridazine-4-carboxamide; N - [(2R) -1-fluoro-3-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3 dihydropyridazine-4 -carboxamide; 6- (4-chlorophenyl) -N- (2-hydroxy-2-methylpropyl) -3-oxo-2- (1,2-thiazol-4-yl) -2,3-dihydropyridazine 4-carboxamide; 2- [1- (difluoromethyl) -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-methylbutan-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-methylbutan-2-yl] -3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; (+) - N-cis-4-hydroxytetrahydrofuran-3-yl-3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] 2,3-dihydropyridazine-4-carboxamide, enantiomer 1; (-) - N- (3,3-difluoro-2-hydroxypropyl) -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4 -carboxamide, enantiomer 2; (-) - N-cis-4-hydroxytetrahydrofuran-3-yl-2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-6- [4- (trifluoromethyl) phenyl] -2.3 β-dihydropyridazine-4-carboxamide, enantiomer 1; 6- (4-chlorophenyl) -2- (5-chloro-3-thienyl) -3-oxo-N - [(2S) -3,3,3-trifluoro-2-hydroxypropyl] -2,3-dihydropyridazine- 4-carboxamide; N - [(2S) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-2- (1,2-thiazol-4-yl) -6- [6- (trifluoromethyl) pyridin-3 yl ] -2,3-dihydropyridazine-4-carboxamide; N - [(2R) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3 dihydropyridazin-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; 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; 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 β-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-thiazol-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-methylbutan-2-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide, enantiomer 1; 6- (4-chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -2- (5-methyl-3-thienyl) -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- (5-chloro-3-thienyl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2,3-dihydropyridazine-4-carboxamide; N - [(2S) -1-hydroxypropan-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 β-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, enantiomer one; 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, enantiomer 1; 6- (4-chlorophenyl) -2- (5-chloro-3-thienyl) -N- (2-hydroxy-2-methylpropyl) -3-oxo-2,3-dihydropuridazine - 207 037978 4-carboxamide; N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (1,2-thiazol-4-yl) -6- [6- (trifluoromethyl) pyridin-3-yl] -2 , 3-dihydropyridazine-4-carboxamide; (-) - N-cis-4-hydroxytetrahydrofuran-3-yl-3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] 2,3-dihydropyridazine-4-carboxamide, enantiomer 2; 6- (4-chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -2- (1,2-oxazol-4-yl) -3-oxo-2,3-dihydropyridazine-4- carboxamide; 6- (4-chlorophenyl) -N - [(1S) -1-cyano-2-hydroxyethyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine 4-carboxamide; N - [(2S) -3-fluoro-2-hydroxypropyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide ; 6- (4-chlorophenyl) -2- [1- (difluoromethyl) -1H-pyrazol-4-yl] -3-oxo-N - [(2S) -3,3,3-trifluoro-2-hydroxypropyl] - 2,3-dihydropyridazine-4-carboxamide; N - [(2R) -1-hydroxy-3-methoxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] 2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -N-cis-2-hydroxycyclobutyl-3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4carboxamide; 6- (4-chlorophenyl) -N - [(1S) -1 -cyclopropyl-2-hydroxyethyl] -2- (5-fluoropyridin-3-yl) -3-oxo-2,3-dihydropyridazine-4-carboxamide; N - [(2S) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-2- (1H-pyrazol-4-yl) -6- [4- (trifluoromethyl) phenyl] -2,3 dihydropyridazine -4-carboxamide; 2- [1- (difluoromethyl) -1H-pyrazol-4-yl] -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-6- [4- (trifluoromethyl) phenyl] -2 , 3-dihydropyridazine-4-carboxamide; 2- [1- (difluoromethyl) -1H-pyrazol-4-yl] -N- (2-hydroxy-2-methylpropyl) -3-oxo-6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine -4-carboxamide; 6- (4-chlorophenyl) -N - [(1-hydroxycyclopropyl) methyl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- [1 - (difluoromethyl) -1H-pyrazol-4-yl] -N - [(2S) -3-hydroxy-3-methylbutan-2-yl] -3 oxo-2 , 3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(2R) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-2- (pyrimidin-5-yl) -2,3-dihydropyridazine-4- carboxamide; N- (2-hydroxy-2-methylpropyl) -3-oxo-2- (1H-pyrazol-4-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide; methyl N - {[6- (4-chlorophenyl) -2- (1-methyl-1H-pyrαzol-4-yl) -3-oxo-2,3-dihydropyridazin-4-yl] carbonyl} -D-serinate; (-) - N-cis-2-hydroxycyclobutyl-3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3-dihydropyridazine-4-carboxamide, enantiomer 2; 6- (4-chlorophenyl) -N- (2-hydroxy-2-methylpropyl) -2- (1,2-oxazol-4-yl) -3-oxo-2,3-dihydropyridazine 4-carboxamide; 6- (4-chlorophenyl) -N - [(2S) -3-fluoro-2-hydroxypropyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -3-oxo-2- (pyrimidin-5-yl) -N - [(2R) -1,1,1-trifluoro-3-hydroxypropan-2-yl] -2,3- dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -2- [1- (difluoromethyl) -1H-pyrazol-4-yl] -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2,3 dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -N - [(1S) -1-cyclopropyl-2-hydroxyethyl] -3-oxo-2- (pyrimidin-5-yl) -2,3-dihydropyridazine-4-carboxamide; methyl N - {[6- (4-chlorophenyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazin-4-yl] carbonyl} -D-serinate; 6- [4- (fluoromethyl) phenyl] -2- (1-methyl-1H-pyrαzol-4-yl) -3-oxo-N - [(2R) -1,1,1-trifluoro-3-hydroxypropane- 2-yl] -2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(2S) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-2- (1H-pyrazol-4-yl) -2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -N- (2-hydroxy-2-methylpropyl) -3-oxo-2- (pyrimidin-5-yl) -2,3-dihydropyridazine 4-carboxamide; 6- (4-chlorophenyl) -2- [1- (difluoromethyl) -1H-pyrazol-4-yl] -N- (2-hydroxy-2-methylpropyl) -3-oxo-2,3 dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(2R) -1-hydroxypropan-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-208 037978 4-carboxamide, enantiomer 2; 6- [4- (fluoromethyl) phenyl] -3-oxo-2- (pyridin-3-yl) -N - [(Zh) -1,1,1-trifluoro-3-hydroxypropan-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-methylbutan-2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo -2,3-dihydropyridazine-4-carboxamide; 6- [4- (fluoromethyl) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide ; 6- [4- (fluoromethyl) phenyl] -N- (2-hydroxy-2-methylpropyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 6- [4- (fluoromethyl) phenyl] -N - [(2S) -1-hydroxypropan-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-methylbutan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine -4-carboxamide; N - [(2R) -1-amino-3-hydroxy-1-oxopropan-2-yl] -6- (4-chlorophenyl) -2- (1-methyl-1H-purazol-4-yl) -3oxo 2,3-dihydropyridazine-4-carboxamide; N-cis-4-hydroxytetrahydrothiophen-3-yl-3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] -2,3 dihydropyridazine-4-carboxamide; (-) - N-cis-4-hydroxytetrahydrothiophene-3-yl-3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethyl) phenyl] 2,3-dihydropyridazine-4-carboxamide, enantiomer 2; 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-methylbutan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] -2,3 dihydropyridazine-4 -carboxamide; N - [(2S) -3,3-difluoro-2-hydroxypropyl] -3-oxo-2- (puridin-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- (puridin-3-yl) -N- (4,4,4-trifluoro-3-hydroxybutan-2-yl) -2,3-dihydropyridazine-4- carboxamide, isomer 1; 6- (4-chlorophenyl) -3-oxo-2- (puridin-3-yl) -N- (4,4,4-trifluoro-3-hydroxybutan-2-yl) -2,3-dihydropyridazine-4- carboxamide, isomer 2; 6- (4-chlorophenyl) -3-oxo-2- (puridin-3-yl) -N- (4,4,4-trifluoro-3-hydroxybutan-2-yl) -2,3-dihydropyridazine-4- carboxamide, isomer 3; 6- (4-chlorophenyl) -3-oxo-2- (puridin-3-yl) -N- (4,4,4-trifluoro-3-hydroxybutan-2-yl) -2,3-dihydropyridazine-4- carboxamide, isomer 4; 6- (4-chlorophenyl) -2- (5-fluoropuridin-3-yl) -N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2,3 dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(2R) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-2- (puridin-3-yl) -2,3-dihydropyridazin-4- carboxamide; 6- (4-chlorophenyl) -2- (5-chloropuridin-3-yl) -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2,3-dihydropyridazine-4-carboxamide; 6- (4-chlorophenyl) -N - [(2S) -1-hydroxypropan-2-yl] -2- (5-methylpyridin-3-yl) -3-oxo-2,3-duhydropyridazine-4-carboxamide; 6- [4- (difluoromethoxy) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-okco-N- (1,1,1-trifluoro-3-hydroxy-3 methylbutane-2 -yl) -2,3-dihydropyridazine-4-carboxamide; 6- [4- (difluoromethoxy) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-okco-N- (1,1,1-trifluoro-3-hydroxy-3 methylbutane-2 -yl) -2,3-dihydropyridazine-4-carboxamide, isomer 1; 6- [4- (difluoromethoxy) phenyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-okco-N- (1,1,1-trifluoro-3-hydroxy-3 methylbutane-2 -yl) -2,3-dihydropyridazine-4-carboxamide, isomer 2; 6- [4- (difluoromethoxy) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine -4-carboxamide; 6- [4- (difluoromethoxy) phenyl] -N - [(2S) -3-hydroxy-3-methylbutan-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-methylbutan-2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3 oxo 2,3-dihydropyridazine-4-carboxamide; 6- [4- (dimethylamino) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine -4-carboxamide; N - [(2S) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-2- (1,2-thiazol-4-yl) -6- [4- (trifluoromethoxy) phenyl] - 209 037978 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- (difluoromethyl) phenyl] -N - [(cis) -4-hydroxytetrahydrofuran-3 -yl] -2- (1-methyl-1H-pyrazol-4yl) -3-oxo-2,3-dihydropyridazine -4-carboxamide, isomer 1; 6- (4-chlorophenyl) -N - [(2S) -3-hydroxy-3-methylbutan-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, isomer one; 6- [4- (difluoromethyl) phenyl] -N - [(2S) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine -4-carboxamide; 6- [4- (difluoromethyl) phenyl] -N - [(cis) -4-hydroxytetrahydrofuran-3 -yl] -2- (1-methyl-1H-pyrazol-4yl) -3-oxo-2,3-dihydropyridazine -4-carboxamide, isomer 2; 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- (difluoromethyl) phenyl] -N - [(cis) -4-hydroxytetrahydrofuran-3-yl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4-carboxamide, isomer 2; 6- (4-chlorophenyl) -N - [(2R) -1-hydroxypropan-2-yl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo-2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -N - [(2R) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-2- (1H-pyrazol-4-yl) -2,3-dihydropyridazine- 4-carboxamide; 6- (4-chlorophenyl) -N - [(2R) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-2- (1,2-thiazol-4-yl) -2,3- dihydropyridazine-4-carboxamide; N - [(2R) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-2- (1,2-thiazol-4-yl) -6- [4- (trifluoromethoxy) phenyl] 2, 3-dihydropyridazine-4-carboxamide; N - [(cis) -2-hydroxy-2-methylcyclopentyl] -3-oxo-2- (pyridin-3-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, isomer 1; N - [(cis) -2-hydroxy-2-methylcyclopentyl] -3-oxo-2- (pyridin-3-yl) -6- [4- (trifluoromethoxy) phenyl] 2,3-dihydropyridazine-4-carboxamide, isomer 2; 6- [4- (difluoromethoxy) phenyl] -N- (2-hydroxy-2-methylpropyl) -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide; 6- [4- (difluoromethoxy) phenyl] -N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3-dihydropyridazine-4-carboxamide ; 6- [4- (difluoromethoxy) phenyl] -N - [(2S) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-2- (pyridin-3-yl) -2,3 dihydropyridazine-4 -carboxamide; 6- [4- (difluoromethoxy) phenyl] -N - [(2S, 3S) -3-hydroxybutan-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-oxo2,3-dihydropyridazine-4- carboxamide; isomer 1; 6- (4-chlorophenyl) -N - [(cis) -2-hydroxy-2-methylcyclopentyl] -2- (1-methyl-1H-pyrazol-4-yl) -3-oxo2,3-dihydropyridazine-4- carboxamide; isomer 2; 2- (5-fluoropyridin-3-yl) -N - [(2S) -1-hydroxy-3-methylbutan-2-yl] -3-oxo-6- [6- (trifluoromethyl) pyridin-3-yl] -2,3-dihydropyridazine-4-carboxamide; 2- (5-fluoropyridin-3-yl) -N - [(1S, 2R) -2-hydroxycyclopentyl] -3-oxo-6- [6- (trifluoromethyl) pyridin3-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 β-dihydropyridazine-4-carboxamide; 2- (5-fluoropyridin-3-yl) -N - [(2S) -3-hydroxy-3-methylbutan-2-yl] -3-oxo-6- [6- (trifluoromethyl) pyridin-3-yl] -2,3-dihydropyridazine-4-carboxamide; N - [(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-methylbutan-2-yl] -3-oxo-6- [6- (trifluoromethyl) pyridin-3-yl] -2,3-dihydropyridazine-4-carboxamide; 1,5-anhydro-2,4-dideoxy-2 - [({2- (5-fluoropyridin-3-yl) -3-oxo-6- [6- (trifluoromethyl) pyridin-3-yl] - 210 037978 2,3-dihydropyridazin-4-yl} carbonyl) amino] -D-erythropentitol; 2- (5-fluoropyridin-3-yl) -N- (2-hydroxy-2-methylpropyl) -3-oxo-6- [6- (trifluoromethyl) pyridin-3-yl] 2,3-dihydropyridazin-4- carboxamide; N - [(2S) -1-hydroxypropan-2-yl] -3-oxo-2- (pyridin-3-yl) -6- [5- (trifluoromethyl) pyridin-2-yl] -2,3 dihydropyridazin-4 -carboxamide; their physiologically acceptable salts and solvates of these salts, and mixtures thereof. 3. A method of obtaining a compound of general formula (I) according to any one of claims 1, 2, which includes the stage of providing the reaction of an intermediate compound of general formula (VII) in which X, R ² , R ³ , R ⁴ and R ⁵ are as defined for a compound of general formula (I) according to claim 1, with a compound of general formula (VIII) H ₂ NR ^X (VIII), in which R ¹ is as defined for a compound of general formula (I) according to claim 1, thus obtaining a compound of general formula (I) in which X, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined for the compound of general formula (I) according to claim 1. 4. A method of obtaining a compound of general formula (I) according to any one of claims 1, 2, which includes the step of providing the reaction of an intermediate compound of general formula (XII) in which X, R ¹ , R ² , R ³ and R ⁴ are as defined for a compound of general formula (I) according to claim 1, with a compound of general formula (XIV) Aoi RO (xiv), in which R ⁵ is as defined for the compound of general formula (I) according to claim 1, and R 'and R''are simultaneously H or C1-C ₄ -alkyl or together form C ₂ - A C ₇ alkylene group as part of a 1,2- or 1,3-diolboronic acid ester or a —CO — CH ₂ - (NCH ₃ ) —CH ₂ —CO— group; thus obtaining a compound of general formula (I) in which X, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined for the compound of general formula (I) according to claim 1. 5. A pharmaceutical composition which contains a compound of general formula (I) according to any one of claims 1, 2 and one or more pharmaceutically acceptable excipients. - 211 037978 6. Pharmaceutical combination, which includes one or more of the first active components, in particular compounds of general formula (I) according to any one of claims 1, 2; and a pharmaceutically active immune checkpoint inhibitor, which is an antibody TRP-3911. 7. Use of a compound of general formula (I) according to any one of claims 1, 2 for the treatment or prevention of a disease associated with aberrant AHR signaling. 8. Use of a compound of general formula (I) according to any one of claims 1, 2 for the preparation of a medicament for the treatment or prevention of a disease associated with aberrant AHR signaling. 9. Use according to claim 7 or 8, wherein the disease is a malignant neoplasm or conditions with dysregulated immune responses or other disorders associated with aberrant AHR signaling, such as tumors of liquid tissues and solid tumors. 10. Compound of general formula (VII) in which X, R ² , R ³ , R ⁴ and R ⁵ are as defined for the compound of general formula (I) according to claim 1. 11. Use of a compound of general formula (VII) in which X, R ² , R ³ , R ⁴ and R ⁵ are as defined for the compound of general formula (I) according to claim 1, to obtain a compound of general formula (I) according to any one of claims 1, 2. 12. Compound of general formula (XII) in which X, R ¹ , R ² , R ³ and R ⁴ are as defined for the compound of general formula (I) according to claim 1. 13. Use of a compound of general formula (XII) in which X, R ¹ , R ² , R ³ and R ⁴ are as defined for a compound of general formula (I) according to claim 1, to obtain a compound of general formula (I) according to any one of claims 1, 2.