OA17445A - Substituted bicyclic dihydropyrimidinones and their use as inhibitors of neutrophil elastase activity - Google Patents

Abstract

This invention relates to substituted bicyclic dihydropyrimidinones of formula (I) and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory diseases of the skin and the eye and other autoimmune and allergic disorders, allograft rejection, and oncological diseases.

Description

This invention relates to substituted bicyclic dihydropyrimidinones of formula 1

and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or m prévention of pulmonary, gastrointestinal and genîtourinary diseases, inflammatory diseases of the skin and the eye and other autoimmune and allergie dîsorders, allograft rejection, and oncological diseases.

BACKGROUND INFORMATION

J5 • The following references describc neutrophil elastase inhibitors with a monocyclic dihydro-pyrimidinone core: GB2392910, W004024700, WO05082864, WO05082863, DE 102006031314, US 100010024, WO 101L 5548, W009080199, DE 102007061 766, WO06136857, W006082412, W012002502.

· The following references describe neutrophil elastase inhibitors with a bicyclic tetrahydropyrrolopyrimidinedione core: W007129060, WO08135537, US090093477, W009013444, W009060206, W009060203, W009060158, US 110034433.

• The following references describe neutrophil elastase inhibitors with core structures other than those herein before mentioned: W004020412, W004020410, W003053930,

WO 10078953, WO09135599, DE 102009004197, WO11110858, WOl 1110859,

W009060158, W009037413, W004024701, US 130065913, WOl3018804,

WO 12002502.

-117445 • For a review on various inhibitors of neutrophil elastase see: P. Sjô (Future Med, Chem. 2012,4, 651-660).

BRIEF SUMMARY OF THE INVENTION

Neutrophil elastase (NE) is a 29 kDa serine protease. It is expressed in bone marrow precursor cells, stored in the granula of peripheral blood granulocytes at high concentrations and it is released upon cellular activation. To the substrates of NE belong major éléments of the extracellular matrix: elastin, fibronectin, laminin, collagen and proteoglycans. Neutrophil elastase activity leads to ECM dégradation, increases migration and chemotaxîs of monocytes and vascular smooth muscle cells and directly affects components of the coagulation and fibrinolytic pathways (PA1-1 and TFPI). Increased activity of neutrophil elastase is associated with chronic inflammatory and fibrotic diseases of several organs. Inhibitors of neutrophil elastase will therefore hâve an important rôle for the treatment of different diseases like COPD, idiopathic pulmonary fibrosis and other fibrotic diseases, cancer, acute lung injury, acute respiratory distress syndrome, bronchiectasis, cystic fibrosis, alpha 1-antitrypsin deficiency and others.

The compounds according to the présent invention, including the physiologically acceptable salts, are effective as inhibitors of neutrophil elastase and exhibit favourable inhibitory potency, as determined by the half maximal inhibitory concentration (IC50), in an enzymatic inhibition assay.

Some compounds according to the présent invention, including the physiologically acceptable salts, are additionally effective as inhibitors of neutrophil serin protease protéinase 3 and exhibit favourable inhibitory potency, as determined by the half maximal inhibitory concentration (IC50), in an enzymatic inhibition assay. This inhibitory activity on a second neutrophil serin protease may be benificial for pharmacological effïcacy.

Some compounds according to the présent invention, including the physiologically acceptable salts, exhibit favourable inhibitory potency, as determined by the half maximal

-217445 effective concentration (EC50), in a plasma or whole-blood assay, for instance as described in T. Stevens et al. (J. Pharm. Exp. Ther. 2011, 339, 313-320).

Some compounds according to the présent invention, including the physiologically acceptable salts, exhibit favourable in vivo potency, as determined, for example, by the half maximal effective dose (ED₅₀), in models of human neutrophil elastase-induced lung injury în mice, rat or hamster, for instance as described in Tremblay et al. (Chest 2002,121, 582588) or T. Stevens et al. (J. Pharm. Exp, Ther. 2011, 339,313-320).

Some compounds according to the présent invention, including the physiologically acceptable salts, exhibit favourable in vivo potency, as determined, for example, by the half maximal effective dose (ED₅₀), in a model of LPS/FMLP-induced lung injury in hamster, for instance as described în Mitsuhashi et al. (Br. J. Pharmacol. 1999,126, 1147-1152).

Some compounds according to the présent invention, including the physiologically acceptable salts, exhibit favourable metabolic stability in an în vitro microsomal assay for metabolic stability as described in E. Kems & L. Di (Drug-likeproperties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, l^st ed, 2008), chapter 29 and references therein.

Some compounds according to the présent invention, including the physiologically acceptable salts, exhibit favourable metabolic stability in an in vitro hépatocytes assay for metabolic stability as described in E. Kems & L. Di (Drug-likeproperties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, l^st ed, 2008), chapter 29 and references therein.

An improved metabolic stability in an in vitro test system is expected to translate into a reduced în vivo clearance (CL), because the metabolic conversion in the liver is reduced. Based on the pharmacokinetic équation CL/F_orai = Dose / AUC (F_orai: oral bioavailability, AUC: area under the curve), a reduced in vivo clearance is expected to lead to higher dosenormalized systemic exposure (AUC) of the drug.

-317445 !

Some compounds according to the présent invention, including the physiologically acceptable salts, exhibit favourable permeability in an in vitro Caco-2 cell layer method for permeability as described in E. Kems & L. Di (Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, l^sl ed, 2008), chapter

26 and references therein. For an oral drug, improved permeability is expected to translate into a higher fraction of the drug absorbed in the intestinal tract, thus, resulting in higher dose-normalized systemîc exposure (AUC).

Some compounds according to the présent invention, including the physiologically ίο acceptable salts, exhibit a favourable, that is low efflux ratio (permeability in the efflux direction divided by the permeability in the influx direction) in an in vitro Caco-2 or MDCK cell layer method as described in E. Kems & L. Di (Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, l^sl ed, 2008), chapter 26 and 27 and references therein. For an oral drug, an improved, that is reduced is efflux ratio is expected to translate into a higher fraction of the drug absorbed in the intestinal tract, thus, resulting in higher dose-normalized systemic exposure (AUC).

Some compounds according to the présent invention, including the physiologically acceptable salts, exhibit favourable aqueous solubility in a kinetic or thermodynamic solubility method as described in E. Kems & L. Di (Drug-likeproperties: concepts, 15 structure design and methods: from ADME to toxicity optimization, Elsevier, l^st ed, 2008), chapter 25 and references therein. For an oral drug, improved aqueous solubility is expected to translate into a higher fraction of the drug absorbed in the intestinal tract resulting in higher dose-normalized systemic exposure (AUC).

Comparatively higher dose-normalized systemic exposure (AUC) can be advantageous in several ways: (1) If a certain systemic exposure (AUC) needs to be achieved for efficacy, the drug can be dosed in a lower amount. Lower dosages hâve the advantages of lower drug load (parent drug and métabolites thereof) for the patient causing potentially less side ίο effects, and lower production costs for the drug product. (2) Comparatively higher dosenormalized systemic exposure (AUC) can lead to increased efficacy or prolonged duration of action of the drug when the same dose is applied. ΑλΛ

-417445

Some compounds according to the présent invention, including the physiologically acceptable salts, exhibit favourable metabolic stability, favourable permeability, favourable efflux ratio and favourable aqueous solubility. Accordingly, some compounds of the présent invention are expected to exhibit favourable pharmacokinetic (PIC) properties after oral dosing, in particular favourable systemic exposure (area under the curve, AUC), thus, Ieading to favourable efficacy in vivo.

Some compounds according to the présent invention, including the physiologically acceptable salts, exhibit favourable pharmacokinetic (PK) properties. The PK properties can be determined in pre-clinical animal species, for example mouse, rat, hamster, dog, guinea pîg, mini pig, cynomolgus monkey, rhésus monkey. The PK properties of a compound can be described, for example, by the following parameters: Mean résidence time (MRT), élimination half-live (t_1/2), volume-of-distribution (Vd), area under the curve (AUC), clearance (CL) and bioavailability after oral administration (F_orai).

The compounds of the invention and métabolites thereof are devoid of the hydrazine substructure that causes structural alerts for mutagenicity and carcinogenicity as described in Benigni et al. (Chem. Rev. 2011, 27, 2507-2536). Thus, compounds of the invention may bear the advantage of reduced genotoxic potential,

Some compounds according to the présent invention, including the physiologically acceptable salts, exhibit favourable inhibition of cytochrome P450 (CYP) isozymes in corresponding in vitro assays for CYP isozyme inhibition as described in E. Kems & L. Di (Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, l^st ed, 2008), chapter 32 and references therein. Reduced inhibition of CYP isozymes is expected to translate into a reduced risk for undesirable drug-drug interactions which is the interférence of one drug with the normal metabolic or pharmacokinetic behaviour of a co-administered drug.

Some compounds according to the présent invention, including the physiologically acceptable salts, exhibit favourable, i.e. low, inhibition of the hERG channel in a patch

-517445 cl amp assay as described in E. Kems & L. Di (Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, l^st ed, 2008), chapter 34 and référencés cited therein.

DETAILED DESCRIPTION OF THE INVENTION

A compound of formula l

wherein

R¹ is phenyl or a five- or six-mcmbercd heteroaryl, wherein one, two or three éléments are replaced by an element independently selected from the group consisting of N, O and S; preferably phenyl or pyridinyl; each ring optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, O2N-, NC-, H2N-, HO-, R^{1 l}, R^{1 l}O-, R^{1 2}, R¹³S-, R¹³(O)S- and R^{1 3}(O)2S-;

R^{1 1} is independently selected from the group consisting of C|.₆-alkyl-,

Cv₍,-cycloalkyl-, C[_6-haloalkyI-, and CYé-lialocycloalkyl;

R^{1 2} is HO-C].6-alkyl- or R¹ ‘-O-Ci.6-alkyl-;

R¹³ is independently selected from the group consisting of H, HO-, R^{1 1} and R¹²; preferably R¹'¹;

R² is phenyl or a five- or six-membered heteroaryl, wherein one or two éléments are replaced by an element independently selected from the group consisting of N, O and S; preferably phenyl and pyridinyl; each ring optionally substituted with a substituent independently selected from the group consisting of halogen, C|_|-alkyl-, C[ 4-haloalkyl- and C]^-alkyl-O-; \j\/~

-617445

R3	is a residue independently selected from the group consisting of
	•	R31-;
	«	R32(O)C-;
	•	R32O(O)C-;
5	e	R3 2O(O)C-A-; preferably R3 2O(O)C-CH2-;
	•	R3 2S-; R3 2tOjS_; r3 2(O)2S_; preferabiy R3 Z(O)2S-;
	•	(R32)2N(O)C and
	•	(R3 2)2N(O)C-A-; preferably (R3 2)2N(O)C-CH2-;
ΙΟ	R31	is independently selected from the group consisting of H, R3'3, R3'4, Ci-6-alkyl-C3.6-cycloalkyl- and C-cycloalkyl-Ci_6-alkyi-, each optionally substituted with one or two substituents independently selected from R
		R3·1'1 is selected from the group consisting of HO-, halogen, NC-, R3 3O-,
15		R3 5, R3 6 and R3 7 or
		R311 dénotés a ring independently selected from phenyl and a
		four-membered heterocyclic ring containing one element independently selected from among N, 0, S, S(O) and S(O)2 or
		R311 dénotés a five- or six-membered heterocyclic or heteroaryl ring
20		containing one, two or three éléments independently selected from among N, 0, S, S(0) and S(0)2; each of the rings optionally substituted with one or two substituents 3 3 independently selected from among HO-, 0=, halogen, NC-, R ‘, R3 3O-, R3 3-(O)C-, R3 4, R3 5, R3 6 and R3 7 or two substituents are
25		together R3'8;
	R32	is independently selected from R31, phenyl or a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three éléments independently selected from N, O, S, S(O) and S(O)2; each ring optionally
30		substituted with one or two substituents independently selected from HO-,

-717445

O=, NC-, halogen, R^{3 3}, R^{3 3}O-, R^{3 3}-(O)C-, R^{3 4}, R^{3 5}, R³'⁶ and R^{3 7} or two

8 substituents are together R ' ;

or two R³'² are together a three-, four-, five- or six-membered monocyclîc or a six-, seven-, eight-, nine- or ten-membered bicyclic heterocyclic or heteroaryl ring optionally containing additional to the nitrogen one or two éléments independently selected from among N, O, S, S(O) and S(O)2; optionally substituted with one or two substituents, independently selected from among HO-, F, 0=-, NC-, R^{3 3}, R^{3 3}O-, R^{3 3}-(O)C-, R³'⁴, R³'⁵, R³'⁶, R³'⁷, phenyl and a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three éléments independently selected from among N, O, S, S(O) and S(O)2; or two substituents are together R^{3 8};

R³'³ is independently selected from the group consisting of C]-6-alkyl-, C3-6-cycloalkyl-, Cj.₆-haloalkyl- and C3_6-halocycloalkyl;

R³⁴ is HO-Ci ô-alkyl- or R^{3 3}-O-C].₆-alkyl-;

R³'⁵ is independently selected from the group consisting of H₂N-, R^{3 3}-HN-, (R^{3 3})₂N-, R^{3 3}-(O)C-HN- and R^{3 3}-(O)C-(R^{3 3})N-;

R^{3 6} is independently selected from the group consisting of R^{3 Î}-(O)S-,

R^{3 3}-(O)₂S-, R^{3 3}(HN)S-, R³³(HN)(O)S-, R^{3 3}(R^{3 3}N)S-, R^{3 3}(R^{3 3}N)(O)S-,

R^{3 3}(R^{3 4}N)S-, R^{3 3}(R^{3 4}N)(O)S-; R^{3 3}(NC-N)S- and R^{3 3}(NC-N)(O)S-;

R³'⁷ îs independently selected from the group consisting of HO(O)C-, H2N(O)C-, R^{3 3}-O-(O)C-, R^{3 3}-NH-(O)C- and (R^{3 3})2N-(O)C-;

R^{3 8} is independently selected from the group consisting of Cj-6-alkylene and Ci-6-haloalkylene, wherein optionally one or two CH2-groups are replaced by -HN-, -(R^{3 3})N-, -(R^{3 4})N-, -(R^{3 3}(O)C-)N-, -(R^{3 4}(O)C-)N-, -O-, -S-, -S(O)- or -S(O)2-;

A is -CH₂-, -CH₂-CH₂- or -CH₂-CH₂-CH₂-; preferably -CH₂-; optionally substituted with one or two substituents independently selected from the group consisting of halogen, R³'³, R^{3 3}O-, R³'⁴ or two substituents together are R^{3 8};

-817445

R⁴ is independently selected from the group consisting of halogen, C i₆-alkyl-, C3-6-cycloalkyl-, C[ ₆-haloalkyl- and (.'3.6-halocycloalkyl; or two R⁴ are together C[_6-alkylene or C]_6-haloalkylene;

m is 0, 1 or 2; preferably 0;

or a sait thereof.

USED TERMS AND DEFINITIONS

Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the spécification, however, unless specified to the contrary, the following terms hâve the meaning indicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, Cps-alkyl means an alkyl group or radical having 1 to 6 carbon atoms.

In general in single groups like HO, H₂N, S(O), S(O)₂, NC (cyano), HOOC, F3C or the like, the skilled artisan can see the radical attachment poînt(s) to the molécule from the free valences of the group itself. For combined groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent aryl-Ci-3alkyl- means an aryl group which is bound to a C'13-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.

In case a compound of the présent invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail. An asterisk is may be used in sub-formulas to indicate the bond which is connected to the core molécule as defined.

For example, the term 3-carboxypropyl-group” represents the following substituent: « λ/

-917445

wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms l-methylpropyl-, 2,2-dîmethylpropyl- or cyclopropylmethyl- group represent the following groups:

-^^CH3 ' h₃c ch₃

The asterisk may be used in sub-formulas to indicate the bond which is connected to the io core molécule as defîned.

Many of the followings terms may be used repeatedly in the définition of a formula or group and in each case hâve one of the meanings given above, independently of one another.

The term substituted as used herein, means that any one or more hydrogens on the designated atom is replaced with a sélection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.

The expressions prévention, prophylaxis, prophylactic treatment or préventive treatment used herein should be understood synonymous and in the sense that the risk to develop a condition mentioned hereînbefore is reduced, especially in a patient having elevated risk for said conditions or a corresponding anamnesis, e.g. elevated risk of developing metabolic disorder such as diabètes or obesity or another disorder mentioned herein. Thus the expression prévention of a disease as used herein means the management and care of an individual at risk of developing the disease prior to the clinical onset of the ^j-~

-1017445 disease. The purpose of prévention is to combat the development of the disease, condition or disorder, and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of related diseases, conditions or disorders. Success of said préventive treatment is reflected statistically by reduced incidence of said condition within a patient population at risk for this condition in comparison to an équivalent patient population without préventive treatment.

The expression treatment or therapy means therapeutic treatment of patients having already developed one or more of said conditions in manifest, acute or chronic form, including symptomatic treatment in order to relieve symptoms of the spécifie indication or causal treatment in order to reverse or partially reverse the condition or to delay the progression of the indication as far as this may be possible, dependîng on the condition and the severity thereof. Thus the expression treatment of a disease as used herein means the management and care of a patient having developed the disease, condition or disorder. The purpose of treatment is to combat the disease, condition or disorder. Treatment includes the administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.

Unless specifically indicated, throughout the spécification and the appended claims, a given chemical formula or name shall encompass tautomers and ali stéréo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc...) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvatés thereof such as for instance hydrates including solvatés of the free compounds or solvatés of a sait of the compound.

Ail isomeric forms (especially ail stereoisomeric forms, e.g. ail chiral, enantiomeric, diastereomeric and racemic forms, ail tautomeric and ail géométrie isomeric forms) of a compound of the présent invention are intended with this invention, unless the spécifie isomer is

-U17445 specifically indicated. Obviously, the isomer which is pharmacologically more potent and/or more efficacîous is preferred.

It will be appreciated that the compounds of the présent invention contain at least one asymmetrically substituted carbon atom, and may therefore be isolated as pure enantiomers or as a racemic or non-racemîc mixture of both enantiomers. It will be appreciated that some of the compounds of the présent invention contain more than one stereogenic center, i.e. more than one asymmetrically substituted carbon or sulfür atom, and may therefore be isolated as pure diastereomers or as diastereomeric mixtures, both in optically active or io racemic forms.

The invention contemplâtes ail conceivable stereoisomers, particulariy the diastereomers and enantiomers mentioned herein, e.g. in substantially pure form, in enriched form (e.g. substantially free of any or ail other undesired enantiomers and/or diastereomers and/or in i5 any mixing ratio, including the racemic forms, as well as the salts thereof.

In general, substantially pure stereoisomers can be obtained according to synthetic principles known to a person skilled in the field, e.g. by séparation of corresponding mixtures, by using stereochemically pure starting materials and/or by stereoselective synthesis. It is known in the art how to préparé optically active forms, such as by resolution of racemic forms or by synthesis, e.g. starting from optically active starting materials and/or by using chiral reagents.

Enantiomerically pure compounds of this invention or intermediates may be prepared via asymmetric synthesis, for example by préparation and subséquent séparation of appropriate diastereomeric compounds or intermediates which can be separated by known methods (e.g. by chromatographie séparation or crystallization) and/or by using chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaires.

so Further, it is known to the person skilled in the art how to préparé enantiomerically pure compounds from the corresponding racemic mixtures, such as by chromatographie séparation of the corresponding racemic mixtures on chiral stationary phases; or by

-1217445 resolution of a racemic mixture using an appropriate resolving agent, e.g. by means of diastereomeric sait formation of the racemic compound with optically active acids or bases, subséquent résolution of the salts and release of the desired compound from the sait; or by derivatization of the corresponding racemic compounds with optically active chiral auxiliary reagents, subséquent diastereomer séparation and removal of the chiral auxiliary group; or by kinetic resolution of a racemate (e.g. by enzymatic resolution); by enantioselective crystallization from a conglomerate of enantiomorphous crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.

The term halogen generally dénotés fluorine, chlorine, bromine and iodine.

As used herein the term prodrug refers to (i) an inactive form of a drug that exerts its effects after metabolic processes within the body converting it to a usable or active form, or (H) a substance that gives rise to a pharmacologically active métabolite, although not itself active (i.e. an inactive precursor).

The terms prodrug” or prodrug dérivative” mean a covalently-bonded dérivative, carrier or precursor of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s). Such prodrugs either hâve metabolically cleavable or otherwise convertible groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood or by activation via oxidation as in case of thioether groups. Most common prodrugs include esters and amide analogs of the parent compounds. The prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity). In general, prodrugs themselves hâve weak or no biological activity and are stable under ordinary conditions. Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: Design and Applications of Prodrugs”; Design of Prodrugs, H.

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Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K.B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K. Widder étal, (eds.), Vol. 42, Academie Press, 1985, particulariy pp. 309-396; Burger’s Médicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed ), John Wiley & Sons, 1995, particulariy Vol. I and pp.

s 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchi and V. Stella (eds.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, E.B. Roche (ed.), Elsevier, 1987, each of which is incorporated herein by reference in their entireties.

The term pharmaceutically acceptable prodrug” as used herein means a prodrug of a io compound of the invention whîch is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animais without undue toxicity, irritation, allergie response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.

is The phrase pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beïngs and animais without excessive toxicity, irritation, allergie response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.

As used herein, pharmaceutically acceptable salts refer to dérivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, minerai or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from ammonia, L-argînine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamîne (2,2’-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-amînoethanol, ethylenedîamine, N-ethyl-glucamine, hydrabamine, lH-imidazole, lysine, magnésium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide,

1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2’,2-nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2.2-dichloro-acetic acid, adîpic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid,

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2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid, (+)-camphor10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (-J-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, galactaric acid, naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, l -hydroxy-2-naphthoic acid, nicotinic acid, nîtric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylîc acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnésium, potassium, sodium, zinc and the like. (also see Pharmaceutical salts, Berge, S.M. et al., J. Pharm. Sci., ( 1977), 66, l -19).

The pharmaceutically acceptable salts of the présent invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, éthanol, isopropanol, or acetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the présent invention (e.g. trifluoro acetate salts) also comprise a part of the invention.

The term Ci._n-alkyl”, wherein n is an integer from 2 to n, either alone or in combination with another radical dénotés an acyclic, saturated, branched or linear hydrocarbon radical with l to n C atoms. For example the term Ci.j-alkyl embraces the radicals H3C-,

-1517445

H₃C-CH₂-, H₃C-CH₂-CH₂-, H₃C-CH(CH₃)-, H₃C-CH₂-CH₂-CH₂-, H₃C-CH₂-CH(CH₃)-> H₃C-CH(CH₃)-CH₂-, H₃C-C(CH₃)₂-, H₃C-CH₂-CH₂-CH₂-CH₂-, H₃C-CH₂-CH₂-CH(CH₃)-, H₃C-CH₂-CH(CH₃)-CH₂-, H₃C-CH(CH₃)-CH₂-CH₂-, H₃C-CH₂-C(CH₃)₂-, H₃C-C(CH₃)₂-CH₂-, H₃C-CH(CH₃)-CH(CH₃)- and H₃C-CH₂-CH(CH₂CH₃)-.

The term Ci._n-alkylene wherein n is an integer 2 to n, either alone or in combination with another radical, dénotés an acyclic, straight or branched chain divalent alkyl radical containing from l to n carbon atoms. For example the term Cj-4-alkylene includes -CH₂-, -CH₂-CH₂-, -CH(CH₃)-, -CH₂-CH₂-CH₂-, -C(CH₃)₂-, -CH(CH₂CH₃)-> -CH(CH₃)-CH₂-, -CH₂-CH(CH₃)-, -CH₂-CH₂-CH₂-CH₂-, -CH₂-CH₂-CH(CH₃)-, -CH(CH₃)-CH₂-CH₂-, -CH₂-CH(CH₃)-CH₂-, -CH₂-C(CH₃)₂-, -C(CH₃)₂-CH₂-, -CH(CH₃)-CH(CH₃)-, -CH₂-CH(CH₂CH₃)-> -CH(CH₂CH₃)-CH₂-, -CH(CH₂CH₂CH₃)-, -CH(CH(CH₃))₂- and -C(CH₃)(CH₂CH₃)-.

The term C₃-_n-cycloalkyl”, wherein n is an integer from 4 to n, either alone or in combination with another radical dénotés a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. For example the term C₃_7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

By the term halo added to a alkyl, alkylene or cycloalkyl group (saturated or unsaturated) is such a alkyl or cycloalkyl group wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred îs fluorine. Examples include: H₂FC-, HF₂C-, F₃C-,

The term aryl” as used herein, either alone or in combination with another radical, dénotés a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second five- or six-membered, carbocyclic group which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

-1617445

The term heterocyclyl’¹ means a saturated or unsaturated mono- or polycyclic-ring system including aromatic ring system contaîning one or more éléments selected from N, O, S, S(O) or S(O)₂₁ consisting of3 to 14 ring atoms wherein none ofthe heteroatoms is part of the aromatic ring. The term heterocyclyl” is intended to include all the possible isomeric s forms; thus, the term heterocyclyl” includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom

-1717445

-1817445

-1917445

The term heteroaryl means a mono- or polycyclic-ring Systems containing one or more éléments selected from N, O, S, S(O) or S(O)2, consisting of 5 to 14 ring atoms wherein at least one of the heteroatoms is part of aromatic ring. The term heteroaryl” is intended to include ail the possible isomeric forms; Thus, the term heteroaryl” includes the following 5 exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:

-2017445

PREFERRED EMBODIMENTS

Preferred are the above compounds of formula 1, wherein R¹ is R^{1 a} and R^la is phenyl or pyridinyl; each ring optionally substîtuted by one, two or three residues independently selected from the group consisting of halogen, O2N-, NC-, H2N-, HO-, R^1-1, R^{1 l}O-, R¹², s R¹³S-, R¹³(O)S- and R' ³(O)2S-,

Preferred are the above compounds of formula 1, wherein R¹ is R^lb and R^{1 b} is phenyl or pyridinyl; each ring optionally substîtuted by one, two or three residues independently selected from the group consisting of halogen, NC-, R^{1 l}, R¹³(O)S- and, R¹³(O)₂S-.

Preferred are the above compounds of formula 1, wherein R¹ is R^{l c} and R^{l c} is phenyl or pyridinyl; each ring optionally substîtuted by one, two or three residues independently selected from the group consisting of F, Cl, Br-, NC-, R¹¹, R¹³(O)S- and R¹³(O)2S-, and R¹¹ is independently selected from the group consisting of Ci.6-alkyl-, C3.₆-cycloalkyl-, Cj.₆-haloalkyl- and Ci._(l-halocycloalkyl;

R¹² is HO-Cj.₆-alkyl- or R^{1 l}-O-Ci_6-alkyl-;

R¹³ is independently selected from the group consisting of H, HO-, R^{1 1} and R¹²;

Preferred are the above compounds of formula 1, wherein R¹ is R^{1 d} and R^ld is phenyl or pyridinyl; each ring optionally substîtuted by one, two or three residues independently selected from the group consisting of F, Cl, Br-, NC-, Me, Et, i-Pr, t-Bu, cyclopropyl, Me(O)S-, Me(O)₂S-, Et(O)₂S-, i-Pr(O)₂S-, t-Bu(O)₂S- and cyclopropyl (O)₂S-. Particularly preferred are the above compounds of formula 1, wherein R¹ is R^{1 d} and R^{l d} is phenyl or pyridinyl; each ring optionally substîtuted by one, two or three residues independently selected from the group consisting of F, Cl, Br-, NC-, Me, Me(O)S-,

Me(O)₂S- and Et(O)₂S-.

Preferred are the above compounds of formula 1, wherein R¹ is R^{1 e} and R^{l e} is phenyl or pyridinyl; each ring optionally substîtuted by one or two residues independently selected from the group consisting of NC-, Me(O)S-, Me(O)₂S and Et(O)₂S.

Preferred are the above compounds of formula 1, wherein R¹ is R^{l f} and R^{1 r} is v/v''

-2117445

Preferred are the above compounds of formula 1, wherein R¹ is R^{1 Ê} and R^{1 Ê} is

CN

O O

Preferred are the above compounds of formula 1, wherein R¹ is R^{l h} and R^{, h} is

Preferred are the above compounds of formula 1, wherein R¹ is R¹'¹ and R¹¹ is

CN

Preferred are the above compounds of formula 1, wherein R¹ is R¹··* and R^{1 j} is

CN

Preferred are the above compounds of formula 1, wherein R² is R^2a and R^2a is phenyl or a six-membered heteroaryl; wherein one or two éléments are replaced by an element

-2217445 independently selected from the group consisting of N, O and S; each ring optionally substituted with a substituent independently selected from the group consisting of halogen, C]..palkyl-, Ci^-haloalkyl- and Cj 4-alkyl-O-.

Preferred are the above compounds of formula 1, wherein R is R and R ’ is phenyl or a six-membered heteroaryl; wherein one or two éléments are replaced by N; each ring optionally substituted with a substituent independently selected from the group consisting of halogen, C].4-alkyl- and C) .4-haloalkyl-.

Preferred are the above compounds of formula 1, wherein R² is R^2c and R^{2 c} is phenyl or pyridinyl; each optionally substituted with a substituent independently selected from the group consisting of halogen, Cj^-alkyl- and Ci^-haloalkyl-.

Preferred are the above compounds of formula 1, wherein R² is R^{2 d} and R^{2 d} is phenyl or pyridinyl; each optionally substituted with a substituent independently selected from among F₃C-, F₂HC- and FH₂C-,

Particulariy preferred are the above compounds of formula 1, wherein R² is R^2d and R^{2 d} is phenyl or pyridinyl; each optionally substituted with a substituent independently selected from among F₃C- and F₂HC-.

Preferred are the above compounds of formula 1, wherein R² is R^{2 e} and R^{2 e} is phenyl, optionally substituted with a substituent independently selected from the group consisting ofF₃C- andF₂HC-.

Preferred are the above compounds of formula 1, wherein R² is R^{2 f} and R^{2 f} is pyridinyl, optionally substituted with a substituent independently selected from the group consisting of F₃C- and F₂HC-.

In a preferred embodiment of the invention R is one of the above mentioned rings carrying the above mentioned substituent in meta-position to the connection of R² with the compound of formula 1.

-2317445

Preferred are the above compounds of formula 1, wherein R² is R²'⁶ and R^2e is

F

-J L 4L

Preferred are the above compounds of formula 1, wherein R is R · and R is

Preferred are the above compounds of formula 1, wherein R² is R²¹ and R²¹ is

F

Preferred are the above compounds of formula 1, wherein R³ is R^{3 a} and R^3a is selected from the group consisting of . R³¹-;

• R³²O(O)C-;

• R^{3 2}O(O)C-CH₂-;

• R³²(O)₂S-;

• (R^{3 2})₂N(O)C- and • (R³²)₂N(O)C-CH₂-.

Preferred are the above compounds of formula 1, wherein R³ is R^{3 b} and R^{3 b} is selected from the group consisting of . R³¹-;

. R³²O(O)C-;

-2417445 • R³²O(O)C-CH₂-;

• R³²(O)₂S-;

• (R^{3 2})₂N(O)C- and • (R³²)₂N(O)C-CH₂-.

Preferred are the above compounds of formula 1, wherein R is independently selected from among HO(O)C-H₂C-, MeO(O)C-H₂C-, H₂N(O)C-H₂C-, MeHN(O)C-H₂C-, Me₂N(O)C-H₂C-, morphoIinyl-(0)C-H₂C-_J azetidinyl-(O)C-H₂C-, pyrrolidinyl-(O)C-H₂C-, MeHN(O)C-, EtHN(O)C-, HO(CH₂)₂HN(O)C-, HO(CMe₂)(CH₂)HN(O)C-, io HO(CH₂)₃HN(O)C-, Me(O)S(CH₂)₂HN(O)C-, Me(O)₂S(CH₂)₂HN(O)C-, Et(O)₂S- and Me(O)₂S~.

-J

Preferred are the above compounds of formula 1, wherein R is independently selected from among HO(O)C-I LC-, MeO(O)C-H₂C-, H₂N(O)C-H₂C-, MeHN(O)C-H₂C-, is Me₂N(O)C-H₂C-, morpholinyl-tOJC-HjC-, azetidinyl-(O)C-H₂C- and pyrrolidinyl-(O)C-H₂C-.

Preferred are the above compounds of formula 1, wherein R³ is independently selected from among MeHN(O)C-, EtHN(O)C-, HO(CH₂)₂HN(O)C-, HO(CMe₂)(CH₂)HN(O)C-,

HO(CH₂)₃HN(O)C-, Me(O)S(CH₂)₂HN(O)C- and Me(O)₂S(CH₂)₂HN(O)C-.

Preferred are the above compounds of formula 1, wherein R³ is selected from among the examples (E#) 1 to 59 of Table 1 R³ - Embodiments of the invention for R³, R^{3 2}, R³'³, R³⁴, R^{3 5}, R^{3 6}, R³'⁷, R^{3 8} (if présent):

TABLE 1 R³ - Embodiments of the invention

E#	R3	R32	R33	R34	R35	R36	R37	R38
1.	RÎ.ka		R3,3a	R34b	R35b	Rlbb	R3.7.b
2.	R3.1,b		R3.3.a	R3.4.b
3.	r3.LC		R3,3a	R34b	R35b	R3.6.b	R37b	Rïïb
4.	R™		R3.3.a	R3.4,b	R3.5.b	R3.6,b	R3,7,b

-2517445

E#	R3	R32	R33	R34	R35	R36	R37	R38
5.	H
6.	Me
7.	-ch2-cn
8.	R32O(O)C-	R32a	R3 3 a	R3.4.b	R3.5.b	R3.6.b	R3.7.b	R38”
9.	R32O(O)C-	R3.2.b	R33®	R34.b
ΙΟ.	R32O(O)C-	R3.2.c
11.	R32O(O)C-	R3.2.d	R33®	R3·4”	R3.5.b	R3.6.b	R3.7.b	R38”
12.	R32O(O)C-	R3·2·”
13.	R3 2O(O)C-CH2-;	R3.2.a	R3.3.a	R3.4.b	R3.5.b	.6.b	R3.7.b	R3.8.b
14.	R3 2O(O)C-CH2-;	R3.2.b	R3.3.a	R3.4.b
15.	R32O(O)C-CH2-;	r3,2c
16.	R3 2O(O)C-CH2-;	R32”	R3.3.a	R3.4.b	R3.5 b	R3.6.b	R3.7.b	R3.8.b
17.	R32O(O)C-CH2-;	R3.2.h
18.	R32(O)2S-;	R3.2.a	R33’	R3.4.b	R35b	R3.6.b	R3.7.b	R3.8.b
19.	R32(O)2S-;	R3.2.b	R3.3a	R34b
20.	R32(O)2S-;	r3.2.c
21.	R32(O)2S-;	R3.2.d	R3.3.a	R3.4.b	R3.5.b	j^3 6.b	R3.7.b	R3.8.b
22.	R32(O)2S-;	Me;
23.	R32(O)2S-;	R3.2.b
24.	R32HN(O)C-	R32a	R3.3.a	R3.4.b	R3.5.b	R3.6.b	R3.7.b	R3.8.b
25.	R32HN(O)C-	R32.b	R3.3.a	R3.4.b
26.	R32HN(O)C-	r3.2.c
27.	R32HN(O)C-	R3.2.d	R3.3.a	R3.4.b	R3.5.b	R3.6.b	R3.7.b	R3.8.b
28.	R32HN(O)C-	R3.2.b
29.	R32HN(O)C-	H
30.	R32HN(O)C-	Me
31.	R32HN(O)C-	Et
32.	R32HN(O)C-	cyclo-Ρτ
33.	R32HN(O)C-	HO(CH2)2-
34.	R32HN(O)C-	HO(CMe2)CH2-
35.	R32HN(O)C-	HO(CH2)3-
36.	R3 2HN(O)C-CH2-	R3.2.a	R3.3.a	R3.4.b	R3,5.b	R3.6.b	R3.7.b	R3.8.b

-2617445

E#	R3	r32	R33	R34	R35	r36	R37	R38
37.	R3 2HN(O)C-CH2-	R3.2.b	R33a	R34b
38.	R3 2HN(O)C-CH2-	r3.2.c
39.	R3 2HN(O)C-CH2-	R3.2.d	R33’	R34b	R35”	R3.6.b	R3.?.b	R3.8.b
40.	R32HN(O)C-CH2-	R3.2.h
41.	(R32)2N(O)C-	R3.2.a	R3.3.a	R3.4.b	R3.5b	R36b	R3.7.b	R3.8.b
42.	(R32)2N(O)C-	R3.2.b	R3.3.a	R3.4.b
43.	(R32)2N(O)C-	R3.2.e	R3.3.a	R3'4b	R3.5.b	R3.6.b	R3.7.b	R3.8.b
44.	(R32)2N(O)C-	R3.2.f	R33a	R3r4b	R3.5.b	R3.6.b	R3.7.b	R3.8.b
45.	(R32)2N(O)C-	R3.2.g	R3.3.a	R3.4.b	R3.5.b	R3.6.b	R3.7.b	R3.8.b
46.	(Rî2)2N(O)C-CH2-	R3’2'8	j^3.3 a	R3.4.b	R3.5.b	R3.6.b	R3.7.b	R3.8.b
47.	(R32)2N(O)C-CH2-	R3.2.b	R33®	R3.4.b
48.	(R32)2N(O)C-CH2-	r3.2.c
49.	(R32)2N(O)C-CH2-	R3r2d	R3.3.a	R3.4.b	R3.5.b	|^3.6. b	R3.7b	R3.8.b
50.	(R3 2)2N(O)C-CH2-	R3.2.e	R3'3'®	R3Ab	R3.5b	R36b	R3.7.b	R3.8.b
51.	(R32)2N(O)C-CH2-	R32t	R33®	R3.4.b	R3.S.b	R3.6.b	R3.7.b	R3.8.b
52.	(R32)2N(O)C-CH2-	R32®	R3.3.a	R3.4.b	R3.5.b	R3.6.b	R3.7.b	R3.8.b
53.	Me(O)2S-
54.	MeHN(O)C-
55.	EtHN(O)C-
56.	cyc/o-PrHN(O)C-
57.	HO(CH2)2HN(O)C-
58.	HO(CMe2)(CH2)HN(O)C-;
59.	HO(CH2)3HN(O)C-

Preferred are the above compounds of formula 1, wherein R³¹ is R^{31 a} and R^{31 a} is

H, R³'³, R^{3 4}, Ci-e-alkyl-Ci-ô-cycIoalkyl·, Cj-6-cycloalkyl-Ci-6-alkyl-, each optionally substituted with one or two substituents independently selected from R³¹¹-; and R^{31 1} is 5 selected from among HO-, halogen, NC-, R^{3 3}O-, R^{3 5}, R^{3 6} and R^{3 7}.

1' 3 I b 31b·

Preferred are the above compounds of formula 1, wherein R is R and R ' is selected from among H, R^{3 3}, R³'⁴, C]_6-alkyl-C3_6-cycloalkyl- and C3.6-cycloalkyl-C].6-alkyl~.

-2717445

Preferred are the above compounds of formula 1, wherein R³¹ is R^3Lc and R^{3 l c} is selected from among H, R³'⁴ and C i_<,-alkyl-, optionally substituted with one or two substituents independently selected from R -; and R ‘ is a ring independently selected from among phenyl and a four-membered heterocyclic ring containing one element independently selected from among N, O, S, S(O) and S(O)2; or

R³¹'¹ dénotés a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three éléments independently selected from among N, O, S, S(O) and S(O)2;

each of the rings optionally substituted with one or two substituents independently selected from among HO-, O=, halogen, NC-, R^{3 3}, R^{3 3}O-, R^{3 3}-(O)C-, R^{3 4}, R^{3 5}, R^{3 6}

7 3 8 and R or two substituents are together R · .

3 1 d 3L d

Preferred are the above compounds of formula 1, wherein R is R and R ' is independently selected from among H, R^{3 4} and Ci-6-alkyl-, optionally substituted with one or two substituents independently selected from among R -; and

R³¹¹ is a ring independently selected from among phenyl and a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three éléments independently selected from among N, O, S, S(O) and S(O)2;

each of the rings optionally substituted with one or two substituents independently selected from HO-, O=, halogen, NC-, R^{3 3}, R^{3 3}O-, R^{3 3}-(O)C-, R^{3 4}, R^{3 5}, R^{3 6} and R³'⁷.

32 3231

Preferred are the above compounds of formula 1, wherein R is R ^a and R ^a is R

32b 32b31b

Preferred are the above compounds of formula 1, wherein R is R ' and R is R '

Preferred are the above compounds of formula 1, wherein R³'² is R^{3 2c} and R³'^2c is phenyl.

3 2 d3 2 d

Preferred are the above compounds of formula 1, wherein R is R and R is a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three éléments independently selected from among N, O, S, S(O) and S(O)î; each ring optionally substituted with one or two substituents independently selected from among HO-, O=, NC-,

-2817445 halogen, R³³, R³³O-, R^{3 3}-(O)C-, R³'⁴, R^{3 5}, R³'⁶ and R^{3 7} or two substituents are together R³⁸.

Preferred are the above compounds of formula 1, wherein R^{3 2} is R^32e and two R^32e are together a three-, four-, five- or six-membered monocyclic or a six-, seven-, eight-, nine- or ten-membered bicyclîc heterocyclic or heterocyclic ring optionally contaîning additional to the nitrogen one or two éléments independently selected from among N, O, S, S(O) and S(O)₂; optionally substituted with one or two substituents, independently selected from among HO-, F, O=, NC-, R^{3 3}, R^{3 3}O-, R^{3 3}-(O)C-, R^{3 4}, R³'⁵, R^{3 7} and R^{3 6} or two substituents are together R .

Preferred are the above compounds of formula 1, wherein R ' is R ' and two R ' are together a three-, four-, five- or six-membered heterocyclic or heteroaryl ring optionally contaîning additional to the nitrogen one or two éléments independently selected from among N, O, S, S(O) and S(O)₂; optionally substituted with one or two substituents, independently selected from the group consisting of HO-, F, O=, NC-, R³³, R³³O-, R³³(O)C-, R^{3 4}, R^{3 5}, R^{3 7}, R^{3 6} or two substituents are together R^{3 8}.

32 32

Preferred are the above compounds of formula 1, wherein R is R ^Ë and two R ^e are together a six-, seven-, eight-, nine- or ten-membered bicyclic heterocyclic or heteroaryl ring optionally contaîning additional to the nitrogen one or two éléments independently selected from the group consisting of N, O, S, S(O) and S(O)₂; optionally substituted with one or two substituents, independently selected from the group consisting of HO-, F, O=, NC-, R^{3 3}, R³³O-, R³³-(O)C-, R^{3 4}, R^{3 s}, R^{3 7} and R^{3 6} or two substituents are together R^{3 8}.

Preferred are the above compounds of formula 1, wherein R is R ' and R îs selected from the group consisting of H, Me, Et, n-Pr, i-Pr and cyclopropyl.

Preferred are the above compounds of formula 1, wherein R³³ is R^{3 3 a} and R^33a is selected from the group consisting of Me, Et, n-Pr, i-Pr, n-Bu, t-Bu, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, F3C-, F₂HC-, F3C-CH2-, F2HC-CH2- and FH2C-CH₂-.

-2917445

Preferred are the above compounds of formula 1, wherein R³⁴is R³'^4a and R^34a is selected from the group consisting of HO-CH2-, HO-CH2-CH2-, HO-CH2-CH2-CH2-, R^33aO-CH2-, R^{3 3 a}O-CH2-CH2- and R^{3 3 a}O-CH2- CH₂-CH₂-.

Preferred are the above compounds of formula 1, wherein R is R and R is selected from the group consisting of HO-CH₂-, HO-CH₂-CH₂-, HO-CH₂-CH₂-CH₂-, MeO-CH₂-, MeO-CH₂-CH₂-, MeO-CH₂-CH₂-CH₂-, EtO-CH₂- EtO-CH₂-CH₂- and EtO-CH₂-CH₂-CH₂-.

Preferred are the above compounds of formula 1, wherein R³’⁵ is R^{3 S a} and R^{3 S a} is selected from the group consisting of H2N-, R³³ ΉΝ-, (R^33a)2N-, R^{33 a} (O)C-HN- and R^{3 3 a}-(O)C-(R^{3 3 a})N-.

Preferred are the above compounds of formula 1, wherein R^{3 5} is R^{3 5 b} and R^35b is selected from the group consisting of H₂N-, MeHN-, (Me)₂N-, EtHN-, (Et)₂N-, i-PrHN-, (i-Pr)(Me)N-, t-BuHN-, (t-Bu)(Me)N-, Me(O)C-HN-, Et(O)C-HN-, n-Pr(O)C-HN-, i-Pr(O)C-HN- and t-Bu(O)C-HN-,

Preferred are the above compounds of formula 1, wherein R³'⁶ is R³'^6-® and R³'^6-® is selected from the group consisting of R^{3 3 a}(O)S-, R^{33 a}(O)₂S-, R^33a(HN)S-, R^{3 3 a}(HN)(O)S-, R^33a(R^{33 a}N)S-, R^{33 a}(R^{33 a}N)(O)S-, R^{33 a}(R³'^{4 a}N)S-, R^33a(R^34aN)(O)S-, R^33a(NC-N)Sand R^{3 3 a}(NC-N)(O)S-,

Preferred are the above compounds of formula 1, wherein R³’⁶ îs R^{3 6 b} and R^{3 6 b} is selected from the group consisting of Me(O)S-, Et(O)S-, i-Pr(O)S-, Me(O)₂S-, Et(O)₂S-, i-Pr(O)₂S-, Me(HN)S-, Et(HN)S-, i-Pr(HN)S-, Me(HN)(O)S-, Et(HN)(O)S-, î-Pr(HN)(O)S-, Me(MeN)S-, Et(MeN)S-, i-Pr(MeN)S-, Me(MeN)(O)S-, Et(MeN)(O)S-, i-Pr(MeN)(O)S-, Me(HOCH₂CH₂N)S-, Et(HOCH₂CH₂N)S-, i-Pr(HOCH₂CH₂N)S-, Me(HOCH₂CH₂N)(O)S-, Et(HOCH₂CH₂N)(O)S-, i-Pr(HOCH₂CH₂N)(O)S-, Me(MeOCH₂CH₂N)S-, Et(MeOCH₂CH₂N)S-, i-Pr(MeOCH₂CH₂N)S-, Me(MeOCH₂CH₂N)(O)S-, Et(MeOCH₂CH₂N)(O)S-and i-Pr(MeOCH₂CH₂N)(O)S-,

-3017445

Preferred are the above compounds of formula 1, wherein R³'⁷ is R³'^7a and R^{3 7 a} is selected from the group consisting of HO(O)C-, H2N(O)C-, R^{3 3 a}O(O)C-, R^{3 3 a}NH(O)C- and (R^33a)2N(O)C-,

37b 37b s Preferred are the above compounds of formula 1, wherein R is R and R ' is selected from the group consisting of HO(O)C-, H₂N(O)C-, MeO(O)C-, Et0(O)C-, i-PrO(O)C-, t-BuO(O)C-, MeNH(O)C-, EtNH(O)C-, i-PrNH(O)C-, t-BuNH(O)C-, (Me)₂N(O)C-, (Et)₂N(O)C-, (i-Pr)(Me)N(O)C-, (t-Bu)(Me)N(O)C-, Et(Me)N(O)C-, i-Pr(Me)N(O)C- and t-Bu(Me)N(O)C-,

Preferred are the above compounds of formula 1, wherein R^{3 8} is R^{3 8 a} and R^{3 8 a} is independently selected from the group consisting of -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂- and -CH₂CH₂CH₂CH₂CH₂-, wherein optionally one or two CH₂-groups are independently replaced by a group selected from among -HN-, -MeN-, -EtN-,

-(Me(O)C-)N-, -(Et(O)C-)N-, -(MeO(O)C-)N-, -(EtO(O)C-)N-, -O-, -S-, -S(O)- and

-S(O)₂-,

3 8 h 38 h

Preferred are the above compounds of formula 1, wherein R isR and R is selected from the group consisting of -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂- and

-CH₂CH₂CH₂CH₂CH₂-, wherein optionally one or two CH₂-groups are independently replaced by a group selected from among -HN-, -MeN-, -EtN-, -O-, -S-, -S(O)- and -S(O)₂-.

Preferred are the above compounds of formula 1, wherein A is A^a and A^a is -CH₂-, optionally substituted with one or two substituents independently selected from the group consisting of halogen, R³’³, R^{3 3}O- and R³'⁴ or two substituents together are -CH₂CH₂-.

Preferred are the above compounds of formula 1, wherein A is A^b and A^b is -CH₂-, optionally substituted with one or two substituents independently selected from the group consisting of F, Me, Et, Î-Pr, MeO, EtO, HOCH₂O- and MeOCH₂-.

Preferred are the above compounds of formula 1, wherein A is A^c and A^c is -CH₂- or -CHMe-,

-3117445

Preferred are the above compounds of formula 1, wherein A is A^d and A^d is -CH2-.

Preferred are the above compounds of formula 1, wherein R⁴ is R^{4 a} and R^{4 a} is selected from the group consisting of halogen, Ci^-alkyl-, C₃.₆-cycloalkyl-, C|.₆-haloalkyl- and Ca-s-halocycloalkyl.

Preferred are the above compounds of formula 1, wherein R⁴ is R^{4 b} and R^{4 b} is F, Me.

Preferred are the above compounds of formula 1, wherein R⁴ is R^4c and R^{4 c} is C].₆-alkyl-. Particularly preferred are the above compounds of formula 1, wherein R⁴ is R^{4 c} and R^{4 c} is Me.

Preferred are the above compounds of formula 1, wherein m is 0.

Preferred is a compound of formula 1, wherein

R¹ is R^{l b} and R^{I b} is phenyl or pyridinyl; each ring optionally substituted by one, two or three residues independently selected from the group consisting of halogen, NC-, 20 R¹·¹, R^{1 3}(O)S- and R¹³(O)₂S-;

R² is R^{2 b} and R^{2 b} is phenyl or a six-membered heteroaryl; wherein one or two éléments are replaced by N; each ring optionally substituted with a substituent independently selected from the group consisting of halogen, C_t^-alkyl- and

C).|-haloalkyl-;

R³ is a residue independently selected from the group consisting of • R³¹-;

• R^{3 2}O(O)C- or R^{3 2}O(O)C-CH₂-;

3ü · R³²(O)₂S-;

• (R^{3 2})₂N(O)C- and • (R³²)₂N(O)C-CH₂-,

-3217445

R³¹ is independently selected from the group consisting of H, R^{3 3}, R^{3 4}, Ci-é-alkyl-Cî-b-cycloalkyl- and Cv6-cycloalkyl-Ci6-alkyl-, each optionally substituted with one or two substituents independently selected from R

R³¹¹ is selected from the group consisting of HO-, halogen, NC-, R^{3 3}O-, R³'⁵, R^{3 6} and R^{3 7} or

R³¹¹ dénotés a ring independently selected from among phenyl and a four-membered heterocyclic ring containing one element independently selected from among N, O, S, S(O) and S(O)₂;

or

R³¹¹ dénotés a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three éléments independently selected from among N, O, S, S(O) and S(O)₂;

each of the rings as defined for R³¹¹ is optionally substituted with one or two substituents independently selected from among HO-, O=, halogen, R^{3 3}, R^{3 3}O-, R^{3 3}-(O)C-, R^{3 4}, R^{3 5}, R^{3 6} and R^{3 7} or two substituents are together R³’⁸;

R³·² îs independently selected from R³ phenyl or a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three éléments independently selected from among N, O, S, S(O) and S(O)₂; each ring optionally substituted with one or two substituents independently selected from among HO-, O=, NC-, halogen, R^{3 3}, R^{3 3}O-, R^{3 3}-(O)C-, R^{3 4}, R³'⁵, R^{3 6} and R or two substituents are together R ;

or two R are together a five- or six-membered monocyclic or a eight-, nine- or ten-membered bicyclic heterocyclic or heteroaryl ring optionally containing additional to the nitrogen one or two éléments independently selected from among N, O, S, S(O) and S(O)₂; optionally substituted with one or two substituents, independently selected from among HO-, F, O=,

-3317445

R³³, R^{3 3}O-, R³³-(O)C-, R³'⁴, R³’⁵, R^{3 7} and R^{3 6} or two substituents are together R³'⁸;

R³³ is independently selected from the group consisting of C].₆-alkyl-, C3-6-cycloalkyl-, Ci.6-haloalkyl- and Cj-ô-halocycloalkyl;

R^{3 4} is HO-Ci-6-alkyI- or R^{3 3}-O-Ci.₆-alkyl-;

R³'⁵ is independently selected from the group consisting of H2N-, R³³-HN-, (R^{3 3})₂N- and R^{3 3}-(O)C-HN-;

R³'⁶ is independently selected from the group consisting of R^{3 3}-(O)S-, R^{3 3}(O)₂S-, R³³(HN)S-, R^{3 3}(HN)(O)S-R³³(R³³N)S-, R^{3 3}(R³³N)(O)S-, R^{3 3}(R^{3 4}N)S- and R³³(R^{3 4}N)(O)S-;

R^{3 7} is independently selected from the group consisting of HO(O)C-, H2N(O)C-, R^{3 3}-O-(O)C-, R³³-NH-(O)C- and (R^{3 3})2N-(O)C-;

R³'⁸ is independently selected from the group consisting of Cj^-alkylene or C].6-haloalkylene, wherein optionally one or two CH2-groups are replaced by a group selected from among -HN-, -(R³³)N-, -(R^3,4)N-, -(R³³(O)C-)N-, -(R^{3 4}(O)C-)N-, -O-, -S-, -S(O)- and -S(O)2-;

R⁴ is independently selected from among halogen and Cj-s-alkyl-.

m is 0, 1 or 2; preferably 0;

or a sait thereof.

Preferred is a compound of formula 1, wherein

R¹ is R^{l d} and R^{l d} is phenyl or pyridinyl; each ring optionally substituted by one, two or three residues independently selected from the group consisting of F, Cl, Br-, NC-, Me, Me(O)₂S-, Et(O)₂S- and Me(O)S-.

-3417445

R² is R^{2 c} and R^{2 c} is phenyl or pyridinyl; each optionally substituted with a substituent independently selected from the group consisting of halogen, Ci.4-alkyl- and Ci-4-haloalkyl-;

R³ is selected of the examples (E#) 1 to 59 of the Table 1 R³ - Embodiments ofthe invention; or

R³ Îs independently selected from among HO(O)C-H₂C-, MeO(O)C-H₂C-, H₂N(O)CH₂C-, MeHN(O)C-H₂C-, Me₂N(O)C-H₂C-, morpholinyl-(O)C-H2C-, azetidinyl-(O)C-H₂C-, pyrrolidinyl-(O)C-H₂C-, MeHN(O)C-, EtHN(O)C-, HO(CH₂)2HN(O)C- and

HO(CMe₂)(CH₂)HN(O)C-;

R⁴ is Ci-6-alkyl;

m is 0, 1 or 2;

or a sait thereof.

Preferred is a compound of formula 1, wherein

R¹ is R^{l e} and R^{I e} is phenyl or pyridinyl; each ring optionally substituted by one or two residues independently selected from among NC-, Me(O)S-, Me(O)2S and Et(0)2S;

R² is R² '¹ and R^{2 d} is phenyl or pyridinyl; each optionally substituted with a substituent independently selected from the group consisting of F3C- and F2HC-;

R is selected from among the examples (E#) 1 to 59 of the Table 1 R - Embodiments of the invention; or

R³ is independently selected from among HO(O)C-H2C-, MeO(O)C-H2C-, H₂N(O)C-H2C-, MeHN(O)C-H₂C-, Me₂N(O)C-H₂C-, morpholinyl-(O)C-H₂C-, azetidinyl-(O)C-H₂C-, pyrrolidinyl-(O)C-H₂C-, MeHN(O)C-, EtHN(O)C-,

HO(CH₂)₂HN(O)C-, HO(CMe₂)(CH₂)HN(0)C-, HO(CH₂)₃HN(O)C-,

Me(O)S(CH₂)₂HN(O)C-, Me(O)₂S(CH₂)₂HN(O)C-, Et(O)₂S- and Me(O)₂S-.

-3517445 m is 0;

or a sait thereof.

Preferred is a compound of formula l, wherein

R^l is R^{l e} and R^{l e} is phenyl or pyridinyl; each ring optionally substituted by one or two residues independently selected from among NC-, Me(O)S-, Me(O)₂S and Et(O)₂S;

R² is R^{2 d} and R^{2 d} is phenyl or pyridinyl; each optionally substituted with a substituent independently selected from among F',C- and F₂HC-;

R³ is one of the examples (E#) 2,4, 5, 6, 7, 11, 12, 16, 17, 21, 22, 23, 27,28, 29, 30, 31, 32, 33, 37, 43, 48 selected from among the examples of the Table 1 R³ Embodiments of the invention; or

R³ is independently selected from among HO(O)C-H₂C-, MeO(O)C-H₂C-, H₂N(O)C-H₂C-, MeHN(O)C-H₂C-, Me₂N(O)C-H₂C-, morpholinyl-(O)C-H₂C-, azetidinyl-(O)C-H₂C-, pyrrolidinyl-(O)C-H₂C-, MeHN(O)C-, EtHN(O)C-, HO(CH₂)₂HN(O)C-, HO(CMe₂)(CH₂)HN(O)C-, HO(CH₂)₃HN(O)C-, Me(O)S(CH₂)₂HN(O)C-, Me(O)₂S(CH₂)₂HN(O)C-, Et(O)₂S- and Me(O)₂S-.

m is 0;

or a sait thereof.

Preferred is a compound of formula 1, wherein

R¹ is R^{l e} and R^{1 e} is phenyl or pyridinyl; each ring optionally substituted by one or two residues independently selected from among NC-, Me(O)S-, Me(O)₂S and Et(O)₂S;

R² is R^{2 d} and R^{2 d} is phenyl or pyridinyl; each optionally substituted with a substituent independently selected from the group consisting of F₃C- or F₂HC-;

-3617445

R³ isoneoftheexamples (E#)2, 5, 6, 11, 16, 17, 21, 22, 23, 27, 33, 37, 43, 48 selected from among the examples of the Table 1 R³ - Embodiments of the invention; or

R³ is independently selected from among HO(O)C-H₂C-, MeO(O)C-H₂C-, H₂N(O)C-H₂C-, MeHN(O)C-H₂C-, Me₂N(O)C-H₂C-, morpholinyl-(O)C-H₂C-, azetidinyl-(O)C-H₂C-, pyrrolidinyl-(O)C-l fC-, MeHN(O)C-, EtHN(O)C-, HO(CH₂)₂HN(O)C-, HO(CMe₂)(CH₂)HN(O)C-, HO(CH₂)₃HN(O)C-, Me(O)S(CH₂)₂HN(O)C-, Me(O)₂S(CH₂)₂HN(O)C-, Et(O)₂S- and Me(O)₂S-, m is 0;

or a sait thereof.

Preferred is a compound of formula 1, wherein R³ is a residue independently selected from the group consisting of . R³¹-;

• R³²O(O)C- or R^{3 2}O(O)C-CH₂-;

• R^{3 2}(O)₂S- and • (R^{3 2})2N(O)C- or (R^{3 2})2N(O)C-CH₂-;

R³'¹ is independently selected from the group consisting of H, R³'³, R^{3 4}, Cj-ô-alkyl-Cî^-cycloalkyl-, C₃^-cycloalkyl-Ci^-alkyl-, each optionally substituted with one or two substituents independently selected from R^{3 l l}-;

R^{31 1} is selected from the group consisting of HO-, halogen, NC-, R^{3 3}O-, R^{3 5}, R^{3 6} and R³'⁷ or

R^{31 1} dénotés a ring independently selected from among phenyl and a four-membered heterocyclic ring containing one element independently selected from N, O, S, S(O) and S(O)₂;

R³·¹·¹ dénotés a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three éléments independently selected from N, O, S, S(O) and

S(O)₂; each of the rings optionally substituted with one or two substituents

-3717445 independently selected from HO-, O=, halogen, R³³, R^{3 3}O-, R^{3 3}-(O)C-, R³⁴,

R³’⁵, R³'⁶ and R³'⁷ or two substituents are together R³'⁸;

R³'² is independently selected from R³ phenyl or a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three éléments independently selected from among N, O, S, S(O) and S(O)₂; each ring optionally substituted with one or two substituents independently selected from HO-, O=, NC-, halogen, R¹³, R^{3 3}O-, R^{3 3}-(O)C-, R^{3 4}, R³⁵, R^{3 6} and R^{3 7} or two substituents are together R^{3 8};

or two R^{3 2} are together a five- or six-membered monocyclic or a eight-, nine- or tenmembered bicyclic heterocyclic or heteroaryl ring optionally containing additional to the nitrogen one or two éléments independently selected from among N, O, S, S(O) and S(O)₂; optionally substituted with one or two substituents, independently selected from HO-, F, O=, R^{3 3}, R^{3 3}O-, R^{3 3}-(O)C-, R^{3 4}, R^{3 5}, R^{3 7} and R^{3 6} or two substituents are together R³’⁸;

R^{3 3} is independently selected from the group consisting of Ci-6-alkyl-, Ci._;>-cycloalkyl-, C|_6-haloalkyl- and Cj^-halocycloalkyl;

R^{3 4} is HO-C^-alkyl- or R^{3 3}-O-Ci.₆-alkyl-;

R³'⁵ is independently selected from the group consisting of H2N-, R^{3 3}-HN-, (R^{3 3})2Nand R^{3 3}-(O)C-HN-;

R ' is independently selected from the group consisting of R ‘ -(O)S-, R -(O)₂S-, R^{3 3}(HN)S-, R^{3 3}(HN)(O)S-R^{3 3}(R^{3 3}N)S-, R^{3 3}(R^{3 3}N)(O)S-, R³³(R¹⁴N)S- and R³³(R³⁴N)(O)S-;

R^{3 7} is independently selected from the group consisting of HO(O)C-, H2N(O)C-, R^{3 3}-O(O)C-, R^{3 3}-NH-(O)C- and (R^{3 3})2N-(O)C-;

R^{3 8} is independently selected from the group consisting of C, «alkylene or C].û-haloalkylene, wherein optionally one or two CH2-groups are replaced by -HN-, -(R^{3 3})N-, -(R^{3 4})N-, -(R^{3 3}(O)C-)N-, -(R^{3 4}(O)C-)N-, -O-, -S-, -S(O)- and -S(O)2-;

or a sait therof. cV'

-3817445

Preferred is a compound of formula 1, wherein

R¹ is independently selected from the group consisting of formulas (a) to (d)

(c) and

R² is independently selected from the group consisting of Phenyl-CF₃, Phenyl-CHF₂and Pyridinyl-CF₃-, preferably selected from the group consisting of formulas (e) to (g)

and

R³ is hydrogen or independently selected from the group consisting of Me, NC-CH₂-, Me(O)₂S-, MeHN(O)C-, EtHN(O)C-, cyclo-PrHN(O)C-, HO(CH₂)₂HN(O)C-, HO(CMe₂)(CH₂)HN(O)C- and HO(CH₂)₃HN(O)C-.

Preferred of ail of the above mentioned embodiments of the invention is a compound of formula 1, wherein configuration of formula 1 is according to formula Γ

or a sait thereof. JJ

-3917445

PREPARATION

The compounds according to the présent invention and their intermediates may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. Preferably, the compounds are obtained in analogous fashion to the methods of préparation explained more fully hereinafter, in particular as described in the experimental section. In some cases, the order in carrying out the reaction steps may be varied. Variants of the reaction methods that are known to the one skilled in the art but not described in detail here may also be used. The general processes for preparing the compounds according to the invention will become apparent to the one skilled in the art studying the following schemes. Starting materials are commercially available or may be prepared by methods that are described in the literature or herein, or may be prepared in an analogous or similar manner. Any functional groups in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at a suitable stage within the reaction sequence using methods familiar to the one skilled in the art.

Compounds of the invention VI are accessible using the synthetic route illustrated in Scheme I ; R¹, R^E ', R^E2 hâve the meanings as defined hereinbefore and hereinafter.

SCHEME 1

-4017445

Intermediates II (Step A, intermediate I —> intermediate II) can be prepared as described in Vovk et al. (Synlett 2006, 3, 375-378) or in PL2004/369318, by heating an aliphatic or aromatic aldéhyde I with a carbamate, for example methyl carbamate, ethyl carbamate (urethane) or benzyl carbamate in the presence of a strong Brensted or a Lewis acid, for example sulfuric acid, hydrogen chloride, p-toluencsulfonic acid, Amberlyst 15, tetrafluoroboric acid, trifluoroacetic acid or boron trifluoride, either without solvent as a melt or in a suitable solvent, such as benzene, toluene, acetonitrile, diethyl ether, chloroform, acetic anhydride or mixtures thereof. The reaction takes place within l to 24 hours. Preferred reaction températures are between room température and 160 °C, or the boiling point of the solvent, respectively. Preferably the reaction is done with molten ethyl carbamate as reactant and a catalytic amount of concentrated sulfuric acid at températures of l40-160°C without any additional solvent.

The chlorination (Step B, intermediate II —> intermediate III) can be done as described in Vovk et al. (Synlett 2006, 3, 375-378) and Sînitsa et al. (J. Org. Chem. USSR 1978, 14, 1107) by heating intermediate II together with a chlorinating agent, for example phosphorous pentachloride, phosphoryl chloride or sulfuryl chloride in an organic solvent, for example benzene or toluene. The reaction takes place within 1 to 24 hours. Preferred reaction températures are between 50 °C and 150 °C.

Altematively, intermediates III can be prepared as described in Jochims et al. (Chem. Ber. 1982, 115, 860-870) by α-halogenation of aliphatic isocyanates, for example benzyl isocyanate, using for example a bromînation agent, for example Λ-bromosuccinimidc. Isocyanates can be synthesized as described in US6207665 and in Charalambides et al. (Synth. Commun. 2007, 37, 1037-1044), by reacting an amine precursor with phosgene.

Intermediates V (Step C, intermediate IV —> intermediates V) can be prepared as described in Chen et al. (Synth. Commun. 2010, 40, 2506-2510) and Tietcheu et al. (J. Heterocyclic Chem. 2002,39, 965-973) by reacting cyclopentane-l,3-dione (IV) and an aliphatic or aromatic amine in the presence of a catalyst, for example Ytterbium triflate [Yb(OTf)₃] or an acid, for example hydrogen chloride or p-toluenesulfonic acid, optionally in a solvent, for example water, acetic acid, acetonitrile, benzene, toluene. The reaction takes place

-4117445 within l -24 hours. Preferred reaction températures are between room température and

120 °C, most preferred room température.

Altematively, ïntermediates V can be prepared as described in Scott et al. (J. Med. Chem.

1993, 36, 1947-1955) by direct condensation of the 1,3-dicarbonyl compound with an amine under reflux in a suitable solvent, for example benzene or toluene with azeotropic removal of water. Altematively, ïntermediates V can be prepared as described in Mariano et al. (J. Org. Chem. 1984, 49, 220-228) by reacting an amine with 3-chloro-2-cyclopenten-lone, which can be prepared from cyclopentane-!,3-dione.

Compounds according to the présent invention (Step D, ïntermediates III —> compounds of the invention VI) can be prepared as described in Vovk et al. (Synlett 2006, 3, 375-378), Vovk et al. (Russ. J. Org. Chem. 2010, 46, 709-715) and Kushnir et al. (Russ. J. Org. Chem. 2011, 47, 1727-1732) by reacting ïntermediates III with ïntermediates V in an organic solvent, for example dichloromethane, chloroform, benzene or toluene. The reaction takes place within 1-24 hours. Preferred reaction températures are between 0 °C and 100 °C.

Compounds according to the présent invention VII, VIII, IX, X and XI are accessible via the synthetic routes depicted în scheme 2; R¹¹, R¹¹¹, R^1V, R^v, R^E!, R^E2, R^E3 hâve the meanings as defined hereinbefore and hereinafter.

-4217445

SCHEME 2

Compounds of the invention VII (Step E, compounds of the invention VI compounds of the invention VII, R^E3 = alkyl or substituted alkyl) can be prepared as described in W004024700 by reacting compounds of the invention VI with an alkylating agent, for example a dialkyl sulfate, for example dîmethyl sulfate, an alkyl halide, for example methyl iodide or an alkyl sulfonylate, for example bcnzyl tosylate, in the presence of a suitable io base, for example sodium hydride, sodium hydroxîde, césium carbonate, lithium diisopropylamide, potassium hexamethyldisilazîde, lithium hexamethyldisîlazide, an organolithium reagent, for example ieri-butyllithium or a Grignard reagent, for example îsopropylmagnesiumchloride, in an organic solvent, for example tetrahydrofuran, jVJV-dimethylformamide, acetonitrile, l ,4-dioxane, dichloromethane or toluene. The i5 reaction takes place within 1-72 hours. Preferred reaction températures are between 0 °C and 100 °C.

-4317445

Compounds of the invention VIII (Step F, compounds of the invention VI compounds of the invention VIII) can be prepared in analogy to compounds of the invention VII (Step

E, compounds of the invention VI —> compounds of the invention VII), using an s appropriate alkyl haloacetate as alkylating agent, for example methyl bromoacetate.

Compounds of the invention IX (Step G, compounds of the invention VIII -> compounds of the invention IX) can be prepared as described in W004024700, by reacting compounds of the invention VIII with water in the presence of a suitable base, for example sodium hyîo droxide, potassium hydroxide, caesium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide or sodium ethoxide in a suitable solvent, for example water, methanol, éthanol, propanol, ΛζΝ-dimethylformamide, tetrahydrofuran, 1,4-dioxane, acetonitrile or mixtures thereof. The reaction takes place within 1-72 hours. Preferred reaction températures are between 0 °C and 100 °C.

The amide coupling (Step H, compounds of the invention IX —> compounds of the invention X) can be achieved by reacting the carboxylic acid intermediate IX with amines RⁱⁿNH2 or RⁿⁱR^lvNH in the presence of an amide coupling reagent, for example -tetramethyl-0-(benzotriazol-l-yl)uronium tetrafluoroborate (TBTU) or /V,..'V.;V',A'-tctramethyl-(')-(bcnzotna/.ol-1 -yl)uronium hexafluorophosphate (HBTU), in the presence of a base, for example triethylamine, ALV-diisopropylcthylamine or A'-mcthylmorpholinc in an organic solvent, for example 7V-methyl-2-pyrrolidone .'V,A^;-dimethyl formamide, A’.A'-dimctliylacetamide or mixtures thereof. The reaction takes place within 1-72 hours. Preferred reaction températures are between 0 °C and 50 °C, most preferred room température.

Compounds of the invention XI (Step J, compounds of the invention VI —> compounds of the invention XI, R^v = alkyl or aryl) can be prepared as described in WO07137874, by reacting compounds of the invention VI with a sulfonylating agent, for example methane30 sulfonyl chloride or para-toluenesulfonyl chloride in the presence of a base, for example sodium hydride, lithium diisopropylamide, potassium hexamethyldisilazide, lithium hexa- Jj—'

-4417445 methyldisilazide, an organolithium reagent, for example terr-butyllithium or a Grignard reagent, for example iso-propylmagnesiumchloride, in an organic solvent, for example tetrahydrofuran, AQV-dimethylfonnamide, acetonitrile, l,4-dioxane or dichloromethane. The reaction takes place within l-72 hours. Preferred reaction températures are between 0 °C and room température.

Compounds according to the présent invention XIII and XIV are accessible via the synthetic routes depicted in scheme 3; R^IM, R^tv,R^vl, R^El, R^E2 hâve the meanings as defined hereinbefore and hereinafter.

SCHEME 3

VI

XII

Intermediates XII (Step K, compounds ofthe invention VI —> intermediates XII) can be prepared as described in W009080199, by reacting compounds of the invention VI with

4-nitrophenyl chloroformate in the presence of a base, for example triethylamine, AQV-diisopropylethylamine or V-methylmorpholine, optionally in the presence of a catalyst, for example 4-dimethylamînopyridine, in an organic solvent, for example dichloromethane, tetrahydrofuran, acetonitrile or 7V,V-dîmethylformamide. The reaction takes place within

-4517445

1- 24 hours. Preferred reaction températures are between 0 °C and 50 °C, most preferred room température.

Compounds of the invention XIII (Step L, intermediates XII —> compounds of the invention XIII) can be prepared as described in W009080199, by reacting intermediates XII with an amine R^llINH₂ or RⁿⁱR^lvNH in an organic solvent, for example dichloromethane, acetonitrile, tetrahydrofuran, 1,4-dioxane, toluene or /V./V-dimethyl formamide. The reaction takes place within 1-72 hours. Preferred reaction températures are between 0 °C and 50 °C, most preferred room température.

Compounds of the invention XIV (Step M, compounds of the invention VI —> compounds of the invention XIV) can be prepared as described in W007046513 or JP2000273087, by reacting compounds of the invention VI with a suitable chloroformate ClCO₂R^Vi, for example methyl chloroformate or benzyl chloroformate, in the presence of a suitable base, for example potassium carbonate, sodium hydride, sodium hydroxide, césium carbonate, lithium diisopropylamide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, an organolithium reagent, for example ter/-butyllithium or a Grignard reagent, for example isopropylmagnesiumchloride, in an organic solvent, for example tetrahydrofuran, TVYdimethylformamide, acetonitrile, 1,4-dioxane, dichloromethane or toluene. The reaction takes place within 1-72 hours. Preferred reaction températures are between 0 °C and 100 °C.

Altematively, compounds of the invention XIV (Step N, intermediates XII —» compounds of the invention XIV) can be prepared as described in WO03101917 or WO11085211, by reacting intermediates XII with a suitable alcohol, for example methanol, iso-propanol,

2- methoxyethanol or benzyl alcohol, in the presence of a suitable base, for example potassium carbonate, potassium teri-butoxide or sodium hexamethyldisilazide in an organic solvent, for example tetrahydrofuran, .V,.V-dimethylformamide, acetonitrile, dichloromethane or dimethylsulfoxide. The reaction takes place within 1-72 hours. Preferred reaction températures are between 0 °C and 100 °C, most preferred room température.

-4617445

Additionally to the synthetic route depicted in Scheme l, compounds of the invention VI are also accessible using the synthetic route depicted in Scheme 4, R^E R^E2 hâve the meanings as defined hereinbefore and hereinafter.

SCHEME 4

Step O

Step P

XV

Step Q

XVII

O

V

Step R

VI

Intermediates XV (Step O, intermediate I intermediate XV) can be prepared as described in Best et al. (J. Am. Chem. Soc. 2012, 134, 18193-18196) or in Yang et al. (Org. Synth. 2009, 86, 11-17), by reacting an aromatic aldéhyde I with a suitable sulfinate, for example sodium benzenesulfinic acid, and a suitable carbamate, for example methyl carbamate or tert-butyl carbamate, in the presence of a suitable acid, for example formic acid, in a suitable solvent, for example tetrahydrofuran, éthanol, methanol or a mixture of solvents, for example tetrahydrofuran and water. Altematively, as described in Reingruber et al. (Adv. Synth. Catal. 2009, 351, 1019-1024) or in W006136305, a suitable lewis acid, for example trimethylsilyl chloride, can be used as acid and acetonitrile or toluene can be used as solvent. The reaction takes place within 1-6 days. Preferred reaction températures are between 0 °C and 50 °C, most preferred room température.

Intermediates XVI (Step P, intermediate XV -> intermediate XVI) can be prepared in analogy to the method described for the préparation of compounds of the invention VI (Scheme 1, Step D, intermediate III -> compound of the invention VI), by reacting intermediates XV with intermediates V in the presence of a suitable base, for example sodium

-4717445 hydride or sodium im-buloxidc, in a suitable organic solvent, for example tetrahydrofuran or 2-methyltetrahydrofuran. The reaction takes place within l -24 h. Preferred reaction températures are between 0 °C and 50 °C, most preferred room température.

Intermediates XVII (Step Q, intermediate XVI —> intermediate XVII) can be prepared by reacting intermediates XVI with a suitable acid, for example hydrogen chloride, in a suitable solvent, for example l ,4-dioxane. The reaction takes place between 1 -72 hours. Preferred reaction températures are between 0 °C and room température, most preferred room température.

Compounds of the invention VI (Step R, intermediate XVII —> compound of the invention VI) can be prepared as described in Csütôrtoki et al. (Tetrahedron Lett. 2011, 67, 85648571) or in WO11042145, by reacting intermediates XVII with a suitable reagent, for example phosgene, triphosgene or carbonyl diimidazole, in the presence of a suitable base, for example triethyl amine, .V,.V-diisopropylethyl amine, pyridine or sodium carbonate, in a suitable solvent, for example acetonitrile, dichloromethane or toluene. The reaction takes place between 1-72 hours. Preferred reaction températures are between 0 °C and 50 °C, most preferred room température.

PRELIMINARY REMARKS

The term room température dénotés a température of about 20 °C. As a rule, 'H NMR spectra and/or mass spectra hâve been obtained of the compounds prepared. Compounds given with a spécifie configuration at a stereocenter are isolated as pure isomers.

The rétention times given are measured under the following conditions (TFA: trifluoroacetic acid, DEA: diethylamine, scCO?: supercritical carbon dioxide):

-4817445

Method Name:	V011S01
Column:	XBridge Cl8,4.6 x 30 mm, 3.5 pm
Column Supplier:	Waters
Gradient/Solvent Time [min]	% Solvent [H2O, o.i%nh3]	% Solvent [acetonitrile] |	Flow .^[ml/min]	Temp [°C]
0.0	97	3	5	60
0.2	97	3	5	60
1.6	0	100	5	60
1.7	0	100	5	60

Method Name: V012_S01
Column:	XBridge C18, 4.6 x 30 mm, 3.5 pm
Column Supplier:	Waters
Gradient/Solvent Time [min]	% Solvent [H2O, 0.1%TFA]	% Solvent [acetonitrile] τ	Flow - [ml/min] *· ’ .....	: Temp [°C]
0.0	97	3	5	60
0.2	97	3	5	60
1.6	0	100	5	60
1.7	0	100	5	60

Nfâhod Namé:: ÿ -	WQ18 S01
	Sunfire C18, 4.6 x 30 mm, 2.5 pm
	Waters
Gradiehl/SoÎvcnt ’ Time [min]	% Solvent [H20,0.1%TFA]	% Solvent [acetonitrile]	Flow [ml/min]	-S· Température [°C]
0.0	97	3	4	60
0.15	97	3	3	60
2.15	0	100	3	60
2.20	0	100	4,5	60
2.40	0	100	4,5	60

-4917445

X012 SOI

Xbridge BEH Cl8, 2.1 x 30 mm, 1,7 μιη

Water s

Gradient/Solvent S-Time [min]	% Solvent [H20,0.1%TFA]	i % Solvent [acetonitrile]	ÎL Flow
0,0	99	1	1.6	60
0.02	99	1	1.6	60
1.00	0	100	1.6	60
1.10	0	100	1.6	60

Col

Column Supplier: Waters
Gradient/Solvent ‘X Time [min] -	STiÆuri >;% Solvent^ [H20,0.1%NH3]	% Solvent ^\£tneth^iol] ί	Flow Ύ [ml/min]'	Température 7 Xi rc) y
0.0	95	5	1.9	60
0.20	95	5	1,9	60
1.55	0	100	1,9	60
1.60	0	100	2.4	60
1.80	0	100	2.4	60

	Z011 S03
Ççfe»àia^iA. .- -½ sæÿa&i	XBridge C18, 3 x 30 mm, 2.5 pm
	Waters
	% Solvent ^¾. [H20,0.1%NH3]	ft/ΰτ t- % Solvent nacetonitrilel^	l y Flow [ml/min] Cg	> Température-
0.00	97	3	2.2	60
0.20	97	3	2.2	60
1.20	0	100	2.2	60
1.25	0	100	3	60
1.40	0	100	3	60

-5017445

		Z017S04
	ZORBAX™ SB-Ci8, 3 x 30 mm, 1.8 pm
afttagawfr gjfegfiMaafeffi· ά· '.v >-? -’^-gaga^g-g^yi		Agilent
Gradient/Solvent Time [min]	% Solvent [H2O, 0.1°/oTFA]	% Solvent [acetonitrile]]®	|H||· Flow^'G®® [ml/min] ®	H- Température [°C]
0.00	97	3	2.2	60
0.20	97	3	2.2	60
1.20	0	100	2.2	60
1.25	0	100	3	60
1.40	0	100	3	60

	Z018 S04
coiuSfc^MI .....		Sunfire, 3 x 30 mm, 2.5 pm
Column SupplieB		Waters
--je·. >b Gradient/Solvent Time [min]	.r % Solvent^. [H2O, 0.1%TFA]	--- · i % Solvent ” [acetonitrile]	HowW^ [ml/min]”'	'-? Température [°C] t*
0.00	97	3	2.2	60
0.20	97	3	2.2	60
1.20	0	100	2.2	60
1.25	0	100	3	60
1.40	0	100	3	60

Method	Z018S04
		Sunfire, 3 x 30 mm, 2.5 pm
		Waters
' · *: w ΕβκίδιάΛδ 1j	fiy>f0.1%TTA] •λ?*- ·· ·	···-’..... --- '- % Solvent ^[acetonitrile]	Flow [ml/min]'..	Température. [ocftsa
0.00	97	3	2.2	60
0.20	97	3	2.2	60
1.20	0	100	2.2	60
1.25	0	100	3	60
1.40	0	100	3	60

-5117445

Method Name:	001CA03
Column:	SunFire Cl 8,4.6 x 30 mm, 3.5 pm
Column Supplier:	Waters
Gradient/Solvent Time [min]	% Solvent & [H20,0.1%TFA]	% Solvent [acetonitrile]	Flow « [ml/min] g.	Température L -r^' r°ri Êslfe
0.0	98	2	2.5	60.0
1.5	0	100	2.5	60.0
1.8	0	100	2.5	60.0

Method Name:	I IB 15 MeOH DEA
	Chîralpak IB 4.6 x 250 mm, 5 μιη
Column Supplier:	Daicel
-^Gradient' : .,s Solvent „:'-- Time [min]	„ % Solvent'® [MeOH,'ÿ 0.2% DEA]	% Solvent [scCChr· - >r4*‘s----»··	' ' Flow [ml/min]	To^craturc • •[°c] T '	Back Pressure [bar] V·-·
10 min	15	85	4	40	150

	I IB 20 MeOH DEA
Column:	Chiralpak IB 4.6 x 250 mm, 5 μτη
Column ^upp^^^^^g^fy	Daicel
····**( ! Gradient/ Solvent . Time [min]	—js’ ---'-..i·- >rf;.· % Solvent “ [MeOH, 0.2% DEA] s	À% Solvent [scCO2]	; - i*·· J Flow [ml/min] > ' - ' ' ’υΛ	Température [°C]	Back Pressure [bar]
10 min	20	80	4	40	150

	I IC 30 MeOH DEA
Columnf* . - <	Chiralpak IC 4.6 x 250 mm, 5 μιη
Column SuppUêr^^'^J^* .	Daicel
Gradient/? - Solvent>‘ Timefmin]^	^•% Solvent,, ’t [MeOH, * 0.2% DEA]	% Solvent = [scCO2]	•^Flow [ml/min] -	. ·*ί i*u.r:.’jv ’ i-Wi'··· Température [OC] >	.Back Pressure [bar] ...iifeSfc
10 min	30	70	4	40	100

-5217445

	X011 S03
^fej^tcBffisEsÎffBÎtt^W'gÎ^^^ÎiSÎKBjtfÎSrrjÎSÎÎfroT^P^^ÆÎjÎ.kÎjÎg^^Sfs-vj» ,	Xbridge BEH C18, 2.1 x 30 mm, 1.7 gm
uujujMâ.j^^iuto ColumaMirBier: gfi		Water s
Gradient/Solvent Time [min]	% Solvent [H2O, 0.1%NH3]	*>- % SoivenfSIi J? [acetonitrile]	isifes Fio^llflg [ml/min]	! ,·Λ Température^ *: [°C] «.
0.0	95	5	1.3	60
0.02	95	5	1.3	60
1.00	0	100	1.3	60
1.10	0	100	1.3	60

	X018S01
	Sunfïre Cl8, 2.1 x 30 mm, 2.5 gm
	Waters
Gradient/Solvent φ Time [min] Γ	% Solvent [H2O, 0.1°/oTFA]	' [â^toriitnle] A	fiOB| [ml/min] -¾	*·^ ··· -j* Température •^#[°C] ’ '
0.0	99	1	1.5	60
0.02	99	1	1.5	60
1.00	0	100	1.5	60
1.10	0	100	1.5	60

Method Name:	Z006 U01
	XBridge Phenyl, 3 x 30 mm, 2.5 gm
	HUll	Waters
Gf aâient/Solvenf orTimc [min]	. % Solvent^ [H2Ô, 0.1%TFÀ]		Flow [ml/min]	•VJ* Température
0.0	50	50	1.9	60
0.20	50	50	1.9	60
1.55	0	100	1.9	60
1.60	0	100	2.4	60
1.80	0	100	2.4	60

-5317445

Method .it > ' rt» i'- * ' *Γ. $WLsSJw®flS	001 CA07
Column: '..	SunFire Cl8, 2.1 x 50 mm, 2.5 μιη
Column Supplier:	Waters
Gradîent/Solvent Time [min]	% Solvent [H2O, 0.1%TFA]	% Solvent [acetonitrile] Λ	X Flow [ml/min] Ijfe	Températureί [°C]
0.0	95	5	1.5	60.0
0.75	0	100	1.5	60.0
0.85	0	100	1.5	60.0

	002 CA03
	SunFire C18, 3.0 x 30 mm, 2.5 pm
Ci^umn	Waters
GmtJiMIzSolvent ®· Time [minf||	îî- ; v % Solvent A· [H2O, 0.1%TFA]	? % Solvent [acetonitrile]	^rtiowft*··^ [ml/min]	V Température Sfera
0.0	99	1	2.0	60.0
0.90	0	100	2.0	60.0
1.1	0	100	2.0	60.0

	002 CA07
	XBridge BEH Cl8, 3 x 30 mm, 1.7 pm
	r· ·/ „	Waters
	Solvent Al ÏH2O,0.1%NH3]	% Solvent f [acetonitrile] ‘ - V.._ *s '	... Tlow.4„ ·.· , [ml/min]s	Température [°C]
0.0	95	5.0	1.5	60.0
0.7	0.1	99.9	1.5	60.0
0.8	0.1	99.9	1.5	60.0
0.81	95	5	1.5
1.1	95	5	1.5

-5417445

MetlSdName:	003 CA04
#*£^^îîîîè*» 3K.C-	XBridge C18, 3 x 30 mm, 2.5 pm
.-«Γι λ rt·'Λ n ,«Cn<·^. ί,... Column Supplier:	Waters
Gradient/Solvent Time [min]	% Solvent [H2O, 0.1%TFA]	% Solvent [acetonitrile]	Flow [ml/min]	Température [°C]
0.0	98	2	2.0	60.0
1.2	0	100	2.0	60.0
1.4	0	100	2.0	60.0

Method Name:			005 CA01
Column:			SunFire C18, 3.0 x 30 mm, 2.5 pm
Column Supplier:		Waters
Gradient/Solvent Time [min]	w. % Solvent [H2O, 0.1%TFA]	% Solvent i [acetonitrile]	Flow [ml/min] U	Température [°C]
0.0	98	2	2.0	60.0
1.2	0	100	2.0	60.0
1.4	0	100	2.0	60.0

Method Name: -l· 3A '	I IA 15 MeOH DEA
Column:	Chiralpak IA 4.6 x 250 mm, 5 pm
Column Supplier; ^>γ·	ifegSU - -, . f	Daicel
Gradient/ Solvent Time [min]	% Solvent [MeOH, 0.2% DEA]	% Solvent [SCCO2]	Flow [ml/min]	•y* . ' Température ; L°c] < “· 1 î3’ , ·	Back Pressure [bar]
10 min	15	85	4	40	150

MethodName: ? ~ '	I„IA 20 MeOH NH3
Column: My	Chiralpak IA 4.6 x 250 mm, 5 pm
Column Supplier: -	Daicel
Gradient/ Solvent Time [min]	% Solvent [MeOH, 20 mM NH3]	frsw...... % Solvent [scCO2] -	Flow [ml/min]	Température [°C]	Back' Pressure [bar]
10 min	20	80	4	40	150

-5517445

Method Name:			J · 111 s- -’F·	I IA 30	MeOH NH3
Column:		:7 . r7 ...	WW	Chiralpak IA 4.6 x 250 mm, 5 pm
Column Supplier:			Daicel
Gradient/ Solvent Time [min]	% Solvent [MeOH, 20 mM NH3]	% Solvent [scCO2]	Flow [ml/min]	Température [°C]	Back Pressure [bar]
10 min	30	70	4	40	150

Method Name:	IIB25Me()HDEA
Column:	Chiralpak IB 4.6 x 250 mm, 5 pm
Column Supplier: jf	Daicel
Gradient/ Solvent Time [min]	% Solvent [MeOH, 0.2% DEA]	% Solvent [scCO2]	y- Flow [ml/min]	Température [°C]	Back Pressure [bar]
10 min	25	75	4	40	150

Method Name:	I IB 25	MeOH NH3
Column:				Chiralpak IB 4.6 x 250 mm, 5 pm
Column Supplier:			Daicel
Gradient/ Solvent Time [min]	% Solvent [MeOH, 20mMNH3]	% Solvent	Flow	Température	Back
[SCCO2]	[ml/min]	[°C]	Pressure [bar]
10 min	25	75	4	40	150

Method Namey..	I IB 30 MeOH DEA
Column: '4.	Chiralpak IB 4.6 x 250 mm, 5 pm
Column Supplier:.	Daicel
Gradient/ Solvent Time [min]	% Solvent [MeOH, 0.2% DEA]	© % Solvent [scCO2] ·.	Flow [ml/min]	Température [°C] •a·»	Back Pressure [bar]
10 min	30	70	4	40	150

-5617445

Method Nameu|h-·	I IB 40 MeOH DEA
Column:	Chiralpak IB 4.6 x 250 mm, 5 pm
Column Supplier:	Daicel
Gradient/ :·®’ Solvent Time [min]	% Solvent [MeOH, 0.2% DEA]	1 ’-j.% Solvent T-^ Flow [SCCO2] 1 [ml/min]	Température [°C] WW g	Back Z' Pressure [bar]
10 min	40	60 1 4	40	150

ASSIGNMENT OF ABSOLUTE CONFIGURATIONS

The absolute configuration of example l A has been assigned unambîgously by X-ray structure analysis to be (Λ). This (R)-enantiomer (example 1 A) is significantly more potent with respect to the inhibition of neutrophil elastase than the (S)-enantiomer (example 1 B), as can 5 be seen from the measured IC50 values of 11.5 nM (example 1 A) and 8040 nM (example

B), respectively. The absolute configuration of ail other pure enantiomers described has been assigned in analogy to example IA, that is, the more potent enantiomer (the eutomer) with respect to the inhibition of neutrophil elastase, i.e. the enantiomer with the lower IC₅₀ value has been assigned to hâve the same absolute configuration as example IA.

io SYNTHESES OF STARTING MATERIALS

The following starting materials are prepared as described in the literature cited:

3-(3-(trifluoromethyl)phenylamino)cyclopent-2-enone: Aust. J. Chem. 2005, 58, 870-876; l-bromo-4-(chloro(isocyanato)methyl)benzene: Synlett 2006, 3, 375-378; teri-butyl (4-cyanophenyl)(phenylsulfonyl)methylcarbamate: J. Am. Chem. Soc. 2011,133, 1248-

1250.

The synthesis of the following starting materials has been described before in the literature cited:

ierributyl (4-brornophenyl)(phenylsulfonyl)methylcarbamate: J. Am. Chem. Soc. 2011, 133, 20 8892-8895; 3-(benzyloxy)cycIopent-2-enone: Chîn. Chem. Lett. 2008,19, 767-770, λαΓ

-5717445

INTERMEDIATE l ^Et°2^C*N

H

_N-CO₂Et

H

Diethyl (4-Cyanophenyl)methylenedicarbamate

In a three-necked round bottom flask equipped with a drying tube fïlled with calcium chloride and an inlet for nitrogen, 4-fonnylbenzonitrile (25.0 g, 191 mmol) and ethyl carbamate (37.4 g, 419 mmol) are heated at 145 °C. The flask is being purged with a flow of nitrogen, and concentrated sulfuric acid (ca. 200 pL, ca. 3 mmol) is added slowly drop by drop. After 7 h the solidified reaction mixture is cooled to room température, crushed, ίο mixed thoroughly with water and dried. Yield: 53.0 g; ESI mass spectrum: [M+Na]⁺ = 314;

Rétention time HPLC: 0.88 min (V01 l_S01 ).

INTERMEDIATE 2

Cl

NCO

4-(Chloro(isocyanato)methyl)benzonitrile

Phosphorous pentachloride (83.3 g, 400 mmol) is added to a suspension of diethyl (4-cyanophenyl)methylenedicarbamate (intermediate 1, 53.0 g, 182 mmol) in benzene (200 mL) and the mixture is heated at reflux for 2 h. The benzene is evaporated and the mixture îs then purified by distillation under reduced pressure. The first fraction (ca. 40 °C, ca. 0.01 mbar) is discarded. The second fraction (ca. 110 °C, ca. 0.6 mbar) is collected.

Yield: 28.4 g; ESI mass spectrum: [M+MeOH-HCl+H]⁺ = 189; Rétention time HPLC:

0.65 min (Z003_004).

-5817445

INTERMEDIATE 3

4-(4-BromophenyI)-l-(3-(trifluoromethyl)phenyl)-3,4,6,7-tetrahydro-l//-cycIopenta[i/|pyrimidine-2,5-dione

A solution of 1 -bromo-4-(chloro(isocyanato)methyl)benzene (14.7 g, 47.6 mmol) in dichloromethane ( 100 mL) is added to a solution of 3-(3-(trifluoromethyl)phenylamino)cydopent-2-enone (11.0 g, 45.6 mmol) in dichloromethane (100 mL) and the mixture is heated at reflux for 1.5 hours. Water is added, and the phases are extracted twice with dichloromethane. The combined organic layers are concentrated and the residue is purified io by flash chromatography on silica (gradient cyclohexane/ethyl acetate 4:1 to ethyl acetate).

Yield: 7.5 g; ESI mass spectrum: ESI mass spectrum: [(⁷⁹Br)-M+ H]⁺ = 451, [(⁸¹Br)-M+H]⁺ = 453; Rétention time HPLC: 1.15 min (V012S01).

INTERMEDIATES 3A AND 3B: ENANTIOMERS OF INTERMEDIATE 3

The enantiomers of racemic 4-(4-bromophenyl)-1-(3-(trifluoromethyl)phenyl)-3,4,6,7-tetra15 hydro-17/-cyclopenta[i/]pyrimidine-2,5-dione (intermediate 3, 2.10g, 4.66 mmol) are separated by préparative supercritical fluid chromatography on a chiral phase (Daicel Chiralpak IB, 10 x 250 mm, 5 μιη, 20% MeOH + 0.2% diethylamine in supercritical CO₂, 40 °C, 150 bar back pressure).

-5917445

INTERMEDIATE 3A:

(Æ)-4-(4-Broniophenyl)-l-(3-(trifliioromethyl)phenyl)-3,4,6,7-tetrahydro-l//-cyclopenta|i/|pvrimidine-2.5-dione

Yield: l .05 g; ESI mass spectrum: [(⁷⁹Br)-M+ H]⁺ =451, [(⁸¹Br)-M+ H]⁺ = 453; Rétention time: 3.76 min (late eluting enantiomer) (I _1B 20.VleOHDLA).

INTERMEDIATE 3B:

(5j-4-(4-BromophenyI)-l-(3-(trifliJOiOincthyl)phenyl)-3,4.6,7-tetrahydro-l//-cycloίο penta[i/|pyrimidine-2.5-dione

Yield: 0.94 g; ESI mass spectrum: [(⁷⁹Br)-M+ H]⁺ = 451, [(^8IBr)-M+ H]⁺ = 453; Rétention time: 3.08 min (early eluting enantiomer) (I_IB_20_MeOH_DEA).

-6017445

INTERMEDIATE 4

4-Nitrophenyl 4-(4-Cyanophenyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-4,5,6,7tetrahydro-1 //-cvclopenta [ d] pyrimidine-3(27/)-carboxylate

4-Nitrophenyl chloroformate (1.11 g, 5.52 mmol) is added to a solution of4-(2,5-dioxo-l(3-(trifluoromethyl)phenyl )-2,3,4,5,6,7-hexahydro-17/-cyclopenta[i/]pyrimidin-4-yl)benzonitrile (example 1, 1.33 g, 3.35 mmol), M/V-diisopropylethylamine (2,28 mL, 13,4 mmol) and 4-(dimethylamîno)pyridîne (409 mg, 3.35 mmol) in dichloromethane (24 mL). After 1 h the mixture is washed with water and concentrated. The residue is purified by flash io chromatography on silica (gradient cyclohexane to cyclohexane/ ethyl acetate 3:7). Yield:

623 mg; ESI mass spectrum [M+H]⁺ = 563; Rétention time HPLC: 0.99 min (Z018_S04).

INTERMEDIATE 5

3-(3-(DifIuoromethyl)phenyIamino)cyclopent-2-enone is A mixture of cyclopentane-l,3-dione (2.00 g, 20.4 mmol), 3-(difluoromethyl)aniline (2.92 g, 20.4 mmol) and Ytterbium(III) trifluormethanesulfonate (63 mg, 0.10 mmol, 0.5 mol%) is stirred at room température for 2 h. Methanol and water are added and the

-6117445 resulting precipitate is filtered and dried. Yield: 2.75 g; ESI mass spectrum: [M+H]⁺ = 224;

Rétention time HPLC: 0.82 min (V012 SOI).

INTERMEDIATE 6

s 4-(4-Bromoph enyl)-l-(3-(difluoromethyl)pheny 1)-3,4,6,7- tetrahydro- l//-cyclopen ta |<7|pyrimidine-2,5-dione

A solution of 1-bromo-4-(chloro(isocyanato)methyl)benzene (240 mg, 0.974 mmol) in dichloromethane (2 mL) is added dropwise to a solution of 3-(3-(di fluoromethyl )phenylamino)cyclopent-2-enone (intermediate 5, 217 mg, 0.974 mmol) in dichloromethane (2 mL) io and the reaction mixture is heated at reflux for 2 h. Water is added, and the phases are extracted twîce with dichloromethane. The combined organic layers are concentrated and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 4:1 to ethyl acetate). Yield: 159 mg; ESI mass spectrum: [(⁷⁹Br)-M+ H]⁺ = 433, [(⁸¹Br)-M+ H] = 435; Rétention time HPLC: 0.56 min (X012_S01).

is INTERMEDIATE 7

Diethyl (4-Bromo-2-niethylsulionyl)phenyl)inethylenedicarbamate

The title compound is prepared in analogy to diethyl (4-cyanophenyl)methylenedicarbamate (intermediate 1), substituting 4-formylbenzonitrile with 4-bromo-2-(methyl- a/

-6217445 sulfonyl)benzaldehyde (4.50 g, 17.1 mmol) and purifying the crude product by flash chromatography on silica (gradient dichloromethane to dichloromethane/methanol 93:7). Yield: 5.05 g; ESI mass spectrum: [(⁷⁹Br)-M+H]⁺ - 423, [(⁸¹Br)-M+Hf = 425; Rétention time HPLC: 0.77 min (Z01 l_S03).

INTERMEDIATE 8

4-(4-Bromo-2-(niethy lsulfonyl) phenyl)-1 -(3-(tr ifluoro methyl) phenyl)-3,4,6,7-tetrahydro-l//-cyclopenta|</|pyrimidine-2,5-dione

Step 1:

4-Bromo-l-(chloro(isocyanato)methyl)-2-(methylsulfonyl)benzene

Phosphorous pentachloride (5.47 g, 26.2 mmol) is added to a suspension of diethyl (4-bromo-2-methyisulfonyl)phenyl)methylenedicarbamate (intermediate 7, 5.05 g,

11.9 mmol) in toluene (30 mL) and the mixture is heated at reflux for 3 h. The toluene is evaporated and the mixture is then purified by distillation under reduced pressure (ca. 160 °C, 0.1 mbar). Yield: 945 mg.

Step 2:

4-(4-Bromo-2-(methylsulfonyl)phenyl)-l-(3-(trifluoromethyI)phenyl)-3,4,6,7-tetrahydro-lZf-cyclopenta[d]pyrimidine-2,5-dione

3-(3-(Trifluoromethyl)phenylamino)cyclopent-2-enone (234 mg, 0.97 mmol) is added to a solution of 4-bromo-l-(chloro(isocyanato)methyl)-2-(methylsulfonyl)benzene (Step 1, 945 mg, 2.91 mmol) in dichloromethane (10 mL). The mixture is heated at reflux over night and then concentrated under reduced pressure. The residue is purified by reversed frf'

-6317445 phase HPLC (Agilent ZORBAX™ SB-Cig, gradient of acetonitrile in water, 0.1% formic acid). Yield: 110 mg; ESI mass spectrum: ESI mass spectrum: [(⁷⁹Br)-M+ H]⁺ = 529, [(^8lBr)-M+H]⁺= 531; Rétention time HPLC: 1.21 min (Z0I7_S04).

INTERMEDIATE 9

-CO₂Et

Diethyl (6-Broniopyridin-3-yl)niethylenedicarbamate

The title compound is prepared in analogy to diethyl (4-cyanophenyl)methylenedicarbamate (intermediate 1 ), substituting 4-formylbenzonitrile with 6-bromonicotinaldehyde (7.00 g, 37.6 mmol) and reducing the reaction time from 7 h to 1 h. Yield: 7.82 g; ESI mass îo spectrum: [(⁷⁹Br)-M+H]⁺ = 346, [(⁸¹Br)-M+H]⁺ = 348; Rétention time HPLC: 0.87 min (V011-S01).

INTERMEDIATE 10

2-ChlorO“5-(chloro(isocyanato)methyl)pyridine is The title compound is prepared in analogy to 4-(chloro(isocyanato)methyl)benzonitrile (intermediate 2), replacing diethyl (4-cyanophenyl)methylenedicarbamate (intermediate 1) with diethyl (6-bromopyrîdin-3-yl)methylenedicarbamate (intermediate 9, 7.82 g,

22.6 mmol) and collecting the appropriate fraction (ca. 85-90 °C, ca. 0.3 mbar). Yield:

1.07 g. ESI mass spectrum: [M-HCl+2MeOH+H]⁺ = 231; Rétention time HPLC: 0.73 min (V011_S01).

-6417445

INTERMEDIATE U

4-(6-Chloropyridin-3-yl)-l-(3-(trifliioromethyl)pheny 1)-3,4,6,7-tetrahydro-lH-cyclopenta [rfj py r imidine-2,5-dione

A solution of 3-(3-(trifluoromethyl)phenylamino)cyclopent-2-enone (900 mg, 3.73 mmol) in dichloromethane (8 mL) is added dropweise to a solution of 2-chloro-5-(chloro(isocyanato)methyl)pyridine (intermediate 10, 757 mg, 3.73 mmol) in dichloromethane (7 mL). The mixture is stirred at room température for 2 h and concentrated, and the residue is purified by reversed phase HPLC (Waters Xbridge™-Ci8, gradient of acetonitrile in water, ίο 0.1% NH₃). Yield: 160 mg; ESI mass spectrum [M+H]⁺ = 408; Rétention time HPLC: 0.98 min (V011-S0I).

INTERMEDIATE 12

ieri-Butyl (4-Cyanophenyl)(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-l15 enyl)methylcarbamate

Sodium hydride (60% in minerai oil, 1.06 g, 26.5 mmol) is added at room température in portions to a mixture of 3-(3-( tri fl uorom ethyl )phenylamino)cyclopent-2-enone (4.31 g,

-6517445

17.9 mmol) and 2-methyltetrahydroftiran. After 20 min tert-butyl (4-cyanophenyl)(phenylsulfonyl)methylcarbamate (10.0 g, 24.2 mmol based on 90% purity) is added, and the mixture is stirred at room température for 1 h.Water is added and the phases are separated.

The organic layer is washed with water and concentrated under reduced pressure, and the residue is recrystallized from tert-butyl methyl ether. Yield: 6.92 g. ESI mass spectrum: [M+H]⁺ = 472; Rétention time HPLC: 0.76 min (X012_S01),

INTERMEDIATE 13

4-(Amino(5-oxo-2-(3-(trifluoroincthyl)plienylamino)cyclopent-l-enyl)methyl)benzoio nitrile hydrochloride

A solution of hydrogen chloride in 1,4-dioxane (4 M, 29.3 mL, 117 mmol) is added to a mixture of tert-butyl (4-cyanophenyl)(5-oxo-2-(3-(trifluoromethyl)phenylainino)cyclopent· l-enyl)methylcarbamate (intermediate 12, 6.92 g, 14.7 mmol) in 1,4-dioxane (30 mL), and the mixture is stirred at room température for 2 h. Ail volatiles are removed under reduced is pressure, and the residue is treated with tert-butyl methyl ether (50 mL). The precipitate is filtered, washed wîth tert-butyl methyl ether and dried. Yield: 6.10 g. ESI mass spectrum: [M+H]⁺ = 372; Rétention time HPLC: 0.62 min (X01 l_S02).

-6617445

INTERMEDIATE 14

tert-Butyl (2-Bromo-4-cvanophenyl)(5-oxo-2-(3-(trifliioromethyl)phenylamino)cvclopent-1 -eny l)methy Icarbamate

Step 1 :

tert-Butyl (2-Bronio-4-cyanoplienvl)(phenvlsulfonyl)niethylcarbamate

Formic acid (3.9 mL, 104 mmol) is added to a solution of tert-butyl carbamate (1.90 g,

16.2 mmol), 2-bromo-4-cyanobenzaldehyde (3.41 g, 16.2 mmol) and sodium bcnzcnesulfinate (2.67 g, 16.2 mmol) in a mixture of tetrahydrofuran (7.0 mL) and water (60 mL), and the mixture is stirred at room température for 6 days. Water (180 mL) is added, and the precipitate is filtered and washed with water. The precipitate is treated with tert-butyl methyl ether (30 mL), and the mixture is stirred for 30 min. The precipitate is filtered, washed with tert-butyl methyl ether, and dried. Yield: 3.35 g. ESI mass spectrum: [(⁷⁹Br)M+H]⁺ = 451, [(⁸¹Br)-M+H]⁺ = 453; Rétention time HPLC: 0.66 min (X012_S01).

Step2:

tert-Butyl (2-Bromo-4-cyanophenyl)(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopen t-1-eny 1) me thy Icarbamate

Sodium hydride (60% in minerai oil, 360 mg, 9.00 mmol) is added in portions to a mixture of 3-(3“(trifluoromethyl)phenylamino)cyclopent-2-enone (2.16 g, 8.96 mmol) and 2methyltetrahydrofuran (30 mL). After 30 min tert-butyl (2-bromo-4-cyanophenyI)(phenylsulfonyl)methylcarbamate (Step 1, 3.35 g, 7.43 mmol) is added and the mixture is stirred at room température for 2 h. Water is added and the phases are separated. The aqueous phase ,

-6717445 is extracted twice with ethyl acetate, and the combined organic phases are washed with water, dried over MgSC>4 and concentrated under reduced pressure. The residue is treated with tert-butyl methyl ether, and the mixture is stirred for 15 min. The precipitate is filtered, washed with tert-butyl methyl ether, and dried. Yield: 3.18 g. ESI mass spectrum: s [(⁷⁹Br)-M+H]⁺ = 550, [(^8lBr)-M+H]⁺= 552; Rétention time HPLC: 0.73 min (X012_S0l).

INTERMEDIATES I4.l - 14.6

The following intermediates are prepared in analogy to tert-butyl (2-bromo-4-cyanophenyl)(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-l-enyl)methylcarbamate (intermediate 14), substituting 2-bromo-4-cyanobenzaldehyde tert-butyl (2-bromo-4-cyanoio phenyl)(phenylsulfonyl)methylcarbamate with the appropriate starting material as indicated în Table 2.

TABLE 2

Intermediate	Starting Material	R1	MS [M+H]+	Rétention time [min]	HPLCMethod
14.1	H^O	à 1 1	506	0.76	X012_S01

-6817445

14.2	A°°	L i do	564	0.77	X012S0I
14.3	o \	à, 1 1	502	0.76	X012_S01
14.4	H%	i 1 1 1	486	0.75	X012_S01
14.5	δ,. H'X)	Br 1 1	571, 573	0.80	X012_S0I
14.6	N ά h Ad	N III ô	473	1.13	Z018_S04

-6917445

INTERMEDIATE I5

tert-Butyl (4-Cyano-2-(methyIsulfonyl)phenyl)(phenylsulfonyl)methylcarbamate Formic acid (6.2 mL, 164 mmol) is added to a solution of tert-butyl carbamate (3.05 g,

26.0 mmol), 4-formyl-3-(rnethylsulfonyl)benzonitrile (5.44 g, 26.0 mmol) and sodium benzenesulfinate (4.27 g, 26.0 mmol) in a mixture of tetrahydrofuran (10 mL) and water (25 mL), and the mixture is stirred at room température for 4 days. Water (30 mL) is added, and the precipitate is filtered, washed with water and acetonitrile and dried Yield: 5.10 g. ESI mass spectrum: [M+H]⁺ = 451; Rétention time HPLC: 0.59 min (X012_S01).

jo INTERMEDIATE 16

tert-Butyl (4-Cyano-2-(methylsulfonyl)phenyl)(2-(3-(difluoi‘oinethyl)phenylainino)-5oxocy dopent-1 -enyl) methylcar bamate

Sodium hydride (60% in minerai oil, 106 mg, 2.67 mmol) is added in portions to a mixture of 3-(3-(difluoromethyl)phenylamino)cyclopent-2-enone (intermediate 5, 595 mg,

2.66 mmol) and 2-methyltetrahydrofuran (20 mL). After 2 h tert-butyl (4-cyano-2-(methyl- fis'

-7017445 sulfonyl)phenyl)(phenylsulfonyl)methylcarbamate (intermediate 15, 1.00 g, 2.20 mmol) is added, and the mixture is stirred at room température for 2 h. Water is added and the mixture is extracted with 2-methyltetrahydrofuran. The organic layer is dried over Na₂SO₄ and concentrated under reduced pressure.The residue is purified by reversed phase HPLC (Waters SunFire™-C₁₈₎ gradient of acetonitrile in water, 0.1% formic acid). Yield: 665 mg;

ESI mass spectrum [M+H]⁺ = 532; Rétention time HPLC: 1.13 min (Z018_S04).

INTERMEDIATE 17

3-(2-(Trifluoromethyl)pyridin-4-ylamino)cyclopent-2-enone ίο A mixture of cyclopentane-l,3-dione (1.51 g, 15.4 mmol), 2-(trifluoromethyl)pyridin-4amine (2.50 g, 15.4 mmol) and acetic acid (7.5 mL) is heated at 130 °C for 5 h, cooled at room température, diluted with water and methanol, and purified by reversed phase HPLC (Waters SunFire™-Cig, gradient of acetonitrile in water, 0.1% formic acid). Yield: 2.26 g; ESI mass spectrum [M+H]⁺ = 243; Rétention time HPLC: 0.77 min (Z018_S04).

INTERMEDIATE 18

/eri-Butyl (4-Cyanophenyl)(5-oxo-2-(2-(trifluoromethyl)pyridïn-4-ylamino)cyciopent- l-enyl)methylcarbamate .jS'

-7117445

Sodium hydride (60% in minerai oil, 895 mg, 22.4 mmol) is added in portions to a mixture of 3-(2-(trifluoromethyl)pyridin-4-ylamino)cyclopent-2-enone (intermediate 17,4.52 g,

18.7 mmol) and 2-methyltetrahydrofuran (30 mL). After 30 min tert-butyl (4-cyanophenyl)(phenylsulfonyl)methylcarbamate (6.90 g, 18.5 mmol) is added, and mixture is stirred at room température for 30 min. Water is added, and the phases are separated. The organic phase is dried over Na₂SC>4 and concentrated under reduced pressure. Yield: 9.20 g; ESI mass spectrum [M+H]⁺ = 473; Rétention time HPLC: l.09 min (Z018 S04).

INTERMEDIATE 19

NH io tert-Butyl (4-Cyano-2-(methylsulfonyl)phenyl)(5-oxo-2-(2-(trifluoromethyI)pyridin-4ylamino)cyclopent-l-enyl)niethykarbamate

Sodium hydride (60% in minerai oil, 515 mg, 12.9 mmol) is added in portions to a mixture of 3-(2-(trifluoromcthyl)pyridin-4-ylamino)cyclopcnt-2-cnonc (intermediate 17, 2.60 g,

10.7 mmol) and 2-methyltetrahydrofuran (40 mL). After 10 min tert-butyl (4-cyano-2- (methylsulfonyl)phenyl)(phenylsulfonyl)methylcarbamate (intermediate 15, 4.83 g,

10.7 mmol) is added, and the mixture is stirred at room température for 30 min. Water and ethyl acetate are added, and the phases are separated. The organic phases is washed twice with water and concentrated under reduced pressure. Yield: 6.20 g; ESI mass spectrum [M+H]⁺= 551; Rétention time HPLC: 1.12 min (Z018 S04).

-7217445

INTERMEDIATE 20

4-(Amino(5-ox o-2-(3-(trifluo romethyl)phenylamino)cy dopent- l-enyl)meth yl)-3bromobenzonitrile hydrochloride

A solution of hydrogen chloride in l,4-dioxane (4 Μ, 15.2 mL, 61 mmol) is added to a mixture of tert-butyl (2-bromo-4-cyanophenyl)(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-l-enyl)methylcarbamate (intermediate 14, 6.71 g, 12.2 mmol) in 1,4-dioxane (30 mL), and the mixture is stirred at room température for 2 h and then cooled in an ice bath. The precipitate is filtered, washed with cold acetonitrile and dîethyl ether and dried.

io Yield: 5.90g. ESI mass spectrum: [(⁷⁹Br)-M+H]⁺ = 450, [(⁸¹Br)-M+H]⁺ = 452; Rétention time HPLC: 1.17 min (V011S01).

INTERMEDIATES 20.1 -20.9

The following intermediates are prepared in analogy to 4-(amino(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-l-enyl)methyl)-3-bromobenzonitrile hydrochloride (inter15 médiate 20), using the appropriate starting material as indicated in Table 3. .-tf

-7317445

TABLE 3

Intermediate	Starting Material	Structure	MS [M+H]+	Rétention time [min]	HPLCMethod
20.1	intermediate 14.1	1 0 1 Cl N H	406	0.51	X012S0I
20.2	intermediate 14,2	a Q jfo’Ô Λγ'ΝΗ/ΗΘΙ N H	464	0.50	X012_S01
20.3	intermediate 14,3	! Q J 0 Λγ^ΝΗ/HCI ^CF,	402	0.50	X012_S01

-7417445

20.4	intermediate 14.4	! Λγ^ΝΗ/HCI 'ήη	386	0.51	X012_S01
20.5	intermediate 14.5	/γ^ΝΗ/ΗΟΙ ^CF,	471,473	0.74	X011JS03
20.6	intermediate 14.6	Ï (J 0 T Λγ^ΝΗ/ΗΟ N H	373	0.82	Z011_S03

λΤ

-7517445

20.7	intermediate 16	l όψ Q T 0 o Λγ^ΝΗ/HCI ''ήη Οψ F	432	0.80	Z0l8_S04
20.8	intermediate 18	a 0 Ζγ^ΝΗ/HCI	373	0.76	Z01IS03
20.9	intermediate 19	! άψ Q JT o o Λγ^ΝΗ/HCI	451	0.76	Z0l8_S04

INTERMEDIATE 21

3-(Benzyloxy)cyciopent-2-enone

A mixture of cyclopentane-l,3-dione (2.00 g, 20.4 mmol), benzyl alcohol (2.11 mL, 20.4 mmoL) and para-toluenesulfonic acid (35 mg, 0.20 mmol) in toluene (10.0 mL) is heated at reflux over night. Water is added, and the mixture is extracted with dichloromethane. The organic layer is concentrated, and the residue is purified by flash chromatography on silica (gradient cyclohexane/ethyl acetate 9:1 to cyclohexane/ethyl acetate 1:4). Yield: 1.66 g;

ESI mass spectrum: [M+H]⁺ = 189; Rétention time HPLC: 0.51 min (X012_S01).

INTERMEDIATE 22

3-(Benzyloxy)-5-methylcyclopent-2-enone

A solution of 3-(benzyloxy)cyclopent-2-enone (intermediate 21, 300 mg, 1.59 mmol) in dry tetrahydrofuran (4.0 mL) is cooled at -50 °C with an acetone/dry ice bath and treated with lithium dîisopropylamide (2.0 M in tetrahydrofuran, 890 mL, 1.78 mmol). After 15 min methyl iodide (100 pL, 1.59 mmol) is added, and the mixture is warmed to room température over night. Water and dichloromethane is added, and the phases are separated. The organic layer is concentrated under reduced pressure, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C[8, gradient of acetonitrile in water, 0.1% TFA). Yield: 210 mg; ESI mass spectrum [M+H]⁺ = 203; Rétention time HPLC: 0.57 min (X012 S0I).

-7717445

INTERMEDIATE 23

5-Methyl-3-(3-(trifluoromethyl)phenylamino)cyclopent-2-enone

A mixture of 3-(benzyloxy)-5-methylcyclopent-2-enone (intermediate 22, 210 mg,

1.04 mmol) and Palladium on carbon ( 10%, 127 mg) in toluene (3.0 mL) is treated with hydrogen (3.4 bar) for 9 h. The mixture is filtered, and the filtrate is treated with 3-(trifluormethyl)aniline (130 μΐ., 1.04 mmol) and Ytterbîum(III) trifluormethanesulfonate (3 mg, 5 μπιοί) and stirred at room température over night. Another portion of 3-(trifluormethyl)aniline (65 pL, 0.52 mmol) is added, and the mixture is stirred over night. Water io and dichloromethane is added, and the phases are separated. The organic phase is concentrated under reduced pressure, and the residue is purified by reversed phase HPLC (Waters Xbridge™-Ci8, gradient of acetonitrile in water, 0.1% TFA). Yield: 136 mg; ESI mass spectrum [M+H]⁺ = 256; Rétention time HPLC: 0.55 min (X012_S01).

INTERMEDIATE 24

4-(Amino(4-methyl-5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-l-enyl)methyl)benzonitrile trifluoroacetate

Sodium hydride (60% in minerai oil, 6 mg, 150 μπιοί) is added to a mixture of 5-methyl-3(3-(trifluoromethyl)phenylamino)cyclopent-2-enone (intermediate 23, 38 mg, 150 μπιοί)

-7817445 and 2-methyltetrahydrofuran (2 mL). After 20 min zm-butyl (4-cyanophenyl)(phenylsulfonyl)methylcarbamate (60 mg, 150 μιηοΐ based on 90% purity) is added, and the mixture is stirred at room température over night. Another portion of sodium hydride (60% in minerai oil, 6 mg, 150 pmol) is added, and the mixture is stirred for 20 min. Another portion of teri-butyl (4-cyanophenyl)(phenylsulfonyl)methylcarbamate (60 mg, 150 pmol based on 90% purity) is added, and the mixture is stirred over night. Water is added, and the mixture is extracted twice with dichloromethane. The combined organic layers are concentrated under reduced pressure, and the residue is treated with 1,4-dioxane and hydrogen chloride (4 M in 1,4-dioxane, 290 pL, 1.1 mmol), The mixture is stirred at room température over night and treated with another portion of hydrogen chloride (4 M in 1,4-dioxane, 290 pL, 1.1 mmol). The mixture is stirred over night and treated with water. The mixture is extracted with dichloromethane, and the organic layer is concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge^IM-C_ls. gradient of acetonitrile in water, 0.1% TFA). Yield: 24 mg; ESI mass spectrum [M+H]⁺ = 386; Rétention time HPLC: 0.49 min (X012_S01).

INTERMEDIATE 25

4-(4-Bromo-2-( methylthio)pheny l)-l-(3-(trifluoromethyl)pheny 1)-3,4,6,7-tetrahydrolZ/-cyclopenta|d|pyrimidine-2,5-dione

Triethylamine (250 pL, 1.81 mmol) is added to a mixture of2-(amino(4-bromo-2-(methylthio)phenyl)methyl)-3-(3-(trifluoromethyl)phenylamino)cyclopent-2-enone hydrochloride (intermediate 20.5, 4.08 g, 7.23 mmol based on 90% purity) and Ι,Γ-carbonyldiimidazole (1.46 g, 9.04 mmol) in acetonitrile (54 mL), and the mixture is stirred at room température for 1 h. Ail volatiles are removed under reduced pressure, and the residue is treated with _w—

-7917445 water. The precipitate is filtered and purified by flash chromatography on silica (gradient dichloromethane to dichloromethane/methanol 95:5). Yield: 3.04 g; ESI mass spectrum: [(⁷⁹Br)-M+ H]⁺ = 497, [(^slBr)-M+ H]⁺ = 499; Rétention time HPLC: 0.65 min (X01 l_S03).

INTERMEDIATE 26

Diethyl (4-Cyano-2-fluorophenyl)methylenedicarbamate

In a three-necked round bottom flask equipped with a drying tube filled with calcium chloride and an inlet for nitrogen, 3-fluoro-4-formylbenzonitrile (5.00 g, 33.5 mmol) and ethyl carbamate (6.57 g, 73.7 mmol) are heated at 150 °C. The flask is being purged with a flow of nitrogen, and concentrated sulfuric acid (200 pL) is added drop by drop within 10 min. The mixture is heated at 150 °C for 6 h and then cooled at room température. The mixture is ground, treated with water (400 mL) and then stirred for 3 h. The precipitate is filtered and dried. Yield: 6.50 g; ESI mass spectrum: [M+Na]⁺ = 332; Rétention time HPLC: 0.58 min (Z0l l_S03).

INTERMEDIATE 27

Methyl 2-(4-(4-Cyanophenyl)-2,5-dioxo-1-(3-( trifliioromethyl)phenyl)-6,7-dihydro-1/7cyclopenta[d]pyrimidin-3(2//,4/7,5f/)-yl)propanoate

-8017445

Césium carbonate (737 mg, 2.26 mmol) is added to a solution of 4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-lf/-cyclopenta[/[pyrimidin-4-yl)benzonitrile (example 1, 300 mg, 0.76 mmol) and methyl 2-bromopropionate (252 mg, 1.51 mmol) in y,7V-dimethylfoimamide (10.0 mL), and the mixture is stirred at 50 °C over night. Water is 5 added, and the mixture is extracted with dichloromethane. The organic layer is washed twice with water, dried over MgSO₄ and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters SunFire™-Ci8, gradient of acetonitrile in water, 0.1% TFA). Yield: 160 mg; ESI mass spectrum: [M+H]⁺ = 484; Rétention time HPLC: 0.85 min (Z018_S04).

ίο INTERMEDIATE 28

2-(4-(4-Cyanophenyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-6,7-dihydro-LH-cyclopenta|d| pyrimidin-3(2//,4//,5//)-yl)propanoic acid

A solution of methyl 2-(4-(4-cyanophenyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-6,715 dihydro-l/f-cyclopenta[d]pyrimidin-3(2/7,4//,5f/)-yl)propanoate (intermediate 27, 125 mg,

0.26 mmol) in 1,4-dioxane (3 mL) is treated with aqueous lithium hydroxide (2.0 M,

390 μL, 0.78 mmol), and the mixture is stirred at room température over night. Water is added, and the mixture is extracted with dichloromethane. The aqueous phase is acidified with 1M aqueous hydrogen chloride and extracted with dichloromethane. The combined organic layers are dried over Na₂SO₄ and concentrated under reduced pressure. Yield:

mg; ESI mass spectrum: [M+H]⁺ = 470; Rétention time HPLC: 0.85 min (Z018_S04). qv-''

-8117445

INTERMEDIATE 29

Ethyl 2-(4-(4-Cyan o-2-( methylsulfonyl)phenyl)”2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-6,7-dihydro-l//-cyclopenta [ d ] pyri midin-3(2//,4//,5H)-yl)acetate

A mixture of 4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-lZ7-cyclopenta[d]pyrimidin-4-yl)-3-(methyl sulfonyl)benzonitrile (example 10, 1.78 g, 3.74 mmol) and césium carbonate ( l .83 g, 5.62 mmol) in .V.V-dimethylfbrmamide (25.0 mL) is treated with ethyl bromoacetate (0.50 mL, 4.50 mml), and the mixture is stirred at room température over night. Water (30ml) is added, and the precipitate is filtered and dried.

io Yield: 1.80 g; ESI mass spectrum: [M+H]⁺ = 562; Rétention time HPLC: 1.05 min (Z018_S04).

INTERMEDIATES 30.1 -30.3

The following intermediates are prepared in analogy to 4-nitrophenyl 4-(4-cyanophenyl)-

2,5-dioxo-1 -(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-l 7f-cyclopenta[d]pyrimidine-

3(2H)-carboxylate (intermediate 4), using the appropriate starting material as indicated in Table 4, and substituting dichloromethane with acetonitrile as solvent. v.V'-8217445

TABLE 4

Intermediate	Starting Material	Structure	MS [M+H]+	Rétention time [min]	HPLCMethod
30.1	example IA	1 oJtx <ίτν°2 X.	563	1.12	Z018_S04
30.2	example 10A	! W dï<rN°2 <AAo X.	641	1.10	Z018_S04
30.3	example 15.5	1 tU <XN°2 'SAo ÎAcf,	564	1.09	Z018_S04

-8317445

EXAMPLE 1

SYNTHESES OF EXAMPLES lil

NH

N A)

4-(2,5-Dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l//-cyclopenta[i/]5 pyrimidin-4-yl)benzonitrile

Method A:

A solution of 3-(3-(trifluoromethyl)phenylamino)cyclopent-2-enone (1.00 g, 4.15 mmol) in dichloromethane ( 10 mL) is added dropweise over the period of 1 h to a solution of 4-(chloro(isocyanato)methyl)benzonitrile (intermediate 2, 1.04 g, 5.39 mmol) in dichloroio methane (15 mL) at 30 °C. The reaction mixture is heated at reflux for 4 h and then stirred over night at room température. The reaction mixture is purified by reversed phase HPLC (Waters Xbridge™-C]8, gradient of acetonitrile in water, 0.1% NH3). Yield: 472 mg; ESI mass spectrum [M+H]⁺ = 398; Rétention time HPLC: 1.00 min (V01 I SO 1 ).

Method B:

Under an atmosphère of argon, a mixture of 4-(4-bromophenyl)-l-(3-(trifluoromethyl)phenyl)-3,4,6,7-tetrahydro-lLLcyclopenta[rf]pyrimidine-2,5-dione (intermediate 3, 500 mg,

1.11 mmol), zinc cyanide (200 mg, 1.70 mmol) and tetrakis(triphenylphosphine)palladium(O) (130 mg, 112 pmol) in AQV-dimethylformamide (5 mL) is heated over night at 110 °C. The reaction mixture is cooled to room température, and water is added. The mixture is extracted twice with dichloromethane, and the combined organic layers are concentrated. The residue is purified by flash column chromatography on silica (gradient

-8417445 dichloromethane to dichloromethane/ methanol 99: l ). Yield: 190 mg; ESI mass spectrum [M+H]⁺ = 398; Rétention time HPLC: l.OO min (V011_S01).

Method C:

A mixture of 4-(amino(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyck)pent-l-enyl)s methyl)benzonitrile hydrochioride (intermediate 13, 11.8 g, 26.1 mmol based on 90% purity) in acetonitrile (100 mL) and Ι,Γ-carbonyldiimidazole (5.28 g, 32.6 mmol) is treated with triethylamine (0.9 mL, 6.5 mmol), and the mixture is stirred at room température for 1 h. Ail volatiles are removed under reduced pressure, and the residue is treated with water. The precipitate is filtered, washed with water and dried. The residue is purified by îo recrystallization from hot toluene (130 mL). Yield: 8.6 g; ESI mass spectrum [M+H]⁺ = 398; Rétention time HPLC: 1.06 min (V01 l_S01). LH4BRM00213

EXAMPLES IA AND IB: ENANTIOMERS OF EXAMPLE 1

The enantiomers of racemic 4-(2,5-dîoxo-l-(3-(tri fluoromethyl)phenyl )-2,3,4,5,6,7-hexahydro-l/7-cyclopenta[i/]pyrimidin-4-yl)benzonitrile (example 1, 190 mg, 1.11 mmol) are is separated by préparative supercritical fluid chromatography on a chiral phase (Daîcel

Chiralpak IC, 10 x 250 mm, 5 pm, 30% MeOH + 0.2% diethylamîne in supercritical CO₂, 40 “C, 100 bar back pressure).

EXAMPLE IA

NH

-8517445 (i)-4-(2,5-Dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-lZ7-cyclopenta[J]pyrimidin-4yl)benzonitrile

Yield 67 mg; ESI mass spectrum [M+H]⁺ = 398; Rétention time: 9.28 min (late eluting enantiomer) (I IC 30 MeOlI_DEA).

EXAMPLE l B

(5)-4-(2,5-Dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-lH-cyclopenta[r/|pyriinidin-4-yl)benzonitrile

Yield 74 mg; ESI mass spectrum [M+H]⁺ = 398; Rétention time: 2.86 min (early eluting enantiomer) (I_IC 30 MeOH DEA).

Altematively, example l A can be prepared as follows:

Under an atmosphère of argon, a mixture of (/?)-4-(4-bromophenyl)-l-(3-(trifluoromethyl)phenyl)-3,4,6,7-tetrahydro-l/f-cyclopenta[J]pyrimidine-2,5-dione (intermediate 3A, l.OO g, 2.22 mmol), zinc cyanide (442 mg, 3.76 mmol) and tetrakis(triphenylphosphine)palIadium(O) (256 mg, 222 pmol) in .V.A-dimethylfonnamidc ( 10 mL) is heated at 110 °C for 1 h. The reaction mixture is cooled to room température and then purified by préparative reversed-phase HPLC (Waters Xbridge™-Ci8, gradient of methanol in water, 0.1% TFA). Yield: 247 mg; ESI mass spectrum [M+H]⁺ = 398; Rétention time HPLC:

0.53 min (X012_S01). w''

-8617445

EXAMPLE 2

4-(3-Metl\vl-2,5-dioxo-l-(3-(trifliioroniethyl)phenyI)-2,3,4,5,6,7-hexahydro-l//-cyclopenta [rf] pyrimidin-4-y l)benzonitr ile

Under an atmosphère of argon, 4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7hexahydro-l/f-cyclopenta[if[pyrimidin-4-yi)benzonitrile (example 1, 200 mg, 0.50 mmol) is added to a suspension of sodium hydride (60% in minerai oil, 24 mg, 0.60 mmol) in dry tetrahydrofuran. After 20 min, methyl iodide (41 pL, 0.66 mmol) is added. After 20 min water is added and the mixture is concentrated. The residue is purified by flash io chromatography on silica (gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate). Yield: 49 mg; ESI mass spectrum [M+H]⁺ = 412; Rétention time HPLC: 0.59 min (X012_S01). EXAMPLE 2A

(R)-4-(3-Methyl-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l//is cyclopenta[J]pyrimidin-4-yl)benzonitrile

-8717445

The title compound is prepared in analogy to 4-(3-methyl-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4.5/),7-hexahydiO-l//-cyclopenta|i/|pyriiiiidin-4-yl)benzonitnlc (example 2), using (R)-4-(2,5 -dioxo-1 -(3 -(tri fluoromethyl )phenyl)-2,3,4,5,6,7-hexahydro-177-cyclopenta[i/]pyrimidin-4-yl)benzonitrile (example IA, 40 mg, 0.10 mmol) as starting material. Yield: 20 mg; ESI mass spectrum [M+H]⁺ = 412; Rétention time HPLC: 0.59 min (X012_S01).

EXAMPLE 3

Methyl 2-(4-(4-Cyanüphenyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-6,7-dihvdro-1/7cyc'lopenta|i/]pyrimidin-3(2//,4/L577)-vl)acetate

A solution of 4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l//-cyclopenta[<7]pyrimidin-4-yl)benzonitrile (example 1, 3.00 g, 7.55 mmol) in dry acetonitrile (45 mL) is cooled in an îce bath and treated dropwise with lithium diisopropylamide (2 M in THF, 7.55 mL, 15.1 mmol), while the température is kept below 5 °C. Methyl 2-bromoacetate (2.31 g, 15.1 mmol) is added and the mixture is stirred for 1.5 h. The mixture is then warmed to room température and stirred at room température over night. Water (0.5 mL) is added, the mixture is concentrated, and the residue is purified by reversed phase HPLC (Waters SunFire™-C[8, gradient of acetonitrile in water, 0.1% TFA). Yield: 2.64 g; ESI mass spectrum [M+H]⁺ = 470; Rétention time HPLC: 1.65 min (W018_S01). u/^

-8817445

EXAMPLE 4

OH

2-(4-(4-Cvanophcnyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-6,7-dihydro-l//-cvclopenta|i/]pyrimidin-3(2//,4//,5//)-yl)acetic acid

Aqueous sodium hydroxide solution (l M, 15.0 mL, 15.0 mmol) is added to a solution of methyl 2-(4-(4-cyanophenyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-6₎7-dihydro-l//cyciopenta[iT|pyrimidin-3(2//,4//.5/7)-vl)acetate (example 3, 2.64 g, 5.62 mmol) in tetrahydrofuran (40 mL) and the mixture is stirred at room température for 4 h. Water is added and the mixture is extracted three times with ethyl acetate. The aqueous layer is acidified io with hydrogen chloride and extracted twice with dichloromethane. These organic layers are combined and concentrated. Yield: 1.84 g; ESI mass spectrum [M+H]⁺ = 456; Rétention time HPLC: 0.84 min (Z018_S04).

EXAMPLE 5

is 2-(4-(4-Cyanophenyl)-2,5-dioxo-l-(3-(trifluoromethyI)phenyI)-6,7-dihydro-UT-cyclopenta[i/]pyrimidin-3(2//,4/7,5//)-yl)acetamide

-8917445 /V./V.;V\;'V'-Tctramcthyl-O-(ben7otriazol-l-yl)uronium tetrafluoroborate (43 mg,

0.13 mmol) is added to a solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-6,7-dihydro-1//-cyclopenta[i/]pyrimidin-3(2//,4//,5H)-yl)acetic acid (example 4, 60 mg, 0.13 mmol) and A^V-diisopropylethylamine (50 pL, 0.29 mmol) in s TV,A'-dimethylformamîde (0.5 mL). After 20 min aqueous ammonia (32%, 8 pL, 0.13 mmol) is added and the mixture is stirred at room température for l h. The mixture is purified by reversed phase HPLC (Waters Xbridge™-Cis, gradient of acetonitrile in water, 0.1% TFA). Yield: 36 mg; ESI mass spectrum [M+H]⁺ = 455; Rétention time HPLC: 0.50 min (X012-S01).

ίο

EXAMPLE 6

4-(2,5-Dioxo-3-(2-oxo-2-thiomorpholinoethyl)-l“(3-(trifluoromethyi)phenyl)2,3,4,5,6,7-hexahydro-l/Z-cyclopenta[rf]pyrimidin-4-yl)benzonitrile

A solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-1 -(3-(trifluoromethyl)phenyl)-6,7-dihydroi5 l/f-cyclopenta[i/]pyrimidin-3(2/7,4/7,5//)-yl)acetic acid (example 4, 30 mg, 66 pmol) and triethylamine (30 pL, 0.22 mmol) in ΛξΤν-dirn ethyl formami de (1.25 mL) is treated with ;V,.'V,_;V',A'^,'-tctramethyl-(7-(benzotriazol· l -yl)uronium tetrafluoroborate (21 mg, 66 pmol) and stirred at room température for 15 min. This mixture is then added to a solution of thiomorpholine (13 mg, 0.13 mmol) in TV,TV-dimethylfonnamide (0.25 mL) and stirred for 72 h.

The mixture is filtered and the filtrate is purified by reversed phase HPLC (Waters Xbridge™-Ci8, gradient of methanol in water, 0.1% NH3). Yield: 20 mg; ESI mass spectrum [M+H]⁺ = 541; Rétention time HPLC: 1.17 min (00l_CA03). U/—

-9017445

EXAMPLES 6.1-6.46

The following examples of Table 5 are prepared in analogy to example 6, replacing thiomorpholine with the appropriate amine as starting material.

TABLE 5

Example	R3	MS [Μ+Η]+	Rétention time [min]	HPLCMethod
6.1	H 0	469	1.14	001_CA03
6.2	-•Ύν 0	483	1.16	001_CA03
6.3	'V3 0	495	0.83	Z018_S04
6.4		495	1.18	001CA03
6.5		509	1.23	001J2A03
6.6	0	509	1.22	001_CA03

-9117445

6.7	0	509	1.24	001_CA03
6.8	H 0	513	1.15	001_CA03
6.9	--'ύέ^7 o	521	0.88	Z011_S03
6.10	0	523	1.29	001_CA03
6.11	0	525	1.01	001_CA03
6.12	0	525	1.17	00ICA03
6.13	o	527	1.19	001_CA03
6.14	o	537	1.36	001CA03
6.15	|^NH 0	538	0.97	001_CA03
6.16	0	538	1.02	001_ CA03
6.17	0	538	0.90	001_CA03

-9217445

6.18	0 <,0	539	1.11	001_CA03
6.19	0	539	1.09	001_CA03
6.20	χ-γΝ^Χ?° Ο	539	1.11	001_CA03
6.21	,.νΆ·>' 0	539	1.18	001CA03
6.22	Η ο ό	545	1.01	001_CA03
6.23	0	549	1.08	001_CA03
6.24	0	551	1.07	00i_CA03
6.25	'ΎΝ^Α0 0	552	1.03	001_CA03
6.26	0 Μ	552	1.04	001CA03
6.27		552	0.91	001__CA03
6.28	0 '	552	0.90	001_CA03

-9317445

6.29	-ΎνίχΊ ο	552	0.91	001_CA03
6.30	/ ο 0	553	1.14	001_CA03
6.31	0 ^-ΟΗ	553	1.05	001_CA03
6.32	0	553	1.08	001_CA03
6.33	0	553	1.15	001_CA03
6.34	Η Ο --''Ύ Ν θ 0	553	1.15	00I_CA03
6.35	Η Η 0 0	554	1.02	001_CA03
6.36	Η 1 0	554	0.91	00ICA03
6.37	Γγ° ο	557	0.98	OO1J2AO3
6.38	γΟ 0	561	1.10	OO1J2AO3

-9417445

6.39	H 0	562	0.99	001J2A03
6.40	H rN'N- 0	563	1.07	001_CA03
6.41	0	564	0.83	001_CA03
6.42	,^nJ 0	564	0.90	001CA03
6.43	r 0	566	1.10	001_CA03
6.44	0	566	1.06	001_CA03
6.45	Ο '	566	1.06	001_CA03
6.46	^OCr° 0	588	1.02	001_CA03

-9517445

EXAMPLE 7

4-(4-Cy anophenyl)-V,A-dimethy 1-2,5-dioxo-l-(3-(trifluoromethyl)pheny 1)-4,5,6,7tetrahydro-l//-cvclopenta|i/|pvrimidine-3(2Z/)-carboxamide

A solution of 4-nîtrophenyl 4-(4-cyanophenyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-

4,5,6,7-tetrahydro-l/f-cyclopenta[d]pyrimidine-3(2//)-carboxylate (intermediate 4, 60 mg, 0.11 mmol) in acetonitrile (1.5 mL) is treated with dimethylamine (2.0 M in tetrahydrofuran, 270 pL, 0.53 mmol) and the mixture is stirred at room température for 30 min. Water and TV^V-dimethylformamide are added and the mixture is purified by reversed phase HPLC io (Waters Xbridge™-Cig, gradient of acetonitrile in water, 0.1% NHa). Yield 28 mg, ESI mass spectrum [M+H]⁺ = 469; Rétention time HPLC: 0.87 min (Z018_S04).

EXAMPLES 7.1-7.11

The following examples of Table 6 are prepared in analogy to example 7, replacing dimethylamine with the appropriate amine as reagent. U—.

-9617445

TABLE 6

Example	R3	MS [M+H]+	Rétention time (min]	HPLCMethod
7.I	-V H	455	0.88	Z011S03
7.2	,ΛΝ-ΧχΟΗ H	485	0.85	Z018S04
7.3	H	499	0.86	Z018_S04
7.4	0 H	499	0.93	Z018_S04
7.5	H	512	0.72	Z018_S04
7.6	? 9 H	531	0.83	Z018 S04
7.7	H n-n \	535	0.91	Z018_S04
7.8	9 H Λί>°	538	0.84	Z018_S04

-9717445

7.9	Z O 1	538	0.85	Z018_S04
7.10	9 °·-0 An^'s^ H	547	0.87	Z0I8S04
7.11	ol	610	0.9	Z018_S04

EXAMPLES 7.1A AND 7.1B: ENANTIOMERS OF EXAMPLE 7.1

The enantiomers of racemic 4-(4-cyanophenyl)-.ZV-methyl-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-lf/-cyclopenta[d]pyrimidine-3(2/Z)-carboxamide (example 7.1, 124 mg, 0.27 mmol) are separated by préparative supercritical fluid chromatography on a chiral phase (Daicel Chiralpak AD-H, 20 x 250 mm, 5 pm, 20% fïo-PrOH + 0.2% diethylamine in supercritical CO₂,40 °C, 150 bar back pressure).

EXAMPLE 7.1 A

(R)-4-(4-Cyanophenyl)-/V-methyl-2,5-dioxo-l-(3-(trifluoromethyI)phenyl)-4,5,6,7io tetrahydro-l/7-cyclopenta[d]pyrimidme-3(2//)-carboxamide

-9817445

Yield: 48 mg; ESI mass spectrum [M+H]⁺ = 455; Rétention time: 1.26 min (early eluting enantiomer) (I IB 30 MeOH_ DEA).

EXAMPLE 7.1 B

(S)-4-(4-Cyanophenyl)-A^r-methyl-2,5-dioxo-l-(3-(trifluoromethyl)phenyI)-4,5,6,7tetrahydro-1/7-cyclopenta[d|pyriniidine-3(2//)-carboxaniide

Yield: 40 mg; ESI mass spectrum [M+H]⁺ = 455; Rétention time: 5.24 min (late eluting enantiomer) (I IB 30 MeOH_DF.A).

EXAMPLES 7.2A AND 7.2B: ENANTIOMERS OF EXAMPLE 7.2 îo The enantiomers of racemic 4-(4-cyanophenyl)-A^r-(2-hydroxyethyl)-2,5-dioxo-l-(3(tri fluoromethyl )phenyl)-4,5,6,7-tetrahydro-17/-cyclopenta[d] pyrimidine-3 (277)carboxamide (example 7.2, 223 mg, 0.46 mmol) are separated by préparative supercritical fluid chromatography on a chiral phase (Daicel Chiralpak IB, 20 x 250 mm, 5 pm, 30% MeOH + 0.2% diethylamîne in supercritical CO₂,40 °C, 120 bar back pressure),

-9917445

EXAMPLE 7.2A

(JÎ)-4-(4-Cyanophenyl)-/V-(2-hydroxyethyl)-2,5-dioxo-l-(3-(trifluoromethyi)phenyl)-

4,5,6,7-tetrahydro-l//-cyclopenta[d]pyrimidine-3(27/)-carboxamide s Yield: 78 mg; ESI mass spectrum [M+H]⁺ = 485; Rétention time: 1.36 min (early eluting enantiomer) (I_IB_30_MeOH_DEA).

EXAMPLE 7.2B

(S)-4-(4-Cyanophenyl)-7V-(2-hydroxyeÉhyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)i o 4,5,6,7-tetrahy dr ο-1 //-cyclopen ta [ d] py rimidine-3(2/7)-ea rboxamide

Yield: 99 mg; ESI mass spectrum [M+H]⁺ = 485; Rétention time: 3.38 min (early eluting enantiomer) (I_IB_30_MeOH_DEA). vJ\T

-10017445

EXAMPLE 8

Methyl 4-(4-Cyanophenyl)-2,5-dioxo-1 -(3-(trifluoromethyl)pheny 1)-4,5,6,7-tetrahydroI//-cyclopenta[d]pyriinidine-3(2//)-carboxylate

A solution of 4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l//-cyclopenta[</]pyrimidin-4-yl)benzonitrile (example 1, 30 mg, 0.076 mmol) in tetrahydrofuran (0.5 mL) is added to a suspension of sodium hydride (60% in minerai oil, 4 mg, 0.1 mmol) in dry tetrahydrofuran. After 20 min methyl chloroformate (6 pL, 0.078 mmol) is added, and the mixture is stirred at room température for 1 h. Water is added and the mixture is io extracted with dichloromethane. The combined organic layers are concentrated, and the residue is purified by reversed phase HPLC (Waters Xbridge™-C]8, gradient of acetonitrile în water, 0.1% NH₃). Yield: 2 mg; ESI mass spectrum [M+H]⁺ = 456; Rétention time HPLC: 1.10 min (V0U S01).

EXAMPLE 9

-10117445

4-(3-(Methylsulfonyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro1 //-cyclopen ta [4| py r imidin-4-yl)benzonitrile

4-(2,5-Dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l//-cyclopenta[J]pyrimidin-4-yl)benzonitrile (example 1, 255 mg, 0.64 mmol) is added to a suspension of sodium hydride (60% in minerai oil, 72 mg, 1.8 mmol) in dry tetrahydrofuran (15 mL) and the mixture is stirred at room température for 10 min. Methanesulfonyl chloride (104 pL, 1.35 mmol) is added and the mixture is stirred at 50 °C for 2 h. Water (1 mL) is added and the the mixture is purified by reversed phase HPLC (Waters SunFire™-C]8, gradient of acetonitrile in water, 0.1% TFA). Yield: 230 mg; ESI mass spectrum [M+H]⁺ = 476; Rétention time HPLC: 0.91 min (Z018_S04).

EXAMPLES 9A AND 9B: ENANTIOMERS OF EXAMPLE 9

The enantiomers of racemîc4-(3-(methylsulfonyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-

2,3,4,5,6,7-hexahydro-17/-cyclopenta[c/]pyrimidin-4-yl)benzonitrile (example 9,230 mg, 0.48 mmol) are separated by préparative supercritical fluid chromatography on a chiral phase (Daicel Chîralpak IB, 20 x 250 mm, 5 pm, 15% MeOH + 0.2% diethylamine in supercritical CO₂, 40 °C, 150 bar back pressure).

EXAMPLE 9A

(Jf)-4-(3-(MethylsuIfonyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7hexahydrο-1H-cyclopenta [rf] pyrimidin-4-yl)benzonitrîle /F

-10217445

Yield 65 mg; ESI mass spectrum [M+H]⁺ = 476; Rétention time: 2.25 min (early eluting enantiomer) (I lB l5 MeOH_DEA).

EXAMPLE 9B

(S)-4-(3-(Methylsulfonyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7hexahydro-l//-cyclopenta[i/|pyrimidin-4-yl)benzonitrik‘

Yield 71 mg; ESI mass spectrum [M+H]⁺ = 476; Rétention time: 3.04 min (late eluting enantiomer) (I_IB_15_MeOH_DEA).

EXAMPLE 10

4-(2,5-Dioxo- l-(3-(trifluoromethyl)pheny I)-2,3,4,5,6,7-h ex ahydro-1 //-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile

-10317445

Under an atmosphère of argon, a mixture of 4-(4-bromo-2-(methylsulfonyl)phenyl)-l-(3(trifluoromethyl)phenyî)-3,4,6,7-tetrahydro-l/Z-cyclopenta[t/]pyrimidine-2,5-dione (intermediate 8, 110 mg, 0,21 mmol), zinc cyanide (32 mg, 0.27 mmol) and tetrakis (triphenylphosphine)palladium(O) (24 mg, 21 μ mol) in AyV-dimethylformamide (2 mL) is s heated at 110 °C over night and then cooled to room température. Water îs added and the mixture is filtered. The precipitate is purified by flash chromatography on silica (gradient cyclohexane/ ethyl acetate 8:2 to 3:7). Yield: 40 mg; ESI mass spectrum: [M+H]⁺ = 476; Rétention time HPLC: 0.94 min (Z017_S04).

EXAMPLES 10A AND 10B: ENANTIOMERS OF EXAMPLE 10 ίο The enantiomers of racemic 4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l/7-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 10, 1.82 g, 3.83 mmol) are separated by préparative supercritical fluid chromatography on a chiral phase (Daîcel Chiralpak IB, 20 x 250 mm, 5 pm, 15% MeOH + 0.2% diethylamine in supercritical CO2, 40 °C, 120 bar back pressure).

EXAMPLE 10A

(5)-4-(2,5-Dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-lZf-cyclopenta [ d [ pv r imidin-4-yl)-3-(niethylsulfonyl)benzonit rile

Yield 620 mg; ESI mass spectrum [M+H]⁺ = 476; Rétention time: 2.52 min (early eluting enantiomer) (I IB 20_McOH DEA).

-10417445

EXAMPLE ΙΟΒ

(JÎ)-4-(2,5-Dioxo-l-(3-(trifluoromethyl)phenyI)-2,3,4,5,6,7-hexahydro-lJ7-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile s Yield 554 mg; ESI mass spectrum [M+H]⁺ = 476; Rétention time: 2.78 min (late eluting enantiomer) (I_IB 20 X4eOH_DEA).

EXAMPLE 11

4-(l-(3-(Difluoromethyl)phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-lH-cydopenta[rf]io pyrimidin-4-yl)benzonitrile

Under an atmosphère of argon, a mixture of 4-(4-bromophenyl)-l-(3-(dîfluoromethyl)phenyl)-3,4,6,7-tetrahydro-l/7-cyclopenta[eZ]pyrimidine-2,5-dione (intermediate 6, 159 mg, 367 pmol), zinc cyanide (73 mg, 620 pmol) and tetrakis(triphenylphosphine)palladium(0) (42 mg, 37 pmol) in WA^-dimethylformamide (2 mL) is heated at 110 °C for 3 h and then cooled to room température. Water is added and the mixture is extracted twice with dichlo

-10517445 romethane. The residue is purified by flash chromatography on silica (gradient cyclohexane/ ethyl acetate 7:3 to ethyl acetate). Yield: 82 mg; ESI mass spectrum: [M+H]⁺ = 380; Rétention time HPLC: 0.49 min (X012_S01).

EXAMPLE 12

5-(2,5-Dioxo-l-(3-(trifluoroniethyl)phenyl)-2,3,4,5,6,7-liexahydro-l/7-cyclopcnta|d|pyriinidin-4-yl)picolinonitrile

Under an atmosphère of argon, a mixture of4-(6-chloropyridîn-3-yl)-l-(3-(trifluoromethyl )phcnyl )-3,4,6.7-tctrahydro-1//-cyclopenta[i7|pyrimidiiic-2,5-dione (intermediate 11, io 120mg, 294 pmol), zinc cyanide (59 mg, 0.50 mmol) and tetrakîs(triphenylphosphine)palladium(O) (34 mg, 29 pmol) in .V,A'-dimcthylfbmiamidc (2 mL) is heated at 110 °C for 24 h. The reaction mixture is cooled to room température and then purified by préparative reversed phase HPLC (Waters Xbridge™-Ci8, gradient of acetonitrile in water, 0.1% TFA). Yield: 10 mg; ESI mass spectrum [M+H]⁺ = 399; Rétention time HPLC: 0.50 min is (V012_S01). Jî/-10617445

EXAMPLE 13

3-Bromo-4-(2,5-dioxo-l-(3-(trifluoromethyl)pheiiyl)-2,3,4,5,6,7-hexahydro-l/7cyclopenta[d]pyrîmidin-4-yl)benzonitrile

Triethylamine (0.43 mL, 3.0 mmol) is added to a mixture of 4-(amino(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-1 -enyl)methyl)-3-bromobenzonitrile hydrochloride (intermediate 20, 5.90 g, 12.1 mmol) and Ι,Γ-carbonyldiimîdazole (2.46 g, 15.2 mmol) in acetonitrile (60 mL), and the mixture is stirred at room température over night. Water (700 mL) is added and the precipitate is filtered, washed with water and dried. Yield: 5.45 g. ESI io mass spectrum: [(⁷⁹Br)-M+H]⁺ = 476, [(⁸¹Br)-M+H]⁺ = 478; Rétention time HPLC: 1.10 min (X011S01).

EXAMPLE 14

4-(2,5-Dioxo-l -(3-(trifluoromethyl)pheny 1)-2,3,4,5,6,7-hexahydro-lf/-cyclopenta [d ] pyrimidin-4-y I)-3-(ethyls ulfonyl)benzonitrile

-10717445

Triethylamine (125 pL, 0.89 mmol) is added to a mixture of 4-(amino(5-oxo-2-(3(trifluoromethyl)phenylamino)cycIopent-l-enyl)methyI)-3-(ethylsuIfonyl)benzonitrile hydrochloride (intermediate 20.2, 1.78 g, 3.56 mmol) and Ι,Γ-carbonyldiimîdazoIe (720 mg, 4.45 mmol) in acetonitrile (20 mL), and the mixture is stirred at room température for 1

h. The mixture is concentrated under reduced pressure, and the residue is treated with water (20 mL). The precipitate is filtered and dried. Yield: 1.61 g. ESI mass spectrum: [M+H]⁺ = 490; Rétention time HPLC: 0.56 min (X012_S01).

EXAMPLES 14A AND 14B: ENANTIOMERS OF EXAMPLE 14

The enantiomers of racemic 4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexaio hydro-lff-cyclopenta[d]pyrimidin-4-yl)-3-(ethylsulfonyl)benzonitrile (example 14, 48 mg, pmol) are separated by préparative supercritical fluid chromatography on a chiral phase (Daicel Chiralpak IB, 20 x 250 mm, 5 pm, 20% MeOH + 0.2% diethylamine in supercritical CO₂,40 °C, 150 bar back pressure).

EXAMPLE 14A

(.Ç)-4-(2,5-l)ioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6.7-hexahydro-l/7-cydopenta [d] py r imidin-4-y l)-3-(ethylsulfonyl)benzonitr île

Yield: 16 mg; ESI mass spectrum [M+H]⁺ = 490; Rétention time: 2.28 min (early eluting enantiomer) (I IB 20 MeOH DEA).

-10817445

EXAMPLE 14B

(7î)-4-(2,5-Dioxo-l-(3-(trÎfluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-lff-cyclopenta [d] py r imidin-4-yl)-3-(ethyls ulfony l)benzonitrile

Yield: 16 mg; ESI mass spectrum [M+H]⁺ = 490; Rétention time: 2.82 min (late eluting enantiomer) (I_IB_20_MeOH_DEA).

EXAMPLE 15

3-Chloro-4-(2,5-dioxo-1 -(3-( trifluo romethyljpheny 1)-2,3,4,5,6,7-hexahydro-1Hio cyclopenta[d]pyrimidin-4-yl)benzonitrile

Triethylamine (0.38 mL, 2.70 mmol) is added to a mixture of 4-(amino(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-l-enyl)methyl)-3-chlorobenzonitrile hydrochloride (intermediate 20.1,660 mg, 1.34 mmol based on 90% purity) and l,l’-carbonyldiimidazole (270 mg, 1.68 mmol) in acetonitrile (5 mL), and the mixture is stirred at room température 15 over night. Water and dichloromethane are added, and the phases are separated. The organic layer is concentrated under reduced pressure and purified by reversed phase HPLC

-10917445 (Waters Xbridge™-Cis, gradient of acetonitrile in water, 0.1% TFA). Yield: 290 mg. ESI mass spectrum: [M+H]⁺ = 432; Rétention time HPLC: 0.61 min (X012 S01 ).

EXAMPLES 15.1 - 15.7

The following examples of Table 7 are prepared în analogy to 3-chloro-4-(2,5-dioxo-l-(35 (trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-lH-cyclopenta[d]pyrimîdin-4-yl)benzonitrile (example 15), using the appropriate startîng material and the purification method as indicated in the table (Method A: Waters Xbridge™-C]8, gradient of acetonitrile in water, 0.1% TFA; Method B: Waters SunFire™-C[8, gradient of acetonitrile in water, 0.1% TFA; Method C: Waters SunFire™-Ci8, gradient of acetonitrile in water, 0.1% formic acid).

TABLE 7

Example	Startîng Material	Structure	Purification Method	MS [M+H]+	Rétention time [min]	HPLCMethod
15.1	intermediate 20.3	X ll o	A	428	0.59	X012_S01

-11017445

15.2	intermediate 20.4	a 0 <χτ 'SZo Ô'CF,	A	412	0.60	X012_S01
15.3	intermediate 20.6	! Ôn O T ÔCT ^CF,	B	399	0.51	X011S03
15.4	intermediate 20.7	! Ôç Q T Oô όψ F	B	458	0.91	Z018_S04

-ni17445

15.5	intermediate 20.8	N 111 0 /TT NH <Aa,	C	399	0.91	Z018_S04
15.6	intermediate 20.9	! όψ Q Too (HH îXf,	B	477	0.90	Z018_S04
15.7	intermediate 24	H 0 -ŒT àcF3	A	412	0.63	X012JS01

EXAMPLES 15.3A AND 15.3B: ENANT10MERS OF EXAMPLE 15.3

The enantiomers of racemic 6-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l//-cyclopenta[d]pyrimidin-4-yI)nicotinonitrile (example 15.3, 650 mg, 1.63 mmol) /Γ

-11217445 are separated by préparative supercritical fluid chromatography on a chiral phase (Daicel Chiralpak IB, 20 x 250 mm, 5 pm, 25% MeOH + 0.2% diethylamine in supercritical CO2, 40 °C, 150 bar back pressure).

EXAMPLE 15.3 A

(5)-6-(2,5-Dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro- l//-cyclopenta|d|pyrimidin-4-yl)nicotinonïtrile

Yield: 140 mg; ESI mass spectrum [M+H]⁺ = 399; Rétention time: 3.24 min (late eluting enantiomer) (IJB 25 MeOH_NH3).

EXAMPLE 15.3B

(Æ)-6-(2,5-Dioxo-l-(3-(trifliioromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l//-cyclopenta[d]pyrimidin-4-yl)nicotinonitrile

Yield: 130 mg; ESI mass spectrum [M+H]⁺ = 399; Rétention time: 2.66 min (early eluting enantiomer) (I_IB_25_MeOH_NH3).

-11317445

EXAMPLES 15.4A AND 15.4B: ENANT10MERS OF EXAMPLE 15.4

The enantiomers of racemic 4-(l-(3-(difluoromethyl)phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-1//-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfbnyl)bcnzonitrilc (example 15.4, 27 mg, 59 pmol) are separated by préparative supercritical fluid chromatography on a chiral phase (Daicel Chiralpak IA, 20 x 250 mm, 5 pm, 30% MeOH + 0.2% diethylamine in supercritical CO₂, 40 °C, 120 bar back pressure).

EXAMPLE I5.4A

(5)-4-(1-(3-( Difluoromethy l)phenyl)-2.5-dioxo-2.3,4,5,6,7-hexahydro-l//-<:y cioio p<?nta|d|pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile

Yield: 10 mg; ESI mass spectrum [M+H]⁺ = 458; Rétention time: 2.37 min (early eluting enantiomer) (I_IA_30_MeOH_NH3).

-11417445

EXAMPLE 15.4B

(//)-4-(1-(3-( Difluorometh y l)phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-lH-cyclopenta [ d] py r Îmidin-4-y l)-3-(me thy Isu lfonyl)benzonitrile

Yield: 10 mg; ESI mass spectrum [M+H]⁺ = 458; Rétention time: 3.00 min (late eluting enantiomer) (I_IA_30_MeOH_NH3).

EXAMPLE 16

4-(2,5-Dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l//-cyclopenta|d|ι o pyriniidiii-4-yl)-3-(methylthio)benzonitrile

Under an atmosphère of argon, a mixture of 4-(4-bromo-2-(methylthio)phenyl)-l-(3(trifluoromethyl)phenyl)-3,4,6,7-tetrahydro-17/-cyclopenta|d]pyrimidine-2,5-dione (intermediate 25, 1.74 g, 2.8 mmol based on 80% purity), zinc cyanide (430 mg, 3.64 mmol) and tetrakïs (triphenylphosphine)palladîum(O) (323 mg, 0.28 mmol) in X,X-dimethyIformamide 15 (12 mL) is heated at 110 °C over night and then cooled to room température. Water is

-11517445 added, and the mixture is extracted with dichloromethane. The organic layer is concentrated under reducd pressure,and the residue is purified by reversed phase HPLC (Waters Xbridge™-Cis, gradient of acetonitrile in water, 0.1% NH₃). Yield: 1.09 g. ESI mass spectrum: [M+H]⁺ = 444; Rétention time HPLC: 0.58 min (X01 l_S03).

s EXAMPLE 17

4-(2,5-Dioxo-1-(3-( trifluoromethyl)phenyI)-2,3,4,5,6,7-hexahydro-1//-cyclopentajd] pyrimidin-4-yl)-3-(methylsulfinyl)benzonitrile meta-Chloroperoxybenzoic acid (77%, 390 mg, 1.74 mmol) is added at room température io to a solution of 4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyI)-2,3,4,5,6,7-hexahydro-l//cyclopenta[d]pyrimidin-4-yl)-3-(methylthio)benzonitrile (example 16, 776 mg, 1.75 mmol) in dichloromethane, and the mixture is stirred for 30 min. Saturated aqueous NaHCO₃ solution is added, and the mixture is extracted with dichloromethane. The combined organic layers are concentrated under reduced pressure, and the residue is purified by flash is chromatography on silica (gradient cyclohexane/ethyl acetate 1:1 to ethyl acetate. Yield: 527 mg; ESI mass spectrum [M+H]⁺ = 460; Rétention time HPLC: 0.48 min (early eluting dîastereomer), 0.49 (late eluting diastereomer) (X012_S01).

EXAMPLES 17A AND 17B: DIASTEREOMERS OF EXAMPLE 17

The diastereomers of 4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro20 17f-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfinyl)benzonitrile (example 17, 35 mg) are

-11617445 separated by by reversed phase HPLC (Waters Xbridge™-Cig, gradient of acetonitrile in water, 0.1% TFA).

Example 17A:

Yield: 11 mg; ESI mass spectrum [M+H]⁺ = 460; Rétention time HPLC: 0.48 min (early 5 elutingdiastereomer) (XOI2_S01).

Example 17B:

Yield: 7 mg; ESI mass spectrum [M+H]⁺ = 460; Rétention time HPLC: 0.50 min (late eluting diastereomer) (X012 S01).

EXAMPLE 18

4-(2,5-Dioxo-l-(3-(trifluorornethyi)phenvl)-2,3,4,5,6,7-hexahydro-l//-cyclopenta|d|pyrimidin-4-yl)-3-fIuorobenzonitrile

-11717445

Step l :

4-(ChIoro(isocyanato)methyi)-3-fluorobenzonitrile

Phosphorous pentachloride (9.63 g, 46.2 mmol) is added to a mixture of dïethyl (4-cyano-2fluorophenyl)methylenedicarbamate (intermediate 26, 6.50 g, 21.0 mmol) in toluene (25.0 mL), and the mixture is heated at reflux for 3 h. The toluene is evaporated, and the mixture is then purified by distillation under reduced pressure. The first fraction (ca. 35 °C, ca. 0.2 mbar) is dîscarded.The second fraction (ca. 112 °C, ca. 0.1 mbar) is collected. Yield: 1.90 g.

Step 2:

4-(2,5-Dioxo- l-(3-(trifluoro methyl) phenyl)-2,3,4,5,6,7-hexahydro-1 H-cyclopenta [d] pyrimidin-4-yl)-3-fluorobenzonitrile

A solution of 4-(chloro(isocyanato)methyl)-3-fluorobenzonitrile (Step 1, 3.05 g,

14.5 mmol) in dîchloromethane (10 mL) is added to a solution of 3-(3-(trifluoromethyl)phenylamino)cyclopent-2-enone (3.50 g, 14.5 mmol) in dîchloromethane (10 mL), and the mixture is heated at reflux over night. Ail volatiles are removed under reduced pressure, and the residue is purified by reversed phase HPLC (Agilent ZORBAX™ SB-Cjg, gradient of acetonitrile in water, 0.1% formic acid). Yield: 474 mg; ESI mass spectrum [M+H]⁺ = 416; Rétention time HPLC: 0.94 min (Z017 S04). LB5FAI00917

EXAMPLE 19

OH

-11817445

2-(4-(4-Cyano-2-(methylsulfonyl)phenyl)-2,5-dioxo-l-(3-(trïfluoromethyl)phenyl)-6,7dihydro-1 J/-cyclopenta[d]pyrimidin-3(2//,4//,5Z/)-yl)acetic acid

Aqueous sodium hydroxide solution (1.0 M, 10.0 mL, 10.0 mmol) is added to a solution of ethyl 2-(4-(4-cyano-2-(methylsulfonyl)phenyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)s 6,7-dihydro-l //-cyclopenta|d|pyrimidin-3(2//,4//,5/7)-yl)acetate (intermediate 29, 1.80 g,

3.20 mmol) in tetrahydrofuran (40 mL), and the mixture is stirred at room température over night. Another portion of aqueous sodium hydroxide solution (4.0 M, 2.0 mL, 8.0 mmol) and methanol (5.0 mL) is added, and mixture is stirred over night, Aqueous hydrogen chloride ( 1.0 M, 10 mL) is added, and the mixture is extracted with ethyl acetate. The jo organic layer is concentrated under reduced pressure, and the residue is purified reversed phase HPLC (Waters SunFire™-C₁₈, gradient of acetonitrile in water, 0.1% TFA). Yield:

229 mg; ESI mass spectrum: [M+H]⁺ = 534; Rétention time HPLC: 0.96 min (Z018_S04).

EXAMPLE 20

2-(4-(4-Cyanophenyl)-2,5-dioxo-l-(3-(trifluoroniethyl)phenyl)-6,7-dihydro-l/7cyclopenta[d]pyrimidin-3(2/f,4if,5Z0-yl)-7V-(2-hydroxyethyl)propanainide

A solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-l -(3-(trifluoromethyl)phenyl)-6,7-dihydrol//-cyclopenta[d]pyrimidin-3(2//,4/f,5/f)-yl)propanoic acid (intermediate 28, 40 mg, pmol) and triethylamine (45 pL, 0.32 mmol) in ΛζΛΜΐιη ethyl formamide (1.5 mL) is treated with 7V,jV,A^r’,À^r’-tetramethyl-0-(benzotriazoM-yl)uronium tetrafluoroborate (27 mg, pmol) and stirred at room température for 15 min. Ethanolamine (12 pL, 0.21 mmol) is added and the mixture is stirred at room température for 1 h. The mixture is diluted with A',;V-dimethylformamide and purified by reversed phase HPLC (Waters SunFire™-C]8, gra-11917445 dient of acetonitrile in water, 0.1% TFA). Yield: 37 mg; ESI mass spectrum [M+H]⁺ = 513;

Rétention time HPLC: 0.81 min (Z018_S04).

EXAMPLE 21

OH

2-(4-(4-Cyano-2-(methylsiilfonyl)phenyI)-2,5-dïoxo-l-(3-(trifluoromethyl)phenyl)-6,7dihydro-l//-cyclopenta[d|pyrimidin-3(2//,4//,5//)-yl)-,V-(2-hydroxyethyl)-.V-niethylacetamide

A solution of 2-(4-(4-cyano-2-(methylsulfonyl)phenyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-6,7-dihydro-I/7-cyclopenta[d]pyrimidin-3(2/7,4/f,5//)-yl)acetic acid (example 19, 23 mg, 43 pmol) and triethylamine (18 pL, 0.13 mmol) in ,V,.V-dimethylformamide (1.0 mL) îs stirred at room température for 5 min and treated with MVJV’pV’-tetramethyl0-(benzotriazol-l-yl)uronium tetrafluoroborate (13 mg, 43 pmol). After 5 min, 2-(methylamino)ethanol (10 pL, 0.13 mmol) is added. The mixture is stirred at room température for 3 h and purified by reversed phase HPLC (Waters Xbridge™-Cis, gradient of acetonitrile in water, 0.1% NH₃). Yield: 15 mg; ESI mass spectrum [M+H]⁺ = 591; Rétention time HPLC: 0.89 min (Z01 l_S03).

EXAMPLES 22.1 -22.9

The following examples of Table 8 are prepared in analogy to 2-(4-(4-cyano-2-(methylsulfonyl)phenyl)-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-6,7-dihydro-1/7-cyclopenta[d]pyrimidin-3(2Ff,47ï,57ï)-yl)-A^f-(2-hydroxyethyl)-?/-methylacetamid (example 21), using the appropriate amine as reagent, xjy'

-12017445

TABLE 8

Example	R3	MS [μ+ηΓ	Rétention time [min]	HPLCMethod
22.1	,-Ύνχ 0	561	0.81	005_CA0l
22.2	-v3 ο	573	0.81	005_CA01
22.3	0	587	0.84	005_CA0l
22.4	0	599	0.87	005_CA0i
22.5	0	603	0.80	005_CA0l
22.6	I 0	605	0.83	005_CA0l
22.7	F ...ΎίΟ ο	605	0.82	005_CA01

-12117445

22.8	rr0 O	631	0.85	005_CA01
22.9	O	641	0.79	005_CA01

EXAMPLE 22

4-(3-(Cyanornethyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro1 //-cy clopen ta [d ] py rimidin-4-y l)benzonitrile

Sodium hydride (60% in minerai oil, 11 mg, 0.29 mmol) is added to a solution of 4-(2,5-dioxo-l-(3-(trifluoro-methyl)phenyl)-2,3_J4,5,6,7-hexahydro-lf/-cyclopenta[if|pyrimidin-4-yl)benzonitrile (example 1, 40 mg, 96 pmol) in acetonitrile (3.0 mL). After 20 min, 2-iodoacetonitrile (7 pL, 0.1 mmol) is added. The mixture is stirred at room température over night and purified by reversed phase HPLC (Waters Xbridge™-Ci8, graio dient of acetonitrile in water, 0.1% TFA). Yield: 11 mg; ESI mass spectrum [M+H]⁺ = 437;

Rétention time HPLC: 0.63 min (X012_S01).

-12217445

EXAMPLE 23

(y)-4-(3-(Cyanoniethyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5.6,7-hexahydrol//-cycIopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile s Sodium hydride (60% in minerai oil, 12 mg, 0.30 mmol) is added to a solution of (5)-4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-lff-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example ÎOA, 50 mg, 105 pmol) in tetrahydrofuran (3.0 mL). After 20 mîn, 2-iodoacetonitrile (8 pL, 0.11 mmol) is added. After 2 h, a second portion of 2-iodoacetonitrile (8 pL, 0.11 mmol) is added. After 2 h, a ίο third portion of 2-iodoacetonitrile (8 pL, 0.11 mmol) is added. The mixture is stirred over night, treated with acetonitrile and purified by reversed phase HPLC (Waters SunFire™Cia, gradient of acetonitrile in water, 0.1% TFA). Yield: 8 mg; ESI mass spectrum [M+H]⁺ = 515; Rétention time HPLC: 1.01 min (Z018_S04).

EXAMPLE 24

-12317445

4-(3-Ethyl-2,5-dÎoxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-lZfcyclopenta [d] pyrimidm-4-y l)-3-(mcthyisulfonyl)benzonitrile

Bromoethane (20 pL, 0.27 mmol) is added to a solution of 4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3_i4,5,6,7-hexahydro-177-cyclopenta[d]pyrimidin-4-yl)-3-(methyl5 sulfonyl)benzonitrile (example 10, 60 mg, 0.11 mmol based on 90% purity) and césium carbonate (74 mg, 0.23 mmol) in /V,AMimethylformamide (2.0 mL). The mixture is stirred at room température over night and purified by reversed phase HPLC (Waters SunFire™C[g, gradient of acetonitrile in water, 0.1% TFA). Yield: 23 mg; ESI mass spectrum [M+H]⁺ = 504; Rétention time HPLC: 0.86 min (005 CA01).

io EXAMPLES 24.1 -24.6

The following examples of Table 9 are prepard in analogy to 4-(3-ethyl-2,5-dioxo-l-(3(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l//-cyclopenta[d]pyrimidin-4-yl)-3(methylsulfonyl)benzonitrile (example 24), substituting bromoethane with the appropriate alkylating reagent and using the purification method indicated in the table (Method A:

Waters SunFire™-C[8, gradient of acetonitrile in water, 0.1% TFA; Method B: Waters

Xbridge™-C]8, gradient of acetonitrile in water, 0.1% NH₃; Method C: Waters Xbridge™Phenyl, gradient of methanol in water, 0.1 % TFA).

TABLE 9

-12417445

Example	R3	Purification Metbod	MS [Μ+ΗΓ	Rétention time [min]	HPLCMethod
24.1		C	534	0.97	Z018_S04
24.2		A	534	0.84	005_CA01
24.3	--V F	A	540	1.07	Z018_S04
24.4		A	548	0.86	005_CA01
24.5	æo	A	574	1.05	Z018_S04
24.6		B	588	0.87	003_CA04

EXAMPLE 25

(^^-(B-Methyl-l^-dioxo-l-tS-ttrifluoromethylJphenyiJ^S^S^Î-hexahydro-l//cyclopenta[d]pyrimidin-4-yl)-3-(methyisulfonyi)benzonitriie

A solution of (5)-4-(2,5-dioxo-l -(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1Hcyclopenta[d]pyrimidin-4-yl)-3 -(methyl sulfonyl)benzonitrile (example 10A, 50 mg,

-12517445

0.11 mmol) in ALV-dimethyl fonnamidc ( l .0 mL) is treated with lithium diisopropylamide (1.8 M in tetrahydrofuran/heptane/ethylbenzene, 63 pL, 0.12 mmol) and methyl iodide (9 pL, 0.14 mmol). After 20 min the mixture is diluted with acetonitrile and purified by reversed phase HPLC (Agilent ZORBAX™ SB-Cig, gradient of acetonitrile in water, 0.1% formic acid).Yield: 15 mg; ESI mass spectrum [M+H]⁺ = 490; Rétention time HPLC: 1.00 min (Z017_S04).

EXAMPLE 26

N O

4-(l-(3-(Difluoromethyi)phenyi)-3-methyl-2,5-dioxo-2,3,4,5,6,7-hexahydro-l/fι o cyclopenta [ d] py r iimdin-4-yl)benzonitrile

Sodium hydride (60% in minerai oil, 13 mg, 0.32 mmol) is added to a solution of 4-(l-(3-(difluoromethyl)phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-17/-cyclopenta[if|pyrimidin-4-yl)benzonitriie (example 11, 100 mg, 0.26 mmol) in tetrahydrofuran. After 20 min methyl iodide (22 pL, 0.35 mmol) is added and the mixture is stirred at room température over night. Water is added and the mixture is purified by reversed phase HPLC (Waters SunFire™-Cis, gradient of acetonitrile în water, 0.1% TFA). Yield: 55 mg; ESI mass spectrum [M+H]⁺ = 394; Rétention time HPLC: 0.74 min (005_CA01).

EXAMPLES 26A AND 26B: ENANTIOMERS OF EXAMPLE 26

The enantiomers of racemic 4-(l-(3-(difluoromethyl)phenyl)-3-methyl-2,5-dioxo20 2,3,4,5,6,7-hexahydro-lf/-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 26, 50 mg,

0.13 mmol) are separated by préparative supercritical fluid chromatography on a chiral

-12617445 phase (Daicel Chiralpak IA, 20 x 250 mm, 5 pm, 20% MeOH + 20 mM NH₃ in supercritical CCK 40 °C, 150 bar back pressure).

EXAMPLE 26A

(ff)-4-( 1-(3-( Difluoromethyl)phenyl)-3-methyl-2,5-dioxo-2,3,4,5,6,7-hexahydr o-l Hcyclopenta [d] pyrimidin-4-yl)benzonitrile

Yield 23 mg; ESI mass spectrum [M+H]⁺ = 394; Rétention time: 2.03 min (early eluting enantiomer) (I_IA_20_MeOH_NH3).

EXAMPLE 26B

(5)-4-(1 -(3-(Difluoromethyl)phenyl)-3-methy 1-2,5-dioxo-2,3,4,5,6,7-hexahydro-1Hcyclopenta [d ] pyrimidm-4-yl)benzonitrile

Yield 23 mg; ESI mass spectrum [M+H]⁺ = 394; Rétention time: 2.62 min (late eluting enantiomer) (Ι ΙΛ 20 McOH NHj).

-12717445

EXAMPLES 26.1-26.4

The following examples of Table 10 are prepared in analog to 4-(l-(3-(difluoromethyl)phenyl)-3-methyl-2,5-dioxo-2,3,4,5,6,7-hexahydro-177-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 26), using the appropriate starting material as indicated in the table and substituting tetrahydrofuran with acetonitrile as solvent.

TABLE 10

Example	Starting Material	R1	MS |Μ+Η]+	Rétention time [min]	HPLCMethod
26.1	example 15.3	ά 1 1 1	413	0.58	X0Il_S03
26.2	example 15.2	ά « « 1	426	0.61	X012_S01
26.3	example 15.1	«	442	0.64	X012S01
26.4	example 15	ά. 1 1	446	0.61	X0I2_S01

AT

-12817445

EXAMPLE 27

4-(l-(3-(Difluoromethyl)phenyl)-3-methyl-2,5-dioxo-2,3,4,5,6,7-hexahydro-lff-cyclopenta[d]pyrimidîn-4-yl)-3-(inethylsulfonyl)benzonitriIe

Methyl idodîde (15 pL, 0.24 mmol) is added to a solution of 4-(l-(3-(difluoromethyl)phenyl)-2,5-dioxo-2,3,4,5,6,7-hcxahydro-l//-cyclopcnta[d]pyrimidin-4-yi)-3-(methylsulfonyl)benzonitrile (example 15.4, 69 mg, 0.15 mmol) and césium carbonate (98 mg, 0.30 mmol) in .V,.V-dimethyl formamide ( 1.0 mL). The mixture is stirred at room température for h and purified by reversed phase HPLC (Waters SunFire™-C]g, gradient of acetonitrile in io water, 0.1% TFA). Yield: 19 mg; ESI mass spectrum [M+H]⁺ = 472; Rétention time HPLC:

0.97 min (Z018_S04).

EXAMPLES 27.1 -27.3

The following examples of Table 11 are prepared in analog to 4-(l-(3-(difluoromethyl)phenyl)-3-methyl-2,5-dioxo-2,3,4,5,6,7-hexahydro-177-cycIopenta[d]pyrimidin-4-yl)-3is (methylsulfonyl)benzonitrile (example 27), using the appropriate starting material as indicated in the table,

-12917445

TABLE 11

Example	Starting Material	R’	MS [M+H]+	Rétention time [min]	HPLCMethod
27.1	example 16	et 1 •	458	1.04	Z017_S04
27.2	example 13	à. 1 1	490, 492	1.18	V011_S01
27.3	example 14	dL ! 0 b	504	0.62	X0I2S01

EXAMPLE 28

4-(3-Methyl-2,5-dioxo-l-(2-(trifluoro methyl) pyridin-4-y 1)-2,3,4,5,6,7-hexahydro- 1Hcyclopenta[d]pyriniidm-4-yl)benzonitrile m/·''

-13017445

Césium carbonate (82 mg, 0.25 mmol) is added to a solution of 4-(2,5-Dioxo-l-(2-(trifluoromethyl)pyridin-4-y 1)-2,3,4,5,6,7-hexahydro-17/-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 15.5, 50 mg, 0.13 mmol) in AyV-dimethylformamide (1.0 mL). Methyl iodide (28 mg, 0.20 mmol) is added, and the mixture is stirred at room température for 1 h 5 and purified by reversed phase HPLC (Waters SunFire™-C]s, gradient of acetonitrile in water, 0.1% TFA). Yield: 43 mg; ESI mass spectrum [M+H]⁺ = 413; Rétention time HPLC: 0.78 min (005 CA01).

EXAMPLE 29

ι o 4-(3-Methy 1-2,5-dioxo-1 -(2-(trifluor omethy l)py ridin-4-yl)-2,3,4,5,6,7-hexahydro-1Hcyclopenta|d|pyrimidin-4-yl)-3-(niethylsulfonyl)benzonitrile

Methyl iodide (2 M in tert-butyl methyl ether, 63 pL, 0.13 mmol) is added to a solution of 4-(2,5-dioxo-l-(2-(trifluoromethyl)pyridin-4-yl)-2,3,4,5,6,7-hexahydro-l/f-cyclopenta[d]pyrimidin-4-yl)-3-(methyl sulfonyl)benzonitrîle (example 15.6, 50 mg, 0.11 mmol) and is césium carbonate (68 mg, 0.21 mmol) in V,V-dimcthylfonnamide (2.0 mL), and the mixture ist stirred at room température over night. Water is added and the mixture is purified by reversed phase HPLC (Waters SunFire™-Ci8, gradient of acetonitrile in water, 0.1% TFA). Yield: 39 mg; ESI mass spectrum [M+H]⁺ = 491 ; Rétention time HPLC: 0.97 min (Z018_S04).

-13117445

EXAMPLES 30A AND 30B: DIASTEREOMERS OF EXAMPLE 30

4-(3-Methyl-2,5-dioxo-l-(3-(trïfluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-17f-cyclopenta[d]pyrimîdin-4-yl)-3-(methylsulfmyl)benzonitrile

A solution of 4-(3-methyl-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydroli/-cyclopenta[d]pyrimidin-4-yl)-3-(rnethylthio)benzonitrile (example 27, l, 20 mg, 0.04 mmol) in dichloromethane (3.0 mL) is treated with meta-chloroperoxybenzoic acid (77%, 10 mg, 0.04 mmol), and the mixture is stirred at room température for 20 min. Ail volatiles are removed under reduced pressure, and the residue is purified by reversed phase ίο HPLC (Waters SunFire™-C]g, gradient of acetonitrile in water, 0.1 % TFA), whereupon the two diastereomers of 4-(3-methyl-2,5-dioxo-l -(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7hexahydro-1 /f-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfinyl)benzonitrile are separated.

Example 30A:

Yield: 9 mg; ESI mass spectrum [M+H]⁺ = 474; Rétention time HPLC: 0.94 min (early eluting diastereomer) (ZO18S04).

Example 30B:

Yield: 8 mg; ESI mass spectrum [M+H]⁺ = 474; Rétention time HPLC: 0.96 min (late eluting diastereomer) (Z018_S04).

-13217445

EXAMPLE 31

Ethyl 4-(4-Cyanopheny l)-2,5-dioxo-l-(3-(trifluoro methyl) phenyl)-4,5,6,7-tetrahydro17/-cyclopenta[d]pyrimidine-3(27/)-carboxylate

A solution of 4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l//cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 1,40 mg, 0.10 mmol) in dichloromethane (1.0 mL) is treated with AQV-dîisopropylethylamine (70 pL, 0.4 mmol) and 4-dimethylaminopyridine (13 mg, 0.11 mmol). Ethyl chloroformate (11 pL, 0.11 mmol) is added and the mixture is stirred at room température for 2 h. Ail volatiles are evaporated ίο and the residue is purified by reversed phase HPLC (Waters Xbridge™-C]8, gradient of acetonitrile in water, 0.1% NH₃). Yield: 46 mg; ESI mass spectrum [M+H]⁺ - 470; Rétention time HPLC: 0.90 min (Z01 l_S03).

EXAMPLES 31.1-31.3

The following compounds of Table 12 are prepared in analogy to ethyl 4-(4-cyanophenyl)15 2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-lf/-cyclopenta[d]pyrimidine3(277)-carboxylate (example 31 ), replacing ethyl chloroformate with the appropriate chloroformate. '

-13317445

TABLE 12

Example	R3	MS ]M+H]+	Rétention time [min]	HPLCMethod
31.1	À-	484	0.94	Z011_S03
31.2	,.Ao^ox	500	0.88	Z011_S03
31.3	fl Q..0	548	0.87	Z018_S04

EXAMPLES 32.1 -32.4

The following compounds of Table 13 are prepared in analog to methyl 4-(4-cyanophenyl)-

2,5-dioxo-1-(3~(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-lf/-cyclopenta[i/]pyrimidine3(2/Z)-carboxylate (example 8), replacing methyl chloroformate with the appropriate chloroformate as reagent. tAZ'

-13417445

TABLE !3

Ex ample	R3	MS [M+H]+	Rétention time [min]	HPLCMethod
32.1	,v	534	0.59	X011S03
32.2	-V	548	0.62	X011S03
32.3		578	0.60	X011S03
32.4	A'-Q	532	0.70	X012S01

-13517445

EXAMPLE 33

(S)-Methyl 4-(4-cyano-2-(methylsulfonyl)phenyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-lZf-cyclopenta[d]pyrimidine-3(2Z0^-carboxylate

The title compound is prepared in analogy to ethyl 4-(4-cyanophenyl)-2,5-dioxo-1 -(3-(trifluoromethyl)phenyl )-4,5,6,7-tetrahydro-l //-cyclopcnta[d]pyrimidinc-3(2//)-carboxylatc (example 31, 110 mg, 0.23 mmol), using (5)-4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-

2,3,4,5,6,7-hexahydro-l/f-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzomtrile (example 1 OA) as starting material and substituting ethyl chloroformate with methyl chloro- io formate. Yield: 76 mg; ESI mass spectrum [M+H]⁺ = 534; Rétention time HPLC: 1.01 min (Z0I8S04).

EXAMPLE 34

Methyl 4-(4-(4-Cyanophenyl)-2,5-dioxo-1-(3-(trifluoroinethyl)phenyl)-6,7-dihydro-l//15 cyd<)penta[d]pyrimidin-3(2//,4//,5//)-ylsulfonyl)butanoate

-13617445

A solution of 4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro- l/Y-cyclopcnta| Jjpyrimidin-4-yl)benzonitri!e (example 1, 70 mg, 0.18 mmol) in a mixture of tetrahydrofuran (1.5 mL) and TY^V-dimethylformamide (150 pL) is treated with sodium hydride (60% in minerai oil, 28 mg, 0.7 mmol) and stirred at room température for 5 min. Methyl

4-(chlorosulfonyl)butanoate ( 106 mg, 0.53 mmol) is added, and the mixture is stincd at °C over night. The mixture is diluted with water and Λ',Λ’-dimethylfonnamidc and purified by reversed phase HPLC (Wate7rs SunFire™-Ci8, gradient of acetonitrile in water, 0.1% TFA). Yield: 48 mg; ESI mass spectrum [M+H]⁺ = 562; Rétention time HPLC: 0.95 min (Z018_S04).

ίο EXAMPLE 35

4-(3-(Ethylsulfonyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydrolZ7-cyclopenta[d]pyrimidin-4-yl)benzonitrile

The title compound is prepared in analogy to methyl 4-(4-(4-cyanophenyl)-2,5-dioxo-l-(3i5 (trifluoromethyl)phenyl)-6,7-dihydro-l/f-cyclopenta[d]pyrimidin-3(2/7_t4Z/,57ï)-ylsulfonyl)butanoate (example 34), substituting 4-(chlorosulfonyl)butanoate with ethanesulfonyl chloride. Yield: 11 mg; ESI mass spectrum [M+H]⁺ = 490; Rétention time HPLC: 0.94 min (Z018_S04).

-13717445

EXAMPLE 36

4-(l-(3-(Difluoromethyl)phenyI)-3-(methylsulfonyl)-2,5-dioxo-2,3,4,5,6,7-hexahydrol//-cyclopenta|d]pyriniidin-4-yl)benzonitrile

4-(l-(3-(Difluoromethyl)phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-l/7-cyclopenta[J]pyrimidin-4-yl)benzonitrile (example 11, 100 mg, 0.26 mmol) is added to a suspension of sodium hydride (60% in minerai oil, 30 mg, 0.74 mmol) in tetrahydrofuran (3.0 mL). After 10 min methanesulfonyl chloride (42 pL, 0.55 mmol) is added and the mixture is heated at 50 °C over night. The mixture is cooled at room température, diluted with water (0.5 mL) io and purified by reversed phase HPLC (Waters SunFire™-Cis, gradient of acetonitrile in water, 0.1% TFA). Yield: 74 mg; ESI mass spectrum [M+H]⁺ = 458; Rétention time HPLC: 0.76 min(005 CA0l).

EXAMPLE 37

-13817445

3-(Methyisulfonyl)-4-(3-(methylsulfonyl)-2,5-dïoxo-l-(3-(trifluoromethyl)phenyi)2,3_î4,5,6,7-hexahydro-17/-cydopenta[d]pyrimidin-4-yl)benzonitrile

Sodium hydride (60% in minerai oil, 20 mg, 0.50 mmol) is added to a solution of (S)-4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l/7-cyclopenta[d]pyrimidin-4-yl)-3-(methyl sulfonyl)benzonitrile (example 10A, 100 mg, 0.18 mmol based on 85% purity) in tetrahydrofuran (4.0 mL), and the mixture ist stined at room température for 20 min. Methanesulfonyl chloride (29 pL, 0.38 mmol) is added and the mixture is stirred at room température for 2 h. Water is added and the mixture is extracted with dichloromethane. The phases are separated and the organic layer is concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge™-Ci8, gradient of acetonitrile in water, 0.1% TFA). Yield: 76 mg; ESI mass spectrum [M+H]⁺ = 554; Rétention time HPLC: 0.57 min (X012 SOI).

EXAMPLES 37.1 -37.4

The following examples of Table 14 are prepared in analogy to 3-(methylsulfonyl)-4-(3(methylsulfonyI)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l/7-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 37), using the appropriate starting material as indicated in the table.

TABLE 14 o f?¹ O, ,0

-13917445

Example	Starting Material	R1	MS [M+H]+	Rétention time [min]	HPLCMethod
37.1	example 15.2	ά 1 1 1	490	0.67	X012S01
37.2	example 15	à 1 1	510	0.66	X012S0I
37.3	example 10	! 0 0	554	0.57	X012_S01
37.4	example 14	! 0 b	568	0.59	X012_S01

EXAMPLES 38.1 -38.2

The following examples of Table 15 are prepared in analogy to 3-(methylsulfonyl)-4-(3(methylsulfonyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l/7-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 37), using the appropriate starting material as indicated în the table and replacing tetrahydrofuran with acetonitrile as solvent.

TABLE 15

-14017445

Example	Starting Material	R1	MS [M+H]+	Rétention time [mini	HPLCMethod
38.1	example 15.3	δ 4 4 1	477	0.61	X011_S03
38.2	example 15.1	et 1 1	506	0.65	X012_S03

EXAMPLE 39

3-(Methy Isulfony 1)-4-(3-( methylsulfonyl)-2,5-diox o-l-(2-(trifluoromethyl)pyridin-4yl)-2,3,4,5,6,7-hexahydro-ljï-cycIopenta|d]pyrimidin-4-yl)benzonitrile s 4-(2,5-dioxo- l-(2-(trifluoromethyl)pyridin-4-yl)-2,3,4,5,6,7-hexahydro-l/f-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyI)benzonitrile (example 15.6, 150 mg, 0.32 mmol) is added to a suspension of sodium hydride (60% in minerai oil, 35 mg, 0.88 mmol) in tetrahydrofuran (8.0 mL). After 10 min methanesulfonyl chloride (49 pL, 0.63 mmol) is added and the mixture is heated at 50 °C for 1.5h. The mixture is cooled at room io température and treated with water (1 mL). The mixture is stirred at room température for min and purified by reversed phase HPLC (first purification: Waters SunFire™-Cj8, gradient of acetonitrile in water, 0.1% TFA; second purification: Waters Xbridge™-C[8, gradi- rfr

-14117445 ent of acetonitrile in water, 0.1% NH₃). Yield: 20 mg; ESI mass spectrum [M+H]⁺ - 555;

Rétention time HPLC: 0.90 min (Z01 l_S03).

EXAMPLE 40

4-(4-Cyanoplienyl)-2.5-dioxo-l-(3-(trifluoromethyl)pherivl)-4,5,6,7-tetrahydro-l/L cyclopenta|d]pyriniidine-3(2/7)-carboxamide

A solution of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-

4,5,6,7-tetrahydro-l//-cyclopenta[d]pyrimîdine-3(27/)-carboxylate (intermediate 4, 25 mg, pmol) in acetonitrile (1.0 mL) is treated with ammonium carbonate (9 mg, 90 pmol), ίο and the mixture is stirred at room température for 30 min and purified by reversed phase

HPLC (Waters SunFire™-C_ls, gradient of acetonitrile în water, 0.1% TFA). Yield: 3 mg;

ESI mass spectrum [M+H]⁺ = 441 ; Rétention time HPLC: 0.65 min (X018_S01 ).

EXAMPLE 41

-14217445

4-(4-Cyanophenyl)-7V-(2-hydroxy-2-methylpropyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-l//-cyclopenta|d|pyrimidine-3(2//)-carboxamide

A solution of 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-

4,5,6,7-tetrahydro-lff-cyclopenta[d]pyrimidine-3(2/7)-carboxylate (intermediate 4, 250 mg, 0.44 mmol) in acetonitrile (5.0 mL) is treated with l-amino-2-methylpropan-2-ol (80 mg, 0.90 mmol), and the mixture is stirred at room température for l h and purified by reversed phase HPLC (Waters Xbridge™-C]8, gradient of acetonitrile in water, 0.1% NH₃). Yield: 179 mg; ESI mass spectrum [M+H]⁺ = 513; Rétention time HPLC: 0.86 min (Z01 l_S03).

EXAMPLES 41A AND 41B: ENANTIOMERS OF EXAMPLE 41

The enantiomers of racemic 4-(4-cyanophenyl)-_J/V-(2-hydroxy-2-methylpropyl)-2,5-dioxo1 -(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1 //-cyclopcnta|d|pyrimidine-3(2H)carboxamide (example 41, 179 mg, 0.35 mmol) are separated by préparative supercritical fluid chromatography on a chiral phase (Daicel Chiralpak IA, 20 x 250 mm, 5 pm, 20% MeOH + 0.2% diethylamine în supercritical CO2, 40 °C, 150 bar back pressure).

EXAMPLE 41A

(7ï)-4-(4-Cyanophenyi)-7V-(2-hydroxy-2-methylpropyl)-2,5-dioxo-l-(3-(trifluoroniethy l)pheny 1)-4,5,6.7-tetr ahydro-1 77-cy clopen ta [d] py r imidine-3 (2//)-carboxamide Yield: 50 mg; ESI mass spectrum [M+H]⁺ = 513; Rétention time: 2.3 min (early eluting enantiomer) (I_IA_20_MeOH_DEA). j_/--14317445

EXAMPLE 41B

(5)-4-(4-Cyanophenyl)-A^f-(2-hydroxy-2-methylpropyl)-2,5-dioxo-l-(3-(trifluoromethyl) phenyl)-4,5,6,7-tetr ahydr ο-1 H-cyclopenta [d ] pv r imidine-3(2//)-carboxaniide

Yield: 47 mg; ESI mass spectrum [M+H]⁺ = 513; Rétention time: 4.1 min (Iate eluting enantiomer) (I_IA_20_MeOH_DEA).

EXAMPLES 41.1 -41.31

The following examples ofTable 16 are prepared in analog to 4-(4-cyanophenyl)-/V-(2hydroxy-2-methylpropyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-l/7io cyclopenta[d]pyrimidine-3(27/)-carboxamide (example 41), using the appropriate amine as reagent.

TABLE 16

-14417445

Example	R3	MS [Μ+Η]+	Rétention time [min]	HPLCMethod
41.1	.ΑΝ^γ0Η	499	0.52	002_CA07
41.2	W	499	0.52	002J3A07
41.3	,ΑνΛ^οη Η	499	0.53	002_CA07
41.4	ΑγθΗ Η	499	0.53	002_CA07
41.5	Λ^οη Η	511	0.53	002_CA07
41.6	ΐ. ο Η	511	0.56	002_CA07
41.7	Η	511	0.89	ZI 1S03
41.8	Ύ	511	0.86	ZUS_03
41.9	Η	513	0.60	002_CA07

-14517445

41.ΙΟ	•''^ν^Α0Η Η	513	0.54	002_CA07
41.11		522	0.55	002_CA07
41.12		523	0.59	002 CA07
41.13	Vq	525	0.90	ZI 1S03
41.14	Λ.0 Η	525	0.59	002_CA07
41.15	Η	525	0.59	002_CA07
41.16	χο Η	525	0.57	002_CA07
41,17	,Λν^^οη Η	527	0.88	Z011S03
41.18	Ν Η 1	527	0.62	002_CA07
41.19	Âr-æ Η	529	0.65	002_CA03

-14617445

41.20	0 Γΐ’	535	0.52	002 CA07
41.21	rQ	535	0.51	002_CA07
41.22		535	0.54	002_CA07
41.23	Vq	539	0.58	002_CA07
41.24	H0< H	539	0.89	005_CA01
41.25	.-'^•N'>rzxO h <u	541	0.56	002_CA07
41.26	..v? H o-	541	0.89	Z011_S03
41.27	î. £>° H	559	0.89	Z018_S04
41.28	H	561	0.54	002_CA07
41.29	Â-O H	573	0.85	Z011_S03

-14717445

41.30	H	573	0.57	001CA07
41.31	î V H 1	575	0.56	002 CA07

EXAMPLE 42

4-(4-Cy anopheny l)-2,5-dioxo-V-( 1,1-dioxo-1 k⁶-thietan-3-y I)- l-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-l //-eyclopenta|d|pyrimidine-3(2/7)-carboxamide

AQV-Diisopropylethylamine (170 pL, 1.00 mmol), 4-dimethylaminopyridine (34 mg,

0.28 mmol) and 4-nitrophenyl chloroformate (56 mg, 0.28 mmol) is added to a solution of 4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l/f-cyclopenta[i/]pyrimidin-4-yl)benzonitrile (example 1, 100 mg, 0.25 mmol) in acetonitrile (2.0 mL), and the mixture is stirred at room température over night. l,l-Dioxo-lX⁶-thiethan-3-amîne io hydrochloride (59 mg, 0.38 mmol) is added, and the mixture is stirred for 1 h and purified by reversed phase HPLC (Waters SunFire™-Cig, gradient of acetonitrile in water, 0.1% TFA). Yield: 73 mg; ESI mass spectrum [M+H]⁺ = 545; Rétention time HPLC: 0.81 min (005_CA01).

-14817445

EXAMPLES 42.1 -42.8

The following examples of Table 17 are prepared in analogy to 4-(4-cyanophenyl)-2,5dioxo-7V-(I ,l-dioxo-lk⁶-thietan-3-yl)-1 -(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-li/cyclopenta[d]pyrimidine-3(2E/)-carboxamide (example 42), using the appropriate amine as reagent.

TABLE 17

Example	R3	MS [M+H]+	Rétention time [min]	HPLCMethod
42.1	H OH	525	0.85	005 CA01
42.2	HO H	525	0.86	005 _CA01
42.3	Λ-Q H OH	525	0.86	005_CA01
42.4	W H OH	525	0.85	005_CA01

-14917445

42.5	HO î ü> H	527	0.53	Z006_U01
42.6	HO, t c° H	527	0.98	Z018_S04
42.7	Â-0 H	541	1.14	Z018_S04
42.8	Â-o H	573	1.02	Z018S04

EXAMPLE 43

4-(4-Cyanophenyl)-2,5-dioxO“jV-(l-oxo-hexahydro-lX⁴-thiopyran-4-yl)-l-(3-(trifluoromethyl)pheny 1)-4,5,6,7-tetrahyd ro-1 W-cyclopen ta [d | py rimidine-3 (2//)-car boxamide

A solution of 4-(4-cyanophenyl)-2,5-dioxo-7V-(tetrahydro-2H-thiopyran-4-yl)-l-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-l/7-cyclopenta[d]pyrimidine-3(2/7)-carboxamide (example 42.7, 94 mg, 0.18 mmol) in éthanol (1.0 mL) is cooled at -78 °C with an acetone/dry ice bath. Aqueous hydrogen peroxide (36%, 87 pL, 1.0 mmol) is added, and the mixture is stirred at at -78 °C for 30 min. Methyltrioxorhenium(VII) (1 mg, 4 pmol) is io added, and the mixture is stirred at -78 °C for 30 min. Another portion of methyltrioxo- λ/

-15017445 rhenîum(VII) (l mg, 4 pmol) is added, and the mixture is stirred at -78 °C for 1 h. Aqueous potassium hydrogen sulfate solution (10%, 0.5 mL) and water is (10 mL) is added, and the mixture is filtered. The precipitate is dissolved in N,7V-dimethyIformamide, and the mixture is purified by reversed phase HPLC (Waters SunFire™-Cj8, gradient of acetonitrile in water, 0.1% TFA). Yield: 40 mg; ESI mass spectrum [M+H]⁺ = 557; Rétention time HPLC: 0.96 min (Z018_S04).

EXAMPLE 44

4-(4-Cyanophenyl)-2,5-dioxo-7V-(l-imino-l-oxo-hexahydro-lk⁶-thiopyran-4-yl)-l-(3io (trifïiioromethyl)phenyl)-4,5,6,7-tetrahydro-l//-cycIopenta[d]pyrimidine-3(2J/)carboxamide

4-(4-Cyanophenyl)-2,5-dioxo-;V-(l -oxo-hexahydro-1 X⁴-thiopyran-4-yl)-l -(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-l/7-cyclopenta[d]pyrimidine-3(2Ff)-carboxamide (example 43, 40 mg, 72 pmol) is added to a solution of O-mesitylenesulfonylhydroxyl15 amine (66 mg, 0.31 mmol) in dichloromethane (1.0 mL), and the mixture is stirred at room température over night. Ail volatiles are removed under reduced pressure, and the residue is purified by reversed phase HPLC (Waters SunFire™-Ci8, gradient of acetonitrile in water, 0.1% TFA). Yield: 9 mg; ESI mass spectrum [M+H]⁺ = 572; Rétention time HPLC: 0.90 min (Z018_S04).

-15117445

EXAMPLES 45.1 -45.6

The following examples of Table 18 are prepared in analogy to 4-(4-cyanophcnyl)-.V-(2hydroxy-2-mcthylpropyl)-2,5-dioxo-l-(3-(trifluoromelhyl)phenyl)-4,5,6,7-tetrahydro-l//cyclopenta[d]pyrimidme-3(277)-carboxamide (example 41), using (7?)-4-nitrophcnyl 4-(4cyanophenyl)-2,5-dioxo-1 -(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-177-cyclopenta[d]pyrimidine-3(2H)-carboxylate (intermediate 30.1) as starting material and the appropriate amine as reagent.

TABLE 18

Ex ample	R3	MS [M+H]+	Rétention time [min]	HPLCMethod
45.1		480	0.82	005_CA01
45.2	U H	481	0.90	005_CA01
45.3	î, . p H F	505	0.88	005_CA01

-15217445

45.4	Λ-Q H OH	525	1.06	Z018_S04
45.5	HO H	527	0.99	Z0I8_S04
45.6	’ N H	545	1.01	Z018JS04

EXAMPLE 46

(7?)-4-(4-Cy anopheny l)-2,5-dioxo-V-( 1,1 clioxo- hexahy dro-1 /Athiopy ran-4-y 1)-1 -(3(tr ifluor omethv l)phenyl)-4,5,6,7-tetrahy dr ο-1 ff-cyclopenta|d] pyri midine-3 (2/7)5 carboxamide jV,jV-Diisopropyl ethyl amine (137 pL, 0.81 mmol), 4-dimethylaminopyridine (27 mg,

0.22 mmol) and 4-nitrophenyl chloroformate (45 mg, 0.22 mmol) is added to a solution of (7ï)-4-(2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-l//-cyclopenta[i/]pyrimidin-4-yl)benzonitrile (example 1 A, 80 mg, 0.20 mmol) in acetonitrile (2.0 mL), and ίο the mixture is stirred at room température over night. l,l-Dioxotetrahydro-2/7-thiopyran-4amine (74 mg, 0.40 mmol) is added, and the mixture is stirred for I h and purified by reversed phase HPLC (Waters SunFire™-Cig, gradient of acetonitrile in water, 0.1% TFA).

Yield: 72 mg; ESI mass spectrum [M+H]⁺ = 573; Rétention time HPLC: 1.01 min (Z018_S04).

-15317445

EXAMPLES 47.1 -47.21

The following examples of Table 19 are prepared in analog to 4-(4-cyanophenyl)-7V-(2hydroxy-2-methylpropyl)-2,5-dioxo-1 -(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-l Hcyclopenta[d]pyrimidine-3(277)-carboxaimde (example 41.0), using (S)-4-nitrophenyl 4-(4-cyano-2-(methylsulfonyl)phenyl)-2,5-dioxo- l-(3-(trifluoromethyl)phenyl)-4,5,6,7tetrahydro-177-cyclopenta[d]pyrimidine-3(2f/)-carboxylate (intermediate 20.2) as starting material and the appropriate amine as reagent.

TABLE 19

Example	R3	MS [M+H]+	Rétention time [min]	HPLCMethod
47.1	A' H	533	0.72	002_CA03
47.2	A- H	547	0.76	002_CA03
47.3	H N	558	1.00	Z018_S04

-15417445

47.4	t Λ H	559	1.06	Z018_S04
47.5	U H	561	0.67	X012S01
47.6		572	1.05	Z018_S04
47.7	Vv	573	1.10	Z018_S04
47.8	t X/0 H	575	0.99	Z018_S04
47.9	H	577	1.03	Z018_S04
47.10	Λγ H F	583	1.05	Z018_S04
47.11		589	1.00	Z018_S04
47.12	,îNx> H	589	1.02	Z018_S04

-15517445

47.13	-W	591	1.00	Z018_S04
47.14	ΛΝΧχΟΗ H	591	1.02	Z018_S04
47.15	AO H	603	1.03	Z018_S04
47.16		603	0.98	Z018S04
47.17	W	603	1.02	Z018_S04
47.18	Â-Q H OH	603	1.03	Z0I8S04
47.19	Â-Q H OH	603	1.02	Z018_S04
47.20	H	605	1.01	Z018_S04
47.21	Â-0 H OH	617	1.05	Z018_S04

-15617445

EXAMPLES 48.1-48.4

The following examples of Table 20 are prepared in analog to 4-(4-cyanophenyl)-2,5dioxo-.V-( 1,1 -dioxo-1 /?-thietan-3-yl)-1 -(3-(trifluoromethyl)phenyl)-4,5,6,7-tctrahydro-1Hcyclopenta|d |pyrimidine-3(2/-/)-carboxamide (example 42), using (S)-4-nitrophenyl 4-(4cyano-2-(methylsulfonyl)phenyl)-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro- l/7-cyclopcnta[d]pyrimidine-3(277)-carboxylate (intermediate 30.2) as startîng material and the appropriate amine as reagent.

TABLE 20

Example	R3	MS (Μ+ΗΓ	Rétention time [min]	HPLCMethod
48.1	H N	584	1.09	Z018_S04
48.2	H	585	1.15	Z018_S04
48.3	txrOH • n H	589	0.97	Z018_S04

-15717445

48.4	ΧΎ’ΟΗ	603	0.99	Z0l8_S04
	H

EXAMPLE 49

4-(4-Cyano-2-fluorophenyl)-jV-methyl-2,5-dïoxo-l-(3-(trifluoromethyl)phenyI)-4,5,6,7tetrahydro-l//-cyclopentald]pyriinidine-3(2Z/)-carboxamide

4-Nitrophenyl chloroformate (23 mg, 0.11 mmol) is added to a solution of 4-(2,5-dioxo-l (3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-lZ7-cyclopenta[d]pyrimidin-4-yl)-3fluorobenzonitrile (example 18, 43 mg, 0.10 mmol), .V./V-diisopropylethylamine (70 pL, 0.41 mmol) and 4-dimethylaminopyridîne (14 mg, O.l l mmol) in acetonitrile (3.0 mL), and the mixture is stirred at room température over night. Another portion of 4-Nitrophenyl ίο chloroformate (50 mg, 0.24 mmol) and 4-dimethylaminopyridine (30 mg, 0.24 mmol) is added, and the mixture is stirred over night. Methylamine (2.0 M in tetrahydrofuran,

155 pL, 0.31 mmol) is added, and the mixture is stirred for 20 min at room température and purified by reversed phase HPLC (Waters SunFire™-Cig, gradient of acetonitrile in water, 0.1% TFA). Yield: 27 mg; ESI mass spectrum [M+HJ⁺ = 473; Rétention time HPLC: 0.59 is min (001CA07).

EXAMPLES 49A AND 49B: ENANTIOMERS OF EXAMPLE 49

-15817445

The enantiomers of racemic 4-(4-cyano-2-fluorophenyl)-A^r-methyl-2,5-dioxo-1 -(3(irifluoromethyl)phenyl)-4,5₁6,7-tetrahydro-l//-cyclopenta[d]pyrimidine-3(2//)carboxamide (example 49, 24 mg, 0.05 mmol) are separated by préparative supercritical fluid chromatography on a chiral phase (Daicel Chiralpak IA,2 x 20 x 250 mm, 5 pm, 15% s MeOH + 0.2% diethylamine in supercritical CO₂, 40 °C, 120 bar back pressure).

EXAMPLE 49A

(A)-4-(4-Cyano-2-fluorophenyl)-A^r-methyl-2,5-dîoxo-l-(3-(trifluoroniethyl)phenyl)4,5,6,7-tetrahydro-1 H-ey clopen ta [d] py rimidine-3 (2iZ)-carboxamide io Yield: 10 mg; ESI mass spectrum [M+H]⁺ = 473; Rétention time: 2.85 min (early eluting enantiomer) (I_IA_15_MeOH_DEA).

EXAMPLE 49B

-15917445 (JÎ)-4-(4-Cyano-2-fluorophenyl)-7V-methyl-2,5-dioxo-l-(3-(trifluoromethyl)phenyl)4,5,6,7-tetrahydro-lH-cyclopenta[d]pyrimidine-3(2/Z)-carboxamide

Yield: 10 mg; ESI mass spectrum [M+H]⁺ ~ 473; Rétention time: 3.72 min (late eluting enantiomer) (I_IA_15_MeOH_DEA).

EXAMPLES 49.1 -49.3

The following examples of Table 21 are prepared in analogy 4-(4-cyano-2-fluorophenyl)A'-mcthyl-2_:5-dioxo-l-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-l/7-cyclopcnta[d|pyrimidine-3(2//)-carboxamidc (example 49), substitutîng methylamine with the appropriate amine as reagent.

TABLE 21

Example	R3	MS [M+H]+	Rétention time [min]	HPLCMethod
49.1	A- H	487	0.80	002_CA03
49.2	H	517	1.06	Z018_S04
49.3	A~£ H	565	0.71	002 C.A03

-16017445

EXAMPLES 50.1 -50.7

The following examples of Table 22 are prepared in analogy to 4-(4-cyano-2-fluorophenyl)-A-mcthyl-2,5-dioxo-1 -(3-(trifluoromethyl)phenyI)-4,5,6,7-tetrahydro-17/-cyclopenta[d]pyrimidine-3(2Z/)-carboxamîde (example 49), using the appropriate starting material as indicated in the table.

TABLE 22

Example	Starting Material	R1	MS [M+H]+	Rétention time [min]	HPLCMethod
50.1	example 15.3	δ 1 1	456	0.61	X011_S03
50.2	example 15.2	à 1 1 t	469	0.87	005_CA01
50.3	example 15.1	\ o δ-{5~	485	0.71	X012S01
50.4	example 15	à 1 1	489	0.76	X012_S01

-16117445

50.5	example 17	êç o	517	0.97	Z017_S04
50.6	example 13	• •	533,535	0.64	X0I2S01
50.7	example 14	! 0 O	547	0.69	X012_S01

EXAMPLES 5l.l -5l.4

The following Examples of Table 23 are prepared in analogy to 4-(4-cyano-2-fluorophenyl)-A^r-methyl-2,5-dioxo-l-(3-(trifluoromethyl)phenyI)-4,5,6,7-tetrahydro-lf/-cyclopenta[d]pyrimidine-3(2//)-carboxamide (example 49), using the appropriate starting material as indicated in the table and the appropriate amine as reagent.

TABLE 23

Example	Starting Material	R1	MS [μ+ηΓ	Rétention time	HPLCMethod
51.1	example 15.1	• •	485	0.71	X012_S01

-16217445

51.2	example 15	à 1 «	503	0.68	X012_S01
51.3	example 14	! 0 0	561	0.65	X012S01
51.4	example 17	g 1 0	531	1.04	Z018_S04

EXAMPLE 52

4-(4-CyanophenyI)-l-(3-(difluoromethyl)phenyl)-j'V-(3-hydroxypropyI)-2,5-dioxo4,5,6,7-tetrahydro-l/7-cyclopenta|d]pyrimidine-3(2/7)-carboxamide

The title compound is prepared in analogy to 4-(4-cyano-2-fluorophenyl)-7V-methyl-2,5dioxo-l-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-l//-cyclopenta[d]pyrimidine-3(2f/)· carboxamide (example 49), using 4-(I-(3-(difluoromethyl)phenyl)-2,5-dioxo-2,3,4,5,6,7hexahydro-l/f-cyclopenta[if]pyrimidin-4-yl)benzonitrile (example 11, 100 mg, 0.26 mmol) as starting material and replacing methylamine with 3-aminopropanol. Yield: 70 mg; ESI ίο mass spectrum [M+H]⁺ = 481; Rétention time HPLC: 0.71 min (005_CA01).

-16317445

EXAMPLES 52A AND 52B: ENANTIOMERS OF EXAMPLE 52

The enantiomers of racemic 4-(4-cyanophenyl)-l-(3-(difluoromethyl)phenyl)-;V-(3hydroxypropyl)-2,5-dioxo-4.5,6,7-tetrahydro-l//-cyclopcnta[d|pyrimidine-3(2H)carboxamide (example 52, 67 mg, 0.14 mmol) are separated by préparative supercritical fluid chromatography on a chiral phase (Daicel Chiralpak IB, 20 x 250 mm, 5 pm. 50%

MeOH + 0.2% diethylamine in supercritical CO₂, 40 °C, 120 bar back pressure).

EXAMPLE 52A

(J!)-4-(4-Cyanophenyl)-l-(3-(difluoromethyl)phenyl)-7V-(3-hydroxypropyl)-2,5-dioxoîo 4,5,6,7-tetrahydiO-l//-cyclopenta[d|pyrimidinc-3(2//)-carboxamide

Yield: 29 mg; ESI mass spectrum [M+H]⁺ = 481; Rétention time: 1.28 min (early eluting enantiomer) (I_IB_40_MeOH_DEA).

-16417445

EXAMPLE 52B

(.S^T)-4-(4-Cyanophenyl)-l-(3-(difluoroniethyl)phenyl)-,V-(3-hydroxypropyl)-2,5-dioxo4,5,6,7-tetr ahydro-1 //-cyclopen ta | d ] py rimidine-3(2/7)-carboxamide

Yield: 28 mg; ESI mass spectrum [M+H]⁺ = 481; Rétention time: 4.31 min (late eluting enantiomer) (I_IB_40_MeOH_DEA).

EXAMPLES 52.1 -52.5

The following examples of Table 24 are prepared in analogy to 4-(4-cyanophenyl)-l-(3(difluoromethyl)phenyl)-X-(3-hydroxypropyl)-2,5-dioxo-4,5,6,7-tetrahydro-lff-cycloio penta[d]pyrimidine-3(2f/)-carboxamide (example 52), replacing 3-aminopropanol with the appropriate amine as reagent.

TABLE 24

-16517445

Example	R3	MS [M+H]+	Rétention time (min)	HPLCMetliod
52.1	Âr H	437	0.97	Z017_S04
52.2	A- H	451	0.73	002_CA03
52.3	,An^OH H	467	0.63	002_CA03
52.4	H	481	0.71	002_CA03
52.5	Λ'χ™	495	0.79	005_CA01

EXAMPLES 53.1-53.5

The following examples of Table 25 are prepared in analogy to 4-(4-cyano-2-fluorophenyi)-;V-mcth yl-2,5-dioxo-l-(3-(trifluoromethyl)phen yl )-4,5,6,7-tctrahydro-lH-cyclopenta[d]pyrimidine-3(2i/)-carboxamide (example 49), using 4-(l-(3-(difluoromethyl)phenyl)-2,5-dioxo-2,3,4,5,6,7-hexahydro-lf/-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 15.4) as starting material and employing the appropriate amine as reagent, jlz-16617445

TABLE 25

Example	R3	MS [μ+ηΓ	Rétention time [min]	HPLCMcthod
53.1	-V H	515	0.97	Z018_S04
53.2	H	529	0.69	002_CA03
53.3	U H	541	1.01	Z018_S04
53.4	TA H	543	0.73	002_CA03
53.5	Va	573	0.95	Z018_S04

EXAMPLES 54.1 —54.4

The following examples of Table 26 are prepared in analogy to 4-(4-cyanophenyl)s A-(2-hydroxy-2-methylpropyl)-2,5-dioxo-l -(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro17/-cyclopenta[d]pyrimidine-3(2f/)-cai'bo^xa^mide (example 41), using 4-nitrophenyl

-16717445

4-(4-cyanophenyl)-2,5-dioxo-l-(2-(trifluoromethyl)pyridin-4-yl )-4,5,6,7-tetrahydro-lifcyclopenta[d]pyrimidine-3(2/f)-carboxylate (intermediate 30.3) as starting material and employing the appropriate amine as reagent.

TABLE 26

Example	R3	MS [M+H]+	Rétention time [min]	HPLCMethod
54.1	f,' H	456	1.00	Z018_S04
54.2	-V H	470	1.04	Z018_S04
54.3	H	482	1.05	Z018_S04
54.4	TA H	484	1.09	Z018_S04

-16817445

EXAMPLE 55

4-(4-Cyanophenyl)-7V-(2-hydroxy-2-methylpropyl)-2,5-dÎoxo-l-(2-(trifluoroniethyl)pyridin-4-yl)-4,5,6,7-tetrahydro-lZZ-cycLopenta[d]pyrimidine-3(2ZZ)-carboxamide

The title compound is prepared in analogy to 4-(4-cyano-2-fluorophenyl)-7V-methyl-2,5dioxo-l-(3-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-liZ-cyclopenta[d]pyrimidine-3(2/7)carboxamide (example 49), using 4-nitrophenyl 4-(4-cyanophenyl)-2,5-dioxo-l-(2-(trifluoromethyl)pyridin-4-yl)-4,5,6,7-tetrahydro-lL/'-cyclopenta[d]pyrimidine-3(2/7)carboxylate (intermediate 30.3, 100 mg, 0.25 mmol) as starting material and employing ίο 1 -amino-2-methylpropan-2-ol as reagent. Yield: 60 mg; ESI mass spectrum [M+H]⁺ = 514;

Rétention time HPLC: 0.97 min (Z018_S04).

EXAMPLES 56.1 -56.2

The following examples of Table 27 are prepared in analogy to 4-(4-cyano-2-fluorophenyl)-7V-methyl-2,5 -dioxo-1 -(3 -(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-1 //-cyclo15 penta[d]pyrimidine-3(2LO-carboxamide (example 49), using 4-(2,5-dioxo-l-(2-(trifluoromethyI)pyridin-4-yl)-2_}3,4,5,6,7-hexahydro-l/7-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 15.6) as starting material and employing the appropriate amine as reagent. w~-16917445

TABLE 27

Example	R3	MS ΙΜ+ΗΓ	Rétention time [min]	HPLCMethod
56.1	-V H	534	0.96	Z018_S04
56.2	-AH	548	1.00	Z018_S04

EXAMPLE 57

4-(3-( IVlethylsulfonyl)-2,5-dioxo-1 - (2 - (tr iiliioroniethy l)py r idin-4-yl)-2,3,4,5,6,7-hexahydro-l//-cyclopenta|d]pyriniidin-4-yl)benzonitrile

The title compound îs prepared in analogy to 3-(methylsulfonyl)-4-(3-(methylsulfonyl)-2,5dioxo-l'(2-(trifluoromethyl)pyridin-4-yl)-2₎3,4,5,6,7-hexahydro-l//-cyclopenta[d]pyrimidin-4-yl)benzonitrile (example 39), using 4-(2,5-dioxo-I-(2-(trifluoromethyl)pyridin

-17017445

4-yl)-2,3,4,5,6,7-hexahydro-lf/-cyclopenta[d]pyrimidin-4-yl)benzonitriIe (example 15.5, 60 mg, 0.15 mmol) as starting material. Yield: 30 mg; ESI mass spectrum [M+H]⁺ = 477; Rétention time HPLC: 0.99 min (Z018 S04).

EXAMPLES

Other features and advantages of the présent invention will become apparent from the following more detailed examples which illustrate, by way of example, the principles of the invention.

HUMAN NEUTROPHIL ELASTASE ASSAY

Materials: Human neutrophil elastase was purchased from Calbiochem (Cat. No.: 324681) and the elastase substrate MeOSuc-Ala-Ala-Pro-Val-AMC from Bachem (Cat. No.: 1-1270). Ail other materials were of the highest grade commercially available.

The following buffers were used: Compound buffer: lOOmM Tris, 500mM NaCl, adjusted to pH 7.5; Assay buffer; lOOmM Tris, 500mM NaCl, adjusted to pH 7.5, containing 0.01%BSA.

Assay conditions: Test compounds were prediluted in DMSO and subsequently in compound buffer (5% DMSO final). 5 pL of these compound dilutions were mixed with 10 pl Neutrophil elastase (9 ng/ml in assay buffer) in a black 384 well OptiPlate (Perkîn Elmer, Cat No.: 6007270) and incubated for 15 min at room température. Subsequently 10 pL substrate solution în assay buffer were added (250 pM final concentration) and the plates were incubated for 60 min at room température. After inactivation of the enzyme, fluorescence intensifies were measured at 380 nm excitation and 460 nm émission wavelengths.

Each plate contains wells with a high value control (DMSO+enzyme+substrate) and wells with a low value control (DMSO+inactivated enzyme+substrate). IC50 values were estimated using a sîgmoidal concentration response curve with variable slope. Means of low values were taken as 0%, means of high values as 100%. The IC50 values of selected compound in the Neutrophil Elastase assay are listed in Table 28.

-17117445

TABLE 28

Example	IC50 |nM]
1	33.3
IA	11.5
IB	8040
2	6.4
2A	2.4
3	17.0
4	10.9
5	11.2
6	3.0
6.1	15.7
6.2	5.8
6.3	3.7
6.4	10.9
6.5	1.1
6.6	2.2
6.7	13.8
6.8	15.8
6.9	3.5
6,10	3.8
6.11	3.9
6.12	3.8
6.13	3.6
6.14	6.0
6.15	3.3
6.16	11.6
6.17	6.3

Example	ICgo [nM]
6.18	18.7
6.19	2.7
6.20	9.1
6.21	3.4
6.22	11.8
6.23	15.7
6.24	9.5
6.25	6.0
6.26	10.0
6.27	18.6
6.28	23.1
6.29	22.6
6.30	3.4
6.31	21.2
6.32	9.7
6.33	6.5
6.34	17.3
6.35	17.0
6.36	13.3
6.37	3.9
6.38	1.7
6.39	20.7
6.40	6.8
6.41	8.3
6.42	8.7
6.43	2.9

-17217445

6.44	9.7
6.45	14.3
6.46	2.9
7	123.7
7.1	< 1
7.1A	< 1
7.1B	621.5
7.2	< 1
7.2A	< 1
7.2B	550.0
7.3	< 1
7.4	< 1
7.5	1.4
7.6	< 1
7.7	1.2
7.8	< 1
7.9	< 1
7.10	< 1
7.11	< 1
8	4.0
9	5.1
9A	3.0
9B	3180
10	5.8
10A	2.6
10B	98.4
11	37.4
12	201.0

13	17.9
14	4.7
14A	1.2
14B	33
15	30.1
15.1	42.1
15.2	28.6
15.3	106.3
15.3A	31.5
I5.3B	1720
15.4	9.7
15.4A	2.9
15.4B	57.7
15.5	109.5
15.6	43.6
15.7	66.0
16	14.9
17A	8.1
17B	9.4
18	44.2
19	1.3
20	9.1
21	< 1
22	25.6
22.1	1.1
22.2	< 1
22.3	< 1
22.4	< 1

-17317445

22.5	1.0
22.6	1.2
22.7	< 1
22.8	< 1
22.9	2.0
23	3.4
24	1.6
24.1	< 1
24.2	1.1
24.3	2.7
24.4	1.0
24.5	1.7
24.6	< 1
25	< 1
26	9.4
26A	2.4
26B	3410
26.1	26.8
26.2	6.4
26.3	9.5
26.4	26.2
27	1.9
27.1	4.6
27.2	7.1
27.3	1.2
28	36.7
29	4.2
30A	1.3

30B	2.0
31	4.2
31.1	2.6
31.2	6.7
31.3	2.6
32.1	< 1
32.2	< 1
32.3	< 1
32.4	14.7
33	< 1
34	3.2
35	2.7
36	7.2
37	< 1
37.1	3.7
37.2	9.3
37.3	1.9
37.4	1.7
38.1	37.7
38.2	34.1
39	7.0
40	2.2
41	1.4
41A	< 1
41B	40.4
41.1	< 1
41.2	1.0
41.3	< 1

-17417445

41.4	< 1
41.5	< 1
41.6	< 1
41.7	< 1
41.8	1.4
41.9	< 1
41.10	< 1
41,11	1.1
41.12	89.5
41.13	< 1
41.14	< 1
41.15	< 1
41.16	< 1
41.17	< 1
41.18	1.1
41.19	< 1
41.20	1.7
41.21	1.5
41.22	< 1
41.23	< 1
41.24	< 1
41.25	1.5
41.26	< 1
41.27	< 1
41.28	< 1
41.29	< 1
41.30	< 1
41.31	< 1

42	< 1
42.1	< 1
42.2	2.9
42.3	< 1
42.4	< 1
42.5	< 1
42.6	< 1
42.7	< 1
42.8	< 1
43	< 1
44	< 1
45.1	< 1
45.2	< 1
45.3	< 1
45.4	< 1
45.5	< 1
45.6	< 1
46	< 1
47.1	< 1
47.2	< 1
47.3	< 1
47.4	< 1
47.5	< 1
47.6	< 1
47.7	< 1
47.8	< 1
47.9	< 1
47.10	< 1

-I7517445

47. II	< 1
47.12	< 1
47.13	< 1
47.14	< 1
47.15	< 1
43.16	< 1
47.17	< 1
47.18	< 1
47.19	< 1
47.20	< 1
47.21	< 1
48.1	< 1
48.2	< 1
48.3	< 1
48.4	< 1
49	1.8
49A	< 1
49B	173.3
49.1	1.2
49.2	1.3
49.3	1.0
50.1	4.0
50.2	< 1
50.3	1.7
50.4	1.2
50.5	< 1
50.6	1.2

50.7	< 1
51.1	1.0
51.2	< 1
51.3	< 1
51.4	< 1
52	< 1
52A	< 1
52B	618.6
52.1	1.1
52.2	< 1
52.3	< 1
52.4	< 1
52.5	< 1
53.1	< 1
53.2	< 1
53.3	< 1
53.4	< 1
53.5	< 1
54.1	4.9
54.2	3.3
54.3	1.5
54.4	2.4
55	6.1
56.1	< 1
56.2	< 1
57	34.9

Ttz

-17617445

ASSAY FOR THE DETERMINATION OF NEUTROPHIL ELASTASE INHIBITORY ACTIVITY IN HUMAN PLASMA

Citrated blood from human healthy donors is mixed with zymosan suspension and incubated at room température. This leads to the stimulation of neutrophils and the release of neutrophil elastase into the plasma. The stimulated blood is centrifuged to generate the neutrophîl elastase enriched plasma.

Préparation of zymosan working solution:

Zymosan (l 00 mg) is mixed with saline (0.9%, 10 mL) and stored at 4 °C for up to one week (note: zymosan does not dissolve in the saline and is used as a suspension).

Whole blood stimulation:

• A single 45 ml blood sample is taken into a 50 ml tube containing citrate (3.13%, mL) and the tube is gently inverted 4 times.

• Immediately after blood sampling, zymosan working solution (5 mL) is added.

• After the addition of zymosan working solution, the tubes are capped, mixed gently and incubated at 22 °C for 15 min on a shaker at 20 rpm.

• Make 10 ml aliquots after the incubation time.

• Centrifuge the 15 ml tubes at 800g for 15 min at 4°C in a Jouan centrifuge.

• Harvest the plasma and make 1-5 ml aliquots.

• Store the plasma at -80 °C.

Various concentrations of the neutrophil elastase inhibitor are incubated with plasma. Subsequently, the enzyme activity is measured using the fluorogenic substrate MeOSucAla-Ala-Pro-Val-AMC (Bachem Cat. No. 1-1270, substrate concentration: 250 μΜ, pH 7.5, 25 inM TRIS buffer, 250 mM NaCl) in analogous fashion as described for the human neutrophil assay. A dose response curve is generated to calculate the EC50 of the inhibitor. The analysis of the data is performed by the calculation of the percentage of fluorescence in the presence of the test compound compared to the fluorescence of the vehicle control after subtractîng the background fluorescence: An inhibitor of the neutrophil elastase enzyme >/>

-17717445 will give values between 100 %control (no inhibition) and 0 %control (complété inhibition). The human plasma shîft of selected compounds can be calculated using the following équation:

Human plasma shift = (ECsq in human plasma assay) / (IC50 in human neutrophil elastase assay)

The EC50 values of selected compounds în the human plasma assay described above are listed in Table 29.

TABLE 29

Example	ECso [μΜ]
IA	0.022
6.2	0.004
6.3	0.004
7.3	0.002
7.5	0.001
7.6	0.001
7.9	0.001
35	0.007
9A	0.002
7.2A	0.001
31	0.014
52.1	< 0.001
52.3	<0.001
41.17	0.006
41.1	0.001
41.5	0.002
41.1	0.003

Example	ECS0 [μΜ]
41.16	0.002
52.2	0.001
41.4	0.002
10A	0.001
25	0.001
47.2	<0.001
7.1A	0.002
47.1	<0.001
49.3	0.007
41A	< 0.001
46	0.001
52A	< 0.001
42.3	0.005
42.4	0.012
42.6	0.001
37.2	0.017
47.5	0.001

-17817445

47.4	<0.001
50.3	0.013
22	0.023
45.4	0.002
26.1	0.013
50.1	0.016
23	< 0.001
53.3	< 0.001
53.4	<0.001
45.5	<0.001
33	< 0.001
54.2	< 0.001
52.5	0.001
29	0.001
49A	0.004

24.1	0.002
14A	0.001
24	0.002
30B	0.002
30A	0.001
15.4 A	0.002
26A	0.002
19	0.002
21	0.001
55	0.003
2A	0.003
22.4	< 0.001
example 8A disclosed in WO 2005/0828683	0.079

Compared to the acyclic methyl ketone dérivative (example 8A disclosed in

WO 2005/0828683), the cyclic ketone example l A exhibits a significantly lower EC₅o value, i.e, signifïcantly improved potency, in the human plasma assay described above.

Furthermore, example IA exhibts a human plasma shift of less than 2 which is signifïcantly lower than the human plasma shift for example 8A in WO 2005/0828683 and îs lîkely attributable to reduced binding to human plasma proteins. This observation is surprising, since example IA differs from example 8A in WO 2005/0828683 by only a single carboncarbon bond.

_i0 ASSAY FOR THE DETERMINATION OF METABOLIC STABILITY WITH HUMAN LIVER MICROSOMES

The metabolic dégradation of the test compound is assayed at 37 °C with pooled human liver microsomes. The final incubation volume of 100 μΐ per time point contains TRIS

-17917445 buffer pH 7.6 (0.1 M), magnésium chloride (5 mM), microsomal protein ( l mg/ml) and the test compound at a final concentration of l μΜ. Following a short preincubation period at 37 °C, the reactions are initiated by addition of beta-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH, 1 mM) and terminated by transfering an aliquot into acetonitrile after different time points. Additionally, the NADPH-independent dégradation is monitored in incubations without NADPH, terminated at the last time point. The [%] remaining test compound after NADPH independent incubation is reflected by the parameter c(control) (metabolic stability). The quenched incubations are pelleted by centrifugation ( 10’000 g, 5 min). An aliquot of the supernatant is assayed by LC-MS/MS for the amount of parent compound.

The half-life (tia INVITRO) is determîned by the slope of the semilogarithmîc plot of the concentration-time profile. The intrinsic clearance (CL_INTRINSIC) is calculated by considering the amount of protein in the incubation:

CL_INTRINSIC [μΐ/min/mg protein] = (ln 2 / (half-life [min] * protein content [mg/ml])) *1’000.

The half-life (ti/z INVITRO) values of selected compounds in the metabolic stability assay described above are listed in Table 30.

TABLE 30

Example	tJ/2 INVITRO [min]
IA	>130
6.3	>130
7.3	>130
7.6	>130
35	>130
9A	>130
7.2A	>130
31	>130

52.1	>130
Example	ti/z INVITRO [min]
52.3	>130
41.17	>130
41.1	>130
41.1	>130
41.16	>130
52.2	>130
41.4	>130

itr'

-18017445

10A	>130
25	>130
47.2	>130
7.1A	>130
47.1	>130
49.3	>130
41A	>130
46	>130
52A	>130
22.4	>130
42.3	>130
42.4	>130
14	>130
47.5	>130
37.4	>130
47.4	>130
50.3	>130
22	>130
45.4	>130
26.1	>130
23	>130

15.4	>130
53.3	>130
53.4	>130
45.5	>130
33	>130
15.6	>130
54.2	>130
52.5	>130
29	>130
49A	>130
24.1	100
14A	>130
24	>130
30B	>130
30A	>130
15.4A	>130
26A	>130
19	>130
21	>130
55	>130
example 8A disclosed in WO 2005/0828683	74

Compared to the acyclic methyl ketone derivative (example 8A disclosed in

WO 2005/0828683), the cyclic ketone example IA exhibits improved half life, i.e. improved stability, in the metabolic stability assay described above. This observation is 5 surprising, since example IA differs from example 8A in WO 2005/0828683 by only a single carbon-carbon bond.

-18117445

ASSAY FOR THE DETERMINATION OF METABOLIC STABILITY WITH HUMAN HEPATOCYTES

The metabolic dégradation of the test compound is assayed in a human hépatocyte suspension. Human hépatocytes (typically cryopreserved) are incubated în an appropriate buffer system (e.g. Dulbecœ's modified eagle medium plus 3.5 pg glucagon / 500 mL, 2.5 mg însulin / 500 mL and 3.75 mg / 500 mL hydrocortison) containing 5% species sérum. Following a (typically) 30 min preincubation in an incubator (37 °C, 10% CO2), 5 pl of test compound solution (80 pM; from 2 mM stock solution in DMSO diluted l :25 with medium) are added into 395 pl hépatocyte suspension (cell density in the range 0.25-5*10⁶ cells/mL, typically l*10⁶ cells/mL; final concentration of test compound lpM, final DMSO concentration 0.05%). The cells are incubated for six hours (incubator, orbital shaker) and samples (25 pl) are taken at 0, 0.5, 1, 2,4 and 6 hours. Samples are transferred into acetonitrile and pelleted by centrifugation (5 min). The supematant is transferred to a new 96-deepwell plate, evaporated under nitrogen and resuspended. The décliné of parent compound is analyzed by LC-MS/MS.

The întrinsic clearance CL_INTRINSIC is calculated as follows:

CLINTRINSIC = Dose / AUC = (Cq/CD) / (AUD + c_(ast/k) * 1Ό00/60 (Co: initial concentration in the incubation [μΜ], CD: cell density of vital cells [10⁶ cells/mL], AUD: area under the data [pM * h], C]_ast: concentration of last data point [pM], k: slope of the régression line for parent décliné [h¹])

The calculated în vitro hepatic intrinsic clearance can be sealed up to the intrinsic in vivo hepatic clearance and used to predict hepatic in vivo blood clearance (CL) by the use of a liver model (well stirred model):

CL_INTRINSIC_INVIVO [ml/min/kg] = (CLJNTRINSIC [pL/min/10⁶ cells] * hepatocellularity [10⁶ cells/g liver] * liver factor [g/kgbodyweight]) / 1’000

-18217445

CL [ml/min/kg] = CL_INTRINSIC_INVIVO [ml/min/kg] * hepatic blood flow [ml/min/kg] / (CL_INTRINSIC_ IN VIVO [ml/min/kg] + hepatic blood flow [ml/min/kg]) ⁵ Qh [%] = CL [ml/min/kg] / hepatic blood flow [ml/min/kg]) (Hepatocellularity, human: 120*10⁶ cells / g liver; Iver factor, human: 25.7 g / kg bodyweight; blood flow, human: 21 ml/(min * kg)) ίο The predicted human hepatic in vivo blood clearance (CL) of selected compounds in the metabolic stability assay described above is listed in Table 31.

TABLE 31

Example	CL [ml/min/kg]
IA	6
6.2	6
6.3	4
7.3	7
9A	0
7.2A	0
41.17	3
41.1	2
52.2	3
41.4	5
10A	0
25	2
47.2	1
7.1A	3
Example	CL [ml/min/kg]

Example	CL [ml/min/kg]
47.1	0
49.3	0
41A	0
52A	8
42.4	0
42.6	5
14	4
50.1	1
23	0
15.4	0
53.3	0
53.4	0
45.5	0
example 8A disclosed in WO 2005/0828683	10

-18317445

Compared to the acyclic methyl ketone dérivative (example 8A disclosed în WO 2005/0828683), the cyclic ketone example l A exhibits reduced clearance, i.e. improved stability, in the metabolic stability assay described above. This observation is surprising, since example IA differs from example 8A in WO 2005/0828683 by only a single carbon-carbon bond.

ASSAY FOR DETERMINATION OF DRUG TRANSPORT ACROSS HUMAN CACO-2 CELLS

The assay provides information on the potential of a compound to pass the cell membrane, on the extent of oral absorption as well as on whether the compound is actively transported by uptake and/or efflux transporters. For the measurement of permeability across polarized, confluent human cancer colon carcinoma cells 2 (Caco-2) cell monolayers grown on permeable filter supports are used as the in vitro absorption model.

Apparent permeability coefficients (PE) of the compounds across the Caco-2 monolayers are measured (pH 7.2, 37 °C) in apical-to-basal (AB) (absorptive) and basal-to-apical (BA) (secretory) transport direction. AB permeability (PEAB) represents drug absorption from the intestine into the blood and BA permeability (PEBA) drug sécrétion from the blood back into the intestine via both passive permeability as well as active transport mechanisms mediated by efflux and uptake transporters that are expressed on the Caco-2 cells. The compounds are assigned to permeability/absorptîon classes by comparison ofthe AB permeabilities with the AB permeabilities of reference compounds with known in vitro permeability and oral absorption in the human. Identical or similar permeabilities in both transport directions indicate passive perméation, vectorial permeability points to additional active transport mechanisms. Higher PEBA than PEAB suggests the involvement of an apical efflux transporter (like P-gp) and/or basolateral uptake transporter; higher PEAB than PEBA permeability suggests involvement of an apical uptake transporter (like PepTl) and/or basolateral efflux transporter (like MRP3). Active transport is concentrationdependently saturable.

Caco-2 cells (1-2 * 10⁵ cells/cm² area) are seeded on filter inserts (Costar transwell polycarbonate or PET fïlters, 0.4 pm pore size) and cultured (DMEM) for 10 to 25 days. λΤ'

-18417445

Compounds are dissolved in appropriate solvent (like DMSO, 1-20 mM stock solutions). Stock solutions are diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KC1, 1 mM MgSO₄, 1.8 mM CaCl₂,4.17 mM NaHCCh, 1.19 mM Na₂HP0₄x7H₂O, 0.41 mM NaH₂PO₄xH₂O, 15 mM HEPES, 20 mM glucose, pH 7.2) to préparé the transport solutions (typically 10 μΜ compound, final DMSO <= 0.5 %). The transport solution (TL) is applied to the apical or basolateral donor side for measuring A-B or B-A permeability (3 filter replîcates), respectively. The receiver side contains HTP-4 buffer supplemented with 2% BSA. Samples are collected at the start and end of experiment from the donor and at various time intervals for up to 2 hours also from the receiver side for concentration ίο measurement by LC-MS/MS or scintillation counting. Sampied receiver volumes are replaced with fresh receiver solution.

The apparent permeability coefficients (PEAB and PEBA) and efflux ratios (PEBA/PEAB) of selected compounds in the Caco-2 drug transport assay described above are listed in is Table 32.

TABLE 32

Example	PEAB [cm/s]	PEBA [cm/s]	Efflux ratio
IA	0.000051	0.0000764	1.5
7.3	0.00000949	0.0000671	7.1
35	0.0000569	0.0000738	1.3
9A	0.0000439	0.000073	1.7
7.2A	0.00000403	0.0000633	15.7
31	0.0000809	0.0000695	0.9
52.1	0.0000571	0.0000583	1.0
41.17	0.0000234	0.0000807	3.5
41.1	0.00000816	0.0000729	8.9
41.5	0.00000885	0.000077	8.7
41.1	0.0000188	0.0000903	4.8
41.16	0.0000589	0.0000577	1.0

-18517445

52.2	0.0000708	0.0000803	1.1
41.4	0.00000941	0.0000815	8.7
10A	0.000004925	0.0000574	14.5
25	0.0000567	0.000074	1.3
47.2	0.0000128	0.0000845	6.6
7.1A	0.0000727	0.0000681	0.9
47.1	0.00000813	0.0000651	8.0
41A	0.0000111	0.0000751	6.8
42.3	0.0000362	0.000086	2.4
42.4	0.0000397	0.000078	2.0
37.2	0.0000849	0.0000998	1.2
47.5	0.0000192	0.0000867	4.5
47.4	0.00000774	0.0000855	11.1
50.3	0.0000724	0.0000681	0.9
22	0.0000365	0.0000545	1.5
45.4	0.0000381	0.0000772	2.0
26.1	0.0000677	0.0000642	0.9
50.1	0.0000667	0.0000661	1.0
23	0.0000103	0.0000935	9.1
53.4	0.00000985	0.0000944	9.6
33	0.00000908	0.0000712	7.8
52.5	0.00000445	0.0000627	14.1
29	0.0000118	0.0000662	5.6
49A	0.0000831	0.0000648	0.8
14A	0.0000103	0.0000948	9.2
24	0.0000625	0.0000856	1.4
30B	0.000012	0.0000714	5.9
30A	0.00000352	0.000039	11.1

-18617445

15.4A	0.000003	0.000046	15.0
26A	0.000072	0.000076	1.1
2A	0.000087	0.000069	0.8
example 4 disclosed in WO 2007/129060	0.0000060	0.000035	5.8
example 44 disclosed in US 2011/0034433	0.0000009	0.000014	15.5
example 38 disclosed in US 2011/0034433	0.0000002	0.0000028	17.1

Compared to the cyclic amide dérivative (example 4 disclosed in WO 2007/129060), the cyclic ketone example IA exhibits improved AB permeability and a reduced efflux ratio. The AB permeability and efflux ratio of example 1A are in the favorable range for an orally 5 administered drug.

Compared to the cyclic amide dérivative (example 44 disclosed in US 2011/0034433), the cyclic ketone example 10A exhibits improved AB permeability.

Compared to the cyclic amide dérivative example 38 disclosed in US 2011/0034433 bearing a carbamoyl (R-NH-C(=O)-) substituent at the dihydropyrimidinone nitrogen, io numerous examples of the invention bearing a carbamoyl (R-NH-C(=O)-) substituent at the dihydropyrimidinone nitrogen exhibit improved AB permeability and/or a reduced efflux ratio.

ASSAY FOR DETERMINATION OF AQUEOUS SOLUBILÏTY

The aqueous solubilïty of a compound is determined by comparing the amount dissolved in is aqueous buffer (containing 2.5% DMSO) to the amount dissolved in an acetonitrile/water (1/1) solution. Starting from a 10 mM DMSO stock solution, aliquots are diluted with acetonitrile/water (1/1) and Mcllvaine buffer pH 6.8, respectively. After 24 h of shaking, the solutions or suspensions are filtered and analyzed by LC-UV. The amount dissolved in buffer Îs compared to the amount dissolved in the acetonitrile/water (1/1) solution.

-18717445

Solubility is measured from 0.001 to 0.125 mg/ml at a DMSO concentration of 2.5%. If more than 90 % of the compound is dissolved in buffer, the value is marked with

The aqueous solubility of selected compounds in the solubility assay described above is 5 listed in Table 33.

TABLE 33

Example	Aqueous solubility [mg/mL]
IA	0.074
6.2	0.077
6.3	0.121
7.3	0.072
7.5	0.104
7.6	0.094
7.9	0,106
7.2A	0.072
52.1	0.041
52.3	0.091
41.17	0.054
41.1	0.097
41.5	0.082
41.1	0.073
52.2	0.016
41.4	0.092
10A	0.0845
25	0.062
47.2	0.045
7.1A	0.023
47.1	0.083

Example	Aqueous solubility [mg/mL]
49.3	0.032
41A	0.079
46	0.01
52A	0.088
42.3	0.02
42.4	0.021
42.6	0.067
14	0.045
47.5	0.016
37.4	0.021
47.4	0.019
22	0.013
45.4	0.028
26.1	0.041
50.1	0.041
23	0.015
15.4	0.069
53.3	0.034
53.4	0.014
45.5	0.056
33	0.043

-18817445

15.6	0.076
54.2	0.044
52.5	0.07
29	0.079
24.1	0.064
14A	0.062
30B	0.065

30A	0.051
15.4A	0.069
26A	0.041
19	0.089
21	0.087
2A	0.07

ASSAY FOR DETERMINATION OF CYTOCHROME P450 2C9 INHIBITION

The inhibition of cytochrome P450 2C9-isoenzyme catalysed hydroxylation of Diclofenac by the test compound is assayed at 37°C with human liver microsomes. Ail assays are carried out on a robotic system in 96 well plates. The final incubation volume contains TRIS buffer (0.1 M), MgCl₂ (5 mM), human liver microsomes (0.1 mg/ml), Diclofenac (10 μΜ) and the test compound at five different concentrations or no compound (high control) in duplicate (e.g. hîghest concentration 10-50 μΜ with subséquent serial 1:4 dilutions). Following a short preincubation period, reactions are started with the cofactor (NADPH, 1 mM) and stopped by cooling the incubation down to 8 °C and subsequently by addition of one volume of acetonitrile. An internai standard solution - usually the stable isotope of the formed métabolite - is added after quenching of incubations. Peak area analyte (=metabolîte formed) and internai standard is determined by LC-MS/MS. The resulting peak area ratio analyte to internai standard in these incubations is compared to a control activity containing no test compound. Within each of the assay runs, the IC50 of a positive control inhibitor (sulfaphenazole) is determined. Experimental ICjg values are calculated by least square régression according to the following équation:

% control activity = (100 % control activîty/(l+(I/IC5o)*S))-B (I = inhibitor concentration, S = slope factor, B = background activity) tA-'⁷

-18917445

If the inhibition of the reaction is already >50% at the lowest concentration of the test compound, the ICsg is assigned < lowest concentration tested (usually <0.4 μΜ). If the inhibition of the reaction is still <50% at the highest concentration of the test compound, the IC₅₀ is assigned > highest concentration tested (usually >50 μΜ).

The IC50 values of selected compounds in the CYP2C9 inhibition assay described above are listed in Table 34.

TABLE 34

Example	CYP2C9 IC50 [μΜ]
IA	>50
10A	>50
9A	> 50
7.2A	> 50
41A	> 50
47.1	> 50
47.2	> 50
example 8A disclosed in WO 2005/0828683	12

Compared to the acyclic methyl ketone dérivative (example 8A disclosed in

WO 2005/0828683), the cyclic ketone example IA exhibits reduced CYP2C9 inhibition in the assay described above. This observation is surprising, since example l A differs from Example 8A in WO 2005/0828683 by only a single carbon-carbon bond.

is ASSAY FOR DETERMINATION OF CYTOCHROME P450 2C19 INHIBITION

The inhibition of cytochrome P450 2C19-isoenzyme catalysed hydroxylation of

Mephenytoin by the test compound is assayed at 37 °C with human liver microsomes. Ail assays are carried out on a robotic system in 96 well plates. The final incubation volume JJ

-19017445 contains TRIS buffer (O.l M), MgCb (5 mM), human liver microsomes (0.5 mg/ml), (5)-Mephenytoin (70 μΜ) and the test compound at five different concentrations or no compound (high control) in duplicate (e.g. highest concentration 10-50 μΜ with subséquent serial 1:4 dilutions). Following a short preincubation period, reactions are started wîth the s cofactor (NADPH, 1 mM) and stopped by cooling the incubation down to 8 °C and subsequently by addition of one volume of acetonitrile. An internai standard solution usually the stable isotope of the formed métabolite - is added after quenching of incubations. Peak area analyte (= métabolite formed) and internai standard is determined by LC-MS/MS. The resulting peak area ratio analyte to internai standard in these incubations ίο is compared to a control activity containing no test compound. Within each of the assay runs, the IC₅₀ of a positive control inhibitor (tranylcypromine) is determined. Experimental IC50 values are calculated by least square régression according to the following équation:

% control activity = (100 % control activity/(l+(I/IC5o)*S))-B (I = inhibitor concentration, S = slope factor, B = background activity)

If the inhibition of the reaction is already >50% at the lowest concentration of the test compound, the IC50 is assigned < lowest concentration tested (usually <0.4 μΜ). If the inhibition of the réaction is still <50% at the highest concentration of the test compound, the IC50 is assigned > highest concentration tested (usually >50 μΜ).

The IC50 values of selected compounds in the CYP2CI9 inhibition assay described above are listed in Table 35.

TABLE 35

Example	CYP2C19 ICsoftiM]
IA	>50
10A	39
9A	>50

-19117445

Example	CYP2C19 IC50 [μΜ]
7.2A	>50
41A	>50
47.1	>50
47.2	>50
example 8A disclosed in	7.3
WO 2005/0828683

Compared to the acyclic methyl ketone dérivative (example 8A in WO 2005/0828683), the cyclic ketone example IA exhibits reduced CYP2C19 inhibition in the assay described above. This observation is surprising, since example 1A differs from example 8A in WO 2005/0828683 by only a single carbon-carbon bond.

ASSAY FOR DETERMINATION OF CYTOCHROME P450 2C8 INHIBITION

The inhibition of cytochrome P450 2C8-îsoenzyme catalysed dééthylation of Amodiaquine by the test compound is assayed at 37°C with human liver microsomes. Ail assays are carried out on a robotic system in 96 well plates. The final incubation volume contains TRIS buffer (0.1 M), MgCl₂ (5 mM), human liver microsomes (0.05 mg/ml), Amodiaquine (1 μΜ) and the test compound at five different concentrations or no compound (high control) in duplicate (e.g. highest concentration 10-50 μΜ with subséquent serial 1:4 dilutions). Following a short preincubation period, reactions are started with the cofactor (NADPH, ImM) and stopped by cooling the incubation down to 8°C and subsequently by addition of one volume of acetonitrile. An internai standard solution - usually the stable isotope of the formed métabolite - is added after quenching of incubations. Peak area analyte (=metabolite formed) and internai standard is determined by LC-MS/MS. The resulting peak area ratio analyte to internai standard in these incubations is compared to a control activity containing no test compound. Within each of the assay runs, the IC₅₀ of a positive control inhibitor (Montelukast) is determined. Experimental IC₅₀ values are calculated by least square régression according to the following équation: 'Λ/'

-19217445 % control activity = (l00 % control activity/(l+(I/ICso)*S))-B (I - inhibitor concentration, S = slope factor, B = background activity)

If the inhibition of the reaction is already >50% at the lowest concentration of the test compound, the IC50 is assigned < lowest concentration tested (usually <0.4 μΜ). If the inhibition of the reaction is still <50% at the highest concentration of the test compound, the IC50 is assigned > highest concentration tested (usually >50 μΜ).

ιο The IC50 values of selected compounds in the CYP2C8 inhibition assay described above are listed in Table 36.

TABLE 36

Example	CYP2C8 IC50[pM]
IA	>50
10A	>50
9A	>50
7.2A	> 50
41A	>50
47.1	>50
47.2	>50
example 8A disclosed in WO 2005/0828683	10.9

Compared to the acyclic methyl ketone dérivative (example 8A disclosed in

WO 2005/0828683), the cyclic ketone example IA exhîbits reduced CYP2C8 inhibition in the assay described above. This observation is surprising, since example 1A differs from example 8A in WO 2005/0828683 by only a single carbon-carbon bond.

COMBINATIONS

-19317445

The compounds of general formula 1 may be used on their own or combined with other active substances of formula 1 according to the invention. The compounds of general formula 1 may optionally also be combined with other pharmacologically active substances. These include, B2-adrenoceptor-agonists (short and long-acting), anticholinergics (short and long-acting), antî-inflammatory steroids (oral and topical corticosteroids), cromoglycate, methylxanthine, dissociated-glucocortîcoidmimetics, PDE3 inhibitors, PDE4- inhibitors, PDE7- inhibitors, LTD4 antagonists, EGFR- inhibitors, Dopamine agonists, PAF antagonists, Lipoxin A4 dérivatives, FPRL1 modulators, LTB4receptor (BLT1, BLT2) antagonists, Histamine H1 receptor antagonists, Histamine H4 receptor antagonists, dual Histamine H1/H3-receptor antagonists, P13-kinase inhibitors, inhibitors of non-receptor tyrosine kinases as for example LYN, LCK, SYK, ZAP-70, FYN, BTK or ITK, inhibitors of MAP kinases as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, inhibitors of the NF-κΒ signalling pathway as for example IKK2 kinase inhibitors, iNOS inhibitors, MRP4 inhibitors, leukotriene biosynthese inhibitors as for example 5-Lîpoxygenase (5-LO) inhibitors, cPLA2 inhibitors, Leukotriene A4 Hydrolase inhibitors or FLAP inhibitors, MMP9-inhibitors, MMP12-inhibitors, non-steroidale anti-inflammatory agents (NSAIDs), Cathepsin C (or DPPI / Dipeptidylaminopeptidase I) inhibitors, CRTH2 antagonists, DPI-receptor modulators, Thromboxane receptor antagonists, CCR3 antagonists, CCR4 antagonists, CCR1 antagonists, CCR5 antagonists, CCR6 antagonists, CCR7 antagonists, CCR8 antagonists, CCR9 antagonists, CCR30 antagonists, CXCR3 antagonists, CXCR4 antagonists, CXCR2 antagonists, CXCR1 antagonists, CXCR5 antagonists, CXCR6 antagonists, CX3CR3 antagonists, Neurokinin (NK1, NK2) antagonists, Sphingosine 1-Phosphate receptor modulators, Sphingosine 1 phosphate lyase inhibitors, Adenosine receptor modulators as for example A2a-agonists, modulators of purinergicreceptors as for example P2X7 inhibitors, Histone Deacetylase (HDAC) activators, Bradykinin (BK.1, BK2) antagonists, TACE inhibitors, PPAR gamma modulators, Rho-kinase inhibitors, interleukin 1-beta converting enzyme (ICE) inhibitors, Toll-Like receptor (TLR) modulators, HMG-CoA reductase inhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIP agonists, GABAa receptor antagonist, ENaC-inhibitors, Prostasin-inhibîtors, Melanocortin receptor (MC1R, MC2R, MC3R, MC4R, MC5R) modulators, CGRP antagonists, Endothelin antagonists, TNFa antagonists, anti-TNF antibodies, anti-GM-CSF antibodies, anti-CD46 antibodies, anti-IL-1 antibodies, anti-IL-2

-19417445 antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL-13 antibodies, anti-IL-4/IL-13 antibodies, anti-TSLP antibodies, anti-OX40 antibodies, mucoregulators, immunotherapeutic agents, compounds against swelling of the aîrways, compounds against cough, VEGF inhibitors, but also combinations of two or three active substances.

Preferred are betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, Cathepsin C inhibitors, CRTH2 inhibitors, 5-LO-inhibitors, Histamine receptor antagoniste and S Y K-inhibitors, especially Cathepsin C inhibitors, but also combinations of two or three active substances, i.e.:

• Betamimetics with corticosteroids, PDE4-inhibitors, CRTH2-inhibitors or LTD4antagonists, • Anticholinergics with betamimetics, corticosteroids, PDE4-inhibitors, CRTH2inhibîtors or LTD4-antagonists, • Corticosteroids with PDE4-inhibîtors, CRTH2-inhîbitors or LTD4-antagonists • P DE4-inhibitors with CRTH2-inhibitors or LTD4-antagonists • CRTH2-inhibitors with LTD4-antagonists.

INDICATIONS

The compounds of the invention and their pharmaceutically acceptable salts hâve activity as pharmaceuticals, in particular as inhibitors of neutrophii elastase, and thus may be used in the treatment of:

1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergie, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of ail severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and éosinophilie bronchitis; emphysema; alphal-antitrypsin deficiency; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonîas, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal

-19517445 infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with înflammatory and secretory conditions of the airways, and iatrogénie cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergie rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus; acute lung injury; acute respiratory distress syndrome;

2. skin: psoriasis, atopie dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoîd, discoid lupus erythematosus, pemphigus, pemphîgoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattem baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lésions; drug-induced disorders including fixed drug éruptions;

3. eyes: blepharitîs; conjunctivitis, including perennial and vemal allergie conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or înflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitîs; sarcoidosîs; infections including viral, fungal, and bacterial;

4. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystîtis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritîs and salpingitis; vulvovaginitis; Peyronie's disease; erectîle dysfunction (both male and female);

5. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or comea or following blood transfusion; or chronic graft versus host disease;

-19617445

6. other auto-immune and allergie disorders including rheumatoid arthritis, irritable bowel syndrome, systemic lupus erythematosus, multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addisoris disease, diabètes mellitus, idiopathic thrombocytopaenic purpura, éosinophilie fasciitis, hyper-IgE syndrome, antiphospholipid syndrome andSazary syndrome;

7. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliférative Systems, such as Hodgkin's and non-Hodgkiris lymphoma; including the prévention and treatment of metastatic disease and tumour récurrences, and paraneoplastic syndromes; and,

8. infectious diseases: virus diseases such as génital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagîosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomégalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as fungal diseases, chlamydia, Candida, aspergillus, cryptococcal menîngitis, Pneumocystis camii, cryptosporidiosîs, histoplasmosis, toxoplasmosis, trypanosome infection and leishmanïasis.

For treatment of the above-described diseases and conditions, a therapeutically effective dose will generally be in the range from about 0.01 mg to about 100 mg/kg of body weight per dosage of a compound of the invention; preferably, from about 0.1 mg to about 20mg/kg of body weight per dosage. For Example, for administration to a 70 kg person, the dosage range would be from about 0.7 mg to about 7000 mg per dosage of a compound of the invention, preferably from about 7.0 mg to about 1400 mg per dosage. Some degree of routine dose optimization may be required to détermine an optimal dosing level and pattern. The active ingrédient may be administered from 1 to 6 times a day. —

-19717445

The actual pharmaceutically effective amount or therapeutic dosage will of course dépend on factors known by those skilled in the art such as âge and weight of the patient, route of administration and severity of disease. In any case the active ingrédient will be admînistered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon patient’s unique condition.

Claims (16)

1. WHAT WE CLAIM

   1. A compound of formula 1 wherein

   R¹ is phenyl or a five- or six-membered heteroaryl, wherein one, two or three éléments are replaced by an element independently selected from the group consisting of N, O or S; each ring optionally substituted with one, two or three substituents independently selected from the group consisting of halogen, O2N-, NC-, H2N-, HO-, R¹’¹, R^llO-, R¹², R^1JS-, R¹³(O)S- and R¹³(O)2S-;

   R¹¹ is independently selected from the group consisting of Ci-6-alkyl-, Cjô-cycloalkyl-, Ci-6-haloalkyl- and Cw.-halocycloalkyl;

   R¹² is HO-C].6-alkyl- or R¹ '-O-Ci.6-alkyl-;

   R¹³ is independently selected from the group consisting of H, HO-, R^u and R¹'²;

   R² is phenyl or a five- or six-membered heteroaryl, wherein one or two éléments are replaced by an element independently selected from the group consisting of N, O or S; each ring optionally substituted with a substituent independently selected from the group consisting of halogen, C^-alkyl-, C^-haloalkyl- and CM-alkyl-O-;

   R³ is a residue independently selected from the group consisting of • R³¹-;

   • R³²(O)C-;

   • R³²O(O)C-;

   • R³²O(O)C-A-;

   • R^{3 2}S-; R^{3 2}(O)S-; R^{3 2}(O)₂S-;

   -19917445 • (R^{3 2})₂N(O)C and • (R³²)₂N(O)C-A-;

   R³¹ is independently selected from the group consisting of H, R^{3 3}, R³’⁴, CQfi-alkyl-Cj.(.-cycloalkyl- and C₃.«cycloalkyl-C[_f,-alkyl·, each optionally substituted with one or two substituents independently selected from R³¹

   R³¹¹ is selected from the group consisting of HO-, halogen, NC-, R^{3 3}O-, R^{3 5}, R^{3 6}and R³'⁷ or

   R³¹'¹ dénotés a ring independently selected from phenyl and a four-membered heterocyclic ring containing one element independently selected from among N, O, S, S(O) and S(O)₂;

   R³¹¹ dénotés a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three éléments independently selected from among N, O, S, S(O) and S(O)₂;

   each of the rings optionally substituted with one or two substituents independently selected from among HO-, O=, halogen, NC-, R^{3 3}, R^{3 3}O-, R^{3 3}-(O)C-, R^{3 4}, R^{3 5}, R^{3 6} and R³'⁷ or two substituents are together R^{3 8};

   R³'² is independently selected from among R³¹, phenyl and a five- or sixmembered heterocyclic or heteroaryl ring containing one, two or three éléments independently selected from among N, O, S, S(O) and S(O)₂; each ring optionally substituted with one or two substituents independently selected from among HO-, O=, NC-, halogen, R^{3 3}, R^{3 3}O-, R^{3 3}-(O)C-, R^{3 4}, R³'⁵, R^{3 6} and R³'⁷ or two substituents are together R^{3 8};

   or two R^{3 2} are together a three-, four-, five- or six-membered monocyclic or a six-, seven-, eight-, nine- or ten-membered bicyclic heterocyclic or heteroaryl ring optionally containing additional to the nitrogen one or two éléments independently selected from among N, O, S, S(O) and S(O)₂;

   optionally substituted with one or two substituents, independently selected

   -20017445 from among HO-, F, O=, NC-, R³ ’, R^{3 3}O-, R^{3 3}-(O)C-, R^{3 4}, R^{3 5}, R¹'⁶, R³ ’, phenyl and a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three éléments independently selected from among N,

   O, S, S(O) and S(O)₂; or two substituents are together R³'⁸;

   R^{3 3} is independently selected from the group consisting ofC'i._;,-alkyl-,

   C3_₆-cycloalkyl-, C].6-haloalkyl- and Cî-ô-halocycloalkyl;

   R³⁴ is HO-C[.6-alkyl- or R¹³-O-C_w-alkyl-;

   R is independently selected from the group consisting of H₂N-, R -HN-, io (R^{3 3})₂N-, R³³-(O)C-HN- and R^{3 3}-(O)C-(R^{3 3})N-;

   R³'⁶ is independently selected from the group consisting of R³'³-(O)S-, R^{3 3}(O)₂S-, R^{3 3}(HN)S-, R^3r3(HN)(O)S-, R^{3 3}(R^{3 3}N)S-, R^{3 3}(R^{3 3}N)(O)S-, R^{3 3}(R³-⁴N)S-, R³³(R^{3 4}N)(O)S-; R³³(NC-N)S and R¹³(NC-N)(O)S-;

   R^{3 7} is independently selected from the group consisting of HO(O)C-, H2N(O)C-, is R^{3 3}-O-(O)C-, R^{3 3}-NH-(O)C- and (R^{3 3})2N-(O)C-;

   R³·⁸ is independently selected from the group consisting of Ci.6-alkylene and C].û-haloalkylene, wherein optionally one or two CH2-groups are replaced by -HN-, -(R^{3 3})N-, -(R^{3 4})N-, -(R^{3 3}(O)C-)N-, -(R^{3 4}(O)C-)N-, -O-, -S-, -S(O)- or -S(O)2-;

   A is -CH₂-, -CH₂-CH₂- or -CH₂-CH₂-CH₂-; optionally substituted with one or two substituents independently selected from the group consisting of halogen, R^{3 3}, R^{3 3}O- and R^{3 4} or two substituents together are R^{3 8};

   25 R⁴ is independently selected from the group consisting of halogen, Ci.6-alkyl-, C₃.₆-cycloalkyl-, C[.6-haloalkyl- and C^.ô-halocycloalkyl; or two R⁴ are together Cj-6-alkylene or Ci^-haloalkylene;

   m is 0, 1 or 2;

   or a sait thereof.

   -20117445
2. 2. A compound of formula 1, according to claim 1, wherein R¹ is R^{l c} and R^{1 c} is phenyl or pyridinyl; each ring optionally substîtuted by one, two or three residues independently selected from the group consisting of F, Cl, Br-, ,NC-, R¹¹, R¹³(O)S- and R¹³(O)₂S-;

   R^{1 1} is independently selected from the group consisting of Ci-6-alkyl-, Cî-û-cycloalkyl-, Ci_6-haloalkyl- and Cj ^-halocycloalkyl;

   R¹² is HO-C].6-alkyl- or R^H-O-Ci.6-alkyl-;

   R^L3 is independently selected from the group consisting of H, HO-, R¹¹ and R¹²; or a sait thereof.
3. 3. A compound of formula 1, according to claiml, wherein R¹ is R^{l e} and R^{l e} is phenyl or pyridinyl; each ring optionally substîtuted by one or two residues independently selected from the group consisting of NC-, Me(O)S-, Me(O)₂S and Et(O)₂S; or a sait thereof.

   2 2 b
4. 4. A compound of formula 1, according to one of the claims 1 to 3, wherein R is R ' and R^2b is phenyl or a six-membered heteroaryl; wherein one or two éléments are replaced by N; each ring optionally substîtuted with a substituent independently selected from the group consisting of halogen, Cj j-alkyl- and Ci^-haloalkyl-; or a sait thereof.
5. 5. A compound of formula 1, according to one of the claims 1 to 3, wherein R² is R^{2 f} and R^2f is pyridinyl, optionally substîtuted with a substituent independently selected from the group consisting of F₃C- and F₂HC-, or a sait thereof.

   b b
6. 6. A compound of formula 1, according to one of the claims 1 to 5, wherein A is A and A îs -CH₂-, optionally substîtuted with one or two substituents independently selected from the group consisting of F, Me, Et, i-Pr, MeO, EtO, HOCH₂O- and MeOCH₂-; or a sait thereof.
7. 7. A compound of formula 1, according to one of the claims 1 to 6, wherein R⁴ is R^4a and R^{4 a} is selected from the group consisting of halogen, Ci^-aikyl-, C₃-6-cycloalkyl-,

   C].6-haloalkyl- and C₃.6-halocycloalkyI; or a sait thereof.

   -20217445
8. 8. A compound of formula 1, according to one of the claims 1 to 7, wherein R³ is a residue independently selected from the group consîsting of • R³¹-;

   • R^{3 2}O(O)C- or R³²O(O)C-CH₂-;

   • R^{3 2}(O)₂S- and • (R^{3 2})2N(O)C- or (R^{3 2})2N(O)C-CH₂-;

   R³¹ is independently selected from the group consîsting of H, R³'³, R^{3 4}, Cj-6-aIkyl-C3.6-cycIoalkyl- and C3.6-cydoalkyl-C|₆-alkyl-, each optionally substituted with one or two substituents independently selected from R³¹

   R³¹¹ is selected from the group consîsting of HO-, halogen, NC-, R^{3 3}O-, R^{3 s}, R^{3 6} and R^{3 7} or

   R³¹¹ is selected from the group consîsting of a ring independently selected from phenyl and a four-membered heterocyclic ring containing one element independently selected from among N, O, S, S(O) and S(O)₂; or

   R³¹¹ dénotés a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three éléments independently selected from among N, O, S, S(O) and S(O)₂; each of the rings optionally substituted with one or two substituents independently selected from among HO-, O=, halogen, R , R^{3 3}O-, R^{3 3}-(O)C-, R³'⁴, R^{3 5}, R^{3 6} and R^{3 7} or two substituents are together R³⁸;

   R^{3 2} is independently selected from R³¹, phenyl or a five- or six-membered heterocyclic or heteroaryl ring containing one, two or three éléments independently selected from among N, O, S, S(O) and S(O)₂; each ring optionally substituted with one or two substituents independently selected from HO-, O=, NC-, halogen, R³'³, R^{3 3}O-, R^{3 3}-(O)C-, R^{3 4}, R³'⁵, R^{3 6} and R^{3 7} or two substituents are together R^{3 8};

   or two R³’² are together a five- or six-membered monocyclic or a eight-, nine- or tenmembered bicyclîc heterocyclic or heteroaryl ring optionally containing additional

   -20317445 to the nitrogen one or two éléments independently selected from among N, O, S, S(O) and S(O)₂; optionally substituted with one or two substituents, independently selected from HO-, F, O=, R^{3 3}, R^{3 3}O-, R^{3 3}-(O)C-, R^{3 4}, R^{3 5}, R^{3 7} and R^{3 6} or two substituents are together R³'⁸;

   R is independently selected from the group consisting of Cj.6-alkyl-, C₃.₆-cycloalkyl-, Ci.<>-haloalkyl- and C₃.6-halocycloalkyl;

   R^{3 4} is HO-Ci-6-alkyl- or R^-O-C^-alkyl-;

   R^{3 5} is independently selected from the group consisting of H2N-, R^{3 3}-HN-, (R^{3 3})2Nand R^{3 3}-(O)C-HN-;

   R^{3 6} is independently selected from the group consisting of R^{3 3}-(O)S-, R^{3 3}-(O)₂S-,

   R^{3 3}(HN)S-, R^{3 3}(HN)(O)S-R^{3 3}(R^{3 3}N)S-, R^{3 3}(R^{3 3}N)(O)S-, R^{3 3}(R^{3 4}N)S- and R³³(R³⁴N)(O)S-;

   R^{3 7} is independently selected from the group consisting of HO(O)C-, H2N(O)C-, R^{3 3}-O(O)C-, R^{3 3}-NH-(O)C- and (R^{3 3})2N-(O)C-;

   R ' is independently selected from the group consisting of Ci.&-alkylene or C]_₆-haloalkylene, wherein optionally one or two CH₂-groups are replaced by -HN-, -(R^{3 3})N-, -(R^{3 4})N-, -(R^{3 3}(O)C-)N-, -(R^{3 4}(O)C-)N-, -O-, -S-, -S(O)- and -S(O)₂-;

   or a sait thereof.
9. 9. A compound of formula 1, according to one of the claims 1 to 7, wherein R³ is independently selected from the group consisting of HO(O)C-H₂C-, MeO(O)C-H₂C-, H₂N(O)C-H₂C-, MeHN(O)C-H₂C-, Me₂N(O)C-H₂C-, morpholinyl-(O)C-H₂C-, azetidinyl(O)C-H₂C-, pyrrolidinyl-(O)C-H₂C-, MeHN(O)C-, EtHN(O)C-, H0(CH₂)₂HN(O)C-, HO(CMe₂)(CH₂)HN(O)C-, HO(CH₂)₃HN(O)C-, Me(O)S(CH₂)₂HN(O)C-, Me(O)₂S(CH₂)₂HN(O)C-, Et(O)₂S- and Me(O)₂S-; or a sait thereof

   -20417445
10. 10. A compound of formula La to I.s, according to claim 1 ou—

    -20517445

    -20617445 or a sait thereof.
11. 11. A compound according to one of the claims 1 to 10, wherein the configuration of formula 1 is formula Γ

    -20717445 or a sait thereof.
12. 12. A compound of formula 1 according to any one claims 1 to 11 for use as a médicament.
13. 13. A compound of formula 1 according to any one claims 1 to 11 for use as a médicament for the treatment of asthma and allergie diseases, gastrointestinal inflammatory diseases, éosinophilie diseases, chronic obstructive pulmonary disease, infection by pathogenic microbes and rheumatoid arthritîs.
14. 14. Pharmaceutical composition, characterised in that it contains one or more compounds of formula 1 according to any one of claims 1 to 11 or a pharmaceutically active sait thereof.
15. 15. Use of a compound of formula 1 according to one of claims 1 to 11 in the manufacture of a médicament for the treatment or prévention of diseases in which neutrophil elastase inhibitors hâve a therapeutic benefit.
16. 16. A pharmaceutical composition comprising additionally to a compound of formula 1, according to any one of claims 1 to 11, a pharmaceutically active compound selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, Cathepsîn C inhibitors, CRTH2 inhibitors, 5-LO-inhibitors, Histamine receptor antagonists and SYK-inhibitors, but also combinations of two or three active substances. t/z- ..... antc_

    JUJL W

    YSAGHT Sari

    YAOUNDE-CAMEROUN

    Tél.- Fax.: 22 31 67 53

    -20817445

    ABSTRACT

    This invention relates to substituted bicyclic dihydropyrimidinones of formula 1 and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prévention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory ίο diseases of the skin and the eye and other autoimmunc and allergie disorders, allograft rejection, and oncological diseases. \j^y