WO2021094208A1

WO2021094208A1 - Substituted imidazo pyrimidine ep3 antagonists

Info

Publication number: WO2021094208A1
Application number: PCT/EP2020/081247
Authority: WO
Inventors: Lisa CANDISH; Frank SÜSSMEIER; Steffen Müller; Christoph Gerdes; Elisabeth Pook; Anja BUCHMÜLLER; Fabienne Zdenka GAUGAZ; Rudolf Schohe-Loop; Markus Follmann; Dieter Lang
Original assignee: Bayer Aktiengesellschaft
Priority date: 2019-11-12
Filing date: 2020-11-06
Publication date: 2021-05-20

Abstract

The invention relates to substituted imidazo pyrimidine derivatives and to processes for their preparation, and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and diabetes, and also urogenital and ophthalmic disorders. These compounds are EP3 antagonists.

Description

SUBSTITUTED IMIDAZO PYRIMIDINE EP3 ANTAGONISTS

The invention relates to substituted imidazo pyrimidine derivatives and to processes for their preparation, and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and diabetes, and also urogenital and ophthalmic disorders.

Atherothrombosis is the main complication of atherosclerosis and underlies several of the most lethal human diseases, such as myocardial infarction (Ml), ischemic stroke (IS) and peripheral arterial occlusive disease (PAOD). The process is initiated by the deposition of lipids and their subsequent oxidation in the arterial wall which induces the recruitment of inflammatory cells and the formation of atherosclerotic plaques. These plaques are covered by a fibrous cap which maintains the plaque content separated from the blood flow. Inside the plaque, pro-inflammatory mechanisms drive inflammatory cells to produce matrix metalloproteases which digest the proteins of the fibrous cap. The thinned cap is called “vulnerable”, meaning that the cap may rupture relatively easily in response to stresses. When the cap ruptures or its endothelial cover erodes, the plaque content comes into contact with the blood and provokes the formation of an intravascular thrombus by activating platelets and blood coagulation. This process, forming a thrombus on plaques, is called atherothrombosis. If obstructive, the resulting intravascular thrombus interrupts blood flow and causes ischemia of downstream tissues with dramatic clinical consequences representing the leading cause of death and morbidity worldwide.

Given the mechanism of atherothrombotic vessel obstruction, current prevention targets the mechanisms of thrombosis, which is the pathological formation of intra-vascular plugs. The mechanisms of thrombosis encompass two intertwined pathways, the coagulation cascade and the aggregation of platelets, which once activated by a vessel injury act synergistically to build the intravascular clot obstructing the vessel lumen. Anticoagulant and anti-aggregant drugs, used to prevent atherothrombosis, have elicited a considerable reduction of the rate of second myocardial infarctions and a decrease of long term mortality from about 30% prior to the 1980s to less than 10% after the 2000s (Arch. Intern. Med. 2002, 162, 2405-2410; Lancet 2011, 377, 2193-2204). Specifically, the COX inhibitor Aspirin and the ADP receptor P2Y12 antagonist Clopidogrel are components of dual antiplatelet therapy. Prasugrel and Ticagrelor are alternative P2Y12 blockers that have demonstrated reductions of cardiovascular ischemic events ( N . Engl. J. Med. 2007, 357, 2001-2015; ibid. 2009, 361, 1045-1057). The coagulation factor Xa inhibitor Rivaroxaban has also shown benefits to patients with stable atherosclerotic vascular disease (N. Engl. J. Med. 2017, 377, 1319-1330). However, activation of platelets and blood coagulation is also crucial for hemostasis to prevent excessive blood loss after vascular injury. Consequently, currently marketed antiplatelet drugs and anticoagulants achieve their therapeutic effect at the cost of increased bleeding rates. Therefore, a safe antithrombotic drug must preserve the competence of hemostasis. An approach to widen the therapeutic window between antithrombotic-effective dose and the hemo stasis-compromising dose is to target mechanisms which are restricted to the site of atherosclerotic vessel walls. It has been widely shown that plaques host and maintain inflammation. A pro- thrombotic mediator produced by inflammatory mechanisms within plaques, but not by healthy vascular walls, would be an ideal target to impact atherothrombosis only at the site of the plaque without an impact on systemic hemostasis. Among other factors, local synthesis of prostanoids from arachidonic acid (AA) in the arterial vessel wall may play a profound role in atherosclerosis. Besides TXA2, the AA pathway generates several other mediators, e.g. prostaglandin E2 (PGE2). Increased PGE2 concentrations have been measured in atherosclerotic vascular walls of mice and humans [Circulation 2001 , 104, 921-927; J. Exp. Med. 2007, 204, 311-320; Cardiovasc. Res. 2014, 101, 482- 491] Once released upon plaque rupture, PGE2 binds on four specific receptors EP1, EP2, EP3 and EP4 on cell membranes. PGE2 has been shown to interfere with human and murine platelet function via EP3 and EP4 receptors ( Eur : J. Pharmacol. 1991, 194, 63-70). Stimulation of EP3 potentiates platelet activation and aggregation induced by primary agonists like collagen or ADP, whereas stimulation of EP4 inhibits platelet activation. This PGE2-dependent balance of platelet activation and inhibition can be tipped by modulation of EP3 or EP4 receptors ( Platelets 2010, 21, 329-342; Prostaglandins & Other Upid Mediators 2015, 121, 4-16).

Therefore, blocking the EP3 receptor by specific antagonists should be a beneficial strategy for prevention and treatment of atherothrombosis by local abrogation of platelet activation without altering hemostasis.

In patients suffering from PAOD, chronically inflamed vessel walls produce PGE2 to activate EP3 receptors not only on platelets but also on vascular smooth muscle cells thus preventing microvascular relaxation and contributing to malperfusion of peripheral tissues. Therefore, an antagonist to the EP3 receptor might be expected to provide therapeutic benefit specifically in PAOD.

Furthermore, PGE2 originating from inflammatory processes has been shown to compromise glucose-stimulated insulin secretion from pancreatic beta cells via the EP3 receptor pathway (Diabetes 2013, 62, 1904-1912). Therefore, EP3 antagonists might represent a beneficial strategy in the treatment of patients with type II diabetes.

In the kidney and urogenital tract, PGE2 participates in the regulation of renal microcirculation, diuresis and bladder excitability. EP3 receptor antagonists might help to improve renal disorders and in particular to resolve bladder hyperactivity, interstitial cystitis or bladder pain syndrome.

Furthermore, for many disorders the combination of antithrombotic and anti-inflammatory principles may also be particularly attractive to prevent the mutual enhancement of coagulation and platelet activation.

In the field of ophthalmology, prostaglandin derivatives participate in the regulation of intraocular pressure and inflammation. Therefore, compounds modulating the respective receptors may have a benefit in the prevention and treatment of ocular diseases.

Moreover, prostaglandin derivates play an essential role via their platelet-activating and pro- inflammatory mechanisms in inflammatory disorders like vasculitides, for example Kawasaki disease, Takayasu arteritis and Thrombangiitis obliterans (Buerger’s disease) as well as myocarditis (EMBO Mol Med 2018, e8536).

Furthermore, EP3 antagonists might contribute to the treatment and/or prophylaxis of diabetes- related end-organ manifestations like diabetic retinopathy and diabetic nephropathy.

Moreover, prostaglandins are involved in the pathogenesis of neurological disorders like neuropathic pain, Alzheimer’s disease and Parkinson’s disease,

In addition, PGE2 and EP3 have been reported to play a role in the pathogenesis of respiratory disorders like chronic cough, asthma and COPD (Am J Respir Crit Care 2009, 923-928).

WO 2016/007736 provides imidazo pyrazines as LSD1 inhibitors for the treatment of cancer. WO2014/015830, WO2014/015675 and WO 2014/015523 provide heteroaryl compounds for the treatment of cancer.

WO 2015/052610 and WO 2016/103097 provide antagonists of prostaglandin EP3 receptor having a pyridinone substituted indazole, indole or quinoline derivative. Amide or pyridinone based EP3 receptor antagonists are also described in ACS Med. Chem. Lett. 2010, 1, 316-320 and in Bioorg. Med. Chem. Lett. 2009, 19, 4292-4295, ibid. 2011, 21, 2806-2811, ibid. 2016, 26, 2670- 2675.

It is therefore an object of the present invention to provide novel compounds for the treatment of cardiovascular disorders, in particular of thrombotic or thromboembolic disorders, in humans and animals, which compounds have a wide therapeutic window and, in addition, a good pharmacokinetic behavior. Surprisingly, it has now been found that certain substituted imidazo pyrimidine derivatives represent highly potent antagonists of prostaglandin EP3 receptor.

The invention provides compounds of the formula (I)

in which R¹ represents CrC6-alkyl, C₂-C₆-halogenoalkyl, C₃-C₆-cycloalkyl or the group -L-R^E, where alkyl may be substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, methoxy and CrC3-halogenoalkoxy, where halogenoalkoxy is substituted by 1 to 3 fluoro substituents, and where halogenoalkyl is substituted by 1 to 6 fluoro substituents and may be further substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy and methoxycarbonyl, and where in the cycloalkyl ring one CH2 group may be replaced by O, SO2 or NR⁴, and where the cycloalkyl may be substituted by 1 substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, hydroxy, trifluoromethyl and phenyl, or may be substituted by 1 or 2 fluoro, where the phenyl may be substituted by 1 or 2 substituents independently selected from the group consisting of fluoro, chloro and cyano, and

R⁴ represents hydrogen, CrC4-alkyl, C2-C6-halogenoalkyl substituted by 1 to 3 fluoro, cyclopropyl, methylcarbonyl or methoxycarbonyl, and

L represents Ci-C₆-alkanediyl, where alkanediyl may be substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, methoxy, methoxycarbonyl, carboxyl and C3-C6- cycloalkyl (which may be substituted by 1 hydroxy), and additionally by up to 3 fluoro,

R^E represents phenyl or pyridinyl, where phenyl may be substituted by 1 or 2 substituents independently selected from the group consisting of halogen, hydroxy, CrC4-alkyl, methoxy and trifluoromethyl, and where pyridinyl may be substituted by 1 or 2 substituents independently selected from the group consisting of chloro, methyl, methoxy and trifluoromethyl,

R² represents a group of the formula where # is the point of attachment to the pyrimidine ring,

Q¹ represents CR^8A or N,

Q² represents CR⁸ or N,

R⁶ represents hydrogen, halogen, CrC₄-alkyl, CrC₄-halogenoalkyl, CrC₄-alkoxy, C₁-C₄- halogenoalkoxy or C₃-C₆-cycloalkyl,

R⁷ represents hydrogen, halogen, CrC₄-alkyl, CrC₄-halogenoalkyl, CrC₄-alkoxy, C₁-C₄- halogenoalkoxy or C₃-C₆-cycloalkyl, with the proviso, that at least one of R⁶ and R⁷ is not hydrogen,

R^7A represents hydrogen,

R⁸ represents hydrogen,

R^8A represents hydrogen or halogen,

X represents CH or N,

Y represents CH or N,

Z¹ represents CR⁹ or N,

Z² represents CR^9a or N, where at most one of X, Y, Z¹ and Z² is N,

R⁹ represents hydrogen, halogen or CrC₄-alkyl,

R^9a represents hydrogen, halogen or CrC₄-alkyl,

R⁵ represents hydrogen or halogen,

R³ represents hydrogen, CrC₄-alkyl, CrC₄-halogenoalkyl or C₃-C₆-cycloalkyl, and the salts thereof, the solvates thereof and the solvates of the salts thereof.

The term “substituted” means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom’s normal valence under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.

As used herein, the term “one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means “1 , 2, 3, 4 or 5, particularly 1 , 2, 3 or 4, more particularly 1 , 2 or 3, even more particularly 1 or 2”.

In the context of the present invention, unless specified otherwise, the substituents are defined as follows:

The term “halogen” or “halogeno” like in combinations e.g. in halogenoalkyl means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom, even more particularly fluorine or chlorine.

The term “Ci-C4-alkyl”, “CrCs-alkyl” and “Ci-C₆-alkyl” means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms, 1, 2, 3, 4 or 5 carbon atoms, and 1 , 2, 3, 4, 5 or 6 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, n-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, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl,

1.2-dimethylbutyl or 1,3-dimethylbutyl group, or an isomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms (“Ci-C4-alkyl”), e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl isobutyl, or tert- butyl group, more particularly 1, 2 or 3 carbon atoms (“Ci-C3-alkyl”), e.g. a methyl, ethyl, n-propyl or isopropyl group.

The term “Ci-C₆-halogenoalkyl”, “C2-C6-halogenoalkyl”, “Ci-C4-halogenoalkyl”, “C2-C4- halogenoalkyl”, “Ci-C3-halogenoalkyl” and “Ci-C2-halogenoalkyl” represents a linear or branched, saturated, monovalent hydrocarbon group in which the term “alkyl” is as defined supra, and in which one or more of the hydrogen atoms are replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said CrC₆-halogenoalkyl group is, for example fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl,

2.2.2-trif luoroethy I , pentafluoroethyl, 3,3,3-trifluoropropan-1-yl, 1,1,1 -trif luoropropan-2-yl , 1,3-diflu- oropropan-2-yl, 3-fluoropropan-1-yl, 1,1,1 -trifluorobutan-2-yl, and 3,3,3-trifluoro-1-methyl-propan- 1-yl.

The term “Ci-C4-halogenoalkoxy” and “Ci-C3-halogenoalkoxy” represents a linear or branched, saturated, monovalent CrC4-alkoxy or CrC3-alkoxy group (where alkoxy represents a straight- chain or branched, saturated, monovalent alkoxy radical having 1 to 4 or 1 to 3 carbon atoms, by way of example and with preference methoxy, ethoxy, n-propoxy, isopropoxy), in which one or more of the hydrogen atoms is replaced, identically or differently, with a halogen atom. Particularly, said halogen atom is a fluorine atom. Said CrC3-halogenoalkoxy group is, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or pentafluoroethoxy. The term “C3-C6-cycloalkyl” means a saturated, monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6 carbon atoms. Said C3-C6-cycloalkyl group is for example a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

The term “Ci-C₆-alkanediyl” and “C2-C5-alkanediyl” represents a linear or branched, divalent alkyl radical having 1 to 6 or 2 to 5 carbon atoms, by way of example and with preference methylene (-CHr-), ethan-1 , 1-diyl [-CH(CH₃)-], ethan-1,2-diyl [-(CH₂)H, propan- 1,1-diyl [-CH(CH₂CH₃)-], propan-1, 2-diyl [-CH₂CH(CH3)-], 2-methylpropan-1, 1-diyl {-CH[CH(CH3)₂]-}, 2-methylpropan- 1,3-diyl {-CH₂[CH(CH₃)]CHr-}, butan- 1,1-diyl {-CH[(CH₂)₂CH₃]-}, butan-1, 2-diyl

[-CH₂CH(CH₂CH₃)-], 3-methylbutan-1, 1-diyl [-(CH₂)₂CH(CH₃)₂-] or 3-methylbutan-1, 2-diyl {-CH₂CH[CH(CH₃)₂]-}.

Compounds according to the invention are the compounds of the formula (I) and the salts, solvates and solvates of the salts thereof, and also the compounds encompassed by formula (I) and specified hereinafter as working example(s), and the salts, solvates and solvates of the salts thereof, to the extent that the compounds encompassed by formula (I) and specified hereinafter are not already salts, solvates and solvates of the salts.

The inventive compounds may, depending on their structure, exist in different stereoisomeric forms, i.e. in the form of configurational isomers or else, if appropriate, of conformational isomers (enantiomers and/or diastereomers, including those in the case of rotamers and atropisomers). The present invention therefore encompasses the enantiomers and diastereomers, and the respective mixtures thereof. The stereoisomerically uniform constituents can be isolated from such mixtures of enantiomers and/or diastereomers in a known manner; chromatography processes are preferably used for this, especially HPLC chromatography on an achiral or chiral phase.

Further, it is possible for the compounds of the present invention to exist as tautomers. For example the compounds of formula (I) encompass the tautomer of formula (la)

(I) (la)

Within this description the compounds according to the invention are drawn in the 4-oxo form.

The present invention includes all possible tautomers of the compounds of the present invention as single tautomers, or as any mixture of said tautomers, in any ratio. In the context of the present invention, the term “enantiomerically pure" is understood to mean that the compound in question with respect to the absolute configuration of the chiral centre is present in an enantiomeric excess of more than 95%, preferably more than 97%. The enantiomeric excess (ee value) is calculated in this case by evaluation of the corresponding HPLC chromatogram on a chiral phase with the aid of the formula below: ee = [E^A (area%) - E^B (area%)] x 100% / [E^A(area%) + E^B (area%)]

(E^A: enantiomer in excess, E^B: enantiomer in deficiency)

The present invention also encompasses all suitable isotopic variants of the compounds according to the invention. An isotopic variant of an inventive compound is understood here as meaning a compound in which at least one atom within the inventive compound has been exchanged for another atom of the same atomic number, but with a different atomic mass than the atomic mass which usually or predominantly occurs in nature. Examples of isotopes which can be incorporated into a compound according to the invention are those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium), ³H (tritium), ¹³C, ¹⁴C, ¹⁵N, ¹⁷0, ¹⁸0, ³²P, ³³P, ³³S, ³⁴S, ³⁵S, ³⁶S, ¹⁸F, ³⁶CI, ⁸²Br, ¹²³l, ¹²⁴l, ¹²⁹l and ¹³¹1. Particular isotopic variants of a compound according to the invention, especially those in which one or more radioactive isotopes have been incorporated, may be beneficial, for example, for the examination of the mechanism of action or of the active ingredient distribution in the body; due to comparatively easy preparability and detectability, especially compounds labelled with ³H or ¹⁴C isotopes are suitable for this purpose. In addition, the incorporation of isotopes, for example of deuterium, may lead to particular therapeutic benefits as a consequence of greater metabolic stability of the compound, for example an extension of the half-life in the body or a reduction in the active dose required; such modifications of the inventive compounds may therefore in some cases also constitute a preferred embodiment of the present invention. Isotopic variants of the compounds according to the invention can be prepared by the processes known to those skilled in the art, for example by the methods described further below and the procedures described in the working examples, by using corresponding isotopic modifications of the respective reagents and/or starting compounds.

Preferred salts in the context of the present invention are physiologically acceptable salts of the compounds according to the invention. However, the invention also encompasses salts which themselves are unsuitable for pharmaceutical applications but which can be used, for example, for the isolation or purification of the compounds according to the invention.

Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulfonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds according to the invention also include salts of conventional bases, by way of example and with preference alkali metal salts (e.g. sodium and potassium salts), alkaline earth metal salts (e.g. calcium and magnesium salts) and ammonium salts derived from ammonia or organic amines having 1 to 16 carbon atoms, by way of example and with preference ethylamine, diethylamine, tri ethyl amine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, /V-methylmorpholine, arginine, lysine, ethylenediamine, N- methylpiperidine and choline.

The present invention includes all possible salts of the compounds according to the invention as single salts, or as any mixture of said salts, in any ratio.

Solvates in the context of the invention are described as those forms of the inventive compounds which form a complex in the solid or liquid state by coordination with solvent molecules. The compounds according to the invention may contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. Hydrates are a specific form of the solvates in which the coordination is with water. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non-stoichiometric ratio. In the case of stoichiometric solvates, e.g. a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.

Further, the compounds according to the invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised in a known manner. The present invention includes all such possible N-oxides.

The present invention additionally also encompasses prodrugs of the inventive compounds. The term “prodrugs” encompasses compounds which for their part may be biologically active or inactive but are converted during their residence time in the body into compounds according to the invention (for example by metabolism or hydrolysis).

In the context of the present invention, the term "treatment" or "treating" includes inhibition, retardation, checking, alleviating, attenuating, restricting, reducing, suppressing, repelling or healing of a disease, a condition, a disorder, an injury or a health problem, or the development, the course or the progression of such states and/or the symptoms of such states. The term "therapy" is understood here to be synonymous with the term "treatment".

The terms "prevention", "prophylaxis" and "preclusion" are used synonymously in the context of the present invention and refer to the avoidance or reduction of the risk of contracting, experiencing, suffering from or having a disease, a condition, a disorder, an injury or a health problem, or a development or advancement of such states and/or the symptoms of such states.

The treatment or prevention of a disease, a condition, a disorder, an injury or a health problem may be partial or complete. In the formulae of the group which may represent R², the end point of the line marked by # in each case does not represent a carbon atom or a CH2 group, but is part of the bond to the atom to which R²is attached.

Preference is given to compounds of the formula (I) in which

R¹ represents C₂-C₆-halogenoalkyl or the group -L-R^E, where halogenoalkyl is substituted by 1 to 6 fluoro substituents and may be further substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy and methoxycarbonyl, and

L represents Ci-C6-alkanediyl, where alkanediyl may be substituted by 1 or 2 hydroxy substituents, and additionally by up to 3 fluoro,

R^E represents phenyl, where phenyl may be substituted by 1 or 2 substituents independently selected from the group consisting of halogen, R² represents a group of the formula

where # is the point of attachment to the pyrimidine ring,

Q¹ represents CR^8A or N,

Q² represents CR⁸,

R⁶ represents hydrogen, halogen, CrC₄-alkyl or CrC₄-halogenoalkyl,

R⁷ represents hydrogen, halogen or CrC₄-alkyl, with the proviso, that at least one of R⁶ and R⁷ is not hydrogen,

R^7A represents hydrogen,

R⁸ represents hydrogen,

R^8A represents hydrogen,

X represents CH,

Y represents N,

Z¹ represents CR⁹,

Z² represents CR^9a, where at most one of X, Y, Z¹ and Z² is N,

R⁹ represents hydrogen or CrC4-alkyl,

R^9a represents hydrogen,

R⁵ represents hydrogen or halogen,

R³ represents hydrogen or CrC4-alkyl, and the salts thereof, the solvates thereof and the solvates of the salts thereof.

Preference is also given to compounds of the formula (I) in which

R¹ represents C2-C4-halogenoalkyl or the group -L-R^E, where halogenoalkyl is substituted by 1 to 6 fluoro substituents and may be further substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy and methoxycarbonyl, and

L represents C2-C5-alkanediyl, where alkanediyl may be substituted by 1 hydroxy substituent, and additionally by up to 3 fluoro,

R^E represents phenyl, where phenyl may be substituted by 1 fluoro substituent,

Q¹ represents CR^8A or N,

Q² represents CR⁸, R⁶ represents hydrogen, chloro, methyl or trifluoromethyl,

R⁷ represents hydrogen, fluoro, chloro or methyl, with the proviso, that at least one of R⁶ and R⁷ is not hydrogen,

R^7A represents hydrogen,

R⁸ represents hydrogen, R^8A represents hydrogen,

X represents CH,

Y represents N,

Z¹ represents CR⁹,

Z² represents CR^9a, where at most one of X, Y, Z¹ and Z² is N,

R⁹ represents hydrogen or methyl,

R^9a represents hydrogen,

R⁵ represents hydrogen or fluoro,

R³ represents hydrogen or methyl, and the salts thereof, the solvates thereof and the solvates of the salts thereof.

Preference is also given to compounds of the formula (I) in which R² represents 3-fluorophenyl, 4- chlorophenyl, 3-chlorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-4-methyl- phenyl, 4-chloro-3-methylphenyl, 3,4-dichlorophenyl, 3,4-dimethylphenyl, 3-methyl-4- (trifluoromethyl)phenyl or 3-fluoro-4-methylphenyl. Preference is also given to compounds of the formula (I) in which R² represents 3-fluorophenyl, 4- chlorophenyl, 3-chlorophenyl, 4-chloro-3-fluorophenyl, 3-chloro-4-methylphenyl, 4-chloro-3- methylphenyl, 3,4-dimethylphenyl, 3-methyl-4-(trifluoromethyl)phenyl or 3-fluoro-4-methylphenyl.

Preference is also given to compounds of the formula (I) in which R³ represents hydrogen or methyl. Preference is also given to compounds of the formula (I) in which R³ represents hydrogen.

Also preferred are compounds having the formula (l-X)

in which R² and R³ are as defined above,

R^x represents CrCs-alkyl, where alkyl may be substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, methoxy, methoxycarbonyl, carboxyl and C3-C6-cycloalkyl (which may be substituted by 1 hydroxy), and additionally by up to 3 fluoro, and

R^y represents hydrogen, halogen, hydroxy, CrC4-alkyl, methoxy or trifluoromethyl. The compounds of the the formula (l-X) are a subgroup of the compounds of the formula (I).

The invention further provides a process for preparing compounds of the formula (I), or salts thereof, solvates thereof or solvates of the salts thereof, wherein

[A] the compounds of the formula (II)

N H₂

R¹/ (II), in which R¹ is as defined above, are reacted with compounds of the formula (III)

(III),

in which R² and R³ are as defined above, in the presence of a dehydrating agent to give compounds of the formula (I), or

[B] the compounds of the formula (IV)

(IV), in which R² is as defined above and

R¹² represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, are reacted with compounds of the formular (V)

in which R¹ and R³ are as defined above, in the presence of a palladium source, a suitable ligand and a base.

The reaction [A] is generally carried out in inert solvents, if appropriate in the presence of a base, preferably in a temperature range from 0°C to 50°C at atmospheric pressure.

Alternatively, the reaction [A] can also be carried out without a solvent only in one base if the base is a liquid at room temperature.

Suitable dehydrating agents here are, for example, carbodiimides such as N,N ’-diethyl-, N,N’- dipro- pyl- N,N ’-diisopropyl-, A/,/\/-dicydohexylcarbodiimide, A/-(3-dimethylaminoisopropyl)-/\/'-ethylcarbo- diimide hydrochloride (EDCI) (optionally in the presence of pentafluorophenol (PFP)), /V-cyclohexyl- carbodiimide-/\/-propyloxymethyl-polystyrene (PS-carbodiimide) or carbonyl compounds such as carbonyldiimidazole (CDI), or 1 ,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium 3- sulphate or 2-terf-butyl-5-methyl-isoxazolium perchlorate, or acylamino compounds such as 2-eth- oxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or propanephosphonic anhydride, or isobutyl chloro- formate, or bis-(2-oxo-3-oxazolidinyl)phosphoryl chloride or benzotriazolyloxytri(dimethylamino)- phosphonium hexafluorophosphate, or 0-(benzotriazol-1-yl)-/\/,/\/,/\/',/\/'-tetramethyluronium hexa- fluorophosphate (HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TPTU), (benzotriazol-l-yloxy)bisdimethylaminomethylium fluoroborate (TBTU) or 0-(7-azabenzo- triazol-1-yl)-/V,/V,/V',/V'-tetramethyluronium hexafluoro-phosphate (HATU), or 1-hydroxybenzotriazole (HOBt), or benzotriazol-1-yloxytris(dimethyl-amino)phosphonium hexafluorophosphate (BOP), or ethyl cyano(hydroxyimino)acetate (Oxyma), or (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)- dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), or N-[(dimethylamino)(3/-/- [1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methylidene]-N-methylmethanaminium hexafluorophosphate, or 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide (T3P), or mixtures of these with bases, the condensation with HATU, being preferred.

Bases are, for example, alkali metal carbonates such as sodium carbonate or potassium carbonate, or sodium bicarbonate or potassium bicarbonate, or organic bases such as trialkylamines, for example triethylamine, /V-methylmorpholine, /V-methylpiperidine, 4-dimethyl- aminopyridine or diisopropylethylamin, or pyridine; preference is given to condensation with diisopropylethylamine.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane or trichloromethane, hydrocarbons such as benzene or toluene, or other solvents such as nitromethane, dioxane, diethyl ether, tetrahydrofuran, ethyl acetate, dimethylformamide, dimethylacetamide, dimethyl sulphoxide, /V-methylpyrrolidne or acetonitrile, or mixtures of the solvents; preference is given to dimethylformamide.

The compounds of the formula (II) are known or can be synthesized from the corresponding starting compounds by known processes.

The reaction [B] is generally carried out in inert solvents, preferably at temperature range from room temperature up to reflux of the solvents at atmospheric pressure.

The palladium source and a suitable ligand are, for example, tetrakis(triphenyl- phosphin)palladium(O) or (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,T-biphenyl)[2-(2'-amino- 1,T-biphenyl)]palladium(ll) methanesulfonate (XPhos-Pd-G3); preference is given to XPhos-Pd- G3.

Bases are, for example, alkali metal carbonates such as sodium carbonate or potassium carbonate, or sodium bicarbonate or potassium bicarbonate, alkali metal hydrogencarbonates such as sodium hydrogencarbonate or potassium hydrogencarbonate, alkali metal hydroxides such as sodium hydroxide or potassium hydroxide; preference is given to sodium carbonate or sodium hydrogencarbonate.

Inert solvents are, for example, ethers such as dioxane, diethyl ether, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulphoxide, N-methylpyrrolidone or acetonitrile, or mixtures of the solvents, or mixtures of solvents with water; preference is given to dioxane/water mixtures or tetrahydrofuran/water mixtures.

The compounds of the formula (IV) are known or can be synthesized from the corresponding starting compounds by known processes. The compounds of the formula (III) are known or can be prepared

[C] by reacting compounds of the formula (VI)

in which

R² and R³ are as defined above,

R¹³ represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, and

R¹⁴ represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, with a base. The reaction [C] is generally carried out in inert solvents, preferably in a temperature range from room temperature up to reflux of the solvents at atmospheric pressure.

Bases are, for example, alkali metal hydroxides such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or alkali metal carbonates such as caesium carbonate, sodium carbonate or potassium carbonate, or alkoxides such as potassium tert- butoxide or sodium tert- butoxide; preference is given to sodium hyroxide.

Inert solvents are, for example, alcohols such as methanol or ethanol, ethers such as diethyl ether, methyl tert- butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethylformamide, dimethylacetamide, acetonitrile or pyridine, or mixtures of solvents, or mixtures of solvents with water; preference is given to a mixture of tetrahydrofuran and water or ethanol and water.

The compounds of the formula (VI) are known or can be prepared [D] by reacting compounds of the formula (VII)

(VII),

in which

R² is as defined above and R¹⁴ represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, with compounds of the formula (VIII)

(VIM), in which

R³ is as defined above,

R¹³ represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, and

X¹ represents chloro, bromo, iodo or triflate.

The reaction [D] is generally carried out in inert solvents, preferably in a temperature range from 0°C up to reflux of the solvents at atmospheric pressure.

Inert solvents are, for example, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride or 1,2-dichloroethane, alcohols such as methanol or ethanol, ethers such as diethyl ether, methyl tert- butyl ether, 1,2-dimethoxyethane, dioxane or tetrahydrofuran, or other solvents such as dimethylformamide, dimethoxy ethane, N-methyl- pyrrolidone, dimethylacetamide, acetonitrile, acetone or pyridine, or mixtures of solvents; preference is given to dimethoxy ethane or ethanol.

The compounds of the formula (VIII) are known or can be synthesized from the corresponding starting compounds by known processes.

The compounds of the formula (VII) are known or can be prepared [E] by reacting compounds of the formula (IX)

(IX),

in which

R¹⁴ represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, with compounds of the formula (X) (X), in which

R² is as defined above, in the presence of a palladium source, a suitable ligand and a base. The reaction [E] is generally carried out in inert solvents, preferably in a temperature range from room temperature up to reflux of the solvents at atmospheric pressure.

The palladium source and a suitable ligand are, for example, tetrakis(triphenyl- phosphin)palladium(O) or (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,T-biphenyl)[2-(2'-amino- 1,T-biphenyl)]palladium(ll) methanesulfonate (XPhos-Pd-G3); preference is given to tetrakis(triphenylphosphin)palladium(0).

Inert solvents are, for example, ethers such as dioxane, diethyl ether, tetrahydrofuran, dimethylformamide, dimethylacetamide, dimethyl sulphoxide, N-methylpyrrolidone or acetonitrile, or mixtures of the solvents, or mixtures of solvents with water; preference is given to dioxane/water mixtures or tetrahydrofuran/water mixtures. The compounds of the formula (IX) and of the formula (X) are known or can be synthesized from the corresponding starting compounds by known processes.

The compounds of the formula (V) are known or can be prepared

[F] by reacting compounds of the formula (XI)

in which

R³ is as defined above, with compounds of the formula (II).

The reaction [F] is generally carried out as described for reaction [A] The compounds of the formula (II) are known or can be synthesized from the corresponding starting compounds by known processes.

The compounds of the formula (XI) are known or can be prepared

[G] by reacting compounds of the formula (XII)

in which

R³ is as defined above,

R¹³ represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, and R¹⁴ represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, with a base.

The reaction [G] is generally carried out as described for reaction [C].

The compounds of the formula (XII) are known or can be prepared [H] by reacting compounds of the formula (XIII)

(XIII),

in which

R¹⁴ represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, with compounds of the formula (VIII).

The reaction [H] is generally carried out as described for reaction [D] The compounds of the formula (VIII) and of the formula (XIII) are known or can be synthesized from the corresponding starting compounds by known processes.

The preparation of the starting compounds and of the compounds of the formula (I) can be illustrated by the synthesis schemes which follow. Scheme 1

Scheme 2

The compounds of the invention have valuable pharmacological properties and can be used for prevention and treatment of diseases in humans and animals.

The compounds according to the invention have an unforeseeable useful pharmacological activity spectrum and good pharmacokinetic behavior, in particular a sufficient exposure of such a compound in the blood above the minimal effective concentration within a given dosing interval after oral administration. Such a profile results in an improved peak-to-trough ratio (quotient of maximum to minimum concentration) within a given dosing interval, which has the advantage that the compound can be administered less frequently and at a significantly lower dose to achieve an effect. They are compounds that inhibit the activation of the EP3 receptor by its ligand Prostaglandin E2 (PGE2). They are therefore suitable for use as medicaments for the treatment and/or prophylaxis of diseases in humans and animals. The present invention further provides for the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, in particular cardiovascular disorders, preferably thrombotic or thromboembolic disorders and/or thrombotic or thromboembolic complications such as acute coronary syndrome or myocardial infarction or ischemic stroke or peripheral arterial occlusive disease , and/or diabetes, and/or ophthalmic disorders and/or urogenital disorders, in particular those associated with excess PGE2.

Increased PGE2 concentrations have been measured in atherosclerotic vascular walls of mice and humans. Once released upon plaque rupture, PGE2 binds on four specific receptors EP1 , EP2, EP3 and EP4 on cell membranes. PGE2 has been shown to interfere with human and murine platelet function via EP3 and EP4 receptors. Stimulation of EP3 potentiates platelet activation and aggregation induced by primary agonists like collagen or ADP, whereas stimulation of EP4 inhibits platelet activation. This PGE2-dependent balance of platelet activation and inhibition can be tipped by modulation of EP3 or EP4 receptors.

In contrast to established platelet antagonists, for example COX inhibitors like acetyl salicylic acid (Aspirin^®) and P2Y12 receptor antagonists like clopidogrel, prasugrel or ticagrelor, modulation of platelet activity via the EP3 receptor does not interfere with physiologic hemostasis and therefore is not expected to induce or increase the risk of bleeding.

For the purpose of the present invention, the "thrombotic or thromboembolic disorders" include disorders which occur preferably in the arterial vasculature and which can be treated with the compounds according to the invention, in particular disorders leading to peripheral arterial occlusive disorders and in the coronary arteries of the heart, such as acute coronary syndrome (ACS), myocardial infarction with ST segment elevation (STEM I) and without ST segment elevation (non-STEMI), stable angina pectoris, unstable angina pectoris, reocclusions and restenoses after coronary interventions such as angioplasty, stent implantation or aortocoronary bypass, but also thrombotic or thromboembolic disorders in cerebrovascular arteries, such as transitory ischaemic attacks (TIA), ischemic strokes including cardioembolic strokes, such as strokes due to atrial fibrillation, non-cardioembolic strokes, such as lacunar stroke, strokes due to large or small artery diseases, or strokes due to undetermined cause, cryptogenic strokes, embolic strokes, embolic strokes of undetermined source, or events of thrombotic and/or thromboembolic origin leading to stroke or TIA.

Moreover, the compounds according to the invention are suitable in particular for the treatment and/or prophylaxis of disorders where, the pro-inflammatory component plays an essential role, including vasculitides like Kawasaki disease, Takayasu arteritis and Thrombangiitis obliterans (Buerger’s disease) as well as inflammatory disorders like myocarditis.

Furthermore, the compounds according to the invention are suitable for the treatment and/or prophylaxis of disorders of the urogenital tract like overactive bladder, interstitial cystitis and bladder pain syndrome.

Moreover, the compounds according to the invention are suitable for the treatment and/or prophylaxis of diabetes mellitus including its end-organ manifestations like diabetic retinopathy and diabetic nephropathy.

Furthermore, the compounds according to the invention are suitable in particular for the treatment and/or prophylaxis of neurological disorders like neuropathic pain, Alzheimer’s disease and Parkinson’s disease. Moreover, the compounds according to the invention are suitable in particular for the treatment and/or prophylaxis of pulmonologic disorders like chronic cough, asthma and COPD.

The present invention further provides for the use of the compounds according to the invention for the treatment and/or prophylaxis of disorders, especially the disorders mentioned above.

The present invention further provides for the use of the compounds according to the invention for production of a medicament for the treatment and/or prophylaxis of disorders, especially the disorders mentioned above.

The present invention further provides a method for the treatment and/or prophylaxis of disorders, especially the disorders mentioned above, using a therapeutically effective amount of a compound according to the invention. The present invention further provides the compounds according to the invention for use in a method for the treatment and/or prophylaxis of disorders, especially the disorders mentioned above, using a therapeutically effective amount of a compound according to the invention.

Particularly the present invention provides the compounds according to the invention for use in a method for the treatment and/or prophylaxis of thrombotic or thromboembolic, in particular atherothrombotic disorders using a therapeutically effective amount of a compound according to the invention.

The present invention further provides medicaments comprising a compound according to the invention and one or more further active compounds. In addition, the compounds according to the invention can also be used for preventing coagulation ex vivo, for example for the protection of organs to be transplanted against organ damage caused by formation of clots and for protecting the organ recipient against thromboemboli from the transplanted organ, for preserving blood and plasma products, for cleaning/pretreating catheters and other medical auxiliaries and instruments, for coating synthetic surfaces of medical auxiliaries and instruments used in vivo or ex vivo or for biological samples which may comprise factor Xla or plasma kallikrein.

The present invention furthermore provides a method for preventing the coagulation of blood in vitro, in particular in banked blood or biological samples which may comprise factor Xla or plasma kallikrein or both enzymes, which method is characterized in that an anticoagulatory effective amount of the compound according to the invention is added.

The compounds of the invention can act systemically and/or locally. For this purpose, they can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, nasal, sublingual, lingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as an implant or stent.

For these administration routes, it is possible for the compounds according to the invention to be administered in suitable administration forms.

For oral administration, it is possible to formulate the compounds according to the invention to dosage forms 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 enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.

Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal). Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.

Suitable for extraocular (topic) administration are administration forms which operate in accordance with the prior art, which release the active compound rapidly and/or in a modified or controlled manner and which contain the active compound in crystalline and/or amorphized and/or dissolved form such as, for example, eye drops, sprays and lotions (e.g. solutions, suspensions, vesicular/colloidal systems, emulsions, aerosols), powders for eye drops, sprays and lotions (e.g. ground active compound, mixtures, lyophilisates, precipitated active compound), semisolid eye preparations (e.g. hydrogels, in-situ hydrogels, creams and ointments), eye inserts (solid and semisolid preparations, e.g. bioadhesives, films/wafers, tablets, contact lenses).

Intraocular administration includes, for example, intravitreal, subretinal, subscleral, intrachoroidal, subconjunctival, retrobulbar and subtenon administration. Suitable for intraocular administration are administration forms which operate in accordance with the prior art, which release the active compound rapidly and/or in a modified or controlled manner and which contain the active compound in crystalline and/or amorphized and/or dissolved form such as, for example, preparations for injection and concentrates for preparations for injection (e.g. solutions, suspensions, vesicular/colloidal systems, emulsions), powders for preparations for injection (e.g. ground active compound, mixtures, lyophilisates, precipitated active compound), gels for preparations for injection (semisolid preparations, e.g. hydrogels, in-situ hydrogels) and implants (solid preparations, e.g. biodegradable and nonbiodegradable implants, implantable pumps).

Preference is given to oral administration or, in the case of ophthalmologic disorders, extraocular and intraocular administration.

Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia 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, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.

The compounds according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients. Pharmaceutically suitable excipients include, inter alia,

• fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel^®), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos^®)),

• ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), · bases for suppositories (for example polyethylene glycols, cacao butter, hard fat),

• solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain- length triglycerides fatty oils, liquid polyethylene glycols, paraffins),

• surfactants, emulsifiers, dispersants or wetters (for example sodium dodecyl sulfate), lecithin, phospholipids, fatty alcohols (such as, for example, Lanette®), sorbitan fatty acid esters (such as, for example, Span®), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween®), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor®), polyoxethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as, for example, Pluronic®),

• buffers, acids and bases (for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine),

• isotonicity agents (for example glucose, sodium chloride),

• adsorbents (for example highly-disperse silicas),

• viscosity-increasing agents, gel formers, thickeners and/or binders (for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol®); alginates, gelatine),

• disintegrants (for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab®), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol®)),

• flow regulators, lubricants, glidants and mould release agents (for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil®)),

• coating materials (for example sugar, shellac) and film formers for films or diffusion membranes which dissolve rapidly or in a modified manner (for example polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit®)),

• capsule materials (for example gelatine, hydroxypropylmethylcellulose),

• synthetic polymers (for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit®), polyvinylpyrrolidones (such as, for example, Kollidon®), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),

• plasticizers (for example polyethylene glycols, propylene glycol, glycerol, triacetine, triacetyl citrate, dibutyl phthalate),

• penetration enhancers,

• stabilisers (for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate),

• preservatives (for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate),

• colourants (for example inorganic pigments such as, for example, iron oxides, titanium dioxide),

• flavourings, sweeteners, flavour- and/or odour-masking agents.

The present invention furthermore relates to a pharmaceutical composition which comprises at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.

An embodiment of the invention are pharmaceutical compositions comprising at least one compound of formula (I) according to the invention, preferably together with at least one inert, non toxic, pharmaceutically suitable auxiliary, and the use of these pharmaceutical compositions for the above cited purposes.

In accordance with another aspect, the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of cardiovascular disorders, preferably thrombotic or thromboembolic disorders, and diabetes, and also urogenital and ophthalmic disorders.

The term “combination” in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of- parts.

A “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity. One example of a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation. Another example of a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.

A non-fixed combination or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit. One example of a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of-parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.

The inventive compounds can be employed alone or, if required, in combination with other active ingredients. The present invention further provides medicaments comprising at least one of the inventive compounds and one or more further active ingredients, especially for treatment and/or prophylaxis of the aforementioned disorders. Preferred examples of suitable active ingredient combinations include:

• organic nitrates and NO donors, for example sodium nitroprusside, nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, molsidomine or SIN-1, and inhaled NO;

• compounds which inhibit the breakdown of cyclic guanosine monophosphate (cGMP), for example inhibitors of phosphodiesterases (PDE) 1, 2 and/or 5, especially PDE 5 inhibitors such as sildenafil, vardenafil, tadalafil, udenafil, desantafil, avanafil, mirodenafil, lodenafil or PF-00489791;

• hypotensive active ingredients, by way of example and with preference from the group of the calcium antagonists, angiotensin All antagonists, ACE inhibitors, NEP-inhibitors, vasopeptidase-inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase-inhibitors and the diuretics;

• antiarrhythmic agents, by way of example and with preference from the group of sodium channel blocker, beta-receptor blocker, potassium channel blocker, calcium antagonists, If- channel blocker, digitalis, parasympatholytics (vagoliytics), sympathomimetics and other antiarrhythmics as adenosin, adenosine receptor agonists as well as vernakalant;

• positive-inotrop agents, by way of example cardiac glycoside (Dogoxin), beta-adrenergic and dopaminergic agonists, such as isoprenalin, adrenalin, noradrenalin, dopamin or dobutamin;

• vasopressin-receptor-antagonists, by way of example and with preference from the group of conivaptan, tolvaptan, lixivaptan, mozavaptan, satavaptan, SR-121463, RWJ 676070 or BAY 86-8050, as well as the compounds described in WO 2010/105770, WO2011/104322 and WO 2016/071212;

• active ingredients which alter lipid metabolism, for example and with preference from the group of the thyroid receptor agonists, cholesterol synthesis inhibitors such as, by way of example and preferably, HMG-CoA reductase inhibitors or squalene synthesis inhibitors, of ACAT inhibitors, CETP inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, lipase inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors and lipoprotein(a) antagonists. • bronchodilatory agents, for example and with preference from the group of the beta-adrenergic rezeptor-agonists, such as, by way of example and preferably, albuterol, isoproterenol, metaproterenol, terbutalin, formoterol or salmeterol, or from the group of the anticholinergics, such as, by way of example and preferably, ipratropiumbromid;

• anti-inflammatory agents, for example and with preference from the group of the gluco corticoids, such as, by way of example and preferably, prednison, prednisolon, methylprednisolon, triamcinolon, dexamethason, beclomethason, betamethason, flunisolid, budesonid or fluticason as well as the non-steroidal anti-inflammatory agents (NSAIDs), by way of example and preferably, acetyl salicylic acid (aspirin), ibuprofen and naproxen, 5-amino salicylic acid-derivates, leukotriene-antagonists, TNF-alpha-inhibitors and chemokin-receptor antagonists, such as CCR1, 2 and/or 5 inhibitors;

• agents modulating the immune system, for example immunoglobulins;

• agents that inhibit the signal transductions cascade, for example and with preference from the group of the kinase inhibitors, byway of example and preferably, from the group of the tyrosine kinase- and/or serine/threonine kinase inhibitors;

• agents, that inhibit the degradation and modification of the extracellular matrix, for example and with preference from the group of the inhibitors of the matrix-metalloproteases (MMPs), by way of example and preferably, inhibitors of chymasee, stromelysine, collagenases, gelatinases and aggrecanases (with preference from the group of MMP-1, MMP-3, MMP-8, MMP-9, MMP-10, MMP-11 and MMP-13) as well as of the metallo-elastase (MMP-12) and neutrophil-elastase (HNE), as for example sivelestat or DX-890;

• agents, that block the bindung of serotonin to its receptor, for example and with preference antagonists of the 5-HT2b-receptor;

• organic nitrates and NO-donators, for example and with preference sodium nitroprussid, nitro glycerine, isosorbid mononitrate, isosorbid dinitrate, molsidomine or SIN-1, as well as inhaled NO;

• NO-independent, but heme-dependent stimulators of the soluble guanylate cyclase, for example and with preference the compounds described in WO 00/06568, WO 00/06569, WO 02/42301, WO 03/095451, WO 2011/147809, WO 2012/004258, WO 2012/028647 and WO 2012/059549;

• NO-independent and heme-independent activators of the soluble guanylate cyclase, for example and with preference the compounds described in WO 01/19355, WO 01/19776, WO 01/19778, WO 01/19780, WO 02/070462 and WO 02/070510 beschriebenen Verbindungen;

• agents, that stimulates the synthesis of cGMP, wie beispielsweise sGC Modulatoren, for example and with preference riociguat, cinaciguat, vericiguat or BAY 1101042;

• prostacyclin-analogs, for example and with preference iloprost, beraprost, treprostinil or epoprostenol;

• agents, that inhibit soulble epoxidhydrolase (sEH), for example and with preference N,N'-Di- cyclohexyl urea, 12-(3-Adamantan-1-yl-ureido)-dodecanic acid or 1-Adamantan-1-yl-3-{5-[2- (2-ethoxyethoxy)ethoxy]pentyl}-urea;

• agents that interact with glucose metabolism, for example and with preference insuline, biguanide, thiazolidinedione, sulfonyl urea, acarbose, DPP4 inhibitors, GLP-1 analogs or SGLT-1 inhibitors;

• natriuretic peptides, for example and with preference atrial natriuretic peptide (ANP), natriuretic peptide type B (BNP, Nesiritid) natriuretic peptide type C (CNP) or urodilatin;

• activators of the cardiac myosin, for example and with preference omecamtiv mecarbil (CK- 1827452);

• calcium-sensitizers, for example and with preference levosimendan;

• agents that affect the energy metabolism of the heart, for example and with preference etomoxir, dichloroacetat, ranolazine or trimetazidine, full or partial adenosine A1 receptor agonists such as GS-9667 (formerly known as CVT-3619), capadenoson, neladenoson and neladenoson bialanate; agents that affect the heart rate, for example and with preference ivabradin; cyclooxygenase inhibitors such as, for example, bromfenac and nepafenac; inhibitors of the kallikrein-kinin system such as, for example, safotibant and ecallantide; inhibitors of the sphingosine 1-phosphate signal paths such as, for example, sonepcizumab; inhibitors of the complement-C5a receptor such as, for example, eculizumab; plasminogen activators (thrombolytics/fibrinolytics) and compounds which promote thrombolysis/fibrinolysis such as inhibitors of the plasminogen activator inhibitor (PAI inhibitors) or inhibitors of the thrombin-activated fibrinolysis inhibitor (TAFI inhibitors) such as, for example, tissue plasminogen activator (t-PA, for example Actilyse^®), streptokinase, reteplase and urokinase or plasminogen-modulating substances causing increased formation of plasmin;

• anticoagulatory substances (anticoagulants) such as, for example, heparin (UFH), low- molecular-weight heparins (LMW), for example tinzaparin, certoparin, parnaparin, nadroparin, ardeparin, enoxaparin, reviparin, dalteparin, danaparoid, semuloparin (AVE 5026), adomiparin (M118) and EP-42675/ORG42675;

• direct thrombin inhibitors (DTI) such as, for example, Pradaxa (dabigatran), atecegatran (AZD- 0837), DP-4088, SSR-182289A, argatroban, bivalirudin and tanogitran (BIBT-986 and prodrug BIBT-1011) and hirudin;

• direct factor Xa inhibitors such as, for example, rivaroxaban, apixaban, edoxaban (DU-176b), betrixaban (PRT-54021), R-1663, darexaban (YM-150), otamixaban (FXV-673/R PR- 130673), letaxaban (TAK-442), razaxaban (DPC-906), DX-9065a, LY-517717, tanogitran (BIBT-986, prodrug: BIBT-1011), idraparinux and fondaparinux;

• inhibitors of coagulation factor XI and Xla such as, for example, FXI ASO-LICA, BAY 121- 3790, MAA868, BMS986177, EP-7041 and AB-022;

• substances which inhibit the aggregation of platelets (platelet aggregation inhibitors, thrombocyte aggregation inhibitors), such as, for example, acetylsalicylic acid (such as, for example, aspirin), P2Y12 antagonists such as, for example, ticlopidine (Ticlid), clopidogrel (Plavix), prasugrel, ticagrelor, cangrelor and elinogrel, and PAR-1 antagonists such as, for example, vorapaxar, and PAR-4 antagonists;

• platelet adhesion inhibitors such as GPVI and/or GPIb antagonists such as, for example, Revacept or caplacizumab;

• fibrinogen receptor antagonists (g lycoprotei n- 11 b/l 11 a antagonists) such as, for example, abciximab, eptifibatide, tirofiban, lamifiban, lefradafiban and fradafiban;

• recombinant human activated protein C such as, for example, Xigris or recombinant thrombomodulin.

Antithrombotic agents are preferably understood to mean compounds from the group of the platelet aggregation inhibitors, the anticoagulants or the profibrinolytic substances.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a platelet aggregation inhibitor, by way of example and with preference aspirin, clopidogrel, prasugrel, ticagrelor, ticlopidin or dipyridamole.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a thrombin inhibitor, by way of example and with preference ximelagatran, dabigatran, melagatran, bivalirudin or clexane.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a GPIIb/llla antagonist such as, by way of example and with preference, tirofiban or abciximab. In a preferred embodiment of the invention, the inventive compounds are administered in combination with a factor Xa inhibitor, by way of example and with preference rivaroxaban (BAY 59- 7939), DU-176b, apixaban, betrixaban, otamixaban, fidexaban, razaxaban, letaxaban, eribaxaban, fondaparinux, idraparinux, PMD-3112, darexaban (YM-150), KFA-1982, EMD-503982, MCM-17, MLN-1021, DX 9065a, DPC 906, JTV 803, SSR-126512 or SSR-128428.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a factor XI or factor Xla inhibitor, by way of example and with preference FXI ASO- LICA, BAY 121-3790, MAA868, BMS986177, EP-7041 or AB-022.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with heparin or with a low molecular weight (LM W) heparin derivative.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a vitamin K antagonist, by way of example and with preference coumarin.

Hypotensive agents are preferably understood to mean compounds from the group of the calcium antagonists, angiotensin All antagonists, ACE inhibitors, endothelin antagonists, renin inhibitors, alpha-receptor blockers, beta-receptor blockers, mineralocorticoid receptor antagonists, rho-kinase inhibitors and the diuretics.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a calcium antagonist, by way of example and with preference nifedipine, amlodipine, verapamil or diltiazem. In a preferred embodiment of the invention, the inventive compounds are administered in combination with an alpha- 1 -receptor blocker, by way of example and with preference prazosin.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a beta-receptor blocker, by way of example and with preference propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol or bucindolol.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with an angiotensin All antagonist, by way of example and with preference losartan, candesartan, valsartan, telmisartan or embusartan or a dual angiotensin All antagonist/neprilysin- inhibitor, by way of example and with preference LCZ696 (valsartan/sacubitril).

In a preferred embodiment of the invention, the inventive compounds are administered in combination with an ACE inhibitor, by way of example and with preference enalapril, captopril, lisinopril, ramipril, delapril, fosinopril, quinopril, perindopril ortrandopril.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with an endothelin antagonist, by way of example and with preference bosentan, darusentan, ambrisentan or sitaxsentan.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a renin inhibitor, by way of example and with preference aliskiren, SPP-600 or SPP-800.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a mineralocorticoid receptor antagonist, by way of example and with preference spironolactone or eplerenone.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a loop diuretic, for example furosemide, torasemide, bumetanide and piretanide, with potassium-sparing diuretics, for example amiloride and triamterene, with aldosterone antagonists, for example spironolactone, potassium canrenoate and eplerenone, and also thiazide diuretics, for example hydrochlorothiazide, chlorthalidone, xipamide and indapamide.

Lipid metabolism modifiers are preferably understood to mean compounds from the group of the CETP inhibitors, thyroid receptor agonists, cholesterol synthesis inhibitors such as HMG-CoA reduc tase inhibitors or squalene synthesis inhibitors, the ACAT inhibitors, MTP inhibitors, PPAR-alpha, PPAR-gamma and/or PPAR-delta agonists, cholesterol absorption inhibitors, polymeric bile acid adsorbents, bile acid reabsorption inhibitors, lipase inhibitors and the lipoprotein(a) antagonists.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a CETP inhibitor, by way of example and with preference dalcetrapib.anacetrapib, torcetrapib (CP- 529414), JJT-705 or CETP vaccine (Avant).

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a thyroid receptor agonist, by way of example and with preference D-thyroxine, 3,5,3'-triiodothyronine (T3), CGS 23425 or axitirome (CGS 26214). In a preferred embodiment of the invention, the inventive compounds are administered in combination with an HMG-CoA reductase inhibitor from the class of statins, by way of example and with preference lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin or pitavastatin.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a squalene synthesis inhibitor, by way of example and with preference BMS- 188494 or TAK-475.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with an ACAT inhibitor, by way of example and with preference avasimibe, melinamide, pactimibe, eflucimibe or SM P-797. In a preferred embodiment of the invention, the inventive compounds are administered in combination with an MTP inhibitor, byway of example and with preference implitapide, BMS-201038, R- 103757 or JTT-130.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a PPAR-gamma agonist, by way of example and with preference pioglitazone or rosiglitazone.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a PPAR-delta agonist, by way of example and with preference GW 501516 or BAY 68-5042. In a preferred embodiment of the invention, the inventive compounds are administered in combination with a cholesterol absorption inhibitor, byway of example and with preference ezetimibe, tiqueside or pamaqueside.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a lipase inhibitor, a preferred example being orlistat. In a preferred embodiment of the invention, the inventive compounds are administered in combination with a polymeric bile acid adsorbent, by way of example and with preference cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a bile acid reabsorption inhibitor, by way of example and with preference ASBT (= IBAT) inhibitors, for example AZD-7806, S-8921, AK-105, BARI-1741, SC-435 or SC-635.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with a lipoprotein(a) antagonist, by way of example and with preference, gemcabene calcium (CI-1027) or nicotinic acid.

In a preferred embodiment of the invention, the inventive compounds are administered in combination with sGC modulators, by way of example and with preference, riociguat, cinaciguat or vericiguat. In a preferred embodiment of the invention, the inventive compounds are administered in combination with an agent affecting the glucose metabolism, by way of example and with preference, insuline, a sulfonyl urea, acarbose, DPP4 inhibitors, GLP-1 analogs or SGLT-1 inhibitors.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a TGFbeta antagonist, by way of example and with preference pirfenidone or fresolimumab.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CCR2 antagonist, by way of example and with preference CCX- 140. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a TNFalpha antagonist, by way of example and with preference adalimumab.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a galectin-3 inhibitor, by way of example and with preference GCS- 100.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a Nrf-2 inhibitor, by way of example and with preference bardoxolone

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a BMP-7 agonist, by way of example and with preference THR- 184.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a NOX1/4 inhibitor, by way of example and with preference GKT- 137831. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a medicament which affects the vitamin D metabolism, by way of example and with preference calcitriol, alfacalcidol, doxercalciferol, maxacalcitol, paricalcitol, cholecalciferol or paracalcitol.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a cytostatic agent, by way of example and with preference cyclophosphamide.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an immunosuppressive agent, by way of example and with preference ciclosporin. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a phosphate binder, by way of example and with preference colestilan, sevelamer hydrochloride and sevelamer carbonate, Lanthanum and lanthanum carbonate.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with renal proximal tubule sodium-phosphate co-transporter, by way of example and with preference, niacin or nicotinamide.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a calcimimetic for therapy of hyperparathyroidism. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with agents for iron deficit therapy, by way of example and with preference iron products.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with agents for the therapy of hyperurikaemia, by way of example and with preference allopurinol or rasburicase.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with glycoprotein hormone for the therapy of anaemia, by way of example and with preference erythropoietin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with biologies for immune therapy, by way of example and with preference abatacept, rituximab, eculizumab or belimumab.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with vasopressin antagonists (group of the vaptanes) for the treatment of heart failure, by way of example and with preference tolvaptan, conivaptan, lixivaptan, mozavaptan, satavaptan or relcovaptan.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with Jak inhibitors, by way of example and with preference ruxolitinib, tofacitinib, baricitinib, CYT387, GSK2586184, lestaurtinib, pacritinib (SB1518) or TG101348.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with prostacyclin analogs for therapy of microthrombi.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an alkali therapy, by way of example and with preference sodium bicarbonate.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an mTOR inhibitor, by way of example and with preference everolimus or rapamycin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an NHE3 inhibitor, by way of example and with preference AZD1722 or tenapanor. In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with an eNOS modulator, by way of example and with preference sapropterin.

In a preferred embodiment of the invention, the compounds according to the invention are administered in combination with a CTGF inhibitor, by way of example and with preference FG-3019.

The total amount of the 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 50 mg/kg body weight per day, and more preferably from about 0.01 mg/kg to about 10 mg/kg body weight per day. Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing. In addition, it is possible for “drug holidays”, in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to contain from about 0.5 mg to about 1500 mg of active ingredient, and can be administered one or more times per day or less than once a day. The average daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.

Of course the specific initial and continuing dosage regimen for each patient will vary according to the nature and severity of the condition as determined by the attending diagnostician, the activity of the specific compound employed, the age and general condition of the patient, time of administration, route of administration, rate of excretion of the drug, drug combinations, and the like. The desired mode of treatment and number of doses of a compound of the present invention or a pharmaceutically acceptable salt or ester or composition thereof can be ascertained by those skilled in the art using conventional treatment tests.

Nevertheless, it may optionally be necessary to deviate from the stated amounts, namely depending on body weight, route of administration, individual response to the active substance, type of preparation and time point or interval when application takes place. Thus, in some cases it may be sufficient to use less than the aforementioned minimum amount, whereas in other cases the stated upper limit must be exceeded. When applying larger amounts, it may be advisable to distribute these in several individual doses throughout the day.

According to a further embodiment, the compounds of formula (I) according to the invention are administered orally once or twice or three times a day. According to a further embodiment, the compounds of formula (I) according to the invention are administered orally once or twice a day. According to a further embodiment, the compounds of formula (I) according to the invention are administered orally once a day. For the oral administration, a rapid release or a modified release dosage form may be used.

Unless stated otherwise, the percentages in the tests and examples which follow are percentages by weight; parts are parts by weight. Solvent ratios, dilution ratios and concentration data for the liquid/liquid solutions are based in each case on volume “w/v” means “weight/volume”. For example, “10% w/v” means: 100 ml of solution or suspension comprise 10 g of substance.

EXPERIMENTAL SECTION

Abbreviations and acronyms: aq. aqueous (solution)

Boc fert.-butoxycarbonyl br. broad (signal in NMR)

CDI 1,T-carbonyldiimidazole

COMU (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino- carbenium hexafluorophosphate d day(s); doublet (in NMR)

DBU 1 ,8-diazabicyclo[5.4.0]undec-7-en

DCI direct chemical ionization (in MS)

DCM dichloromethane dd doublet of doublets (in NMR)

DIPEA A/,/\/-diisopropylethylamine

DMAP 4-/\/,/\/-dimethylaminopyridine

DMF A/,/\/-dimethylformamide

DMSO dimethylsulfoxide dppp 1 ,3-bis(diphenylphosphino)propane

EDC /V-ethyl-/V-(3-dirnethylarninopropyl)carbodiirnide hydrochloride

EDCI 1-(3-dimethyla inopropyl)-3-ethylcarbodii ide equiv. equivalent(s)

ESI electrospray ionization (in MS) h hour(s)

HATU 0-(7-azabenzotriazol-1-yl)-/V,/\/,/\/',/\/-tetramethyluronium-hexafluorophosphate

HOAt 1-hydroxy-7-azabenzotriazole

HOBt 1 -hydroxy- 1/-/-benzotriazole hydrate

HPLC high-pressure / high-performance liquid chromatography

HV high vacuum

LC-MS liquid chromatography-coupled mass spectrometry m multiplet (in NMR) min minute(s)

MS mass spectrometry

MTBE methyl tert.- butyl ether

NMP /V-methylpyrrolidone

NMM /V-methylmorpholine

NMR nuclear magnetic resonance spectrometry

PTSA p-toluenesulfonic acid q quartet or quadruplet (in NMR) quant. quantitative (yield) quin quintet (in NMR)

RP reverse phase (in HPLC)

RT or rt room temperature

R_t retention time (in HPLC, LC-MS) s singlet (in NMR) sep septet (in NMR) sext sextet (in NMR)

SFC supercritical fluid chromatography t triplet (in NMR)

TFA trifluoroacetic acid

THF tetrahydrofuran

TLC thin-layer chromatography

T3P^® propylphosphonic anhydride (2,4,6-tripropyl-1 ,3,5,2,4,6-trioxatriphosphinane

2, 4, 6- trioxide)

Other abbreviations not specified herein have their meanings customary to the skilled person.

The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way. All publications mentioned herein are incorporated by reference in their entirety.

The example testing experiments described herein serve to illustrate the present invention and the invention is not limited to the examples given.

EXPERIMENTAL SECTION - GENERAL PART All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.

NMR peak forms are stated as they appear in the spectra, possible higher order effects have not been considered. The ¹H-NMR data of selected compounds are listed in the form of ¹H-NMR peaklists. For each signal peak the d value in ppm is given, followed by the signal intensity, reported in round brackets. The d value-signal intensity pairs from different peaks are separated by commas. Therefore, a peaklist is described by the general form: di (intensityi), 62 (intens^), ... , d, (intensity,), ... , d_h (intensity^. The intensity of a sharp signal correlates with the height (in cm) of the signal in a printed NMR spectrum. When compared with other signals, this data can be correlated to the real ratios of the signal intensities. In the case of broad signals, more than one peak, or the center of the signal along with their relative intensity, compared to the most intense signal displayed in the spectrum, are shown. A ¹H-NMR peaklist is similar to a classical ¹H-NMR readout, and thus usually contains all the peaks listed in a classical NMR interpretation. Moreover, similar to classical ¹H-NMR printouts, peaklists can show solvent signals, signals derived from stereoisomers of target compounds (also the subject of the invention), and/or peaks of impurities. The peaks of stereoisomers, and/or peaks of impurities are typically displayed with a lower intensity compared to the peaks of the target compounds (e.g., with a purity of >90%). Such stereoisomers and/or impurities may be typical for the particular manufacturing process, and therefore their peaks may help to identify the reproduction of our manufacturing process on the basis of "by-product fingerprints". An expert who calculates the peaks of the target compounds by known methods (MestReC, ACD simulation, or by use of empirically evaluated expectation values), can isolate the peaks of target compounds as required, optionally using additional intensity filters. Such an operation would be similar to peak-picking in classical ¹H-NMR interpretation. A detailed description of the reporting of NMR data in the form of peaklists can be found in the publication "Citation of NMR Peaklist Data within Patent Applications" (cf. Research Disclosure Database Number 605005, 2014, 01 Aug 2014, or http://www.researchdisclosure.com/searching- disclosures). In the peak picking routine, as described in the Research Disclosure Database Number 605005, the parameter "MinimumHeight" can be adjusted between 1% and 4%. Depending on the chemical structure and/or depending on the concentration of the measured compound it may be reasonable to set the parameter "MinimumHeight" <1%.

In NMR spectra of mixtures of stereoisomers, numbers mentioned with 7” indicate that the stereoisomers show separate signals for the respective hydrogen atom, i.e. “.... / . (2s, 1 H)” means that one hydrogen atom is represented by 2 singlets, each singlet from one or more different stereoisomer(s). lUPAC names of the following intermediates and example compounds were generated using the ACD/Name software (batch version 14.00; Advanced Chemistry Development, Inc.) or the naming tool implemented in the BIOVIA Draw software (version 4.2 SP1; Dassault Systemes SE).

Analytical LC-MS methods

Method 1: Column: Shim-pack XR-ODS (Shimadzu), 2.2 p , 3.0 ^c 50 mm; mobile phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA in acetonitrile; gradient: 0.0 min 5% B ® 1.2 min 95% B ® 1.7 min 95% B; column oven: 40°C; flow rate: 1.5 ml/min. Method 2: Column: Kinetex EVO, 2.6 pm, 3.0 ^c 50 m ; mobile phase A: 0.03% ammonia in water, mobile phase B: acetonitrile; gradient: 0.0 min 10% B ® 2.0 min 95% B ® 2.6 min 95% B; column oven: 40°C; flow rate: 1.2 ml/min.

Method 3: Column: Shim-pack XR-ODS (Shimadzu), 2.2 pm, 3.0 ^c 50 mm; mobile phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA in acetonitrile; gradient: 0.0 min 5% B ® 2.0 min 95% B ® 2.7 min 95% B; column oven: 40°C; flow rate: 1.5 ml/min.

Method 4: Column: Poroshell HPH-C18 (Agilent), 2.7 pm, 3.0 ^c 50 mm; mobile phase A: 6.5 mMammonium hydrogent carbonate + ammonia in water, mobile phase B: acetonitrile; gradient: 0.0 min 10% B ^ 2.1 min 95% B ® 2.7 min 95% B; column oven: 40°C; flow rate: 1.2 ml/min Method 5: Column: Shim-pack XR-ODS (Shimadzu), 2.2 pm, 3.0 ^c 50 mm; mobile phase A: 0.05% TFA in water, mobile phase B: 0.05% TFA in acetonitrile; gradient: 0.0 min 5% B ® 2.5 min 30% B ® 3.2 min 95% B ® 4.2 min 95% B; column oven: 40°C; flow rate: 1.5 ml/min.

Method 6: MS instrument: Thermo Scientific FT-MS; instrument UHPLC+: Thermo Scientific UltiMate 3000; column: Waters HSS T3, 2.1 ^c 75 mm, C18 1.8 pm; eluent A: 1 L water + 0.01% formic acid, eluent B: 1 L acetonitrile + 0.01% formic acid; gradient: 0.0 min 10% B ® 2.5 min 95% B ® 3.5 min 95% B; oven: 50°C; flow rate: 0.90 ml/min; UV detection: 210 nm/optimum integration path 210-300 nm.

Method 7: MS instrument: Agilent MS Quad 6150; HPLC: Agilent 1290; Column: Waters Acquity UPLC HSS T3 1.8 pm 50 x 2.1 mm; eluent A: 1 L water + 0.25 ml formic acid, eluent B: 1 L acetonitrile + 0.25 ml formic acid; gradient: 0.0 min 90% A 0.3 min 90% A 1.7 min 5% A 3.0 min 5% A; oven: 50°C; flow rate: 1.20 ml/min; UV-Detection: 205 - 305 nm

Method 8: Instrument: Waters Acquity SQD UPLC System; column: Waters Acquity UPLC HSS T3 1.8 pm, 50 x 1 mm; eluent A: 1 L water + 0.25 ml formic acid, eluent B: 1 L acetonitrile + 0.25 ml formic acid; gradient: 0.0 min 90% A ® 1.2 min 5% A ® 2.0 min 5% A; column oven: 50°C; flow rate: 0.40 ml/min; UV detection: 208-400 nm.

Method 9: MS instrument: Waters Single Quad MS System; Waters UPLC Acquity; column: Waters BEH C18, 1.7 pm, 50 ^c 2.1 mm; eluent A: 1 L water + 1.0 ml aq. ammonium hydroxide solution (25% ammonia), eluent B: 1 L acetonitrile; gradient: 0.0 min 92% A ® 0.1 min 92% A ® 1.8 min 5% A ® 3.5 min 5% A; column oven: 50°C; flow rate: 0.45 ml/min; UV detection: 210 nm (208-400 nm).

Preparative HPLC methods

Method P1: Column: Reprosil C18, 10 pM, 125 x 30 mm; eluent: A = water + 0.01% formic acid, eluent B = acetonitrile; gradient: 0.0-5.00 min = 10% B, 6.50 min = 20% B, 17.0-19.75 min = 100% B, 19.75-23.00 min 90% B; flow rate: 75 ml/min, UV-Detection: 210 nm.

Method P2: Column: Reprosil C18, 10pm, 205 ^c 50 mm; eluent A: water + 0.1% of formic acid; eluent B: acetonitrile; gradient: 0.0-5.0 min 10% B, 5.0-17.5 min 10% B to 95% B, 17.5-21.0 min 95% B; flow rate: 150 ml/min, UV-Detection: 210 nm.

Method P3: Column: Reprosil C18, 10 pM, 250 x 30 mm; eluent: A = water + 0.1% of formic acid, eluent B = acetonitrile; gradient: 0.0-4.25 min = 10% B, 4.25-4.50 min, 10% B to 40% B,

4.50 to 11.50 min, 40% B to 60% B, 11.50 to 11.74 min = 60% B to 100% B, 11.74 to 13.00 min = 100% B; flow rate: 50 ml/min, UV-Detection: 210 nm. Method P4: Column: Chromatorex C18, 10 pM, 125 x 30 mm; eluent: A = water + 0.05% of TFA, eluent B = acetonitrile; gradient: 0.0-4.25 min = 10% B, 4.25-4.50 min, 10% B to 40% B, 4.50 to

11.50 min, 40% B to 60% B, 11.50 to 11.74 min = 60% B to 100% B, 11.74 to 13.00 min = 100% B; flow rate: 50 ml/min, UV-Detection: 210 nm. Microwave: Reactions employing microwave irradiation may be run with a Biotage Initator® microwave oven optionally equipped with a robotic unit. The reported reaction times employing microwave heating are intended to be understood as fixed reaction times after reaching the indicated reaction temperature. When compounds according to the invention are purified by preparative HPLC by the above- described methods in which the eluents contain additives, for example trifluoroacetic acid, formic acid or ammonia, the compounds according to the invention may be obtained in salt form, for example as trifluoroacetate, formate or ammonium salt, if the compounds according to the invention contain a sufficiently basic or acidic functionality. Such a salt can be converted to the corresponding free base or acid by various methods known to the person skilled in the art.

In the case of the synthesis intermediates and working examples of the invention described hereinafter, any compound specified in the form of a salt of the corresponding base or acid is generally a salt of unknown exact stoichiometric composition, as obtained by the respective preparation and/or purification process. Unless specified in more detail, additions to names and structural formulae, such as “hydrochloride”, “trifluoroacetate”, “sodium salt” or "x HCI", "x CF3COOH", "x Na⁺" should not therefore be understood in a stoichiometric sense in the case of such salts, but have merely descriptive character with regard to the salt-forming components present therein. This applies correspondingly if synthesis intermediates or working examples or salts thereof were obtained in the form of solvates, for example hydrates, of unknown stoichiometric composition (if they are of a defined type) by the preparation and/or purification processes described.

Starting compounds and intermediates

Intermediate 1A

6-(3,4-Dimethylphenyl)-2-(methylsulfanyl)pyrimidin-4-amine

A solution of 6-chloro-2-(methylsulfanyl)pyrimidin-4-amine (7.00 g, 39.9 mmol), (3,4- dimethylphenyl)boronic acid (7.17 g, 47.8 mmol), sodium carbonate (8.45 g, 79.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.39 g, 1.20 mmol; CAS-RN:[14221-01-3]) in 1,4- dioxane (100 ml) and water (30 ml) was degassed with argon and stirred under an argon atmosphere at RT for 2 h. The reaction was concentrated and the crude residue was washed three times with water, triturated with ethyl acetate/cyclohexane (1:1), filtered and dried to afford 8.50 g (81% of theory, 97% puritiy) of the title compound.

LC-MS (Method 1): R_t = 0.90 min; MS (ESIpos): m/z = 246 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): d [ppm] 7.78-7.67 (m, 2H), 7.28-7.21 (m, 1H), 6.94 (s, 2H), 6.60 (s, 1H), 2.51 (s, 3H), 2.29 (s, 3H), 2.27 (s, 3H). Intermediate 2A

Ethyl 7-(3,4-dimethylphenyl)-3-methyl-5-(methylsulfanyl)imidazo[1,2-c]pyrimidine-2-carboxylate

To a solution of 6-(3,4-dimethylphenyl)-2-(methylsulfanyl)pyrimidin-4-amine (Intermediate 1A, 5.00 g, 90% purity, 18.3 mmol) in 1 ,2-dimethoxyethane (400 ml) was added ethyl 3-bromo-2- oxobutanoate (5.75 g, 27.5 mmol) dropwise at RT. The reaction mixture was stirred at 100°C for 4 days then cooled to RT and concentrated. Methanol (100 ml) was added to the crude residue and the mixture was stirred at RT for 30 min. The resulting precipitate was filtered, washed with methanol and dried to afford 5.0 g (74% of theory, 97% purity) of the title compound.

LC-MS (Method 2): R_t = 2.02 min; MS (ESIpos): m/z = 356 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): d [ppm] 8.00-7.90 (m, 2H), 7.80 (s, 1H), 7.35-7.25 (m, 1H), 4.36 (q, 2H), 3.17 (s, 3H), 2.84 (s, 3H), 2.31 (s, 3H), 2.28 (s, 3H), 1.35 (t, 3H). Intermediate 3A

7-(3,4-Dimethylphenyl)-3-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid

To a solution of ethyl 7-(3,4-dimethylphenyl)-3-methyl-5-(methylsulfanyl)imidazo[1,2-c]pyrimidine- 2-carboxylate (Intermediate 2A, 3.50 g, 97% purity, 9.55 mmol) in ethanol (280 ml) and water (70 ml) was added sodium hydroxide (3.06 g, 76.4 mmol) at RT. The reaction was stirred at 75°C for 24 h, then the mixture was concentrated to remove the ethanol and the pH of the mixture was adjusted to 1 with hydrochloric acid (1.0 N aqueous solution). The mixture was concentrated by half and the precipitate was filtered, washed with water and dried to afford 1.59 g (45% of theory, 82% purity) of the title compound. LC-MS (Method 3): R_t = 1.06 min; MS (ESIpos): m/z = 298 [M+H]⁺

¹H-NMR (300 MHz, DMSO-d₆): d [ppm] 12.59 (s, 1H), 11.52 (s, 1H), 7.65-7.58 (m, 1H), 7.55-7.45 (m, 1H), 7.31-7.22 (m, 1H), 6.59 (s, 1H), 2.95 (s, 3H), 2.30 (s, 3H), 2.28 (s, 3H).

Intermediate 4A

6-(3-Fluoro-4-methylphenyl)-2-(methylsulfanyl)pyrimidin-4-amine A solution of 6-chloro-2-(methylsulfanyl)pyrimidin-4-amine (7.00 g, 39.9 mmol), (3-fluoro-4- methylphenyl)boronic acid (7.36 g, 47.8 mmol), sodium carbonate (8.45 g, 79.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.39 g, 1.20 mmol; CAS-RN:[14221-01-3]) in 1,4- dioxane (100 ml) and water (30 ml) was degassed with argon and stirred under an argon atmosphere at RT for 2 h. The reaction was concentrated and the crude residue was washed three times with water and triturated with ethyl acetate/cyclohexane (1:1), filtered and dried to afford 8.50 g (82% of theory, 96% puritiy) of the title compound.

LC-MS (Method 1): R_t = 0.97 min; MS (ESIpos): m/z = 250 [M+H]⁺ ¹H-NMR (400 MHz, DMSO-d₆): d [ppm] 7.79 -7.68 (m, 2H), 7.45-7.35 (m, 1H), 7.03 (s, 2H), 6.63 (s, 1H), 2.50 (s, 3H), 2.29 (s, 3H).

Intermediate 5A

Ethyl 7-(3-fluoro-4-methylphenyl)-3-methyl-5-(methylsulfanyl)imidazo[1 ,2-c]pyrimidine-2- carboxylate

To a solution of 6-(3-fluoro-4-methylphenyl)-2-(methylsulfanyl)pyrimidin-4-amine (I ntermediate 4A, 5.00 g, 96% purity, 19.3 mmol) in 1 ,2-dimethoxyethane (400 ml) was added ethyl 3-bromo-2- oxobutanoate (5.23 g, 25.0 mmol) dropwise at RT. The reaction mixture was stirred at 100°C for 4 days, then cooled to RT and concentrated. Methanol (100 ml) was added to the crude residue and the mixture was stirred at RT for 30 min. The resulting precipitate was filtered, washed with methanol and dried to afford 3.4 g (48% of theory, 99% purity) of the title compound.

LC-MS (Method 4): R_t = 2.06 min; MS (ESIpos): m/z = 360 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): d [ppm] 8.01-7.98 (m, 2H), 7.50-7.40 (m, 1H), 6.64 (s, 1H), 4.33 (t, 2H), 2.83 (s, 3H), 2.55 (s, 3H), 2.31 (s, 3H), 1.34 (t, 3H). Intermediate 6A

7-(3-Fluoro-4-methylphenyl)-3-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid

To a solution of ethyl 7-(3-fluoro-4-methylphenyl)-3-methyl-5-(methylsulfanyl)imidazo[1,2- c]pyrimidine-2-carboxylate (Intermediate 5A, 3.20 g, 99% purity, 8.81 mmol) in THF (280 ml) and water (70 ml) was added sodium hydroxide (2.82 g, 70.5 mmol) at RT. The reaction was stirred at 75°C for 24 h, then the mixture was concentrated to remove the ethanol and the pH of the mixture was adjusted to 1 with hydrochloric acid (1.0 N aqueous solution). The mixture was concentrated by half and the precipitate was filtered, washed with water and dried to afford 1.87 g (66% of theory, 95% purity) of the title compound.

LC-MS (Method 3): R_t = 1.04 min; MS (ESIpos): m/z = 302 [M+H]⁺

¹H-NMR (400 MHz, DMSO-de): d [ppm] 12.75 (bs, 1H), 11.59 (s, 1H), 7.69-7.61 (m, 1H), 7.58-7.51 (m, 1H), 7.45-7.36 (m, 1H), 6.64 (s, 1H), 2.95 (s, 3H), 2.29 (s, 3H). Intermediate 7A

Ethyl 7-chloro-3-methyl-5-methylsulfanyl-imidazo[1 ,2-c]pyrimidine-2-carboxylate

To a solution of 6-chloro-2-(methylsulfanyl)pyrimidin-4-amine (115 mg, 0.88 mmol) in 1,2- dimethoxyethane (1.6 ml) was added ethyl 3-bromo-2-oxobutanoate (240 mg, 1.15 mmol) dropwise at RT. The reaction was stirred at 100°C for 2 days, then cooled to RT, diluted with DMSO and purified by preparative HPLC (Method P2). The product containing fractions were collected and concentrated to afford 42 mg (16% of theory, 95% purity) of the title compound.

LC-MS (Method 3): R_t = 1.61 min; MS (ESIpos): m/z = 593 [M+Na]⁺

Intermediate 8A 7-Chloro-3-methyl-5-oxo-5,6-dihydroimidazo[1 ,2-c]pyrimidine-2-carboxylic acid To a solution of ethyl 7-chloro-3-methyl-5-(methylsulfanyl)imidazo[1,2-c]pyrimidine-2-carboxylate (Intermediate 7A, 4.80 g, 84% purity, 14.1 mmol) in THF (50 ml) was added sodium hydroxide (50 ml of a 1.4 M aqueous solution, 70.55 mmol) at RT. The resulting reaction was stirred overnight at 50°C, then the mixture was concentrated to remove the THF and the pH of the solution was adjusted to 1 with hydrochloric acid (1.0 N aqueous solution). The mixture was concentrated by half and the precipitate was filtered, washed with water and dried to afford 2.73 g (72% of theory, 85% purity) of the title compound.

LC-MS (Method 5): R_t = 0.91 min; MS (ESIpos): m/z = 228 [M+H]⁺ ¹H-NMR (400 MHz, DMSO-d₆): d [ppm] 12.11-13.25 (m, 2H), 6.62 (s, 1H), 2.89 (s, 3H).

Intermediate 9A

7-Chloro-/\/-[(1 S)-1-(4-fluorophenyl)-2-hydroxy-2-methylpropyl]-3-methyl-5-oxo-5,6- dihydroimidazo[1,2-c]pyrimidine-2-carboxamide

To a solution of 7-chloro-3-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid (Intermediate 8A, 1.00 g, 3.73 mmol) and (1S)-1-amino-1-(4-fluorophenyl)-2-methylpropan-2-ol (Intermediate 10A, 886 mg, 4.83 mmol) in DMF was added HATU (2.00 g, 5.27 mmol) and DIPEA (1.5 ml, 8.8 mmol). The reaction was stirred overnight at RT, then water was added and the resulting precipitate was collected by filtration, washed with water and dried. The crude material was purified by silica gel column chromatography (elutent: dichloromethane/methanol, 20:1) to afford 1.30 g (76% of theory, 86% purity) of the title compound.

LC-MS (Method 6): R_t = 1.45 min; MS (ESIpos): m/z = 393 [M+H]⁺

Ή-NMR (600 MHz, DMSO-d₆) d [ppm]: -0.008 (0.76), 0.938 (10.10), 1.229 (11.51), 1.753 (0.69), 2.081 (0.60), 2.684 (4.65), 2.852 (2.89), 2.855 (16.00), 2.885 (1.03), 2.956 (0.66), 3.336 (0.77), 3.595 (0.58), 4.747 (2.22), 4.762 (2.20), 4.974 (0.43), 6.798 (4.19), 6.902 (0.60), 7.087 (1.95), 7.102 (3.98), 7.117 (2.10), 7.370 (1.96), 7.380 (2.29), 7.384 (2.20), 7.394 (1.85), 8.347 (1.67), 8.362 (1.62).

Intermediate 10A

(7S)-1-Amino-1-(4-fluorophenyl)-2-methylpropan-2-ol

Methylmagnesium bromide (13 ml of a 1.0 M solution in THF, 13 mmol) was added slowly to a solution of methyl (2S)-amino(4-fluorophenyl)ethanoate hydrochloride (485 mg, 2.21 mmol) in THF (9.7 ml). After complete addition, the reaction mixture was slowly warmed to RT and stirred at this temperature overnight. Hydrochloric acid solution (1.0 M aqueous solution) was then added, and the mixture was washed with MTBE. The layers were separated and the organic layer was discarded. The aqueous layer was brought to basic pH by addition of sodium hydroxide (1.0 M aqueous solution) and was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (basified silica gel, eluent: gradient of methanol in dichloromethane). Yield: 203 mg (48% of theory, 95% purity).

LC/MS (Method 9): R_t = 1.08 min; MS (ESIpos): m/z = 184 [M+H]⁺.

¹H-NMR (500 MHz, DMSO-de): d [ppm] = 7.44-7.30 (m, 2H), 7.13-7.03 (m, 2H), 4.36 (br. s, 1H), 3.69 (s, 1H), 2.07-1.75 (m, 2H), 1.00 (s, 3H), 0.94 (s, 3H).

Intermediate 1A (S)-/\/-[(4-Fluorophenyl)methylene]-2-methyl-propane-2-sulfinamide

To a solution of 4-fluorobenzaldehyde (30 g, 242 mmol) and copper(ll) sulfate (116 g, 725 mmol) in dichloromethane (300 ml) were added 2-methylpropane-2-sulfinamide (29.3 g, 242 mmol) and PTSA (1.50 g, 8.70 mmol) and the mixture was stirred at 30°C for 60 hours under nitrogen atmosphere. The reaction mixture was filtered and the filter cake was washed with dichloromethane. The filtrate was washed with sodium bicarbonate solution (120 ml of a saturated aqueous solution) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated to afford (44.5 g, 195.7 mmol, 81% of theory) the title compound.

¹H-NMR (400 MHz, CHCb-cf): d [ppm] = 8.55 (s, 1H), 7.87 (m, 2H), 7.17 (m, 2H), 1.69 (s, 1H), 1.27 (s, 9H).

Intermediate 12A

Ethyl (3S)-3-[[(S)-te/f-butylsulfinyl]amino]-2,2-difluoro-3-(4-fluorophenyl)propanoate

A suspension of zinc (153 g, 2.30 mol) in THF (600 ml) was stirred in 30°C at nitrogen atmosphere. Chloro(trimethyl)silane (6.80 g, 63.0 mmol) was added and the mixture was stirred for 15 min. Then ethyl 2-bromo-2,2-difluoro-acetate (237 g, 1.17 mol, 150 ml) in THF (700 ml) was added dropwise and the temperature of the reaction was kept below 50°C. The mixture was stirred and cooled to RT and (S)-/\/-[(4-fluorophenyl)methylene]-2-methyl-propane-2-sulfinamide (Intermediate 11A, 53.0 g, 233 mmol) in THF (200 ml) was added. The mixture was stirred at 30°C for 20 hours under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated, quenched with ammonium chloride (1.6 L of a saturated aqueous solution), washed with brine (1.0 L) and dried with anhydrous sodium sulfate. The mixture was purified by silica gel column chromatography (eluent: gradient of ethyl acetate in cyclohexane). The compound was purified for second time by silica gel column chromatography (eluent: gradient of ethyl acetate in cyclohexane), to afford 47.7 g (58% of theory) of the title compound.

¹H-NMR (400 MHz, CHC l₃-d): d [ppm] = 7.37 (m, 2H), 7.06-7.10 (m, 2H), 5.01-4.94 (dd, 1H), 4.4 (m, 1H), 4.26 (m, 2H), 1.29 (dd, 3H), 1.24 (s, 9H).

Intermediate 2A

Ethyl (3S)-3-amino-2,2-difluoro-3-(4-fluorophenyl)propanoate hydrochloride To a solution of ethyl (3S)-3-[[(S)-te/f-butylsulfinyl]amino]-2,2-difluoro-3-(4-fluorophenyl) propanoate (Intermediate 12A, 46.0 g, 131 mmol) in ethanol (300 ml) was added hydrochloric acid (350 ml of a 4.0 M solution in 1,4-dioxane) and the mixture was stirred at 30°C for 2 hours. The mixture was concentrated, then MTBE (500 ml) was added and the suspension was stirred for 1 hour and filtered to give the title compound (29.3 g, 102.3 mmol, 78% of theory, 99% purity, 91.9% ee) as solid. From this, a part was recrystallized (14.2 g, 50.1 mmol) from a mixture of ethyl acetate/methanol (1.5:1, 125 ml) to give ethyl (3S)-3-amino-2,2-difluoro-3-(4- fluorophenyl)propanoate (3.28 g, 11.6 mmol, 23% of theory, 96.7% ee) as solid. ¹H-NMR (400 MHz, DMSO-de): d [ppm] = 9.42-9.38 (br s, 2H), 7.61 (br s, 2H), 7.39-7.33 (m, 2H), 5.36-5.29 (m, 1H), 4.24-4.19 (dd, 2H), 1.12 (dd, 3H).

Intermediate 3A

(3S)-3-Amino-2,2-difluoro-3-(4-fluorophenyl)propan-1-ol

To a suspension of lithium borohydride (1.43 g, 65.6 mmol) in THF (100 ml) at 0°C was added ethyl (3S)-3-amino-2,2-difluoro-3-(4-fluorophenyl)propanoate (Intermediate 13A, 6.20 g, 21.8 mmol). The mixture was warmed to RT and stirred for 2 hours. The reaction mixture was poured to a solution of ammonium hydroxide (20 ml) and water (50 ml). The mixture was stirred for 1 hour, then extracted with ethyl acetate (3 ^c 150 ml), washed with brine (100 ml), dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC (Method P3) to afford 3.5 g (75% of theory, 96% purity) of the title compound.

¹H-NMR (400 MHz, DMSO-de): d [ppm] = 7.46-7.42 (dd, 2H), 7.18-7.14 (m, 2H), 5.46 (br s, 1H), 4.28-4.22 (m, 1 H), 3.77 (m, 1 H), 3.54 (m, 1 H), 2.21 (br s, 2H). Intermediate 15A

Ethyl 7-(3,4-dimethylphenyl)-5-(methylsulfanyl)imidazo[1,2-c]pyrimidine-2-carboxylate

To a solution of 6-(3,4-dimethylphenyl)-2-(methylsulfanyl)pyrimidin-4-amine (2.40 g, 9.78 mmol) in ethanol (24 ml) was added ethyl 3-bromo-2-oxobutanoate (3.36 g, 85% purity, 14.7 mmol) at RT. The reaction mixture was stirred at 100°C. After 2 h another portion of ethyl 3-bromo-2- oxobutanoate (1.68 g, 85% purity, 7.35 mmol) was added and the reaction stirred overnight at 100°C. After cooling the reaction mixture was filtrated and the residue washed with ethanol. The filtrate was concentrated and the residue was purified by preparative HPLC (Method P3) to afford 0.37 g (11% of theory) of the title compound

LC-MS (Method 6): R_t = 2.35 min; MS (ESIpos): m/z = 342 [M+H]⁺

¹H-NMR (400 MHz, DMSO-d₆): d [ppm] 8.30 (s, 1H), 8.00 (s, 1H), 7.95 (m, 2H), 7.28 (d, 1H), 4.35 (q, 2H), 2.90 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 1.35 (t, 3H).

Intermediate 16A 7-(3,4-Dimethylphenyl)-5-oxo-5,6-dihydroimidazo[1 ,2-c]pyrimidine-2-carboxylic acid

To a solution of ethyl 7-(3,4-dimethylphenyl)-5-(methylsulfanyl)imidazo[1,2-c]pyrimidine-2- carboxylate (Intermediate 15A, 0.37 g, 1.08 mmol) in ethanol (10.8 ml) and water (2.17 ml) was added sodium hydroxide (0.35 mg, 8.67 mmol) at RT. The reaction was stirred at 100°C for 3 h. After cooling, the mixture was adjusted to pH 1 with hydrochloric acid (1.0 N aqueous solution) and the mixture was concentrated by half and the precipitate was filtered, washed with water and dried to afford 0.26 g (85% of theory) of the title compound.

LC-MS (Method 8): R_t = 0.62 min; MS (ESIpos): m/z = 284 [M+H]⁺ ¹H-NMR (300 MHz, DMSO-de): d [ppm] 12.87 (br s, 1H), 11.84 (s, 1H), 8.18 (s, 1H), 7.61 (s, 1H), 7.52 (d, 1H), 7.26 (d, 1H), 6.90 (s, 1H), 2.28 (s, 6H).

Intermediate 17A

Ethyl 7-chloro-5-(methylsulfanyl)imidazo[1,2-c]pyrimidine-2-carboxylate

To a solution of 6-chloro-2-(methylthio)pyrimidin-4-amine (7.00 g, 39.0 mmol) in ethanol (105 ml) was added ethyl 3-bromo-2-oxobutanoate (16.7 g, 90% purity, 77.3 mmol) at RT. The reaction mixture was stirred at 90°C overnight. The mixture was concentrated and the residue was suspended in ethyl acetate, the precipitate was filtered, washed with ethylacetate and dried to get 7.93 g (53% of theory, 71% purity) of the title compound. This compound was used without further purification.

LC-MS (Method 6): R_t = 1.63 min; MS (ESIpos): m/z = 272 [M+H]⁺

Intermediate 18A

7-Chloro-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid

To a suspension of ethyl 7-chloro-5-(methylsulfanyl)imidazo[1,2-c]pyrimidine-2-carboxylate (Intermediate 17A, 7.93 g, 71% purity, 20.6 mmol) in ethanol (206 ml) was added sodium hydroxide (68.7 ml of a 3.0 M aqueous solution, 206 mmol) at RT. The reaction mixture was stirred at 100°C for 3 h and after cooling the mixture was adjusted to pH 1 with hydrochloric acid (1.0 N aqueous solution). The mixture was concentrated until a volume of about 20 ml and the precipitate was filtered, washed with a solution of ethanol in water (26 ml x 2, 50 vvol%) and dried to afford 4.26 g (67% of theory, 70% purity) of the title compound. This compound was used without further purification.

LC-MS (Method 8): R_t = 0.35 min; MS (ESIpos): m/z = 214 [M+H]⁺ ¹H-NMR (500 MHz, DMSO-de): d [ppm] 14.10-11.40 (br s, 2H), 8.15 (s, 1H), 6.81 (s, 1H). Intermediate 19A

7-Chloro-/\/-[(1R)-1-(4-fluorophenyl)-3-hydroxypropyl]-5-oxo-5,6-dihydroimidazo[1 ,2- c]pyrimidine-2-carboxamide

To a suspension of 7-chloro-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid (Intermediate 18A, 0.50 g, 2.34 mmol) in DMF (15.8 ml) was added under icebath cooling EDC (0.67 g, 3.51 mmol) and 4-dimethylaminopyridine (0.86 g, 7.02 mmol) and stirred for 5 minutes at 0°C. (3R)-3-Amino-3-(4-fluorophenyl)propan-1-ol (0.40 g, 2.34 mmol) was added and the reaction mixture was stirred overnight at RT. The reaction mixture was diluted with 100 ml water and washed three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtrated and concentrated. The residue was purified by preparative HPLC (Method P3) to afford 0.11 g (13% of theory) of the title compound.

LC-MS (Method 6): R_t = 1.12 min; MS (ESIpos): m/z = 365 [M+H]⁺

Intermediate 20A 7-Chloro-/\/-[(1R)-1-(4-fluorophenyl)ethyl]-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2- carboxamide

To a suspension of 7-chloro-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid (Intermediate 18A, 0.25 g, 1.17 mmol) in DMF (5.67 ml) was added under icebath cooling HATU (0.53 g, 1.41 mmol) and DIPEA (0.61 ml, 3.51 mmol) and stirred for 5 minutes at 0°C. (1R)-1-(4- fluorophenyl)ethanamine (0.18 g, 1.29 mmol) was added and the mixture was stirred for another 30 minutes at 0°C. The reaction mixture was diluted with water and washed three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtrated and concentrated. The residue was suspended in acetonitrile, filtrated and dried under vacuum to afford 0.17 g (41% of theory, 93% purity) of the title compound.

LC-MS (Method 6): R_t = 1.40 min; MS (ESIpos): m/z = 335 [M+H]⁺

Intermediate 21A 7-Chloro-/\/-[(1R)-1-(4-fluorophenyl)-3-hydroxypropyl]-3-methyl-5-oxo-5,6-dihydroimidazo[1,2- c]pyrimidine-2-carboxamide

To a suspension of 7-chloro-3-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid (Intermediate 8A, 100 mg, 439 pmol) in DMF (4.4 ml) was added under icebath cooling HATU (184 mg, 483 pmol) and DIPEA (150 pi, 880 pmol) and stirred for 5 minutes at 0°C. (3R)-3-Amino-

3-(4-fluorophenyl)propan-1-ol (74.3 mg, 439 pmol) was added and the mixture was stirred for another 30 minutes at 0°C. The reaction mixture was diluted with water and washed three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtrated and concentrated. The residue was purified by preparative HPLC (Method P3) to afford 0.14 g (84% of theory) of the title compound.

LC-MS (Method 7): R_t = 0.95 min; MS (ESIneg): m/z = 377 [M-H]-

Intermediate 22A

7-Chloro-N-[(1S)-1-(4-fluorophenyl)-2-hydroxy-2-methylpropyl]-5-oxo-5,6-dihydroimidazo[1,2- c]pyrimidine-2-carboxamide

To a suspension of 7-chloro-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-2-carboxylic acid (Intermediate 18A, 200 mg, 936 pmol) in DMF (5.0 ml) was added HATU (427 mg, 1.12 mmol) and stirred for 5 minutes at 0°C. (1 S)-1-Amino-1-(4-fluorophenyl)-2-methylpropan-2-ol (Intermediate 10A, 172 mg, 936 pmol) was added and the reaction mixture was stirred overnight at RT. The crude mixture was purified by preparative HPLC (Method P2) to afford 275 mg (78% of theory) of the title compound. LC-MS (Method 6): R_t = 1.30 min; MS (ESIpos): m/z = 379 [M+H]⁺

Example compounds

Example 1-1

7-(3-Chloro-4-methylphenyl)-/\/-[(1R)-1-(4-fluorophenyl)-3-hydroxypropyl]-5-oxo-5,6- dihydroimidazo[1 ,2-c]pyrimidine-2-carboxamide

To a solution of 7-chloro-/\/-[(1R)-1-(4-fluorophenyl)-3-hydroxypropyl]-5-oxo-5,6- dihydroimidazo[1,2-c]pyrimidine-2-carboxamide (Intermediate 19A, 25.0 mg, 68.5 pmol) and (3- chloro-4-methylphenyl)boronic acid (14.0 mg, 82.2 pmol) in 1,4-dioxane (230 pi) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium(0) (3.96 mg, 3.43 pmol; CAS- RN:[14221-01-3]) and sodium carbonate (140 pi of a 2.0 M aqueous solution, 270 pmol). The reaction was heated to 110°C for 15 min, then a second portion of (3-chloro-4- methylphenyl)boronic acid (14.0 mg, 82.2 pmol), tetrakis(triphenylphosphine)palladium(0) (3.96 mg, 3.43 pmol; CAS-RN:[14221-01-3]) and sodium carbonate (140 pi of a 2.0 M aqueous solution, 270 pmol) were added under argon and the reaction was heated to 110°C for 20 min. A third portion of (3-chloro-4-methylphenyl)boronic acid (14.0 mg, 82.2 pmol), tetrakis(triphenylphosphine)palladium(0) (3.96 mg, 3.43 pmol; CAS-RN:[14221-01-3]) and sodium carbonate (140 pi of a 2.0 M aqueous solution, 270 pmol) were added under argon and the reaction was heated to 110°C for 15 min. The reaction was cooled to RT, acidified with hydrochloric acid (4.0 M aqueous solution), diluted with methanol and passed through a Millipore filter. The crude mixture was purified by preparative HPLC (Method P3) to afford 11.0 mg (35% of theory, 100% purity) of the title compound.

LC-MS (Method 6): R_t = 1.72 min; MS (ESIpos): m/z = 455 [M+H]⁺ Ή-NMR (500 MHz, DMSO-d₆) d [ppm]: -0.007 (0.94), 0.007 (0.85), 1.919 (0.58), 1.934 (1.00), 1.946 (1.07), 1.961 (0.91), 2.058 (0.80), 2.063 (0.51), 2.069 (0.58), 2.074 (1.11), 2.085 (1.03), 2.102 (0.58), 2.396 (16.00), 2.520 (0.51), 3.307 (1.60), 3.332 (1.49), 3.337 (0.85), 3.342 (0.78), 3.387 (1.03), 3.399 (1.98), 3.404 (1.74), 3.408 (2.34), 3.418 (1.63), 3.428 (0.82), 4.617 (1.83), 4.626 (4.21), 4.636 (1.83), 5.157 (0.62), 5.173 (1.34), 5.185 (1.29), 5.202 (0.60), 6.944 (7.04),

7.124 (3.01), 7.128 (1.11), 7.137 (1.31), 7.142 (6.04), 7.155 (1.11), 7.160 (3.30), 7.426 (2.90),

7.430 (1.38), 7.437 (3.25), 7.444 (3.10), 7.451 (1.25), 7.455 (2.70), 7.491 (2.52), 7.508 (3.08),

7.672 (2.27), 7.676 (2.34), 7.688 (1.81), 7.692 (1.94), 7.877 (4.10), 7.880 (4.08), 8.066 (6.95),

8.067 (7.11), 8.775 (2.27), 8.792 (2.18), 11.975 (2.47). Example 1-2

A/-[(1f?)-1-(4-Fluorophenyl)-3-hydroxypropyl]-7-(8-fluoroquinolin-3-yl)-5-oxo-5,6- dihydroimidazo[1,2-c]pyri idine-2-carboxa ide

To a solution of 7-chloro-/\/-[(1R)-1-(4-fluorophenyl)-3-hydroxypropyl]-5-oxo-5,6- dihydroimidazo[1,2-c]pyri idine-2-carboxa ide (Intermediate 19A, 30.0 mg, 82.2 pmol) and (8- fluoroquinolin-3-yl)boronic acid (18.8 mg, 98.7 pmol) in 1,4-dioxane (280 pi) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium(0) (4.75 mg, 4.11 pmol; CAS- RN:[14221-01-3]) and sodium carbonate (160 pi of a 2.0 M aqueous solution, 330 pmol). The reaction was heated to 110°C for 15 min, then a second portion of (8-fluoroquinolin-3-yl)boronic acid (0.6 equiv.) and tetrakis(triphenylphosphine)palladium(0) (4.75 mg, 4.11 pmol; CAS- RN:[14221-01-3]) were added under argon and the reaction was heated to 110°C for 30 min. The reaction was cooled to RT, acidified with hydrochloric acid (4.0 M aqueous solution), diluted with methanol and passed through a Millipore filter. The crude mixture was purified by preparative HPLC (Method P3) to afford 16.0 mg (37% of theory, 90% purity) of the title compound. LC-MS (Method 6): R_t = 1.43 min; MS (ESIpos): m/z = 476 [M+H]⁺

Ή-NMR (500 MHz, DMSO-d₆) d [ppm]: 1.234 (1.41), 1.919 (0.82), 1.931 (1.85), 1.945 (2.76),

1.958 (3.01), 1.972 (2.50), 1.985 (1.03), 2.069 (2.28), 2.086 (2.97), 2.097 (2.68), 2.113 (1.56),

2.364 (0.51), 2.444 (0.49), 2.637 (0.55), 3.419 (6.72), 3.508 (0.47), 4.638 (3.72), 5.171 (1.82),

5.188 (3.76), 5.200 (3.60), 5.217 (1.60), 6.882 (0.55), 7.132 (6.50), 7.149 (12.95), 7.167 (7.16), 7.220 (16.00), 7.440 (7.35), 7.451 (8.53), 7.457 (8.30), 7.468 (6.42), 7.522 (0.95), 7.662 (1.38),

7.677 (7.66), 7.691 (11.27), 7.698 (5.87), 7.703 (4.80), 7.792 (0.43), 7.903 (4.78), 7.909 (4.74),

7.922 (4.27), 8.060 (0.58), 8.094 (14.68), 8.143 (2.19), 8.807 (5.63), 8.824 (5.46), 8.894 (9.01),

9.367 (9.65), 9.371 (9.55). Example 1-3

7-(3,4-Dimethylphenyl)-/\/-[(1R)-1-(4-fluorophenyl)-3-hydroxypropyl]-3-methyl-5-oxo-5,6- dihydroimidazo[1,2-c]pyrimidine-2-carboxamide

To a solution of 7-chloro-/\/-[(1R)-1-(4-fluorophenyl)-3-hydroxypropyl]-3-methyl-5-oxo-5,6- dihydroimidazo[1,2-c]pyrimidine-2-carboxamide (Intermediate 21 A, 65.0 g, 172 pmol) and (3,4- dimethylphenyl)boronic acid (30.9 mg, 206 pmol) in 1,4-dioxane (1.7 ml) under an argon atmosphere was added tetrakis(triphenylphosphine)palladium(0) (9.91 mg, 8.58 pmol; CAS- RN:[14221-01-3]) and sodium carbonate (260 pi of a 2.0 M aqueous solution, 520 pmol). The reaction was heated in a microwave to 120°C for 1 h. The mixture was cooled to RT, filtered and purified by preparative HPLC (Method P4) to afford 40.0 mg (52% of theory, 100% purity) of the title compound.

LC-MS (Method 7): R_t = 1.25 min; MS (ESIneg): m/z = 447 [M-H]-

Ή-NMR (400 MHz, DMSO-d₆) d [ppm]: 0.008 (0.45), 1.906 (0.43), 1.923 (0.66), 1.941 (0.80),

I.957 (0.72), 2.031 (0.59), 2.052 (0.80), 2.065 (0.66), 2.276 (10.46), 2.290 (11.90), 2.328 (0.40), 2.925 (16.00), 3.376 (0.84), 3.390 (1.81), 3.402 (1.71), 4.604 (0.90), 4.616 (1.86), 4.627 (0.85),

5.127 (0.47), 5.148 (0.97), 5.163 (0.90), 5.184 (0.41), 6.701 (3.15), 6.705 (3.25), 7.117 (2.02),

7.139 (4.19), 7.161 (2.34), 7.249 (1.80), 7.269 (2.10), 7.410 (2.09), 7.424 (2.38), 7.432 (2.23),

7.446 (1.90), 7.487 (1.31), 7.491 (1.38), 7.511 (1.20), 7.578 (2.36), 8.572 (1.62), 8.593 (1.59),

I I.490 (1.92). Example 1-4

7-(4-Chloro-3-methylphenyl)-/\/-[(1R)-1-(4-fluorophenyl)-3-hydroxypropyl]-5-oxo-5,6- dihydroimidazo[1,2-c]pyrimidine-2-carboxamide To a solution of 7-chloro-/\/-[(1R)-1-(4-fluorophenyl)-3-hydroxypropyl]-5-oxo-5,6- dihydroimidazo[1,2-c]pyrimidine-2-carboxamide (Intermediate 19A, 50.0 g, 49% purity, 66.9 pmol) and (4-chloro-3-methylphenyl)boronic acid (11.4 mg, 66.9 pmol) in DMF under an argon atmosphere was added 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane complex (550 pg, 0.67 pmol; CAS-RN:[ 95464-05-4]) and sodium carbonate (100 pi of a 2.0 M aqueous solution, 200 pmol) and the reaction was heated to 90°C overnight. A second portion of (4-chloro-3-methylphenyl)boronic acid (11.4 mg, 66.9 pmol), 1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane complex (550 pg, 0.67 pmol; CAS-RN:[ 95464-05-4]) and sodium carbonate (100 pi of a 2.0 M aqueous solution, 200 pmol) were added and the reaction was heater to 90°C for a further 72 h. After this time, a third portion of (4-chloro-3-methylphenyl)boronic acid (11.4 mg, 66.9 pmol) and tetrakis(triphenylphosphine)palladium(0) (7.73 mg, 6.69 pmol; CAS-RN:[14221-01-3]) were added and the reaction was heated to 110°C overnight. The reaction was cooled to RT, acidified with formic acid and passed through a Millipore filter. The crude mixture was purified by preparative HPLC (Method P3) to afford 18.0 mg (53% of theory, 90% purity) of the title compound.

LC-MS (Method 6): R_t = 1.70 min; MS (ESIpos): m/z = 455 [M+H]⁺

Ή-NMR (600 MHz, DMSO-d₆) d [ppm]: 0.855 (0.41), 1.176 (2.02), 1.188 (3.83), 1.200 (2.26), 1.235 (1.97), 1.297 (2.08), 1.308 (3.74), 1.320 (1.86), 1.866 (1.06), 1.924 (1.26), 1.935 (1.36), 1.947 (1.11), 2.062 (1.37), 2.071 (1.27), 2.275 (0.55), 2.303 (0.47), 2.357 (1.49), 2.393 (16.00),

2.441 (6.44), 2.616 (0.71), 2.731 (1.03), 2.891 (1.18), 3.394 (7.20), 3.404 (7.09), 3.415 (6.15),

3.510 (9.42), 4.183 (0.88), 4.195 (2.09), 4.207 (2.07), 4.218 (0.85), 4.296 (0.85), 4.308 (1.98),

4.320 (2.04), 4.332 (0.84), 5.139 (0.77), 5.153 (1.68), 5.162 (1.63), 5.446 (0.40), 6.239 (3.72),

6.791 (5.78), 7.125 (2.53), 7.140 (5.14), 7.154 (3.05), 7.361 (2.56), 7.407 (3.02), 7.421 (3.44), 7.429 (3.27), 7.442 (3.95), 7.452 (3.18), 7.555 (0.81), 7.605 (0.69), 7.623 (0.85), 7.662 (1.21),

7.676 (1.38), 7.757 (5.38), 7.792 (2.13), 7.806 (2.06), 7.890 (0.89), 7.904 (0.86), 7.983 (3.64),

8.039 (0.46), 8.063 (1.50), 8.458 (5.06), 8.563 (2.33), 8.577 (2.34). Example 1-5

A/-[(1R)-1-(4-Fluorophenyl)-3-hydroxypropyl]-7-(5-methylquinolin-3-yl)-5-oxo-5,6- dihydroimidazo[1,2-c]pyrimidine-2-carboxamide

A solution of 7-chloro-/\/-[(1R)-1-(4-fluorophenyl)-3-hydroxypropyl]-5-oxo-5,6-dihydroimidazo[1,2- c]pyrimidine-2-carboxamide (Intermediate 19A, 60.0 g, 164 pmol), 5-methyl-3-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (57.6 mg, 214 pmol) and sodium carbonate (82.9 mg, 987 pmol) in a THF/water mixture (1.8 ml, 2:1) was degassed with argon for 5 min, then (2- dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 '-biphenyl)[2-(2'-amino-1 , 1 '-biphenyl)]palladium(ll) methanesulfonate (XPhos-Pd-G3) (13.9 mg, 16.4 pmol; CAS-RN:[ 1445085-55-1]) was added and the mixture was degassed for a further 5 min. The reaction was heated to 110°C in a microwave for 15 min, then the reaction was cooled to RT, acidified with formic acid and passed through a Millipore filter. The crude mixture was purified by preparative HPLC (Method P3) to afford 13.3 mg (17% of theory, 100% of purity) of the title compound. LC-MS (Method 6): R_t = 1.48 min; MS (ESIpos): m/z = 472 [M+H]⁺

Ή-NMR (500 MHz, DMSO-d₆) d [ppm]: -0.006 (1.46), 0.006 (1.08), 1.933 (0.64), 1.947 (1.02), 1.960 (1.14), 1.975 (0.94), 2.069 (0.85), 2.085 (1.16), 2.096 (1.04), 2.113 (0.59), 2.777 (16.00), 3.415 (2.17), 3.424 (2.27), 4.635 (1.21), 4.644 (2.32), 4.654 (1.14), 5.174 (0.66), 5.191 (1.41),

5.203 (1.37), 5.220 (0.62), 7.134 (2.87), 7.152 (5.71), 7.170 (3.07), 7.297 (7.15), 7.440 (2.96), 7.451 (3.36), 7.457 (3.15), 7.468 (2.64), 7.530 (2.17), 7.544 (2.53), 7.717 (2.12), 7.733 (2.60),

7.747 (2.14), 7.912 (2.65), 7.928 (2.19), 8.118 (6.99), 8.138 (0.42), 8.809 (2.38), 8.826 (2.27),

8.881 (3.41), 8.885 (3.36), 9.323 (4.36), 9.328 (4.16), 12.307 (0.52).

Example 1-6

7-(5,6-Dimethylpyridin-3-yl)-/\/-[(1R)-1-(4-fluorophenyl)-3-hydroxypropyl]-5-oxo-5,6- dihydroimidazo[1 ,2-c]pyrimidine-2-carboxamide A solution of 7-chloro-/\/-[(1R)-1-(4-fluorophenyl)-3-hydroxypropyl]-5-oxo-5,6-dihydroimidazo[1 ,2- c]pyrimidine-2-carboxamide (Intermediate 19A, 40.0 g, 110 pmol), 2,3-dimethyl-5-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (33.2 mg, 143 pmol) and sodium carbonate (55.3 mg, 658 pmol) in a THF/water mixture (1.2 ml, 2:1) was degassed with argon for 5 min, then (2- dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 '-biphenyl)[2-(2'-amino-1 , 1 '-biphenyl)]palladium(ll) methanesulfonate (XPhos-Pd-G3) (9.28 mg, 11.0 pmol; CAS-RN:[ 1445085-55-1]) was added and the mixture was degassed for a further 5 min. The reaction was heated to 110°C in a microwave for 15 min. A second portion of 2,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (33.2 mg, 143 pmol) and sodium carbonate (55.3 mg, 658 pmol) were added and the reaction was degassed with argon for 5 min, then (2-dicyclohexylphosphino-2',4',6'-triisopropyl-

I,T-biphenyl)[2-(2'-amino-1,T-biphenyl)]palladium(ll) methanesulfonate (XPhos-Pd-G3) (9.28 mg,

I I.0 pmol; CAS-RN:[ 1445085-55-1]) was added and the mixture was degassed for a further 5 min. The reaction was heated to 110°C in a microwave for 60 min. The reaction was cooled to RT, acidified with formic acid and passed through a Millipore filter. The crude mixture was purified by preparative HPLC (Method P3) to afford 20.8 mg (44% of theory, 100% of purity) of the title compound.

LC-MS (Method 6): R_t = 1.17 min; MS (ESIpos): m/z = 436 [M+H]⁺

Ή-NMR (400 MHz, DMSO-d₆) d [ppm]: -0.008 (2.17), 1.912 (0.58), 1.929 (0.82), 1.944 (1.03), 1.962 (0.84), 2.070 (1.01), 2.084 (0.90), 2.328 (16.00), 2.366 (0.56), 2.670 (1.04), 2.709 (0.64),

3.397 (2.20), 3.409 (2.10), 4.613 (1.20), 4.625 (2.91), 4.636 (1.30), 5.149 (0.59), 5.170 (1.29),

5.185 (1.22), 6.946 (6.57), 7.119 (2.51), 7.141 (5.19), 7.163 (2.81), 7.421 (2.73), 7.436 (2.96),

7.443 (2.81), 7.457 (2.36), 7.943 (2.92), 8.055 (6.38), 8.140 (0.77), 8.681 (3.18), 8.686 (3.02),

8.774 (1.78), 8.795 (1.78), 12.072 (0.42). Example 1-7

A/-[(1 S)-1-(4-Fluorophenyl)-2-hydroxy-2-methylpropyl]-7-[3-methyl-4-(trifluoromethyl)phenyl]-5- oxo-5, 6-dihydroimidazo[1 ,2-c]pyrimidine-2-carboxamide A solution of 7-chloro-/\/-[(1S)-1-(4-fluorophenyl)-2-hydroxy-2-methylpropyl]-5-oxo-5,6- dihydroimidazo[1,2-c]pyrimidine-2-carboxamide (Intermediate 22A, 56.0 g, 148 pmol), 4, 4,5,5- tetramethyl-2-[3-methyl-4-(trifluoromethyl)phenyl]-1,3,2-dioxaborolane (55.0 mg, 192 pmol) and sodium carbonate (74.5 mg, 887 pmol) in a THF/water mixture (1.6 ml, 2:1) was degassed with argon for 5 min, then (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'- biphenyl)]palladium(ll) methanesulfonate (XPhos-Pd-G3) (12.5 mg, 14.8 pmol; CAS- RN:[ 1445085-55-1]) was added and the mixture was degassed for a further 5 min. The reaction was heated to 110°C in a microwave for 15 min, then the reaction was cooled to RT and the crude mixture was purified by preparative HPLC (Method P2) to afford 21.8 mg (29% of theory, 100% of purity) of the title compound.

LC-MS (Method 6): R_t = 1.92 min; MS (ESIpos): m/z = 503 [M+H]⁺

¹H-NMR (600 MHz, DMSO-de): d [ppm] = 12.12 (br s, 1H), 8.43 (d, 1H), 8.06 (s, 1H), 7.92 (s, 1H), 7.84-7.79 (m, 2H), 7.46-7.40 (m, 2H), 7.19 (s, 1H), 7.16-7.11 (m, 2H), 5.04 (s, 1H), 4.82 (d, 1H), 2.53 (s, 3H), 1.26 (s, 3H), 0.96 (s, 3H).

Example 1-8

7-(2H-1,3-Benzodioxol-5-yl)-/\/-[(1S)-1-(4-fluorophenyl)-2-hydroxy-2-methylpropyl]-5-oxo-5,6- dihydroimidazo[1,2-c]pyrimidine-2-carboxamide

A solution of 7-chloro-/\/-[(1S)-1-(4-fluorophenyl)-2-hydroxy-2-methylpropyl]-5-oxo-5,6- dihydroimidazo[1,2-c]pyrimidine-2-carboxamide (Intermediate 22A, 65.0 mg, 70% purity, 120 pmol), 2H-1,3-benzodioxol-5-ylboronic acid (25.9 mg, 156 pmol) and sodium carbonate (60.5 mg, 721 pmol) in a THF/water mixture (1.6 ml, 2:1) was degassed with argon for 5 min, then (2- dicyclohexylphosphino-2',4',6'-triisopropyl-1 , 1 '-biphenyl)[2-(2'-amino-1 , 1 '-biphenyl)]palladium(ll) methanesulfonate (XPhos-Pd-G3) (10.2 mg, 12.0 pmol; CAS-RN:[ 1445085-55-1]) was added and the mixture was degassed for a further 5 min. The reaction was heated to 110°C in a microwave for 15 min, then the reaction was cooled to RT and the crude mixture was purified by preparative HPLC (Method P2) to afford 8.30 mg (15% of theory, 98% of purity) of the title compound.

LC-MS (Method 6): R_t = 1.57 min; MS (ESIpos): m/z = 465 [M+H]⁺

¹H-NMR (600 MHz, DMSO-cfe): d [ppm] = 11.86 (br s, 1H), 8.41 (d, 1H), 8.01 (s, 1H), 7.44-7.39 (m, 3H), 7.34 (dd, 1H), 7.15-7.10 (m, 2H), 7.07 (d, 1H), 6.98 (s, 1H), 6.13 (s, 2H), 5.04 (s, 1H), 4.82 (d, 1H), 1.25 (s, 3H), 0.96 (s, 3H). Example 1-9

7-(4-Chloro-3-methylphenyl)-/\/-[(1R)-1-(4-fluorophenyl)ethyl]-5-oxo-5,6-dihydroimidazo[1,2- c]pyrimidine-2-carboxamide

To a solution of 7-chloro-/V-[(1R)-1-(4-fluorophenyl)ethyl]-5-oxo-5,6-dihydroimidazo[1,2- c]pyrimidine-2-carboxamide (Intermediate 20A, 50.0 mg, 149 pmol), (4-chloro-3- methylphenyl)boronic acid (33.1 mg, 194 pmol) and 1,T-bis(diphenylphosphino)- ferrocene]dichloropalladium(ll) dichloromethane complex (1.22 mg, 1.49 pmol; CAS-RN:[ 95464- 05-4]) in DMF (2.5 ml) under an argon atmosphere was added sodium carbonate (220 pi of a 2.0 M aqueous solution, 450 pmol) and the reaction was heated overnight at 90°C. A second portion of (4-chloro-3-methylphenyl)boronic acid (33.1 mg, 194 pmol), 1,T-bis(diphenylphosphino)- ferrocene]dichloropalladium(ll) dichloromethane complex (1.22 mg, 1.49 pmol; CAS-RN:[ 95464- 05-4]) and base was added and the reaction was heated at 90°C for 72 h. The reaction was cooled to RT, acidified with formic acid and passed through a Millipore filter. The crude mixture was purified by preparative HPLC (Method P3) to afford 30.2 mg (47% of theory, 98% of purity) of the title compound.

LC-MS (Method 6): R_t = 2.01 min; MS (ESIpos): m/z = 425 [M+H]⁺

Ή-NMR (500 MHz, DMSO-d₆) d [ppm]: 1.492 (7.97), 1.506 (7.81), 2.225 (0.91), 2.378 (1.09),

2.394 (1.50), 2.408 (16.00), 5.146 (1.14), 5.161 (1.54), 5.177 (1.09), 6.895 (6.18), 6.921 (0.51),

7.125 (2.88), 7.142 (5.87), 7.160 (3.09), 7.447 (3.10), 7.458 (3.58), 7.464 (3.23), 7.475 (2.69), 7.547 (2.86), 7.564 (3.97), 7.631 (2.10), 7.635 (1.98), 7.648 (1.54), 7.652 (1.45), 7.810 (3.15), 7.813 (2.80), 8.030 (0.48), 8.090 (5.90), 8.628 (2.11), 8.644 (2.03).

Example 1-10

7-(1,3-Benzothiazol-5-yl)-/\/-[(1R)-1-(4-fluorophenyl)ethyl]-5-oxo-5,6-dihydroimidazo[1,2- c]pyrimidine-2-carboxamide

To a solution of 7-chloro-/\/-[(1R)-1-(4-fluorophenyl)ethyl]-5-oxo-5,6-dihydroimidazo[1,2- c]pyrimidine-2-carboxamide (Intermediate 20A, 60.0 g, 179 pmol), 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3-benzothiazole (84.6 mg, 72% purity, 233 pmol) and 1,T- bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane complex (270 pi, 2.0 M, 540 pmol; CAS-RN:[497-19-8]) in DMF (540 pi) under an argon atmosphere was added sodium carbonate (270 pi of a 2.0 M aqueous solution, 540 pmol) and the reaction was heated overnight at 90°C. A second portion of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazole (84.6 mg, 72% purity, 233 pmol), 1,T-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane complex (270 pi, 2.0 M, 540 pmol; CAS-RN: [497- 19-8]) and base was added and the reaction was heated at 90°C overnight. A third portion of 5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1,3-benzothiazole (84.6 mg, 72% purity, 233 pmol), 1,T-bis(diphenyl- phosphino)ferrocene]dichloropalladium(ll) dichloromethane complex (270 pi, 2.0 M, 540 pmol; CAS-RN:[497-19-8]) and base was added and the reaction was heated at 90°C for 72 h. The reaction was cooled to RT, acidified with formic acid and passed through a Millipore filter. The crude mixture was purified by preparative HPLC (Method P3) to afford 8.50 mg (10% of theory, 95% of purity) of the title compound.

LC-MS (Method 8): R_t = 0.86 min; MS (ESIpos): m/z = 434 [M+H]⁺

Ή-NMR (500 MHz, DMSO-d₆) d [ppm]: -0.120 (0.73), -0.006 (9.77), 0.006 (7.01), 0.117 (0.72), 1.296 (1.58), 1.335 (1.46), 1.501 (16.00), 1.515 (15.77), 2.363 (0.47), 2.637 (0.46), 5.143 (0.70),

5.157 (2.37), 5.173 (3.22), 5.188 (2.31), 5.201 (0.65), 6.512 (0.46), 7.016 (12.93), 7.129 (5.89), 7.147 (11.59), 7.165 (6.36), 7.457 (6.39), 7.468 (7.41), 7.474 (6.99), 7.486 (5.85), 7.564 (0.63), 7.602 (0.52), 7.626 (0.60), 7.887 (4.24), 7.890 (4.21), 7.903 (4.47), 7.907 (4.49), 8.116 (12.28), 8.135 (0.85), 8.224 (0.55), 8.322 (7.80), 8.339 (6.96), 8.532 (8.46), 8.535 (8.46), 8.667 (4.31), 8.684 (4.24), 9.509 (15.06), 12.132 (1.11).

Example 1-11

7-(3-Fluorophenyl)-/\/-[(1S)-1-(4-fluorophenyl)-2-hydroxy-2-methylpropyl]-3-methyl-5-oxo-5,6- dihydroimidazo[1 ,2-c]pyrimidine-2-carboxamide

To a 7-chloro-/V-[(1 S)-1-(4-fluorophenyl)-2-hydroxy-2-methylpropyl]-3-methyl-5-oxo-5,6- dihydroimidazo[1,2-c]pyrimidine-2-carboxamide (Intermediate 9A, 100 g, 255 pmol) and (3- fluorophenyl)boronic acid (53.4 mg, 382 pmol) in DMF (1.0 ml) was added sodium hydrogen carbonate (380 pi of a 2.0 M aqueous solution, 760 pmol) under an argon atmosphere. The mixture was degassed with argon for 5 min, then 1,1-bis(diphenylphosphino)ferrocene)- dichloropalladium(ll) (9.31 mg, 12.7 pmol; CAS-RN:[72287-26-4]) was added and the reaction was heated to 80°C overnight. The crude mixture was purified by preparative HPLC (Method P1) to afford 16.6 mg (14% of theory, 100% of purity) of the title compound. LC-MS (Method 8): R_t = 0.92 min; MS (ESIpos): m/z = 453 [M+H]⁺

Ή-NMR (400 MHz, DMSO-d₆) d [ppm]: 0.954 (9.51), 1.250 (11.04), 2.925 (16.00), 4.759 (2.10), 4.781 (2.13), 4.984 (1.47), 7.046 (3.53), 7.051 (3.62), 7.095 (2.01), 7.117 (4.10), 7.139 (2.34),

7.315 (0.55), 7.320 (0.60), 7.337 (1.12), 7.342 (1.21), 7.358 (0.72), 7.362 (0.76), 7.382 (2.18),

7.396 (2.50), 7.404 (2.44), 7.413 (1.06), 7.418 (2.08), 7.526 (0.84), 7.542 (0.95), 7.547 (1.58), 7.562 (1.59), 7.567 (1.07), 7.582 (0.97), 7.660 (1.97), 7.662 (1.87), 7.667 (1.28), 7.673 (1.52),

7.677 (2.31), 7.693 (1.12), 7.699 (1.35), 7.703 (0.92), 8.405 (1.75), 8.427 (1.74), 11.622 (2.08).

Example 1-12

7-(4-Chlorophenyl)-/\/-[(1S)-1-(4-fluorophenyl)-2-hydroxy-2-methylpropyl]-3-methyl-5-oxo-5,6- dihydroimidazo[1,2-c]pyrimidine-2-carboxamide To a 7-chloro-/V-[(1 S)-1-(4-fluorophenyl)-2-hydroxy-2-methylpropyl]-3-methyl-5-oxo-5,6- dihydroimidazo[1,2-c]pyrimidine-2-carboxamide (Intermediate 9A, 100 mg, 255 pmol) and (4- chlorophenyl)boronic acid (59.7 mg, 382 pmol) in DMF (1.0 ml) was added sodium hydrogen carbonate (380 pi of a 2.0 M aqueous solution, 760 pmol) under an argon atmosphere. The mixture was degassed with argon for 5 min, then 1,1-bis(diphenylphosphino)ferrocene)- dichloropalladium(ll) (9.31 mg, 12.7 pmol; CAS-RN:[72287-26-4]) was added and the reaction was heated to 80°C overnight. The crude mixture was purified by preparative HPLC (Method P1) followed by silica gel column chromatography to afford 4.5 mg (4% of theory, 100% of purity) of the title compound.

LC-MS (Method 6): R_t = 1.88 min; MS (ESIpos): m/z = 469 [M+H]⁺

Ή-NMR (500 MHz, DMSO-d₆) d [ppm]: 0.956 (11.54), 1.144 (0.69), 1.176 (0.55), 1.231 (0.84),

I.251 (12.85), 1.990 (0.67), 2.087 (2.39), 2.924 (16.00), 4.764 (2.42), 4.782 (2.39), 4.984 (4.75),

6.970 (4.45), 7.100 (2.22), 7.118 (4.37), 7.136 (2.34), 7.389 (2.49), 7.400 (3.05), 7.405 (2.78), 7.417 (2.19), 7.567 (4.73), 7.584 (5.20), 7.804 (5.29), 7.821 (4.47), 8.404 (2.12), 8.422 (2.03),

I I.642 (2.93).

The example compounds specified in the following table were prepared by means of standard amide coupling reactions and separation of diastereoisomers, for those products that were afforded as diastereomeric mixtures. The chemistry was performed using the following general procedures.

General procedure 1-A

To a solution of carboxylic acid (1.0 equiv.), HATU (1.2 equiv.) and DIPEA (2.0 to 3.0 equiv.) in DMF at either 0°C or RT was added the required amine (1.1 equiv.) and the reaction was stirred at RT. Upon consumption of the carboxylic acid, the reaction mixture was purified by either preparative HPLC or silica gel column chromatography.

General procedure 1-B

The diastereomeric mixture was separated by preparative HPLC (column: Daicel Chiralpak OD-H, 5 pm, 250 ^c 20 mm; flow rate: 20 ml/min; temperature: 30°C; eluent: 50% n-heptane, 50% ethanol; to afford the product as a single diastereoisomer.

Table 1

EXPERIMENTAL SECTION - BIOLOGICAL ASSAYS

Biological investigations

The following assays can be used to illustrate the commercial utility of the compounds according to the present invention.

Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein

• the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and

• the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more than once, data from biological assays represent average values calculated utilizing data sets obtained from testing of one or more synthetic batch.

The in vitro activity of the compounds of the present invention can be demonstrated in the following assays.

Biological assays

B-1. Cellular in vitro assay for determining EP3 receptor activity

The identification of antagonists of the EP3 receptor from humans and rats as well as the quantification of the activity of the compounds of the invention was carried out using recombinant cell lines. These cell lines originally derive from a hamster's ovary epithelial cell (Chinese Hamster Ovary, CHO K1, ATCC: American Type Culture Collection, Manassas, VA 20108, USA). The test cell lines constitutively express the human or rat EP3 receptors. The naturally G_ai-coupled human and rat EP3 receptors were stably co-transfected with G-ne into cells that are also stably transfected with a mitochondrial form of the calcium-sensitive photoproteins Clytin (human EP3) or Photina (rat EP3), which, after reconstitution with the cofactor coelenterazine, emit light when there are increases in free calcium concentrations ( Nature 1992, 358, 325-327; Gene 1995, 153 (2), 273-274). The resulting EP3 receptor cells react to stimulation of the recombinantly expressed EP3 receptors by the agonist sulprostone with intracellular release of calcium ions, which can be quantified by the resulting photoprotein luminescence. Antagonists inhibit the receptor signaling, leading to reduced calcium release and luminescence. The bioluminescence of the cell lines is detected using a suitable luminometer (Trends Pharmacol. Sci. 1996, 17, 235-237).

Test procedure:

Human and rat EP3 cell lines:

On the day before the assay, the cells are plated out in culture medium (OptiMEM, 1% FCS, 2 mM glutamine, 10 mM HEPES, 5 pg/ml coelenterazine) in 384-well microtiter plates and kept in a cell incubator (96% humidity, 5% v/v CO2, 37°C). On the day of the assay, test compounds in various concentrations are placed for 10 minutes in the wells of the microtiter plate before the agonist sulprostone at EC50 concentration is added. The resulting light signal is measured immediately in a luminometer. All concentrations are measured in quadruples. Table A:

B-2. Inhibition of human platelet aggregation in vitro

Blood collection

Human blood is collected by antecubital venipuncture using a 20G multifly set (Sarstedt, Num- brecht, Germany) into plastic tubes (Sarstedt 9 NC/10 ml monovettes) containing 3.8% (w/v) sodium citrate (1/10 v/v) from healthy donors who denied having taken any medication for at least 7 days prior to the study. Tubes are gently mixed to prevent coagulation.

Preparation of platelet rich plasma (PRP) and platelet poor plasma (PPP)

Blood is centrifuged at 140 g for 20 min at room temperature and the supernatant PRP is immediately collected into Falcon tubes. PRP is further centrifuged (11.000 rpm, 1 min) to produce platelet poor plasma (PPP). Measurement of platelet aggregation

Platelet aggregation is analyzed by light transmittance aggregometry according to the method of Born (J. Physiol. 1963, 168, 178-195) using APACT aggregometers (Rolf Greiner BioChemicals, Flacht, Germany). 178 mI of PRP is incubated with test compound in various concentrations dissolved in 2 pi DMSO in the aggregation cuvette at 37°C for 5 min. Then 2 mI sulprostone is added and is incubated at 37°C for 2 min. Aggregation is started by addition of 20 mI of collagen. The following concentrations of agonists are used: sulprostone 0.02 mM-2.5mM (Sigma-Aldrich), collagen 0.05-0.6 pg/ml (Horm^®, Nycomed). The reaction is followed by monitoring changes in light transmission on PRP aliquots against PPP control. Light transmittance is recorded for 5 minutes and the maximal aggregation value is used for IC50 calculations.

Statistical analysis

IC50 is calculated with GrapPad Prism (sigmoidal dose-response). All values are expressed as means ± SEM, with n denoting the number of blood donors.

B-3. EP3 Binding Assay to identify inhibitors of PGE2 binding using scintillation proximity assay technique

To compound of interest (in DMSO, 2 mI, typical final concentration up to 20 mM) the following reagents are added in a total volume of 152 mI in reaction buffer (50 mM Tris/HCI, pH 7.5; 10 mM MgCI2; 1 mM EDTA) in a suitable 96 well clear bottom plate:

[3H] Prostaglandin E2 ([5,6,8, 11 , 12, 14, 15-3H(N)] in a final concentration of 1.5 nM;

EP3 Prostanoid Receptor Membrane Preparation (2 mg/ml) and

PVT-WGA Beads in a final concentration of 2.5 mg/ml.

The mixture is incubated for 2 h at room temperature. Scintillation is monitored in a suitable microplate reader equipped with 3H-SPA program. The values are used to plot dose response curves and calculate EC50 values for the test compounds.

B-4. Determination of the effect on laser-induced thrombus formation in mice (in vivo)

This study serves to investigate the efficacy of a test substance on thrombus formation, stability and resolution induced by laser injury to microvessels of atherosclerotic mice. Animals

Male ApoE -/- mice (Charles River) are fed an atherogenic diet (Ssniff S0602-S170, 20.85% fat, 0.15% cholesterol, 19.5% casein) from 6 weeks of age for at least 3 months. Test compound treatment is performed either orally via gavage to conscious animals before anesthesia or intravenously to anesthetized animals prior to injury.

Thrombus induction

For oral treatment, animals are dosed by gavage in appropriate formulations by gavage prior to anesthesia. For intravenous treatment, a venous catheter will be implanted in the jugular vein for bolus or infusion drug delivery prior to the injury procedure. Mice are anesthetized by intraperitoneal injection of Ketamin (65 mg/kg) and Xylazin (15 mg/kg) The cremaster muscle is exposed after opening the scrotum and removal of a testis with attention to preserve blood supply from the circulation of the mouse. A stainless steel wire loop (Unimed 30.065, diameter 0.4 mm) is used to spread the inverted cremaster pocket in an organ bath constantly perfused with Dulbecco’s phosphate buffered saline temperated at 37°C. The tissue preparation is positioned on top of a transparent macrolon plastic stage for intravital microscopy (Leica AS LMD, water immersion objective Leica 506155 HC APO/ L40x/0.80). Video images are acquired by a digital camera (Basler PCO.EDGE 5.5) for identification of arterioles suitable for vascular wall injury (50 - 100 pm diameter, bifurcation-free segment). A microdissection UV-Laser (wavelength 355 nm, Cell Surgeon, LLS Rowiak, Hannover, Germany) coupled into the optical path of the intravital microscope is used for 2-stage injury of the vessel wall: (1) Linear detachment of the endothelium along a length of approximately 150 pm. (2) Punctiform deep injury with local damage of the media. The resulting thrombus formation is visualized and recorded over a duration of 5 minutes. The lesion procedure will be repeated on an upstream segment of the identical vessel for at least two times.

Statistical analysis

Video sequences of thrombus development are quantified by morphometric analysis of images at 10-second intervals using a customized software for semi-automatic vessel and thrombus detection (Zeta, Fraunhofer-lnstitut fur Angewandte Informationstechnik FIT, St. Augustin, Germany). Thrombus area and degree of stenosis are calculated to generate a thrombus-over-time-curve. The main derived result is the time above 75% occlusion of the vessel lumen. The mean of at least three repeated injuries per animal will be calculated. In case of intravenous testing, the treatment effect will be compared to baseline control injuries in the identical animals (t-test for repeated measurements). In case of oral treatment, thrombus development will be compared to vehicle- treated animals (ANOVA and t-test for independent measurements). A minimum of 5 animals will be tested to obtain sufficient statistical power.

Claims

1. Compound of the formula (I)

in which

R¹ represents CrC₆-alkyl, C2-C6-halogenoalkyl, C3-C6-cycloalkyl or the group -L-R^E, where alkyl may be substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, methoxy and CrC3-halogenoalkoxy, where halogeno- alkoxy is substituted by 1 to 3 fluoro substituents, and where halogenoalkyl is substituted by 1 to 6 fluoro substituents and may be further substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy and methoxycarbonyl, and where in the cycloalkyl ring one CH2 group may be replaced by O, SO2 or NR⁴, and where the cycloalkyl may be substituted by 1 substituent selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, hydroxy, trifluoromethyl and phenyl, or may be substituted by 1 or 2 fluoro, where the phenyl may be substituted by 1 or 2 substituents independently selected from the group consisting of fluoro, chloro and cyano, and

L represents Ci-C₆-alkanediyl, where alkanediyl may be substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy, methoxy, methoxycarbonyl, carboxyl and C3-C6-cycloalkyl (which may be substituted by 1 hydroxy), and additionally by up to 3 fluoro,

R² represents a group of the formula

where # is the point of attachment to the pyrimidine ring,

Q¹ represents CR^8A or N,

Q² represents CR⁸ or N,

R⁶ represents hydrogen, halogen, CrC₄-alkyl, CrC₄-halogenoalkyl, CrC₄-alkoxy, CrC₄-halogenoalkoxy or C₃-C₆-cycloalkyl,

R⁷ represents hydrogen, halogen, CrC₄-alkyl, CrC₄-halogenoalkyl, CrC₄-alkoxy, CrC₄-halogenoalkoxy or C₃-C₆-cycloalkyl, with the proviso, that at least one of R⁶ and R⁷ is not hydrogen,

R^7A represents hydrogen,

R⁸ represents hydrogen,

R^8A represents hydrogen or halogen,

X represents CH or N,

Y represents CH or N,

Z¹ represents CR⁹ or N,

Z² represents CR^9a or N, where at most one of X, Y, Z¹ and Z² is N,

R⁹ represents hydrogen, halogen or CrC4-alkyl, R^9a represents hydrogen, halogen or CrC4-alkyl,

R⁵ represents hydrogen or halogen,

R³ represents hydrogen, CrC4-alkyl, CrC4-halogenoalkyl or C3-C6-cycloalkyl, or one of the salts thereof, solvates thereof or solvates of the salts thereof.

2. Compound according to Claim 1, characterized in that

R¹ represents C2-C6-halogenoalkyl or the group -L-R^E, where halogenoalkyl is substituted by 1 to 6 fluoro substituents and may be further substituted by 1 or 2 substituents independently selected from the group consisting of hydroxy and methoxycarbonyl, and

L represents Ci-C₆-alkanediyl, where alkanediyl may be substituted by 1 or 2 hydroxy substituents, and additionally by up to 3 fluoro,

R^E represents phenyl, where phenyl may be substituted by 1 or 2 substituents independently selected from the group consisting of halogen,

R² represents a group of the formula

where # is the point of attachment to the pyrimidine ring,

Q¹ represents CR^8A or N,

Q² represents CR⁸,

R⁶ represents hydrogen, halogen, CrC4-alkyl or CrC4-halogenoalkyl,

R⁷ represents hydrogen, halogen or CrC4-alkyl, with the proviso, that at least one of R⁶ and R⁷ is not hydrogen,

R^7A represents hydrogen, R⁸ represents hydrogen,

R^8A represents hydrogen,

X represents CH,

Y represents N,

Z¹ represents CR⁹,

Z² represents CR^9a, where at most one of X, Y, Z¹ and Z² is N,

R⁹ represents hydrogen or CrC4-alkyl,

R^9a represents hydrogen,

R⁵ represents hydrogen or halogen,

R³ represents hydrogen or CrC4-alkyl, or one of the salts thereof, solvates thereof or solvates of the salts thereof.

3. Compound according to Claim 1 or 2, characterized in that

R^E represents phenyl, where phenyl may be substituted by 1 fluoro substituent,

Q¹ represents CR^8A or N,

R^7A represents hydrogen,

R⁸ represents hydrogen, R^8A represents hydrogen,

X represents CH,

Y represents N,

Z¹ represents CR⁹,

Z² represents CR^9a, where at most one of X, Y, Z¹ and Z² is N,

R⁹ represents hydrogen or methyl,

R^9a represents hydrogen,

R⁵ represents hydrogen or fluoro,

R³ represents hydrogen or methyl, or one of the salts thereof, solvates thereof or solvates of the salts thereof.

4. A process for preparing a compound of the formula (I) or one of the salts thereof, solvates thereof or solvates of the salts thereof according to one of Claims 1 to 3, characterized in that

[A] a compound of the formula (II) (II), in which R¹ is as defined in Claims 1 to 3, is reacted with a compound of the formula (III)

(III),

in which R² and R³ are as defined in claims 1 to 3, in the presence of a dehydrating agent to give a compound of the formula (I), or

[B] a compound of the formula (IV)

in which R² is as defined in claims 1 to 3 and

R¹² represents methyl, ethyl, propyl, isopropyl, tert- butyl or benzyl, is reacted with a compound of the formular (V)

in which R¹ and R³ are as defined in claims 1 to 3, in the presence of a palladium source, a suitable ligand and a base.

5. A compound according to any of Claims 1 to 3 for the treatment and/or prophylaxis of diseases.

6. A compound according to any of Claims 1 to 3 for the treatment and/or prophylaxis of thrombotic or thromboembolic disorders, diabetes, urogenital and ophthalmic disorders.

7. Use of a compound according to any of Claims 1 to 3 for producing a medicament for the treatment and/or prophylaxis of diseases.

8. Use of a compound according to any of Claims 1 to 3 for producing a medicament for the treatment and/or prophylaxis of thrombotic or thromboembolic disorders, diabetes, urogenital and ophthalmic disorders.

9. Medicament comprising a compound according to any of Claims 1 to 3 in combination with an inert, nontoxic, pharmaceutically suitable excipient.

10. Medicament according to Claim 9 for the treatment and/or prophylaxis of thrombotic or thromboembolic disorders, diabetes, urogenital and ophthalmic disorders.

11. Method for the treatment and/or prophylaxis of thrombotic or thromboembolic disorders, diabetes, urogenital and ophthalmic disorders in humans and animals by administration of a therapeutically effective amount of at least one compound according to any of Claims 1 to

3, of a medicament according to Claim 9 or 10 or of a medicament obtained according to Claim 7 or 8.