OA17884A - Acylamino-substituted cyclic carboxylic acid derivatives and their use as pharmaceuticals. - Google Patents

Abstract

The present invention relates to compounds of the formula (I) wherein A, Y, Z, R20 to R22 and R50 have the meanings indicated in the claims, which are valuable pharmaceutical active compounds. Specifically, they are inhibitors of the endothelial differentiation gene receptor 2 (Edg-2, EDG2), which is activated by lysophosphatidic acid (LPA) and is also termed as LPA1 receptor, and are useful for the treatment of diseases such as atherosclerosis, myocardial infarction and heart failure, for example. The invention furthermore relates to processes for the preparation of the compounds of the formula (I), their use and pharmaceutical compositions comprising them.

Description

ACYLAMINO-SUBSTITUTED CYCLIC CARBOXYLIC ACID DERIVATIVES AND THEIR USE

AS PHARMACEUTICALS

The présent invention relates to compounds ofthe formula I,

wherein A, Y, Z, R²⁰ to R²² and R⁵⁰ hâve the meanings indicated below, which are valuable pharmaceutical active compounds. Specifically, they are inhibitors ofthe endothélial différentiation gene receptor 2 (Edg-2, EDG2), which is activated by lysophosphatidic acid (LPA) and is also termed as LPA-ι receptor, and are useful for the treatment of diseases such as atherosclerosis, myocardial infarction and heart failure, for example. The invention furthermore relates to processes for the préparation ofthe compounds ofthe formula I, their use and pharmaceutical compositions comprising them.

LPA is a group of endogenous lysophospholipid dérivatives including 1-oleoyl-sn-glycerol 3phosphate, for example. LPA activâtes G-protein-coupled receptors (GPCR's) from the endothélial différentiation gene receptor family which belong to the lysophospholipid receptors. LPA signaling exerts a variety of pléïotropie biological responses on many different cell types which interfère with processes such as cell prolifération, cell growth, cell hypertrophy, redifferentiation, cell retraction, cell contraction, cell migration, cell survival or inflammation. The Edg receptor family, originally identified as a family of orphan GPCR's, currently comprises eight different members which were recently termed according to their respective ligand as LPA receptors or S1P receptors (sphingosine-1-phosphate receptors). According to the nomenclature ofthe International Union of Basicand Clinical Pharmacology (IUPHAR), LPA receptors Edg-2, Edg-4 and Edg-7 are now also termed as LPAj, LPA₂ and LPA₃ receptor (cf. I. Ishii et al., Annu. Rev. Biochem. 73 (2004), 321-354).

LPA is generated mainly in the extracellular compartiment by different pathways predominantly by the cancer cell motility factor autotaxin which was recently found to be identical with lysophospholipase D. LPA can also be generated by alternative routes involving phospholipase hydrolysis (PLAi and PLA₂) or other mechanisms such as de novo phospholipid synthesis.

Although LPA, in contrast to other phospholipids, is highly soluble in water, in plasma it is carried by different binding proteins such as albumin and gelsolin which display a high affinity to LPA and from which it can be released. Under pathophysiological conditions, levels of LPA can be elevated to an undesirable amount and thus increase LPA-mediated signaling and lead to detrimental processes such as abnormal cell prolifération, for example. Blocking LPA signaling, for example by Edg-2 inhibitors, allows to prevent such processes.

For example, increased libération of LPA was observed during platelet activation and blood clotting and at sites of inflammation (T. Sano et. al., J. Biol. Chem. 277 (2002), 21197-21206). After acute myocardial infarction (AMI) in humans, LPA sérum levels were significantly raised in humans to about 6-fold higher concentrations, and LPA was regarded to be involved in the pathophysiological processes in the cardiovascular system related to AMI (X. Chen et al., Scand. J. Clin. Lab. Invest. 63 (2003), 497-503). The importance of LPA and its receptor Edg-2 for the pathophysiological processes after myocardial infarction such as cardiac remodeling and for the prévention of cardiac hypertrophy and heart failure was confirmed in further investigations (J. Chen et al., J. Cell. Biochem. 103 (2008), 1718-1731). LPA was shown to be generated during mild oxidation of low density lipoprotein (LDL) particles and to be accumulated in the lipid core of human atherosclerotic plaques (W. Siess et al., Proc. Natl. Acad. Soi. 96 (1999), 6931-6936). Furthermore, LPA was identified as an important bioactive component of moxLDL (mildly oxidized low density lipoprotein) leading to platelet activation, and it was shown that the effects of LPA, moxLDL or lipid core extracts from human atherosclerotic plaques on platelet activation could be abrogated by the Edg-2/Edg-7 receptor inhibitor dioctanoylglycerol pyrophosphate DGPP(8:0), implicating a causative rôle of LPA-mediated Edg receptor signaling in platelet aggregation and usefulness of such LPA receptor inhibitors in the treatment of cardiovascular diseases (E. Rotheretal., Circulation 108 (2003), 741-747).

Further findings underiine the detrimental rôle of LPA during initiation and progression of cardiovascular diseases such as atherosclerosis, left ventricular remodeling and heart failure. LPA leads to pertussis toxin-sensitive, NFkB (nuclear factor kappa B)-mediated proinflammatory responses of endothélial cells including upregulation of chemokines like monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL8) (A. Palmetshofer et al., Thromb. Haemost. 82 (1999), 1532-1537) and exposure of endothélial cell adhesion molécules like Eselectin or intercellular adhesion molecule-1 (ICAM-1) (H. Lee et al., Am. J. Physiol. 287 (2004), C1657-C1666). Direct evidence for the involvement of Edg-2 receptors arises from recent studies which demonstrate that LPA induces oxidative stress in vascular smooth muscle cells and endothélial cells which was attenuated by pharmacological inhibition by DGPP(8:0) or

THG1603, a spécifie Edg-2 receptor antagonist (U. Kaneyuki et al., Vascular Pharmacology 46 (2007), 286-292; S. Brault et al., Am. J. Physiol. Regul. Integr. Comp. Physiol. 292 (2007), R1174-R1183). In vascular smooth muscle cells, LPA leads to pertussis toxin-sensitive Ca²⁺ release from internai stores, to activation of 42 kDa mitogen-activated protein kinase (p42MAPK) and to cell prolifération (S. Seewald et al., Atherosclerosis 130 (1997), 121-131). lntravascular injection of LPA was shown to induce neointima formation in vivo (K. Yoshida et al., Circulation 108 (2003),1746-1752). On isolated adult cardiac myocytes, LPA leads to cellular hypertrophy and to activation of different kinases known to be relevant for a hypertrophie response (Y.-J. Xu et al., Biochemical Pharmacology 59 (2000), 1163-1171). Studies on néonatal myocytes confirmed a rôle of LPA in the induction of hypertrophy and revealed the relevance of a rho kinase-dependent pathway (R. Hilal-Dandan et al., J. Mol. Cell. Cardiol. 36 (2004), 481-493). The relevance of rho kinase underlines the involvement ofthe Edg-2 receptors which, in contrastto Edg-7 receptors, are coupled to G_a12/13 proteins. LPA furthermore atténuâtes the force of contraction in human myocardial ventricular and atrial préparations and impairs isoprenaline-induced fractional shortening of isolated adult rat ventricular myocytes. The latter effects were reverted after pre-incubation with pertussis toxin indicating the relevance of a GPCR-mediated and G_ai/₀-mediated pathway (B. Cremers et al., J. Mol. Cell. Cardiol. 35 (2003), 71-80). LPA was also found to lead to enhanced matrix génération and prolifération of cardiac fibroblasts (J. Chen et al., FEBS Letters 580 (2006), 4737-4745).

The importance of influencing Edg-2 receptor signaling and LPA-mediated effects for many diseases was confirmed by pharmacological approaches using spécifie tool compounds or Edg2 receptor knock-out mice or by experimental silencing ofthe Edg-2 receptors. For example, the relevance of LPA-activated Edg receptors for rénal diseases was demonstrated by different kinds of Edg-2/Edg-7 receptor inhibitors. In one approach, it was shown that the LPA-induced proliférative response of mesangial cells could be inhibited by the compound DGPP(8:0) (Y. Xing et al., Am. J. Physiol. Cell Physiol. 287 (2004), F1250-F1257). In another approach using the Edg-2/Edg-7 receptor inhibitor VPC12249 it was demonstrated in an in vivo model of mouse rénal ischemia reperfusion that LPA displays a dual rôle in renoprotection. While Edg-4 receptor signaling was shown to be bénéficiai, Edg-2 and Edg-7 receptor signaling aggravated rénal injury, most probably due to enhanced infiltration of leukocytes into the rénal tissue, and should therefore be blocked for treating or preventing ischemia/reperfusion-induced acute rénal failure (M. D. Okusa et al., Am. J. Physiol. Rénal Physiol. 285 (2003), F565-F574). The crucial rôle of Edg-2 receptors in the development of tubulointerstitial fibrosis was confirmed in a model of unilatéral urétéral obstruction (J. P. Pradere et al., J. Am. Soc. Nephrol. 18 (2007), 3110-3118). In this model, rénal injury was attenuated in Edg-2 receptor knock-out mice or by pharmacological treatmentwith the Edg-2/Edg-7 receptor inhibitor KI16425. The impact ofthe LPA/Edg-2 receptor system in pulmonary fibrosis and vascular leakage was recently confirmed by the finding that the bioactive content of LPA was increased in bronchoalveolar fluid of humans suffering from idiopathic pulmonary fibrosis. Edg-2 receptor knock-out mice were protected from bleomycin-induced lung injury and vascular leakage, as compared to wild-type littermates (A. M. Tager et al., Nat. Med. 14 (2008), 45-54).

Direct involvement of Edg-2 receptors was recently demonstrated for the progression of bone metastasis in vivo. Progression was reduced under pharmacological treatment with the Edg2/Edg-7 receptor inhibitor KÏ16425 as well as after spécifie silencing ofthe Edg-2 receptors in the same order of magnitude (A. Boucharaba et al., Proc. Natl. Acad. Sci. 103 (2006), 96439648). The relevance of Edg-2 receptors was also shown in vitro with respect to prostate cancer cell prolifération and metastatic potential of human colon carcinoma cells (R. Guo et al., Endocrinology 147 (2006), 4883-4892; D. Shida et al., Cancer Res. 63 (2003), 1706-1711).

The relevance of LPA-mediated Edg-2 receptor signaling was also demonstrated in an in vivo model of neuropathie pain. Intrathecal injection of LPA mimicked behavioral, morphological and biochemical alterations similar to those observed after peripheral nerve injury. Non-redundant function of Edg-2 receptors was demonstrated in Edg-2 receptor déficient mice which did not develop signs of neuropathie pain after nerve injury. Therefore, Edg-2 receptor signaling is regarded as crucial in the initiation of neuropathie pain (M. Inoue et al., Nat. Med. 10 (2004), 712-718). Thus, it is évidentthat inhibition ofthe Edg-2 receptor and the effects of LPA by suitable inhibitors is an attractive approach for treating various diseases.

Certain compounds which exhibit Edg-2 inhibitory activity, hâve already been described. For example, as compounds which are structurally related to LPA, the above-mentioned compounds DGPP(8:0) or VPC12249 may be mentioned. In WO 02/29001 and WO 2005/115150 amino compounds comprising a phosphate group, phosphonate group or hydroxy group are described which hâve activity as agonists or antagonists of LPA receptors. LPA receptor antagonistic azole compounds which are characterized by a carbamate group in the 4position ofthe azole ring, are described in EP 1258484. The use of azole compounds, further heterocycles and other compounds for modulating the Edg-2, Edg-3, Edg-4 and Edg-7 receptor is described in WO 03/062392. Compounds which hâve LPA receptor, especially Edg-2, antagonistic activity and which comprise a β-alanine moiety carrying a biphenyl-2-carbonyl group on the amino group, or an alcohol group and at least three cyclic groups, are described in EP 1533294 and EP 1695955, respectively. But there still is a need for further Edg-2 inhibitors which exhibit a favorable property profile and can be used in the treatment of diseases such as the above-mentioned ones and other diseases in which LPA signaling and Edg-2 receptors play a rôle. The présent invention satisfies this need by providing the acylamino-substituted cyclic carboxylic acid dérivatives ofthe formula I defined below.

Certain acylamino-substituted cyclic carboxylic acid dérivatives hâve already been described. In WO 2004/011457, which relates to 1-phenylpiperidin-3-one dérivatives carrying a 1acylaminocyclohexylcarbonylamino substituent in the 4-position ofthe piperidine ring and exhibiting cysteine protease inhibitory activity, the compounds 1-[(biphenyl-4-carbonyl)-amino]cyclohexanecarboxylic acid, 1-[4-(2-oxo-pyrrolidin-1-yl)-benzoylamino]-cyclohexanecarboxylic acid, 1-[4-(2-pyrrolidin-1-yl-ethoxy)-benzoylamino]-cyclohexanecarboxylic acid, 1 -[4-(2-piperidin1 -yl-ethoxy)-benzoylamino]-cyclohexanecarboxylic acid and 1 -{[4-(2-oxo-pyrrolidin-1 -yl)-furan-2carbonyl]-amino}-cyclohexanecarboxylic acid, i.e. the compounds ofthe formula I in which the ring A is an unsubstituted cyclohexane ring, R²⁰ is hydrogen, R⁵⁰ is hydroxy and the ring comprising Y and Z and carrying R²¹ and R²² is biphenyl-4-yl, 4-(2-oxo-pyrrolidin-1-yl)-phenyl, 4(2-pyrrolidin-1 -yl-ethoxy)-phenyl, 4-(2-piperidin-1-yl-ethoxy)-phenyl and 4-(2-oxo-pyrrolidin-1-yl)furan-2-yl, are disclosed as intermediates in the synthesis ofthe pharmacological active compounds. In WO 2004/052921, which relates to acylamino-substituted carboxamides carrying a cyano group in the substituent on the carboxamide nitrogen atom and exhibiting likewise cysteine protease inhibitory activity, the compound 1-(2',3-dichloro-biphen-4-ylcarbonylamino)cycloheptanecarboxylic acid (= 1-[(2',3-dichloro-biphenyl-4-carbonyl)-amino]cycloheptanecarboxylic acid), i.e. the compound ofthe formula I in which the ring A is an unsubstituted cycloheptane ring, R²⁰ is hydrogen, R⁵⁰ is hydroxy and the ring comprising Y and Z and carrying R²¹ and R²² is 2',3-dichloro-biphen-4-yl (= 2',3-dichloro-biphenyl-4-yI), is disclosed as an intermediate in the synthesis of the pharmacological active compounds. Elsewhere the said compound disclosed in WO 2004/052921 is identified as 1-[[(2,2'dichloro[1,T]biphenyl)-4-yl)carbonyl)-amino]cycloheptanecarboxylic acid (= 1-[(2,2'-dichlorobiphenyl-4-carbonyl)-amino]-cycloheptanecarboxylic acid), i.e. as the compound ofthe formula I in which the ring A is an unsubstituted cycloheptane ring, R²⁰ is hydrogen, R⁵⁰ is hydroxy and the ring comprising Y and Z and carrying R²¹ and R²² is 2,2'-dichloro-biphenyl-4-yl. In US 4871387, which relates to pyri(mi)dyl-oxy- and -thio-benzoic acid dérivatives exhibiting herbicidal and plant growth regulatory activity, the compound 1-(4-(4,6-dimethyl-pyrimidin-2ylsulfanyl)-benzoylamino]-cyclopentanecarboxylic acid ethyl ester, i.e. the compound of the formula I in which the ring A is an unsubstituted cyclopentane ring, R²⁰ is hydrogen, R⁵⁰ is ethoxy and the ring comprising Y and Z and carrying R²¹ and R²² is 4-(4,6-dimethyl-pyrimidin-2ylsulfanyl)-phenyl, is disclosed. In WO 02/06232, which relates to azacycloalkanes carrying a phenyl group on the ring nitrogen atom and a hydroxyalkyl-amino substituent on a ring carbon atom and exhibiting agonistic activity on β₃ adrenergic receptors, the compound 1-[4-(4-oxopiperidin-1-yl)-benzoylamino]-cyclopropanecarboxylic acid methyl ester, i.e. the compound of the formula l in which the ring A is an unsubstituted cyclopropane ring, R²⁰ is hydrogen, R⁵⁰ is méthoxy and the ring comprising Y and Z and carrying R²¹ and R²² is 4-(4-oxo-piperidin-1-yl)phenyl, is disclosed as an intermediate in the synthesis ofthe pharmacological active compounds. In WO 99/49856, which relates to very broadly defined compounds which médiate immune or inflammatory response through the CD11/CD18 family of cellular adhesion molécules, the compound 1-[2-chloro-4-(3-hydroxy-benzylcarbamoyl)-benzoylamino]cyclopropanecarboxylic acid, i.e. the compound ofthe formula l in which the ring A is an unsubstituted cyclopropane ring, R²⁰ is hydrogen, R⁵⁰ is hydroxy and the ring comprising Y and Z and carrying R²¹ and R²² is 2-chloro-4-(3-hydroxy-benzylcarbamoyl)-phenyl, is disclosed.

A subject ofthe présent invention is a compound ofthe formula I, in any of its stereoisomeric forrns or a mixture of stereoisomeric forrns in any ratio, or a physiologically acceptable sait thereof,

wherein ring A is a 3-membered to 12-membered monocyclic, bicyclic or spirocyclic ring which comprises 0, 1 or 2 identical or different hetero ring members chosen from the sériés consisting of N, N(R°), O, S, S(O) and S(O)₂, and which is saturated or comprises 1 double bond, provided that ring A is not a bicyclo[3.1.0]hexane or bicyclo[3.2.0]heptane ring carrying the groups N(R²⁰) and C(O)-R⁵⁰ in its position 3, and not an octahydropentalene, octahydroindene or decahydroazulene ring carrying the groups N(R²⁰) and C(O)-R⁵⁰ in its position 2, wherein ring A is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the sériés consisting of halogen, R¹, R², (C2-C6)-alkenyl, HO-, R¹-O-, phenyl-(Cr C4)-alkyl-O-, R¹-C(O)-O-, R¹-S(O)2-O-, R¹-S(O)m-, H₂N-, R¹-NH-, R¹-N(R¹)-, R¹-C(O)-NH-, R¹C(O)-N(R¹)-, R¹-S(O)2-NH-, R¹-S(O)2-N(R¹)-, R¹-C(O)-, HO-C(O)-, R¹-O-C(O)-, H2N-C(O)-, r¹NH-C(O)-, R¹-N(R¹)-C(O)-, H2N-S(O)₂-, R¹-NH-S(O)2-, R¹-N(R¹)-S(O)2-, F₅S-, NC-, oxo and methylene;

Y is chosen from the sériés consisting of N(R¹⁰), S, O, C(R¹²)=C(R¹³), N=C(R¹⁴) and C(R¹⁵)=N;

Z is chosen from the sériés consisting of N and C(R¹⁶);

R° is chosen from the sériés consisting of hydrogen and R¹;

R¹ is chosen from the sériés consisting of (Ci-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)cycloalkyl-(C-|-C4)-alkyl-;

R² is (C_rC₄)-alkyl which is substituted by one or more identical or different substituents chosen from the sériés consisting of HO- and (C_rC₄)-alkyl-O-;

R¹⁰ is chosen from the sériés consisting of hydrogen and R¹¹;

R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ are, independently of each other group R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, chosen from the sériés consisting of (Ci-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂C₆)-alkynyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl- which are ail optionally substituted by one or more identical or different substituents R⁷⁰;

R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently of each other chosen from the sériés consisting of hydrogen, halogen, (Ci-C₄)-alkyl, HO-(C₁-C₄)-alkyl-, (Ci-C₄)-alkyl-O-, (C₁-C₄)-alkyl-S(O)_m-, H₂N-, (C₁-C₄)-alkyl-NH-, (C₁-C₄)-alkyl-N((C₁-C₄)-alkyl)-, (C_rC₄)-alkyl-C(O)- and NC-, or R¹³ or R¹⁴, togetherwith the one ofthe groups R²¹ and R²²which is not the group ofthe formula II, forms a chain consisting of 3 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members chosen from the sériés consisting of N(R¹⁷), O and S, but two hetero chain members cannot be présent in adjacent positions, and the other chain members are identical or different groups C(R^1S)(R¹⁸);

R¹⁷ and R²⁵ are independently of each other chosen from the sériés consisting of hydrogen and (Ci-C₄)-alkyl;

R¹⁸, independently of each other group R¹⁸, is chosen from the sériés consisting of hydrogen, fluorine and (Ci-C₄)-alkyl, or two ofthe groups R¹⁸ bonded to the same carbon atom, together with the carbon atom carrying them, form a 3-membered to 6-membered cycloalkane ring which is optionally substituted by one more identical or different substituents chosen from the sériés consisting of fluorine and (C_rC₄)-alkyl;

R²⁰ is chosen from the sériés consisting of hydrogen and (Ch-C^-alkyl;

one ofthe groups R²¹ and R²² is a group oftheformula II

R²⁴-R²³- Il and the other ofthe groups R²¹ and R²² is chosen from the sériés consisting of hydrogen, halogen, R³⁰, HO-, R³⁰-O-, R³⁰-C(O)-O-, R³⁰-S(O)2-O-, R³⁰-S(O)m-, H_ZN-, R³⁰-NH-, R³⁰-N(R³⁰)-, R³⁰-C(O)-NH-, R³⁰-C(O)-N(R⁷¹)-, R³⁰-S(O)2-NH-, R³⁰-S(O)2-N(R⁷¹)-, R³⁰-C(O)-, HO-C(O)-, r³⁰-oC(O)-, H2N-C(O)-, R³⁰-NH-C(O)-, R³⁰-N(R³⁰)-C(O)-, H2N-S(O)₂-, R³⁰-NH-S(O)2-, R³⁰-N(R³⁰)S(O)2-, NC-, O₂N- and Het¹, or together with R¹³ or R¹⁴ forms a chain as specified in the définition of R¹³ and R¹⁴;

R²³ is a direct bond or a chain consisting of 1 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members chosen from the sériés consisting of N(R²⁵), O, S, S(O) and S(O)₂, but two hetero chain members can be présent in adjacent positions only if one of them is chosen from the sériés consisting of S(O) and S(O)₂ and the other is chosen from the sériés consisting of N(R²⁵), O and S, and the other chain members are identical or different groups C(R²⁶)(R²⁶);

R²⁴ is a 3-membered to 10-membered, monocyclic or bicyclic ring, which is saturated and contains 0 or 1 hetero ring members, or is unsaturated and contains 0, 1 or 2 identical or different hetero ring members, wherein the hetero ring members are chosen from the sériés consisting of N, N(R³²), O, S, S(O) and S(O)2, and wherein the ring is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the sériés consisting of halogen, R³³, oxetanyl, HO-, R³³-O-, R³³-C(O)-O-, R³³-S(O)2-O-, R³³-S(O)m-, H2N-, R³³-NH-, R³³-N(R³³)-, R³³-C(O)-NH-, R³³-C(O)-N(R⁷¹)-, R³³-S(O)2-NH-, R³³-S(O)2-N(R⁷¹)-, HzN-S(O)₂-NH-, R³³-NH-S(O)2-NH-, R³³-N(R³³)-S(O)2-NH-, H₂N-S(O)₂-N(R⁷¹)-, R³³-NH-S(O)2N(R⁷¹)-, R³³-N(R³³)-S(O)2-N(R⁷¹)-, R³³-C(O)-, HO-C(O)-, R³³-O-C(O)-, H2N-C(O)-, R³³-NH-C(O)-, R³³-N(R³³)-C(O)-, H2N-S(O)₂-, R³³-NH-S(O)2-, R³³-N(R³³)-S(O)2-, NC-, O₂N- and oxo ;

R²⁶, independently of each other group R^2S, is chosen from the sériés consisting of hydrogen, fluorine, (Ci-C₄)-alkyl and HO-, or two groups R²⁶ bonded to the same carbon atom together are oxo, or two of the groups R²⁶ or one group R²⁵ and one group R²⁶, together with the comprised chain members, form a 3-membered to 7-membered monocyclic ring which is saturated and contains 0, 1 or 2 identical or different hetero ring members chosen from the sériés consisting of N, N(R³⁴), O, S, S(O) and S(O)₂, which ring is optionally substituted on ring carbon atoms by one more identical or different substituents chosen from the sériés consisting of fluorine and (CrC^-alkyl;

R³² and R³⁴ are independently of each other chosen from the sériés consisting of hydrogen, R³⁵, R³⁵-S(O)₂-, R³⁵-C(O)-, R³⁵-O-C(O)- and phenyl;

R⁵⁰ is chosen from the sériés consisting of R⁵¹-O- and R⁵²-N(R⁵³)-;

R⁵¹ is chosen from the sériés consisting of hydrogen and R⁵⁴;

R⁵² is chosen from the sériés consisting of hydrogen, R⁵⁵, NC- and R⁵⁶-S(O)₂-;

R⁵³ is chosen from the sériés consisting of hydrogen and R⁵⁷;

R⁵⁶ is chosen from the sériés consisting of R⁵⁸ and phenyl;

R⁶⁰, independently of each other group R⁶⁰, is chosen from the sériés consisting of hydrogen and (C-|-C₄)-alkyl;

R⁷⁰ is chosen from the sériés consisting of HO-, R⁷¹-O-, R⁷¹-C(O)-O-, R⁷¹-S(O)m-, H2N-, R⁷¹-NH-, R⁷¹-N(R⁷¹)-, R⁷¹-C(O)-NH-, R⁷¹-C(O)-N(R⁷¹)-, R⁷¹-S(O)2-NH-, R⁷¹-S(O)2-N(R⁷¹)-, HO-C(O)-, R⁷¹O-C(O)-, H2N-C(O)-, R⁷¹-NH-C(O)-, R⁷¹-N(R⁷¹)-C(O)-, H2N-S(O)2-, R⁷¹-NH-S(O)2-, R⁷¹-N(R⁷¹)S(O)₂- and oxo;

R⁷¹, independently of each other group R⁷¹, is chosen from (C₁-C₄)-alkyl, (C₃-C₄)-cycloalkyl and (C₃-C₄)-cycloalkyl-(C₁-C₂)-alkyl-;

Het¹ is a monocyclic 4-membered to 7-membered heterocyclic ring which comprises 1 or 2 identical or different hetero ring members chosen from the sériés consisting of N, N(R⁶⁰), O, S, S(O) and S(O)₂, which ring is saturated and is optionally substituted by one or more identical or different substituents chosen from the sériés consisting of fluorine and (C^C^-alkyl;

m, independently of each other number m, is an integer chosen from the sériés consisting of 0, and 2;

phenyl, independently of each other group phenyl, is optionally substituted by one or more identical or different substituents chosen from the sériés consisting of halogen, (Ci-C₄)-aIkyl, (Ci-C₄)-alkyl-O- and NC-, unless specified otherwise;

cycloalkyl, independently of each other group cycloalkyl, and independently of any other substituents on cycloalkyl, is optionally substituted by one or more identical or different substituents chosen from fluorine and (C₁-C₄)-alkyl;

alkyl, alkenyl and alkynyl, independently of each other group alkyl, alkenyl and alkynyl, and independently of any other substituents on alkyl, alkenyl and alkynyl, is optionally substituted by one or more fluorine substituents;

provided that the compound of the formula I is not 1-[(biphenyl-4-carbonyl)-amino]cyclohexanecarboxylic acid, 1 -[4-(2-pyrrolidin-1 -yl-ethoxy)-benzoylamino]cyclohexanecarboxylic acid, 1 -[4-(2-piperidin-1 -yl-ethoxy)-benzoylamino]-cyclohexanecarboxylic acid, 1-[4-(2-oxo-pyrrolidin-1-yl)-benzoylamino]-cyclohexanecarboxylic acid, 1-{[4-(2-oxopyrrolidin-1-yl)-furan-2-carbonyl]-amino}-cyclohexanecarboxylic acid, 1-[(2',3-dichloro-biphenyl4-carbonyl)-amino]-cycloheptanecarboxylic acid, 1-(4-(4,6-dimethyl-pyrimidin-2-ylsulfanyl)benzoylamino]-cyclopentanecarboxylic acid ethyl ester, 1-[4-(4-oxo-piperidin-1-yl)benzoylamino]-cyclopropanecarboxylic acid methyl ester or 1-[2-chloro-4-(3-hydroxybenzylcarbamoyl)-benzoylamino]-cyclopropanecarboxylic acid.

If structural éléments such as groups, substituents or numbers, for example, can occur several times in the compounds of the formula I, they are ail independent of each other and can in each case hâve any of the indicated meanings, and they can in each case be identical to or different from any other such element. ln a dialkylamino group, for example, the alkyl groups can be identical or different.

Alkyl groups, i.e. saturated hydrocarbon residues, can be linear (straight-chain) or branched. This also applies if these groups are substituted or are part of another group, for example an alkyl-O- group (alkyloxy group, alkoxy group) or an HO-substituted alkyl group (hydroxyalkyl group). Depending on the respective définition, the number of carbon atoms in an alkyl group can be 1, 2, 3, 4, 5 or 6, or 1, 2, 3 or 4, or 1, 2 or 3, or 1 or 2, or 1. ln one embodiment of the invention, a (C-t-Csj-alkyl group présent in any position ofthe compounds ofthe formula I is a (Ci-C₄)-alkyl group, in another embodiment a (C₁-C₃)-aIkyl group, in another embodiment a (C_r C₂)-alkyl group, in another embodiment a (C₂-C₃)-alkyl group, in another embodiment a methyl group, where any (CpCej-alkyl group présent in the compounds ofthe formula I can independently of each other (C₄ -C₆)-alkyl group be a group of any of these embodiments. In one embodiment ofthe invention, a (C_rC₄)-alkyl group présent in any position ofthe compounds of the formula I is a (C_rC₃)-alkyl group, in another embodiment a (CrC₂)-alkyl group, in another embodiment a (C₂-C₃)-alkyl group, in another embodiment a methyl group, where any (CrC₄)alkyl group présent in the compounds ofthe formula I can independently of each other (CrC₄)alkyl group be a group of any of these embodiments. Examples of alkyl are methyl, ethyl, propyl including n-propyl and isopropyl, butyl including n-butyl, sec-butyl, isobutyl and tert-butyl, pentyl including n-pentyl, 1-methylbutyl, isopentyl, neopentyl and tert-pentyl, and hexyl including nhexyl, 3,3-dimethylbutyl and isohexyl. Examples of alkyl-O- groups are methoxy, ethoxy, npropoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy. Examples of alkyl-S(O)_m- are methylsulfanyl- (CH₃-S-), methanesulfinyl- (CH₃-S(O)-), methanesulfonyl (CH₃-S(O)₂-), ethylsulfanyl- (CH₃-CH₂-S-), ethanesulfinyl- (CH₃-CH₂-S(O)-), ethanesulfonyl (CH₃-CH₂-S(O)₂-), 1-methylethylsulfanyl- ((CH₃)₂CH-S-), 1-methylethanesulfinyl- ((CH₃)₂CH-S(O)-), 1methylethanesulfonyl ((CH₃)₂CH-S(O)₂-). In one embodiment ofthe invention the number m is chosen from 0 and 2, wherein ail numbers m are independent of each other and can be identical or different. In another embodiment the number m in any of its occurrences is, independent of its meaning in other occurrences, 0. In another embodiment the number m in any of its occurrences is, independent of its meaning in other occurrences, 2.

A substituted alkyl group can be substituted in any positions, provided that the respective compound is sufficiently stable and is suitable as a pharmaceutical active compound. The prerequisite that a spécifie group and a compound oftheformula I are sufficiently stable and suitable as a pharmaceutical active compound, applies in general with respect to the définitions of ail groups in the compounds of the formula I. An alkyl group which is optionally substituted by one or more fluorine substituents can be unsubstituted, i.e. not carry fluorine substituents, or substituted, for example by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 fluorine substituents, or by 1, 2, 3, 4, 5, 6 or 7 fluorine substituents, or by 1, 2, 3, 4 or 5 fluorine substituents, or by 1, 2 or 3 fluorine substituents, which can be located in any positions. For example, in a fluoro-substituted alkyl group one or more methyl groups can carry three fluorine substituents each and be présent as trifluoromethyl groups, and/or one or more methylene groups (CH₂) can carry two fluorine substituents each and be présent as difluoromethylene groups. The explanations with respect to the substitution of a group by fluorine also apply if the group additionally carries other substituents and/or is part of another group, for example of an alkyl-O- group. Examples of fluoro-substituted alkyl groups are trifluoromethyl, 2-fluoroethyl, 1-fluoroethyl, 1,1 -difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3,3-pentafluoropropyl, 4,4,4trifluorobutyl and heptafluoroisopropyl. Examples of fluoro-substituted alkyl-O- groups are trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and 3,3,3-trifluoropropoxy. Examples of fluoro-substituted alkyl-S(O)_m-groups are trifluoromethylsulfanyl- (CF₃-S-), trifluoromethanesulfinyl- (CF₃-S(O)-) and trifluoromethanesulfonyl (CF₃-S(O)₂-).

The above explanations with respect to alkyl groups apply correspondingly to unsaturated hydrocarbon residues, i.e. alkenyl groups, which in one embodiment ofthe invention contain one double bond, and alkynyl groups, which in one embodiment ofthe invention contain one triple bond. Thus, for example, alkenyl groups and alkynyl groups can likewise be linear or branched, and substituted alkenyl and alkynyl groups can be substituted in any positions, provided that the resulting compound is sufficiently stable and is suitable as a pharmaceutical active compound. Double bonds and triple bonds can be présent in any positions. The number of carbon atoms in an alkenyl or alkynyl group can be 2, 3, 4, 5 or 6, for example 2, 3, 4 or 5, or 2, 3 or 4. Examples of alkenyl and alkynyl are ethenyl (vinyl), prop-1-enyl, prop-2-enyl (allyl), but-2-enyl, 2-methylprop-2-enyl, 3-methylbut-2-enyl, hex-3-enyl, hex-4-enyl, 4-methylhex-4-enyl, ethynyl, prop-1-ynyl, prop-2-ynyl (propargyl), but-2-ynyl, but-3-ynyl, 4-methylpent-2-ynyl, hex-4ynyl and hex-5-ynyl. In one embodiment ofthe invention, an alkenyl or alkynyl group contains at least three carbon atoms and is bonded to the remainder ofthe molécule via a carbon atom which is not part of a double bond or triple bond.

The above explanations with respect to alkyl groups apply correspondingly to alkanediyl groups (divalent alkyl groups), including chains of one or more groups C(R²⁶)(R²⁶) and chains of one or more groups C(R¹⁸)(R¹⁸) which groups as such and chains of such groups are alkanediyl groups in case R²⁶ and R¹⁸ is chosen from hydrogen and (CrC^-alkyl, or are substituted alkanediyl groups in case any ofthe groups R²⁶ and R¹⁸ has a meaning different from hydrogen and (C_r C₄)-alkyl. Likewise, the alkyl part of a substituted alkyl group can also be regarded as an alkanediyl group. Thus, alkanediyl groups can also be linear or branched, the bonds to the adjacent groups can be located in any positions and can start from the same carbon atom or from different carbon atoms, and they can be substituted by fluorine substituents. Examples of alkanediyl groups are -CH₂-, -CH₂-CH₂-, -CH₂-CH₂-CH₂-, -CH₂-CH₂-CH₂-CH₂-, -CH₂-CH₂-CH₂-CH₂-CH₂-, -CH(CH₃)-, -C(CH₃)₂-CH(CH₃)-CH₂-, -CH₂-CH(CH₃)-, -C(CH₃)₂-CH₂-, -CH₂-C(CH₃)₂~. Examples of fluoro-substituted alkanediyl groups, which can contain 1, 2, 3, 4, 5 or 6 fluorine substituents, or 1, 2, 3 or 4 fluorine substituents, or 1 or 2 fluorine substituents for example, are -CHF-, -CF₂-, -CF₂-CH₂-, -CH₂-CF₂-, -CF₂-CF₂-, -CF(CH₃)-, -C(CF₃)₂-, -C(CH₃)₂-CF₂-, -CF₂-C(CH₃)₂-,

The number of ring carbon atoms in a (C₃-C₇)-cycloalkyl group can be 3, 4, 5, 6 or 7. Examples of cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cycloalkyl groups which are optionally substituted by one or more (CrC^-alkyl substituents, can be unsubstituted, i.e. not carry alkyl substituents, or substituted, for example by 1, 2, 3 or 4, or by 1 or 2, identical or different (CrC^-alkyl substituents, for example by methyl groups, which substituents can be located in any positions. Examples of such alkyl-substituted cycloalkyl groups are 1-methylcyclopropyl, 2,2-dimethylcyclopropyl, 1-methylcyclopentyl, 2,3dimethylcyclopentyl, 1-methylcyclohexyl, 4-methylcyclohexyl, 4-isopropylcyclohexyl, 4-tertbutylcyclohexyl and 3,3,5,5-tetramethylcyclohexyl. Cycloalkyl groups which are optionally substituted by one or more fluorine substituents, can be unsubstituted, i.e. not carry fluorine substituents, or substituted, for example by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 fluorine substituents, or by 1, 2, 3, 4, 5 or 6 fluorine substituents, or by 1, 2, 3 or 4 fluorine substituents, or by 1 or 2 fluorine substituents. The fluorine substituents can be located in any positions of the cycloalkyl group and can also be located in an alkyl substituent on the cycloalkyl group. Examples of fluoro-substituted cycloalkyl groups are 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, 3,3difluorocyclobutyl, 1-fluorocyclohexyl, 4,4-difluorocyclohexyl and 3,3,4,4,5,5hexafluorocyclohexyl. Cycloalkyl groups can also be substituted simultaneously by fluorine and alkyl. Examples ofthe group (Cs-Cyj-cycloalkyl-fCrC^-alkyl- are cyclopropylmethyl-, cyclobutylmethyl-, cyclopentylmethyl-, cyclohexylmethyl-, cycloheptylmethyl-, 1cyclopropylethyl-, 2-cyclopropylethyl-, 1-cyclobutylethyl-, 2-cyclobutylethyl-, 1-cyclopentylethyl-,

2-cyclopentylethyl-, 1-cyclohexylethyl-, 2-cyclohexylethyl-, 1 -cycloheptylethyl-, 2cycloheptylethyl-. The explanations with respect cycloalkyl groups apply correspondingly to unsaturated cycloalkyl groups such as cycloalkenyl groups which can occur in the group R²⁴ and which in one embodiment ofthe invention contain one double bond which can be présent in any positions, and to divalent cycloalkyl groups (cycloalkanediyl groups), which latter groups can occur in case two ofthe groups R²⁶ togetherwith the comprised chain members form a ring ortwo ofthe groups R¹⁸ togetherwith the carbon atom carrying them form a ring. Likewise, the cycloalkyl part of a substituted cycloalkyl group can also be regarded as a cycloalkanediyl group. Thus, for example, the bonds through which a cycloalkanediyl group, such as a ring formed by two ofthe groups R²⁶ together with the comprised chain members, is connected to the adjacent groups, can be located in any positions and can start from the same ring carbon atom or from different ring carbon atoms, unless specified otherwise.

In substituted phenyl groups, including phenyl groups which representthe 3-membered to 10membered, monocyclic or bicyclic ring representing R²⁴, the substituents can be located in any positions. In monosubstituted phenyl groups, the substituent can be located in the 2-position, the 3-position or the 4-position. In disubstituted phenyl groups, the substituents can be located in 2,3-position, 2,4-position, 2,5-position, 2,6-position, 3,4-position or 3,5-position. In trisubstituted phenyl groups, the substituents can be located in 2,3,4-position, 2,3,5-position, 2,3,6-position, 2,4,5-position, 2,4,6-position or 3,4,5-position. If a phenyl group carries four substituents, some of which can be fluorine atoms, for example, the substituents can be located in 2,3,4,5-position, 2,3,4,6-position or 2,3,5,6-position. If a polysubstituted phenyl group or any other polysubstituted group such as a heteroaryl group carries different substituents, each substituent can be located in any suitable position, and the présent invention comprises ail positional isomers. The number of substituents in a substituted phenyl group can be 1, 2, 3, 4 or 5. In one embodiment ofthe invention, a substituted phenyl group, and likewise another substituted group such as a heteroaryl group, carries 1, 2 or 3, for example 1 or 2, identical or different substituents.

In heterocyclic groups, including the group Het¹ and heterocyclic rings which can be présent in structural éléments in the compounds ofthe formula I, such as the ring A, or the 3-membered to 10-membered ring representing R²⁴, or a ring formed by a group R²⁵ and a group R²⁶ together with the comprised chain members, or a ring formed by a group R¹³ or R¹⁴ with one ofthe groups R²¹ and R²² and the carbon atoms carrying these groups, for example, the hetero ring members specified in the respective définition can be présent in any combination and located in any suitable ring positions, provided that the resulting group and the compound of the formula I are sufficiently stable and suitable as a pharmaceutical active compound. In one embodiment of the invention two oxygen atoms in any heterocyclic ring in the compounds of the formula I cannot be présent in adjacent ring positions. In another embodiment ofthe invention two hetero ring members in any non-aromatic heterocyclic ring in the compounds ofthe formula I cannot be présent in adjacent ring positions. In another embodiment two hetero ring members from the sériés consisting of O, S and N atoms carrying a hydrogen atom or a substituent, cannot be présent in adjacent ring positions. Examples of such sériés are the hetero ring members O, S and N(R°), or O, S and N(R³²), or O, S and N(R³⁴), or O, S and N(R⁶⁰), or the hetero chain members O, S and N(R¹⁷) which are part of a ring. In another embodiment ofthe invention two hetero ring members from the sériés consisting of S(O) and S(O)₂ cannot be présent in adjacent ring positions, in an aromatic heterocyclic ring the choice of hetero ring members and their positions is limited by the prerequisite that the ring is aromatic, i.e. it comprises a cyclic system of six delocalized pi électrons. The residue of a monocyclic, 5-membered or 6-membered, aromatic heterocyclic ring, which can occur as the 3-membered to 10 membered ring representing R²⁴, can also be designated as monocyclic, 5-membered or 6-membered heteroaryl group. The ring nitrogen atom in such a heteroaryl group which carries the group R³², is the ring nitrogen atom in a 5-membered ring such as pyrrole, pyrazole or imidazole to which an exocyclic atom or group such as a hydrogen atom is bonded, and can be présent once only in a 5-membered aromatic ring just as the hetero ring members O and S. Examples of rings from which such a heteroaryl group can be derived are pyrrole, furan, thiophene, imidazole, pyrazole, oxazole ([1,3]oxazole), isoxazole ([1,2]oxazole), thiazole ([1,3]thiazole), isothiazole ([1,2]thiazole), pyridine, pyridazine, pyrimidine, pyrazine. In one embodiment ofthe invention, a monocyclic, 5-membered or 6-membered heteroaryl group comprises one hetero ring member which is defined as indicated, and in another embodiment ofthe invention such a heteroaryl group is chosen from thiophenyl, thiazolyl and pyridinyl, in another embodiment from thiophenyl and pyrazolyl, in another embodiment from pyridinyl, thiophenyl and pyrazolyl, in another embodiment from thiophenyl and pyridinyl, and in another embodiment it is thiophenyl. A monocyclic, 5-membered or 6-membered heteroaryl group can be bonded via any ring carbon atom or, in the case of a 5-membered ring comprising a hetero ring member N(R³²), via a ring nitrogen atom, wherein in the latter case the bond via which the heteroaryl group is attached to the remainder ofthe molécule, replaces the group R³². In one embodiment ofthe invention, a monocyclic, 5-membered or 6-membered heteroaryl group is bonded via a ring carbon atom.

For example, a thiophenyl group (thienyl group) can be thiophen-2-yl (2-thienyl) or thiophen-3-yl (3-thienyl), furanyl can befuran-2-yl or furan-3-yl, pyridinyl (pyridyi) can be pyridin-2-yl, pyridin-

3-yl or pyridin-4-yl, pyrazolyl can be 1 H-pyrazol-3-yl, 1 H-pyrazol-4-yl or 2H-pyrazol-3-yl, imidazolyl can be 1 H-imidazol-1 -yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl or 3H-imidazolyl-4-yl, thiazolyl can be thiazol-2-yl, thiazol-4-yl or thiazol-5-yl.

In substituted monocyclic, 5-membered or 6-membered heteroaryl groups, the substituents can be located in any positions, for example in a thiophen-2-yl group or a furan-2-yl group in the 3position and/or in the 4-position and/or in the 5-position, in a thiophen-3-yl group or a furan-3-yl group in the 2-position and/or in the 4-position and/or in the 5-position, in a pyridin-2-yl group in the 3-position and/or in the 4-position and/or in the 5-position and/or in the 6-position, in a pyridin-3-yl group in the 2-position and/or in the 4-position and/or in the 5-position and/or in the

6-position, in a pyridin-4-yl group in the 2-position and/or in the 3-position and/or in the 5position and/or in the 6-position. In one embodiment ofthe invention, a substituted monocyclic, 5-membered or 6-membered heteroaryl group is substituted by 1, 2 or 3, for example 1 or 2, identical or different substituents. Generally, besides optionally carrying the substituents indicated in the définition of the group, suitable ring nitrogen atoms in a monocyclic, 5membered or 6-membered heteroaryl group representing R²⁴ or the aromatic ring comprising the groups Y and Z which are depicted in formula I, for example the nitrogen atom in a pyridinyl group, can also carry an oxido substituent -0“ and be présent as an N-oxide.

The above explanations with respect to monocyclic, 5-membered or 6-membered aromatic heterocyclic groups apply correspondingly to the bicyclic aromatic heterocyclic groups discussed below which can occur in the 3-membered to 10-membered ring representing R²⁴ and which can also be designated as a bicyclic heteroaryl group.

The rings ofthe groups Het¹ can be 4-membered, 5-membered, 6-membered or 7-membered, for example 4-membered, 5-membered or 6-membered, or 4-membered or 5-membered, or 5membered or 6-membered. The group Het¹ can be bonded via any ring carbon atom or ring nitrogen atom. In one embodiment ofthe invention, Het¹ is bonded via a ring carbon atom. Examples ofthe group Het¹ from any one or more of which Het¹ can be chosen, are azetidinyl including azetidin-1 -yl, oxetanyl including oxetan-3-yl, tetrahydrofuranyl including tetrahydrofuran-2-yl and tetrahydrofuran-3-yl, tetrahydrothiophenyl including tetrahydrothiophen2-yl and tetrahydrothiophen-3-yl, 1-oxo-tetrahydrothiophenyl including 1-oxotetrahydrothiophen-2-yl and 1-oxo-tetrahydrothiophen-3-yl, 1,1-dioxo-tetrahydrothiophenyl including 1,1-dioxo-tetrahydrothiophen-2-yl and 1,1-dioxo-tetrahydrothiophen-3-yl, pyrrolidinyl including pyrrolidin-1-yl, pyrrolidin-2-yl and pyrrolidin-3-yl, tetrahydropyranyl including tetrahydropyran-2-yl, tetrahydropyran-3-yl and tetrahydropyran-4-yl, tetrahydrothiopyranyl including tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl and tetrahydrothiopyran-4-yl, piperidinyl including piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and piperidin-4-yl, oxepanyl including oxepan-2-yl, oxepan-3-yl and oxepan-4-yl, azepanyl including azepan-1-yl, azepan-2yl, azepan-3-yl and azepan-4-yl, 1,3-dioxolanyl including 1,3-dioxolan-2-yl and 1,3-dioxolan-4-yl, imidazolidinyl including imidazolidin-1 -yl, imidazolidin-2-yl and imidazolidin-4-yl, [1,3]oxazolidinyl including [1,3]oxazolidin-2-yl, [1,3]oxazolidin-3-yl, [1,3]oxazolidin-4-yl and [1,3]oxazolidin-5-yl,

[1.3] thiazolidinyl including [1,3]thiazolidin-2-yl, [1,3]thiazolidin-3-yl, [1,3]thiazolidin-4-yl and

[1.3] thiazolidin-5-yl, [1,3]dioxanyl including [1,3]dioxan-2-yl, [1,3]dioxan-4-yl and [1,3]dioxan-5yl, [1,4]dioxanyl including [1,4]dioxan-2-yl, piperazinyl including piperazin-1-yl and piperazin-2yl, morpholinyl including morpholin-2-yl, morpholin-3-yl and morpholin-4-yl, thiomorpholinyl including thiomorpholin-2-yl, thiomorpholin-3-yl and thiomorpholin-4-yl, 1-oxo-thiomorphoiinyl including 1-oxo-thiomorpholin-2-yl, 1-oxo-thiomorpholin-3-yl and 1-oxo-thiomorpholin-4-yl, 1,1dioxo-thiomorpholinyl including 1,1-dioxo-thiomorpholin-2~yl, 1,1-dioxo-thiomorpholin-3-yl and 1,1-dioxo-thiomorpholin-4-yl, [1,3]diazepanyl, [1,4]diazepanyl, [1,4]oxazepanyl or

[1,4]thiazepanyl. Besicles by oxo groups in the ring members S(O) and S(O)₂ and alkyl groups representing R⁶⁰, the group Het¹ is optionally substituted on ring carbon atoms by one or more, for example 1, 2, 3, 4 or 5, or 1, 2, 3 or 4, or 1, 2 or 3, or 1 or 2, identical or different substituents as indicated, which can be located in any positions.

The 3-membered to 10-membered, monocyclic or bicyclic ring which is saturated or unsaturated and which contains 0, 1 or 2 identical or different hetero ring members chosen from the sériés consisting of N, N(R³²), O, S, S(O) and S(O)2, which ring represents R²⁴, can comprise 3, 4, 5, 6, 7, 8, 9 or 10 ring members. In one embodiment ofthe invention, a bicyclic ring representing R²⁴ is fused or bridged. An unsaturated ring can be partially unsaturated, i.e. non-aromatic, and contain, for example, one or two double bonds within the ring, or it can be aromatic and be a ring such as a benzene ring, for example, and altogether the number of double bonds within an unsaturated ring can be one, two, three, four or five. In a bicyclic ring, the two individual rings can independently of each other be saturated or partially unsaturated or aromatic. In one embodiment ofthe invention, a 3-membered or 4-membered ring representing R²⁴ is saturated. The 3-membered to 10-membered, monocyclic or bicyclic ring can be a carbocyclic ring, i.e. contain 0 (zéro) hetero ring members, or a heterocyclic ring in which hetero ring members can be présent as indicated above. In a bicyclic heterocyclic ring one or both individual rings can contain hetero ring members. In case nitrogen atoms are présent as hetero ring members in a bicyclic ring, they can also be présent at a fusion position or a bridgehead position. The free bond via which the ring is bonded to the group R²³, can be located at any suitable ring carbon atom or ring nitrogen atom. In one embodiment ofthe invention the free bond is located at a ring carbon atom. In general, besides by oxo groups in the ring members S(O) and S(O)2 and substituents R³² on ring nitrogen atoms, the 3-membered to 10 membered ring is optionally substituted on ring carbon atoms by one or more, for example 1, 2, 3, 4 or 5, or 1, 2, 3 or 4, or 1, 2 or 3, or 1 or 2, identical or different substituents as indicated, which can be located in any positions.

The 3-membered to 10-membered, monocyclic or bicyclic ring representing R²⁴ comprises (C₃C₇)-cycloalkyl groups, phenyl groups, monocyclic, 5-membered or6-membered aromatic heterocyclic groups and monocyclic 4-membered to 7-membered saturated groups as are comprised by the définitions of the group Het¹ referred to above. Ail these groups thus are examples ofthe said 3-membered to 10-membered ring, and ail explanations given above with respect to these groups apply correspondingly to the said 3-membered to 10-membered ring unless specified otherwise in the définition ofthe said 3-membered to 10-membered ring. Thus, for example, the substituents in these groups when representing the said 3-membered to 1017884 membered ring, such as in a phenyl group representing the said 3-membered to 10-membered ring, can then be as is specified in the définition of R²⁴. As further examples of cyclic groups which are comprised by the said 3-membered to 10-membered ring, (C₅-C₇)-cycloalkenyl groups, naphthalenyl groups and hydrogenated naphthalenyl groups, indenyl groups and hydrogenated indenyl groups, bicyclic heterocyclic groups, and bicycloalkyl and bicycloalkenyl groups and hetero analogs thereof may be mentioned.

In a (C₅-C₇)-cycloalkenyl group representing R²⁴, the number of ring carbon atoms can be 5, 6 or 7. Examples of cycloalkenyl groups are cyclopentenyl including cyclopent-1-enyl, cyclopent2-enyl and cyclopent-3-enyl, cyclohexyl including cyclohex-1-enyl, cyclohex-2-enyl and cyclohex-3-enyl, and cycloheptyl including cyclohept-1-enyl, cyclohept-2-enyl, cyclohept-3-enyl and cyclohept-4-enyl. Cycloalkenyl groups representing R²⁴ can be unsubstituted or substituted as indicated with respect to the 3-membered to 10-membered ring representing R²⁴, for example by one or more, or 1, 2, 3 or 4, or 1, 2 or 3, identical or different (Cf-C^-alkyl substituents, for example by methyl groups, which can be located in any positions. Examples of such alkyl-substituted cycloalkenyl groups are 1-methylcyclopent-2-enyl, 1-methylcyclopent-3enyl, 2,3-dimethylcyclohex-2-enyl and 3,4-dimethylcyclohex-3-enyl. Cycloalkenyl groups also are optionally substituted by one or more fluorine substituents, i.e., they can be unsubstituted by fluorine and not carry any fluorine substituents, or substituted, for example by 1, 2, 3, 4, 5, 6 or 7, or by 1, 2, 3, 4 or 5, or by 1, 2, 3 or 4, fluorine substituents. Cycloalkenyl groups can also be substituted simultaneously by fluorine and alkyl. The fluorine atoms can be located in any positions ofthe cycloalkenyl group and can also be located in an alkyl substituent on the cycloalkenyl group. Examples of fluoro-substituted cycloalkyl groups are 1-fluorocyclohex-2enyl, 1-fluorocyclohex-3-enyl and 4,4-difluorocyclohex-2-enyl.

Naphthalenyl groups (naphthyl groups) representing R²⁴ can be naphthalen-1-yl (1-naphthyl) and naphthalen-2-yl (2-naphthyl) groups, and are optionally substituted by one or more, for example by 1, 2, 3, 4 or 5, or by 1, 2 or 3, for example by 1 or 2, identical or different substituents as indicated above. The substituents in a substituted naphthalenyl group can be located in any positions, for example in the 2-position, 3-position, 4-position, 5-position, 6position, 7-position or 8-position in the case of a monosubstituted naphthalen-1-yl group and in the 1-position, 3-position, 4-position, 5-position, 6-position, 7-position or 8-position in the case of a monosubstituted naphthalen-2-yl group. Likewise, in a naphthalenyl group which carries two or more substituents, the substituents can be located in the ring to which the remainder ofthe molécule is bonded, and/or in the other ring. Examples of hydrogenated naphthalenyl groups representing R²⁴ are dihydronaphthalenyl including 1,4-dihydronaphthalenyl, tetrahydronaphthalenyl including 1,2,3,4-tetrahydronaphthalenyl and 5,6,7,8tetrahydronaphthalenyl, octahydronaphthalenyl including 1,2,3,4,5,6,7,8-octahydronaphthalenyl, and decahydronaphthalenyl. Hydrogenated naphthalenyl groups can be bonded to the remainder ofthe molécule via any ring carbon atom in a saturated or partially unsaturated or aromatic ring and are optionally substituted by one or more, for example by 1, 2, 3, 4 or 5, or by 1, 2 or 3, for example by 1 or 2, identical or different substituents as indicated above which can be located in any positions.

Indenyl groups representing R²⁴ can be 1 H-inden-1-yl, 1H-inden-2-yl, 1 H-inden-3-yl, 1H-inden-

4-yl, 1 H-inden-5-yl, 1H-inden-6-yl or 1H-inden-7-yl, for example, and are optionally substituted by one or more, for example by 1,2, 3, 4 or 5, or by 1, 2 or 3, for example by 1 or 2, identical or different substituents as indicated above which can be located in any positions. Examples of hydrogenated indenyl groups representing R²⁴ are indanyl (2,3-dihydro-1H-indenyl) and octahydroindenyl (= octahydro-1H-indenyl), which can be bonded to the remainder ofthe molécule via any ring carbon atom in a saturated or partially unsaturated or aromatic ring, for example via the 1-position, 2-position, 4-position or 5-position in the case of an indanyl group, and are optionally substituted by one or more, for example by 1, 2, 3, 4 or 5, or by 1, 2 or 3, for example by 1 or 2, identical or different substituents as indicated above which can be located in any positions.

In one embodiment of the invention, bicyclic heterocyclic groups representing R²⁴ are fused bicyclic groups in which the two rings hâve a bond in common, and can be saturated, partially unsaturated or aromatic as indicated above with respect to the 3-membered to 10-membered ring representing R²⁴ in general. They can contain 1,2, 3, 4 or 5 double bonds within the rings. Both ofthe rings can be saturated, or one ofthe rings can be saturated or partially unsaturated and the other ring partially unsaturated or aromatic, or both rings can be aromatic, i.e. comprise a cyclic system of six delocalized pi électrons. In one embodiment ofthe invention, both rings are aromatic or one of the rings is aromatic and the other ring is partially unsaturated and comprises at least one double bond due to the condensation to the aromatic ring. In one embodiment ofthe invention, a bicyclic heterocyclic group comprises 8, 9 or 10 ring members and two fused 5-membered rings or two fused 6-membered rings or a 6-membered ring fused to a 5-membered ring or a 7-membered ring fused to a 5-membered ring, in another embodiment 9 or 10 ring members and two fused 6-membered rings or a 6-membered ring fused to a 5membered ring. Hetero ring members can be présent in both rings of a bicyclic heterocyclic group or in one ofthe rings only and the other ring contain no hetero ring members. Ring nitrogen atoms can also be common to both rings. Besides being a hetero ring member in a 317884 membered to 10-membered rings representing R²⁴ such as saturated rings, a ring nitrogen atom carrying a group R³² can be the ring nitrogen atom in a fused 5-membered ring in an aromatic bicyclic heterocyclic group, such as in a fused pyrrole, pyrazole or imidazole, to which an exocyclic atom or group is bonded. Examples of rings from which a fused bicyclic heterocyclic group can be derived, are indole, isoindole, benzo[b]thiophene, benzofuran, benzo[1,3]dioxole ([1,3]benzodioxole, 1,2-methylenedioxybenzene), benzo[1,3]oxazole, benzo[1,3]thiazole, benzoimidazole, chromane, isochromane, benzo[1,4]dioxane ([1,4]benzodioxane, 1,2ethylenedioxybenzene), quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, phthalazine, pyrroloazepines, imidazoazepines, thienothiophenes, thienopyrroles, thienopyridines, naphthyridines, and the respective rings in which one or some or ail ofthe double bonds are hydrogenated, i.e. replaced with single bonds, such as 2,3-dihydro-1 H-indole, 2,3-dihydro-1Hisoindole, 2,3-dihydrobenzofuran, 1,2,3,4-tetrahydroquinoline, 5,6,7,8-tetrahydroquinoline, decahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, 5,6,7,8-tetrahydroisoquinoline, decahydroisoquinoline, for example. A bicyclic heterocyclic group can be bonded via any ring carbon atom or ring nitrogen atom. In one embodiment of the invention, a bicyclic heteroaromatic group is bonded via a ring carbon atom. For example, an indolyl group can be indol-1 -yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6- or indol-7-yl, a benzoimidazolyl group can be 1H-benzoimidazol-1-yl, 1 H-benzoimidazol-2-yl, 1 H-benzoimidazol-4-yl, 1Hbenzoimidazol-5-yl, 1H-benzoimidazol-6-yl or 1H-benzoimidazol-7-yl, a benzo[1,4]dioxanyl group can be benzo[1,4]dioxan-2-yl, benzo[1,4]dioxan-5-yl or benzo[1,4]dioxan-6-yl, a quinolinyl group (quinolyl group) can be quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6yl, quinolin-7-yl or quinolin-8-yl, an isoquinolinyl group can be isoquinolin-1-yl, isoquinolin-3-yl, isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yl or isoquinolin-8-yl. In a substituted bicyclic heteroaromatic group, the substituents can be located in any desired positions such as, for example, in an indol-2-yl group in the 1-position and/or the 3-position and/or the 4-position and/or the 5-position and/or the 6-position and/or the 7-position, in an indol-5-yl group in the 1-position and/or the 2-position and/or the 3-position and/or the 4-position and/or the 6-position and/or the 7-position, in a 1H-benzoimidazol-2-yl group in the 1-position and/or the 4-position and/or the 5-position and/or the 6-position and/or the 7-position. Generally, besides the substituents indicated above, a bicyclic heterocyclic group can also carry on suitable ring nitrogen atoms in aromatic rings, for example the nitrogen atom in a quinolinyl group or isoquinolinyl group, an oxido substituent -O and be présent as an N-oxide.

In one embodiment ofthe invention, bicycloalkyl and bicycloalkenyl groups representing R²⁴ are bridged 6-membered to 10-membered, in another embodiment 7-membered to 10-membered and bicyclic groups which can contain carbon atoms only as ring members, i.e. they can be derived from carbocyclic bicycloalkanes and bicycloalkenes, or which can also contain hetero ring members as indicated above, i.e. they can be derived from the respective heteroanalogous aza-, oxa- and thia-bicycloalkanes and -bicycloalkenes. If they contain hetero ring members, in one embodiment they contain one hetero ring member, for example one ring member chosen from the sériés consisting of N, N(R³²) and O. The hetero ring members can be présent in any desired positions in the bicyclic system including positions in the bridges and, in the case of nitrogen atoms, positions at the bridgeheads. Bicycloalkenyl and their hetero analogs can contain one or more double bonds within the rings. In one embodiment ofthe invention they contain one or two double bonds, in another embodiment one double bond, within the ring. Bicycloalkyl and bicycloalkenyl can be bonded to the remainder ofthe molécule via any ring carbon atom or ring nitrogen atom. The free bond can be located in any stereochemical position, for example in an exo position or an endo position. Bicycloalkyl and bicycloalkenyl and their hetero analogs are optionally substituted as indicated above, for example by substituents chosen from the sériés consisting of (CrC^-alkyl, (C₂-C₅)-alkenyl, HO-, HO-CH₂(hydroxymethyl-) and oxo, in any positions. Examples of bicycloalkyl and bicycloalkenyl groups and hetero analogs thereof are norbomyl (bicyclo[2.2.1]heptyl), bicyclo[3.1.1]heptyl, bicyclo[3.1.1]hept-2-enyl, bicyclo[2.2.2]octyl, bicyclo[2.2.2]oct-2-enyl, bicyclo[3.2.1 Joctyl, 7azabicyclo[2.2.1]heptyl, 1-azabicyclo[2.2.2]octyl, bicyclo[2.2.2.]oct-2-en-yl.

Halogen is fluorine, chlorine, bromine or iodine. In one embodiment ofthe invention, halogen is fluorine, chlorine or bromine, in another embodiment fluorine or chlorine, in another embodiment fluorine.

An oxo group, i.e. an oxygen atom which is bonded via a double bond, when bonded to a carbon atom, replaces two hydrogen atoms on the carbon atom ofthe parent system to which it is bonded. Thus, if a CH₂ group is substituted by oxo, it becomes a carbonyl group (C(O), C=O). An oxo group cannot occur as a substituent on a carbon atom in an aromatic ring such as in a phenyl group. Similarly, a methylene group which can occur as a substituent on the ring A and in this case is a group CH₂ bonded via a double bond, replaces two hydrogen atoms on the carbon atom ofthe parent system to which it is bonded, thus forming the group C=CH₂.

The présent invention comprises ail stereoisomeric forms ofthe compounds ofthe formula I, for example ail enantiomers and diastereomers including cis/trans isomers. The invention likewise comprises mixtures of two or more stereoisomeric forms, for example mixtures of enantiomers and/or diastereomers including cis/trans isomers, in ail ratios. Asymmetric centers contained in the compounds ofthe formula I, for example in unsubstituted or substituted alkyl groups, can ail independently of each other hâve the S configuration or the R configuration. The invention relates to enantiomers, both the levorotatory and the dextrorotatory antipode, in enantiomerically pure form and essentially enantiomerically pure form, for example with a molar ratio ofthe two enantiomers of 99 :1 orgreater, and in the form of racemates and in the form of mixtures ofthe two enantiomers in ail ratios. The invention likewise relates to diastereomers in the form of pure and essentially pure diastereomers and in the form of mixtures of two or more diastereomers in ail ratios. The invention aiso comprises ail cis/trans isomers ofthe compounds ofthe formula I in pure form and essentially pure form, for example with a molar ratio ofthe cis/trans isomers of 99 :1 or greater, and in the form of mixtures of the cis isomer and the trans isomer in ail ratios. Cis/trans isomerism can occur in substituted rings, such as the ring A, and on double bonds, for example. The préparation of individual stereoisomers, if desired, can be carried out by resolution of a mixture according to customary methods, for example, by chromatography or crystallization, or by use of stereochemically uniform starting compounds in the synthesis or by stereoselective reactions. Optionally, before a séparation of stereoisomers a derivatization can be carried out. The séparation of a mixture of stereoisomers can be carried out at the stage of the compound of the formula I or at the stage of an intermediate in the course ofthe synthesis. The invention also comprises ail tautomericforms ofthe compounds of the formula I.

Physiologically acceptable salts, including pharmaceutically utilizable salts, of the compounds of the formula I generally comprise a nontoxic sait component. They can contain inorganic or organic sait components. Such salts can be formed, for example, from compounds of the formula l which contain an acidic group, for example a carboxylic acid group (hydroxycarbonyl group, HO-C(O)-), and nontoxic inorganic or organic bases. Suitable bases are, for example, alkali métal compounds or alkaline earth métal compounds, such as sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogencarbonate, or ammonia, organic amino compounds and quatemary ammonium hydroxides. Reactions of compounds ofthe formula I with bases for the préparation ofthe salts are in general carried out according to customary procedures in a solvent or diluent. Examples of salts of acidic groups thus are sodium, potassium, magnésium or calcium salts or ammonium salts which can also carry one or more organic groups on the nitrogen atom. Compounds ofthe formula I which contain a basic, i.e. protonatable, group, for example an amino group or a basic heterocycle, can be présent in the form of their acid addition salts with physiologically acceptable acids, for example as sait with hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, acetic acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid, which in general can be prepared from the compounds ofthe formula I by reaction with an acid in a solvent or diluent according to customary procedures. If the compounds ofthe formula I simultaneously contain an acidic and a basic group in the molécule, the invention also includes internai salts (betaines, zwitterions) in addition to the sait forrns mentioned. The présent invention also comprises ail salts ofthe compounds ofthe formula I which, because of low physiological tolerability, are not directly suitable for use as a pharmaceutical, but are suitable as intermediates for chemical reactions or for the préparation of physiologically acceptable salts, for example by means of anion exchange or cation exchange. The présent invention also comprises active métabolites of compounds of the formula I and prodrugs ofthe compounds ofthe formula I, i.e. compounds which in vitro may not necessarily exhibit pharmacological activity but which in vivo are converted into pharmacologically active compounds ofthe formula I, for example compounds which are converted by metabolic hydrolysis into a compound ofthe formula I, such as compounds in which a carboxylic acid group is présent in esterified form or in the form of an amide.

The ring A can be monocyclic, i.e. comprise one ring only, or bicyclic, i.e. comprise two rings which hâve two or more ring members and one or more bonds in common and can thus be bridged or fused, or spirocyclic, i.e. comprise two rings which hâve one ring member in common. The number of ring members in the ring A can be 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12. In one embodiment ofthe invention, the ring A is 3-membered to 11-membered, in another embodiment 3-membered to 10-membered, in another embodiment 3-membered to 8membered, in another embodiment 3-membered to 7-membered, in another embodiment 5membered to 10-membered, in another embodiment 5-membered to 8-membered, in another embodiment 5-membered to 7-membered, in another embodiment 6-membered to 8membered, in another embodiment 6-membered or 7-membered. In one embodiment of the invention, a monocyclic ring representing A is 3-membered to 8-membered, in another embodiment 3-membered to 7-membered, in another embodiment 5-membered to 8membered, in another embodiment 5-membered to 7-membered, in another embodiment 6membered to 8-membered, in another embodiment 6-membered or 7-membered, in another embodiment 3-membered, 6-membered or7-membered. In one embodiment ofthe invention, a bicyclic ring representing A is 6-membered to 12-membered, in another embodiment 7membered to 12-membered, in another embodiment 6-membered to 10-membered, in another embodiment 7-membered to 10-membered, in another embodiment 6-membered to 8membered, in another embodiment 7-membered or 8-membered. In one embodiment ofthe invention, a spirocyclic ring representing A is 7-membered to 12-membered, in another embodiment 8-membered to 12-membered, in another embodiment 7-membered to 11membered, in another embodiment 8-membered to 11-membered. In ail these embodiments can the number of ring members in the ring A hâve ail those values from the general number of ring members, i.e. 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12, which are comprised by the respective embodiment. In case the ring A is a spiro-fused ring, in one embodiment ofthe invention comprises the ring which does not carry the groups N(R²⁰) and C(O)-R⁵⁰, 3, 4, 5 or 6 ring members including the spiro atom, in another embodiment 3, 4 or 5 ring members including the spiro atom. In one embodiment ofthe invention, the ring A is a monocyclic or bicyclic ring, in another embodiment a monocyclic or spirocyclic ring, in another embodiment it is a monocyclic ring, in another embodiment it is a bicyclic ring, in another embodiment it is a spirocyclic ring, wherein in ail these embodiments the rings are as indicated above or below herein.

The carbon atom in the ring A which carries the two groups N(R²⁰) and C(O)-R⁵⁰, can be présent in any ring position which allows for the binding of two groups. The hetero ring members in the ring A can be présent in any combination and can be located in any suitable position, wherein generally the two ring members in the ring A which are adjacent to the ring carbon atom carrying the groups N(R²⁰) and C(O)-R⁵⁰ are carbon atoms, as is also depicted in formula I by the two vertices (corners) in the circumferential line of ring A which, like the vertex in the circumferential line representing the carbon atom which carries the two groups N(R²⁰) and C(O)-R⁵⁰, represent carbon atoms as usual in such structural formulae. In bicyclic rings representing A, the hetero ring members can be présent in the bridges and, in the case of nitrogen atoms, at the bridgeheads. Likewise as mentioned with respect to heterocyclic rings in the compounds ofthe formula I in general, in one embodiment ofthe invention two hetero ring members from the sériés consisting of N(R°), O and S are not présent in adjacent ring positions, in another embodiment two hetero ring members from the sériés consisting of N(R°), O and S are separated by at least two ring carbon atoms, in another embodiment two hetero ring members are not présent in adjacent ring positions, in another embodiment two hetero ring members are separated by at leasttwo ring carbon atoms. In one embodiment ofthe invention, the number of hetero ring members in the ring A is 0 or 1, in another embodiment it is 1, and in another embodiment it is 0, i.e. in this latter embodiment the ring A is a carbocyclic ring. In one embodiment ofthe invention, the hetero ring members in a heterocyclic ring representing A are chosen from O, S, S(O) and S(O)₂, in another embodiment from S, S(O) and S(O)₂, in another embodiment from S(O) and S(O)₂, in another embodiment from O and S, in another embodiment from O and N(R°), in another embodiment they are O atoms, in another embodiment they are S atoms, in another embodiment they are N(R°) groups. The double bond which can be présent in the ring A, can be located in any suitable position. In one embodiment ofthe invention, the ring A is a 3-membered to 12-membered ring in case it is saturated, and a

5-membered to 12-membered ring in case it comprises a double bond, wherein in these embodiments ail otherfeatures ofthe rings are as indicated above or below. In one embodiment ofthe invention, the ring A is saturated and thus does not comprise a double bond in the ring, in another embodiment the ring A comprises one double bond.

Examples of rings A from any one or more of which the ring A is chosen in one embodiment of the invention, are (C₃-C₈)-cycloalkane rings, (C₅-C₈)-cycloalkane rings, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, (C₅-C₈)cycloalkene rings, cyclopent-3-ene wherein the carbon atom carrying the two groups N(R²⁰) and C(O)-R⁵⁰ is in position 1, cyclohex-3-ene wherein the carbon atom carrying the two groups N(R²⁰) and C(O)-R⁵⁰ is in position 1, cyclohept-3-ene wherein the carbon atom carrying the two groups N(R²⁰) and C(O)-R⁵⁰ is in position 1, cyclohept-4-ene wherein the carbon atom carrying the two groups N(R²⁰) and C(O)-R⁵⁰ is in position 1, tetrahydrofuran with binding position 3, tetrahydrothiophene and 1-oxo-tetrahydrothiophene and 1,1-dioxo-tetrahydrothiophene ali with binding position 3, pyran with binding position 3, pyran with binding position 4, tetrahydrothiopyran and 1-oxo-tetrahydrothiopyran and 1,1-dioxo-tetrahydrothiopyran ail with binding position 3, tetrahydrothiopyran and 1-oxo-tetrahydrothiopyran and 1,1-dioxotetrahydrothiopyran ail with binding position 4, oxepane with binding position 3, oxepane with binding position 4, thiepane and 1-oxo-thiepane and 1,1-dioxo-thiepane ail with binding position 3, thiepane and 1-oxo-thiepane and 1,1-dioxo-thiepane ali with binding position 4, bicyclo[2.2.1]heptane with binding position 2, bicyclo[3.1.1]heptane with binding position 3, bicyclo[3.2.1]octane with binding position 3, bicyclo[5.1.0]octane with binding position 4, bicyclo[2.2.1]hept-5-ene with binding position 2, 7-oxabicyclo[2.2.1]heptane with binding position 2, spiro[2.4]heptane with binding position 5, spiro[2.5]octane with binding position 6, spiro[2,6]nonane with binding position 5, spiro[2.6]nonane with binding position 6, 1,4-dioxaspiro[4,4]nonane with binding position 7, 1,4-dioxa-spiro[4.5]decane with binding position 8, 1,4dioxa-spiro[4.6]undecane with binding position 7, or 1,4-dioxa-spiro[4.6]undecane with binding position 8, which ail are optionally substituted as indicated above or below including, for example, substituted cyclohexane rings such as 2-fluoro-cyclohexane, 3-fluoro-cyclohexane, 4fluoro-cyclohexane, 4-[(C₁-C₄)-alkyl]-cyclohexane, 4-methyl-cyclohexane, 4-ethyl-cyclohexane, 4-propyl-cyclohexane, 4-[(C₁-C₄)-alkyl-O]-cyclohexane, 4-methoxy-cyclohexane or 4-ethoxycyclohexane, wherein in ali these substituted cyclohexane ring the carbon atom carrying the two groups N(R²⁰) and C(O)-R⁵⁰ is in position 1, and wherein the statement with binding position means with respect to ail listed groups that the carbon atom carrying the two groups N(R²⁰) and C(O)-R⁵⁰ is in the specified position ofthe respective ring.

The number ofthe substituents which are optionally présent on the ring A, dépends on the size and the kind ofthe ring A and the number of hetero ring members. In one embodiment ofthe invention the number of optional substituents on ring carbon atoms in ring A is 1, 2, 3 4 or 5, in another embodiment 1,2, 3 or 4, in another embodiment 1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1. ln ail positions on ring carbon atoms in ring A which do not carry a substituent, hydrogen atoms are présent. Substituents on the ring A can be présent in any suitable position. In case ring A is a 4-membered to 12-membered ring, in one embodiment of the invention substituents are optionally présent only on ring carbon atoms which are not adjacent to the carbon atom carrying the group N(R²⁰) and C(O)-R⁵⁰, but not in the positions adjacent to the said carbon atom. In one embodiment of the invention, the substituents which are optionally présent on carbon atoms in the ring A, are chosen from the sériés consisting of halogen, R¹, R², (C2-C6)-alkenyl, HO-, R¹-O-, phenyl-ÎC-rC^-alkyl-O-, R¹-C(O)-O-, R¹-S(O)2-O-, H₂N-, R¹-NH-, R¹-N(R¹)-, R¹-C(O)-NH-, R¹-C(O)-N(R¹)-, R¹-S(O)2-NH-, R¹-S(O)2-N(R¹)-, R¹C(O)-, HO-C(O)-, R¹-O-C(O)-, H2N-C(O)-, R¹-NH-C(O)-, R¹-N(R¹)-C(O)-, NC-, oxo and methylene, in another embodiment from the sériés consisting of halogen, R¹, R², (C2-C₆)alkenyl, HO-, R¹-O-, phenyl-(C1-C4)-alkyl-O-, R¹-C(O)-O-, R¹-S(O)2-O-, R¹-C(O)-, HO-C(O)-, R¹O-C(O)-, H2N-C(O)-, R¹-NH-C(O)-, R¹-N(R¹)-C(O)-, NC-, oxo and methylene, in another embodiment from the sériés consisting of halogen, R¹, R², (C2-C₆)-alkenyl, HO-, R¹-O-, phenyl(CrC^-alkyl-O-, R¹-C(O)-O-, R¹-S(O)2-O-, H2N-, R¹-NH-, R¹-N(R¹)-, R¹-C(O)-NH-, R¹-C(O)N(R¹)-, R¹-S(O)2-NH-, R¹-S(O)2-N(R¹)-, oxo and methylene, in another embodiment from the sériés consisting of halogen, R¹, R^z, (C2-C₆)-alkenyl, HO-, R¹-O-, phenyl-(C1-C4)-alky!-O-, R¹C(O)-O-, R¹-S(O)2-O-, R¹-C(O)-, HO-C(O)-, R¹-O-C(O)-, HzN-C(O)-, R¹-NH-C(O)-, R¹-N(R¹)C(O)-, oxo and methylene, in another embodiment from the sériés consisting of halogen, R¹, R², (C2-C₆)-alkenyl, HO-, R¹-O-, phenylJCrC^-alkyl-O-, R¹-C(O)-O-, R¹-S(O)2-O-, HO-C(O)-, R¹-OC(O)-, H2N-C(O)-, R¹-NH-C(O)-, R¹-N(R¹)-C(O)-, oxo and methylene, in another embodiment from the sériés consisting of halogen, R¹, R², (C2-C6)-alkenyl, HO-, R¹-0-, phenyl-(CrC₄)-alkylO-, R¹-C(O)-O-, R¹-S(O)2-O-, HO-C(O)-, R¹-O-C(O)-, H2N-C(O)-, R¹-NH-C(O)-, R¹-N(R¹)C(0)- and oxo, in another embodiment from the sériés consisting of halogen, R¹, R², (C2-C6)alkenyl, HO-, R¹-0-, phenyl-CCrC^-alkyl-O-, R¹-C(O)-O-, R¹-S(O)2-O-, HO-C(O)-, R¹-O-C(O)oxo and methylene, in another embodiment from the sériés consisting of halogen, R¹, R², (C2C6)-alkenyl, HO-, R¹-0-, phenyl-(CrC₄)-alkyl-O-, R¹-C(O)-O-, R¹-S(O)₂-O-, HO-C(O)-, R¹-0C(0)- and oxo, in another embodiment from the sériés consisting of halogen, R¹, R², HO-, R¹O-, phenyl-ÎCpC^-alkyl-O-, R¹-C(O)-O-, HO-C(O)-, R¹-O-C(O)-, oxo and methylene, in another embodiment from the sériés consisting of halogen, R¹, R², HO-, R¹-0-, R¹-C(O)-O- and oxo, in another embodiment from the sériés consisting of halogen, R¹, R², HO-, R¹-0- and oxo, in another embodiment from the sériés consisting of halogen, R¹, R², HO- and R¹-0-, in another embodiment from the sériés consisting of halogen, R¹, R² and R¹-O-, in another embodiment from the sériés consisting of halogen, R¹ and R², in another embodiment from the sériés consisting of halogen, R¹, HO- and R¹-O-, in another embodiment from the sériés consisting of halogen, R¹ and R¹-O-in another embodiment from the sériés consisting of halogen, HO- and R¹-O-, in another embodiment from the sériés consisting of halogen and R¹, and in another embodiment the substituents which are optionally présent on carbon atoms in the ring A are substituents R¹, wherein ali substituents can be identical or different, and wherein ali alkyl, alkenyl and cycloalkyl groups in the substituents on the ring A are optionally substituted by one or more fluorine substituents and cycloalkyl groups additionally are optionally substituted by one or more (C-i-C^-alkyl substituents, as applies in general to alkyl, alkenyl and cycloalkyl groups in the compounds ofthe formula I. In one embodiment ofthe invention, an individual carbon atom in the ring A does not carry more than one substituent chosen from the sériés consisting of HO-, R¹-O-, phenyl-(C_rC₄)-alkyl-O-, R¹-C(O)-O-, R¹-S(O)2-O-, R¹-S(O)m-, H₂N-, R¹-NH-, R¹-N(R¹)-, R¹-C(O)-NH-, R¹-C(O)-N(R¹)-, R¹-S(O)2-NH-, R¹-S(O)2-N(R¹)-, H₂N-S(O)₂-, R¹-NH-S(O)2-, R¹N(R¹)-S(O)2- and F₅S-. In one embodiment ofthe invention, the number of F₅S- substituents on the ring A is not greater than one. In one embodiment of the invention, the number of oxo substituents on the ring A is not greater than two, and in another embodiment it is not greater than one. In one embodiment ofthe invention, the number of methylene substituents on the ring A is not greater than two, and in another embodiment it is not greater than one. In one embodiment ofthe invention, halogen substituents on the ring A are fluorine substituents.

In case the ring A is a cyclohexane ring or cycloheptane ring, for example, the compounds of the formula I can also be represented by the formulae la and Ib, respectively,

O O la Ib wherein Y, Z, R²⁰ to R²² and R⁵⁰ are defined as in the compounds ofthe formula I, R⁷ is defined as the substituents which are optionally présent in the ring A in the compounds ofthe formula I, i.e. R⁷ is chosen from the sériés consisting of halogen, R¹, R², (C₂-C₆)-alkenyl, HO-, R¹-O-, phenyl-iCrC^-alkyl-O-, R¹-C(O)-O-, R¹-S(O)2-O-, R¹-S(O)m-, H₂N-, R¹-NH-, R¹-N(R¹)-, R¹-C(O)NH-, R¹-C(O)-N(R¹)-, R¹-S(O)₂-NH-, R¹-S(O)2-N(R¹)-, R¹-C(O)-, HO-C(O)-, R¹-O-C(O)-, H2NC(O)-, R¹-NH-C(O)-, R¹-N(R¹)-C(O)-, H₂N-S(O)₂-, R¹-NH-S(O)2-, R¹-N(R¹)-S(O)2-, F₅S-, NC-, oxo and methylene, or from any of the other sériés of substituents indicated herein, for example from the sériés consisting of halogen, R¹, R², HO-, R¹-O- and oxo, or from the sériés consisting of halogen and R¹, and the number r can be up to 10 in the compounds ofthe formula la and up to 12 in the compounds ofthe formula Ib, such as in case the cyclohexane or cycloheptane ring is perfluorinated. In one embodiment ofthe invention, the number r in the compounds ofthe formulae la and Ib is 0, 1, 2, 3, 4 or 5, in another embodiment 0, 1, 2, 3 or 4, in another embodiment 0, 1, 2 or 3, in another embodiment 0, 1 or 2, in another embodiment 0 or 1, in another embodiment the number r is 1, and in another embodiment the number r is 0, i.e. in this latter embodiment the cyclohexane ring or cycloheptane ring depicted in formulae and Ib does not carry a substituent R⁷ but only hydrogen atoms. The substituents R⁷ can be présent on any ofthe carbon atoms ofthe cyclohexane and cycloheptane ring depicted in formulae la and Ib.

in the group C(R¹²)=C(R¹³) representing the divalent group Y, the carbon atom carrying the group R¹³ is bonded to the ring carbon atom carrying the group R²¹ and the carbon atom carrying the group R¹² is bonded to the ring carbon atom carrying the group C(O)-N(R²⁰). In the group N=C(R¹⁴), the carbon atom carrying the group R¹⁴ is bonded to the ring carbon atom carrying the group R²¹ and the nitrogen atom is bonded to the ring carbon atom carrying the group C(O)-N(R²⁰). In the group C(R^1S)=N, the nitrogen atom is bonded to the ring carbon atom carrying the group R²¹ and the carbon atom carrying the group R¹⁵ is bonded to the ring carbon atom carrying the group C(O)-N(R²⁰). In one embodiment ofthe invention, Y is chosen from the sériés consisting of S, C(R¹²)=C(R¹³), N=C(R¹⁴) and C(R¹⁵)=N, in another embodiment from the sériés consisting of S, C(R¹²)=C(R¹³) and C(R^1S)=N. In one embodiment ofthe invention Y is chosen from the sériés consisting of S and C(R¹²)=C(R¹³), in another embodiment from the sériés consisting of C(R¹²)=C(R¹³) and C(R¹⁵)=N. In another embodiment ofthe invention, Y is C(R¹²)=C(R¹³). In another embodiment ofthe invention, Y is C(R¹⁵)=N.

In one embodiment ofthe invention, the trivalent group Z is C(R¹⁶). In another embodiment Z is C(R¹⁶) and Y is chosen from the sériés consisting of S, C(R^1Z)=C(R¹³) and C(R¹⁵)=N. In another embodiment Z is C(R¹⁶) and Y is chosen from the sériés consisting of S and C(R¹²)=C(R¹³). In another embodiment Z is C(R¹⁶) and Y is chosen from the sériés consisting of C(R¹⁵)=N and C(R¹²)=C(R¹³). In this latter embodiment, the aromatic ring in the compounds ofthe formula I comprising the ring members Y and Z is a pyridine ring or a benzene ring, respectively, and the compounds of the formula I are compounds of the formula le or of the formula Id,

le

Id wherein A, R^{10 * 12}, R^{13 *}, R¹⁵, R^{16 *}, R²⁰ to R²² and R⁵⁰ are defined as in the compounds ofthe formula

I or hâve any of their other indicated meanings. In one embodiment ofthe invention the group Z is C(R¹⁶) and the group Y is S. In another embodiment ofthe invention the group Z is C(R¹⁶) and the group Y is C(R^1S)=N. In another embodiment ofthe invention the group Z is C(R¹⁶) and the group Y is C(R¹²)=C(R¹³), i.e., in this embodimentthe compounds ofthe formula I are compounds oftheformula Id.

In one embodiment ofthe invention, in the compounds ofthe formula la the group Z is C(R¹⁶) and the group Y is C(R¹²)=C(R¹³), i.e., compounds of this embodiment are compounds ofthe formula le, in another embodiment in the compounds ofthe formula lb the group Z is C(R¹⁶) and the group Y is C(R¹²)=C(R¹³), i.e., compounds ofthis embodiment are compounds ofthe formula If, in another embodiment in the compounds ofthe formula la the group Z is C(R¹⁶) and the group Y is C(R¹⁵)=N, i.e., compounds of this embodiment are compounds ofthe formula Ig, and in another embodiment in the compounds ofthe formula lb the group Z is C(R¹⁶) and the group Y is C(R¹⁵)=N, i.e., compounds ofthis embodiment are compounds ofthe formula Ih,

le

If

O

'9 Ih wherein R¹², R¹³, R¹⁵, R¹⁶, R²⁰ to R²² and R⁵⁰ in these compounds are defined as in the compounds ofthe formula I or hâve any of their other indicated meanings, and R⁷ and r are defined as in the compounds ofthe formulae la and lb and, like in the compounds ofthe formulae la and lb, the substituents R⁷ can be présent on any ofthe carbon atoms ofthe cyclohexane and cycloheptane rings depicted in formulae le, If, Ig and Ih. Ail explanations on groups and ail définitions and embodiments specified above or below with respect to the compounds ofthe formula I apply correspondingly to the compounds of ail formulae which represent subgroups ofthe compounds ofthe formula I, including the compounds ofthe formulae la to Ih.

In one embodiment ofthe invention, R° is chosen from the sériés consisting of hydrogen and (C_rC₄)-alkyl, in another embodiment from the sériés consisting of hydrogen and methyl. In one embodiment ofthe invention, R° is hydrogen. In another embodiment ofthe invention R° is (C_r C₄)-alkyl, for example methyl.

In one embodiment ofthe invention, R¹ is chosen from the sériés consisting of (Ci-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, in another embodiment from the sériés consisting of (Ci-C₆)-alkyl, (C₃-C₆)-cycloalkyl and (C₃-C₆)-cycloalkyl-(Ci-C₂)-alkyl-, in another embodiment from the sériés consisting of (CrCgJ-alkyl, (C₃-C₆)-cycloalkyl and (C₃-C₆)cycloalkyl-CH₂-, in another embodiment from the sériés consisting of (C_rC₆)-alkyl, (C₃-C₄)cycloalkyl and (C₃-C₄)-cycloalkyl-CH₂-, in another embodiment from the sériés consisting of (Cr C₆)-alkyl and (C₃-C₆)-cycloalkyl, in another embodiment from the sériés consisting of (C_rC₆)alkyl and (C₃-C₄)-cycloalkyl, in another embodiment from the sériés consisting of (CrC^-alkyl, in another embodiment from the sériés consisting of (C-i-C^-alkyl, wherein ail these groups are ail optionally substituted by one or more fluorine substituents and in the case of cycloalkyl groups by one or more identical or different (C-i-C^-alkyl substituents, and thus can also be groups such as fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1-methylcyclopropyl or 2,2-dimethyl-cyclopropyl, for example.

In one embodiment ofthe invention, the (Cj-C^-alkyl group representing R² is a (CrC^-alkyl group, in another embodiment a (Ci-C2)-alkyl group, in another embodiment a methyl group. In one embodiment of the invention, the number of substituents HO- and (C-j-C4)alkyl-O- in R² is 1, 2 or 3, in another embodiment 1 or 2, in another embodiment 1. In one embodiment ofthe invention, an individual carbon atom in R² does not carry more than one substituent chosen from the sériés consisting of HO- and (C1-C₄)alkyl-O-, Examples of R², from any one or more of which R² is chosen in one embodiment ofthe invention, are hydroxymethyl, 1-hydroxyethyl, 2hydroxyethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl, methoxymethyl, propoxymethyl, 2methoxyethyl or 3-methoxypropyl.

In one embodiment ofthe invention, R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ are, independently of each other group R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, chosen from the sériés consisting of (CrCej-alkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl, (C3-C7)-cycloalkyl and (Cs-Cyj-cycloalkyl-ÎCj-C^alkyl-, in another embodiment from the sériés consisting of (C1-C4)-alkyl, (C2-C4)-alkenyl, (C2C4)-alkynyl, (C3-C7)-cycloalkyl and (C3-C7)-cycloalkyl-(Cf-C2)-alkyl-, in another embodiment from the sériés consisting of (C1-C6)-alkyl, (C3-C7)-cycloalkyl and (C3-C7)-cycloalkyl-(CrC2)-alkyl-, in another embodiment from the sériés consisting of (Ci-C4)-alkyl, (C3-C7)-cycloalkyl and (C3-C7)cycloalkyl-(Ci-C2)-alkyl-, in another embodiment from the sériés consisting of (Ci-C6)-alkyl, (C3C7)-cycloalkyl and (C3-C7)-cycloalkyl-CH2-alkyl-, in another embodiment from the sériés consisting of (Ci-C6)-alkyl and (C3-C7)-cycloalkyl, in another embodiment from the sériés consisting of (C1-C4)-alkyl and (C3-C7)-cycloalkyl, which are ail optionally substituted by one or more identical or different substituents R⁷⁰, wherein in these groups besides any substituents R⁷⁰ one or more fluorine substituents are optionally présent and in cycloalkyl groups one or more (CrC₄)-alkyl substituents are optionally présent as applies to alkyl, alkenyl, alkynyl and cycloalkyl groups in general. In one embodiment ofthe invention R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ are, independently of each other group R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, chosen from the sériés consisting of (C1-C6)-alkyl, in another embodiment from the sériés consisting of (Ci-C4)-alkyl, which are ail optionally substituted by one or more identical or different substituents R⁷⁰. In one embodiment ofthe invention, (C3-C₇)-cycloalkyl groups occurring in R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ are, independently of each other group R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, (C₃-C₆)-cycloalkyl, in another embodiment (C₃-C₄)-cycloalkyl, for example cyclopropyl, in another embodiment (C₅-C₆)-cycloalkyl, for example cyclohexyl. In one embodiment ofthe invention, the number of substituents R⁷⁰ in any ofthe groups R¹¹, R³⁰, R³³,

R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ is, independently of each other group R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, 0, 1, 2, 3 or 4, in another embodiment 0, 1, 2 or 3, in another embodiment 0, 1 or 2, in another embodiment 0 or 1. In one embodiment ofthe invention, any ofthe groups R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, independently of each other group R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, does not carry a substituent R⁷⁰, but merely is optionally substituted by one or more fluorine substituents and, in the case of cycloalkyl groups, one or more (CrC4)-alkyl substituents. In another embodiment ofthe invention, any ofthe groups R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, independently of each other group R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, does neither carry a substituent R⁷⁰ nor fluorine substituents nor, in the case of cycloalkyl groups, (CrC₄)-alkyl substituents. As examples of R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ which examplarily carry a hydroxy or alkyl-O- group as a substituent R⁷⁰, from any one or more of which examples any of the groups R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ is chosen in one embodiment ofthe invention, HO-(C_rC₄)-alkyl-, HO-(C₂-C₃)-alkyl-, HO-CH₂-CH₂-, CH₃-CH(OH)-, HO-CH₂-, (C_rC₄)alkyl-O-(Ci-C₄)-alkyl-, (C-j-Csj-aikyl-CMC-i-Csj-alkyl-, (Ci-C₂)-alkyl-O-(C₂-C₃)-alkyl-, (C_rC₂)-alkylO-(Ci-C₂)-alkyl-, CH₃-O-CH₂-CH₂-, (C₁-C4)-alkyl-O-CH₂-, CH₃-O-CH₂- may be mentioned.

In one embodiment ofthe invention, R¹⁰ is chosen from the sériés consisting of hydrogen and methyl. In another embodiment R¹⁰ is hydrogen. In anotherembodiment ofthe invention R¹⁰ is (C₁-C₄)-alkyl, for example methyl.

In case R¹³ or R¹⁴, togetherwith the one ofthe groups R²¹ and R²²which is not the group ofthe formula II, forms a chain consisting of 3 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members chosen from the sériés consisting of N(R¹⁷), O and S, but two hetero chain members cannot be présent in adjacent positions, and the other chain members are identical or different groups C(R¹⁸)(R¹⁸), the group R²² is the group ofthe formula II and the group R²¹ forms a chain together with R¹³ or R¹⁴. The formed chain, together with the carbon atom carrying R²¹ and the carbon atom carrying R¹³ or R¹⁴ forms a 5-membered to 7-membered ring, which is fused to the aromatic ring comprising the groups Y and Z depicted in formula I and which has the bond between the group Y and the carbon atom carrying R²¹ in common with the said ring comprising Y and Z. In one embodiment ofthe invention, the said chain consists of 3 to 4 chain members and the formed ring thus is 5-membered to 6membered, and in another embodiment the said chain consists of 3 chain members and the formed ring thus is 5-membered. The hetero chain members can be présent in any position in the said chain, provided that two hetero chain members cannot be présent in adjacent positions. If hetero chain members are présent, in one embodiment ofthe invention one hetero chain member is présent in a terminal position of the said chain, in another embodiment one hetero chain member is présent in the terminal position ofthe said chain which is attached tothe carbon atom in the ring comprising Y and Z depicted in formula I which carries the group R²¹, in anotherembodiment one hetero chain member is présent in the terminal position ofthe said chain which is attached to the carbon atom in the group CR¹²=CR¹³ or the group N=CR¹⁴ representing Y which carries the group R¹³ or R¹⁴, respectively, in another embodiment two hetero chain members are présent in the two terminal positions of the said chain which are attached to the carbon atom in the ring comprising Y and Z depicted in formula I which carries the group R²¹, and to the carbon atom in the group CR¹²=CR¹³ or the group N=CR¹⁴ representing Y which carries the group R¹³ or R¹⁴, respectively. In one embodiment ofthe invention, 0 (zéro) hetero chain members are présent in the said chain, in another embodiment 0 or 1 hetero chain members are présent, in another embodiment 1 or 2 hetero chain members are présent, and in another embodiment 2 hetero chain members are présent. In one embodiment ofthe invention, hetero chain members in the said chain are chosen from N(R¹⁷) and O, in another embodiment from O and S, and in another embodiment they are O (oxygen atoms). Examples of chains formed by R¹³ or R¹⁴ together with the one of the groups R²¹ and R²² which is not the group ofthe formula ll, from any one or more ofwhich the said chain is chosen in one embodiment ofthe invention, are -CH2-CH2-CH2-,

-CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-CH2-, -O-CH2-CH2- and -O-CH2-CH2-CH2- wherein in the latter two chains the oxygen atom is attached to the carbon atom in the group CR¹²=CR¹³ or the group N=CR¹⁴ representing Y which carries the group R¹³ or R¹⁴, respectively, -CH2-CH2~Oand -CH2-CH2-CH2-O- wherein in the latter two chains the oxygen atom is attached to the carbon atom in the ring comprising Y and Z depicted in formula I which carries the group R²¹, CH2-O-CH2-, -O-C(R¹⁸)(R¹⁸)-O- including -O-CH2-O-, -O-CF₂-O- and -O-C(CH₃)₂-O-, -OC(R¹⁸)(R¹⁸)-C(R¹⁸)(R¹⁸)-O- including -O-CH₂-CH₂-O-, -O-CH2-CH2-CH2-O-, or -N(CH₃)-CH₂-CH₂O- wherein in the latter chain the nitrogen atom is attached to the carbon atom in the group CR¹²=CR¹³ or the group N=CR¹⁴ representing Y which carries the group R¹³ or R¹⁴, respectively.

In one embodiment ofthe invention, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently of each other chosen from the sériés consisting of hydrogen, halogen, (C_rC₄)-alkyl, HO-ÎC-i-C^-alkyl-, (C_r C₄)-alkyl-O-, H₂N-, (Ct-C₄)-alkyl-NH-, (Ci-C^-alkyl-N^CrC^-alkyl)- and NC-, in another embodiment from the sériés consisting of hydrogen, halogen, (C₁-C₄)-alkyl, (Ci-C₄)-alkyl-O-, H₂N-, (C₁-C₄)-alkyl-NH-, (C₁-C₄)-alkyl-N((C₁-C₄)-alkyl)- and NC-, in another embodiment from the sériés consisting of hydrogen, halogen, (C₁-C₄)-alkyl and (Ci-C₄)-alkyl-O-, in another embodiment from the sériés consisting of hydrogen, halogen and (CrC^-alkyl-O-, in another embodiment from the sériés consisting of hydrogen and halogen, or in ail these embodiments R¹³ or R¹⁴, together with the one of the groups R²¹ and R²² which is not the group of the formula

II, forms a chain consisting of 3 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members chosen from the sériés consisting of N(R¹⁷), O and S, but two hetero chain members cannot be présent in adjacent positions, and the other chain members are identical or different groups C(R¹⁸)(R¹⁸). In one embodiment ofthe invention, R¹² and R¹³ are independently of each other chosen from the sériés consisting of hydrogen, halogen, (Ci-C4)-alkyl and (C1-C4)-alkyl-O-, in another embodiment from the sériés consisting of hydrogen, halogen and (C-|-C4)-alkyl-O-, in another embodiment from the sériés consisting of hydrogen and halogen, in another embodiment from the sériés consisting of hydrogen, chlorine and fluorine, in another embodiment from the sériés consisting of hydrogen and fluorine, or in ail these embodiments R¹³, together with the one of the groups R²¹ and R²² which is not the group of the formula II, forms a chain consisting of 3 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members chosen from the sériés consisting of N(R¹⁷), O and S, but two hetero chain members cannot be présent in adjacent positions, and the other chain members are identical or different groups C(R¹⁸)(R¹⁸). In one embodiment ofthe invention, R¹² and R¹³ are independently of each other chosen from the sériés consisting of hydrogen, halogen, (C1-C₄)-alkyl and (Ci-C₄)-alkyl-O-, in another embodiment from the sériés consisting of hydrogen, halogen and (C-i-C^-alkyl-O-, in another embodiment from the sériés consisting of hydrogen and halogen, in another embodiment from the sériés consisting of hydrogen, chlorine and fluorine, in another embodiment from the sériés consisting of hydrogen and fluorine. In one embodiment ofthe invention, R¹² is chosen from the sériés consisting of hydrogen, halogen, (CrC4)-alkyl and (CrC4)-alkyl-O-, in another embodiment from the sériés consisting of hydrogen, halogen and (CrC^-alkyl-O-, in another embodiment from the sériés consisting of hydrogen and halogen, in another embodiment from the sériés consisting of hydrogen, chlorine and fluorine, in another embodiment from the sériés consisting of hydrogen and fluorine, and R¹³, together with the one of the groups R²¹ and R²² which is not the group of the formula II, forms a chain consisting of 3 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members chosen from the sériés consisting of N(R¹⁷), O and S, but two hetero chain members cannot be présent in adjacent positions, and the other chain members are identical or different groups C(R¹⁸)(R¹⁸). In one embodiment of the invention, R¹² is hydrogen and R¹³ is fluorine, or R¹² is fluorine and R¹³ is hydrogen. In another embodiment R¹² and R¹³ are hydrogen. In one embodiment ofthe invention, R¹⁴ and R¹⁵ are independently of each other chosen from the sériés consisting of hydrogen, halogen, (CrC₄)alkyl and (Ci-C₄)-alkyl-O-, in another embodiment from the sériés consisting of hydrogen, halogen and (Cr^J-alkyl, in another embodiment from the sériés consisting of hydrogen and halogen, in another embodiment from the sériés consisting of hydrogen, chlorine and fluorine. In another embodiment ofthe invention, R¹⁴ and R¹⁵ are hydrogen. In one embodiment ofthe invention, R¹⁶ is chosen from the sériés consisting of hydrogen, halogen, (Ci-C₄)-alkyl and (C_r C₄)-alkyl-O-, in another embodiment from the sériés consisting of hydrogen, halogen and (C_r C₄)-alkyl, in another embodiment from the sériés consisting of hydrogen and halogen, in another embodiment from the sériés consisting of hydrogen, chlorine and fluorine. In another embodiment ofthe invention, R¹⁶ is hydrogen.

In one embodiment ofthe invention, R¹⁷ and R²⁵ are independently of each other chosen from the sériés consisting of hydrogen and methyl, in another embodiment they are hydrogen. In another embodiment ofthe invention, R¹⁷ and R²⁵ are independently of each other chosen from the sériés consisting of (CrC₄)-alkyl, and in another embodiment they are methyl.

In case two groups R¹⁸ bonded to the same carbon atom, together with the carbon atom carrying them, form a 3-membered to 6-membered cycloalkane ring, the formed cycloalkane ring is spiro-fused to the ring which is optionally formed by R¹³ or R¹⁴ together with the one of the groups R²¹ and R²² which is not the group ofthe formula II, and the carbon atom carrying R²¹ and the carbon atom carrying R¹³ or R¹⁴. In one embodiment ofthe invention, the cycloalkane ring formed bytwo ofthe groups R¹⁸ is 3-membered to 5-membered, in another embodiment it is 3-membered or 4-membered, in another embodiment it is 3-membered, i.e. in this latter embodiment a cyclopropane ring is formed. In one embodiment ofthe invention, R¹⁸, independently of each other group R¹⁸, is chosen from the sériés consisting of hydrogen, fluorine and (C-i-Czj-alkyl, in another embodiment from the sériés consisting of hydrogen, fluorine and methyl, in another embodiment from the sériés consisting of hydrogen and fluorine, and in another embodiment the groups R¹⁸ are hydrogen, or in ail these embodiments two ofthe groups R¹⁸ bonded to the same carbon atom, together with the carbon atom carrying them, form a 3-membered to 6-membered cycloalkane ring which is optionally substituted as indicated. In one embodiment of the invention, R¹⁸, independently of each other group R¹⁸, is chosen from the sériés consisting of hydrogen, fluorine and (CrCaj-alkyl, in another embodiment from the sériés consisting of hydrogen, fluorine and methyl, in another embodiment from the sériés consisting of hydrogen and fluorine, and in another embodiment the groups R¹⁸ are hydrogen. In one embodiment ofthe invention, not more than one cycloalkane ring which is formed by two of the groups R¹⁸ bonded to the same carbon atom together with the carbon atom carrying them, is présent in the compounds ofthe formula I. In one embodiment ofthe invention, the number of substituents chosen from the sériés consisting of fluorine and (Ci-C₄)-alkyl, which are optionally présent on a cycloalkane ring formed by two of the groups R¹⁸ bonded to the same carbon atom together with the carbon atom carrying them, is 1, 2, 3 or 4, in another embodiment it is 1, 2 or 3, in another embodiment it is 1 or 2, and in another embodiment such a cycloalkane ring does not carry any substituents, i.e. in this latter embodiment it is unsubstituted. In one embodiment ofthe invention, the substituents which are optionally présent on a cycloalkane ring formed by two ofthe groups R¹⁸ bonded to the same carbon atom togetherwith the carbon atom carrying them, are chosen from fluorine and methyl, and in another embodiment they are fluorine substituents.

In one embodiment ofthe invention, R²⁰ is chosen from the sériés consisting of hydrogen and methyl. In another embodiment R²⁰ is hydrogen. In another embodiment R²⁰ is (C_rC₄)-alkyl, for example methyl.

In one embodiment ofthe invention the group R²¹ is the one ofthe groups R²¹ and R²² which is a group ofthe formula II, i.e. a group ofthe formula R²⁴-R²³- which is bonded to the remainderof the molécule through the moiety R²³ as is symbolized with respect to this group and in general by a terminal hyphen representing thefree bond, and the group R²² is chosen from the sériés consisting of hydrogen, halogen, R³⁰, HO-, R³⁰-O-, R³⁰-C(O)-O-, R³⁰-S(O)2-O-, R³°-S(O)m-, H₂N-, R³⁰-NH-, R³⁰-N(R³⁰)-, R³⁰-C(O)-NH-, R³⁰-C(O)-N(R⁷¹)-, R³⁰-S(O)2-NH-, R³⁰-S(O)2-N(R⁷¹)-, R³⁰C(O)-, HO-C(O)-, R³⁰-O-C(O)-, H2N-C(O)-, R³⁰-NH-C(O)-, R³⁰-N(R³⁰)-C(O)-, H2N-S(O)₂-, r³⁰NH-S(O)2-, R³⁰-N(R³⁰)-S(O)2-, NC-, O₂N- and Het¹. In another embodiment, the group R²² is the one ofthe groups R²¹ and R²² which is a group ofthe formula II and the group R²¹ is chosen from the sériés consisting of hydrogen, halogen, R³⁰, HO-, R³⁰-O-, R³⁰-C(O)-O-, R³⁰-S(O)2-O-, R³⁰-S(O)m-, H₂N-, R³⁰-NH-, R³⁰-N(R³⁰)-, R³⁰-C(O)-NH-, R³⁰-C(O)-N(R⁷¹)-, R³⁰-S(O)2-NH-, R³⁰S(O)2-N(R⁷¹)-, R³⁰-C(O)-, HO-C(O)-, R³⁰-O-C(O)-, H2N-C(O)-, R³⁰-NH-C(O)-, R³⁰-N(R³⁰)-C(O)-, H2N-S(O)z-, R³⁰-NH-S(O)2-, R³⁰-N(R^3D)-S(O)2-, NC-, O₂N- and Het¹, or together with R¹³ or R¹⁴ forms a chain as specified in the définition of R¹³ and R¹⁴.

In one embodiment ofthe invention, the one ofthe groups R²¹ and R²² which is not a group of the formula II, is chosen from the sériés consisting of hydrogen, halogen, R³⁰, R³⁰-O-, R³⁰-C(O)O-, R³⁰-S(O)m-, H2N-, R³⁰-NH-, R³⁰-N(R³⁰)-, R³⁰-C(O)-NH-, R³⁰-C(O)-, NC- and Het¹, in another embodiment from the sériés consisting of hydrogen, halogen, (C1-C₄)-alkyl, HO-(C_rC₄)-alkyl-, (C₁-C₄)-alkyl-O-(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O-, HO-(C₁-C₄)-alkyl-O-, (Ci-C^-alkyl-O-tC·^)alkyl-O-, (C_rC₄)-alkyl-S(O)_m-, H_ZN-, (CrC^-alkyl-NH-, ditfCrC^-alkyON-, (C_rC₄)-alkyl-C(O)-, Het¹ and NC-, in another embodiment from the sériés consisting of hydrogen, halogen, (C-|-C4)alkyl, HO-(C1-C4)-alkyl-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-, (C1-C4)-alkyl-O-, HO-(C1-C4)-alkyl-O-, (CrC^-alkyl-O-ÎCvC^-alkyl-O-, (C1-C4)-alkyl-S(O)m-, (C^C^-alkyl-C/O)-, Het¹ and NC-, in another embodiment from the sériés consisting of hydrogen, halogen, (C^C^-alkyl, HO-(C1-C₄)alkyl-, (C₁-C₄)-alkyl-O-(C₁-C₄)-alkyl-, (C₁-C₄)-alkyl-O-(C₁-C₄)-alkyl-, (CrC^-alkyl-O-, HO-(C_rC₄)17884 alkyl-O-, (C₁-C₄)-alkyl-O-(C₁-C₄)-alkyl-O-, (C_rC₄)-alkyl-S(O)_m-, (Ci-C₄)-alkyl-C(O)- and Het¹, in another embodiment from the sériés consisting of hydrogen, halogen, (C1-C4)-alkyl, HO-ÎCpC^alkyl-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-, (CrC4)-alkyl-O-, HO-(Ci-C4)-alkyl-O-, (CrC^-alkyl-O-ÎCr C4)-alkyl-O-, (C-Walkyl-CXO)- and Het¹, in another embodiment from the sériés consisting of hydrogen, halogen, (CfC^-alkyl, HO-(Ci-C4)-alkyl-, (Cf-C^-alkyl-O^C^C^-alkyl-, (C-|-C₄)-alkylO-, HO-V-CD-alkyl-O-, (C₁-C₄)-alkyl-O-(C₁-C₄)-alkyl-O- and Het¹, in another embodiment from the sériés consisting of hydrogen, halogen, (Ci-C4)-alkyl, HO-(CrC4)-alkyl-, (C1-C4)-alkyl-O-(C1C4)-alkyl-, (C-i-C^-alkyl-O-, HO-(C-|-C4)-alkyl-O- and (Ci-C4)-alkyl-O-(Ci-C4)-alkyl-O-, in another embodiment from the sériés consisting of halogen, (CrC^-alkyl, HO-(Ci-C4)-alkyl-, (C4-C4)alkyl-O-iCrC^-alkyl-, (CrC4)-alkyl-O-, HO-(CrC4)-alkyl-O-, (C1-C4)-alkyl-O-(C1-C4)-alkyl-O-, (Ci-C4)-alkyl-C(O)- and Het¹, in another embodiment from the sériés consisting of halogen, (Cr C₄)-alkyl, HO-(C_rC₄)-alkyl-, (C_rC₄)-alkyl-O-, HO-tC-i-C^-alkyl-O-, (CrC^-alkyl-O-iCrC^-alkylO-, (Ci-C₄)-alkyl-C(O)- and Het¹,in another embodiment from the sériés consisting of halogen, (Ci-C4)-alkyl, HO-(CrC4)-alkyl-, (CrC^-alkyl-O-^rC^-alkyl-, (CrC^-alkyl-O-, HO-(CrC4)alkyl-O-, (CrC^-alkyl-O-iCrC^-alkyl-O- and Het¹, in another embodiment from the sériés consisting of halogen, (CrC^-alkyl, HO-(C1-C₄)-alkyl-, (Ci-C₄)-alkyl-O-(C_rC₄)-alkyl-, (CrC^alkyl-O-, HO-(Ci-C₄)-alkyl-O- and (C₁-C₄)-alkyl-O-(C₁-C₄)-alkyl-O-, in another embodiment from the sériés consisting of (CrC^-alkyl, HO-(Ci-C₄)-alkyl-, (C₁-C₄)-alkyl-O-(C₁-C₄)-alkyl-, (CW alkyl-O-, HO-(Ci-C₄)-alkyl-O-, (CrC^-alkyl-O-iCrC^-alkyl-O-, (C_rC₄)-alkyl-C(O)- and Het¹, in another embodiment from the sériés consisting of (Ci-C4)-alkyl, HO-(Ci-C4)-alkyl-, (C-i-C^-alkylO-tCrC^-alkyl-, (CrC4)-alkyl-O-, HO-(C1-C4)-alkyl-O-, (CrC4)-alkyl-O-(Ci-C4)-alkyl-O- and Het¹, in another embodiment from the sériés consisting of (CrC₄)-alkyl, HO-(C-|-C₄)-alkyl-, (C_r C^-alkyl-O-ÎC-i-C^-alkyl-, (C₁-C₄)-alkyl-O-, HO-tCrC^-alkyl-O- and (CrC^-alkyl-O-tCrC^alkyl-O-, in another embodiment from the sériés consisting of (CrC₄)-alkyl, HO-(C-j-C₄)-alkyl-, (C₁-C₄)-alkyl-O-(C₁-C₄)-alkyl-, (C_rC₄)-alkyl-O-, (C_rC₄)-alkyl-C(O)- and Het¹, in another embodiment from the sériés consisting of (Ci-C4)-alkyl, HO-tC-i-C^-alkyl-, (C-|-C4)-alkyl-O- and (CrC4)-alkyl-C(O)-, in another embodiment from the sériés consisting of (CrC4)-alkyl and (C-iC4)-alkyl-O-, in another embodiment from the sériés consisting of (CrC^-alkyl-O-, or in ail these embodiments together with R¹³ or R¹⁴ forrns a chain as specified in the définition of R¹³ and R¹⁴. In one embodiment ofthe invention, the one ofthe groups R²¹ and R²²which is not a group of the formula II, is chosen from the sériés consisting of (CfC4)-alkyl and (CrC^-alkyl-O-, In another embodiment, the one ofthe groups R²¹ and R²² which is not a group ofthe formula II, is (CrC^-alkyl-O-, for example méthoxy or ethoxy.

In one embodiment of the invention, in case the group R²¹ is the one of the groups R²¹ and R²² which is a group ofthe formula II, the group R²² is chosen from the sériés consisting of (Cj-C^17884 alkyl and (C₁-C₄)-alkyl-O-, and in another embodiment it is (C_rC₄)-aIkyl-O-, and in case the group R²² is the one of the groups R²¹ and R²² which is the group ofthe formula II, the group R²¹ is chosen from the sériés consisting of hydrogen, halogen, R³⁰, HO-, R³⁰-O-, R³⁰-C(O)-O-, R³⁰S(O)2-O-, R³⁰-S(O)m-, H_ZN-, R³⁰-NH-, R³⁰-N(R³⁰)-, R³⁰-C(O)-NH-, R³⁰-C(O)-N(R⁷¹)-, R³⁰-S(O)2NH-, R³⁰-S(O)2-N(R⁷¹)-, R³⁰-C(O)-, HO-C(O)-, R³⁰-O-C(O)-, H2N-C(O)-, R³⁰-NH-C(O)-, r³⁰N(R³⁰)-C(O)-, H2N-S(O)₂-, R³⁰-NH-S(O)2-, R³⁰-N(R³⁰)-S(O)2-, NC-, O₂N- and Het¹, or together with R¹³ or R¹⁴ forms a chain as specified in the définition of R¹³ and R¹⁴, or is defined as in any ofthe embodiments or other définitions of R²¹ specified herein.

The chain members in a chain representing R²³ are connected to each other by single bonds. The number of chain members in a chain representing R²³ can be 1, 2, 3, 4 or 5. In one embodiment ofthe invention, the divalent group R²³ is a direct bond, i.e. the group R²⁴ is directly bonded to the ring comprising the groups Y and Z which is depicted in formula I. In another embodiment R²³ is a direct bond or a chain consisting of 1, 2, 3 or 4 chain members. In another embodiment R²³ is a direct bond or a chain consisting of 2, 3 or 4 chain members, in another embodiment a direct bond or a chain consisting of 2 or 3 chain members, in another embodiment a direct bond or a chain consisting of 3 chain members, wherein in these embodiments the chain members are defined as above or below. In another embodiment R²³ is a chain consisting of 1, 2, 3, 4 or 5 chain members, in another embodiment a chain consisting of 1, 2, 3 or 4 chain members, in another embodiment a chain consisting of 2, 3 or 4 chain members, in another embodiment a chain consisting of 2 or 3 chain members, in another embodiment a chain consisting of 3 chain members, wherein in these embodiments the chain members are defined as above or below. In one embodiment ofthe invention, zéro or one ofthe chain members in a chain representing R²³ are hetero chain members, in another embodiment one ofthe chain members in a chain representing R²³ is a hetero chain member, and in another embodiment zéro ofthe chain members in a chain representing R²³ is a hetero chain member, wherein in these embodiments the hetero chain members are defined as above or below. In one embodiment ofthe invention, the hetero chain members in a chain representing R²³ are chosen from the sériés consisting of N(R²⁵), O, S and S(O)2. In anotherembodiment ofthe invention, the hetero chain members in a chain representing R²³ are chosen from the sériés consisting of N(R²⁵), O and S, in another embodiment from the sériés consisting of N(R²⁵) and O, in another embodiment from the sériés consisting of O and S, in another embodiment from the sériés consisting of N(R²⁵), O and S(O)2, in another embodiment from the sériés consisting of N(R²⁵) and S(O)₂, in another embodiment from the sériés consisting of O and S(O)₂. In another embodiment of the invention, the hetero chain members which can be présent in a chain representing R²³, are O (oxygen), and in another embodiment the hetero chain members which can be présent in a chain representing R²³, are S. In another embodiment ofthe invention, zéro or one hetero chain member is présent in a chain representing R²³ which is O (oxygen), and in another embodiment one hetero chain member is présent which is O. In another embodiment of the invention, zéro or one hetero chain member is présent in a chain representing R²³ which is S, and in another embodiment one hetero chain member is présent which is S.

Hetero chain members in a chain representing R²³ can be présent in any positions ofthe chain provided that the resulting moiety compiles with the prerequisites specified above with respect to R²³ and the compounds ofthe invention in general. Hetero chain members can be présent in any one ofthe terminal positions ofthe chain or in both terminal positions ofthe chain, and can thus be directly bonded to the group R²⁴ and/or the ring comprising the groups Y and Z which is depicted in formula I, and/or they can be présent inside the chain. In case one or two hetero chain members are présent in a chain representing R²³, in one embodiment ofthe invention at least one ofthe terminal chain members is a hetero chain member, and in another embodiment the terminal chain member which is bonded to the group R²⁴ is a hetero chain member, and in another embodiment the terminal chain member which is bonded to the ring comprising the groups Y and Z is a hetero chain member. In one embodiment ofthe invention, one ofthe chain members in a chain representing R²³ is a hetero chain member and this hetero chain member is the terminal chain member bonded to the group R²⁴. In another embodiment, one ofthe chain members in a chain representing R²³ is a hetero chain member and this hetero chain member is the terminal chain member bonded to the ring comprising the groups Y and Z which is depicted in formula I.

In one embodiment ofthe invention R²³ is chosen from a direct bond and from any one or more ofthe chains which are présent in the following examples of groups ofthe formula II, which groups are bonded to the ring comprising the groups Y and Z which is depicted in formula I by the free bond represented by the terminal hyphen, and from which groups of the formula II the groups R²³ themselves are obtained by removing the group R²⁴:

R²⁴-C(R²⁶)(R²⁶)-C(R²⁶)(R²⁶)-,

R²⁴-C(R²⁶)(R²⁶)-S-,

R²⁴-S(O)₂-O-,

R²⁴-C(R²⁶)(R²⁶)-C(R²⁶)(R²⁶)-O-,

R²⁴-C(R²⁶)(R²⁶)-O-C(R²⁶)(R²⁶)-,

R²⁴-C(R²⁶)(R²⁶)-S-C(R²⁶)(R²⁶)-, r²⁴-C(R²⁶)(R²⁶)-,

R²⁴-C(R²⁶)(R²⁶)-O-,

R²⁴-C(R²⁶)(R²⁶)-N(R²⁵)-,

R²⁴-C(R²⁶)(R²⁶)-C(R²⁶)(R²⁶)-C(R²⁶)(R²⁶)-,

R²⁴-O-C(R²⁶)(R²⁶)-C(R²⁶)(R²⁶)-,

R²⁴-C(R²⁶)(R²⁶)-C(R²⁶)(R²⁶)-S-,

R²⁴-S-C(R²⁶)(R²⁶)-C(R²⁶)(R²⁶)-,

R²⁴-C(R²⁶)(R²⁶)-C(R²⁶)(R²⁶)-N(R²⁵)-, wherein in these groups ofthe formula II the groups R²⁴, R²⁵ and R²⁶ are defined as above or below.

In one embodiment ofthe invention, a 3-membered to 10-membered, monocyclic or bicyclic ring representing R²⁴ is a monocyclic ring, which is ali optionally substituted as indicated above or below. In one embodiment ofthe invention, a monocyclic ring representing R²⁴ is 3-membered to 7-membered, in another embodiment 3-membered or 5-membered to 7-membered, in another embodiment 3-membered, 5-membered or 6-membered, in another embodiment 5membered or 6-membered, in another embodiment 6-membered, which rings are ail optionally substituted as indicated above or below. In one embodiment ofthe invention, a bicyclic ring representing R²⁴ is 7-membered to 10-membered which is optionally substituted as indicated above or below. In one embodiment ofthe invention, a ring representing R²⁴ is a saturated ring or an unsaturated ring including a partially unsaturated, i.e. non-aromatic, ring which contains zéro, one, two or three, for example zéro, one or two, double bonds, within the ring, or an aromatic ring, which rings are ali optionally substituted as indicated above or below. In another embodiment, a ring representing R²⁴ is a saturated ring or a partially unsaturated ring which contains zéro, one, two or three, for example zéro, one or two, double bonds within the ring, which rings are ali optionally substituted as indicated above or below. In another embodiment of the invention, a ring representing R²⁴ is an aromatic ring, in another embodiment an aromatic ring chosen from benzene, aromatic 5-membered and 6-membered monocyclic heterocycles, naphthalene and aromatic 9-membered and 10-membered bicyclic heterocycles, in another embodiment an aromatic ring chosen from benzene and aromatic 5-membered and 6membered monocyclic heterocycles, in another embodiment an aromatic ring chosen from benzene and thiophene, which rings are ail optionally substituted as indicated above or below.

In another embodiment, a ring representing R²⁴ is a benzene ring which is optionally substituted as indicated above or below, i.e. by the substituents specified above or below with respect to the 3-membered to 10-membered ring representing R²⁴, in terms of residues, in this latter embodiment R²⁴ is a phenyl group which is optionally substituted as indicated above or below, i.e. by the substituents specified above or below with respect to the 3-membered to 10membered ring representing R²⁴.

In one embodiment ofthe invention, the number of hetero ring members which can be présent in a saturated 3-membered to 10-membered ring representing R²⁴ is 0, in another embodiment it is 1. In one embodiment ofthe invention, the number of hetero ring members which can be présent in an unsaturated 3-membered to 10-membered ring representing R²⁴ is 0 or 1, and in another embodiment it is 1 or 2, in another embodiment it is 1, and in another embodiment the number of hetero ring members is 0 (zéro), i.e., in this latter embodiment a 3-membered to 10membered ring representing R²⁴ is a carbocyclic ring, which rings are ali optionally substituted as indicated above or below. In one embodiment ofthe invention, the hetero ring members which can be présent in a 3-membered to 10-membered ring representing R²⁴ are chosen from N, N(R³²), O, S and S(O)₂, in another embodiment from N, N(R³²), O and S, in another embodiment from N, O and S, in another embodiment from N(R³²), O and S, in another embodiment from N and S, in another embodiment they are N (nitrogen), and in another embodiment they are S (sulfur).

In one embodiment ofthe invention, the number of substituents which are optionally présent on ring carbon atoms in a 3-membered to 10-membered ring representing R²⁴ is 1, 2, 3, 4, or 5, in another embodiment the number of substituents which are optionally présent on ring carbon atoms is 1, 2, 3 or 4, in another embodiment the number of substituents which are optionally présent on ring carbon atoms is 1,2 or 3, in another embodiment the number of substituents which are optionally présent on ring carbon atoms is 1 or 2, and in another embodiment the number of substituents which are optionally présent on ring carbon atoms is 1.

In one embodiment ofthe invention, the substituents which are optionally présent on ring carbon atoms in a 3-membered to 10-membered ring representing R²⁴, including a benzene ring or a phenyl group, respectively, representing R²⁴, are chosen from the sériés consisting of halogen, R³³, oxetanyl, HO-, R³³-O-, R³³-S(O)m-, H2N-, R³³-NH-, R³³-N(R³³)-, R³³-C(O)-NH-, R³³C(O)-N(R⁷¹)-, R³³-S(O)2-NH-, R³³-S(O)2-N(R⁷¹)-, H2N-S(O)₂-NH-, R³³-NH-S(O)2-NH-, R³³-N(R³³)S(O)2-NH-, H₂N-S(O)₂-N(R⁷¹)-, R³³-NH-S(O)2-N(R⁷¹)-, R³³-N(R³³)-S(O)2-N(R⁷¹)-, HO-C(O)-, r³³O-C(O)-, H₂N-C(O)-, R³³-NH-C(O)-, R³³-N(R³³)-C(O)-, NC- and oxo, in another embodiment from the sériés consisting of halogen, R³³, oxetanyl, HO-, R³³-O-, R³³-S(O)m-, H2N-, R³³-NH-, R³³-N(R³³)-, R³³-C(O)-NH-, R³³-C(O)-N(R⁷¹)-, R³³-S(O)2-NH-, R³³-S(O)2-N(R⁷¹)-, H2N-S(O)₂-NH-, R³³-NH-S(O)2-NH-, R³³-N(R³³)-S(O)2-NH-, H₂N-S(O)₂-N(R⁷¹)-, R³³-NH-S(O)₂-N(R⁷¹)-, R³³-N(R³³)S(O)2-N(R⁷¹)-, HO-C(O)-, R³³-O-C(O)-, H2N-C(O)-, R³³-NH-C(O)-, R³³-N(R³³)-C(O)- and NC-, in another embodiment from the sériés consisting of halogen, R³³, oxetanyl, HO-, R³³-O-, R³³-S(O)m-, H2N-, R³³-NH-, R³³-N(R³³)-, R³³-C(O)-NH-, R³³-S(O)2-NH-, H₂N-S(O)₂-NH-, r³³-nhS(O)2-NH-, R³³-N(R³³)-S(O)2-NH-, HO-C(O)-, R³³-O-C(O)-, H₂N-C(O)-, R³³-NH-C(O)-, R³³-N(R³³)-C(O)- and NC-, in another embodiment from the sériés consisting of halogen, R³³, oxetanyl, HO-, R³³-O-, R³³-S(O)m-, H2N-, R³³-NH-, R³³-N(R³³)-, R³³-C(O)-NH-, R³³-S(O)2-NH-, H₂N-S(O)₂-NH-, R³³-NH-S(O)2-NH-, R³³-N(R³³)-S(O)2-NH-, H_zN-C(O)-, R³³-NH-C(O)-,

R³³-N(R³³)-C(O)- and NC-, in another embodiment from the sériés consisting of halogen, R³³, oxetanyl, HO-, R³³-O-, R³³-S(O)m-, H2N-, R³³-NH-, R³³-N(R³³)-, R³³-C(O)-NH-, R³³-S(O)2-NH-, H₂N-C(O)-, R³³-NH-C(O)-, R³³-N(R³³)-C(O)- and NC-, in another embodiment from the sériés consisting of halogen, R³³, oxetanyl, HO-, R³³-O-, R³³-S(O)m-, H2N-, R³³-NH-, R³³-N(R³³)-, R³³-C(O)-NH-, R³³-C(O)-N(R⁷¹)-, R³³-S(O)2-NH-, R³³-S(O)2-N(R⁷¹)-, H2N-C(O)-, R³³-NH-C(O)-, R³³-N(R³³)-C(O)- and NC-, in another embodiment from the sériés consisting of halogen, R³³, oxetanyl, HO-, R³³-O-, R³³-S(O)m-, R³³-C(O)-NH-, R³³-C(O)-N(R⁷¹)-, R³³-S(O)2-NH-, R³³-S(O)2N(R⁷¹)-, HZN-C(O)-, R³³-NH-C(O)-, R³³-N(R³³)-C(O)- and NC-, in another embodiment from the sériés consisting of halogen, R³³, oxetanyl, HO-, R³³-O-, R³³-S(O)m-, R³³-C(O)-NH-, R³³-S(O)2NH-, H₂N-C(O)-, R³³-NH-C(O)-, R³³-N(R³³)-C(O)-and NC-, in another embodiment from the sériés consisting of halogen, R³³, oxetanyl, HO-, R³³-O-, R³³-C(O)-NH-, R³³-S(O)2-NH-, H2NC(O)-, R³³-NH-C(O)-, R³³-N(R³³)-C(O)- and NC-, in another embodiment from the sériés consisting of halogen, R³³, oxetanyl, R³³-O-, R³³-C(O)-NH-, R³³-S(O)2-NH-, H₂N-C(O)-, R³³-NHC(O)-, R³³-N(R³³)-C(O)- and NC-, in another embodiment from the sériés consisting of halogen, R³³, oxetanyl, R³³-O- and NC-, in another embodiment from the sériés consisting of halogen, R³³, oxetanyl, and R³³-O-, in another embodiment from the sériés consisting of halogen, R³³ and oxetanyl, in another embodiment from the sériés consisting of halogen, R³³, R³³-O- and NC-, in another embodiment from the sériés consisting of halogen, R³³, and R³³-O-, in another embodiment from the sériés consisting of halogen and R³³, wherein in ail these embodiments R³³ and R⁷¹ are defined as indicated above or below and R³³ is optionally substituted by one or more identical or different substituents R⁷⁰. In one embodiment ofthe invention, the groups R³³ in these substituents on a ring representing R²⁴ are independently of each other chosen from the sériés consisting of (Ci-C6)-alkyl, (C3-C7)-cycloalkyl and (C3-C7)-cycloalkyl-(Ci-C4)-alkyl-, in another embodiment from the sériés consisting of (CrCgj-alkyl, (C3-C6)-cycloalkyl and (C3-C6)cycloalkyl-(Ci-C2)-alkyl-, in another embodiment from the sériés consisting of (CrCeJ-alkyl, (C3C6)-cycloalkyl and (C3-C6)-cycloalkyl-CH2-, in another embodiment from the sériés consisting of (CrC6)-alkyl, cyclopropyl and cyclopropyl-CH2-, for example from the sériés consisting of (Cr C6)-alkyl, in another embodiment from the sériés consisting of (Ci-C4)-alkyl, cyclopropyl and cyclopropyl-CH2-, for example from the sériés consisting of (C1-C4)-alkyI. In one embodiment of the invention, the number of substituents R⁷⁰, which are optionally présent in these groups R³³ besides any fluorine substituents and, in the case of cycloalkyl groups, any (CrC₄)-alkyl substituents, is independently of each other 0, 1, 2 or 3, in another embodiment 0, 1 or 2, in another embodiment 0 or 1, in another embodiment 0. In one embodiment ofthe invention, the substituents R⁷⁰ in these groups R³³ are independently of each other chosen from the sériés consisting of HO-, R⁷¹-O-, R⁷¹-C(O)-O-, H2N-, R⁷¹-NH-, R⁷¹-N(R⁷¹)-, R⁷¹-C(O)-NH-, R⁷¹-C(O)N(R⁷¹)-, R⁷¹-S(O)2-NH-and R⁷¹-S(O)₂-N(R⁷¹)-, in another embodiment from the sériés consisting of HO-, R⁷¹-C(O)-O-, H2N-, R⁷¹-C(O)-NH- and R⁷¹-S(O)2-NH-, in another embodiment from the sériés consisting of HO-, R⁷¹-C(O)-O- and R⁷¹-C(O)-NH-, in another embodiment from the sériés consisting of HO- and R⁷¹-C(O)-NH-, in another embodiment from the sériés consisting of HOand R⁷¹-O-, and in another embodiment ofthe invention substituents R⁷⁰ in these groups R³³ are HO-. In one embodiment ofthe invention, the groups R⁷¹ présent in these groups R³³ are independently of each other chosen from the sériés consisting of (C-|-C₄)-alkyl, cyclopropyl and cyclopropyl-CH₂-, in another embodiment from the sériés consisting of (Ch-CD-alkyl and cyclopropyl, in another embodiment from the sériés consisting of (C-j-C^-alkyl. In one embodiment ofthe invention, the number of nitro substituents (O₂N-) on the ring R²⁴ is not greaterthan two, in anotherembodiment not greaterthan one. In one embodiment ofthe invention, the total number of nitro groups in a compound ofthe formula I is not greaterthan two. In one embodiment of the invention, R²⁴ is a benzene ring or a thiophene ring, for example a benzene ring, or, in terms ofthe respective residues, R²⁴ is a phenyl group or a thiophenyl (thienyl) group, for example a phenyl group, which are ail optionally substituted as indicated afore.

Examples of spécifie residues of benzene and thiophene rings, i.e. of spécifie phenyl and thiophenyl groups, representing R²⁴, from any one or more of which examples the group R²⁴ is chosen in one embodiment ofthe invention, are phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 2chloro-phenyl, 3-chloro-phenyl, 4-chloro-phenyl, 3-bromo-phenyl, 2,3-dichloro-phenyl, 3,4dichloro-phenyl, 2,5-difluoro-phenyl, 2,5-dichloro-phenyl, 2-chloro-6-fluoro-phenyl, 3,4,5trifluoro-phenyl, 3-methyl-phenyl (m-tolyl), 3-ethyl-phenyl, 3-isopropyl-phenyl, 3-cyclopropylphenyl, 3-tert-butyl-phenyl, 3-trifluoromethyl-phenyl, 3-(2-hydroxyethyl)-phenyl, 3-(2-hydroxy-2methyl-propyl)-phenyl, 3-(2-acetylaminoethyl)-phenyl, 2-fluoro-5-methyl-phenyl, 3-chloro-2methyl-phenyl, 5-chloro-2-methyl-phenyl, 5-chloro-2-fluoro-3-methyl-phenyl, 2-fluoro-3trifluoromethyl-phenyl, 2-fluoro-5-trifluoromethyl-phenyl, 4-fluoro-3-trifluoromethyl-phenyl, 5fluoro-3-trifluoromethyl-phenyl, 3-chloro-4-trifluoromethyl-phenyl, 5-chloro-2-trifluoromethylphenyl, 5-chloro-3-trifluoromethyl-phenyl, 3-ethoxy-phenyl, 2-propoxy-phenyl, 3-isopropoxyphenyl, 3-trifluoromethoxy-phenyl, 3-(2,2,2-trifluoroethoxy)-phenyl, 5-chloro-2-methoxy-phenyl, 3-chloro-4-methoxy-phenyl, 5-fluoro-3-isopropoxy-phenyl, 2-fluoro-3-trifluoromethoxy-phenyl, 4methoxy-3,5-dimethyl-phenyl, 3-methoxy-5-trifluoromethyl-phenyl, 3-methylsulfanyl-phenyl, 3ethylsulfanyl-phenyl, 3-trifluoromethylsulfanyl-phenyl, 3-ethanesulfonyl-phenyl, 3-acetylaminophenyl, 3-methanesulfonylamino-phenyl, 3-dimethylaminosulfonylamino-phenyl, 3-cyanophenyl, 2-thienyl, 3-thienyl, 4-methyl-2-thienyl, 5-methyl-3-thienyl.

In one embodiment of the invention, R²⁶, independently of each other group R²⁶, is chosen from the sériés consisting of hydrogen, fluorine, methyl and HO-, in another embodiment from the sériés consisting of hydrogen, fluorine and (CrC4)-alkyl, in another embodiment from the sériés consisting of hydrogen, fluorine and methyl, in another embodiment from the sériés consisting of hydrogen and fluorine, in another embodiment from the sériés consisting of hydrogen and methyl, and in another embodiment R²⁶ is hydrogen, or in ail these embodiments two groups R²⁶ bonded to the same carbon atom together are oxo, or two of the groups R²⁶ or one group R²⁵ and one group R²⁶, together with the comprised chain members, form a 3-membered to 7membered monocyclic ring which is saturated and contains 0, 1 or 2 identical or different hetero ring members chosen from the sériés consisting of N, N(R³⁴), O, S, S(O) and S(O)2, which ring is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the sériés consisting offluorine and (C₁-C₄)-alkyl. In anotherembodiment ofthe invention, R²⁶, independently of each other group R²⁶, is chosen from the sériés consisting of hydrogen, fluorine, methyl and HO-, in another embodiment from the sériés consisting of hydrogen, fluorine and (C1-C4)-alkyl, in another embodiment from the sériés consisting of hydrogen, fluorine and methyl, in another embodiment from the sériés consisting of hydrogen and fluorine, in another embodiment from the sériés consisting of hydrogen and methyl, and in another embodiment R²⁶ is hydrogen, or in ail these embodiments two ofthe groups R²⁶ or one group R²⁵ and one group R²⁶, together with the comprised chain members, form a 3-membered to 7-membered monocyclic ring which is saturated and contains 0, 1 or 2 identical or different hetero ring members chosen from the sériés consisting of N, N(R³⁴), O, S, S(O) and S(O)2, which ring is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the sériés consisting of fluorine and (CrC^-alkyl. In another embodiment ofthe invention, R²⁶, independently of each othergroup R²⁶, is chosen from the sériés consisting of hydrogen, fluorine, methyl and HO-, in another embodiment from the sériés consisting of hydrogen, fluorine and (C_rC₄)-alkyl, in another embodiment from the sériés consisting of hydrogen, fluorine and methyl, in another embodiment from the sériés consisting of hydrogen and fluorine, in another embodiment from the sériés consisting of hydrogen and methyl, and in another embodiment ail groups R²⁶ are hydrogen.

In one embodiment ofthe invention, the number of groups R²⁶ in a chain representing R²³ which are HO-, is zéro, one or two, in another embodiment zéro or one, in another embodiment zéro, in another embodiment one. In one embodiment ofthe invention, a HO- group representing R²⁶ is not présent on a carbon atom which is adjacent to a hetero chain member in a chain representing R²³. In one embodiment ofthe invention the numberofgroups R²⁶ in a chain representing R²³ which are (Ci-C₄)-alkyl such as methyl, is zéro, one or two, in another embodiment zéro or one, in another embodiment zéro, in another embodiment one, in another embodiment two. In one embodiment ofthe invention the number of groups R²⁶ in a chain representing R²³ which are fluorine, is zéro, one, two, three or four, in another embodiment zéro, one, two or three, in another embodiment zéro, one or two, in another embodiment zéro or one, in another embodiment zéro, in another embodiment one, in another embodiment two. In one embodiment ofthe invention, the number of oxo substituents in a chain representing R²³which are formed by two groups R²⁶ bonded to the same carbon atom, is zéro, one or two, in another embodiment zéro or one, in another embodiment zéro, in another embodiment one. In one embodiment of the invention, an oxo substituent in a chain representing R²³ is not présent on a carbon atom which is adjacent to a hetero chain member chosen from the sériés consisting of S(O) and S(O)₂, in another embodiment from the sériés consisting of S, S(O) and S(O)₂, in another embodiment from the sériés consisting of O, S, S(O) and S(O)₂.

In one embodiment of the invention, the number of rings which are formed by two of the groups R²⁶ or one group R²⁵ and one group R²⁶, together with the comprised chain members, is zéro, one or two, in another embodiment zéro or one, in another embodiment one, in another embodiment zéro. In one embodiment ofthe invention a ring formed by two ofthe groups R²⁶ or one group R²⁵ and one group R²⁶, together with the comprised chain members, is a 3membered, 4-membered, 5-membered or 6-membered ring, in another embodiment a 3membered, 5-membered or 6-membered ring, in another embodiment a 3-membered ring, in anotherembodiment a 5-membered or6-membered ring. In one embodiment ofthe invention, it is possible for two ofthe groups R²⁶, together with the comprised chain members, to form a ring, but not for one group R²⁵ and one group R²⁶. In one embodiment of the invention the number of chain members which is comprised by a ring formed by two ofthe groups R²⁶ or one group R²⁵ and one group R²⁶, is one, two, three or four, in another embodiment it is one, two or three, in another embodiment it is one or two, in another embodiment it is one. In case such ring comprises only one chain member, the two of the groups R²⁶ forming the ring are bonded to the same carbon atom in the chain and the said one chain member is the carbon atom carrying the two groups R²⁶. Examples of rings, which are formed by two groups R²⁶ bonded to the same carbon atom and the one comprised chain member, are cycloalkane rings such as cyclopropane, cyclobutane, cyclopentane or cyclohexane, and heterocyclic rings such as tetrahydrothiophene, tetrahydrothiopyran, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine or piperidine, for example cyclopropane, which carry any adjacent chain members of a chain representing R²³ and/or the group R²⁴ and/or the ring comprising the groups Y and Z which is depicted in formula I, on the same ring carbon atom, and which rings can ali be substituted as indicated. In case a ring formed by two ofthe groups R²⁶ or one group R²⁵ and one group R²⁶, together with the comprised chain members, comprises two chain members, the two groups R²⁶ forming the ring are bonded to two adjacent carbon atoms in the chain or the one group R²⁶ is bonded to a carbon atom which is adjacent to the group N(R²⁵), respectively. Examples of rings, which are formed in such case, are likewise cycloalkane rings such as cyclopropane, cyclobutane, cyclopentane or cyclohexane, and heterocyclic rings such as tetrahydrothiophene, tetrahydrothiopyran, oxetane, tetrahydrofuran, tetrahydropyran, azetidine, pyrrolidine or piperidine, for example cyclopropane, which carry any adjacent chain members of a chain representing R²³ and/or the group R²⁴ and/or the ring comprising the groups Y and Z which is depicted in formula I, on two adjacent ring carbon atoms or on the ring nitrogen atom and an adjacent ring carbon atom, and which rings can ail be substituted as indicated.

In case a ring formed by two of the groups R²⁶ or one group R²⁵ and one group R²⁶, together with the comprised chain members, comprises more than one chain members, besides being the group C(R²⁶)(R²⁶) the comprised chain members can also be hetero chain members including the group N(R²⁵), which then are hetero ring members ofthe formed ring, wherein ar least one group C(R²⁶)(R²⁶) is présent. In one embodiment ofthe invention, the total number of hetero ring members in such a ring is zéro, one or two, in another embodiment zéro or one, in another embodiment zéro, in another embodiment one. In one embodiment ofthe invention, hetero ring members in such a ring are chosen from the sériés consisting of N, N(R³⁴), O and S, in another embodiment form the sériés consisting of N, N(R³⁴) and O, in another embodiment from the sériés consisting of N and N(R³⁴), in another embodiment from the sériés consisting of N(R³⁴) and O, in another embodiment from the sériés consisting of N(R³⁴), and in another embodiment hetero ring members in such a ring are N, and in still another embodiment hetero ring members in such a ring are O, wherein a hetero ring member N in a ring formed by two of the groups R²⁶ or one group R²⁵ and one group R²⁶, together with the comprised chain members, is the nitrogen atom of a hetero chain member N(R²⁵).

In one embodiment ofthe invention, the number of substituents which are optionally présent in a ring formed by two of the groups R^2S or one group R²⁵ and one group R²⁶, together with the comprised chain members, is 0, 1, 2, 3 or 4, in another embodiment 0, 1, 2 or 3, in another embodiment 0, 1 or 2, in another embodiment 0 or 1, in another embodiment 0. In one embodiment ofthe invention, (Ci-C₄)-alkyl substituents which are présent in a ring formed by two ofthe groups R²⁶ or one group R²⁵ and one group R²⁶, togetherwith the comprised chain members, are methyl. In one embodiment ofthe invention substituents présent in a ring formed by two of the groups R²⁶ or one group R²⁵ and one group R²⁶, together with the comprised chain members, are fluorine, in another embodiment they are identical or different (C-i-C^-alkyl groups, for example methyl.

Examples of spécifie groups R²³ including spécifie groups R²⁶ contained therein are given in the 5 following examples of groups of the formula II, which groups are bonded to the ring comprising the groups Y and Z which is depicted in formula I by the free bond represented by the terminal hyphen or the terminal line in the structural formula, and from which groups of the formula II the groups R²³ themselves are obtained by removing the group R²⁴, wherein in these groups ofthe formula II the group R²⁴ is defined as above or below:

R²⁴-CH₂-CH₂-,

R²⁴-CH2-O-, r²⁴-ch2-s-, r²⁴-ch₂-nh-,

R²⁴-C(O)-NH-, r²⁴-ch2-ch2-ch2-, r²⁴-cf2-ch₂-ch₂-, R²⁴-CH₂-CH₂-CH(OH)-, r²⁴-cf₂-o-, r²⁴-cf₂-s-,

R²⁴-CH₂-N(CH₃)-,

R²⁴-S(O)2-O-, r²⁴-ch2-ch₂-cf₂-, R²⁴-CH(OH)-CH₂-CH₂-,

R²⁴-CH₂-CH₂-C(CH₃)₂-,

R²⁴-C(CH₃)₂-CH₂-CH₂-

CH—

r²⁴-ch₂-cf₂-o-, r²⁴-cf₂-ch₂-o-,

R²⁴-CH(CH3)-CH2-OR²⁴-CH(F)-CH2-O-, r²⁴-cf2-cf2-o-, R²⁴-C(CH3)₂-CH₂-O-_:

R²⁴-O-CF₂-CH₂-, r²⁴-o-cf₂-cf₂-, r²-o-ch₂-^^ r²⁴-cf₂-o-ch₂-,

V R-^-O-CH—

R²⁴-CH₂-CH₂-S-, r²⁴-s-ch₂-ch₂-,

R²⁴-CH₂-CH₂-N(CH₃)-, r²⁴-o-ch₂-ch₂-, r²⁴-o-ch2-cf2R²⁴— 0^Z_CH— r²⁴-ch₂-o-ch₂-, r²⁴-ch₂-o-cf₂-,

R²⁴—CH2-O-^Zr²⁴-ch2-s-ch₂-, r²⁴-ch2-ch2-nh-, R²⁴-CH2-C(O)-NH-.

In one embodiment ofthe invention, R²³ is chosen from a direct bond and any one or more of the chains R²³ in the preceding examples of groups ofthe formula II and, likewise, the group of the formula II is chosen from the group R²⁴ and any one or more ofthe preceding examples of the groups ofthe formula II.

In one embodiment of the invention, R³² and R³⁴ are independently of each other chosen from the sériés consisting of hydrogen, R³⁵, R³⁵-C(O)-, R³⁵-O-C(O)- and phenyl, in another embodiment from the sériés consisting of hydrogen, R³⁵, R³⁵-C(O)- and R³⁵-O-C(O)-, in another embodiment from the sériés consisting of hydrogen, R³⁵ and R³⁵-C(O)~, in another embodiment from the sériés consisting of hydrogen, R³⁵ and phenyl, in another embodiment from the sériés consisting of hydrogen and R³⁵. In one embodiment ofthe invention, the groups R³⁵ occurring in R³² and R³⁴ are independently of each other chosen from (Ci-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, in another embodiment from (C₁-C₆)-alkyl, (C₃-C₇)-cycloalkyl and (Ca-Cyj-cycloalkyl-tCvC^-alkyl-, in another embodiment from (C-i-C₆)-alkyl, (C₃-C₇)cycloalkyl and (C₃-C₇)-cycloalkyl-CH₂-, in another embodiment from (CrC^-alkyl and (C₃-C₇)cycloalkyl, in another embodiment from (CrC₆)-alkyl, in another embodiment from (C-|-C₄)-alkyl, which are ail optionally substituted by one or more identical or different substituents R⁷⁰ and wherein in these groups besides any substituents R⁷⁰ one or more fluorine substituents are optionally présent and in cycloalkyl groups one or more (CrC^-alkyl substituents are optionally présent as applies to alkyl and cycloalkyl groups in general.

In one embodiment ofthe invention, the number of substituents R⁷⁰ which are optionally présent in a group R³⁵ occurring in R³² and R³⁴ besides any fluorine substituents and, in the case of a cycloalkyl group, alkyl substituents, is, independently of each other group, 0, 1, 2, 3 or 4, in another embodiment 0, 1, 2 or 3, in another embodiment 0, 1 or 2, in another embodiment 0 or 1, in anotherembodiment 0. In one embodiment ofthe invention, substituents R⁷⁰ which are optionally présent in a group R³⁵ occurring in R³² and R³⁴ are, independently of each other group, chosen from the sériés consisting of HO- and R⁷¹-O-,

In one embodiment ofthe invention, R⁵⁰ is chosen from R⁵¹-O- and R⁵²-NH-, in another embodiment from R⁵¹-O- and H₂N-. In another embodiment R⁵⁰ is R^S1-O-,

In one embodiment ofthe invention, R⁵¹ is hydrogen. In another embodiment ofthe invention, R⁵¹ is R⁵⁴.

In one embodiment ofthe invention, R⁵² is chosen from the sériés consisting of hydrogen, R⁵⁵ and R⁵⁶-S(O)2-, in another embodiment from the sériés consisting of hydrogen, (CrC4)-alkyl which is optionally substituted by one or more identical or different substituents R⁷⁰, and R^5SS(O)2-, in another embodiment from the sériés consisting of hydrogen, unsubstituted (C_rC₄)alkyl and R⁵⁶-S(O)2-, in another embodiment from the sériés consisting of hydrogen, unsubstituted methyl and R⁵⁶-S(O)2-, in another embodiment from the sériés consisting of hydrogen and (C_rC₄)-alkyl which is optionally substituted by one or more identical or different substituents R⁷⁰, in another embodiment from the sériés consisting of hydrogen and unsubstituted (C_rC₄)-alkyl, in another embodiment from the sériés consisting of hydrogen and unsubstituted methyl. In another embodiment ofthe invention, R⁵² is hydrogen.

In one embodiment ofthe invention, R⁵³ is chosen from the sériés consisting of hydrogen and (CrC4)-alkyl which is optionally substituted by one or more identical or different substituents R⁷⁰, in another embodiment from the sériés consisting of hydrogen and unsubstituted (CrC^alkyl, in another embodiment from the sériés consisting of hydrogen and unsubstituted methyl. In another embodiment ofthe invention, R⁵³ is hydrogen. In one embodiment ofthe invention, R⁵¹, R⁵² and R⁵³ are independently of each other chosen from the sériés consisting of hydrogen and unsubstituted (CrC^-alkyl, in another embodiment from the sériés consisting of hydrogen and unsubstituted (Cf-Csj-alkyl, in another embodiment from the sériés consisting of hydrogen and unsubstituted (Ci-C2)-alkyl.

ln one embodiment of the invention, R⁵⁴ is chosen from (CrC^-alkyl, (C3-C7)-cycloalkyl and (C3C7)-cycloalkyl-(Ci-C4)-alkyl-, in another embodiment from (Ci-C6)-alkyl, (C3-C7)-cycloalkyl and (C3-C7)-cycloalkyl-(C1-C2)-alkyl-, in another embodiment from (CrC6)-alkyl, (C3-C7)-cycloalkyl and (C3-C7)-cycloalkyl-CH2-, in another embodiment from (CvCej-alkyl and (C3-C7)-cycloalkyl, in another embodiment from (Ci-C6)-alkyl, in another embodiment from (C4-C4)-alkyl, in another embodiment from (CrC3)-alkyl, which are ail optionally substituted by one or more identical or different substituents R⁷⁰ and wherein in these groups besides any substituents R⁷⁰ one or more fluorine substituents are optionally présent and in cycloalkyl groups one or more (CrC₄)-alkyl substituents are optionally présent as applies to alkyl and cycloalkyl groups in general, ln one embodiment of the invention, the number of substituents R⁷⁰ which are optionally présent in a group R⁵⁴ besides any fluorine substituents and, in the case of a cycloalkyl group, any alkyl substituents, is 0, 1 or 2, in another embodiment 0 or 1, in another embodiment 1, in another embodiment 0. In another embodiment of the invention, a group R⁵⁴ is neither substituted by R⁷⁰ nor by fluorine substituents nor, in the case of a cycloalkyl group, by alkyl substituents, and R⁵⁴ in this embodiment thus is chosen, for example, from the sériés consisting of C-i-Cej-alkyl, (C₂C₆)-alkenyl, (C₂-C₆)-alkynyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₄)-alkyl-, or from the sériés consisting of (CrC^-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-CH₂-, or from the sériés consisting of (C-|-C₆)-alkyl, or from the sériés consisting of (Ci-C₄)-alkyl, or from the sériés consisting of (C₄-C₃)-alkyl, which are ail unsubstituted. In one embodiment of the invention, substituents R⁷⁰ which are optionally présent in a group R⁵⁴, are independently of each other chosen from the sériés consisting of HO-, R⁷¹-O-, R⁷¹-C(O)-O-, HO-C(O)- and R⁷¹-OC(O)-, in another embodiment from the sériés consisting of HO-, R⁷¹-O- and R⁷¹-C(O)-O-, in another embodiment from the sériés consisting of HO- and R⁷¹-C(O)-O-.

In one embodiment of the invention, R⁵⁶ is chosen from the sériés consisting of phenyl which is optionally substituted as indicated above or below, and unsubstituted (C_rC₄)-alkyl, in another embodiment from the sériés consisting of phenyl which is optionally substituted as indicated above or below, and unsubstituted methyl, in another embodiment from unsubstituted (C!-C₄)alkyl, in another embodiment from unsubstituted(Ci-C₃)-alkyl. ln another embodiment R⁵⁶ is unsubstituted methyl, in another embodiment phenyl which is optionally substituted as indicated.

In one embodiment of the invention, R⁶⁰ is chosen from the sériés consisting of hydrogen and methyl. In another embodiment R⁶⁰ is hydrogen. In another embodiment R⁶⁰ is (Ci-C₄)-alkyl, for example methyl.

In one embodiment ofthe invention, a group R⁷⁰ in any of its occurrences is, independently of groups R⁷⁰ in other occurrences and unless specified otherwise, chosen from the sériés consisting of HO-, R⁷¹-O-, R⁷¹-C(O)-O-, R⁷¹-S(O)m-, H2N-, R⁷¹-NH-, R⁷¹-N(R⁷¹)-, R⁷¹-C(O)-NH-, R⁷¹-C(O)-N(R⁷¹)-, R⁷¹-S(O)2-NH-, R⁷¹-S(O)2-N(R⁷¹)-, HO-C(O)-, R⁷¹-O-C(O)-, HZN-C(O)-, R⁷¹NH-C(O)-, R⁷¹-N(R⁷¹)-C(O)- and oxo, in another embodiment from the sériés consisting of HO-, R⁷¹-O-, R⁷¹-C(O)-O-, R⁷¹-S(O)m-, H2N-, R⁷¹-NH-, R⁷¹-N(R⁷¹)-, R⁷¹-C(O)-NH-, R⁷¹-S(O)2-NH-, HOC(O)-, R⁷¹-O-C(O)-, H2N-C(O)-, R⁷¹-NH-C(O)-, R⁷¹-N(R⁷¹)-C(O)- and oxo, in another embodiment from the sériés consisting of HO-, R⁷¹-O-, R⁷¹-C(O)-O-, R⁷¹-S(O)m-, HO-C(O)-, R⁷¹O-C(O)-, H2N-C(O)-, R⁷¹-NH-C(O)-, R⁷¹-N(R⁷¹)-C(O)- and oxo, in another embodiment from the sériés consisting of HO-, R⁷¹-O-, R⁷¹-C(O)-O-, R⁷¹-S(O)m-, H_ZN-, R⁷¹-NH-, R⁷¹-N(R⁷¹)-, R⁷¹-C(O)NH-, R⁷¹-S(O)2-NH- and oxo, in another embodiment from the sériés consisting of HO-, R⁷¹-O-, R⁷¹-C(O)-O-, R⁷¹-S(O)m- and oxo, in another embodiment from the sériés consisting of HO-, R⁷¹O-, R⁷¹-S(O)m- and oxo, in another embodiment from the sériés consisting of HO-, R⁷¹-O-, R⁷¹C(O)-O- and R⁷¹-S(O)m-, in another embodiment from the sériés consisting of HO- and R⁷¹-O-, in another embodiment from the sériés consisting of HO- and R⁷¹-C(O)-O-, in another embodiment from the sériés consisting of HO-C(O)-, R⁷¹-O-C(O)-, H2N-C(O)-, R⁷¹-NH-C(O)-, R⁷¹-N(R⁷¹)-C(O)-, in another embodiment from the sériés consisting of HO-C(O)-, and R⁷¹-OC(O)-, and in another embodiment R⁷⁰ is HO-, wherein R⁷¹ is defined as indicated above or below. In the latter embodiment, in which R⁷⁰ is HO-, a (C^Oej-alkyl group, for example, which is optionally substituted by the said R⁷⁰, can among others be a group such as (Ci-C6)-alkyl, HO-(Ci-C₆)-alkyl-, i.e. hydroxy-(Ci-C₆)-alkyl-, (HO)₂(C₂-C₆)-alkyl-, i.e. dihydroxy-(C₂-C₆)-alkyl-, and a (C₁-C₄)-alkyl group which is optionally substituted by R⁷⁰, can among others be a group such as (Ci-C₄)-alkyl, HO-(C₁-C₄)-alkyl-, i.e. hydroxy-(C₁-C₄)-alkyl-, (HO)₂(C₂-C₄)-alkyl-, i.e. dihydroxy-(C₂-C₄)-alkyl-, wherein the alkyl groups are optionally substituted by one or more fluorine substituents. In one embodiment ofthe invention, a carbon atom does not carry more than one HO- group.

In one embodiment ofthe invention, R⁷¹ is chosen from (C₁-C₄)-alkyl, cyclopropyl and cyclopropyl-CH₂-, in another embodiment from (Ci-C₄)-alkyl and cyclopropyl, in another embodiment from (C₁-C₄)-alkyl, in another embodiment from (Ci-C₃)-alkyl, unless specified otherwise.

A subject ofthe invention are ail compounds ofthe formula I wherein any one or more structural éléments such as groups, substituents and numbers are defined as in any ofthe specified embodiments or définitions ofthe éléments or hâve one or more ofthe spécifie meanings which are mentioned herein as examples of éléments, wherein ail combinations of one or more specified embodiments and/or définitions and/or spécifie meanings ofthe éléments are a subject ofthe présent invention. Also with respect to ail such compounds of the formula I, ail their stereoisomeric forms and mixtures of stereoisomeric forms in any ratios, and their physiologically acceptable salts are a subject ofthe présent invention.

Likewise, also with respect to ail spécifie compounds disclosed herein, such as the example compounds which represent embodiments ofthe invention wherein the various groups and numbers in the general définition ofthe compounds ofthe formula I hâve the spécifie meanings présent in the respective spécifie compound, it applies that all their stereoisomeric forms and mixtures of stereoisomeric forms in any ratio, and their physiologically acceptable salts are a subject ofthe présent invention. A subject ofthe invention also are all spécifie compounds disclosed herein, irrespective thereof whether they are disclosed as a free compound and/or as a spécifie sait, both in the form ofthe free compound and in the form of all its physiologically acceptable salts. Thus, a subject ofthe invention also is a compound ofthe formula I which is chosen from any ofthe spécifie compounds oftheformula I which are disclosed herein, or is any one ofthe spécifie compounds ofthe formula I which are disclosed herein, irrespective thereof whether they are disclosed as a free compound and/or as a spécifie sait, or a physiologically acceptable saitthereof, wherein the compound ofthe formula I is a subject ofthe invention in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio where applicable.

As an example of compounds of the invention which with respect to any structural éléments are defined as in specified embodiments ofthe invention or définitions of such éléments, compounds of the formula I may be mentioned wherein ring A is a 3-membered to 8-membered monocyclic ring which comprises 0, 1 or 2 identical or different hetero ring members chosen from the sériés consisting of N, N(R°), O, S, S(O) and S(O)₂, and which is saturated or comprises 1 double bond, wherein ring A is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the sériés consisting of halogen, R¹, R², (C2-C6)-alkenyl, HO-, R¹-O-, phenyl-(CrC₄)-aIkyl-O-, R¹-C(O)-O-, R¹-S(O)2-O-, R¹-S(O)m-, H₂N-, R¹-NH-, R¹-N(R¹)-, R¹-C(O)-NH-, R¹-C(O)-N(R¹)-, R¹S(O)2-NH-, R¹-S(O)2-N(R¹)-, R¹-C(O)-, HO-C(O)-, R¹-O-C(O)-, HZN-C(O)-, R¹-NH-C(O)-, R¹N(R¹)-C(O)-, H2N-S(O)₂-, R¹-NH-S(O)2-, R¹-N(R¹)-S(O)2-, F₅S-, NC-, oxo and methylene;

Y is chosen from the sériés consisting of S, C(R¹²)=C(R¹³), and C(R¹⁵)=N;

Z is C(R¹⁶);

R²⁰ is hydrogen;

and ail othergroups and numbers are defined as in the general définition ofthe compounds of the formula I or in any specified embodiments ofthe invention or définitions of structural éléments, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts.

As another such example compounds ofthe formula I may be mentioned, wherein ring A is a cyclohexane ring or cycloheptane ring which is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the sériés consisting of halogen, R¹, R², (C2-C6)-alkenyl, HO-, R¹-O-, phenyl-(CrC₄)-alkyl-O-, R¹-C(O)-O-, R¹-S(O)2-O-, R¹-S(O)m-, H₂N-, R¹-NH-, R¹-N(R¹)-, R¹-C(O)-NH-, R¹-C(O)-N(R¹)-, R¹-S(O)2-NH-, R¹-S(O)2N(R¹)-, R¹-C(O)-, HO-C(O)-, R¹-O-C(O)-, H2N-C(O)-, R¹-NH-C(O)-, R¹-N(R¹)-C(O)-, H2N-S(O)₂-, R¹-NH-S(O)2-, R¹-N(R¹)-S(O)2-, F₅S-, NC-, oxo and methylene;

Y is chosen from the sériés consisting of S, C(R¹²)=C(R¹³) and C(R¹⁵)=N;

Z is C(R¹⁶);

R²⁰ is hydrogen;

and ail other groups and numbers are defined as in the general définition ofthe compounds of the formula I or in any specified embodiments of the invention or définitions of structural éléments, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts.

As another such example compounds ofthe formula I may be mentioned, wherein

R²¹ is chosen from the sériés consisting of hydrogen, halogen, (C₁-C₄)-alkyl, HO-iCrC^-alkyl-, (CrC^-alkyl-O-tCrC^-alkyl-, (C^-alkyl-O-, HO-(C_rC₄)-alkyl-O-, (CrC^-alkyl-O-ÎCr^)alkyl-O-, (Ci-C₄)-alkyl~S(O)_m-, (C₁-C₄)-alkyl-C(O)-, NC- and Het¹, or together with R¹³ or R¹⁴ forms a chain as specified in the définition of R¹³ and R¹⁴;

R²² is a group ofthe formula II r²⁴-r²³.

Il

R²³ is a direct bond or a chain consisting of 2, 3 or 4 chain members of which 0 or 1 chain members are hetero chain members chosen from the sériés consisting of N(R²⁵), O, S, S(O) and S(O)₂ and the other chain members are identical or different groups C(R²⁶)(R²⁶);

and ail othergroups and numbers are defined as in the general définition ofthe compounds of the formula I or in any specified embodiments ofthe invention or définitions of structural éléments, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts.

As another such example compounds ofthe formula I may be mentioned, wherein ring A is a cyclohexane ring or a cycloheptane ring which is optionally substituted by one or two identical or different substituents chosen from the sériés consisting of halogen, (CrC₄)-alkyl and (Ci-C₄)-alkyl-O-;

Y is chosen from the sériés consisting of C(R¹²)=C(R¹³) and C(R^1S)=N;

Z is C(R¹⁶);

R¹², R¹³, R¹⁵ and R¹⁶ are independently of each other chosen from the sériés consisting of hydrogen, halogen, (Ci-C4)-alkyl; or R¹³ forms together with R²¹ a chain which is chosen from the sériés consisting of-O- C(R¹⁸)(R¹⁸)-O-, -CH2-CH₂-CH₂, -CH₂-O-CH₂-, -CH₂-CH₂-CH₂-CH₂- and -O-C(R¹⁸)(R¹⁸)- C(R¹⁸)(R¹⁸)-O;

R¹⁸ is chosen from the sériés consisting of hydrogen or fluorine;

R²¹ is chosen from the sériés consisting of hydrogen, halogen, (C₁-C₄)-alkyl, HO-(C_rC₄)-alkyl-, (C_rC₄)-alkyl-O-, (CrC^-alkyl-CXO)-, (CrC^-alkyl-CHCrC^alkyl-, HCHCrC^-alkyl-O-, (C_rC₄)alkyl-O-iCrC^-alkyl-O-, NC- and oxetanyl, or together with R¹³ forms a chain as specified in the définition of R¹³;

R²² is a group ofthe formula II

R²⁴-R²³- Il

R²³ is a direct bond or a chain consisting of 2, 3 or 4 chain members of which 0 or 1 chain members are hetero chain members chosen from the sériés consisting of O and S, and the other chain members are identical or different groups C(R²⁶)(R²⁶);

R²⁴ is a benzene ring which is optionally substituted by one or more identical or different substituents chosen from the sériés consisting of halogen, R³³, oxetanyl, HO-, R³³-O-, R³³-S(O)m-, H2N-, R³³-NH-, R³³-N(R³³)-, R³³-C(O)-NH-, R³³-S(O)2-NH-, HO-C(O)-, R³³-O-C(O)-, H₂N-C(O)-, R³³-NH-C(O)-, R³³-N(R³³)-C(O)- and NC-;

R²⁶, independently of each other group R²⁶, is chosen from the sériés consisting of hydrogen, fluorine, (Cf-C^-alkyl, ortwo ofthe groups R²⁶ which are bonded to the same carbon atom in the chain, together with the carbon atom carrying them, form a cyclopropane ring or an oxetane ring;

R³³, independently of each other group R³³, is chosen from the sériés consisting of (C₁-C₄)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C7)-cycloalkyl-(C-|-C₂)-alkyl-, which are ail optionally substituted by one or more identical or different substituents R⁷⁰;

R⁵⁰ is chosen from the sériés consisting of R⁵¹0- and R⁵²(R⁵³)N-;

R⁵¹, R⁵² and R⁵³ are independently of each other chosen from the sériés consisting of hydrogen and (C-|-C₄)-alkyl;

R⁷⁰ is chosen from the sériés consisting of HO- and R⁷¹-O-;

R⁷¹ is (CrC₄)-alkyl;

m, independently of each other number m, is an integer chosen from the sériés consisting of 0 and 2;

cycloalkyl, independently of each other group cycloalkyl, and independently of any other substituents on cycloalkyl, is optionally substituted by one or more identical or different substituents chosen from fluorine and (CrC₄)-alkyl;

alkyl, independently of each other group alkyl, and independently of any other substituents on alkyl, is optionally substituted by one or more fluorine substituents;

in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts.

A subject ofthe présent invention is a compound ofthe formula I, which is trans-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methylcyclohexanecarboxylic acid, cis-1-[(5-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-4methyl-cyclohexanecarboxylic acid, trans-1-[(5-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-4methyl-cyclohexanecarboxylic acid, cis-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid, cis-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid, trans-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid, trans-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid, cis-1-{[5-(3-Chloro-4-methoxy-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-methylcyclohexanecarboxylic acid, trans-1-{[5-(3-Chloro-4-methoxy-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-methylcyclohexanecarboxylic acid, cis-1-[(3'-Chloro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-ethyl-cyclohexanecarboxylic acid, trans-1-[(3'-Chloro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-ethyl-cyclohexanecarboxylic acid, trans-4-Ethyl-1-[(6-methoxy-5-phenethyloxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylic acid, cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methylcyclohexanecarboxylic acid, cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-ethylcyclohexanecarboxylic acid, cis-4-Ethyl-1-[(6-methoxy-5-phenethyloxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylic acid, trans-4-Ethyl-1-{[6-(2-hydroxy-ethoxy)-3'-trifluoromethyl-biphenyl-3-carbonyl]-amino}cyclohexanecarboxylic acid, trans-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-ethylcyclohexanecarboxylic acid, trans-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-4-ethylcyclohexanecarboxylic acid, cis-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-4-ethylcyclohexanecarboxylic acid,

Trans-1-[(3'-Chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methylcyclohexanecarboxylic acid,

Cis-1-[(3'-chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-ethylcyclohexanecarboxylic acid,

Cis-1-[(3'-Chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-trifluoromethylcyclohexanecarboxylic acid, or cis-4-Ethyl-1-{[6-(2-hydroxy-ethoxy)-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts.

Another subject of the présent invention are processes for the préparation of the compounds of the formula I which are outlined below and by which the compounds are obtainable. For example, the préparation ofthe compounds ofthe formula I can be carried out by reacting a compound ofthe formula III with a compound ofthe formula IVwith formation of an amide bond.

The ring A and the groups Y, Z, R²⁰ to R²² and R⁵⁰ in the compounds ofthe formulae III and IV are defined as in the compounds ofthe formula I and additionally functional groups can be présent in protected form or in the form of a precursor group which is later converted into the final group. As an example of a precursor group which can favorably be employed in the reaction ofthe compounds ofthe formulae III and IV, the carbonitrile group NC- (cyano group) may by mentioned as a precursor ofthe group -C(O)-R⁵⁰. Thus, compounds ofthe formula I can also be prepared by reacting a compound oftheformula V, which carries a NC- group in the position ofthe group

-C(O)-R⁵⁰, with a compound ofthe formula IVto give a compound ofthe formula VI which likewise carries a NC- group in the position ofthe group -C(O)-R⁵⁰ in the compounds ofthe formula I, and then converting the NC- group into the desired group -C(O)-R⁵⁰, for example into a carboxylic acid group or a carboxamide group by the well-known techniques for hydrolyzing carbonitriles. For example, the NC- group can be converted into the group -C(O)-R⁵⁰ in a two step, one pot procedure by initial alcoholysis ofthe nitrile to the imino ester in a alcohol like ethanoi or méthanol in the presence of an acid such as hydrogen chloride under anhydrous conditions, and the formed imino ester converted into a carboxylic acid ester, i.e. a compound of the formula I in which R⁵⁰ is R⁵¹O, by subséquent addition of water. The ring A and the groups Y, Z, R²⁰ to R²² in the compounds of the formulae V and VI are defined as in the compounds of the formula I, and additionally can functional groups be présent in protected form or in the form of a precursor group.

The group G in the compounds ofthe formula IV can be HO- (hydroxy), i.e. the compound of the formula IV can thus be a carboxylic acid, or another group which can be replaced by the group N(R²⁰) in the compound of the formula III or V in a substitution reaction, for example an aryloxy group such as optionally substituted phenoxy or an alkyloxy group such as a (C1-C4)alkyl-O- group, for example a (C₁-C₃)-alkyl-O- group like methoxy or ethoxy, or halogen, for example chlorine or bromine, and the compound of the formula IV can thus be a reactive ester like an aryl ester or alkyl ester, for example a methyl ester or ethyl ester, or an acid halide, for example an acid chloride or acid bromide, ofthe respective carboxylic acid. The compound of the formulae III and V and/orthe compound ofthe formula IV can also be employed, and the compounds ofthe formulae I and VI obtained, in the form of a sait, for example an acid addition sait such as an hydrohalide, for example a hydrochloride, ofthe compound ofthe formulae III and V and/or an alkaline métal sait, for example a sodium sait, of a compound of the formula IV in which G is HO-. Likewise, in ail other reactions in the préparation ofthe compounds ofthe formula I, including the préparation of starting compounds, compounds can also be employed and/or products obtained in the form a sait.

In case a compound ofthe formula IV is employed in which G is HO-, the carboxylic acid group HO-C(O)- is generaliy activated in situ by means of a customary amide coupling reagent or converted into a reactive carboxylic acid dérivative which can be prepared in situ or isolated. For example, the compound ofthe formula IV in which G is HO- can be converted into an acid halide, e. g. the compound of the formula IV in which G is Cl or Br, by treatment with thionyl chloride, phosphorus pentachloride, phosphorus tribromide or oxalyl chloride, or treated with an alkyl chloroformate like ethyl chloroformate or isobutyl chloroformate to give a mixed anhydride. Customary coupling reagents which can be employed, are propanephosphonic anhydride, N,N’carbonyldiazoles like Ν,Ν'-carbonyldiimidazoIe (CDI), carbodiimides like 1,3diisopropylcarbodiimide (DIC), 1,3-dicyclohexylcarbodiimide (DCC) or 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbodiimides together with additives like 1-hydroxy-benzotriazole (HOBT) or 1-hydroxy-7-azabenzotriazole (HOAT), uronium-based coupling reagents like 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), 0-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or O-(cyano(ethoxycarbonyl)methyleneamino)-N,N,N',N'tetramethyluronium tetrafluoroborate (TOTU), and phosphonium-based coupling reagents like (benzotriazol-1 -yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP) or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP).

The reaction conditions for the préparation ofthe compounds ofthe formulae I and VI from compounds ofthe formulae III and V and compounds ofthe formula IV dépend on the particulars ofthe spécifie case, for example the meaning ofthe group G or the employed coupling reagent, and are well known to a skilled person in view of the general knowledge in the art. For example, in case a compound ofthe formula IV in which G is alkyl-O-, like methoxy or ethoxy, is reacted with a compound ofthe formula III or V, generaliy the reaction is carried out in an inert solvent, for example a hydrocarbon or chlorinated hydrocarbon like benzene, toluene, xylene, chlorobenzene, dichloromethane, chloroform or dichloroethane, an ether like tetrahydrofuran (THF), dioxane, dibutyl ether, diisopropyl ether or dimethoxyethane (DME), or a mixture of solvents, at elevated températures, for example at températures from about 40 °C to about 140 °C, in particular at températures from about 50 °C to about 120 °C, for example at about the boiling température ofthe solvent. In case a compound ofthe formula IV in which G is halogen, like chlorine or bromine, is reacted with a compound ofthe formula III orV, generally the reaction is likewise carried out in an inert solvent, for example a hydrocarbon or chlorinated hydrocarbon or ether like the aforementioned ones, an ester like ethyl acetate or butyl acetate, a nitrile like acetonitrile, or water, or a mixture of solvents including a mixture of water and an organic solvent which is miscible or immiscible with water, at températures from about -10 °C to about 100 °C, in particular at températures from about 0 °C to about 80 °C, for example at about room température. Favorably, the reaction of a compound ofthe formula IV in which G is halogen with a compound of the formula III or V is carried out in the presence of a base such as a tertiary amine, like triethylamine, ethyldiisopropylamine, N-methylmorpholine or pyridine, or an inorganic base such as an alkaline métal hydroxide, carbonate or hydrogencarbonate, like sodium hydroxide, potassium hydroxide, sodium carbonate or sodium hydrogencarbonate.

In case a compound ofthe formula IV in which G is HO- is reacted with a compound ofthe formula III or V and the carboxylic acid group is activated by means of an amide coupling reagent such as, for example, a carbodiimide orTOTU, the reaction is generally carried out under anhydrous conditions in an inert aprotic solvent, for example an ether like THF, dioxane or DME, an amide like Ν,Ν-dimethylformamide (DMF) or N-methylpyrrolidone (NMP), at températures from about -10 °C to about 40 °C, in particular at températures from about 0 °C to about 30 °C in the presence of a base such as a tertiary amine, like triethylamine, ethyldiisopropylamine or N-methylmorpholine. In case the compound ofthe formula III or V is employed in the form of an acid addition sait in the reaction with the compound ofthe formula IV, usually a sufficient amount of a base is added in orderto liberate the free compound ofthe formula III or V.

As indicated above, during the formation ofthe amide bond between the compounds of the formulae III and V and compounds ofthe formula IV functional groups in the compounds ofthe formulae III, IV and V can be présent in protected form or in the form of a precursor group. Depending on the particulars ofthe spécifie case, it may be necessary or advisable for avoiding an undesired course of the reaction or side reactions to temporarily block any functional groups by protective groups and remove them later, or to let functional groups be présent in the form of a precursor group which is later converted into the desired final group. This applies correspondingly to ail reactions in the course ofthe synthesis ofthe compounds ofthe formula I including the synthesis of intermediates outlined below and the synthesis of starting compounds and building blocks. Respective synthetic strategies are commonly used in the art. Details about protective groups and their introduction and removal are found in P. G. M. Wuts and T. W.

Greene, Greene's Protective Groups in Organic Synthesis, 4. ed. (2007), John Wiley & Sons, for example. Examples of protective groups which may be mentioned, are benzyl protective groups which may occur in the form of benzyl ethers of hydroxy groups and benzyl esters of carboxylic acid groups from which the benzyl group can be removed by catalytic hydrogénation in the presence of a palladium catalyst, tert-butyl protective groups which may occur in the form of tert-butyl esters of carboxylic acid groups from which the tert-butyl group can be removed by treatment with trifluoroacetic acid, acyl protective groups which may be used to protect hydroxy groups and amino groups in the form of esters and amides and which can be cleaved by acidic or basic hydrolysis, and aikyloxycarbonyl protective groups which may occur in the form of tertbutoxycarbonyl dérivatives of amino groups which can be cleaved by treatment with trifluoroacetic acid. Undesired reactions of carboxylic acid groups, for example the carboxylic acid group présent in the compound ofthe formula III in case R⁵⁰ is HO-, can also be avoided by employing them in the reaction ofthe compounds ofthe formulae III and IV in the form of other esters, for example in the form of alkyl esters like the methyl or ethyl ester which can be cleaved by hydrolysis, for example by means of an alkaline métal hydroxide like sodium hydroxide or lithium hydroxide. Another example of precursor groups besides cyano groups (NC-, N^C-), which were already mentioned, are nitro groups which can be converted into amino groups by catalytic hydrogénation or by réduction with sodium dithionite, for example. A further example of a precursor group is an oxo group, which may initially be présent in the course ofthe synthesis of compounds of the formula I containing a hydroxy group, and which can be reduced, for example with a complex hydride such as sodium borohydride, or reacted with an organometallic compound, for example a Grignard compound. If any protective groups or precursor groups are présent in the compounds ofthe formulae III, IV and V and the direct product ofthe reaction of the compound ofthe formula III or Vwith the compound ofthe formula IV is not yet the desired final compound, the removal ofthe protective group or conversion into the desired compound can in general also be carried out in situ.

The compounds ofthe formula IV are commercially available or can be obtained according to, or analogously to, procedures described in the literature. Customarily, in synthetic procedures forthe préparation of compounds oftheformula IV compounds are prepared in which the group G in the compounds ofthe formula IV is a group like (C-j-CD-alkyl-O- and the group G-C(O)thus is a (CrC^-alkyl ester group, or the group G-C(O)- is any other ester group such as a benzyl ester phenyl-CH₂-O-C(O)- and the group G thus is a benzyloxy group. Compounds of the formula IV in which G is HO-, can be obtained from such compounds ofthe formula IV by acidic or basic hydrolysis of alkyl esters or by hydrogénation of benzyl esters under standard conditions. Compounds ofthe formula IV in which G is HO- can then be converted into compounds ofthe formula IV in which G is halogen as already explained above, which latter compounds can be converted into compounds in which G is aryloxy, for example by reaction with a hydroxyarene such as phénol. In the following, various synthetic procedures for the préparation of compounds oftheformula IV in which the group R²³ in the group R²⁴-R²³-, i.e. in the group ofthe formula II which represents one ofthe groups R²¹ and R²², has different meanings, are exemplarily outlined.

In a procedure for the préparation of compounds of the formula IV in which the group R²³ is a chain wherein the terminal chain member which is bonded to the ring comprising the groups Y and Z, is a hetero chain member, a compound ofthe formula VII is reacted with a compound of the formula VIII to give a compound ofthe formula IVa.

R²⁴—R²—L² O

-------► G

VIII

R⁸⁰ _z X-R²^_R ²⁴

VII

IVa

In the compounds ofthe formulae IVa, VII and VIII the groups Y, Z and R²⁴ are defined as in the compounds ofthe formula I. The group R⁸⁰ is chosen from the sériés consisting of hydrogen, halogen, R³⁰, HO-, R³⁰-O-, R³⁰-C(O)-O-, R³⁰-S(O)2-O-, R³⁰-S(O)m-, H_ZN-, R³⁰-NH-, R³⁰-N(R³⁰)-, R³⁰-C(O)-NH-, R³⁰-C(O)-N(R⁷¹)-, R³⁰-S(O)2-NH-, R³⁰-S(O)2-N(R⁷¹)-, R³⁰-C(O)-, HO-C(O)-, r³⁰-oC(O)-, H2N-C(O)-, R³⁰-NH-C(O)-, R³⁰-N(R³⁰)-C(O)-, H2N-S(O)₂-, R³⁰-NH-S(O)2-, R³⁰-N(R³⁰)S(O)2-, NC-, O₂N- and Het¹; or together with R¹³ or R¹⁴ forms a chain as specified in the définition of R¹³ and R¹⁴; i.e. R⁸⁰ has the meaning ofthe one ofthe groups R²¹ and R²² in the compounds ofthe formula I which is not a group ofthe formula II. Additionally, functional groups in the compounds of the formulae IVa, VII and VIII can be présent in protected form or in the form of a precursor group which is later converted into the final group. The group G¹-C(O)- is an ester group and the group G¹ a group such as (C1-C4)-alkyl-O- or benzyloxy. The group X is a hetero chain member as specified in the définition of R²³, i.e. a group chosen from the sériés consisting of N(R²⁵), O, S, S(O) and S(O)2, in particular from the sériés consisting of N(R²⁵), O and S. The groups R^23a and X together represent the group R²³ as specified above wherein a terminal chain member which is a hetero chain member, is bonded to the ring comprising the groups Y and Z. R^23a thus is a direct bond or a chain consisting of 1 to 4 chain members of which 0 or 1 chain member is a hetero chain member chosen from the sériés consisting of N(R²⁵), O, S, S(O) and S(O)₂, provided that the terminal chain member adjacent to the group L² can only be a hetero chain memberwhich leads to the formation of compound ofthe formula IVa in which one of the group X and the said terminal chain member is chosen from the sériés consisting of S(O) and S(O)₂ and the other is chosen from the sériés consisting of N(R²⁵), O and S, and the other chain members are identical or different groups C(R²⁶)(R²⁶). As is symbolized by the bonds connecting the groups R⁸⁰ and XH in the compounds of the formula VII, as well as the groups R⁸⁰ and X-R^23a-R²⁴ in the compounds ofthe formula IVa, which bonds are not directed to a spécifie ring carbon atom, each ofthe said two groups can be located in each of the two positions ofthe moiety C=C in the ring comprising the groups Y and Zwhich is depicted in the formulae. Le., R⁸⁰ can be located on the ring carbon which is adjacent to the group Y and the other ofthe two groups on the ring carbon atom which is adjacentto the group Z, as well as R⁸⁰ can be located on the ring carbon which is adjacent to the group Z and the other ofthe two groups on the ring carbon atom which is adjacent to the group Y. This applies to ail compounds defined below containing a group R⁸⁰ and a second group in which the bonds connecting the group to the ring comprising the groups Y and Z are not directed to a spécifie ring carbon atoms. The group L² in the compounds ofthe formula VIII is a leaving group which can be replaced with the group X, such as halogen, fore example chlorine or bromine, a sulfonyloxy group, for example methanesulfonyloxy, trifluoromethanesulfonyloxy or toluene-4-sulfonyloxy, or hydroxy, for example.

The reaction of a compound of the formula VII with a compound of the formula VIII is a nucleophilic substitution reaction which can be carried out under standard conditions for such reactions which are well known to a person skilled in the art. Generally, the reaction is performed in an inert solvent, for example a hydrocarbon or chlorinated hydrocarbon like benzene, toluene, xylene, chlorobenzene, dichloromethane, chloroform or dichloroethane, an ether like THF, dioxane, dibutyl ether, diisopropyl ether or DME, an alcohol like methanol, éthanol or isopropanol, a ketone like acetone or butan-2-one, an ester like ethyl acetate or butyl acetate, a nitrile like acetonitrile, an amide like DMF or NMP, a sulfoxide like DMSO or a sulfone like sulfolane, or a mixture of solvents, at températures from about -10 °C to about 120 °C, in particular at températures from about 0 °C to about 100 °C, depending on the particulars ofthe spécifie case. In many cases it is favorable for enhancing the nucleophilicity ofthe compound of the formula VII and/or binding an acid which is liberated during the reaction, to add a base, for example a tertiary amine, such as triethylamine, ethyldiisopropylamine or N-methylmorpholine, or an inorganic base such as an alkaline métal hydride, hydroxide, carbonate or hydrogencarbonate like sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, césium carbonate or sodium hydrogencarbonate, or an alkoxide or amide such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium tert-butoxide, sodium amide or lithium diisopropylamide. A compound ofthe formula VII can also be treated with a base and converted into a sait in a separate step. Compounds of the formula VIII in which the group L² is hydroxy can favorably be reacted with compounds of the formula VII underthe conditions ofthe Mitsunobu reaction in the presence of an azodicarboxylate like diethyl azodicarboxylate or diisopropyl azodicarboxylate and a phosphine like triphenylphosphine ortributylphosphine in an inert aprotic solvent such as an ether like THF or dioxane (cf. O. Mitsunobu, Synthesis (1981), 1-28).

In another procedure, compounds oftheformula IVa can be obtained by reacting a compound of the formula IX with a compound of the formula X.

In the compounds ofthe formulae IX and Xthe groups Y, Z and R²⁴ are defined as in the compounds ofthe formula I. The group R⁸⁰ is defined as in the compounds ofthe formulae IVa and VII, i.e. it has the meaning ofthe one ofthe groups R²¹ and R²² in the compounds ofthe formula I which is not a group ofthe formula II. Additionally, functional groups in the compounds ofthe formulae IX and X can be présent in protected form or in the form of a precursor group which is later converted into the final group. The group G¹-C(O)- is an ester group and the group G¹ a group such as (CrC^-alkyl-O- or benzyloxy. The group X is a hetero chain member as specified in the définition of R²³, i.e. a group chosen from the sériés consisting of N(R²⁵), O, S, S(O) and S(O)2, in particular from the sériés consisting of N(R²⁵), O and S. In the compound of the formula X the groups R^23a and X together represent the group R²³ as specified above wherein a terminal chain member which is a hetero chain member, is bonded to the ring comprising the groups Y and Z in the obtained compounds ofthe formula IVa. R^23a thus is a direct bond or a chain consisting of 1 to 4 chain members of which 0 or 1 chain member is a hetero chain member chosen from the sériés consisting of N(R²⁵), O, S, S(O) and S(O)2, provided that the terminal chain member adjacent to the group X can only be a hetero chain member if one ofthe group X and the said terminal chain memberis chosen from the sériés consisting of S(O) and S(O)₂ and the other is chosen from the sériés consisting of N(R²⁵), O and S, and the other chain members are identical or different groups C(R²⁶)(R²⁶). The group L³ in the compounds of the formulae IX is a leaving group which can be replaced with the group X, such as halogen like fluorine, chlorine, bromine or iodine, or a sulfonyloxy group like methanesulfonyloxy or trifluoromethanesulfonyloxy, for example. The reaction of a compound of the formula IXwith a compound ofthe formula Xformally is a nucleophilic substitution reaction at the ring comprising the groups Y and Z which can in particular be performed in case of compounds ofthe formulae IX which are susceptible to such a reaction because ofthe presence of electron-withdrawing substituents or ring hetero atoms. The reaction can be carried out under standard conditions for such reactions which are well known to a person skilled in the art. The explanations on the reaction conditions such as solvents or bases which are favorably added, which are given above with respect to the reaction of a compound ofthe formula Vil with a compound ofthe formula VIII apply correspondingly to the reaction of a compound ofthe formula IXwith a compound ofthe formula X.

The explanations on the reaction of a compound ofthe formula Vil with a compound ofthe formula VIII also apply correspondingly to reactions for the préparation of compounds ofthe formula I in which a hetero chain member in the group R²³ is not présent in the terminal position ofthe chain which is adjacentto the ring comprising the groups Y and Z, but is separated from the said ring by one or more groups C(R²⁶)(R²⁶), which reactions are of the same type as the reactions outlined above. As an example, the préparation of a compound oftheformula IVb from a compound of the formula XI and a compound of the formula XII may be illustrated.

xi IVb

In the compounds ofthe formulae IVb, XI and XII the groups Y, Z and R²⁴ are defined as in the compounds of the formula I. The group R⁸⁰ is defined as in the compounds of the formulae IVa and Vil, i.e. it has the meaning ofthe one ofthe groups R²¹ and R²² in the compounds ofthe formula I which is not a group ofthe formula II. Additionally, functional groups in the compounds ofthe formulae IX and X can be présent in protected form or in the form of a precursor group which is later converted into the final group. Additionally, functional groups in the compounds of the formulae IVb, XI and XII can be présent in protected form or in the form of a precursor group which is later converted into the final group. The group G¹-C(O)- is an ester group and the group G¹ a group such as (Ci-C₄)-alkyl-O- or benzyloxy. The group X is a hetero chain member as specified in the définition of R²³, i.e. a group chosen from the sériés consisting of N(R²⁵), O, S,

S(O) and S(O)₂, in particular from the sériés consisting of N(R²⁵), O and S. The groups R^23b, R^23c and X in the compounds of the formulae IVb together represent the group R²³ as specified above wherein X is a said hetero chain member. In case R²³ comprises only one hetero chain member, the group R^23b in the compounds ofthe formulae IVb and XI is a chain consisting of 1 to 4 identical or different groups C(R²⁶)(R²⁶) and the group R^23c in the compounds ofthe formulae IVb and XII is a direct bond or a chain consisting of 1 to 3 identical or different groups C(R²⁶)(R^2B), provided that the total number of groups C(R²⁶)(R²⁶) is not greater than 4. In the group R^23c in the compounds ofthe formulae IVb and XII a further hetero chain member chosen from the sériés consisting of N(R²⁵), O, S, S(O) and S(O)2 can be présent instead of one ofthe groups C(R²⁶)(R²⁶), provided that such further hetero chain member can only be présent in the terminal position adjacent to the group L² if one ofthe group X and the said chain member in the terminal position is chosen from the sériés consisting of S(O) and S(O)2 and the other is chosen from the sériés consisting of N(R²⁵), O and S. The leaving group L² in the compounds ofthe formula XII is defined as in the compounds ofthe formula VIII. Correspondingly as outlined above with respect to the synthesis ofthe compounds of the formula IVa, which can be prepared by reacting a compound ofthe formula VII with a compound ofthe formula VIII as well as by reacting a compound ofthe formula IXwith a compound ofthe formula X, compounds of the formula IVb can also be prepared by reacting a compound which is defined as the compound ofthe formula XI but contains a group L² instead ofthe group XH, with a compound which is defined as the compound ofthe formula XII but contains a group XH instead ofthe group L².

In a procedure for the préparation of compounds of the formula IV in which the group R²³ is a chain which does not comprise any hetero chain member, a carbonyl compound of the formula XIII is condensed with a compound ofthe formula XIVto give an olefin ofthe formula IVc which can subsequently be hydrogenated to give a compound of the formula IVd, respectively, or reacted with an organometallic compound ofthe formula XV to give an alcohol ofthe formula IVe which likewise can subsequently be hydrogenated to give a compound ofthe formula IVf.

In the compounds ofthe formulae IVcto IVf, XIII, XIV and XVthe groups Y, Z and R²⁴ are defined as in the compounds of the formula I. The group R⁸⁰ is defined as in the compounds of the formulae IVa and VII, i.e. it has the meaning ofthe one ofthe groups R²¹ and R²² in the compounds ofthe formula I which is not a group ofthe formula II. Additionally, functional groups in the compounds ofthe formulae IVc to IVf, XIII, XIV and XV can be présent in protected form or in the form of a precursor group which is later converted into the final group. The group G¹C(O)- is an ester group and the group G¹ a group such as (C₁-C₄)-alkyl-O- or benzyloxy. The groups R^a and R^b are independently of each other chosen from hydrogen and (Ci-C₄)-alkyl. The group R^23d is a direct bond or a chain consisting of 1 to 3 identical or different groups C(R²⁶)(R²⁶), the group R^23e a direct bond or a chain consisting of 1 to 4 identical or different groups C(R²⁶)(R²⁶). The group L⁴ in the compounds ofthe formula XIV is group which allows for the formation of a double bond between the carbon atom carrying the group L⁴ and the carbon atom of the aldéhyde group or ketone group carrying the group R^a in the compound of the formula XIII in a condensation reaction. Examples of suitable condensation reactions are the Wittig reaction and the Wittig-Horner reaction, and examples of suitable groups L⁴ thus are trisubstituted phosphonio groups, such as the triphenylphosphonio group, having an anion, such as a halide anion, as counterion, and di((C₁-C₄)-alkyl)phosphonyl groups, such as the diethylphosphonyl group. The group L⁵ in the compounds of the formula XV is a métal such as lithium or a magnésium halide group like MgCI, MgBr or Mgl, and the compound of the formula XV thus an organolithium compound or a Grignard compound. The Wittig reaction and WittigHorner reaction and the addition of the organometallic compound of the formula XV to the compound ofthe formula XIII can be performed under standard conditions in an inert solvent such as a hydrocarbon like benzene or toluene or an ether like diethyl ether, THF, dioxane or DME. The Wittig reaction and the Wittig-Horner reaction are performed in the presence of a base such as a hydride like sodium hydride, an amide like sodium amide or lithium diisopropylamide, or an alkoxide like potassium tert-butoxide. Depending on the particular case, instead of employing a phosphonium sait and deprotonating it, also stable phosphorus ylides can directly be employed in the reaction. The hydrogénation ofthe double bond in the compounds of the formula IVc to give the compounds of the formulae IVd, or of the benzylic hydroxy group in the compounds ofthe formulae IVe to give the compounds ofthe formulae IVf, can be performed in the presence of a hydrogénation catalyst such as palladium on charcoal.

Depending on the particulars of the spécifie case, various other reactions can be used for preparing compounds ofthe formula IV. As an example ofthe préparation of compounds in which the group R²³ is a chain comprising three groups C(R²⁶)(R²⁶) and no hetero chain members, an aldol-type reaction of a compound ofthe formula XIIla, which is a compound of the formula XIII in which the group R^a is methyl, with an aldéhyde of the formula XVI may be mentioned which leads to a compound ofthe formula IVg orthe formula IVm which can be reduced to a compound of the formula IVh, IVk or IVn, for example.

In the compounds of the formulae IVg to IVn and XIIla the groups Y and Z are defined as in the compounds ofthe formula I. The group R^24a in the compounds ofthe formulae IVg to IVn and

XVI is a group R³¹ or a 3-membered to 10-membered ring as it can represent the group R²⁴ in the compounds ofthe formula I which is bonded via a ring carbon atom, in particular an aromatic ring such as an optionally substituted phenyl, naphthyl or heteroaryl group. The group R⁸⁰ is defined as in the compounds ofthe formulae IVa and VII, i.e. it has the meaning of the one ofthe groups R²¹ and R²² in the compounds ofthe formula I which is not a group ofthe formula II. Additionally, functional groups in the compounds ofthe formulae IVg to IVn, Xllla and

XVI can be présent in protected form or in the form of a precursor group which is later converted into the final group. The group G¹-C(O)- is an ester group and the group G¹ a group such as (CrC^-alkyl-O- or benzyloxy.

The reaction of a compound of the formula Xllla with a compound of the formula XIV to give an aldol addition product ofthe formula IVm or a condensation product ofthe formula IVg can be carried under standard conditions for the aldol reaction in the presence of a base, such as an alkaline métal hydroxide like sodium hydroxide or potassium hydroxide, an alkoxide like sodium methoxide or sodium ethoxide or an amide like lithium diisopropylamide, in a solvent such as an alcohol like methanol or éthanol or an ether like diethyl ether, THF or dioxane. At lower températures, for example at températures from about -80 °C to about -30 °C, the compound of the formula IVm can be obtained, at higher températures, for example at températures from about 10 °C to about 60 °C, or by treatment of the compound of the formula IVm with an acid, the compound of the formula IVg can be obtained. The ketone function in the compounds of the formulae IVg and IVm can be reduced to an alcohol function, for example with a complex hydride such as a borohydride like lithium borohydride or sodium borohydride, to give a compound of the formula IVh or IVn, respectively, which can be converted into a compound of the formula IVk by déhydration in the presence of an acid and/or hydrogénation in the presence of a catalyst such as palladium on charcoal, for example.

As a further example of reactions which can be used for preparing compounds of the formula IV, transition metal-catalyzed C-C coupling reactions may be mentioned by which compounds can be obtained wherein the group R²³ is a direct bond. Such compounds can be obtained from a compound of the formula IX and a boronic acid, for example an optionally substituted phenylboronic acid, cycloalkylboronic acid or heteroarylboronic acid. As catalyst in such reactions, a palladium compound such as bis(triphenylphosphine)palladium(ll) chloride or tetrakis(trîphenylphosphine)palladium(0) and a copper compound such as copper(l) iodide can be used. Further details on such reactions are found in N. Miyaura et al., Chem. Rev. 95 (1995), 2457-2483; and R. Chinchilla et al., Chem. Rev. 107 (2007), 874-922, for example.

The order in which groups are introduced in the course of the synthesis of a compound of the formula I, can also be different from the ones outlined above. For example, instead of first preparing a compound of the formula IVa from a compound of the formula VII and a compound of the formula VIII, or from a compound of the formula IX and a compound of theformula X, and then reacting the compound of the formula IVa with a compound of the formula lll to give a compound of the formula I, a compound of the formula lll can also be reacted with a compound of the formula VII or a compound of the formula IX and the obtained compound of the formula XVII or XVIII reacted with a compound of the formula VIII orX, respectively, to give a compound of the formula Ik. This reaction sequence can also be performed with compounds of the formula V instead of with compounds of the formula lll, and in the obtained compounds the nitrile group converted into the group -C(O)-R⁵⁰ to give compounds of the formula Ik.

In the compounds ofthe formulae Ik, XVII and XVIII the ring A and the groups Y, Z, R²⁰, R²⁴ and R⁵⁰ are defined as in the compounds ofthe formula I. The groups X, R^23a and R⁸⁰ are defined as in the compounds of the formula IVa. Thus, R⁸⁰ has the meaning of the one of the groups R²¹ and R²² in the compounds ofthe formula I which is not a group oftheformula II. The groupX is a hetero chain member as specified in the définition of R²³, i.e. a group chosen from the sériés consisting of N(R²⁵), O, S, S(O) and S(O)₂, in particular from the sériés consisting of N(R²⁵), O and S. The groups R^23a and X together represent the group R²³ as specified above wherein a 10 terminal chain member which is a hetero chain member, is bonded to the ring comprising the groups Y and Z. R^23a thus is a direct bond or a chain consisting of 1 to 4 chain members of which 0 or 1 chain member is a hetero chain member chosen from the sériés consisting of N(R²⁵), O, S, S(O) and S(O)₂, provided that the terminal chain member adjacent to the group X can only be a hetero chain member if one ofthe group X and the said terminal chain member is 15 chosen from the sériés consisting of S(O) and S(O)₂ and the other is chosen from the sériés consisting of N(R²⁵), O and S, and the other chain members are identical or different groups C(R²⁶)(R²⁶). Additionally, functional groups in the compounds ofthe formulae Ik, XVII and XVIII can be présent in protected form or in the form of a precursor group which is later converted into the final group. As indicated above and as applies to ail compounds which contain a group R⁸⁰ and another group which are connected to the ring comprising the groups Y and Z by bonds which are not directed to a spécifie ring carbon atom, the groups R⁸⁰ and X in the compounds of the formula XVII, the groups R⁸⁰ and L³ in the compounds ofthe formula XVIII, and the groups R⁸⁰ and X-R^23a-R²⁴ in the compounds ofthe formula Ik can be located in each ofthe two positions of the moiety C=C in the ring comprising the groups Y and Z. The explanations given above with respecttothe reaction of a compound oftheformula III with a compound ofthe formula IV, the reaction of a compound ofthe formula VII with a compound oftheformula VIII, and the reaction of a compound ofthe formula IX with a compound of the formula X apply correspondingly to the reaction of a compound ofthe formula III with a compound oftheformula VII or a compound ofthe formula IX, the reaction of a compound ofthe formula XVII with a compound ofthe formula VIII, and the reaction of a compound ofthe formula XVIII with a compound ofthe formula X. The order in which groups are introduced in the course ofthe synthesis of a compound ofthe formula I, can also be varied with respectto other reactions. For example, a compound ofthe formula XVIII can be employed in a transition-métal catalyzed C-C coupling reaction as referred to above, or a compound of the formula XI11a can be reacted with a compound ofthe formula III and the obtained compound modified at the CH₃-C(O)- groupto give a compound ofthe formula I.

Like the compounds ofthe formula IV, the compounds ofthe formulae III and V are commercially available or can be obtained according to, or analogously to, procedures described in the literature, for example according to the Bucherer-Bergs hydantoin procedure or the Strecker procedure for the préparation of amino acids and amino acid nitriles, respectively. The following scheme illustrâtes the Bucherer-Bergs hydantoin procedure for the synthesis of amino acids.

XX Ilia nib

In the Bucherer-Bergs procedure, a ketone ofthe formula XIX is converted into a hydantoin of the formula XX by reaction with a cyanide source, such as an alkaline métal cyanide like sodium cyanide (NaCN), and ammonium carbonate ((NH4)₂CO₃) in an inert solvent like a mixture of an alcohol such as a (Cq-C^-alkanol and water, for example a mixture of éthanol and water, at températures from about 0 °C to about 150 °C, in particular at températures from about 20 °C to about 120 °C, for example at the reflux température ofthe employed solvent. The obtained hydantoin can be converted into the respective amino acid ofthe formula Ilia by hydrolysis, for example by hydrolysis with an aqueous acid like sulfuric acid or hydrochloric acid or by hydrolysis with an aqueous bases like sodium hydroxide or potassium hydroxide, at elevated températures, for example atthe reflux température ofthe reaction mixture. For the reaction with the compound ofthe formula IV, the amino acid ofthe formula Ilia can be protected by conversion into an amino acid ester ofthe formula lllb in which R⁹⁰ is a group such as (CrC₄)alkyl, for example methyl or ethyl, or benzyl, by standard methods which are well known to a person skilled in the art, for example by estérification with an alcohol like methanol or éthanol in the presence of an acid like hydrogen chloride. The group A in the compounds ofthe formulae XIX, XX, Ilia and lllb is defined as in the compounds ofthe formula I and additionally functional groups can be présent in protected form or in the form of a precursor group which is later converted into the final group.

The following scheme illustrâtes the Strecker procedure for the synthesis of amino acid nitriles.

In the Strecker procedure, a ketone oftheformula XIX is converted into the corresponding amino acid nitrile oftheformula V by réaction with a cyanide source, such as an alkaline métal cyanide like potassium cyanide (KCN), and a sait of an amine ofthe formula R²⁰-NH2, wherein R²⁰ is defined as in the compounds ofthe formula I, for example ammonium chloride (NH4CI) in case R²⁰ is hydrogen or méthylammonium chloride (CH₃-NH₃CI) in case R²⁰ is methyl, in an inert solvent like water or an alcohol such as a (C-j-C^-alkanol like methanol or éthanol or a mixture thereof with water, for example a mixture of éthanol and water, at températures from about 0 °C to about 150 °C, in particular at températures from about 20 °C to about 120 °C or at températures from room température to the reflux température ofthe employed solvent. The obtained amino acid nitrile ofthe formula V can be hydrolyzed to the amino acid ofthe formula IIle, for example by hydrolysis with an aqueous acid like sulfuric acid or hydrochloric acid, or by hydrolysis with an aqueous base like sodium hydroxide or potassium hydroxide, at elevated température, for example at températures from about 50 °C to about 150 °C, for example at the reflux température ofthe reaction mixture, and the amino acid then esterified to give a compound ofthe formula llld ,for use in the reaction with the compound ofthe formula IV, as mentioned above with respect to the amino acids ofthe formula Ilia. Altematively, the amino acid nitrile of the formula V can directly be reacted with a compound of the formula IV and the nitrile group hydrolyzed subsequently, as outlined above. The groups A and R²⁰ in the compounds ofthe formulae lllc and llld and in the amines ofthe formula R²⁰-NH₂ are defined as in the compounds ofthe formula I and additionally functional groups can be présent in protected form or in the form of a precursor group which is later converted into the final group. The group R⁹⁰ in the compounds oftheformula llld is defined as in the compounds ofthe formula lllb.

The Bucherer-Bergs procedure and the Strecker procedure were found to give different results with respect to the stereochemistry in case the prepared amino acid or amino acid nitriles contain additional substituents in the ring A. It was described in the literature (cf. L. Munday, J. Chem. Soc. (1961), 4372-79) that, if the ring A is a substituted cyclohexane ring, the BuchererBergs procedure delivers products in which the substituent is in cis position with respect to the amino group in the obtained amino acid in case the substituent is in 2-position or 4-position of the ring, but products in which the substituent is in trans position with respect to the amino group in case the substituent is in the 3-position ofthe ring, whereas the Strecker procedure delivers products in which the substituent is in trans position with respect to the amino group in case the substituent is in 2-position or 4-position, but products in which the substituent is in cis position with respect to the amino group in case the substituent is in the 3-position.

The cyclic ketones ofthe formula XIXwhich are employed in the Bucherer-Bergs procedure and the Strecker procedure, are commercially available or can be synthesized by a broad variety of synthetic methods which are well known to a person skilled in the art. For example, a cyclic ketone ofthe formula XIX can be synthesized by ring expansion ofthe respective ketone of smaller ring size ofthe formula XXI, which contains one ring carbon less, with diazomethane (CH₂N₂), for example according to the procedure described in F. Alonso et al., Tetrahedron 51 (1995), 10259-10280.

XXI χΐχ

The ring expansion reaction with diazomethane is generally carried out in an inert solvent, for example an ether like diethyl ether, tetrahydrofuran (THF), dioxane, dibutyl ether, diisopropyl ether or dimethoxyethane (DME), éthanol, méthanol, a hydrocarbon, dichloromethane, chloroform or dichloroethane, or a mixture of solvents, at températures from about -78 °C to 50 °C, in particular at températures from about -40 °C to about room température, for example at about 0 °C. Diazomethane can be used as solution in an inert solvent, for example diethyl ether or THF, or can be generated in situ from an appropriate source for diazomethane like N-methylN-nitroso-p-toluenesulfonamide (Diazald®) or N-methyl-N-nitrosourea. For example, N-methylN-nitroso-p-toluenesulfonamide can be added to a solution ofthe ketone in an inert solvent like a mixture of éthanol, méthanol and water containing a base like potassium hydroxide to generate diazomethane in situ. Alternatively, trimethylsilyl diazomethane can be added to a solution ofthe ketone and an acid or silyl scavanger like boron trifluoride etherate in an inert solvent like dichloromethane to generate a diazomethane équivalent and to perform the ring enlargement reaction. As applies in general and is well known to a person skilled in the art, the reaction conditions for ring enlargement of a ketone dépend on the particulars of the spécifie case, for example on the substituents on the ring A.

An alternative synthetic approach to amino acid dérivatives ofthe formulae Ilia and lllb starts from malonic acid dérivatives oftheformula XXIII which can be dialkylated with a divalent alkylating compound ofthe formula XXII to give a cyclic dicarboxylic acid dérivative ofthe formula XXIV analogously as described in V. Prelog et al., Helv. Chim. Acta 65 (1982), 26222644, and illustrated in the following scheme.

The moiety A' in the divalent alkylating compound of the formula XXII corresponds to the ring A in the compounds of the formula I except that it does not contain the ring carbon atom présent in A which carries the groups N(R²⁰) and C(O)-R⁵⁰, and is defined accordingly, and the groups L¹¹ and L¹² are leaving groups such as halogen, for example chlorine or bromine, or sulfonyloxy groups, for example methanesulfonyloxy or trifluoromethanesulfonyloxy. The groups PG¹ and PG² in the malonic acid dérivative ofthe formula XXIII and the compounds ofthe formulae XXIV, XXV, XXVI and XXVII hâve the function of protective groups ofthe carboxylic acid groups and can be identical or different groups such as (C_rC₄)-alkyl, for example methyl, ethyl or tertbutyl, or benzyl. The alkylation reaction ofthe compounds oftheformulae XXII and XXXIII is generally carried out in the presence of a base, for example an alkaline métal hydride such as sodium hydride or an alkaline métal alkoxide such as potassium tert-butoxide, in an inert solvent such as an ether like THF or diethyl ether or an amide like DMF or NMP or a nitrile like acetonitrile at températures from about 0 °C to about 100 °C, depending on the particulars of the spécifie case. Subséquent to the alkylation reaction, one of the protective groups, for example PG², is cleaved, for example by treatment with an aqueous base like sodium hydroxide or potassium hydroxide in the case of methyl or ethyl group. In the obtained compound of the formula XXV can the free carboxylic acid group be degraded to an amino group by dégradation reactions which are well known to a person skilled in the art. For example, the carboxylic acid can be activated by formation of a mixed anhydride, for example by reaction with a chloroformic acid ester like isobutyl chloroformate in the presence of a base like triethylamine or Nmethylmorpholine in an inert solvent like acetone, the mixed anhydride reacted in situ with an alkaline métal azide like sodium azide to give the acid azide ofthe formula XXVI, which is subsequently heated in an inert solvent, for example a hydrocarbon like toluene or xylene, to give the degraded isocyanate which can be hydrolyzed, for example with aqueous acid like hydrochloric acid to give the amino acid dérivative ofthe formula XXVII which already constitutes a compound ofthe formula lllb or in which the protective group PG¹ can be cleaved to give a compound ofthe formula Ilia which can in turn be esterified as mentioned above to give a compound of the formula lllb. Alternatively, the free carboxylic acid group in the compound of the formula XXV can be reacted with an azide transfer reagent like diphenylphosphoryl azide to yield the acid azide ofthe formula XXVI which can be degraded as indicated. Further details on the dégradation procedures and the hydrolysis ofthe intermediary isocyanate can be found in T. N. Wheeler, Synth. Commun. 18 (1988), 141-149, and M. Oba et al., Tetrahedron 61 (2005), 593-598, for example. The group A in the compounds of the formulae XXIV, XXV, XXVI and XXVII is defined as in the compounds ofthe formula I and additionally can functional groups be présent in protected form or in the form of a precursor group which is later converted into the final group.

The starting compounds and building blocks for the synthesis of the compounds of the formula I can generally be prepared according to procedures described in the literature or analogously to such procedures, or are commercially available. Exemplarily the préparation of compounds of the formula VIII in which R²⁴ is an optionally substituted phenyl or naphthyl group, R^23a is an optionally alkyl-substituted CH₂CH₂ group and L² is a hydroxy group, may be mentioned in which use can be made of the procedure for the coupling of aryl halides with ester enolates described by M. Jorgensen et al., J. Am. Chem. Soc. 124 (2002), 12557-12565. In the said procedure an optionally alkyl-substituted acetic acid ester, for example acetic acid tert-butyl ester or isobutyric acid methyl ester, is deprotonated with a base such as lithium dicyclohexylamide and reacted with an optionally substituted aryl bromide in the presence of a palladium compound such as bis(dibenzylideneacetone)palladium or tris(dibenzylideneactone)dipalladium and tri(tert-butyl)phosphine to give a 2-(optionally substituted aryl)acetic acid ester which is optionally alkyl-substituted in the 2-position of the acetic acid moiety. Réduction ofthe ester function under standard conditions, for example with lithium aluminium hydride, then affords the 2-(optionally substituted aryl)ethanol which is optionally alkyl-substituted in the 2-position.

For obtaining further compounds ofthe formula I, various transformations offunctional groups can be carried out understandard conditions in compounds oftheformula I or intermediates or starting compounds in the synthesis ofthe compounds ofthe formula I. For example, a hydroxy group can be esterified to give a carboxylic acid ester or a sulfonic acid ester, or etherified.

Ethérifications of hydroxy groups can favorably be performed by alkylation with the respective halogen compound, for example a bromide or iodide, in the presence of a base such an alkali métal carbonate like potassium carbonate or césium carbonate in an inert solvent such as an amide like DMF or NMP or a ketone like acetone or butan-2-one, or with the respective alcohol underthe conditions ofthe Mitsunobu reaction referred to above. A hydroxy group can be converted into a halide by treatment with a halogenating agent. A halogen atom can be replaced with a variety of groups in a substitution reaction which may also be a transition-métal catalyzed reaction. A nitro group can be reduced to an amino group, for example by catalytic hydrogénation. An amino group can be modified under standard conditions for alkylation, for example by reaction with a halogen compound or by reductive amination of a carbonyl compound, or for acylation or sulfonylation, for example by reaction with an activated carboxylic acid or a carboxylic acid derivate like an acid chloride or anhydride or a sulfonic acid chloride. A carboxylic ester group can be hydrolyzed under acidic or basic conditions to give a carboxylic acid. A carboxylic acid group can be activated or converted into a reactive dérivative as outlined above with respect to the compounds ofthe formula IX and reacted with an alcohol or an amine or ammonia to give an ester or amide. A primary amide can be dehydrated to give a nitrile. A sulfur atom in an alkyl-S- group or in a heterocyclic ring or a sulfur atom occurring in a chain representing the group R²³ can be oxidized with a peroxide like hydrogen peroxide or a peracid to give a sulfoxide moiety S(O) or a sulfone moiety S(O)₂. A carboxylic acid group, carboxylic acid ester group and a ketone group can be reduced to an alcohol, for example with a complex hydride such al lithium aluminium hydride, lithium borohydride or sodium borohydride. Ail reactions in the préparation ofthe compounds ofthe formula I are known per se and can be carried out in a manner familiar to a person skilled in the art according to, or analogously, to procedures which are described in the standard literature, for example in Houben-Weyl, Methods of Organic Chemistry, Thieme; or Organic Reactions, John Wiley & Sons; or R. C. Larock, Comprehensive Organic Transformations: A Guide to Functional Group Préparations, 2. ed. (1999), John Wiley & Sons, and the references quoted therein. Furthermore, besides by techniques of solution chemistry, the compounds of the formula I can also be obtained by solid phase chemistry.

Another subject ofthe présent invention are the novel starting compounds and intermediates occurring in the synthesis ofthe compounds ofthe formula I, including the compounds ofthe formulae III, Ilia, lllb, lllc, llld, IV, IVb, IVc, IVd, IVe, IVf, IVg, IVh, IVk, IVm, IVn, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIII, XXIV, XXV, XXVI and XXVII wherein the ring A and the groups G, G¹, L², L³, L¹¹, L¹², PG¹, PG², X, Y, Z, R²⁰ to R²³, R^23a, R^23b, R^23c, R²⁴, R^24a, R⁵⁰, R⁸⁰, R^a and R^b are defined as above, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their salts, and their use as synthetic intermediates or starting compounds. Ail general explanations, spécifications of embodiments and définitions of numbers and groups given above with respect to the compounds ofthe formula I apply correspondingly to the said intermediates and starting compounds. A subject of the invention are in particular the novel spécifie starting compounds and intermediates described herein. Independently thereof whether they are described as a free compound and/or as a spécifie sait, they are a subject ofthe invention both in the form ofthe free compounds and in the form of their salts, and if a spécifie sait is described, additionally in the form of this spécifie sait.

The compounds ofthe formula I inhibitthe Edg-2 receptor (LPA-ι receptor) as can be demonstrated in the pharmacological test described below and in other tests which are known to a person skilled in the art. The compounds ofthe formula I and their physiologically acceptable salts are valuable pharmaceutical active compounds. The compounds ofthe formula I and their physiologically acceptable salts can be used for the treatment of cardiovascular diseases such as heart failure including systolic heart failure, diastolic heart failure, diabetic heart failure and heart failure with preserved éjection fraction, cardiomyopathy, myocardial infarction, myocardial remodeling including myocardial remodeling after infarction or after cardiac surgery, vascular remodeling including vascular stiffness, hypertension including pulmonary hypertension, portai hypertension and systolic hypertension, atherosclerosis, peripheral arterial occlusive disease (PAOD), restenosis, thrombosis or vascular permeability disorders, for cardioprotection such as cardioprotection after myocardial infarction or after cardiac surgery, for renoprotection, or for the treatment of inflammation or inflammatory diseases such as rheumatoid arthritis, osteoarthritis, rénal diseases such as rénal papillary necrosis or rénal failure including rénal failure after ischemia/reperfusion, pulmonary diseases such as chronic obstructive pulmonary disease (COPD), asthma or acute respiratory dystress syndrome (ARDS), immunological diseases, allergie diseases, tumor growth, metastasis, metabolic diseases, fibrotic diseases such as pulmonary fibrosis including idiopathic lung fibrosis, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, rénal fibrosis including rénal tubulointerstitial fibrosis, liver fibrosis, fibrosing skin conditions including keloid formation, collagenosis, scleroderma, progressive systemic sclerosis and nephrogenic fibrosing dermopathy, or other types of fibrosis including Dupuytren's contracture, psoriasis, pain such as neuropathie pain, diabetic pain or inflammatory pain, pruritus, retinal ischemia/reperfusion damage, macular degeneration, psychiatrie disorders, neurodegenerative diseases, cérébral nerve disorders, peripheral nerve disorders, endocrinie disorders such as hyperthyroidism, scarring disorders or wound healing disorders, for example. The treatment of diseases is to be understood as meaning both the therapy of existing pathological changes or malfunctions ofthe organism or of existing symptoms with the aim of relief, alleviation or cure, and the prophylaxis or prévention of pathological changes or malfunctions of the organism or of symptoms in humans or animais which are susceptible thereto and are in need of such a prophylaxis or prévention, with the aim of a prévention or suppression of their occurrence or of an atténuation in the case of their occurrence. For example, in patients who on account of their disease history are susceptible to myocardial infarction, by means of the prophylactic or préventive médicinal treatment the occurrence or re-occurrence of a myocardial infarction can be prevented or its extent and sequelae decreased, or in patients who are susceptible to disturbed wound healing, by means ofthe prophylactic or préventive médicinal treatment wound healing after surgery can favorably be influenced. The treatment of diseases can occur both in acute cases and in chronic cases. The efficacy ofthe compounds ofthe formula I can be demonstrated in the pharmacological tests described below and in other tests which are known to a person skilled in the art

The compounds ofthe formula I and their physiologically acceptable salts can therefore be used in animais, in particular in mammals and specifically in humans, as a pharmaceutical or médicament on their own, in mixtures with one another or in the form of pharmaceutical compositions. A subject ofthe présent invention also are the compounds ofthe formula I and their physiologically acceptable salts for use as a pharmaceutical, as well as pharmaceutical compositions and médicaments which comprise an efficacious dose of at least one compound of the formula I and/or a physiologically acceptable sait thereof as an active ingrédient and a pharmaceutically acceptable carrier, i.e. one or more pharmaceutically innocuous, or nonhazardous, vehicles and/or excipients, and optionally one or more other pharmaceutical active compounds. A subject ofthe présent invention furthermore are the compounds ofthe formula I and their physiologically acceptable salts for use in the treatment ofthe diseases mentioned above or below, including the treatment of any one of the mentioned diseases, for example heart failure or fibrotic diseases such as pulmonary fibrosis, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, rénal fibrosis, liver fibrosis or fibrosing skin conditions, the use of the compounds ofthe formula I and their physiologically acceptable salts forthe manufacture of a médicament for the treatment ofthe diseases mentioned above or below, including the treatment of any one ofthe mentioned diseases, for example heart failure or fibrotic diseases such as pulmonary fibrosis, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, rénal fibrosis, liver fibrosis or fibrosing skin conditions, wherein the treatment of diseases comprises their therapy and prophylaxis as mentioned above, as well as their use for the manufacture of a médicament for the inhibition of the Edg-2 receptor (LPAi receptor). A subject of the invention also are methods forthe treatment ofthe diseases mentioned above or below, including the treatment of any one of the mentioned diseases, for example heart failure or fibrotic diseases such as pulmonary fibrosis, cardiac fibrosis, vascular fibrosis, perivascularfibrosis, rénal fibrosis, liver fibrosis or fibrosing skin conditions, which comprise administering an efficacious amount of at least one compound oftheformula I and/or a physiologically acceptable sait thereof to a human or an animal which is in need thereof. The compounds ofthe formula I and pharmaceutical compositions and médicaments comprising them can be administered enterally, for example by oral, sublingual or rectal administration, parenterally, for example by intravenous, intramuscular, subcutaneous or intraperitoneal injection or infusion, or by another type of administration such as topical, percutaneous, transdermal, intra-articular, intranasal or intraocular administration.

The compounds ofthe formula I and their physiologically acceptable salts can also be used in combination with other pharmaceutical active compounds, wherein in such a combination use the compounds ofthe formula I and/or their physiologically acceptable salts and one or more other pharmaceutical active compounds can be présent in one and the same pharmaceutical composition or in two or more pharmaceutical compositions for separate, simultaneous or sequential administration. Examples of such other pharmaceutical active compounds are angiotensin converting enzyme (ACE) inhibitors, ramipril, angiotensin II receptor subtype 1 (AT1) antagonists, irbesartan, antiarrhythmics, dronedarone, peroxisome proliferator-activated receptor-alpha (PPAR-α) activators, peroxisome proliferator-activated receptor-gamma (PPARγ) activators, pioglitazone, rosiglitazone, prostanoids, endothelin receptor antagonists, bosentan, elastase inhibitors, calcium antagonists, beta blockers, diuretics, aldostérone receptor antagonists, eplerenone, renin inhibitors, rho kinase inhibitors, soluble guanylate cyclase (sGC) activators, sGC sensitizers, phosphodiesterase (PDE) inhibitors, phosphodiesterase type 5 (PDE5) inhibitors, NO donors, digitalis drugs, angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitors, statins, bile acid reuptake inhibitors, platelet derived growth factor (PDGF) receptor antagonists, vasopressin antagonists, aquaretics, sodium hydrogen exchanger subtype 1 (NHE1) inhibitors, factor ll/factor lia antagonists, factor IX/factor IXa antagonists, factor X/factor Xa antagonists, factor XIll/factor XIIIa antagonists, anticoagulants, antithrombotics, platelet inhibitors, profibrinolytics, thrombinactivatable fibrinolysis inhibitors (TAFI), plasminogen activator inhibitor-1 (PAI 1), coumarins, heparins, thromboxane antagonists, serotonin antagonists, cyclooxygenase inhibitors, acetylsalicylic acid, therapeutic antibodies, glycoprotein llb/llla (GPIIb/llla) antagonists including abciximab, chymase inhibitors, cytostatics, taxanes, paclitaxel, docetaxel, aromatase inhibitors, estrogen receptor antagonists, sélective estrogen receptor modulators (SERM), tyrosine kinase inhibitors, imatinib, receptor tyrosine kinase inhibitors, RAF kinase inhibitors, p38 mitogenactivated protein kinase (p38 MAPK) inhibitors, pirfenidone, multi-kinase inhibitors, and sorafenib. A subject of the présent invention also is the said combination use of any one or more ofthe compounds ofthe formula I disclosed herein and their physiologically acceptable salts, with any one or more, for example one or two, of the mentioned other pharmaceutical active compounds.

The pharmaceutical compositions and médicaments according to the invention normally contain from about 0.5 to about 90 percent by weight of compounds ofthe formula I and/or physiologically acceptable salts thereof, and an amount of active ingrédient ofthe formula I and/or its physiologically acceptable sait which in general is from about 0.2 mg to about 1000 mg, in particular from about 0.2 mg to about 500 mg, for example from about 1 mg to about 300 mg, per unit dose. Depending on the kind ofthe pharmaceutical composition and other particulars of the spécifie case, the amount may deviate from the indicated ones. The production ofthe pharmaceutical compositions and médicaments can be carried out in a manner known per se. For this, the compounds of the formula I and/or their physiologically acceptable salts are mixed together with one or more solid or liquid vehicles and/or excipients, if desired also in combination with one or more other pharmaceutical active compounds such as those mentioned above, and brought into a suitable form for dosage and administration, which can then be used in human medicine or veterinary medicine.

As vehicles, which may also be looked upon as diluents or bulking agents, and excipients suitable organic and inorganic substances can be used which do not react in an undesired mannerwith the compounds ofthe formula I. As examples of types of excipients, or additives, which can be contained in the pharmaceutical compositions and médicaments, lubricants, preservatives, thickeners, stabilizers, disintegrants, wetting agents, agents for achieving a depot effect, emulsifiers, salts, for example for influencing the osmotic pressure, buffer substances, colorants, flavorings and aromatic substances may be mentioned. Examples of vehicles and excipients are water, vegetable oils, waxes, alcohols such as éthanol, isopropanol, 1,2propanediol, benzyl alcohols, glycérol, polyols, polyethylene glycols or polypropylene glycols, glycérol triacetate, polyvinylpyrrolidone, gelatin, cellulose, carbohydrates such as lactose or starch like com starch, sodium chloride, stearic acid and its salts such as magnésium stéarate, talc, lanolin, petroleum jelly, or mixtures thereof, for example saline or mixtures of water with one or more organic solvents such as mixtures of water with alcohols. For oral and rectal use, pharmaceutical forms such as, for example, tablets, film-coated tablets, sugar-coated tablets, granules, hard and soft gelatin capsules, suppositories, solutions, including oily, alcoholic or aqueous solutions, syrups, juices or drops, furthermore suspensions or émulsions, can be used. For parentéral use, for example by injection or infusion, pharmaceutical forms such as solutions, for example aqueous solutions, can be used. Fortopical use, pharmaceutical forms such as ointments, creams, pastes, lotions, gels, sprays, foams, aérosols, solutions or powders can be used. Further suitable pharmaceutical forms are, for example, implants and patches and forms adapted to inhalation. The compounds ofthe formula I and their physiologically acceptable salts can also be lyophilized and the obtained lyophilizates used, for example, for the production of injectable compositions. In particularfortopical application, also liposomal compositions are suitable. The pharmaceutical compositions and médicaments can also contain one or more other active ingrédients and/or, for example, one or more vitamins.

As usual, the dosage ofthe compounds ofthe formula I dépends on the circumstances ofthe spécifie case and is adjusted by the physician according to the customary rules and procedures. It dépends, for example, on the compound ofthe formula I administered and its potency and duration of action, on the nature and severity ofthe individual syndrome, on the sex, âge, weight and the individual responsiveness ofthe human or animal to be treated, on whetherthe treatment is acute or chronic or prophylactic, or on whether further pharmaceutical active compounds are administered in addition to a compound ofthe formula I. Normally, in the case of administration to an adult weighing about 75 kg, a dose from about 0.1 mg to about 100 mg per kg per day, in particular from about 1 mg to about 10 mg per kg per day (in each case in mg per kg of body weight), is sufficient. The daily dose can be administered in the form of a single dose or divided into a number of individual doses, for example two, three or four individual doses. The administration can also be carried out continuously, for example by continuous injection or infusion. Depending on the individual behavior in a spécifie case, it may be necessary to deviate upward or downward from the indicated dosages.

Besides as a pharmaceutical active compound in human medicine and veterinary medicine, the compounds ofthe formula I can also be employed as an aid in biochemical investigations or as a scientific tool or for diagnostic purposes, for example in in-vitro diagnoses of biological samples, if an inhibition ofthe Edg-2 receptor is intended. The compounds ofthe formula I and their salts can also be used as intermediates for the préparation of further pharmaceutical active substances.

The following examples illustrate the invention.

Abbreviations

ACN	acetonitrile
DCM	dichloromethane
DIAD	diisopropyl azodicarboxylate
DMF	dimethylformamide
DMSO	dimethyl sulfoxide
EA	ethyl acetate
EDIA	N-ethyldiisopropylamine
EDC	1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
HEP	heptane
HOBT	1 -hydroxy-benzotriazole
TFA	trifluoroacetic acid
THF	tetra hydrofuran

In general, reactions were carried out under argon. When example compounds containing a basic group were purified by préparative high pressure liquid chromatography (HPLC) on reversed phase (RP) column material and, as customary, the eluent was a gradient mixture of water and acetonitrile containing trifluoroacetic acid, they were in part obtained in the form of their acid addition salts with trifluoroacetic acid, depending on the details ofthe workup such as évaporation or lyophilization conditions. In the names ofthe example compounds and the structural formulae such contained trifluoroacetic acid is not specified.

The prepared compounds were in general characterized by spectroscopic data and chromatographie data, in particular mass spectra (MS) and HPLC rétention times (Rt; in min) which were obtained by combined analytical HPLC/MS characterization (LC/MS), and/or thin layer chromatography (TLC) Rf values, and/or nuclear magnetic résonance (NMR) spectra. Unless specified otherwise, ¹H-NMR spectra were recorded at 500 MHz in D₆-DMSO as solvent at 298 K. In the NMR characterization, the chemical shift δ (in ppm), the number of hydrogen atoms (H) and the multiplicity (s: singlet, d: doublet, dd: doublet of doublets, ddd: doublet of doublets of doublets, t: triplet, dt: doublet of triplets, tt: triplet of triplets, q: quartet, dq: doublet of quartets, m: multiplet; br: broad) ofthe peaks as determined on printouts are given. In the MS characterization, in general the mass number (m/z) ofthe peak ofthe molecular ion [M], e.g. [M⁺], or of a related ion such as the ion [M+1 ], e.g. [(M+1 )⁺], i.e. the protonated molecular ion [(M+H)⁺] abbreviated as [MH⁺], or the ion [M-1], e.g. [(M-1)^, i.e. the deprotonated molecular ion [(M-H)^-], which was formed depending on the ionization method used, is given. Generally, the ionization method was electrospray ionization (ESI).The particulars of the LC/MS methods used are as follows.

Method LC1

Column: Merck Chromolith FastGradient RP-18e, 50x2 mm; flow: 2 ml/min; 50 °C; eluent A: ACN + 0.05 % TFA; eluent B: water + 0.05 % TFA; gradient: 2 % A + 98 % B for 0.2 min, then to 98 % A + 2 % B within 2.2 min, then 98 % A + 2 % B for 0.8 min; MS ionization method: ESI⁺

Method LC2

Column: Merck Chromolith FastGradient RP-18e, 50x2 mm; flow: 2.4 ml/min; 50 °C; eluent A: ACN + 0.05 % TFA; eluent B: water + 0.05 % TFA; gradient: 2 % A + 98 % B for 0.2 min, then to 98 % A + 2 % B within 2.2 min, then 98 % A + 2 % B for 0.8 min; MS ionization method: ESI⁺

Method LC3

Column: YMC J’sphere H80, 33x2.1 mm, 4 pm; flow: 1 ml/min; eluent A: methanol + 0.05 % TFA; eluent B: water + 0.05 % TFA; gradient: 2 % A + 98 % B for 1 min, then to 95 % A + 5 % B within 4 min, then 95 % A + 5 % B for 1.25 min; MS ionization method: ESI⁺

Method LC4

Column: Waters Acquity UPLC BEH C18, 50x2.1 mm; 1.7 pm; flow: 0.9 ml/min; 55 °C; eluent A: ACN + 0.08 % formic acid; eluent B: water + 0.1 % formic acid; from gradient: 5 % A + 95 % B to 95 % A + 5 % B within 1.1 min, then 95 % A + 5 % B for 0.6 min; MS ionization method: ESI⁺ or ESF

Method LC5

Column: Waters XBridge C18, 50x4.6 mm, 2.5 pm; flow: 1.3 ml/min; eluent A: ACN + 0.08 % formic acid; eluent B: water + 0.1 % formic acid; gradient: from 3 % A + 97 % B to 60 % A + 40 % B within 3.5 min, then to 98 % A + 2 % B within 0.5 min, then 98 % A + 2 % B for 1 min; MS ionization method: ESF

Method LC6

Column: Waters XBridge C18, 50x4.6 mm, 2.5 pm; flow: 1.3 ml/min; 45 °C; eluent A: ACN + 0.1 % formic acid; eluent B: water + 0.1 % formic acid; gradient: from 3 % A + 97 % B to 60 % A + 40 % B within 3.5 min, then to 98 % A + 2 % B within 0.5 min, then 98 % A + 2 % B for 1 min; MS ionization method: ESI⁺ or ESF

Method LC7

Column: Waters XBridge C18, 50x4.6 mm, 2.5 pm; flow: 1.7 ml/min; 40 °C; eluent A: ACN + 0.05 % TFA; eluent B: water + 0.05 % TFA; gradient: 5 % A + 95 % B for 0.2 min, then to 95 % A + 5 % B within 2.2 min, then 95 % A + 5 % B for 0.8 min; MS ionization method: ESI⁺

Method LC8

Column: Waters XBridge C18, 50x4.6 mm, 2.5 pm; flow: 1.7 ml/min; 50 °C; eluent A: ACN + 0.05 % TFA; eluent B: water + 0.05 % TFA; gradient: 5 % A + 95 % B for 0.2 min, then to 95 % A + 5 % B within 2.2 min, then 95 % A + 5 % B for 1.1 min; MS ionization method: ESI⁺

Method LC9

Column: Waters XBridge C18, 50x4.6 mm, 2.5 pm; flow: 1.3 ml/min; 40 °C; eluent A; ACN + 0.05 % TFA; eluent B: water + 0.05 % TFA; gradient: 5 % A + 95 % B for 0.3 min, then to 95 % A + 5 % B within 3.2 min, then 95 % A + 5 % B for 0.5 min; MS ionization method: ESI⁺

Method LC 10

Column: YMC J'sphere H80, 33x2.1 mm, 4 pm; flow: 1 ml/min; eluent A: ACN + 0.05 % TFA; eluent B: water + 0.05 % TFA; gradient: 2 % A + 98 % B for 1 min, then to 95 % A + 5 % B within 4 min, then 95 % A + 5 % B for 1.25 min; MS ionization method: ESI⁺

Method LC11

Column: Thermo Javelin C18, 40x2.1 mm, 5 pm; flow: 1 ml/min; eluent A: ACN + 0.1 % TFA; eluent B: water + 0.1 % TFA; gradient: from 2 % A + 98 % B to 80 % A + 20 % B within 7 min, then to 100 % A + 0 % B within 0.2 min; MS ionization method: ESI⁺

Method LC 12

Column: Zorbax Eclipse XDB-C18, 50x4.6 mm, 1.8 pm; flow: 1.5 ml/min; 40 °C; eluent A: ACN + 0.1 % TFA; eluent B: water + 0.1 % TFA; gradient: from 2 % A + 98 % B to 100 % A + 0 % B within 2 min; MS ionization method: ESI⁺

Method LC 13

Column: YMC J'sphere H80, 20x2.1 mm, 4 pm; 30 °C; flow: 1.0 ml/min; eluent A: ACN; eluent B: water + 0.05 % TFA; gradient: from 4 % A + 96 % B to 95 % A + 5 % B within 2.4 min, then to 4 % A + 96 % B within 0.05 min, then 4 % A + 96 % B for 0.05 min; MS ionization method: ESl⁺

Example 1

1-{3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoylamino)-cycloheptanecarboxylic acid

Step 1: 3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoic acid methyl ester 2-(2Fluoro-5-methyl-phenyl)-ethanol (508 mg, 3.29 mmol) was dissolved in THF (23 ml). Triphenylphosphine (1.08 g, 4.12 mmol) and 3-hydroxy-4-methoxy-benzoic acid methyl ester (500 mg, 2.75 mmol) were added, the mixture was cooled in an ice bath, and DIAD (832 mg, 4.12 mmol) was added slowly with stirring. The ice bath was removed and stirring was continued ovemight at room température. The volatiles were evaporated in vacuo, and the residue was purified by RP HPLC (water/ACN gradient) to give 530 mg of the title compound. ¹H-NMR: δ = 7.59 (dd, 1H); 7.45 (d, 1H); 7.24 (d, 1H); 7.10-7.02 (m, 3H); 4.20 (t, 2H); 3.82 (s, 3H); 3.80 (s, 3H); 3.04 (t, 2H); 2.26 (s, 3H)

Step 2: 3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoic acid

The compound of step 1 (530 mg, 1.66 mmol) was dissolved in dioxane (8.3 ml). Lithium hydroxide (8.3 ml of an aqueous 1 M solution) was added and the mixture was kept for 20 min at 60 °C. After cooling, the mixture was partitioned between an excess of 2 N hydrochloric acid and EA and the aqueous phase extracted with EA. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness in vacuo. The residue was stirred ovemight with a mixture of diethyl ether and HEP, filtered, and the solid was dried in vacuo to give 500 mg of the title compound.

¹H-NMR: δ = 12.5 (br s, 1H); 7.56 (dd, 1H); 7.44 (d, 1H); 7.23 (d, 1H); 7.10-7.02 (m, 3H); 4.20 (t, 2H); 3.82 (s, 3H); 3.04 (t, 2H); 2.26 (s, 3H)

Step 3: 1-{3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}cycloheptanecarboxylic acid methyl ester

The compound of step 2 (285 mg, 0.937 mmol) was dissolved in an excess of thionyl chloride (0.7 ml) and stirred for 20 min at 60 °C. The solution was evaporated to dryness in vacuo. The residue was dissolved in a little DCM and added to a well-stirred mixture of 1-aminocycloheptanecarboxylic acid methyl ester hydrochloride (195 mg, 0.937 mmol), EA and an excess of a saturated aqueous sodium hydrogencarbonate solution. The mixture was stirred for 30 min at room température. The layers were separated, the aqueous phase was extracted with EA, the combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. This residue was purified by préparative RP HPLC (water/ACN gradient) to give 160 mg ofthetitle compound.

Step 4: 1-{3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}cycloheptanecarboxylic acid

The compound of step 3 (160 mg, 0.35 mmol) was dissolved in dioxane (1.8 ml). 1 M aqueous lithium hydroxide (1.8 ml) was added, the mixture was stirred at 60 °C for 30 min, cooled, and partitioned between 2 N hydrochloric acid and EA. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness. The residue was stirred in ether and the solid material which formed was filtered and dried in vacuo to yield the title compound (126 mg).

¹H-NMR: δ = 12 (brs, 1H); 8.07 (s, 1H); 7.50 (dd, 1H); 7.41 (d, 1H); 7.24 (d, 1H); 7.10-7.00 (m, 3H); 4.20 (t, 2H); 3.80 (s, 3H); 3.04 (t, 2H); 2.26 (s, 3H); 2.13-2.01 (m, 4H); 1.58-1.42 (m, 8H)

Example 2 1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

Step 1: 4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid

From 3-hydroxy-4-methoxy-benzoic acid methyl ester, the title compound was obtained by reaction with 2-m-tolyl-ethanol (2-(3-methyl-phenyl)-ethanol) in analogy to step 1 of example 1 and hydrolysis of the ester group in analogy to step 2 of example 1.

¹H-NMR: δ = 12.65 (brs, 1H);7.56 (dd, 1H);7.44 (d, 1H); 7.19 (t, 1H); 7.17-7.15 (m, 1H);7.12 (d, 1H); 7.06-7.02 (m, 2H); 4.19 (t, 2H); 3.83 (s, 3H); 3.01 (t, 2H); 2.29 (s, 3H)

Step 2: 1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

The title compound was synthesized in analogy to example 1, steps 3 and 4.

LC/MS (Method LC10): Rt = 3.67 min; m/z = 426.23 [MH⁺]

Example 3

1-{3-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-cycloheptanecarboxylic acid

Step 1; 1-(3-Acetoxy-4-methoxy-benzoylamino)-cycloheptanecarboxylic acid methyl ester 3-Acetoxy-4-methoxy-benzoic acid (7.10 g, 33.8 mmol) was dissolved in DMF (70 ml). The solution was cooled in an ice bath and 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (7.72 g, 37.2 mmol), EDIA (24.4 ml, 135 mmol) and TOTU (16.6 g, 50.7 mmol) were added sequentially. Stirring was continued at room température for 1 h. Water was added and stirring was continued for 1 h. The solid material which formed was collected by filtration, washed with water and dried in vacuo. The obtained material was stirred with a diethyl ether/HEP mixture, filtered and dried in vacuo to yield the title compound (9.03 g).

¹H-NMR; δ = 8.81 (s, 1 H); 7.78 (dd, 1H); 7.62 (d, 1H); 7.19 (d, 1H); 3.82 (s, 3H); 3.55 (s, 3H); 2.28 (s, 3H); 2.13-2.02 (m, 4H); 1.60-1.41 (m, 8H)

Step 2: 1-(3-Hydroxy-4-methoxy-benzoylamino)-cycloheptanecarboxylic acid methyl ester The compound of step 1 (10.6 g, 29.4 mmol) was dissolved in méthanol (100 ml), potassium carbonate (812 mg, 5.88 mmol) was added and the mixture was stirred overnight at room température. An excess of 2 N hydrochloric acid was added, the méthanol was evaporated in vacuo and the residue partitioned between EA and water. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness to give the title compound (6.81 g).

¹H-NMR: δ = 9.15 (s, 1H); 8.17 (s, 1H); 7.31 (dd, 1H); 7.28(d, 1H); 6.95 (d, 1H); 3.81 (s, 3H); 3.54 (s, 3H); 2.10-2.00 (m, 4H); 1.57-1.40 (m, 8H)

Step 3: 1 -{3-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}cycloheptanecarboxylic acid methyl ester

The compound of step 2 (80 mg, 0.249 mmol) and triphenylphosphine (98 mg, 0.374 mmol) were dissolved in THF. 2-(5-Chloro-2-fluoro-phenyl)-ethanol (48 mg, 0.274 mmol) and DIAD (80.3 mg, 0.374 mmol) were added and the mixture was stirred at room température for 2 h. The volatiles were evaporated in vacuo and the residue was purified by préparative RP HPLC (water/ACN gradient) to give 85 mg ofthe title compound.

¹H-NMR: δ = 8.21 (s, 1H); 7.58 (dd, 1H); 7.51 (dd, 1 H); 7.41 (d, 1H); 7.38-7.33 (m, 1H); 7.25 (t, 1H); 7.02 (d, 1H); 4.23 (t, 2H); 3.80 (s, 3H); 3.54 (s, 3H); 3.09 (t, 2H); 2.12-2.01 (m, 4H); 1.571.40 (m, 8H)

Step 4: 1-{3-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}cycloheptanecarboxylic acid

The compound of step 3 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

¹H-NMR: δ = 8.07 (s, 1H); 7.58 (dd, 1H); 7.51 (dd, 1H); 7.42 (d, 1H); 7.38-7.33 (m, 1H); 7.24 (t, 1H); 7.01 (d, 1H); 4.22 (t, 2H); 3.80 (s, 3H); 3.10 (t, 2H); 2.12-2.02 (m, 4H); 1.59-1.42 (m, 8H)

In analogy to example 3, the example compounds oftheformula 1-1 listed in table 1 were prepared. The compounds can be named as 1-[3-(R¹⁰¹-oxy)-4-methoxy-benzoylamino]cycloheptanecarboxylic acid, for example as 1-{3-[2-(thiophen-3-yl)-ethoxy]-4-methoxybenzoylaminoj-cycloheptanecarboxylic acid in the case of example 11.

Table 1. Example compounds oftheformula 1-1

Example	R101	LC/MS Method	m/z [MH+]	Rétention time [min]
4	2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethyl	LC10	430.18	2.57
5	2-(2-fluoro-5-trifluoromethoxy-phenyl)~ ethyl	LC10	514.11	3.87
6	2-(thiophen-2-yl)-ethyl	LC8	418.17	2.36
7	2-(3-methoxy-phenyl)-ethyl	LC8	442.23	2.39
8	2-phenyl-ethyl	LC8	412.22	2.41
9	2-phenyl-propyl	LC8	426.22	2.49
10	2-(3-chloro-phenyl)-ethyl	LC8	446.17	2.51
11	2-(thiophen-3-yl)-ethyl	LC8	418.16	2.37
12	(cyclohex-3-enyl)-methyl	LC8	402.22	2.49
13	2-(2-fluoro-phenyl)-ethyl	LC8	430.17	2.41
14	2-phenyl-butyl	LC8	440.21	2.59
15	2-(2,4-dichloro-phenyl)-ethyl	LC8	480.11	2.66
16	2-(2-chloro-6-fluoro-phenyl)-ethyl	LC8	464.12	2.50
17	2-(2,5-dichloro-phenyl)-ethyl	LC8	480.1	2.62
18	2-(2,5-dimethyl-phenyl)-ethyl	LC8	440.2	2.58
19	2-(2-methyl-phenyl)-ethyl	LC8	426.2	2.49
20	2-(2,5-difluoro-phenyl)-ethyl	LC8	448.15	2.42
21	2-(3-chloro-2-fluoro-phenyl)-ethyl	LC8	464.13	2.51
22	(3-phenyl-oxetan-3-yl)-methyl	LC2	454.3	1.55

Example 23

1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclooctanecarboxylic acid

The title compound was synthesized in analogy to example 3 using 1-aminocyclooctanecarboxylic acid methyl ester hydrochloride instead of 1-aminocycloheptanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC9): Rt = 3.56 min; m/z = 440.21 [MH⁺]

Example 24 1-{3-[2-(2-Fluoro-5-methyl-phenyl)-ethoxy]-4-methoxy-benzoylamino}-cyclooctanecarboxylic acid

F

The title compound was synthesized in analogy to example 23.

LC/MS (Method LC9): Rt = 3.58 min; m/z = 458.2 [MH⁺]

Example 25

4-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-oxepane-4-carboxylic acid

4-Amino-oxepane-4-carboxylic acid methyl ester hydrochloride (synthesized from oxepan-4-one via the Bucherer-Bergs hydantoin route in analogy to the procedure described in J. W. Tsang et al., J. Med. Chem. 27 (1984), 1663-1668; oxepan-4-one was synthesized from tetrahydropyran4-one by the in-situ diazomethane route described in F. Alonso et al., Tetrahedron 51 (1995), 10259-10280) was reacted with 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid and the obtained methyl ester hydrolyzed in analogy to steps 3 and 4 of example 1.

¹H-NMR: δ = 12.15 (brs, 1H); 8.19 (s, 1H); 7.50 (dd, 1H); 7.41 (d, 1H); 7.21-7.15 (m, 2H); 7.12 (d, 1H); 7.06-6.99 (m, 2H); 4.20 (t, 2H); 3.80 (s, 3H); 3.65-3.55 (m, 4H); 3.01 (t, 2H); 2.35-2.22 (m, 5H, therein 2.29 (s, 3H)); 2.15-2.01 (m, 2H); 1.81-1.71 (m, 1 H); 1.65-1.57 (m, 1H)

By coupling 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid to the respective amino acid methyl ester via the carboxylic acid chloride route as described in step 3 of example 1 or the TOTU coupling route as described in step 1 of example 3, the example compounds of the formula I-2 listed in table 2 were prepared. The amino acid methyl esters or the amino acids were commercially available or were prepared from the respective ketone in analogy to example 25. In the formulae ofthe groups R¹⁰² in table 2 the line crossed with the symbol ~ represents the free bond via which the group R¹⁰² is bonded to the nitrogen atom ofthe amide group depicted in formula I-2. I.e., in the formula ofthe complété molécule the terminal endpoint ofthe line crossed with the said symbol ends on the nitrogen atom ofthe amide group.

I-2

Table 2. Example compounds ofthe formula I-2

Example	R102—	Starting material	LC/MS Method	m/z [MH+]	Rétention time [min]
26	A θ’”1 0	(a)	LC2	440.33	1.77
27	•CYXo„ oz	(a)	LC10	426.14	3.72
28	F’°<Xo„ 0	(a)	LC2	480.25	1.28
29	H3x<X H3C f- OH 0	(a)	LC10	454.39	3.99
30	“ΉΧ. oz	(a)	LC1	440.27	1.89
31	k o	(a)	LC2	438.31	1.29

Example	R102-^—	Starting material	LC/MS Method	m/z [MH+]	Rétention time [min]
32	CH4» oz	(a)	LC2	426.27	1.31
33	oz	(a)	LC2	412.26	1.29
34	tari	(b)	LC12	384.2	1.97
35	0	(b)	LC12	398.2	2.02
36	<Χ0„ oz	(b)	LC11	430.2	4.29
37	<x» oz	(b)	LC11	414.2	3.7

Example	R102—	Starting material	LC/MS Method	m/z [MH+]	Rétention time [min]
38	Q o'	—OH		(b)	LC1	412.21	1.75
39	ch3 H3C-( .H		(b)	LC1	466.17	1.87
	h3c	oz	OH
40		0	-OH	(b)	LC2	396.27	1.24
41	H3C^	0	-OH	Example 42	LC2	398.29	1.25

(a) The amino acid ester was prepared from the respective ketone.

(b) The amino acid ester or amino acid was commercially available.

Example 42

1-Amino-2-ethylcyclopropanecarboxylic acid ethyl ester (starting compound) 1-tert-Butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (50 mg, 0.196 mmol) was dissolved in methanol (3 ml), azodicarboxylic acid dipotassium sait (D. J. Pasto et al., Organic Reactions 40 (1991), 91-155; 229 mg, 1.16 mmol) was added, the mixture was cooled in an ice bath and acetic acid (141 mg, 2.35 mmol) was added slowly. This mixture was warmed to 30 °C and stirred for 1 h. The addition of azodicarboxylic acid dipotassium sait and acetic acid and stirring at 30 °C was repeated until completion of the réduction. The mixture was evaporated to dryness and partitioned between EA and an aqueous sodium hydrogencarbonate solution. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium chloride and evaporated to dryness. The residue was dissolved in a mixture of DCM and TFA (1:1) and stirred for 1 h. The mixture was evaporated to dryness and the obtained crude title compound (obtained in the form of the trifluoroacetic acid sait) used in the amide coupling step.

Example 43 trans-1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylic acid

Step 1 : N-(trans-1-Cyano-4-methyl-cyclohexyl)-4-methoxy-3-(2-m-tolyl-ethoxy)-benzamide 4-Methyl-cyclohexanone was reacted in a Strecker aminonitrile synthesis in analogy to the procedure described in I. L. Munday, J. Chem. Soc. (1961), 4372-4379 to yield trans-1-amino-4methyl-cyciohexanecarbonitrile which was coupled with 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid via the TOTU coupling route as described in step 1 of example 3.

¹H-NMR: δ = 8.42 (s, 1H); 7.50 (dd, 1H); 7.41 (d, 1 H); 7.21-7.15 (m, 2H); 7.12 (d, 1H); 7.04 (d, 2H); 4.19 (t, 2H); 3.81 (s, 3H); 3.02 (t, 2H); 2.50-2.43 (m, 2H); 2.28 (s, 3H); 1.80-1.71 (m, 2H); 1.65-1.55 (m, 2H); 1.48-1.38 (m, 1H); 1.27-1.14 (m, 2H); 0.91 (d, 3H)

Step 2: trans-1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylic acid ethyl ester

The compound of step 1 (810 mg, 1.99 mmol) was dissolved in éthanol (10 ml). The solution was cooled in an acetone/dry ice bath, acetyl chloride (2.3 ml, 30 mmol) was added and the mixture was warmed to room température and stirred for 3 days. Then 2 N hydrochloric acid was added and the mixture was stirred overnight to hydrolyze the imino ester. After évaporation of the éthanol, the residue was partitioned between EA and 2 N hydrochloric acid. The phases were separated, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (DCM/EA gradient) to yield the title compound (0.78 g).

¹H-NMR: δ = 8.20 (s, 1H); 7.45 (dd, 1H); 7.39 (d, 1H); 7.22-7.15 (m, 2H); 7.12 (d, 1H); 7.05-6.99 (m, 2H); 4.18 (t, 2H); 4.03 (q, 2H); 3.80 (s, 3H); 3.01 (t, 2H); 2.31-2.25 (m, 5H, therein 2.29 (s, 3H)); 1.65-1.54 (m, 4H); 1.52-1.41 (m, 1H); 1.30-1.18 (m, 2H); 1.10 (t, 3H); 0.88 (d, 3H)

Step 3: trans-1 -[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylic acid

The compound of step 2 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

¹H-NMR: δ = 12.0 (s, 1H); 8.09 (s, 1H); 7.48 (dd, 1 H); 7.40 (d, 1H); 7.21-7.13 (m, 2H); 7.12 (d, 1H); 7.04 (d, 1H); 7.00 (d, 1 H); 4.19 (t, 2H); 3.80 (s, 3H); 3.02 (t, 2H); 2.32-2.22 (m, 5H, therein 2.29 (s, 3H)); 1.65-1.51 (m, 4H); 1.51-1.40 (m, 1H); 1.31-1.20 (m, 2H); 0.86 (d, 3H)

In analogy to example 43, by employing the respective ketone instead of 4-methylcyclohexanone in the initial Strecker aminonitrile step, the example compounds oftheformula I3 listed in table 3 were prepared. In the formulae ofthe groups R¹⁰³ in table 3 the line crossed with the symbol ----- represents the free bond via which the group R¹⁰³ is bonded to the nitrogen atom ofthe amide group depicted in formula I-3. I.e., in the formula ofthe complété molécule the terminal endpoint ofthe line crossed with the said symbol ends on the nitrogen atom ofthe amide group.

Table 3. Example compounds ofthe formula I-3

Example	R103—	LC/MS Method	m/z [MH+]	Rétention time [min]
44	Ό	LC2	430.18	1.58
45	HW h3c ^-7 Voh 0	LC1	440.25	1.85
46	0 <a)	LC1	440.24	1.85
47	. 0 (a)	LC1	438.25	1.78
48	ch3 c^0H 0 (a)	LC2	426.38	1.30
49	ch3 A 0	LC2	412.33	1.30

100

Example	p103 } R	LC/MS Method	m/z [MH+]	Rétention time [min]
50	Hs ΥΛ-OH 0 (a)	LC1	440.25	1.87

(a) Other diastereomer than in example 26, example 30, example 31 and example 32, respectively.

Example 51

8-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acid

Step 1: 8-Benzyloxycarbonylamino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acid and 1benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid 8-Amino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acid was synthesized from 1,4-dioxaspiro[4.6]undecan-8-one (F. Alonso et al., Tetrahedron 51 (1995), 10259-10280) via the Bucherer-Bergs route in analogy to the procedure described in J. W. Tsang et al., J. Med. Chem. 27 (1984), 1663-1668. The intermediate was suspended in dioxane/water (2.5 ml/5 ml), sodium carbonate (0.732 g, 6.90 mmol) was added, the mixture was cooled in an ice bath and benzyl chloroformate (0.392 ml, dissolved in 2.5 ml of dioxane) was added with stirring. After 4 h, the mixture was partitioned between 2 N hydrochloric acid and EA, the aqueous phase was extracted with EA, the combined organic phrases were washed with water, dried over sodium sulfate and evaporated to dryness to yield a mixture of 8-benzyloxycarbonylamino-1,4-dioxaspiro[4.6]undecane-8-carboxylic acid and 1-benzyloxycarbonylamino-4-oxocycloheptanecarboxylic acid.

101

Step 2: 8-Benzyloxycarbonylamino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acid methyl ester and 1-benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid methyl ester

The mixture obtained in step 1 (200 mg) was dissolved in DMF (2 ml), césium carbonate (280 mg, 0.86 mmol), EDIA (149 mg, 1.14 mmol) and iodomethane (121 mg, 0.858 mmol) were added and the mixture was stirred at room température for 2 h. The volatiles were evaporated in vacuo, the residue was partitioned between EA and saturated aqueous sodium hydrogencarbonate solution. The aqueous phase was extracted with EA, and the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield 66 mg of 8-benzyloxycarbonylamino-1,4dioxa-spiro[4.6]undecane-8-carboxylic acid methyl ester and 83 mg of 1benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid methyl ester.

8-Benzyloxycarbonylamino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acid methyl ester ¹H-NMR: δ = 7.75 (s, 1H); 7.45-7.25 (m, 5H); 5.00 (s, 2H); 3.85-3.75 (m, 4H); 3.56 (s, 3H); 2.51.4 (m, 10 H)

1-Benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid methyl ester ¹H-NMR: δ = 7.76 (s, 1H); 7.40-7.28 (m, 5H); 5.02 (s, 2H); 3.60 (s, 3H); 2.6-1.6 (m, 10 H)

Step 3: 8-Amino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acid methyl ester mg of 8-benzyloxycarbonylamino-1,4-dioxa-spiro[4.6]undecane-8-carboxylic acid methyl ester was dissolved in methanol and hydrogenated in an H-cube™ hydrogénation reactor (ThalesNano, Budapest, Hungary) at a hydrogen pressure of 100 bar at 40 °C over a cartridge with 10 % palladium on charcoal. The mixture was evaporated to dryness to yield the crude title compound (32 mg).

Step 4: 8-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1,4-dioxa-spiro[4.6]undecane-8carboxylic acid

The title compound was prepared from the compound of step 3 and 4-methoxy-3-(2-m-tolylethoxy)-benzoic acid in analogy to steps 3 and 4 of example 1.

¹H-NMR: δ = 12.1 (brs, 1H); 8.5-8.1 (brs, 1H); 7.45-7.33 (m, 2H); 7.22-7.15 (m, 2H), 7.11 (d, 1H); 7.03 (d, 1H); 6.98 (d, 1H); 4.20 (t, 2H); 3.84-3.76 (m, 7H); 3.01 (t, 2H), 2.29 (s, 3H); 2.271.90(m,4H); 1.86-1.50 (m, 6 H)

102

Example 52

1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-oxo-cycloheptanecarboxylic acid

1-Benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid methyl ester (83 mg) was hydrogenated in analogy to step 3 of example 51 and transformed into the title compound in analogy to step 4 of example 51.

¹H-NMR: δ = 12.35 (s, 1H); 8.15 (s, 1H); 7.45 (dd, 1 H); 7.39 (d, 1H); 7.21-7.15 (m, 2H), 7.11 (d, 1H); 7.05-7.00 (m, 2H); 4.20 (t, 2H); 3.81 (s, 3H); 3.01 (t, 2H), 2.65-2.50 (m, 2H); 2.42-2.11 (m, 8H, therein 2.30 (s, 3H)); 1.92-1.69 (m, 3H)

Example 53

4-Hydroxy-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

HO

Step 1: 1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-oxo-cycloheptanecarboxylic acid methyl ester

1-Benzyloxycarbonylamino-4-oxo-cycloheptanecarboxylic acid methyl ester was hydrogenated in analogy to step 3 of example 51 and transformed into the title compound by reaction with 4methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid in analogy to step 3 of example 1.

LC/MS (Method LC5): Rt = 4.62 min; m/z = 454.32 [MH⁺]

Step 2: 4-Hydroxy-1 -[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic

103

The compound of step 1 (67 mg, 0.148 mmol) was dissolved in THF (1 ml) and cooled in an ice bath. Sodium borohydride (5.7 mg, 0.148 mmol) was added. Subsequently méthanol (0.3 ml) was added dropwise. The ice bath was removed and after stirring for 45 min at room température the mixture was partitioned between EA and 2 N hydrochloric acid. The aqueous phase was extracted with EA, and the combined organic phases were dried over sodium sulfate and evaporated to dryness to yield the title compound (65 mg).

LC/MS (Method LC6): Rt = 4.27 min; m/z = 456.36 [MH⁺]

Step 3: 4-Hydroxy-1 -[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

The compound of step 2 (63 mg, 0.138 mmol) was hydrolyzed in analogy to step 4 of example 1 to yield the title compound (49 mg) as mixture of diastereomers.

¹H-NMR: δ = 12.0 (s, 1 H); 8.12/8.06 (2s, 1H); 7.49 (dd, 1H); 7.40 (d, 1H); 7.22-7.10 (m, 3H), 7.08-6.99 (m, 2H); 4.46/4.40 (2d, 1H); 4.22-4.15 (m, 2H); 3.80 (s, 3H); 3.67-3.58 (m, 1H); 3.01 (t, 2H); 2.28 (s, 3H); 2.30-1.25 (m, 10H)

Example 54

8-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid

The title compound was synthesized in analogy to example 51 starting from commercially available 8-amino-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid.

LC/MS (Method LC1): Rt = 1.63 min; m/z = 470.2 [MH⁺]

Example 55

-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-oxo-cyclohexanecarboxylic acid

104

Step 1: 1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-oxo-cyclohexanecarboxylic acid methyl ester 8-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-1,4-dioxa-spiro[4.5]decane-8-carboxylic acid methyl ester (4.7 g, 9.7 mmol; intermediate in the synthesis of example 54) was dissolved in dioxane (70 ml), 2 N aqueous hydrochloric acid (10 ml) was added and the mixture was stirred at room température ovemight. The material was partitioned between EA and saturated aqueous sodium chloride solution, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness to yield the title compound.

LC/MS (Method LC1); Rt = 1.66 min; m/z = 440.21 [MH⁺]

Step 2; 1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-oxo-cyclohexanecarboxylic acid The compound of step 1 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC4); Rt = 1.15 min; m/z = 425.74 [MH⁺]

Example 56 1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methylene-cyclohexanecarboxylic acid

Step 1: 1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methylene-cyclohexanecarboxylic acid methyl ester

105

Methyltriphenylphosphonium bromide (4.88 g, 13.7 mmol) was suspended in THF. Potassium bis(trimethylsilyl)amide (13.6 mmol, solution in toluene) was added slowly and the mixture was stirred at room température for 1 h. The mixture was cooled in a acetone/dry ice bath and the compound of step 1 of example 55 (3.00 g, 6.83 mmol) was added. The mixture was warmed to room température and stirred ovemight. Methanol and an aqueous sodium dihydrogenphosphate solution were added. The mixture was extracted with diethyl ether, the combined extracts were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound (1.40 g). LC/MS (Method LC1): Rt = 1.91 min; m/z = 438.22 [MH⁺]

Step 2: 1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methylene-cyclohexanecarboxylic acid

The compound of step 1 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC10): Rt = 3.70 min; m/z = 424.25 [MH⁺]

Example 57

6-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-spiro[2.5]octane-6-carboxylic acid

The compound of step 1 of example 56 (400 mg, 0.91 mmol) was dissolved in toluene (8 ml) and diethylzinc (2.7 ml, 2.7 mmol, solution in hexane) was added. The mixture was heated to 60 °C and diiodomethane (1.10 g, 4.11 mmol) was added with stirring. This mixture was reacted at 60 °C ovemight, the addition of diethyl zinc and diiodomethane was repeated and stirring continued for another night. The mixture was partitioned between EA and 2 N hydrochloric acid, the aqueous phase was extracted with EA, the combined organic phases were washed with aqueous sodium hydrogencarbonate solution, dried over sodium sulfate and evaporated to dryness. The obtained methyl ester was hydrolyzed in analogy to step 4 of example 1 to yield the title compound (15 mg).

LC/MS (Method LC10): Rt = 3.70 min; m/z = 438.29 [MH⁺]

106

Example 58

4-Hydroxymethyl-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylic acid

Step 1:4-Hydroxymethyl-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]cyclohexanecarboxylic acid methyl ester

The compound of step 1 of example 56 (500 mg, 1.14 mmol) was dissolved in THF (5 ml) and cooled to -25 °C. Borane-tetrahydrofuran complex (2.29 ml of a 1 M solution in THF, 2.29 mmol) was added and the mixture was kept ovemight at 0 °C. Hydrogen peroxide (2.5 ml, 30 % in water) and sodium hydroxide (2.5 ml, 20 % in water) were added sequentially and stirring was continued at room température. The mixture was partitioned between water and EA, the aqueous phase extracted with EA, and the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound.

LC/MS (Method LC1): Rt = 1.62 min; m/z = 456.18 [MH⁺]

Step 2: 4-Hydroxymethyl-1 -[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]cyclohexanecarboxylic acid

The compound of step 1 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound as mixture of the cis isomer and the trans isomer.

¹H-NMR: δ = 12.0 (s, 1 H); 8.09/7.96 (2s, 1H); 7.52-7.46 (m, 1 H); 7.41 (s, 1H); 7.22-7.16 (m, 2H); 7.12 (d, 1H); 7.08-6.98 (m, 2H); 4.42-4.36 (m, 1H); 4.24-4.18 (m, 2H); 3.81 (s, 3H); 3.22/3.20 (2t, 2H); 3.01 (t, 2H); 2.32-2.22 (m, 5H, therein 2.28 (s, 3H)); 1.68-1.50 (m, 4H); 1.48-1.33 (m, 1H); 1.32-1.22 (m, 1H); 1.22-1.11 (m, 1H)

Example 59 4-Fluoromethyl-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylic acid

107

The compound of step 1 of example 58 (100 mg, 0.220 mmol) was dissolved in DCM (2 ml), diethylaminosulfur trifluoride (35 mg, 0.22 mmol) was added and the mixture was stirred at room température for 72 h. The mixture was partitioned between EA and aqueous sodium hydrogencarbonate solution. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) and hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

¹H-NMR: δ = 12.15 (s, 1H); 8.15/8.02 (2s, 1H); 7.53-7.48 (m, 1 H); 7.41 (s, 1H); 7.23-7.16 (m, 2H); 7.12 (d, 1 H); 7.09-7.00 (m, 2H); 4.35-4.26 (m, 3H); 3.81 (s, 3H); 3.02 (t, 2H); 2.39-2.30 (m, 2H); 2.29 (s, 3H); 1.80-1.53 (m, 5H); 1.48-1.22 (m, 2H)

Example 60

1-[4-Acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

Step 1: 1-(4-Acetyl-3-hydroxy-benzoylamino)-cycloheptanecarboxylic acid methyl ester 1-Amino-cycloheptanecarboxylic acid methyl ester hydrochloride (968 mg, 4.66 mmol), HOBT (105 mg, 0.78 mmol) and 4-acetyl-3-hydroxy-benzoic acid (700 mg, 3.89 mmol) were dissolved in DMF (5 ml). EDIA (3.01 g, 23.3 mmol) and EDC were added and the mixture was stirred at room température for 72 h. Then the mixture was partitioned between EA and saturated sodium chloride solution, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield the title compound.

108

LC/MS (Method LC9): Rt = 3.19 min; m/z = 334.17 [MH⁺]

Step 2: 1-[4-Acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid methyl ester The compound of step 1 and 2-m-tolylethanol were reacted in analogy to step 1 of example 1 to yield the title compound.

LC/MS (Method LC9): Rt = 3.98 min; m/z = 452.21 [MH⁺]

Step 3: 1-[4-Acetyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

The compound of step 2 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC9): Rt = 3.53 min; m/z = 438.18 [MH⁺]

Example 61

1-[4-(1-Hydroxy-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

The compound of example 60 (300 mg, 0.686 mmol) was dissolved in methanol (6 ml) and cooled in an ice bath. Sodium borohydride (79 mg, 2.06 mmol) was added, the mixture was kept at 0 °C for 72 h, and then evaporated to dryness. The residue was partitioned between EA and 2 N hydrochloric acid, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was stirred with diethyl ether and the solidified material was filtered and dried in vacuo to yield the title compound (50 mg). From the mother liquor a further batch ofthe title compounds was isolated by RP HPLC (water/ACN gradient).

LC/MS (Method LC9): Rt = 3.32 min; m/z = 440.23 [MH⁺]

Example 62

1-[4-Ethyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

The compound of example 61 (100 mg) was dissolved in éthanol (10 ml) and hydrogenated in an H-cube™ hydrogénation reactor at a hydrogen pressure of 10 bar at 35 °C over a cartridge with 10 % palladium on charcoal. The reaction mixture was evaporated to dryness and purified by RP HPLC (water/ACN gradient) to yield the title compound (60 mg).

¹H-NMR: δ = 12.00 (s, 1H); 8.12 (s, 1H); 7.38 (dd, 1H); 7.32 (d, 1H); 7.22-7.13 (m, 3H); 7.11 (d, 1 H); 7.03 (d, 1H); 4.23 (t, 2H); 3.03 (t, 2H); 2.53 (q, 2H); 2.28 (s, 3H); 2.10-2.04 (m, 4H); 1.571.43 (m, 8H); 1.03 (t, 3H)

Example 63 1-[4-(1-Fluoro-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

The compound of step 2 of example 60 (110 mg, 0.244 mmol) was dissolved in methanol (1.1 ml) and cooled in an ice bath. Sodium borohydride (9.2 mg, 0.244 mmol) was added and stirring continued for 1 h. This mixture was partitioned between EA and saturated sodium hydrogencarbonate solution, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue (100 mg) was dissolved in DCM (2 ml) and diethylaminosulfurtrifluoride (36 mg, 0.22 mmol) was added. The mixture was stirred for 3 h, partitioned between EA and saturated sodium hydrogencarbonate solution, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The obtained ester was hydroiyzed in analogy to step 4 of example 1 to yield the title compound.

110 ¹H-NMR: δ = 12.05 (s, 1 H); 8.24 (s, 1H); 7.48 (d, 1H); 7.41-7.36 (m, 2H); 7.20 (t, 1H); 7.15 (s,

1H); 7.12 (d, 1H); 7.03 (d, 1H); 5.81 (dq, 1H); 4.28 (t, 2H); 3.03 (t, 2H); 2.30 (s, 3H); 2.12-2.02 (m, 4H); 1.56-1.42 (m, 8H); 1.40 (dd, 3H)

Example 64

1-[4-Chloro-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

Step 1: 3-Acetoxy-4-chlorobenzoic acid

4-Chloro-3-hydroxybenzoic acid (1.00 g, 5.80 mmol) was suspended in acetic anhydride (11 ml) and heated to reflux for 3 h. After cooling, water (11 ml) was added and the mixture was refluxed again for 1 h. After cooling, crystals formed ovemight which were collected by suction filtration and dried in vacuo to yield the title compound (630 mg).

¹H-NMR: δ = 13.5 (br s, 1H); 7.88-7.81 (m, 2H); 7.71 (d, 1H); 2.34 (s, 3H)

Step 2: 1-(3-Acetoxy-4-chloro-benzoylamino)-cycloheptanecarboxylic acid methyl ester

The compound of step 1 (200 mg, 0.932 mmol) was dissolved in DCM (16 ml), DMF (12 mg) and oxalyl chloride (362 mg, 2.80 mmol) were added and the mixture was stirred at room température until completion ofthe reaction. The volatiles were evaporated in vacuo and the residue dissolved in DCM. The solution was added to a stirred mixture of 1-aminocycloheptanecarboxylic acid methyl ester hydrochloride (194 mg, 0.932 mmol) in EA/saturated sodium hydrogencarbonate solution with cooling in an ice bath. Stirring continued at room température for 2 h. The phases were separated, aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound (430 mg).

LC/MS (Method LC9): Rt = 3.48 min; m/z = 368.12 [MH⁺]

Step 3: 1-(4-Chloro-3-hydroxy-benzoylamino)-cycloheptanecarboxylic acid methyl ester

111

The compound of step 2 (400 mg, 1.088 mmol) was dissolved in methanol (3.5 ml), potassium carbonate (3 mg, 0.02 mmol) was added, and the mixture was stirred at room température for 6 h and evaporated to dryness to yield the title compound (300 mg).

LC/MS (Method LC9): Rt = 3.05 min; m/z = 326.22 [MH⁺]

Step 4: 1-[4-Chloro-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

The compound of step 3 was etherified with 2-m-tolylethanol in analogy to step 1 of example 1, and the intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC9): Rt = 3.78 min; m/z = 430.16 [MH⁺]

Example 65

1-[4-Bromo-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

The title compound was synthesized in analogy to example 64 starting with 4-bromo-3hydroxybenzoic acid in step 1.

LC/MS (Method LC9): Rt = 3.83 min; m/z = 474.11 [MIT]

Example 66

2-Benzyloxy-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclopentanecarboxylic acid, diastereomer 1 and diastereomer 2

O

112

Step 1: 1-Amino-2-benzyloxy-cyclopentanecarbonitrile, diastereomer 1 and diastereomer 2

2-Benzyloxycyclopentanone (A. B. Smith et al., J. Am. Chem. Soc. 108 (1986), 3040-3048; 310 mg, 1.63 mmol) was reacted in a Strecker aminonitrile synthesis in analogy to step 1 of example 43 to give the two racemic diastereomers ofthe title compound which were separated by silica gel chromatography (HEP/EA gradient).

Diastereomer 1 ¹H-NMR: δ = 7.40-7.32 (m, 4H); 7.31-7.25 (m, 1H); 4.60 (d, 1H); 4.56 (d, 1H); 3.75-3.72 (m, 1H); 2.07-1.92 (m, 2H); 1.83-1.77 (m, 1 H); 1.77-1.67 (m 3H)

Diastereomer 2 ¹H-NMR: δ = 7.40-7.32 (m, 4H); 7.31-7.25 (m, 1H); 4.68 (d, 1H); 4.61 (d, 1H); 4.02 (dd, 1H); 1.98-1.62 (m, 5H); 1.62-1.51 (m, 1H)

Step 2a: 2-Benzyloxy-1 -[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclopentanecarboxylic acid, diastereomer 1

The compound of step 1, diastereomer 1, was coupled with 4-methoxy-3-(2-m-tolyl-ethoxy)benzoic acid via the carboxylic acid chloride in analogy to step 3 of example 1. The obtained nitrile was reacted with éthanol in analogy to step 2 of example 43, and the obtained ethyl ester was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC6): Rt = 4.81 min; m/z = 502.16 [M-H⁺]

Step 2b: 2-Benzyloxy-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclopentanecarboxylic acid, diastereomer 2

The compound of step 1, diastereomer 2, was reacted in analogy to step 2a to yield the title compound.

LC/MS (Method LC1); Rt = 1.91 min; m/z = 504.18 [MH⁺]

Example 67

2-Hydroxy-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclopentanecarboxylic acid, diastereomer 1 and diastereomer 2

Diastereomer 1 and diastereomer2 ofthe compound of example 66 were separately dissolved in éthanol and hydrogenated with palladium 10 % on charcoal at room température with 1 bar hydrogen pressure until completion ofthe reaction. Afterfiltration, the solutions were evaporated to dryness and the residues purified by RP HPLC (water/ACN gradient) to yield the two diastereomers of the title compound separately.

Diastereomer 1 ¹H-NMR: δ = 8.52 (brs, 1H); 7.36-7.30 (m, 1 H); 7.22-7.15 (m, 2H); 7.12 (d, 1H); 7.06-7.00 (m, 2H); 4.60 (brs, 1H); 4.18 (t, 2H); 4.14-4.09 (m, 1H); 3.80 (s, 3H); 3.01 (t, 2H); 2.29 (s, 3H); 2.202.11 (m, 1H); 2.09-1.93 (m, 2H); 1.77-1.65 (m, 2H); 1.62-1.52 (m, 1H)

Diastereomer 2 ¹H-NMR: δ = 12.0 (brs, 1H); 8.11 (s, 1H); 7.45 (dd, 1H); 7.40 (d, 1 H); 7.23-7.14 (m, 2H); 7.11 (d, 1H); 7.06-7.00 (m, 2H); 5.11 (brs, 1H); 4.29 (t, 1H); 4.19 (t, 2H); 3.80 (s, 3H); 3.01 (t, 2H); 2.29 (s, 3H); 2.03-1.95 (m, 1H); 1.94-1.85 (m, 1H); 1.80-1.68 (m, 1H); 1.58-1.50 (m, 2H)

Example 68 2-Methoxy-1-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclopentanecarboxylic acid

114

The title compound was synthesized in analogy to example 60 starting with 2-methoxycyclopentanone (B. Foehlisch et al., Chem. Ber. 120 (1987), 1951-1960) and obtained as a mixture of diastereomers which was not separated.

LC/MS (Method LC4): Rt = 1.21 min; m/z = 428.25 [MH⁺]

Example 69 1-[2-Fluoro-4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

Step 1: 3-Fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester and 2-Fluoro-3-hydroxy-4methoxybenzoic acid methyl ester

3-Acetoxy-4-methoxybenzoic acid methyl ester (WO 2005/009389; 3.58 g, 16.0 mmol) and 1chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor®; 14.1 g, 39.9 mmol) were suspended in ACN (50 ml) and heated in a microwave oven for 7 min at 170 °C. After cooling, water was added and the mixture was repeatedly extracted with diethyl ether. The combined extracts were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient). The obtained mixture of fluorinated species, which were partially deacetylated, was dissolved in methanol (20 ml), potassium carbonate (80 mg) was added and the mixture was stirred for 3 h at 60 °C. The methanol was evaporated, the residue was partitioned between EA and 2 N hydrochloric acid, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. This residue was purified by RP HPLC (water/ACN gradient) to yield two regioisomers.

3-Fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester ¹H-NMR: δ = 10.2 (s, 1H); 7.30 (d, 1H); 7.21 (dd, 1H); 3.88 (s, 3H); 3.81 (s, 3H)

2-Fluoro-3-hydroxy-4-methoxybenzoic acid methyl ester ¹H-NMR: δ = 10.55 (s, 1H); 7.61 (d, 1H); 6.80 (dd, 1H); (d, 1H); 3.94 (d, 3H); 3.84 (s, 3H); 2.32 (s, 3H)

115

Step 2: 1-[2-Fluoro-4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid 2-Fluoro-3-hydroxy-4-methoxybenzoic acid methyl ester was coupled to 2-m-tolylethanol, the intermediate hydrolyzed, coupled to 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride and the obtained ester hydrolyzed in analogy to steps 1 to 4 of example 1 to yield the title compound.

LC/MS (Method LC7): Rt = 2.74 min; m/z = 444.24 [MH⁺]

Example 70 1-[3-Fluoro-4-methoxy-5-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

The title compound was synthesized in analogy to step 2 of example 69 from 3-fluoro-5hydroxy-4-methoxybenzoic acid methyl ester (prepared in step 1 of example 69). LC/MS (Method LC7): Rt = 2.64 min; m/z = 444.22 [MH⁺]

Example 71

1-(3-(2,2-Difluoro-2-phenyl-ethoxy)-4-methoxy-benzoylamino]-cycloheptanecarboxylic acid

Step 1: Trifluoromethanesulfonic acid 2,2-difluoro-2-phenyl-ethyl ester

2,2-Difluoro-2-phenyl-ethanol (200 mg, 1.27 mmol) was dissolved in DCM (2 ml) and treated at °C with EDIA (0.27 ml, 1.52 mmol) and trifluoromethanesulfonic acid anhydride (0.43 g, 1.52

116 mmol). After completion of the reaction (monitored by TLC (silica gel, DCM/methanol 98:2)), the mixture was partitioned between water and EA. The aqueous phase was extracted with EA, the combined organic phases were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness. This intermediate was used without further purification.

Step 2: 1-(3-(2,2-Difluoro-2-phenyl-ethoxy)-4-methoxy-benzoylamino]-cycloheptanecarboxylic acid methyl ester

To a mixture of 1-(3-hydroxy-4-methoxy-benzoylamino)-cycloheptanecarboxylic acid methyl ester (80 mg, 0.249 mmol) and potassium carbonate (83 mg, 0.60 mmol) in 0.5 ml of acetone and 0.5 ml of DMF was added slowly a solution ofthe compound of step 1 (0.22 g, 0.374 mmol) as solution in acetone. The mixture was stirred for 3 d at room température and then evaporated. The residue was purified by préparative RP HPLC (water/ACN gradient) to give the title compound (87 mg).

LC/MS (Method LC10): Rt = 3.90 min; m/z = 462.12 [MH⁺]

Step 3: 1-[3-(2,2-Difluoro-2-phenyI-ethoxy)-4-methoxy-benzoylamino]-cycloheptanecarboxylic acid

The compound of step 2 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC8): Rt = 2.41 min; m/z = 448.19 [MH⁺]

Example 72

1-[4-Methoxy-3-(3-m-tolyl-propyl)-benzoylamino]-cycloheptanecarboxylic acid

Step 1: 1 -[3-(1,3-Dihydroxy-3-m-tolyl-propyl)-4-methoxy-benzoylamino]-cycloheptanecarboxylic acid methyl ester

3-Acetyl-4-methoxy-benzoic acid methyl ester (150 mg, 0.720 mmol) was dissolved in THF (3 ml), cooled to -78 °C, and a freshly prepared solution of lithium diisopropylamide (obtained by

117 addition of n-butyllithium in n-hexane (0.317 ml, 2.5 M solution) to diisopropylamine (80.1 mg, 0.792 mmol) in THF (3 ml) at 0 °C and stirring for 10 min) was slowly added with stirring. After 10 min, 3-methylbenzaldehyde (86.5 mg, 0.720 mmol) was added at -78 °C. After 30 min at -78 °C, 2 N hydrochloric acid and EA were added, the cooling bath was removed, the mixture was brought to room température. The phases were separated, the aqueous phase was extracted three times with EA, the combined organic phases were dried over sodium chloride, decanted and evaporated to dryness. The residue was dissolved in méthanol (5 ml), sodium borohydride (28.7 mg, 0.761 mmol) was added, and the mixture was stirred at room température for 30 min. The mixture was evaporated to dryness and the residue was purified by silica gel chromatography (HEP/EA gradient) to give 140 mg of the title compound as a mixture of diastereomers.

LC/MS (Method LC13): Rt = 1.32 min; m/z = 353.1 [MNa⁺], 683.2 [2MNa⁺]

Step 2: 4-Methoxy-3-(3-m-tolyl-propyl)-benzoic acid methyl ester

The compound of step 1 (140 mg, 0.424 mmol) was dissolved in éthanol (10 ml), 12 N hydrochloric acid (0.2 ml) and palladium on charcoal (10 %) was added, and the mixture was hydrogenated at a hydrogen pressure of 6 bar at room température overnight. After filtration and évaporation, the residue was purified by silica gel chromatography (HEP/EA gradient) to give 80 mg of the title compound.

¹H-NMR: δ = 7.83 (dd, 1 H); 7.72 (d, 1H); 7.16 (dd, 1H); 7.06 (d, 1H); 7.03-6.96 (m, 3H); 3.85 (s, 3H); 3.80 (s, 3H); 2.65-2.53 (m, 4H); 2.27 (s, 3H); 1.82 (m, 2H)

Step 3: 1-[4-Methoxy-3-(3-m-tolyl-propyl)-benzoylamino]-cycloheptanecarboxylic acid

From the compound of step 2, the title compound was obtained by hydrolysis of the ester group in analogy to example 1 step 2, reaction of the obtained carboxylic acid with 1-aminocycloheptanecarboxylic acid methyl ester hydrochloride in analogy to step 3 of example 1, and hydrolysis of the ester group in analogy to step 4 of example 1.

¹H-NMR: δ = 11.95 (brs, 1H); 8.03 (s, 1H);7.73 (dd, 1H);7.64 (d, 1H); 7.14 (t, 1H); 7.03-6.95 (m, 4H); 3.83 (s, 3H); 2.63-2.55 (m, 4H); 2.27 (s, 3H); 2.12-2.03 (m, 4H); 1.83 (tt, 2H); 1.56-1.45 (m 8H)

Example 73 1-[3-(2-Hydroxy-2-m-tolyl-ethoxy)-4-methoxy-benzoylamino]-cycloheptanecarboxylic acid

118

Step 1: 4-Methoxy~3-(2-oxo-2-m-tolyl-ethoxy)-benzoic acid methyl ester

3-Hydroxy-4-methoxybenzoic acid methyl ester (2.50 g, 13.7 mmol) was dissolved in méthanol (20 ml), potassium carbonate (3.72 g, 27.4 mmol) and 2-bromo-1-m-tolyl-ethanone (2.92 g, 13.7 mmol) were added and the mixture was stirred overnight at room température. The volatiles were evaporated, the crude material was partitioned between EA and water, the aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by préparative RP HPLC (water/ACN gradient) to yield the title compound.

LC/MS (Method LC2): Rt = 1.57 min; m/z = 315.17 [MH⁺]

Step 2:1-[4-Methoxy-3-(2-oxo-2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid ethyl ester

The compound of step 2 was hydrolyzed in analogy to step 2 of example 1, and the carboxylic acid intermediate was coupled to 1-amino-cycloheptanecarboxylic acid ethyl ester hydrochloride in analogy to step 1 of example 3 to yield the title compound.

LC/MS (Method LC2): Rt = 1.74 min; m/z = 468.23 [MH⁺]

Step 3: 1-[3-(2-Hydroxy-2-m-tolyl-ethoxy)-4-methoxy-benzoylamino]-cycloheptanecarboxylic acid

The compound of step 2 was reduced with sodium borohydride in analogy to step 2 of example 53, the ester intermediate purified by RP HPLC (water/ACN gradient) and hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC2): Rt = 1.51 min; m/z = 442.29 [MH⁺]

Example 74

1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohept-4-enecarboxylic acid

1-Amino-cyclohept-4-enecarboxylic acid methyl ester (K. Hammer et al., Tetrahedron 53 (1997), 2309-2322) was coupled to 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid analogy to step 1 of example 3. The ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC1): Rt = 1.76 min; m/z = 424.29 [MH⁺]

Example 75

4-[4-Methyl-3-(2-m-tolyl-ethoxy)-benzoylamino]-bicyclo[5.1.0]octane-4-carboxylic acid

1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohept-4-enecarboxylic acid methyl ester (0.418 g, 0.955 mmol) was dissolved in toluene (4.5 ml), diethylzinc (2.86 mmol, 1.5 M solution in toluene) was added and the mixture was warmed to 60 °C. Diiodomethane (1.16 g, 4.30 mmol) was added dropwise and the mixture was stirred ovemight at 60 °C. The addition of diethyl zinc and diiodomethane was repeated until completion ofthe reaction. The mixture was partitioned between EA and 2 N hydrochloric acid, the aqueous phase extracted with EA, and the combined organic phases were dried over sodium sulfate and evaporated to dryness. The obtained ester was hydrolyzed in analogy to step 4 of example 1. The title compound was purified by préparative RP HPLC (water/ACN gradient).

LC/MS (Method LC4): Rt = 1.32 min; m/z = 438.35 [MH⁺]

Example 76 1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-3-methyl-cyclobutanecarboxylic acid

120

Step 1: 1-Amino-3-methyl-cyclobutanecarboxylic acid ethyl ester hydrochloride 3-Methyl-cyclobutane-1,1-dicarboxylic acid ethyl ester (V. Prelog et al., Helv. Chim. Acta 65 (1982), 2622-2644; 200 mg, 1.074 mmol) was suspended in acetone (20 ml) and stirred in an ice bath. Triethylamine (152 mg, 1.50 mmol) and isobutyl chloroformate (191 mg, 1.40 mmol) were added, the mixture was stirred at 0 °C for 30 min, then sodium azide (129 mg, 1.99 mmol) as solution in water (10 ml) was added, and stirring was continued for 15 min. Then diethyl ether (50 ml) was added, the phases were separated. The organic layer was washed with water, dried over sodium sulfate, filtered and added to refluxing toluene in a flask with distillation bridge. The toluene solution was refluxed for 4 h, the volatiles were evaporated in vacuo, the residue was dissolved in dioxane, 2 N hydrochloric acid was added in excess, and the mixture was stirred until the isocyanate was completely decomposed (approximately 20 min). The volatiles were evaporated and the obtained amino acid ester hydrochloride was used without further purification.

Step 2: 1-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-3-methyl-cyclobutanecarboxylic acid The compound of step 1 (65 mg, 0.413 mmol) was coupled to 4-methoxy-3-(2-m-tolyl-ethoxy)benzoic acid in analogy to step 1 of example 3. The ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound as mixture ofthe cis isomer and the trans isomer.

¹H-NMR: δ = 12.2 (s, 1H); 8.75/8.70 (2 s, 1H); 7.55-7.45 (m, 2H); 7.23-7.11 (m, 3H); 7.08-6.98 (m, 2H); 4.23-4.14 (m, 2H); 3.81 (2s, 3H); 3.02 (t, 2H); 2.73-2.68 (m, 1 H); 2.55-2.25 (m, 5H, therein 2.29 (s, 3H)); 2.20-2.12 (m, 1H); 1.90-1.80 (m, 1H); 1.05 (d, 3H)

Example 77 1-{[6-Methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-cycloheptanecarboxylic acid

121

6-Chloro-5-nitro-nicotinic acid methyl ester was prepared according to the procedure described in WO 2005/021544 and transformed into 5-hydroxy-6-methoxy-nicotinic acid methyl ester according to the procedure described in WO 95/04045. The intermediate was transformed into the title compound by éthérification with 2-m-tolyl-ethanol in analogy to step 1 of example 1, hydrolysis of the ester group in analogy to step 2 of example 1, reaction of the obtained carboxylic acid with 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride in analogy to step 3 of example 1 and hydrolysis in analogy to step 4 of example 1.

¹H-NMR: δ = 12.0 (s, 1H); 8.21 (d, 1H); 8.20 (s, 1H); 7.63 (d, 1H); 7.23-7.17 (m, 2H); 7.12 (d, 1H); 7.03 (d, 1 H); 4.23 (t, 2H); 3.91 (s, 3H); 3.02 (t, 2H); 2.29 (s, 3H); 2.13-2.00 (m, 4H); 1.551.45(m, 8H)

Example 78

1-{[6-Methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-cyclooctanecarboxylic acid

The title compound was synthesized in analogy to example 77 using 1-aminocyclooctanecarboxylic acid methyl ester hydrochloride instead of 1-aminocycloheptanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC9): Rt = 3.66 min; m/z = 441.19 [MH⁺]

Example 79 cis-1-{[6-Methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-4-methylcyclohexanecarboxylic acid

122

The title compound was synthesized in analogy to example 77 using cis-1-amino-4-methylcyclohexanecarboxylic acid methyl ester hydrochloride (prepared in analogy to example 25) instead of 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride.

¹H-NMR: δ = 12.2 (s, 1H); 8.23 (s, 1 H); 8.11 (s, 1H); 7.61 (s, 1H); 7.22-7.15 (m, 2H); 7.12 (d, 1H); 7.03 (d, 1H); 4.26 (t, 2H); 3.91 (s, 3H); 3.02 (t, 2H); 2.30-2.22 (m, 5H, therein 2.28 (s, 3H));

1.70-1.61 (m, 2H); 1.54-1.48 (m, 2H); 1.42-1.32 (m, 1H); 1.25-1.12 (m, 2H); 0.88 (d, 3H)

Example 80 trans-1-{[6-Methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-4-methylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 77 using trans-1-amino-1cyclohexanecarbonitrile (step 1 of example 43) instead of 1-amino-cyc!oheptanecarboxylic acid methyl ester hydrochloride and hydrolysis ofthe carbonitrile in analogy to example 43, steps 2 and 3.

¹H-NMR: δ = 12.1 (s, 1H); 8.22 (s, 1H); 8.20 (s, 1H); 7.62 (s, 1 H); 7.22-7.15 (m, 2H); 7.12 (d, 1H); 7.05 (d, 1 H); 4.22 (t, 2H); 3.91 (s, 3H); 3.04 (t, 2H); 2.31-2.24 (m, 5H, therein 2.28 (s, 3H)); 1.62-1.53 (m, 4H); 1.51-1.40 (m, 1H); 1.32-1.22 (m, 2H); 0.88 (d, 3H)

Example 81

123 trans-1-({5-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4methyl-cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 80 using 2-(5-chloro-2-fluorophenyl)-ethanol in the éthérification step.

LC/MS (Method LC1): Rt = 1.81 min; m/z = 464.16 [MIT]

Example 82 trans-1-({5-[2-(2-Fluoro-5-trifluoromethoxy-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}amino)-4-methyl-cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 80 using 2-(2-fluoro-5trifluoromethoxy-phenyl)-ethanol in the éthérification step.

LC/MS (Method LC4): Rt = 1.31 min; m/z = 513.76 [MH*]

Example 83 trans-1-{[6-Methoxy-5-(2-phenyl-ethoxy)-pyridine-3-carbonyl]-amino}-4-methylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 80 using 2-phenyl-ethanol in the éthérification step.

LC/MS (Method LC4): Rt = 1.27 min; m/z = 413.24 [MH⁺]

Example 84 trans-1-({5-[2-(2,5-Dimethyl-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 80 using 2-(2,5-dimethyl-phenyl)ethanol in the éthérification step.

LC/MS (Method LC4): Rt = 1.34 min; m/z = 441.26 [MH⁺]

Example 85 trans-1-({5-[2-(3-chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 80 using 2-(3-chloro-phenyl)ethanol in the éthérification step.

LC/MS (Method LC4): Rt = 1.31 min; m/z = 447.18 [MH⁺]

Example 86 cis-1-({5-[2-(2,5-Dimethyl-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 79 using 2-(2,5-dimethyl-phenyl)ethanol in the éthérification step.

LC/MS (Method LC4): Rt = 1.34 min; m/z = 441.3 [MH⁺]

Example 87

1-({5-[2-(2,5-Dimethyl-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)cycloheptanecarboxylic acid

126

The title compound was synthesized in analogy to example 77 using 2-(2,5-dimethyl-phenyl)ethanol in the éthérification step.

LC/MS (Method LC4): Rt = 1.33 min; m/z = 439.29 [M-H⁺]

Example 88

1-{[5-(2-Phenyl-ethoxy)-6-methoxy-pyridine-3-carbonyl]-amino}-cycloheptanecarboxylic acid

The title compound was synthesized in analogy to example 77 using 2-phenyl-ethanol in the éthérification step.

LC/MS (Method LC4): Rt = 1.26 min; m/z = 413.3 [MH⁺]

Example 89 trans-4-tert-Butyl-1-{[6-methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid

H

127

The title compound was synthesized in analogy to example 80 using 1-amino-4-tert-butylcyclohexanecarbonitrile in the amide coupling step.

LC/MS (Method LC4): Rt = 1.36 min; m/z = 469.4 [MH⁺]

Example 90 trans-1-[(5-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-4methyl-cyclohexanecarboxylic acid

5-Hydroxy-6-methoxy-nicotinic acid methyl ester was etherified with 2-[3-(2-hydroxy-ethyl)phenyl]-ethanol in analogy to step 1 of example 1. Hydrolysis of the ester group in analogy to step 2 of example 1, coupling ofthe obtained carboxylic acid to trans-1-amino-4-methylcyclohexanecarboxylic acid methyl ester hydrochloride in analogy to step 1 of example 3 and hydrolysis of the methyl ester in analogy to step 4 of example 1 yielded the title compound. LC/MS (Method LC1 ): Rt = 1.53 min; m/z = 457.24 [MH*]

Example 91 cis-1-[(5-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-4methyl-cyclohexanecarboxylic acid

128

The title compound was synthesized in analogy to example 90 using cis-1-amino-4-methylcyclohexanecarboxylic acid methyl ester hydrochloride instead of trans-1-amino-4-methylcyclohexanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.16 min; m/z = 457.37 [MH⁺]

Example 92 1-{[5-(3-Cyano-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-cycloheptanecarboxylic acid

CN

Step 1: 5-Bromo-6-methoxy-nicotinic acid

5-Bromo-6-methoxy-nicotinic acid methyl ester (W. J. Thompson et al., J. Org. Chem. 49 (1984), 5237-5243; 2.00 g, 8.13 mmol) was dissolved in dioxane (40 ml), lithium hydroxide (40 ml of a 1 M solution in water) was added and subsequently sufficient méthanol to achieve complété dissolution. The mixture was stirred at 60 °C for 2 h. The méthanol was evaporated in vacuo and the remaining mixture was acidified with 2 N hydrochloric acid and extracted with EA. The combined extracts were dried over sodium sulfate, filtered and evaporated to dryness to yield the title compound.

¹H-NMR: δ = 13.3 (s, 1H); 8.68 (d, 1H); 8.35 (d, 1H); 4.01 (s, 3H)

Step 2: 1-{[5-Bromo-6-methoxy-pyridine-3-carbonyl]-amino}-cycloheptanecarboxylic acid methyl ester

The compound of step 1 (1.85 g, 7.97 mmol) was dissolved in thionyl chloride (6 ml) and stirred for 30 min at 60 °C. The volatiles were evaporated in vacuo, the residue was dissolved in DCM and added to a stirred mixture of 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride, EA and saturated sodium hydrogencarbonate solution with ice cooling. The mixture was stirred at room température overnight, the phases were separated and the aqueous phase was extracted with EA. The combined organic phases were dried over sodium sulfate and evaporated to dryness to yield the title compound (2.80 g).

¹H-NMR: δ = 8.62 (d, 1 H); 8.52 (s, 1 H); 8.48 (d, 1H); 3.99 (s, 3H); 3.57 (s, 3H); 2.15-2.01 (m, 4H); 1.65-1.43 (m, 8H)

129

Step 3: 1-{[5-(3-Cyano-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-cycloheptanecarboxylic acid methyl ester

The compound of step 2 (300 mg, 0.779 mmol), 3-cyano-phenylboronic acid (171 mg, 1.17 mmol), tris(dibenzyiideneacetone)dipaliadium(0) (214 mg, 0.234 mmol), potassium fluoride (149 mg, 2.57 mmol) and tri-tert-butylphosphonium tetrafluoroborate (136 mg, 0.47 mmol) in aflask were thoroughly flushed with argon, dioxane (3 ml) was added and the mixture was stirred for 2 h at 50 °C. The mixture was filtered over silica gel and evaporated to dryness. This residue was purified by RP HPLC (water/ACN gradient) to yield 200 mg of the title compound.

LC/MS (Method LC9): Rt = 3.44 min; m/z = 408.6 [MH⁺]

Step 4: 1-{[5-(3-Cyano-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-cycloheptanecarboxylic acid

The compound of step 3 was hydrolyzed in analogy to step 4 of example 1 at a hydrolysis température of 40 °C. The residue obtained after évaporation of the EA extracts was purified by RP HPLC (water/ACN gradient) to yield the title compound.

¹H-NMR: δ = 12.1 (s, 1H); 8.68 (d, 1H); 8.32 (s, 1H); 8.24 (d, 1H); 8.09 (s, 1H); 7.96 (d, 1H); 7.88 (d, 1H); 7.69 (t, 1H); 3.95 (s, 3H); 2.15-2.04 (m, 4H); 1.60-1.45 (m, 8H) ln analogy to example 92, the example compounds of the formula I-4 listed in table 4 were prepared by using the respective substituted phenylboronic acid instead of 3-cyanophenylboronic acid. The compounds of the formula I-4 listed in table 4 can be named as 1-[(5R¹⁰⁴-6-methoxy-pyridine-3-carbonyl)-amino]-cycloheptanecarboxylic acid, for example as 1-{[5(3-chloro-phenyl)-6-methoxy-pyridyl-3-carbonyl]-amino}-cycloheptanecarboxylic acid in the case of example 94.

130

Table 4. Example compounds oftheformula I-4

Example	R104	LC/MS Method	m/z	Rétention time [min]
93	3-dimethylaminosulfonylaminophenyl	LC9	491.17 [MH+]	2.99
94	3-chloro-phenyl	LC9	403.16 [MH+]	3.44
95	3-isopropyl-phenyl	LC5	409.22 [M-H]’	5.04
96	3-trifluoromethoxy-phenyl	LC4	453.22 [MH+]	1.34
97	2,3-dichloro-phenyl	LC4	437.16 [MH+]	1.32
98	3,4,5-trifluoro-phenyl	LC4	423.2 [MH+]	1.33
99	3-chloro-5-trifluoromethyl-phenyl	LC4	471.2 [MH+]	1.39
100	3-trifluoromethyl-phenyl	LC4	437.23 [MH+]	1.34

Example 101

1-{[5-(3-Chloro-4-methoxy-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}5 cycloheptanecarboxylic acid

The compound can be prepared in analogy to example 92.

Example 102

1-{[5-(2-Fluoro-3-trifluoromethyl-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}cycloheptanecarboxylic acid

The compound can be prepared in analogy to example 92.

In analogy to example 92, the example compounds ofthe formula I-5 listed in table 5 were prepared by synthesizing the intermediate 1-(3-bromo-4-methoxy-benzoylamino)cycloheptanecarboxylic acid methyl ester in analogy to step 2 of example 92 using 3-bromo-4methoxybenzoic acid instead of 5-bromo-6-methoxy-nicotinic acid. The intermediate was transformed into the example compounds in analogy to example 92, steps 3 and 4, using the appropriate phenylboronic acid. The compounds can be named as 1-[(substituted biphenyl-3carbonyl)-amino]-cycloheptanecarboxylic acid, for example as 1-[(3'-cyano-6-methoxy-biphenyl3-carbonyl)-amino]-cycloheptanecarboxylic acid in the case of example 104 in which the group R¹⁰⁵ is 3-chloro-phenyl and the group 3-(R¹⁰⁵)-4-methoxy-phenyl-C(O) depicted in formula I-5 thus is the group 3’-cyano-6-methoxy-biphenyl-3-carbonyl.

Table 5. Example compounds ofthe formula I-5

Example	R105	LC/MS Method	m/z [MH+]	Rétention time [min]
103	3-dimethylaminosulfonylamino-phenyl	LC10	490.27	3.29
104	3-chloro-phenyl	LC9	402.14	3.49
105	3-isopropyl-phenyl	LC10	410.29	3.93

132

Example	R105	LC/MS Method	m/z [MH+]	Rétention time [min]
106	3-cyano-phenyl	LC9	393.17	3.28

Example 107

1-(3-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-cycloheptanecarboxylic acid

Step 1: 3-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoic acid 2-[3-(2-Hydroxy-ethyl)-phenyl]-ethanol and 3-hydroxy-4-methoxybenzoic acid methyl ester were coupled in analogy to step 1 of example 1 and the methyl ester was hydrolyzed in analogy to step 2 of example 1 to yield the title compound.

LC/MS (Method LC9): Rt = 2.69 min; m/z = 317.18 [MH⁺]

Step 2: 1-(3-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)cycloheptanecarboxylic acid methyl ester

The compound of step 1 (280 mg, 0.885 mmol) was dissolved in DMF (1.3 ml) and HOBT (24 mg), 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride (221 mg, 1.06 mmol) and EDIA (578 mg, 4.43 mmol) were added. The mixture was cooled in an ice bath and EDC (254 mg, 1.33 mmol) was added. The mixture was stirred at room température for 3 days and partitioned between EA and water. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield the title compound (120 mg).

LC/MS (Method LC9): Rt = 3.29 min; m/z = 470.25 [MH⁺]

Step 3: 1-(3-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)cycloheptanecarboxylic acid

133

The compound of step 2 was hydrolyzed in analogy to step 4 of example 1 to yield the title compound (89 mg).

¹H-NMR: δ = 12.0 (s, 1H); 8.07 (s, 1H); 7.50 (dd, 1H); 7.40 (s, 1H); 7.23-7.18 (m, 2H); 7.15 (d, 1H); 7.06 (d, 1H); 7.01 (d, 1H); 4.61 (t, 1 H); 4.21 (t, 2H); 3.80 (s, 3H); 3.59 (dt, 2H); 3.02 (t, 2H); 2.70 (t, 2H); 2.12-2.02 (m, 4H); 1.57-1.42 (m, 8H)

Example 108

1-(3-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-cyclooctanecarboxylic acid

The title compound was synthesized in analogy to example 107 using 1-aminocyclooctanecarboxylic acid methyl ester hydrochloride instead of 1-aminocycloheptanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC9): Rt = 3.21 min; m/z = 470.25 [MH⁺]

Example 109 cis-1-(3-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)-4-methylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 107 using cis-1-amino-4-methylcyclohexanecarboxylic acid methyl ester hydrochloride instead of 1-aminocycloheptanecarboxylic acid methyl ester hydrochloride.

134

LC/MS (Method LC4): Rt = 1.21 min; m/z = 456.34 [MIT]

Example 110 trans-1-(3-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}~4-methoxy-benzoylamino)-4-methylcyclohexanecarboxylic acid

H

The title compound was synthesized in analogy to example 107 using trans-1-amino-4-methylcyclohexanecarboxylic acid methyl ester hydrochloride instead of 1-aminocycloheptanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.21 min; m/z = 456.33 [MIT]

Example 111 cis-4-Ethyl-1-(3-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)cyclohexanecarboxylic acid

OH

The title compound was synthesized in analogy to example 107 using cis-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloride instead of 1-aminocycloheptanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.25 min; m/z = 470.36 [MH⁺]

Example 112

135 trans-4-Ethyl-1-(3-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino)cyclohexanecarboxylic acid

OH

The title compound was synthesized in analogy to example 107 using trans-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloride instead of 1-aminocycloheptanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC3): Rt = 4.30 min; m/z = 470.36 [MH⁺]

Example 113 cis-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-methoxy-ethoxy)-benzoylamio]-4-methylcyclohexanecarboxylic acid

Cl

Step 1: 3-Acetoxy-4-hydroxy-benzoic acid ethyl ester 3,4-Dihydroxy-benzoic acid ethyl ester (550 mg, 3.02 mmol) was dissolved in DMF (5 ml), potassium tert-butylate (210 mg, 2.87 mmol) was added and the mixture stirred for 10 min. Acetic anhydride (339 mg, 3.32 mmol) was added and stirring continued for 10 min. The mixture was partitioned between EA and 2 N hydrochloric acid, the aqueous phase extracted with EA, the combined organic phases were dried over sodium chloride, decanted and evaporated to dryness. The residue was purified by RP HPLC (water/ACN gradient) to yield the title compound.

¹H-NMR: δ = 10.6 (s, 1H); 7.71 (dd, 1H); 7.58 (d, 1H); 7.00 (d, 1H); 4.25 (q, 2H); 2.27 (s, 3H); 1.29 (t, 3H)

136

Step 2: 3-Acetoxy-4-benzyloxy-benzoic acid ethyl ester

The compound of step 1 (20 g, 89.2 mmol) was dissolved in DMF (100 ml) and cooled in an ice bath. Potassium carbonate (18.4 g, 134 mmol) and, immediately thereafter, benzyl bromide (15.2 g, 89.2 mmol) were added. This mixture was stirred for 30 min at room température, poured on a mixture of 2 N hydrochloric acid and diethyl ether, filtered and washed repeatedly with diethyl ether. The combined ethereal phases were washed with water, dried over sodium chloride, decanted and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield the title compound (21 g).

¹H-NMR: δ = 7.82 (dd, 1H); 7.67 (d, 1H); 7.43-7.37 (m, 5H); 7.30 (d, 1H); 5.24 (s, 2H); 4.27 (q, 2H); 2.26 (s, 3H); 1.30 (t, 3H)

Step 3: 4-Benzyloxy-3-hydroxy-benzoic acid ethyl ester

The compound of step 2 (10 g, 31.8 mmol) was dissolved in methanol, potassium carbonate (88 mg, 0.636 mmol) was added and the mixture was stirred for 2 h under reflux. The solution was evaporated to dryness and the residue used without further purification.

¹H-NMR: δ = 9.7 (brs, 1H); 7.48 (d, 2H); 7.42-7.30 (m, 5H); 7.06 (d, 1H); 5.19 (s, 2H); 4.22 (q, 2H); 1.28 (t, 3H)

Step 4: 4-Benzyloxy-3-[2-(3-chloro-phenyl)-ethoxy]-benzoic acid ethyl ester

The compound of step 3 was coupled to 2-(3-chloro-phenyl)-ethanol in analogy to step 1 of example 1 to yield the title compound.

¹H-NMR: δ = 7.57 (dd, 1H); 7.49-7.24 (m, 10H); 7.17 (d, 1H); 5.17 (s, 2H), 4.31-4.21 (m. 4H); 3.06 (t, 2H); 1.29 (t, 3H)

Step 5: 4-Benzyloxy-3-[2-(3-chloro-phenyl)-ethoxy]-benzoic acid

The compound of step 4 was hydrolyzed in analogy to step 2 of example 1 to yield the title compound.

¹H-NMR: δ = 12.7 (s, 1H); 7.53 (dd, 1H); 7.48-7.26 (m, 9H); 7.12 (d, 1H); 5.17 (s, 2H); 4.26 (t, 2H); 3.07 (t, 2H)

Step 6: cis-1 -{4-Benzyloxy-3-[2-(3-chloro-phenyl)-ethoxy]-benzoylamino}-4-methylcyclohexanecarboxylic acid methyl ester

The compound of step 5 was coupled to cis-1-amino-4-methyl-cyclohexanecarboxylic acid methyl ester hydrochloride in analogy to step 2 of example 64 to yield the title compound.

137 ¹H-NMR: δ = 8.12 (s, 1H); 7.49-7.25 (m, 11 H); 7.08 (d, 1H); 5.12 (s, 2H); 4.28 (t, 2H); 3.55 (s, 3H); 3.08 (t, 2H); 2.22 (d, 2H); 1.69-1.59 (m, 2H); 1.53-1.44 (m, 2H); 1.41-1.30 (m, 1H); 1.241.12 (m, 2H); 0.87 (d, 3H)

Step 7: cis-1-{3-[2-(3-Chloro-phenyl)-ethoxy]-4-hydroxy-benzoylamino}-4-methylcyclohexanecarboxylic acid methyl ester

The compound of step 6 (410 mg, 0.765 mmol) was dissolved in methanol (3 ml), cooled in an acetone/dry ice bath, and acetyl chloride ( 2.7 ml, 38.2 mmol) was added with stirring. This mixture was stirred for 72 h at room température and evaporated to dryness.

¹H-NMR: δ = 9.58 (s, 1H); 8.01 (s, 1H); 7.49-7.27 (m, 6H); 6.82 (d, 1H); 4.22 (t, 2H); 3.55 (s, 3H); 3.08 (t, 2H); 2.26-2.19 (m, 2H); 1.68-1.59 (m, 2H); 1.52-1.48 (m, 2H); 1.42-1.32 (m, 1 H); 1.23-1.12 (m, 2H); 0.85 (d, 3H)

Step 8: cis-1 -[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-methoxy-ethoxy)-benzoylamino]-4-methylcyclohexanecarboxylic acid methyl ester

The compound of step 7 (150 mg, 0.337 mmol) was dissolved in DMF (7 ml), and potassium carbonate (233 mg, 1.68 mmol) and 2-bromoethyl methyl ether (70 mg, 0.51 mmol) were added subsequently. The mixture was stirred for 48 h and then partitioned between water and EA. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness to yield the title compound (145 mg).

¹H-NMR: δ = 8.11 (s, 1H); 7.48-7.26 (m, 6H); 7.02 (d, 1H); 4.29-4.20 (m, 2H); 4.13 (t, 2H); 3.69 (t, 2H); 3.56 (s, 3H); 3.30 (s, 3H); 3.08 (t, 2H); 2.27-2.20 (m, 2H); 1.69-1.61 (m, 2H); 1.53-1.49 (m, 2H); 1.42-1.33 (m, 1H); 1.25-1.15 (m, 2H); 0.88 (d, 3H)

Step 9: cis-1 -[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-methoxy-ethoxy)-benzoylamio]-4-methylcyclohexanecarboxylic acid

The compound of step 8 was hydrolyzed on analogy to step 4 of example 1.

¹H-NMR: δ = 12.1 (brs, 1H); 7.98 (s, 1H); 7.49-7.38 (m, 3H); 7.37-7.21 (m, 3H);

7.02 (d, 1H); 4.23 (t, 2H); 4.11 (t, 2H); 3.68 (t, 2H); 3.32 (s, 3H); 3.08 (t, 2H); 2.28 (d, 2H); 1.681.59 (m, 2H); 1.51 (d, 2H); 1.42-1.32 (m, 1H); 1.24-1.12 (m, 2H); 0.86 (d, 3H)

In analogy to example 113, the compounds of examples 114 and 115 were synthesized using the respective amino acid methyl ester hydrochloride in the amide coupling step 6.

Example 114

138 trans-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-methoxy-ethoxy)-benzoylamino]-4-methylcyclohexanecarboxylic acid

¹H-NMR: δ = 12.0 (s, 1H); 8.09 (s, 1H); 7.48-7.38 (m, 3H); 7.36-7.24 (m, 3H); 7.01 (d, 1H); 4.21 (t, 2H); 4.11 (dd, 2H); 3.68 (dd, 2H); 3.32 (s, 3H); 3.07 (t, 2H); 2.30-2.22 (m, 2H); 1.65-1.51 (m,

4H); 1,50-1.38 (m, 1H); 1.32-1.19 (m, 2H); 0.89 (d, 3H)

Example 115

1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-methoxy-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

¹H-NMR: δ = 11.98 (s, 1H); 8.07 (s, 1H); 7.50-7.42 (m, 2H); 7.41 (s, 1H); 7.38-7.25 (m, 3H); 7.01 (d, 1H); 4.22 (t, 2H); 4.11 (dd, 2H); 3.69 (dd, 2H); 3.30 (s, 3H); 3.07 (t, 2H); 2.12-2.02 (m, 4H); 1.60-1-42 (m, 8H)

In analogy to example 113, the compounds of examples 116 to 118 were synthesized using the respective alcohol in the éthérification step 4 and the respective amino acid methyl ester hydrochloride in the amide coupling step 6. In step 7, cleavage of the benzyl ether was accomplished by dissolution ofthe starting material in méthanol, addition of palladium on charcoal (10 %), hydrogénation under 1 bar hydrogen pressure for 1 h, filtration and évaporation to dryness.

139

Example 116

1-[4-(2-Methoxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

¹H-NMR: δ = 11.9 (s, 1H); 8.07 (s, 1H); 7.46 (dd, 1H); 7.41 (s, 1H); 7.19-7.11 (m, 3H); 7.02 (t,

2H); 4.19 (t, 2H); 4.11 (t, 2H); 3.68 (t, 2H); 3.31 (s, 3H); 3.00 (t, 2H); 2.29 (s, 3H); 2.10-2.00 (m,

4H); 1.58-1.42 (m, 8H)

Exampie 117 trans-1-[4-(2-Methoxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylic acid

¹H-NMR: δ = 12.00 (s, 1H); 8.08 (s, 1H); 7.44 (dd, 1 H); 7.40 (d, 1H); 7.20-7.11 (m, 3H); 7.01 (d, 1H); 6.99 (d, 1H); 4.20 (t, 2H); 4.11 (ddd, 2H); 3.68 (ddd, 2H); 3.30 (s, 3H); 3.00 (t, 2H); 2.30 (s, 3H); 2.30-2.23 (m, 2H); 1.62-1.52 (m, 4H); 1.50-1.41 (m, 1H); 1.31-1.20 (m, 2H); 0.89 (d, 3H)

Example 118 cis-1-[4-(2-Methoxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylic acid

140

¹H-NMR: δ = 12.1 (s, 1H); 7.99 (s, 1H); 7.46 (dd, 1H); 7.41 (s, 1H); 7.20-7.11 (m, 3H); 7.02 (d, 2H); 4.21 (t, 2H); 4.11 (ddd, 2H); 3.68 (ddd, 2H); 3.30 (s, 3H); 3.01 (t, 2H); 2.29 (s, 3H); 2.272.22 (m, 2H); 1.69-1.59 (m, 2H); 1.53-1.47 (m, 2H); 1.42-1.31 (m, 1H); 1.22-1.12 (m, 2H); 0.87 (d, 3H)

Example 119 cis-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-4-methylcyclohexanecarboxylic acid

The title compound of step 7 of example 113 (150 mg, 0.337 mmol) was reacted in analogy to step 8 of example 113 using 2-bromoethyl acetate as alkylating agent, followed by hydrolysis in analogy to step 4 of example 1 to yield the title compound.

¹H-NMR: δ = 12.1 (s, 1 H); 7.97 (s, 1 H); 7.51-7.27 (m, 6H); 7.03 (d, 1H); 4.85 (t, 1H); 4.25 (t, 2H); 4.07-3.99 (m, 2H); 3.78-3.70 (m, 2H); 3.08 (t, 2H); 2.28 (d, 2H); 1.70-1.57 (m, 2H); 1.53-1.42 (m, 2H); 1.42-1.31 (m, 1H); 1.23-1.11 (m, 2H); 0.88 (d, 3H)

In analogy to example 119, the compounds of examples 120 and 121 were synthesized using the respective amino acid methyl ester hydrochloride in the amide coupling step.

Example 120 trans-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-4-methylcyclohexanecarboxylic acid

141

¹H-NMR: δ = 12.0 (s, 1H); 8.08 (s, 1H); 7.49-7.26 (m, 6H); 7.02 (d, 1H); 4.82 (t, 1H); 4.22 (t, 2H); 4.02 (t, 2H); 3.80-3.70 (m, 2H); 3.08 (t, 2H); 2.29 (d, 2H); 1.63-1.40 (m, 4H); 1.32-1.18 (m, 3H); 0.88 (d, 3H)

Example 121

1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-cycloheptane-carboxylic acid

¹H-NMR: δ = 12.0 (s, 1H); 8.08 (s, 1H); 7.50-7.25 (m, 6H); 7.02 (d, 1H); 4.82 (t, 1H); 4.22 (t, 2H); 4.01 (t, 2H); 3.78-3.70 (m, 2H); 3.09 (t, 2H); 2.12-2.02 (m, 4H); 1.58-1.42 (m, 8H)

In analogy to example 119, the compounds of examples 122 to 124 were synthesized using 2m-tolyl-ethanol in the ether coupling step 4 of example 113 and the respective amino acid methyl ester hydrochloride in the amide coupling step 6. In step 7, cleavage of the benzyl ether was accomplished by dissolution of the starting material in méthanol, addition of palladium on charcoal (10 %), hydrogénation under 1 bar hydrogen pressure for 1 h, filtration and évaporation to dryness.

Example 122 trans-1-[4-(2-Hydroxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methylcyclohexanecarboxylic acid

142

¹H-NMR: δ = 12.0 (s, 1H); 8.08 (s, 1H); 7.46-7.38 (m, 2H); 7.20-7.11 (m, 3H); 7.03-6.99 (m, 2H);

4.84 (t, 1H); 4.19 (t, 2H); 4.01 (t, 2H); 3.72 (dt, 2H); 3.00 (t. 2H); 2.30 (s, 3H); 2.29-2.21 (m, 2H);

1.61-1.51 (m, 4H); 1.51-1.39 (m, 1H); 1.30-1.18 (m, 2H); 0.88 (d, 3H)

Example 123 cis-1-[4-(2-Hydroxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-methyl-cyclohexanecarboxylic acid

¹H-NMR: δ = 12.1 (s, 1H); 7.97 (s, 1H); 7.48 (dd, 1H); 7.39 (d, 1 H); 7.19-7.11 (m, 3H); 7.02 (d,

2H); 4.82 (t, 1H); 4.21 (t, 2H); 4.02 (t, 2H); 3.72 (dt, 2H); 3.01 (t, 2H); 2.29 (s, 3H); 2.29-2.22 (m,

2H); 1.68-1.59 (m, 2H); 1.51-1.44 (m, 2H); 1.41-1.31 (m, 1H); 1.21-1.11 (m, 2H); 0.88 (d, 3H)

Example 124

1-[4-(2-Hydroxy-ethoxy)-3-(2-m-tolyl-ethoxy)-benzoylamino]-cycloheptanecarboxylic acid

¹H-NMR: δ = 12.0 (s, 1 H); 8.08 (s, 1H); 7.47 (dd, 1H); 7.60 (d, 1H); 7.21-7.12 (m, 3H); 7.05-7.00 (m, 2H); 4.82 (t, 1H); 4.20 (t, 1H); 4.01 (t, 2H); 3.72 (dt, 2H); 2.99 (t, 2H); 2.29 (s, 3H); 2.11-2.00 (m, 4H); 1.57-1.42 (m, 8H)

Example 125 cis-1-[(3'-Chloro-4'-methoxy-6-trifluoromethyl-biphenyl-3-carbonyl)-amino]-4-ethylcyclohexanecarboxylic acid

Step 1: 3'-Chloro-4'-methoxy-6-trifluoromethyl-biphenyl-3-carboxylic acid

3-Bromo-4-trifluoromethyl-benzoic acid (0.484 g, 1.80 mmol), 3-chloro-4-methoxy-phenylboronic acid (0.503 g, 2.70 mmol), tri-tert-butylphosphonium tetrafluoroborate (0.313 g, 1.08 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.494 g, 0.54 mmol) and potassium fluoride (0.345 g, 5.93 mmol) were weighed into a flask and dioxane (10 ml) was added under argon, and the mixture was stirred for 24 h at 50 °C. The mixture was filtered over celite and evaporated to dryness. The residue was purified by préparative RP HPLC (water/ACN gradient) to yield the title compound.

Step 2: cis-1-[(3'-Chloro-4'-methoxy-6-trifluoromethyl-biphenyl-3-carbonyl)-amino]-4-ethylcyclohexanecarboxylic acid

144

The compound of step 1 was coupled with cis-1-amino-4-ethy)-cyclohexanecarboxylic acid methyl ester hydrochloride in analogy to step 1 of example 3 and hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC4): Rt = 1.39 min; m/z = 484.31 [MH⁺]

Example 126 (1R,2S,4S)-2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2carboxylic acid and (1S,2R,4R)-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxabicyclo[2.2.1 ]heptane-2-carboxylic acid

Step 1 : Spiro[imidazolidine-2,4-dione-5,2'-7-oxabicyclo[2.2.1]heptane]

27.6 g of ammonium carbonate were dissolved in 200 ml of water and 200 ml of éthanol. 12.4 g of 7-oxa-bicyclo[2.2.1]heptan-2-one (A. Warm et al., Helv. Chim. Acta 70 (1987), 690-700) were added and the mixture was stirred at 50 °C for 4 h. Then a solution of 7.2 g of potassium cyanide in 55 ml of water and 55 ml of éthanol was added and the mixture stirred at 50 °C for 16 h. Afterwards the mixture was concentrated to a volume of about 100 ml, 3 g of sodium chloride were added and the mixture was stirred at room température for 2 h. The precipitate was filtered off, washed with water and dried to yield 10.4 g ofthe title compound as a racemic mixture.

Step 2: 2-Amino-7-oxa-bicycIo[2.2.1]heptane-2-carboxylic acid

9.0 g of spiro[imidazolidine-2,4-dione-5,2'-7-oxabicyclo[2.2.1]heptane] and 77.9 g of barium hydroxide octahydrate were dissolved in 135 ml of water, divided into 9 portions and treated under microwave irradiation at 190 °C for 30 min. The pooled mixture were diluted with 300 ml of water, heated to 90 °C and the precipitate was filtered off by suction. Then 4.5 g of ammonium carbonate were added to the filtrate and the mixture was heated to 90 °C. 50 g of solid carbon dioxide were then added and the mixture was stirred at 90 °C for 10 min. The

145 precipitated barium carbonate was filtered off by suction. Then another 50 g of solid carbon dioxide were added to the filtrate and the mixture was stirred at 50 °C for 1 h. The precipitated barium carbonate was filtered off by suction. The filtrate was evaporated in vacuo to yield 6.3 g ofthe title compound as a racemic mixture.

Step 3: 2-Amino-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester

3.0 g of 2-amino-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid were suspended in 100 ml of methanol and 11.4 g of thionyl chloride were added at room température. The mixture was left at room température for 24 h. Then the volatiles were evaporated in vacuo to yield 3.9 g ofthe title compound as a racemic mixture.

LC/MS (Method LC6): Rt = 0.53 min; m/z = 172.21 [MH⁺]

Step 4: 2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2carboxylic acid methyl ester)

550 mg of 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 300 mg of 2-amino-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid methyl ester and 410 mg of 4methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid (example 2) were stirred in 20 ml of anhydrous DMF for 15 h at room température. The mixture was diluted with 150 ml of EA and washed three times with 50 ml each of a saturated aqueous sodium carbonate solution and then three times with 50 ml each of a 10 % aqueous sodium hydrogensulfate solution. The organic layer was dried with magnésium sulfate, evaporated to dryness and the residue purified by silica gel chromatography (HEP/EA gradient) to yield 630 mg ofthe title compound as a racemic mixture. LC/MS (Method LC4): Rt = 1.22 min; m/z = 440.34 [MH⁺]

Step 5: (1 R,2S,4S)-2-[4-Methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid and (1S,2R,4R)-2-[4-methoxy-3-(2-m-tolyl-ethoxy)benzoylamino]-7-oxa-bicyclo[2.2.1 ]heptane-2-carboxylic acid

630 mg of 2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2carboxylic acid methyl ester was dissolved in 10 ml of methanol, and 2.2 ml of a 1 N solution of sodium hydroxide in water were added at room température. The mixture was stirred at 40 °C for 5 h, then another 1.1 ml of a 1 N solution of sodium hydroxide in water were added and the mixture stirred at 40 °C for another 4 h. The mixture was then diluted with 40 ml of water, the methanol was evaporated, the pH adjusted to 2 and the mixture stirred at room température of 1 h. The precipitated product was filtered off and dried in vacuo to yield 400 mg of 2-[4-methoxy3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa-bicyclo[2.2.1]heptane-2-carboxylic acid as a racemic mixture of (1 R,2S,4S)-2-[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoylamino]-7-oxa17884

146 bicyclo[2.2.1]heptane-2-carboxylic acid and (1S,2R,4R)-2-[4-methoxy-3-(2-m-tolyl-ethoxy)benzoylamino]-7-oxa-bicyclo[2.2.1 ]heptane-2-carboxylic acid.

LC/MS (Method LC3): Rt = 4.00 min; m/z = 426.18 [MH⁺]

Example 127 cis-4-Ethyl-1-{4-methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}cyclohexanecarboxylic acid

Step 1: 3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-phenylboronic acid

50.0 g of [2-(3-bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane were dissolved in 500 ml of anhydrous THF. 64.6 ml of a 2.7 M solution of n-butyllithium in n-heptane were added dropwise at -70 °C. The mixture was stirred for 1h at -70 °C. Then 40.2 ml of triisopropyl borate were added dropwise at -70 °C. Stirring was continued for 30 min at -70 °C and the mixture allowed to warm up to -20 °C. 500 ml of water were added and the mixture was extracted three time with 500 ml each of DCM. The combined organic layers were dried with magnésium sulfate and evaporated to yield 43.6 g ofthe title compound.

LC/MS (Method LC4): Rt = 1.32 min; m/z = 325.13 [M-H+HCOOH]^-

Step 2: tert-Butyl-dimethyl-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-silane

4.6 g of 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-phenylboronic acid, 130 mg of nickel iodide, 5.0 g of sodium bis(trimethylsilyl)amide and 62 mg of (1R,2R)-2-amino-cyclohexanol were placed in a microwave vial and 3.5 ml of isopropanol were added. The mixture was stirred for 10 min at room température. Then a solution of 3-iodooxetane in 1.5 ml of isopropanol was added and the mixture treated under microwave irradiation at 80 °C for 30 min. The obtained mixture was combined with the mixtures obtained in three further runs ofthe synthesis, poured into 50 ml of a saturated aqueous sodium hydrogencarbonate solution and extracted three time with 50 ml each of EA. The combined organic layers were dried with magnésium sulfate and evaporated to yield 9.0 g ofthe title compound.

147

Step 3: 2-(3-Oxetan-3-yl-phenyl)-ethanol

9.0 g of tert-butyl-dimethyl-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-silane and 92.3 ml of a 1 N solution of tetra-n-butylammonium fluoride were dissolved in 200 ml of anhydrous THF. The mixture was stirred for 3 h at room température. Then the mixture was poured into 200 ml of a saturated aqueous solution of sodium hydrogencarbonate and extracted three times with 500 ml each of EA The combined organic layers were dried with magnésium sulfate and evaporated. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield 4.9 g of the title compound.

Step 4: Toluene-4-sulfonic acid 2-(3-oxetan-3-yl-phenyl)-ethyl ester

4.9 g of 2-(3-oxetan-3-yl-phenyl)-ethanol were dissolved in 30 ml of DCM and 9.5 ml of pyridine were added at room température. The mixture was cooled to 0 °C and 6.3 g of p-toluenesulfonyl chloride were added at 0 °C. Stirring was continued for 6 h at room température. Then the volatiles were evaporated, the residue was dissolved in 100 ml of EA and washed with 100 ml of a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted two times with 100 ml each of EA. The combined organic layers were dried with magnésium sulfate and evaporated. Silica gel chromatography (EA/HEP 1:1) of the residue yielded 2.0 g of the title compound.

LC/MS (Method LC4): Rt = 1.26 min; m/z = 333.16 [MH]⁺

Step 5: 3-Acetoxy-4-methoxy-benzoic acid

17.0 g of 3-hydroxy-4-methoxy-benzoic acid and 51.6 g of acetic anhydride were combined and stirred at 140 °C for 3 h. Then 50 ml of water were added at 100 °C, the mixture was heated under reflux for 30 min, another 200 ml of water were added and the mixture heated under reflux for 30 min. The mixture was cooled to 0 °C, and the product was filtered off, washed with water and dried in vacuo to yield 18.8 g of the title compound.

LC/MS (Method LC4): Rt = 0.93 min; m/z = 209.14 [M-H]

Step 6: Acetic acid 5-chlorocarbonyl-2-methoxy-phenyl ester

700 mg of 3-acetoxy-4-methoxy-benzoic acid were suspended in 6 ml of anhydrous DCM and 24 pl of DMF were added. Then 5.0 ml of a 2 M solution of oxalyl chloride in DCM were added dropwise. The mixture was stirred until the évolution of gas had ceased (about 30 min). The volatiles were removed in vacuo, the residue was dissolved in 10 ml of DCM and evaporated to yield 750 mg of the title compound which was used in the subséquent step without further purification.

148

Step 7: cis-1-(3-Acetoxy-4-methoxy-benzoylamino)-4-ethyl-cyclohexanecarboxylic acid methyl ester

100 mg of 1-amino-4-ethyl-cyclohexanecarboxylic acid methyl ester (prepared in analogy to example 25) were dissolved in 5 ml of EA and 10 ml of a saturated aqueous solution of sodium hydrogencarbonate were added. A solution of 103 mg of acetic acid 5-chlorocarbonyl-2methoxy-phenyl ester in 3 ml of DCM was added dropwise at 0 °C over a period of 5 min. Stirring was continued for 1 h at room température. The phases were allowed to separate. The aqueous layer was extracted two times with 15 ml each of EA. The combined organic layers were dried with magnésium sulfate and evaporated to yield 109 mg ofthe title compound.

Step 8: cis-4-Ethyl-1-(3-hydroxy-4-methoxy-benzoylamino)-cyclohexanecarboxylic acid methyl ester

109 mg of 1-(3-acetoxy-4-methoxy-benzoylamino)-4-ethyl-cyclohexanecarboxylic acid methyl ester were dissolved in 5 ml of methanol and 8.0 mg of potassium carbonate were added. The mixture was stirred at room température for 1 h, then poured into 10 ml of 1 N hydrochloric acid and extracted three times with 10 ml of EA. The combined organic layers were washed two times with 10 ml each of a saturated aqueous solution of sodium hydrogencarbonate, once with 10 ml of 1 N hydrochloric acid and once with 10 ml of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnésium sulfate and evaporated. Silica gel chromatography (EA/HEP 1:1) ofthe residue yielded 18 mg ofthe title compound.

LC/MS (Method LC4): Rt = 1.21 min; m/z = 336.22 [MH⁺]

Step 9: cis-4-EthyI-1 -{4-methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}cyclohexanecarboxylic acid methyl ester

17.8 mg of toluene-4-sulfonic acid 2-(3-oxetan-3-yl-phenyl)-ethyl ester, 18.0 mg of 4-ethyl-1-(3hydroxy-4-methoxy-benzoylamino)-cyclohexanecarboxylic acid methyl ester and 22.3 mg of potassium carbonate were stirred in 1 ml of DMF for 6 h at 40 °C. Then 9.0 mg of toluene-4sulfonic acid 2-(3-oxetan-3-yl-phenyl)-ethyl ester were added and the mixture was stirred for 5 h at 40 °C. The reaction mixture was then diluted with 10 ml of EA and washed with 10 ml of a saturated aqueous solution of sodium chloride. The aqueous layer was extracted two times with 10 ml of EA. The combined organic layers were dried with magnésium sulfate, and evaporated. Silica gel chromatography (EA/HEP, 1:1) ofthe residue yielded 20 mg ofthe title compound. LC/MS (Method LC4): Rt = 1.34 min; m/z = 496.29 [MH⁺]

Step 10: cis-4-Ethy 1-1 -{4-methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}cyclohexanecarboxylic acid

149 mg of 4-ethyl-1-{4-methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}cyclohexanecarboxylic acid methyl ester were dissolved in 1 ml of méthanol and 48 pi of a 1 M aqueous solution of sodium hydroxide were added. The mixture was stirred for 7 h at 60 °C and then poured into 10 ml of water. The pH was adjusted to 5 with a 5 % aqueous solution of sodium hydrogensulfate. The mixture was extracted three time with 15 ml each of EA. The combined organic layers were dried with magnésium sulfate and evaporated to yield 14 mg of the title compound.

LC/MS (Method LC4): Rt = 1.28 min; m/z = 480.38 [M-H]

Example 128 trans-1-{4-Methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-4-methylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 127.

LC/MS (Method LC4): Rt = 1.24 min; m/z = 466.2 [M-H]

Example 129

1-{4-Methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-cycloheptanecarboxylic acid

The title compound was synthesized in analogy to example 127.

LC/MS (Method LC4): Rt = 1.23 min; m/z = 466.37 [M-H]“

150

Example 130 cis-4-Ethyl-1-[4-oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylic acid

Step 1: 4-lodo-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester

10.0 g of 3-hydroxy-4-iodo-benzoic acid methyl ester, 7.2 g of 1-(2-bromo-ethyl)-3-methylbenzene and 10.0 g of potassium carbonate were stirred in 100 ml of anhydrous DMF for 28 h at 80 °C. The solvent was evaporated and the residue dissolved in 200 ml of water and 400 ml of EA. The organic layer was separated, washed with 200 ml of water, dried with magnésium sulfate and evaporated. Silica gel chromatography (EA/HEP gradient) ofthe residue yielded 4.66 g ofthe title compound.

Step 2: 4-Borono-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester

2.3 g of bis(2-dimethylaminoethyl)ether were dissolved in 50 ml of anhydrous THF and 7.1 ml of a 2 M solution of isopropylmagnesium chloride added at 15 °C. The mixture was stirred for 20 min at 15 °C. Then a solution of 4.7 g of 4-iodo-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester in 20 ml of anhydrous THF was added at room température. The mixture was stirred for 10 min at 20 °C, and then 2.4 g of trimethyl borate were added dropwise at 0 °C and the mixture stirred for 20 min at 0 °C. 100 ml of 0.1 N hydrochloric acid were added, and the mixture was extracted three times with 100 ml of EA. The combined organic layers were washed with 100 ml of water, dried with magnésium sulfate and evaporated. Silica gel chromatography (EA/HEP 1:5) of the residue yielded 2.1 g ofthetitle compound.

TLC (silica gel, EA/HEP 1:5): Rf = 0.16

Step 3: 4-Oxetan~3-yl-3-(2-m-tolyl-ethoxy)-benzoic acid isopropyl ester

2.0 g of 4-borono-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester, 51 mg of nickel iodide, 2.0 g of sodium bis(trimethylsilyl)amide and 25 mg of trans-2-aminocyclohexanol hydrochloride were placed into a microwave vial and 10 ml of anhydrous 2-propanol added. The mixture was stirred for 10 min. Then a solution of 1.0 g of 3-iodo-oxetane in 3 ml of anhydrous 2-propanol was added and the mixture reacted for 40 min at 80 °C under microwave irradiation. The mixture

151 was then poured into 150 ml of EA and washed three times with 30 ml each of a saturated aqueous sodium hydrogensulfate solution and three times with 30 ml each of a saturated aqueous sodium carbonate solution. The organic layer was dried with magnésium sulfate and evaporated. Silica gel chromatography (EA/HEP 1:5) ofthe residue yielded 120 mg ofthe title compound.

TLC (silica gel, EA/HEP 1:5): Rf = 0.20

Step 4: 4-Oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoic acid

120 mg of 4-oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoic acid isopropyl ester were dissolved in 3 ml of methanol and 0.2 ml of a 2 N aqueous solution of sodium hydroxide added. The mixture was left at room température for 6 days and then evaporated. The residue was dissolved in 10 ml of water, the pH adjusted to 2 with an aqueous sodium hydrogensulfate solution, and the mixture extracted three times using 20 ml each of DCM. The combined extracts were dried with magnésium sulfate and evaporated to yield 105 mg ofthe title compound.

Step 5: cis-4-Ethy 1-1 -[4-oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylic acid cis-4-Ethyl-1-[4-oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoylamino]-cyclohexanecarboxylic acid methyl ester was synthesized from 4-oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoic acid and cis-1amino-4-ethyl-cyclohexanecarboxylic acid methyl ester hydrochloride in analogy to example 126, step 4, and the ester hydrolyzed to the title compound in analogy to example 126, step 5. LC/MS (Method LC4): Rt = 1.36 min; m/z = 466.33 [MH⁺]

Example 131 cis-1-[4-Oxetan-3-yl-3-(2-m-tolyl-ethoxy)-benzoylamino]-4-trifluoromethyl-cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 130.

LC/MS (Method LC4): Rt = 1.31 min; m/z = 504.44 [M-H]~

152

Example 132

1-{[7-(2-m-Tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-cycloheptanecarboxylic acid

Step 1: 7-(2-m-Tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acid 2-m-tolyl-ethyl ester

2.5 g of 7-hydroxy-benzo[1,3]dioxole-5-carboxylic acid, 6.8 g of 1-(2-bromo-ethyl)-3-methylbenzene and 7.6 g of potassium carbonate were stirred in 100 ml of anhydrous DMF for 10 h at 80 °C. Then another 1.4 g of 1-(2-bromo-ethyl)-3-methyl-benzene and 1.5 g of potassium carbonate were added and the mixture was stirred for 5 h at 90 °C. The solvent was removed in vacuo and the residue dissolved in 200 ml of water and 200 ml of EA. The organic layer was separated, washed with 100 ml of a saturated aqueous sodium carbonate solution, dried with magnésium sulfate and evaporated to yield 4.5 g ofthe title compound.

Step 2: 7-(2-m-Tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acid

4.5 g of 7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acid 2-m-tolyl-ethyl ester and 650 mg of sodium hydroxide were dissolved in 50 ml of methanol, 50 ml of THF and 5 ml of water. The mixture was kept at room température for 20 h, then stirred at 50 °C for 5 h and evaporated. The residue was dissolved in 300 ml of a 0.1 M aqueous solution of sodium hydroxide and washed three times with 50 ml each of diisopropyl ether. The pH was adjusted to 2 with sodium hydrogensulfate and the mixture stirred for 30 min at room température. The product was collected by filtration, washed and dried in vacuo to yield 3.1 g of the title compound.

LC/MS (Method LC4): Rt = 1.23 min; m/z = 299.16 [M-H]

Step 3: 1-{[7-(2-m-Tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-cycloheptanecarboxylic acid methyl ester

153

The title compound was synthesized from 7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acid and 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride in analogy to example 126, step 4.

LC/MS (Method LC4): Rt = 1.4 min; m/z = 454.31 [MH⁺]

Step 4: 1-{[7-(2-m-Tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-cycloheptanecarboxylic acid

The title compound was synthesized from 1-{[7-(2-m-Tolyl-ethoxy)-benzo[1,3]dioxole-5carbonyl]-amino}-cycloheptanecarboxylic acid methyl ester in analogy to example 126, step 5. LC/MS (Method LC4): Rt = 1.33 min; m/z = 440.24 [MH⁺]

Example 133 cis-1-{[7-(2-m-Tolyl-ethoxy)-benzo[1,3]dioxoie-5-carbonyl]-amino}-4-trifluoromethylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 132.

LC/MS (Method LC4): Rt = 1.33 min; m/z = 494.25 [MH⁺]

Example 134 cis-4-Ethyl-1-{[7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-cyclohexanecarboxylic acid

154

The title compound was synthesized in analogy to example 132.

LC/MS (Method LC4): Rt = 1.37 min; m/z = 454.29 [MH*]

In analogy to example 3, the example compounds ofthe formula I-6 listed in table 6 were prepared. The compounds can be named as cis-1-[3-(R¹⁰⁶-oxy)-4-methoxy-benzoylamino]-4methyl-cyclohexane-1-carboxylic acid, for example as cis-1-{3-[2-(4-methoxy-phenyl)-ethoxy]-4methoxy-benzoylamino]-4-methyl-cyclohexane-1-carboxylic acid in the case of example 135.

Table 6. Example compounds ofthe formula I-6

Example	R106	LC/MS Method	m/z [MH+]	Rétention time [min]
135	2-(4-methoxy-phenyl)-ethyl	LC4	442.32	1.29
136	2-cyclohexyl-ethyl	LC4	418.35	1.39
137	2-(3-trifluoromethyl-phenyl)-ethyl	LC4	480.3	1.34
138	2-(thiophen-2-yl)-ethyl	LC4	418.26	1.28
139	2-(3-fluoro-phenyl)-ethyl	LC4	430.29	1.3
140	2-(3,4-dimethoxy-phenyl)-ethyl	LC4	472.34	1.25
141	2-(4-chloro-phenyl)-ethyl	LC4	446.27	1.34
142	2-(4-tert-butyl-phenyl)-ethyl	LC4	468.37	1.4
143	2-phenyl-propyl	LC4	426.3	1.33
144	2-(2-trifluoromethyl-phenyl)-ethyl	LC4	480.32	1.34

155

Example	R106	LC/MS Method	m/z [MIT]	Rétention time [min]
145	2-(3-chloro-phenyl)-ethyl	LC4	446.26	1.34
146	2-(4-cyano-phenyl)-ethyl	LC4	437.3	1.26
147	2-(thiophen-3-yl)-ethyl	LC4	418.27	1.28
148	2-(2,4-dichloro-phenyl)-ethyl	LC4	480.24	1.38
149	2-(2-chloro-4-fluoro-phenyl)-ethyl	LC4	464.26	1.34
150	[1-(4-chioro-phenyl)-cyclopropyl]methyl	LC4	472.29	1.37
151	2-(2-fluoro-phenyl)-ethyl	LC4	430.29	1.3
152	2-(2-chloro-6-fluoro-phenyl)-ethyl	LC4	464.25	1.33
153	2-(2-methyl-phenyl)-ethyl	LC4	426.32	1.33
154	2-(4-fluoro-phenyl)-ethyi	LC4	430.29	1.3
155	2-(3-methoxy-phenyl)-ethyl	LC4	442.31	1.29
156	2-(2-chloro-phenyl)-ethyl	LC4	446.25	1.33
157	2-(2,5-dichloro-phenyl)-ethyl	LC4	480.22	1.37

In analogy to example 3, the example compounds oftheformula I-7 listed in table 7 were prepared. The compounds can be named as trans-1-[3-(R¹⁰⁷-oxy)-4-methoxy-benzoylamino]-4methyl-cyclohexane-1-carboxylic acid, for example as trans-1-{3-[2-(4-methoxy-phenyl)-ethoxy]5 4-methoxy-benzoy)amino]-4-methyl-cyclohexane-1-carboxylic acid in the case of example 158.

O

I-7

156

Table 7. Example compounds ofthe formula l-7

Example	R107	LC/MS Method	m/z [MH+]	Rétention time [min]
158	2-(4-methoxy-phenyl)-ethyl	LC4	442.3	1.28
159	2-cyclohexyl-ethyl	LC4	418.35	1.38
160	2-(3-trifluoromethyl-phenyl)-ethyl	LC4	480.29	1.34
161	2-(thiophen-2-yl)-ethyl	LC4	418.24	1.28
162	2-(3-fluoro-phenyl)-ethyl	LC4	430.28	1.3
163	2-phenyl-ethyl	LC4	412.29	1.29
164	2-(2-methoxy-phenyl)-ethyl	LC4	442.3	1.3
165	2-(3,4-dimethoxy-phenyl)-ethyl	LC4	470.47	1.25
166	2-(4-chloro-phenyl)-ethyl	LC4	446.26	1.33
167	2-(4-tert-butyl-phenyl)-ethyl	LC4	468.39	1.4
168	2-phenyl-propyl	LC4	426.33	1.32
169	2-(4-methyl-phenyl)-ethyl	LC4	426.32	1.33
170	2-(2-trifluoromethyl-phenyl)-ethyl	LC4	480.29	1.34
171	2-(3-chloro-phenyl)-ethyl	LC4	446.27	1.33
172	2-(4-cyano-phenyl)-ethyl	LC4	437.3	1.25
173	2-(2,4,6-trimethyl-phenyl)-ethyl	LC4	454.36	1.38
174	2-(thiophen-3-yl)-ethyl	LC4	418.26	1.28
175	2-(2,4-dichloro-phenyl)-ethyl	LC4	480.23	1.37
176	2-(2-chloro-4-fluoro-phenyl)-ethyl	LC4	464.27	1.33

157

Example	R107	LC/MS Method	i- —1 N X E 1.	Rétention time [min]
177	2-(2-fluoro-phenyl)-ethyl	LC4	430.28	1.3
178	2-phenyl-butyl	LC4	440.34	1.35
179	2-(2-chloro-6-fluoro-phenyl)-ethyl	LC4	464.28	1.32
180	2-(2-methyl-phenyl)-ethyl	LC4	426.31	1.32
181	2-(2,5-difluoro-phenyl)-ethyl	LC4	448.28	1.3
182	2-(3-chloro-2-fluoro-phenyl)-ethyl	LC4	464.27	1.33
183	2-(4-fluoro-phenyl)-ethyl	LC4	430.29	1.29
184	2-(indol-3-yl)-ethyl	LC4	451.34	1.26
185	2-(3-methoxy-phenyl)-ethyl	LC4	442.32	1.28
186	2-(2-chloro-phenyl)-ethyl	LC4	446.26	1.32
187	2-(2,5-dimethyl-phenyl)-ethyl	LC4	440.34	1.35
188	2-(2,5-dichloro-phenyl)-ethyl	LC4	480.24	1.36
189	2-(3,5-dimethyl-phenyl)-ethyl	LC4	440.33	1.36
190	1 -methyl-2-phenyl-ethyl	LC4	426.31	1.31
191	4-methoxy-benzyl	LC4	442.31	1.3
192	4-trifluoromethoxy-benzyl	LC4	482.27	1.33
193	3-(4-methoxy-phenyl)-propyl	LC4	456.34	1.3
194	2-phenylsulfanyl-ethyl	LC4	444.27	1.3
195	3-chloro-benzyl	LC4	432.25	1.31
196	2-(naphthalen-1 -y l)-ethy I	LC4	462.33	1.35

158

Example	R107	LC/MS Method	m/z [MH+]	Rétention time [min]
197	(2,3-dihydro-benzo[1,4]dioxin-2-yl)- methyl	LC4	456.31	1.29
198	3-phenyl-propyl	LC4	426.32	1.32
199	3-fluoro-benzyl	LC4	416.28	1.28
200	cyclohexyl-methyl	LC4	404.32	1.36
201	3-cyclopentyl-propyl	LC4	418.34	1.39
202	2,5-dimethyl-benzyl	LC4	426.32	1.33
203	2-(4-fluoro-phenylsulfanyl)-ethyl	LC4	462.29	1.31
204	2-(6,6-dimethyl-bicyclo[3.1.1 ]hept-2en-2-yl)-ethyl	LC4	456.39	1.43

In analogy to example 3, the example compounds of the formulae I-8 and I-9 listed in table 8, in which R¹⁰⁸ and R¹⁰⁹ hâve the meanings given in table 8, were prepared.

I-8

O

I-9

159

Table 8. Example compounds of the formulae I-8 and I-9

Example	Formula	/ R109	LC/MS Method	m/z [MH+]	Rétention time [min]
205	I-8	2-phenyl-ethyl	LC4	426.30	1.34
206	I-9	2-phenyl-ethyl	LC4	426.29	1.22
207	I-8	2-(3-chloro-phenyl)-ethyl	LC4	460.27	1.38
208	I-9	2-(3-chloro-phenyl)-ethyl	LC3	460.29	4.75

In analogy to example 3, the compounds ofthe formulae I-8 and I-9 listed in table 9, in which R¹⁰⁸ and R¹⁰⁹ hâve the meanings given in table 9, can be prepared.

I-9

I-8

Table 9. Compounds of the formulae I-8 and I-9

Example (formula)	Example (formula)	j^108 i
209 (I-8)	210 (I-9)	2-(4-methoxy-phenyl)-ethyl
211 (I-8)	212 (l-9)	2-cyclohexyl-ethyl
213 (I-8)	214 (I-9)	2-(3-trifluoromethyl-phenyl)-ethyl
215 (I-8	216 (I-9)	2-(thiophen-2-yl)-ethyl
217 (I-8)	218 (I-9)	2-(3-fluoro-phenyl)-ethyl
219 (I-8)	220 (I-9)	2-(2-methoxy-phenyl)-ethyl
221 (I-8)	222 (I-9)	2-(3,4-dimethoxy-phenyl)-ethyl

160

Example (formula)	Example (formula)	r108 i |^109
223 (I-8)	224 (I-9)	2-(4-chloro-phenyl)-ethyl
225 (I-8)	226 (I-9)	2-(4-tert-butyl-phenyl)-ethyl
227 (I-8)	228 (I-9)	2-phenyl-propyl
229 (I-8)	230 (I-9)	2-(4-methyl-phenyl)-ethyl
231 (I-8)	232 (I-9)	2-(2-trifluoromethyl-phenyl)-ethyl
233 (I-8)	234 (I-9)	2-(4-cyano-phenyl)-ethyl
235 (I-8)	236 (I-9)	2-(2,4,6-trimethyl-phenyl)-ethyl
237 (I-8)	238 (I-9)	2-(thiophen-3-yl)-ethyl
239 (I-8)	240 (I-9)	2-(2,4-dichloro-phenyl)-ethyl
241 (I-8)	242 (I-9)	2-(2-chloro-4-fluoro-phenyl)-ethyl
243 (I-8)	244 (I-9)	2-(2-fluoro-phenyl)-ethyl
245 (I-8)	246 (I-9)	2-phenyl-butyl
247 (I-8)	248 (I-9)	2-(2-chloro-6-fluoro-phenyl)-ethyl
249 (I-8)	250 (I-9)	2-(2-methyl-phenyl)-ethyl
251 (I-8)	252 (I-9)	2-(2,5-difluoro-phenyl)-ethyl
253 (I-8)	254 (I-9)	2-(3-chloro-2-fluoro-phenyl)-ethyl
255 (I-8)	256 (I-9)	2-(4-fluoro-phenyl)-ethyl
257 (I-8)	258 (I-9)	2-(indol-3-yl)-ethyl
259 (I-8)	260 (I-9)	2-(3-methoxy-phenyl)-ethyl
261 (I-8)	262 (I-9)	2-(2-chloro-phenyl)-ethyl
263 (I-8)	264 (I-9)	2-(2,5-dimethyl-phenyl)-ethyl

161

Example (formula)	Example (formula)	f^108 i |^109
265 (I-8)	266 (I-9)	2-(2,5-dichloro-phenyl)-ethyl
267 (I-8)	268 (I-9)	2-(3,5-dimethyl-phenyl)-ethyl
269 (I-8)	270 (I-9)	1 -methyl-2-phenyl-ethyl
271 (I-8)	272 (I-9)	4-methoxy-benzyl
273 (I-8)	274 (i-9)	4-trifluoromethoxy-benzyl
275 (I-8)	276 (I-9)	3-(4-methoxy-phenyl)-propyl
277 (I-8)	278 (I-9)	2-phenylsulfanyl-ethyl
279 (I-8)	280 (I-9)	3-chloro-benzyl
281 (I-8)	282 (I-9)	2-(naphthalen-1 -y l)-ethy I
283 (I-8)	284 (I-9)	(2,3-dihydro-benzo[1,4]dioxin-2-yl)- methyl
285 (I-8)	286 (I-9)	3-phenyl-propyl
287 (I-8)	288 (I-9)	3-fluoro-benzyl
289 (I-8)	290 (l-9)	cyclohexyl-methyl
291 (I-8)	292 (I-9)	3-cyclopentyi-propyl
293 (I-8)	294 (I-9)	2,5-dimethyl-benzyl
295 (I-8)	296 (I-9)	2-(4-fluoro-phenylsulfanyl)-ethyl
297 (I-8)	298 (I-9)	2-(6,6-dimethyl-bicyclo[3.1.1 ]hept-2-en- 2-yl)-ethyl

In analogy to example 92, the example compounds ofthe formula 1-10 listed in table 10 were synthesized by reacting cis-1-amino-4-ethyI-cyclohexanecarboxylic acid methyl ester hydrochloride instead of 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride with

162

5-bromo-6-methoxy-nicotinic acid in analogy to step 2 of example 92, and reacting the obtained cis-1-[(5-bromo-6-methoxy-pyridine-3-carbonyl)-amino]-4-ethyl-cyclohexanecarboxylic acid methyl ester with the respective phenylboronic acid and hydrolyzing the obtained methyl ester in analogy to steps 3 and 4, respectively, of example 92. The compounds can be named as cis-45 ethyl-1-[(5-R¹¹⁰-6-methoxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylic acid, for example as cis-4-ethyl-1-{[6-methoxy-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid in the case of example 299.

Table 10. Example compounds oftheformula 1-10

Example	R110	LC/MS Method	m/z [MIT]	Rétention time [min]
299	3-trifluoromethoxy-phenyl	LC4	467.3	1.37
300	2,3-dichloro-phenyl	LC4	451.23	1.35
301	3,4,5-trifluoro-phenyl	LC4	437.28	1.36
302	3-chloro-5-trifluoromethyl-phenyl	LC4	485.3	1.40
303	3-trifluoromethyl-phenyl	LC6	451.31	4.89
304	2-fluoro-3-trifluoromethyl-phenyl	LC4	469.26	1.34

Example 305 cis-1-{[5-(3-Chloro-4-methoxy-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-ethyl15 cyclohexanecarboxylic acid

The compound was prepared in analogy to example 92 using cis-1-amino-4ethylcyclohexanecarboxylic acid methyl ester hydrochloride instead of 1-aminocycloheptanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.17 min; m/z = 466.23 [MH⁺]

In analogy to example 92, the example compounds of the formulae 1-11,1-12 and 1-13 listed in table 11, in which R¹¹¹, R¹¹² and R¹¹³ hâve the meanings given in table 11, were prepared.

Table 11. Example compounds of the formulae 1-11, 1-12 and 1-13

Example	Formula	R111/R112/R113	LC/MS Method	m/z [MH+]	Rétention time [min]
306	1-11	3-trifluoromethoxy-phenyl	LC4	467.28	1.39
307	1-12	3-trifluoromethoxy-phenyl	LC4	453.25	1.36
308	1-13	3-trifluoromethoxy-phenyl	LC4	453.25	1.35

164

Example	Formula	R111/R112/R113	LC/MS Method	m/z [MH*]	Rétention time [min]
309	1-11	2,3-dichloro-phenyl	LC4	451.21	1.37
310	1-12	2,3-dichloro-phenyl	LC4	437.19	1.34
311	1-13	2,3-dichloro-phenyl	LC4	437.17	1.34
312	1-11	3,4,5-trifluoro-phenyl	LC4	437.25	1.37
313	1-12	3,4,5-trifluoro-phenyl	LC4	423.21	1.34
314	1-13	3,4,5-trifluoro-phenyl	LC4	423.22	1.33
315	1-13	3-chloro-5-trifluoromethylphenyl	LC4	471.22	1.39
316	1-11	3-trifluoromethyl-phenyl	LC4	451.27	1.38
317	1-12	3-trifluoromethyl-phenyI	LC4	437.24	1.35
318	1-13	3-trifluoromethyl-phenyl	LC4	437.24	1.34
319	1-12	3-chloro-4-methoxy-phenyl	LC4	433.21	1.32
320	1-13	3-chloro-4-methoxy-phenyl	LC4	433.21	1.31

In analogy to example 92, the compounds ofthe formulae 1-11, 1-12 and 1-13 listed in table 12, in which R¹¹¹, R¹¹² and R¹¹³ hâve the meanings given in table 12, can be prepared.

1-11

Table 12. Compounds of the formulae 1-11,1-12 and 1-13

Example	Formula	R111 / R112 / R113	LC/MS Method	m/z [MH+]	Rétention time [min]
321	1-11	3-chloro-5-trifluoromethyl- phenyl
322	1-12	3-chloro-5-trifluoromethylphenyl
323	1-11	2-fluoro-3-trifluoromethylphenyl
324	1-12	2-fluoro-3-trifluoromethyl- phenyl
325	1-13	2-fluoro-3-trifluoromethylphenyl
326	1-11	3-chloro-4-methoxy-phenyl	LC4	447.17	1.34

In analogy to example 92, the example compounds of the formulae 1-14,1-15, 1-16 and 1-17 listed in table 13, in which R¹¹⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ hâve the meanings given in table 13, were prepared.

166

1-14 1-15

1-16 1-17

Table 13. Example compounds of the formulae 1-14, 1-15, 1-16 and 1-17

Example	Formula	R114/R115/R116/R117	LC/MS Method	m/z [MH+]	Rétention time [min]
327	1-14	3-trifluoromethoxy-phenyl	LC4	466.25	1.40
328	1-15	3-trifluoromethoxy-phenyl	LC4	466.25	1.39
329	1-16	3-trifluoromethoxy-phenyl	LC4	452.17	1.37
330	1-17	3-trifluoromethoxy-pheny	LC4	452.22	1.36
331	1-14	3-trifluoromethyl-phenyl	LC4	450.2	1.38
332	1-15	3-trifluoromethyl-phenyl	LC4	450.2	1.38
333	1-16	3-trifluoromethyl-phenyl	LC4	436.2	1.35
334	1-17	3-trifluoromethyl-phenyl	LC4	436.17	1.35

In analogy to example 92, the compounds ofthe formulae 1-14, 1-15, 1-16 and 1-17 listed in table 14, in which R¹¹⁴, R¹¹⁵, R¹¹⁶ and R¹¹⁷ hâve the meanings given in table 14, can be prepared.

167

Table 14. Compounds of the formulae 1-14,1-15, 1-16 and 1-17

Example (formula)	Example (formula)	Example (formula)	Example (formula)	R114/R115/R116/R117
335 (1-14)	336 (1-15)	337 (1-16)	338 (1-17)	2,3-dichloro-phenyl
339 (1-14)	340 (1-15)	341 (1-16)	342 (1-17)	3,4,5-trifluoro-phenyl
343 (1-14)	344 (1-15)	345 (1-16)	346 (1-17)	3-chloro-5-trifluoromethylphenyl
347 (1-14)	348 (1-15)	349 (1-16)	350 (1-17)	2-fluoro-3-trifluoromethylphenyl
351 (1-14)	352 (1-15)	353 (1-16)	354 (1-17)	3-chloro-4-methoxy-phenyl

Example	Formula	R114/R115/R116/R117	LC/MS Method	m/z [MH+]	Rétention time [min]
351	1-14	3-chloro-4-methoxy-phenyl	LC4	446.21	1.35
352	1-15	3-chloro-4-methoxy-phenyl	LC4	446.21	1.34

168

Example	Formula	R114/R115/R116/R117	LC/MS Method	m/z [MH+]	Rétention time [min]

Example 355 trans-4-EthyJ-1-[(6-methoxy-5-phenethylQxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylic acid

Step 1: trans-1-Amino-4-ethyl-cyclohexanecarboxylic acid methyl ester hydrochloride 4-Ethyl-cyclohexanone was reacted in a Strecker aminonitrile synthesis in analogy to the procedure described in I, L. Munday, J. Chem. Soc. (1961), 4372-4379 to yield trans-1-amino-4ethyl-cyclohexanecarbonitrile. This intermediate (10 g, 65.8 mmol) was stirred in 150 ml of 8 N hydrochloric acid under reflux for 72 h. The volatiles were evaporated, the residue was twice evaporated with water, resuspended in water and adjusted to pH = 6 with sodium hydroxide. After cooling in an ice bath, the precipitate was fîltered off, washed with water and acetone and dried in vacuo. The obtained amino acid was suspended in methanol, cooled to -30 °C and thionyl chloride (3 équivalents) was added. The mixture was warmed to room température and stirred ovemight. The volatiles were evaporated to yield the title compound.

Step 2: trans-4-Ethyl-1 -[(6-methoxy-5-phenethyloxy-pyridine-3-carbonyl)-amino]cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 77 using 2-phenylethanol in the éthérification step and using the compound of step 1 as amino acid methyl ester hydrochloride intermediate.

LC/MS (Method LC4): Rt = 1.33 min; m/z = 427.29 [MH⁺]

Example 356

169 cis-1-((5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 79 using 2-(3-chlorophenyl)ethanol in the éthérification step.

LC/MS (Method LC4): Rt = 1.29 min; m/z = 447.28 [MH*]

Example 357 cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-ethylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 77 using 2-(3-chlorophenyl)ethanol in the éthérification step and cis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl ester hydrochloride (synthesized from 4-ethylcyclohexanone via the Bucherer-Bergs hydantoin route in analogy to the procedure described in J. W. Tsang et al., J. Med. Chem. 27 (1984), 16631668) instead of 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.38 min; m/z = 461.25 [MH⁺]

Example 358 cis-4-Ethyl-1-[(6-methoxy-5-phenethyloxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylic acid

170

The title compound was synthesized in analogy to example 77 using 2-phenylethanol in the éthérification step and cis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl ester hydrochloride instead of 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride. LC/MS (Method LC4): Rt = 1.34 min; m/z = 427.3 [MH⁺]

Example 359 cis-1-{[5-(3,4-Difluoro-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-ethylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 92 using 3,4-difluoro-phenylboronic acid in the Suzuki coupling step and cis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl ester hydrochloride instead of 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride. LC/MS (Method LC4): Rt = 1.36 min; m/z = 419.26 [MH⁺]

Example 360 cis-1-{[5-(3,5-Difluoro-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-ethylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 92 using 3,5-difluoro-phenylboronic acid in the Suzuki coupling step and cis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl ester hydrochloride instead of 1-amino-cycloheptanecarboxylic acid methyl ester hydrochloride. LC/MS (Method LC4): Rt = 1.36 min; m/z = 419.21 [MIT]

Example 361 (1R,2R)-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-2-ethylcyclopropanecarboxylic acid

Step 1: (1R,2R)-1-Amino-2-ethyl-cyclopropanecarboxylic acid ethyl ester (1R,2S)-1-tert-Butoxycarbonylamino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (400 mg, 1.57 mmol) was dissolved in methanol (5 ml) and added to a suspension of azodicarboxylic acid dipotassium sait (1.46 g, 7.5 mmol; cf. D. J. Pasto et al., Organic Reactions 40 (1991), 91-155) in methanol (10 ml). Acetic acid (1.12 g, 18.8 mmol) was added in the course of 10 min and the mixture was stirred for 1 h at room température. Azodicarboxylic acid dipotassium sait (1.46 g) and acetic acid (1.12 g) were added once again and the mixture stirred for 1 h. LC/MS analysis then indicated complété conversion. The volatiles were evaporated, the residue was partitioned between EA and a saturated sodium hydrogencarbonate solution, and the combined organic extracts were dried over sodium chloride, decanted over a small plug of silica gel and evaporated to dryness. The obtained intermediate was dissolved in a mixture of DCM (5 ml) and TFA (1 ml) and stirred for 1 h at room température. The volatiles were evaporated, and the

172 residue was partitioned between diethyl ether and saturated sodium hydrogencarbonate solution. The combined organic extracts were dried over sodium chloride, decanted and evaporated to dryness to yield the title compound.

Step 2: (1 R,2R)-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-2ethyl-cyclopropanecarboxylic acid

The title compound was synthesized in analogy to example 77 using 2-(3-chlorophenyl)ethanol in the éthérification step and using the compound of step 1 instead of 1-aminocycloheptanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.27 min; m/z = 419.14 [MH⁺]

Example 362 trans-4-Ethyl-1-{[5-fluoro-6-(2-hydroxy-ethoxy)-3'-trifluoromethyl-biphenyl-3-carbonyl]-amino}cyclohexanecarboxylic acid

Step 1: 4-(2-Acetoxy-ethoxy)-3-bromo-5-fluoro-benzoic acid methyl ester 3-Bromo-5-fluoro-4-hydroxybenzoic acid methyl ester (500 mg, 2.01 mmol; T. Kline et al., J.

Med. Chem. 45 (2002), 3112-3129), potassium carbonate (971 mg, 7.03 mmol) and 2bromoethyl acetate (503 mg, 3.01 mmol) were reacted in DMF (5 ml) at room température for 72 h. Then the mixture was partitioned between EA and 2 N hydrochloric acid, and the combined organic extracts were dried over sodium chloride, decanted and evaporated to dryness. The raw material was purified by silica gel chromatography (EA/HEP gradient 0:1 to 4:6) to yield the title compound.

¹H-NMR: δ = 7.97 (d, 1H); 7.81 (dd, 1 H); 4.45-4.40 (m, 2H); 4.33-4.29 (m, 2H); 3.85 (s, 3H); 2.01 (s, 3H)

Step 2: trans-4-Ethyl-1-{[5-fluoro-6-(2-hydroxy-ethoxy)-3'-trifluoromethyl-biphenyl-3-carbonyl]aminoj-cyclohexanecarboxylic acid

173

The compound of step 1 was coupled to 3-trifluoromethyl-phenylboronic acid in analogy to step 3 of example 92, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield 5-fluoro-6-(2-hydroxy-ethoxy)-3'-trifluoromethyl-biphenyl-3-carboxylic acid. This intermediate was coupled to the compound of step 1 of example 355 in analogy to step 1 of example 3, and the obtained ester intermediate hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC4): Rt = 1.32 min; m/z = 498.23 [MIT]

In analogy to example 3, the example compounds ofthe formula 1-1 listed in table 15 were prepared.

Table 15. Example compounds oftheformula 1-1

Example	R101	LC/MS Method	m/z	Rétention time [min]
363	2-(3-trifluoromethylphenyl)-ethyl	LC8	480.20 [MIT]	2.54
364	2-(2-chlorophenyl)-ethyl	LC8	446.18 [MIT]	2.50
365	2-(3-fluorophenyl)-ethyl	LC6	428.08 [M-T]	2.57

By coupling 4-methoxy-3-(2-m-tolyl-ethoxy)-benzoic acid to the respective amino acid methyl ester via the carboxylic acid chloride route as described in step 3 of example 1 or the TOTU coupling route as described in step 1 of example 3, the example compounds of the formula I-2 listed in table 16 were prepared. The amino acid methyl esters or the amino acids were commercially available or were prepared from the respective ketone in analogy to example 25. In the formulae of the groups R¹⁰² in table 2 the line crossed with the symbol ~~ represents the free bond via which the group R¹⁰² is bonded to the nitrogen atom ofthe amide group

174 depicted in formula I-2. I.e., in the formula ofthe complété molécule the terminal endpoint ofthe line crossed with the said symbol ends on the nitrogen atom ofthe amide group.

Table 16. Example compounds oftheformula I-2

Example	RTO2-j-	Starting material	LC/MS Method	m/z [MH+]	Rétention time [min]
366	h3c3A3v h3c ^-oh 0	(a)	LC10	468.37	4.10
367	h3c ... 0	(a)	LC6	426.36	4.78
368	... 0	(b)	LC4	370.15	1.18

(a) The amino acid ester was prepared from the respective ketone.

(b) The amino acid ester or amino acid was commercially available.

In analogy to example 43, by employing the respective ketone instead of 4-methyl10 cyclohexanone in the initial Strecker aminonitrile step, the example compounds of the formula I3 listed in table 17 were prepared. In the formulae ofthe groups R¹⁰³ in table 17 the line crossed with the symbol represents the free bond via which the group R¹⁰³ is bonded to the

175 nitrogen atom ofthe amide group depicted in formula I-3. I.e., in the formula ofthe complété moiecule the terminal endpoint ofthe line crossed with the said symbol ends on the nitrogen atom ofthe amide group.

Table 17. Example compounds ofthe formula I-3

Example		LC/MS Method	m/z [MH+]	Rétention time [min]
369	0 (a)	LC1	480.22	1.81
370	H3C /--- H3C '--/,7 0H 0 (a)	LC10	454.35	3.97
371	H3C ^OH 0 (a)	LC4	468.34	1.35
372	H3C :. 0 (a)	LC4	426.46	1.3

176

373	Hî(W ^^-oh 0 (a)	LC4	412.28	1.28
374	'· .. 0	LC4	442.13	1.15

(a) Other diastereomer than in example 28, example 29, example 366, example 367, example 33, respectively.

In analogy to example 92, the example compounds of the formula I-23 listed in table 18, in which R¹²³ has the meaning given in table 18, were prepared. The respective cis-1-amino-4trifluoromethylcyclohexanecarboxylic acid methyl ester hydrochloride was prepared as for example 28

177

Table 18. Example compounds oftheformulae I-23

Example	R123	LC/MS Method	m/z [MH+]	Rétention time [min]
375	3,4,5-trifluorophenyl	LC4	477.28	1.32
376	3-trifluoromethylphenyl	LC4	491.33	1.35
377	2-fluoro-3- trifluoromethylphenyl	LC4	509.34	1.34
378	2,3-dichlorophenyl	LC4	491.21	1.32
379	3-trifluoromethoxyphenyl	LC4	507.2	1.32
380	3-chloro-5- trifluoromethylphenyl	LC4	525.16	1.36

In analogy to example 362, the example compounds ofthe formula 1-18 listed in table 19, in which R¹¹⁸ has the meaning given in table 19, were prepared.

1-18

Table 19. Example compounds ofthe formula 1-18

Example	R118	LC/MS Method	m/z [MIT]	Rétention time [min]
381	3-chloro-4-methoxy-phenyl	LC4	494.20	1.30
382	3-trifluoromethoxy-phenyl	LC4	514.23	1.34
383	3-trifluoromethyl-phenyl	LC4	498.31	1.20

178

Example	R118	LC/MS Method	m/z [MH+]	Rétention time [min]
384	3,4-difluorophenyl	LC4	466.24	1.17
385	3,5-difluorophenyl	LC4	466.23	1.17

Example 386 trans-4-Ethyl-1-{[6-(2-hydroxy-ethoxy)-3'-trifluoromethyl-biphenyl-3-carbonyl]-amino} -cyclohexanecarboxylic acid

Stepl : 4-(2-Acetoxy-ethoxy)-3-bromo-benzoic acid 2-acetoxy-ethyl ester 3-Bromo-4-hydroxy-benzoic acid (3.00g, 13.8 mmol), caesium carbonate (9.01 g, 27.6 mmol) and 2-bromoethyl acetate (4.62 g, 27.6 mmol) were stirred in DMF for 3 days at room température. Volatiles were evaporated in vacuo, the remainder was partitioned between ethyl acetate and water, the combined organic extracts were dried over sodium chloride and evaporated to dryness. The raw material was titurated in ether, filtered and dried in vacuo to yield the title compound (4.66 g).

LC/MS (Method LC4): Rt = 1.25 min; m/z = 389.04 [MH⁺]

Step 2: trans-4-Ethyl-1-{[6-(2-hydroxy-ethoxy)-3'-trifluoromethyl-biphenyl-3-carbonyl]-amino}cyclohexanecarboxylic acid

The compound of step 1 was coupled to 3-trifluoromethyl-phenylboronic acid in analogy to step 3 of example 92, the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield 6-(2-Hydroxy-ethoxy)-3'-trifluoromethyl-biphenyl-3-carboxylic acid. This intermediate was coupled to trans-1-amino-4-ethylcyclohexanecarboxylicacid methylester hydrochloride in analogy to step 1 of example 3, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC4): Rt = 1.30 min; m/z = 480.19 [MH⁺]

179

In analogy to example 386, the example compounds ofthe formula 1-19 listed in table 20, in which R¹¹⁹ has the meaning given in table 20, were prepared.

O

1-19

Table 20. Example compounds ofthe formula 1-19

Example	R119	LC/MS Method	m/z [MH+]	Rétention time [min]
387	3-trifluoromethyl-phenyl	LC4	480.21	1.31
388	3,4-difluoro-phenyl	LC4	448.19	1.28
389	3,5-difluoro-phenyl	LC6	448.19	4.52
390	3-trifluoromethoxy-phenyl	LC6	496.16	4.69
391	3-chloro-4-methoxy-phenyl	LC4	476.22	1.27

Example 392 trans-1 -(3-Fluoro -5-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy -benzoylamino)-4-

180

3-Fluoro-5-hydroxy-4-methoxybenzoic acid methyl ester (see example 69) was etherified with 2[3-(2-hydroxy-ethyl)-phenyl]-ethanol in analogy to step 1 of example 1. Hydrolysis ofthe ester group in analogy to step 2 of example 1, coupling of the obtained carboxylic acid to trans-1amino-4-methyl-cyclohexanecarboxylic acid methyl ester hydrochloride in analogy to step 1 of example 3 and hydrolysis ofthe methyl ester in analogy to step 4 of example 1 yielded the title compound.

LC/MS (Method LC4): Rt = 1.25 min; m/z = 474.32 [MH⁺]

Example 393

1-(3-Fluoro-5-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy)-4-methoxy-benzoylamino)-

The title compound was synthesized in analogy to example 392 using 1-aminocycloheptanecarboxylic acid methyl ester hydrochloride instead of trans-1-amino-4-methylcyclohexanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.24 min; m/z = 474.29 [MH⁺]

Example 394 trans-4-Ethyl-1-(3-fluoro-5-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-4-methoxy-benzoylamino) cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 392 using trans-1-amino-4-ethyl cyclohexanecarboxylic acid methyl ester hydrochloride instead of trans-1-amino-4-methyl cyclohexanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.29 min; m/z = 488.32 [MH⁺]

181

Example 395 trans-4-Ethyl-1-{[6-methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 355 using 2-m-tolyl-ethanol in the éthérification step.

LC/MS (Method LC3): Rt = 4.67 min; m/z = 441.31 [MIT]

Example 396 cis-4-Ethyl-1-{[6-methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 357 using 2-m-tolyl-ethanol in the éthérification step.

LC/MS (Method LC4): Rt = 1.37 min; m/z = 441.36 [MH⁺]

Example 397 trans-1-([5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-ethylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 355 using 2-(3-chlorophenyl)ethanol in the éthérification step.

LC/MS (Method LC4): Rt = 1.36 min; m/z = 461.27 [MIT]

Example 398 trans- 4-Ethyl-1-({6-methoxy-5-[2-(3-trifluoromethoxy-phenyl)-ethoxy]-pyridine-3-carbonyl}amino)-cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 355 using 2-(3trifluoromethoxyphenyl)-ethanol in the éthérification step.

LC/MS (Method LC4): Rt = 1.38 min; m/z = 511.29 [MIT]

Example 399 cis- 4-Ethyl-1-({6-methoxy-5-[2-(3-trifluoromethoxy-phenyl)-ethoxy]-pyridine-3-carbonyl}-amino)cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 357 using 2-(3trifluoromethoxyphenyl)-ethanol in the éthérification step.

LC/MS (Method LC4): Rt = 1.39 min; m/z = 511.29 [MH⁺]

183

Example 400 cis-1-([6-Methoxy-5-(2-phenyl-ethoxy)-pyridine-3-carbonyl]-amino}-4-methylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 79 using 2-phenylethanol instead of 2-m-tolylethanol.

LC/MS (Method LC4): Rt = 1.25 min; m/z = 413.37 [MH⁺]

Example 401

1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)cycloheptanecarboxylic acid

The title compound was synthesized in analogy to example 77 using 2-(3-chlorophenyl)ethanol instead of 2-m-tolylethanol.

LC/MS (Method LC4): Rt = 1.31 min; m/z = 447.15 [MH⁺]

Example 402 cis-1-{[6-Methoxy-5-(2-m-tolyl-ethoxy)-pyridine-3-carbonyl]-amino}-4-trifluoromethylcyclohexanecarboxylic acid

184

The title compound was synthesized in analogy to example 77 using cis-1-amino-4trifluoromethylcyclohexanecarboxylic acid methyl ester hydrochloride instead of 1aminocycloheptanecarboxylic acid methyl ester hydrochloride in the amide coupling step.

LC/MS (Method LC4): Rt = 1.28 min; m/z = 481.36 [MH⁺]

Example 403 cis- 4-Ethyl-1-{4-methoxy-3-[2-(3-trifluoromethoxy-phenyl)-ethoxy]-benzoylamino}-

cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 3 using 2-(3trifluoromethoxyphenyl)-ethanol in the éthérification step and cis-1-amino-4ethylcyclohexanecarboxylicacid methylester hydrochloride in the amide coupling step. LC/MS (Method LC4): Rt = 1.39 min; m/z = 510.30 [MH⁺]

Example 404 cis-1-{3-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-4-methoxy-benzoylamino}-4-methyl-

F

185

The title compound was synthesized in analogy to example 3 using cis-1-amino-4methylcyclohexanecarboxylic acid methyl ester hydrochloride instead of 1-aminocycloheptanecarboxylic acid methyl ester hydrochloride in the amide coupling step.

LC/MS (Method LC3): Rt = 4.57 min; m/z = 464.21 [MH⁺]

Example 405 cis- 1-{3-[2-(2-Fluoro-5-trifluoromethoxy-phenyl)-ethoxy]-4-methoxy-benzoylamino}-4-methylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 404 using 2-(2-fluoro-5trifluoromethoxyphenyl)ethanol instead of 2-(5-chloro-2-fluorophenyl)ethanol in the éthérification step.

LC/MS (Method LC4): Rt = 1.34 min; m/z = 514.27 [MH*]

Example 406 cis-1 -(4-Methoxy-3-phenethyloxy-benzoylamino)-4-methyl-cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 404 using 2-phenylethanol instead of 2-(5-chloro-2-fluorophenyl)ethanol in the éthérification step.

LC/MS (Method LC4): Rt = 1.30 min; m/z = 412.29 [MH*]

In analogy to example 92, the example compounds of the formulae 1-10,1-11 and 1-12 listed in table 21, in which R¹¹⁰, R¹¹¹ and R¹¹² hâve the meanings given in table 21, were prepared.

186

Table 21. Example compounds of the formulae 1-10, 1-11 and 1-12

Example	Formula	R110/R111	LC/MS Method	m/z [MH+]	Rétention time [min]
407	1-10	4-fluoro-phenyl	LC4	401.23	1.34
408	1-11	4-chloro-3-trifluoromethylphenyl	LC4	485.23	1.41
409	1-10	3-fluoro-phenyl	LC4	401.19	1.34
410	1-12	3,5-difluoro-phenyl	LC4	405.14	1.32
411	1-10	3-fluoro-4-methoxy-phenyl	LC4	431.20	1.32
412	1-11	3-fluoro-4-methoxy-phenyl	LC4	431.23	1.31

Example 413

4-Ethyl-1-{[6-(2-hydroxy-ethoxy)-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid

Step 1: 5-Bromo-6-chloro-nicotinic acid 2-hydroxy-ethyl ester 5-Bromo-6-chloro-nicotinoyl chloride (W. J. Thompson et al., J. Org. Chem. 49 (1984), 52375243, raw material; 7.00g, apx 50 % purity) was diluted with dichloromethane (50 ml), ethylenglycol (17 g) was added slowly and the mixture was stirred at room température over night. The mixture was partitioned between ether and water and the aqueous phase was extracted three times with ether. Each ether extract was washed with new water. The combined organic layers were dried over sodium chloride and evaporated to dryness in vacuo to yield the title compound (6.0 g) as raw material.

Step 2: 6-(2-Acetoxy-ethoxy)-5-bromo-nicotinic acid 2-acetoxy-ethyl ester

Sodium hydride (1.29 g, 60 % purity in minerai oil) was dissolved in ethylene glycol (25 ml) and the raw material of step 1 was added. This mixture was stirred at 60°C for 1 h. Volatiles were evaporated at 95°C, 1 mbar. The remainderwas suspended in pyridine (25 ml), acetic anhydride (25 g) was added slowly during 30 minutes with stirring and stirring continued for 1 h. The mixture was partitioned between ethyl acetate and water, the organic phase was washed with 2N HCl and saturated sodium bicarbonate solution, dried over sodium chloride and evaporated to dryness in vacuo. The remainder was titurated in diethyl ether, cooled in an ice bath and filtered to yield 2.5 g ofthe title compound.

¹H-NMR: δ = 8.70 (d, 1 H); 8.40 (d, 1 H); 4.65-4.62 (m, 2H); 4.47-4.45 (m, 2H); 4.40-4.37 (m, 2H); 4.36-4.32 (m, 2H); 2.02 (s, 3H); 2.01 (s, 3H)

Step 3: 4-Ethyl-1 -{[6-(2-hydroxy-ethoxy)-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]amino}-cyclohexanecarboxylic acid

The compound of step 2 was coupled to 3-trifluorophenylbenzene boronic acid in analogy to step 3 of example 92, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield 6-(2-Hydroxy-ethoxy)-5-(3-trifluoro methyl-phenyl)-nicotinic acid. This intermediate was coupled to cis-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloride in analogy to step 1 of example 3, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

188

LC/MS (Method LC4): Rt = 1.30 min; m/z = 481.16 [MH⁺] ¹H-NMR: δ = 12.2 (s, 1H); 8.64 (d, 1H); 8.24-8.18 (m, 2H); 8.06 (s, 1H); 8.01 (d, 1H); 7.78-7.70 (m, 2H); 4.78 (t, 1H); 4.44 (t, 2H); 3.71 (dt, 2H); 2.33-2.27 (m, 2H); 1.72-1.52 (m, 4H); 1.30-1.15 (m, 5H); 0.85 (t, 3H)

In analogy to example 413, the example compounds ofthe formula I-20 listed in table 22, in which R¹²⁰ has the meaning given in table 22, were prepared.

O

I-20

Table 22. Example compounds ofthe formula I-20

Example	R120	LC/MS Method	m/z [MH4]	Rétention time [min]
414	3,4-difluoro-phenyl	LC4	449.20	1.27
415	3,5-difluoro-phenyl	LC4	449.21	1.27
416	3-trifluoromethoxy-phenyl	LC4	497.25	1.32
417	3-chloro-4-methoxy-phenyl	LC4	477.24	1.27

In analogy to example 119, the compounds of examples 418 and 419 were synthesized using the respective amino acid methyl ester hydrochloride in the amide coupling step.

Example 418 trans- 1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-4-ethylcyclohexanecarboxylic acid

189

¹H-NMR: δ = 12.0 (s, 1H); 8.0& (s, 1 H); 7.48-7.44 (m, 2H); 7.42-7.38 (m, 1 H); 7.37-7.25 (m, 3H); 7.03 (d, 1H); 4.82 (t, 1H); 4.22 (t, 2H); 4.02 (t, 2H); 3.78-3.70 (m, 2H); 3.06 (t, 2H); 2.31-2.22 (m, 2H); 1.68-1.52 (m, 4H); 1.32-1.12 (m, 5H); 0.85 (t, 3H)

Example 419 cis- 1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-4-ethylcyclohexanecarboxylic acid

¹H-NMR: δ = 12.1 (s, 1H); 7.97 (s, 1H); 7.49-7.43 (m, 2H); 7.41-7.38 (m, 1H); 7.37-7.26 (m, 3H); 7.03 (d, 1H); 4.82 (t, 1H); 4.23 (t, 2H); 4.02 (t, 2H); 3.78-3.70 (m, 2H); 3.08 (t, 2H); 2.34-2.24 (m, 2H); 1.68-1.50 (m, 4H); 1.27-1.11 (m, 5H); 0.83 (t, 3H)

In analogy to example 119, the compounds of examples 420, 421 and 422 were synthesized using 2-phenylethanol in the éthérification step and the respective amino acid methyl ester hydrochloride in the amide coupling step.

Example 420 trans- 1-[4-(2-Hydroxy-ethoxy)-3-phenethyloxy-benzoylamino]-4-methyl-cyclohexanecarboxylic acid

LC/MS (Method LC4): Rt = 1.22 min; m/z = 442.30 [MH⁺]

Example 421 cis- 1-[4-(2-Hydroxy-ethoxy)-3-phenethyloxy-benzoylamino]-4-methyl-cyclohexanecarboxylic acid

LC/MS (Method LC4): Rt = 1.21 min; m/z = 442.29 [MH⁺]

Example 422

1-[4-(2-Hydroxy-ethoxy)-3-phenethyloxy-benzoylamino]cycloheptanecarboxylic acid

LC/MS (Method LC4): Rt = 1.20 min; m/z = 442.27 [MH⁺]

Example 423 cis- 4-Ethyl-1-[(5-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)aminoj-cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 90 using cis-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloride instead of trans-1-amino-4-methylcyclohexanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.13 min; m/z = 471.32 [MH⁺]

Example 424 trans- 4-Ethyl-1-[(5-{2-[3-(2-hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)amino]-cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 90 using trans-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloride instead of trans-1-amino-4-methylcyclohexanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.12 min; m/z = 471.33 [MH⁺]

Example 425 cis-4-Ethyl-1-[(3'-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-cyclohexanecarboxylic acid

Step 1: 3'-Fluoro-6,4'-dimethoxy-biphenyl-3-carboxylic acid methyl ester

3-Bromo-4-methoxybenzoic acid methyl ester (500 mg, 2.04 mmol), 3-fluoro-4methoxyphenylboronic acid (381 mg, 2.24 mmol), Tetrakis(triphenylphosphine)palladium(0) (117 mmol, 0.10 mmol), and sodium bicarbonate (514 mg, 6.12 mmol) were partitioned between toluene (5 ml) and water (5 ml) and stirred in reflux for 36 hours. The mixture was partitioned between ethyl acetate and water, the combined organic extracts were dried over sodium sulfate and evaporated to dryness. The raw material was purified by silica gel chromatography with a heptane/ethyl acetate gradient, to yield the title compound (500 mg).

¹H-NMR: δ = 7.95 (dd, 1H); 7.82 (d, 1H), 7.38 (dd, 1 H); 7.30-7.19 (m, 3H); 3.88 (s, 3H); 3.87 (s, 3H), 3.83 (s, 3H).

Step 2: cis-4-Ethyl-1 -[(3'-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]cyclohexanecarboxylic acid

Hydrolysis of the ester group in analogy to step 2 of example 1, coupling of the obtained carboxylic acid to cis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl ester hydrochloride in analogy to step 1 of example 3 and hydrolysis ofthe methyl ester in analogy to step 4 of example 1 yielded the title compound.

¹H-NMR: δ = 12.1 (brs, 1H); 8.06 (s, 1H); 7.84 (dd, 1H); 7.80 (d, 1H); 7.40 (dd, 1H); 7.32 (dd,

H); 7.23 (dd, 1H), 7.18 (d, 1 H); 3.88 (s, 3H); 3.83 (s, 3H); 2.85-2.77 (m, 2H); 1.70-1.50 (m, 4H); 1.25-1.10 (m, 5H); 0.85 (t, 3H).

Example 426 cis-4-Ethyl-1-{[6-hydroxy-5-(3-trifluoromethyi-phenyl)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid

Step 1: 6-Methoxy-5-(3-trifluoromethyl-phenyl)-nicotinic acid methyl ester 5-Bromo-6-methoxy-nicotinic acid methyl ester (1.03 g, 4.18 mmol), 3trifluoromethylbenzeneboronic acid (0.795 g, 4.19 mmol), tetrakis(triphenylphosphine)palladium(0) (24 mg, 0.021 mmol) and sodium bicarbonate (1.05 g, 12.5 mmol) were partitioned between toluene (10 ml) and water (10ml) under argon and stirred in reflux for 1 h. The material was partitioned between ethyl acetate and water, the combined organic extracts were dried over sodium chloride, fîltered over a small plug of silica and evaporated to dryness. The solid material was titured with methanol, fîltered and dried in vacuo to yield the title compound (1.4 g) sufficiently pure for further synthesis.

¹H-NMR: δ = 8.80 (d, 1 H); 8.20 (d, 1 H); 7.93 (s, 1H); 7.90 (d, 1 H); 7.78 (d, 1H); 7.71 (t, 1 H); 3.97 (s, 3H); 3.88 (s, 3H).

Step 2: 6-Methoxy-5-(3-trifluoromethyl-phenyl)-nicotinic acid FFC.GFN2.004.4

The compound of step 1 was hydrolysed in analogy to step 2 of example 1 to yield the title compound.

¹H-NMR: δ = 13.2 (brs, 1H); 8.78 (d, 1H); 8.19 (d, 1H); 7.93 (s, 1H); 7.90 (d, 1H); 7.78 (d, 1H); 7.70 (t, 1 H); 3.97 (s, 3H).

Step 3: cis-4-Ethy 1-1 -{[6-hydroxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid methyl ester as mixture with cis-4-ethyl-1-{[6-methoxy-5-(3trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic acid methyl ester The compound of step 3 (1.09 g, 3.67 mmol) was dissolved in thionyl chloride (5 ml) and stirred for 30 minutes at 60°C. Volatiles were evaporated, the remainder was dissolved in dichloromethane and added to a stirred mixture of cis-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloride (0.813 g, 3.67 mmol) and sodium bicarbonate (1.5 g, 18.3 mmol) in ethyl acetate (25 ml)/water (25 ml). Stirring continued over night, phases were separated, the aqueous phase was extracted twice with ethyl acetate, the combined organic extracts were dried over sodium chloride, decanted and evaporated to dryness in vacuo to yield the title compounds as mixture.

194

Step 4: cis-4-Ethy 1-1 -{[6-hydroxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid

The compound of step 3 (1.71 g, 3.6 mmol)) was dissolved in dioxane (14 ml). 1 M aqueous lithium hydroxide (7 ml) was added, the mixture was stirred at 60 °C for 1 h, cooled, and partitioned between 2 N hydrochloric acid and EA. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium chloride, filtered and evaporated to dryness. The residue was stirred in ethyl acetate (5 ml) and filtered, again to yield the title compound (0.28 g) ¹H-NMR: δ = 12.7 (brs, 1H); 8.16 (s, 1H); 8.14-8.05 (m, 2H); 8.01 (d, 1H); 7.80-7.55 (m, 3H); 2.4-2.25 (m, 2H); 1.65-1.45 (m, 4H); 1.23-1.00 (m, 5H); 0.82 (t, 3H).

Example 427 (1R,2R)-2-Ethyl-1-[(6-methoxy-3'-trifluoromethyl-biphenyl-3-carbonyl)-amino]cyclopropanecarboxylic acid

3-bromo-4-methoxybenzoic acid methyl ester was coupled to 3-trifluoromethyl-phenylboronic acid in analogy to step 3 of example 92, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield 6-methoxy-3'-trifluoromethyl-biphenyl-3-carboxylic acid. This intermediate was coupled to the compound of step 1 of example 361 in analogy to step 1 of example 3, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC4): Rt = 1.30 min; m/z = 408.14 [MH⁺]

Example 428 cis-4-Ethyl-1-[(6-formyl-3'-trifluoromethyl-biphenyl-3-carbonyl)-amino]-cyclohexanecarboxylic acid

Step 1: 6-Methyl-3'-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester 3-trifluoromethylphenylboronic acid (278 mg, 1.46 mmol), tris(dibenzylideneacetone)dipalladium(O) (61 mg, 0.066 mmol), potassium fluoride (255 mg, 4.38 mmol) and tri-tertbutylphosphonium tetrafluoroborate (46 mg, 0.159 mmol) in a flask were thoroughly flushed with argon. 3-bromo-4-methylbenzoic acid methyl ester (304 mg, 1.32 mmol) was added as solution in dioxane (5 ml), the mixture was stirred at 70°C for 3h, filtered over silica and evaporated to dryness. The raw material was purified by silica gel chromatography with a hetane/ethyl acetate gradient to yield the title compound (323 mg).

¹H-NMR: δ = 7.91 (d, 1H); 7.82-7.77 (m, 2H); 7.75-7.70 (m, 3H); 7.51 (d, 1H); 3.85 (s, 3H); 2.30 (s, 3H)

Step 2: 6-Dibromomethyl-3'-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester

The compound of step 1 (1.48 g, 5.03 mmol), N-bromosuccinimide (2.27 g, 12.8 mmol) and dibenzoylperoxide (60 mg, 0.25 mmol) were suspended in tetrachloromethane and stirred for 3 h in reflux. The material was filtered over silica, eluted with diethyl ether and evaporated to dryness to yield the title compound as raw material.

Step 3: 6-Formyl-3'-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester

The compound of step 2 (2.1 g, 4.65 mmol) was dissolved in acetonitrile (25 ml). Silver nitrate (1.97 g, 11.6 mmol) was dissolved in water (3 ml) and this solution was added to the acetonitrile solution. This mixture was stirred for 1 h in reflux. Acetonitrile was evaporated in vacuo, the remainder was partitioned between ethyl acetate and water,the combined organic extracts were dried over sodium chloride, filtered over a small plug of silica and evaporated to dryness. A crystalline crop was yielded on addition of methanol and filtration. The mother liquor was evaporated to dryness and purified by silica gel chromatography with a heptane/ethyl acetate gradient to yield a second crop. Both were combined to yield the title compound (1.0 g). ¹H-NMR: δ = 9.9 (s, 1H); 8.18 (d, 1H); 8.10 (d, 1 H); 8.02 (s, 1H); 7.90 (s, 1H); 7.88 (d, 1 H); 7.83 (d, 1H); 7.76 (t, 1H); 3.91 (s, 3H)

196

Step 4: cis-4-EthyI-1 -[(6-formyl-3'-trifluoromethyl-biphenyl-3-carbonyl)-amino]cyclohexanecarboxylic acid

The title compound of step 3 was hydrolysed in analogy to step 4 of example 1. This intermediate was coupled to cis-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloride in analogy to step 1 of example 3, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC4): Rt = 1.36 min; m/z = 448.18 [MH⁺]

Example 429 trans-4-Ethyl-1-[(6-formyl-3'-trifluoromethyl-biphenyl-3-carbonyl)-amino]-cyclohexanecarboxylic acid

This compound was synthesized in analogy to example 428 using trans-1-amino-4ethylcyclohexanecarboxylic acid methyl ester hydrochloride in the amide coupling step. LC/MS (Method LC4): Rt = 1.35 min; m/z = 448.15 [MH⁺]

Example 430 cis-4-Ethyl-1-[(6-hydroxymethyl-3'-trifluoromethyl-biphenyl-3-carbonyl)-amino]cyclohexanecarboxylic acid

The compound of example 429 (21 mg, 0.047 mmol) was dissolved in tetrahydrofurane (1 ml), cooled in an ice bath, sodium borohydride (2 mg, 0.047 mmol) was added and thereafter methanol (0.2 ml) was added slowly with stirring. After 45 minutes, the mixture was partitioned between ethyl acetate and 2N hydrochloric acid, the combined organic layers were dried over sodium chloride and evaporated to dryness. The remainder was titured with heptane/diethylether and filtered to yield the title compound as white solid.

197

LC/MS (Method LC4): Rt = 1.30 min; m/z = 450.22 [MH⁺]

Example 431 trans-4-Ethyl-1-[(6-hydroxymethyl-3'-trifluoromethyl-biphenyl-3-carbonyl)-amino]-

This compound was synthesized in analogy to example 430 using the title compound of example 429 instead of example 428.

LC/MS (Method LC4): Rt = 1.30 min; m/z = 450.20 [MH⁺]

Example 432 trans-4-Ethyl-1-{[6-(3-hydroxy-propyl)-3'-trifluoromethyl-biphenyl-3-carbonyl]-amino}-

Step 1 6-(2-Carboxy-vinyl)-3'-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester

The compound of step 3 of example 428 (400 mg, 1.30 mmol), malonic acid (262 mg, 2.52 mmol) and piperidine (16 mg, 0.19 mmol) were dissolved in pyridine (0.7 ml) and stirred in reflux for 1h. The material was partitioned between 2N hydrochloric acid and ethyl acetate (product is only sparingly soluble). The combined organic extracts were dried over sodium chloride and evaporated to dryness to yield the title compound.

¹H-NMR: δ = 12.55 (s, 1H); 8.09 (d, 1H); 8.03 (d, 1H); 7.92 (s, 1 H); 7,87 (d, 1H); 7.76 (t, 1 H); 7.74-7.68 (m, 2H); 7.40 (d, 1H); 7.61 (d, 1 H); 3.88 (s, 3H)

LC/MS (Method LC4): Rt = 1.30 min; m/z = 349.16 [M-H⁺]

Step 2: 6-(2-Carboxy-ethyl)-3'-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester

198

The compound of step 1 (400 mg, 1.14 mmol) and Palladium (10 %) on charcoal (23 mg) were suspended in methanol (30 ml). The mixture was hydrogenated for 3 h at 4 bar hydrogen pressure, subsequently filtered over Celite and evaporated to dryness to yield the title compound (372 mg).

¹H-NMR: δ = 12.2 (brs, 1 H); 7.95 (d, 1 H); 7.81 (d, 1 H); 7.78-7.63 (m, 4H); 7.57 (d, 1H); 3.84 (s, 1H); 2.80 (t, 2H); 2.45 (t, 2H)

LC/MS (Method LC4): Rt = 1.29 min; m/z = 351.18 [M-H⁺]

Step 3: 6-(3-Hydroxy-propyl)-3'-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester

The compound of step 2 (150 mg, 0.428 mmol) was dissolved in THF. N-methylmorpholine (56 mg, 0.556 mmol) and isobutylchloroformate (70 mg, 0.514 mmol) were added at room température. After stirring for 2 minutes, the mixture was filtered and rinsed with THF. Sodium borohydride (65 mg, 1.71 mmol) was added to the filtrate and thereafter slowly methanol until intensive foaming indicated the start of the reaction. After 5 minutes the reaction was complété as indicated by LC-MS analytics. Volatiles were evaporated in vacuo, the remainder was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the combined organic extracts were dried over sodium chloride and evaporated to dryness. This raw material was purified by silica gel chromatography with a hetpane/ethyl acetate gradient to yield the title compound (106 mg) ¹H-NMR: δ = 7.95 (dd, 1H); 7.80 (d, 1H); 7.75-7.66 (m, 4H); 7.52 (d, 1H); 4.40 (t, 1H); 3.85 (s, 3H); 3.30-3.25 (m, 2H); 2.64-2.58 (m, 2H); 1.62-1.55 (m, 2H);

Step 4: 4-EthyI-1 -{[6-(3-hydroxy-propyl)-3'-trifluoromethyl-biphenyl-3-carbonyl]-amino}cyclohexanecarboxylic acid

The title compound of step 3 was hydrolysed in analogy to step 4 of example 1. This intermediate was coupled to trans-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloride in analogy to step 1 of example 3, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC4): Rt = 1.32 min; m/z = 478.22 [MH⁺]

Example 433 cis-4-Ethyl-1-{[6-(3-hydroxy-propyl)-3'-trifluoromethyl-biphenyl-3-carbonyl]-amino}cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 432 using cis-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloride instead of trans-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.32 min; m/z = 478.20 [MH⁺]

Example 434 cis-1-{[6-(3-Hydroxy-propyl)-3'-trifluoromethyl-biphenyl-3-carbonyl]-amino}-4-methylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 432 using cis-1-amino-4-methylcyclohexanecarboxylic acid methyl ester hydrochloride instead of trans-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.29 min; m/z = 464.24 [MH⁺]

Example 435 cis- 1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-ethyl-pyridine-3-carbonyl}-amino)-4-methylcyclohexanecarboxylic acid

Step 1: 5-[2-(3-Chloro-phenyl)-ethoxy]-nicotinic acid ethyl ester

5-Hydroxy-nicotinic acid ethyl ester and 2-(3-chlorophenyl)ethanol were etherified in a Mitsunobu reaction in analogy to step 3 of example 3 to yield the titie compound.

O

200

LC/MS (Method LC4): Rt = 1.36 min; m/z = 306.12 [MH⁺]

Step 2: 5-[2-(3-Chloro-phenyl)-ethoxy]-4-ethyl-4H-pyridine-1,3-dicarboxylic acid 3-ethyl ester 1phenyl ester

The compound of step 1 (100 mg, 0.327 mmol) was dissolved in THF (1.5 ml) and the mixture was cooled to -30°C. Phenyl chloroformate (77.6 mg, 0.49 mmol) was added and the mixture was stirred for 10 minutes. Ethyl magnesiumbromide (0.589 ml, 1M in THF) was added at -30°C and the mixture was stirred for 30 minutes, partitioned between diethylether and aqueous ammonium chloride solution, the combined organic extracts were dried over sodium chloride and evaporated to dryness in vacuo. The raw material was purified by silica gel chromatography with a heptane/ethyl acetate gradient to yield the title compound (84 mg).

LC/MS (Method LC4): Rt = 1.51 min; m/z = 456.19 [MH⁺]

Step 3: 5-[2-(3-Chloro-phenyl)-ethoxy]-4-ethyl-nicotinic acid ethyl ester

The title compound of step 2 (80 mg, 0.175 mmol)) was dissolved in dichlorométhane. 2,3dichloro-5,6-dicyano-1,4-benzoquinone (80 mg, 0.35 mmol) was added and the mixture was stirred over night at room température. The mixture was partitioned between ethyl acetate and saturated sodium hydrogencarbonate solution with addition of some sodium sulfit. The combined organic extracts were dried over sodium chloride und avaporated to dryness in vacuo. The material was titured with diethyl ether, the solid material was separated by suction filtration, the filtrate was evaporated to dryness, again, to yield the title compound.

LC/MS (Method LC6): Rt = 5.01 min; m/z = 334.11 [MH⁺]

Step 4: cis- 1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-ethyl-pyridine-3-carbonyl}-amino)-4-methylcyclohexanecarboxylic acid

The title compound of step 3 was hydrolysed in analogy to step 2 of example 1, for extraction purpose, the aqueous phase was neutralised but not acidified. The crude acid was titured with ether and filtered but was reacted further as raw material with cis-1-amino-4methylcyclohexanecarboxylic acid methyl ester hydrochloride in analogy to step 1 of example 3, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC4): Rt = 1.34 min; m/z = 445.18 [MH⁺]

Example 436 trans-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-ethyl-pyridine-3-carbonyl}-amino)-4-methylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 435 using trans-1-amino-4-methylcyclohexanecarboxylic acid methyl ester hydrochloride instead of cis-1 -amino-4-methylcyclohexanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.33 min; m/z = 445.17 [MH⁺]

Example 437 cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-ethyl-pyridine-3-carbonyl}-amino)-4-ethylcyclohexanecarboxylic acid

O

The title compound was synthesized in analogy to example 435 using cis-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloride instead of cis-1-amino-4-methylcyclohexanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.38 min; m/z = 459.20 [MH⁺]

Example 438 trans-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-ethyl-pyridine-3-carbonyl}-amino)-4-ethyicyclohexanecarboxylic acid

O

202

The title compound was synthesized in analogy to example 435 using trans-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloride instead of cis-1-amino-4-methylcyclohexanecarboxylic acid methyl ester hydrochloride.

LC/MS (Method LC4): Rt = 1.23 min; m/z = 459.26 [MH⁺]

Example 439 trans-1-({5-Acetyl-4-[2-(3-chloro-phenyl)-ethoxy]-thiophene-2-carbonyl}-amino)-4-ethylcyclohexanecarboxylic acid

5-Acetyl-4-hydroxythiophene-2-carboxylic acid methyl ester and 2-(3-chlorophenyl)ethanol were etherified in a Mitsunobu reaction in analogy to step 3 of example 3. This intermediate was hydrolysed in analogy to step 2 of example 1, coupled with trans-1-amino-4ethylcyclohexanecarboxylic acid methyl ester hydrochloride in analogy to step 1 of example 3, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound.

LC/MS (Method LC4): Rt = 1.37 min; m/z = 478.15 [MH⁺]

Example 440 trans- 1-({4-[2-(3-Chloro-phenyl)-ethoxy]-5-ethyl-thiophene-2-carbonyl}-amino)-4-ethylcyclohexanecarboxylic acid

5-Acetyl-4-[2-(3-chloro-phenyl)-ethoxy]-thiophene-2-carboxylic acid methyl ester (78 mg, 0.23 mmol) was dissolved in 0.5 M methanolic hydrogen chloride and hydrogenated with15 mg Palladium 10% on charcoal at room température with 3 bar hydrogen pressure for 14 days. The mixture was filtered over Celite, evaporated to dryness in vacuo and purified by silica gel chromatography with a heptane/ethyl acetate gradient. This intermediate was hydrolysed in

203 analogy to step 2 of example 1, coupled with trans-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester hydrochloride in analogy to step 1 of example 3, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound. LC/MS (Method LC4): Rt = 1.31 min; m/z = 464.22 [MH⁺]

Example 441 trans- 4-Ethyl-1-{[4-methoxy-3-(2-m-tolyl-ethoxy)-benzoyl]-methyl-amino}-cyclohexanecarboxylic acid

H

O

Trans-4-ethyl-1-methylaminocyclohexanecarboxylic acid methyl ester hydrochloride was synthesized in via a Strecker aminonitrile synthesis using N-methylamine hydrochloride instead of ammonium chloride, subséquent acidic hydrolysis ofthe nitrile to the carboxylic acid and acidic esterificationin in methanol. This intermediate was coupled to 4-methoxy-3-(2-m-tolylethoxy)-benzoic acid chloride in analogy to step 3 of example 1, and the obtained ester intermediate was hydrolyzed in analogy to step 4 of example 1 to yield the title compound. LC/MS (Method LC4): Rt = 1.39 min; m/z = 454.33 [MH⁺]

Example 442 (R,S)-trans-4-Methyl-1-[4-(2-m-tolyl-ethoxy)-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzoylamino]cyclohexanecarboxylic acid

O

204

Step 1: 3-Formyl-4-(2-m-tolyl-ethoxy)-benzoic acid 2-m-tolyl-ethyl ester

4.0g 3-Formyl-4hydroxybenzoic acid, 9.6g 1-(2-Bromo-ethyl)-3-methyl-benzene, and 13.3g K₂CO₃ were added to 100ml of anhydrous DMF and stirred at 90°C for 14h. Then 300ml of water were added, and extracted three times with 200ml EA each. The organic layer was then washed with 200ml of water, dried using MgSO₄, and evaporated yielding 8.0g ofthe title compound that was used without further purification.

Step 2: 3-Formyl-4-(2-m-tolyl-ethoxy)-benzoic acid

8.0g of 3-Formyl-4-(2-m-tolyl-ethoxy)-benzoic acid 2-m-tolyl-ethyl ester and 1,7g of LiOH (Monohydrate) were stirred in 30ml of THF and 2ml of water at room température for 16h. Then, an additional 1g of LiOH (monohydrate) was added and the mixture stirred at room température for 4h. Then, 100ml of water were added, the THF evaporated and the aqueous layer was washed twice with diisopropylether, 100ml each. The aqueous layer was then acidified to pH = 3 using aqueous HCI-solution and the crude product collected by filtration. Chromatography on silica gel using a gradient EA/HEP to EA yielded 1.2g of the title compound that was used without further purification.

Step 3: (R,S) 4-(2-m-Tolyl-ethoxy)-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzoic acid

0.75g of 3-Formyl-4-(2-m-tolyl-ethoxy)-benzoic acid, 8.9mg of 1,3-Bis(1-adamantyl)imidazol-2ylidene, and 1.9g of (Trifluormethyl)trimethylsilane were dissolved in 10ml of anhydrous DMF and stirred at room température for 24h. Then, another 5mg of 1,3-Bis(1-adamantyl)imidazol-2ylidene and 1.0g of (Trifluormethyl)trimethylsilane were added and stirring was continued at room température for 24h. Then, 10ml of a 2n aqueous solution of HCl were added and the mixture was stirred at room température for 4h. Then, 50ml of water were added and the mixture extracted tree times using 30ml EA each. The organic layer was dried using MgSO₄ and the solvent evaporated to yield 0.7g of the title compound that was used without further purification.

Step 4: 4-Methyl-1 -[4-(2-m-tolyl-ethoxy)-3-(2,2,2-trifluoro-1 -hydroxy-ethyl)-benzoylamino]cyclohexanecarboxylic acid methyl ester

The title compound was synthesized form (R,S) 4-(2-m-Tolyl-ethoxy)-3-(2,2,2-trifluoro-1hydroxy-ethyl)-benzoic acid and trans-1-Amino-4-methyl-cyclohexanecarboxylic acid methyl ester in analogy to example 126, step 4.

R_f (EA/HEP 1:2) = 0.28

205

Step 5: 4-Methyl-1 -[4-(2-m-tolyl-ethoxy)-3-(2,2,2-trifluoro-1 -hydroxy-ethyl)-benzoylamino]cyclohexanecarboxylic acid

170mg of 4-Methyl-1-[4-(2-m-tolyl-ethoxy)-3-(2,2,2-trifluoro-1-hydroxy-ethyl)-benzoylamino]cyclohexanecarboxylic acid methyl ester and 28mg of lithium hydroxide were stirred in 50ml of methanol and 1ml of water for 5h at 40°C. The reaction mixture was then diluted using 10ml of water, the methanol evaporated and acidified to pH = 2 using aqueous NaHS0₄-solution. The mixture was then stirred for 30 minutes at room température, the product isolated by filtration and dried in vacuo to yield 138mg ofthe title compound.

LC/MS (Method LC4): Rt = 1.32 min. m/z = 494.29 [MH⁺]

Example 443 Trans-1-{[3'-Chloro-6-(3,3-difluoro-cyclobutoxy)-4'-methoxy-biphenyl-3-carbonyl]-amino}-4methyl-cyclohexanecarboxylïc acid

Step 1: 4-(3,3-Difluoro-cyclobutoxy)-3-nitro-benzoic acid methyl ester

1.0g of Methyl 4-fluoro-3-nitrobenzoate, 1.6g of 3,3-Difluoro-cyclobutanol, and 3.3g of Cs₂CO₃ were stirred in 10ml of anhydrous DMF for 7h at 60°C. The reaction mixture was then poured into 100ml of water and extracted three times using 30ml of EA each. The organic layer was dried using MgSO₄ and volatiles were evaporated to yield 1.4g ofthe title compound that was used without further purification.

Step 2: 3-Amino-4-(3,3-difluoro-cyclobutoxy)-benzoic acid methyl ester

1.4g of 4-(3,3-Difluoro-cyclobutoxy)-3-nitro-benzoic acid methyl ester were dissolved using 50ml of EA and 10ml of acetic acid, 200mg of Pd/C 10% (50% water) added and hydrogenated under

206 an atmosphère of hydrogen at normal pressure for 16h at room température. The reaction mixture was filtrated, 100ml of EA added and washed twice using 30ml of a saturated aqueous Na₂CO₃-solution. The organic layer was dried using MgSO₄ and volatiles were evaporated to yield 1.0g ofthe title compound that was used without further purification.

Step 3: 3-Bromo-4-(3,3-difluoro-cyclobutoxy)-benzoic acid methyl ester

1.0g of 3-Amino-4-(3,3-difluoro-cyclobutoxy)-benzoic acid methyl ester was dissolved in 100ml of half-concentrated aqueous HBr-solution. Then, a solution of 295mg NaNO₂ in 5ml of water was added dropwise at 0°C. Stirring was continued at 0°C for 15 minutes. Then, a solution of 558mg CuBr in 10ml of half-concentrated aqueous HBr-solution was added dropwise and the reaction mixture was stirred for 2h at room température. Then, the reaction mixture was extracted three times using 100ml of EA each. The organic layer was then washed three times using 100ml of a saturated aqueous NaHCO₃-solution, dried using MgSO₄ and volatiles were evaporated to yield 150mg ofthe title compound that was used without further purification.

Step 4: 3'-Chloro-6-(3,3-difluoro-cyclobutoxy)-4'-methoxy-biphenyl-3-carboxylic acid methyl ester

150mg of 3-Bromo-4-(3,3-difluoro-cyclobutoxy)-benzoic acid methyl ester, 113mg of 3-chloro-4methoxyphenylboronic acid,129mg K₂CO₃, 10mg of palladium(ll)acetate, and 25mg of triphenylphosphine were dissolved using 10ml of DMF and 0.5ml of water. The reaction mixture was stirred at 120°C for 2h, then cooled to room température, 50ml of water added and extracted three times using 30ml of EA each. The organic layer was dried using MgSO₄ and volatiles were evaporated. Chromatography on silica gel using EA/HEP 1:5 yielded 90mg ofthe title compound, viscous oil.

R_f (EA/HEP 1:5) = 0.37

Step 5: 3'-Chloro-6-(3,3-difluoro-cyclobutoxy)-4'-methoxy-biphenyl-3-carboxylic acid 85mg of 3'-Chloro-6-(3,3-difluoro-cyclobutoxy)-4'-methoxy-biphenyl-3-carboxylic acid methyl ester and 14mg of LiOH (monohydrate) were dissolved using 5ml of methanol and 0.5ml of water. The mixture was stirred for 15h at room température. Then, 14mg of LiOH (monohydrate) were added and the reaction mixture stirred for 24h at room température. Then, 10ml of water were added and the methanol evaporated. The mixture was then acidified to pH = 2 using aqueous NaHS0₄-solution. The mixture was stirred for 30 minutes at room température. The productwas then collected byfiltration and dried in vacuo to yield 65mg ofthe title compound that was used without further purification.

207

Step 6: 1 -{[3'-Chloro-6-(3,3-difluoro-cyclobutoxy)-4'-methoxy-biphenyl-3-carbonyl]-amino}-4methyl-cyclohexanecarboxylic acid methyl ester

The title compound was synthesized form 3'-Chloro-6-(3,3-difluoro-cyclobutoxy)-4'-methoxybiphenyl-3-carboxylic acid and trans-1-Amino-4-methyl-cyclohexanecarboxylic acid methyl ester in analogy to example 126, step 4.

R_f (EA/HEP 1:1) = 0.40

Step 7: Trans-1-{[3'-Chloro-6-(3,3-difluoro--cyclobutoxy)-4'-methoxy-biphenyl-3-carbonyl]amino}-4-methyl-cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 442, step 5.

LC/MS (Method LC4): Rt = 1.35 min. m/z = 508.18 [MIT]

Example 444 1-[(2',6'-Difluoro-4'-methoxy-6-trifluoromethyl-biphenyl-3-carbonyl)-amino]-4-methylcyclohexanecarboxylic acid

Step 1: 3-Bromo-4-trifluoromethyl-benzoic acid

5.0g of 3-amino-4-trifluoromethyl-benzoic acid were dissolved using 50ml of acetic acid. Then, 50g of ice and 50ml of a saturated aqueous HBr-solution were added and a solution of 2.0g NaNO₂ in 10ml of water was added dropwise at 0°C. The reaction mixture was then stirred at room température for 10 minutes. Then, the reaction mixture was added dropwise to a suspension of 7.0g CuBr and 10.9g CuBr2 in 100ml of a half-concentrated aqueous solution of HBr. The resulting mixture was then stirred for 2h at room température, then diluted using 2I of water, stirred for 1 h and finally the precipitate was isolated by filtration. The precipitate was dried in vacuo to yield 5.2 g ofthe title compound that was used without further purification.

208

Step 2: 1-(3-Bromo-4-trifluoromethyl-benzoylamino)-4-methyl-cyclohexanecarboxylic acid methyl ester

The title compound was synthesized form 3-Bromo-4-trifluoromethyl-benzoic acid and trans-1Amino-4-methyl-cyclohexanecarboxylic acid methyl ester in analogy to example 126, step 4. R_f (EA/HEP 1:2) = 0.31

Step 3: 1 -[(2',6'-Difluoro-4'-methoxy-6-trifluoromethyl-biphenyl-3-carbonyl)-amino]-4-methylcyclohexanecarboxylic acid methyl ester

300mg of 1-(3-Bromo-4-trifluoromethyl-benzoylamino)-4-methyl-cyclohexanecarboxylic acid methyl ester, 267mg of 2,6-difluoro-4-methoxyphenylboronic acid, 65mg of tris(dibenzylideneacetone)di-paliadium(0), 96mg of bis(2-dicyclohexylphosphinophenyl)ether, 453mg of K₃PO₄, and 1g of molecular sieve 4A were added to 10ml of toluene. The mixture was made oxygen-free by passing argon through it. Then, the mixture was kept at 160°C under microwave irradiation for2h. Then, 267mg of 2,6-difluoro-4-methoxyphenylboronic acid, 65mg of tris(dibenzyiideneacetone)di-pailadium(0), 96mg of bis(2-dicyclohexylphosphinophenyl)ether were added and the mixture was kept at 160°C under microwave irradiation for 2h. The mixture was cooled to room température and 100ml of EA added. The mixture was then washed twice using 20ml of a saturated aqueous Na₂CO₃-solution each. The organic layer was dried using MgSO₄ and the solvent evaporated. Chromatography on silica gel using EA/HEP 1:5 yielded 16mg ofthe title compound, viscous oil.

Step 4: 1-[(2',6'-Difluoro-4'-methoxy-6-trifluoromethyl-biphenyl-3-carbonyl)-amino]-4-methylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 442, step 5.

LC/MS (Method LC4): Rt = 1.34 min. m/z = 472.14 [MH⁺]

Example 445 1-[(3'-Chloro-2',6'-difluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methylcyclohexanecarboxylic acid

209

Step 1: 3-Chloro-2,6-difluoro-4-methoxyphenylboronic acid

5.1g of 2,2,6,6-tetramethylpiperidine were dissolved using 200ml of anhydrous THF. 12.4ml ofa 2.7M solution of n-butyllithium in heptane were added at -10°C and the mixture was stirred for 10 minutes at -10°C. The mixture was then cooled to -70°C and a solution of 5.0g 2-chloro-3,5difluoroanisole in 40ml of anhydrous THF added dropwise at -70°C. Stirring was continued for 1h at -75°C. Then, 7.9g of triisopropyl borat were added and the mixture was allowed to warm to room température. Stirring was continued for 1h at room température. Then, the reaction mixture was poured into 200ml of a saturated aqueous NaHS0₄-solution and extracted twice using 100ml EA each. The organic layer was washed using 100ml ofa saturated aqueous NaHSO₄-solution, dried using MgSO₄ and evaporated to yield 5.6g ofthe title compound that was used without further purification.

Step 2: 1-(3-Bromo-4-methoxy-benzoylamino)-4-methyl-cyclohexanecarboxylic acid methyl ester

The title compound was synthesized form 3-bromo-4-methoxy-benzoic acid and trans-1-amino4-methyl-cyclohexanecarboxylic acid methyl ester in analogy to example 126, step 4.

R_f (EA/HEP 1:2) = 0.12

Step 3: 1-[(3'-Chloro-2',6'-difluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]--4-methylcyclohexanecarboxylic acid methyl ester

300mg of 1-(3-Bromo-4-methoxy-benzoylamino)-4-methyl-cyclohexanecarboxylic acid methyl ester, 36 mg of trîs(dibenzylideneacetone)di-palladium(0), 150mg of KF, 27mg of tri-tertbutylphosphonium tetrafluoroborate, and 347mg of 3-Chloro-2,6-difluoro-4methoxyphenylboronic acid were suspended using 5ml of anhydrous dioxane and oxygen was

210 removed by passing argon through. Then, 12mg of Ν,Ν-diisopropylethylamine were added and again argon passed through the suspension. Stirring was continued for 24h at room température. The reaction mixture was then filtered and evaporated. The residue was purified by préparative RP HPLC (water/ACN gradient) to yield 150mg ofthe title compound, viscous oil.

Step 4: 1 -[(3'-Chloro-2',6'-difluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methylcyclohexanecarboxylic acid

150mg of 1-[(3'-Chloro-2’,6'-difluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methylcyclohexanecarboxylic acid methyl ester and 25mg NaOH were dissoled using 5ml of dioxane and 0.5ml of water. The mixture was stirred at 80°C for 6h. Then, 15ml of water were added, the dioxane evaporated and acidified to pH = 3 using aqueous NaHSO₄-solution. The mixture was stirred for 30 minutes at room température. The product was then isolated by filtration and dried in vacuo to yield 110mg of the title compound.

LC/MS (Method LC4): Rt = 1.32 min. m/z = 468.16 [MH⁺]

Example 446 Trans-1-[(3'-Chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methylcyclohexanecarboxylic acid

O

F

Step 1: 3-Bromo-5-fluoro-4-hydroxy-benzoic acid methyl ester

3.9g of 3-fluoro-4-hydroxy-benzoic acid methyl ester were dissolved using 25ml of acetic acid and 25ml of DCM. The mixture was cooled to 0°C and 1.4ml bromine added slowly (30 minutes) at 0°C. Stirring was continued at room température for 18h. Then, 200ml of EA and a solution of 7.6g Na₂SO₃ in 50ml of water were added and the resulting mixture was stirred for 10 minutes at room température. The layers were separated, and the organic layer was washed using first 50ml of water and second 50mi of a saturated aqueous NaCI-solution. The organic layer was

211 dried using MgSO₄ and evaporated to yield 5.0g of the title compound that was used without further purification.

Step 2: 3-Bromo-5-fluoro-4-methoxy-benzoic acid methyl ester

5.0g of 3-Bromo-5-fluoro-4-hydroxy-benzoic acid methyl ester were dissolved using 50ml of acetone. Then, 8.3g of K₂CO₃ and 2.5ml of CH₃I were added and the reaction mixture stirred at room température for 48h. The reaction mixture was then filtrated and evaporated. Chromatography on silica gel using EA/HEP 1:2 yielded 2.0g ofthe title compound, oil.

Step 3: 3'-Chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carboxylic acid methyl ester 500mg of 3-Bromo-5-fluoro-4-methoxy-benzoic acid methyl ester, 532mg of 3-chloro-4methoxyphenylboronic acid, 110mg of tetrakis(triphenylphosphine) palladium(O), and 2.5g Cs₂CO₃ were dissolved using 16.5ml of DMF and 3.5ml of water. The reaction mixture was stirred at 45°C for 2h and then poured into 75ml of water. The reaction mixture was then extracted three times using 50ml of EA each. The organic layer was washed twice using 25ml of a half-saturated aqueous NaCI-solution, dried using MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP 1:3 yielded 500mg ofthe title compound, viscous oil.

Step 4: 3'-Chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carboxylic acid 500mg of 3'-Chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carboxylic acid methyl ester were dissolved using 10ml of methanol and 1.8ml of a 1M aqueous NaOH-solution added. The reaction mixture was stirred at 60°C for 5h and was then allowed to cool to room température. The reaction mixture was then poured into 25ml of water and acidified to pH = 4 using aqueous NaHS0₄-solution. The mixture was extracted three times using 20ml of EA each. The organic layer was dried using MgSO₄ and evaporated to yield 430mg ofthe title compound that was used without further purification.

Step 5: 1-[(3'-Chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methylcyclohexanecarboxylic acid methyl ester

The title compound was synthesized form 3'-Chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3carboxylic acid and trans-1-amino-4-methyl-cyclohexanecarboxylic acid methyl ester in analogy to example 126, step 4.

Step 6: 1-[(3'-Chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methylcyclohexanecarboxylic acid

212

The title compound was synthesized form 1-[(3'-Chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3carbonyl)-amino]-4-methyl-cyclohexanecarboxylic acid methyl ester in analogy to example 126, step 5.

LC/MS (Method LC4): Rt = 1.34 min. m/z = 450.11 [MH⁺]

Example 447

Cis-1-[(3'-chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-ethylcyclohexanecarboxylic acid

The title compound synthesized in analogy to example XX+4 using cis-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester instead of trans-1-amino-4-methylcyclohexanecarboxylic acid methyl ester.

LC/MS (Method LC4): Rt = 1.38 min. m/z = 464.14 [MH⁺]

Example 448

Cis-1-[(3'-Chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-trifluoromethylcyclohexanecarboxylic acid

213

The title compound synthesized in analogy to example 446 using cis- 1-Amino-4-trifluoromethylcyclohexanecarboxylic acid methyl ester hydrochloride instead of trans-1-amino-4-methylcyclohexanecarboxylic acid methyl ester.

LC/MS (Method LC4): Rt = 1.34 min. m/z = 504.1 [MH⁺]

Example 449 1-[3-(5-Chloro-6-methoxy-pyridin-3-yl)-5-fluoro-4-methoxy-benzoylamino]-4-methylcyclohexanecarboxylic acid

O

F

The title compound was synthesized in analogy to example 446, but using 5-Chloro-6-methoxypyridine-3-boronic acid instead of 3-chloro-4-methoxyphenylboronic acid in step 3

LC/MS (Method LC4): Rt = 1.34 min. m/z = 451.12 [MH*]

Example 450

1-[3-(5-Chloro-6-methoxy-pyridin-3-yl)-5-fluoro-4-methoxy-benzoylamino]-4-ethylcyclohexanecarboxylic acid

Cl

F

214

The title compound was synthesized in analogy to example 449, but using cis-1-amino-4-ethylcyclohexanecarboxylic acid methyl ester instead of trans-1-amino-4-methylcyclohexanecarboxylic acid methyl ester.

LC/MS (Method LC4): Rt = 1.38 min. m/z = 465.14 [MH⁺]

Example 451 1-{[5-(3-Chloro-4-methoxy-phenyl)-pyridine-3-carbonyl]-amino}-4-trifluoromethylcyclohexanecarboxylic acid

Cl

The title compound was synthesized in analogy to examples 446 and 448, but using 5-Bromonicotinic acid methyl ester instead of 3-Bromo-5-fluoro-4-methoxy-benzoic acid methyl ester. LC/MS (Method LC4): Rt = 1.24 min. m/z = 457.11 [MH⁺]

Example 452 1-(3-lndol-1-yl-4-trifluoromethyl-benzoylamino)-4-methyl-cyclohexanecarboxylic acid

F

N

Step 1: 3-Amino-4-trifluoromethyl-benzoic acid methyl ester

2.5g of 3-Amino-4-trifluoromethyl-benzoic acid were dissolved using 50ml of diethyl ether and 25ml of methanol. Then, 6.1ml of a 2M solution of trimethylsilyldiazomethane in hexane were

215 added at 10-20°C. The reaction mixture was stirred at room température for 1h. Then, 6.1ml of a 2M solution of trimethylsilyldiazomethane in hexane were added at 10-20°C. The reaction mixture was stirred at room température for 1h. The reaction mixture was then evaporated. Chromatography on silica gel using EA/HEP 1:2 yielded 2.3g ofthe title compound, viscous oil.

Step 2: 3-lndol-1-yl-4-trifluoromethyl-benzoic acid methyl ester

690mg of 3-Amino-4-trifluoromethyl-benzoic acid methyl ester, 650mg of K₂CO₃, 30mg of Cul, and 28mg of Ν,Ν’-dimethylethylendiamine were suspended using 4.1ml of anhydrous toluene.

410mg of o-bromo-(2-bromo)vinylbenzene were added and the reaction mixture stirred at 110°C for 14h. The reaction mixture was allowed to cool to room température, 50ml of EA added, filtrated, and evaporated. Chromatography on silica gel using EA/HEP (gradient) yielded 220mg ofthe title compound, viscous oil.

Step 3: 1-(3-lndol-1-yl-4-trifluoromethyl-benzoylamino)-4-methyl-cyclohexanecarboxylic acid methyl ester

The title compound synthesized in analogy to example 126, step 4.

Step 4: 1-(3-lndol-1-yl-4-trifluoromethyl-benzoylamino)-4-methyl-cyclohexanecarboxylic acid The title compound synthesized in analogy to example 126, step 5.

LC/MS (Method LC4): Rt = 1.23 min. m/z = 445.22 [MH⁺]

Example 453 1-{[5-(3-Chloro-4-methoxy-phenyl)-pyridine-3-carbonyl]-amino]-4-ethyl-cyclohexanecarboxylic acid

Cl

The title compound was synthesized in analogy to example 451. LC/MS (Method LC4): Rt = 1.17 min. m/z = 417.09 [MH⁺]

216

Example 454

Cis-1-{[2,2-Difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-4-trifluoromethylcyclohexanecarboxylic acid

O

Step 1: 2,2-Difluoro-7-triethylsilanyl-benzo[1,3]dioxole-5-carboxylic acid

200ml of anhydrous diethyl ether were poured to 1.9g of Mg turnings and 2.0g of (6-bromo-2,2difluoro-benzo[1,3]dioxol-4-yl)-triethyl-silane (Eur. J. Org. Chem. 2004, 1,64) added. The mixture was then stirred at 35°C for 30 minutes. Then, the heating was shut down and 23.4g of (6-bromo-2,2-difluoro-benzo[1,3]dioxol-4-yl)-triethyl-silane was added dropwise to the stirred mixture at a rate that ensured gentle boiling. Stirring was continued at 35°C for 2h. Then, the mixture was intensly stirred at room température under an excess of anhydrous CO₂ for 2h. The reaction mixture was then poured into 300ml of a saturated aqueous NH₄CI-solution, acidified to pH = 3 using aqueous HCI-solution and the organic layer separated. The aqueous layer was then extracted using 200ml of diethyl ether. The combined organic layer was dried using MgSO₄ and evaporated to yield 22.0g of the title compound that was used without further purification.

Step 2: 2,2-Difluoro-7-triethylsilanyl-benzo[1,3]dioxole-5-carboxylic acid methyl ester

22.0g of 2,2-difluoro-7-triethylsilanyl-benzo[1,3]dioxole-5-carboxylic acid were dissolved using 200ml of diethyl ether and 100ml of methanol. Then, 35.0ml of a 2M solution of trimethylsilyldiazomethane was added at 10°C-20°C. Stirring was continued for 1h at room température and the mixture then evaporated. Chromatography on silica gel using EA/HEP 1:10 yielded 17.0g of the title compound, colorless oil. R_f (EA/HEP 1:20) = 0.39 Step 3: 2,2-Difluoro-7-iodo-benzo[1,3]dioxole-5-carboxylic acid methyl ester

17.0g of 2,2-difluoro-7-triethylsilanyl-benzo[1,3]dioxole-5-carboxylic acid methyl ester were dissolved using 100ml of CCI₄ and 2.9ml of ICI added. The mixture was then stirred for 3h at 77°C, 1.5ml of ICI added and stirred for 2h at 77°C. The mixture was then allowed to cool to

217 room température, 200ml of CH₂CI₂ added, and washed three times using 300ml of a saturated aqueous Na₂S0₃-soiution each. The organic layer was then dried using MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP 1:20 yielded 10.2g ofthe title compound, colorless oil. R_f (EA/HEP 1:20) = 0.30

Step 4: 7-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester

8.5g of 2,2-difluoro-7-iodo-benzo[1,3]dioxole-5-carboxylic acid methyl ester, 11.2g of bis(neopentyl glycolato)diboron, 9.8g of K₂CO₃, and 1.8g of 1,1’bis(diphenylphosphino)ferrocene-palladium(ll)dichloride were added to 100ml of anhydrous DMSO and the mixture stirred at 80°C for 5h. The mixture was then allowed to cool to room température, 500ml of EA added, and washed three times using 300ml of water each. The organic layerwas dried using MgSO₄ and evaporated to yield 8.2g ofthe title compound that was used without further purification.

Step 5: 2,2-Difluoro-7-hydroxy-benzo[1,3]dioxole-5-carboxylic acid methyl ester

6.0g of 7-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester were dissolved using 200ml of methanol and 30ml of a 33% aqueous solution of H₂O₂ added. Stirring was continued for 30 minutes at room température. The reaction mixture was then concentrated to 20ml and 100ml of water and 100ml of a saturated aqueous NaCIsolution added. The reaction mixture was then extracted three times using 100ml of CH₂CI₂ each, dried using MgSO₄, and evaporated. Chromatography on silica gel using EA/HEP 1:4 yielded 1.8g ofthe title compound, colorless oil.

Step 6: 2,2-Difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acid methyl ester

1.8g of 2,2-difluoro-7-hydroxy-benzo[1,3]dioxole-5-carboxylic acid methyl ester, 4.6g of 1(bromo-ethyl)-3-methyl-benzene, and 3.2g of K₂CO₃ were added to 70ml of anhydrous DMF and the reaction mixture stirred at 80°C for 3h. The reaction mixture was then allowed to cool to room température, 300ml of water added and extracted three times using 100ml of EA each. The organic layer was then dried using MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP 1:4 yielded 2.4g ofthe title compound, colorless oil. R_f (EA/HEP 1:4) = 0.32

Step 7: 2,2-Difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carboxylic acid

The title compound was synthesized from 2,2-difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5carboxylic acid methyl ester in analogy to example 443, step 5.

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Step 8: Cis-1-{[2,2-Difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-4trifluoromethyl-cyclohexanecarboxylic acid methyl ester

The title compound was synthesized from 2,2-difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5carboxylic acid and cis-1-amino-4-trifluoromethyl-cyclohexanecarboxylic acid methyl ester in analogy to example 126, step 4.

R_f (EA/HEP 1:2) = 0.22

Step 9: Cis-1-{[2,2-Difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-4trifluoromethyl-cyclohexanecarboxylic acid

100mg of cis-1-{[2,2-difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-4trifluoromethyl-cyclohexanecarboxylic acid methyl ester were dissolved using 10ml of methanol, 10ml of THF, and 2ml of water. 15.4mg of lithium hydroxide monohydrate were then added and the reaction mixture was stirred at room température for 14h. Stirring was continued for 5h at 40°C. Then, the mixture was evaporated, 10ml of water added and acidified to pH = 2 using aqueous NaHS0₄-solution. The resulting mixture was then stirred for 1 h at room température, and extracted three times using 10ml of CH₂CI₂. The organic layer was then dried using MgSO₄ and evaporated to yield 55mg ofthe title compound, amorphous solid.

LC/MS (Method LC4): Rt = 1.38 min. m/z = 530.33 [MH⁺]

Example 455

1-{[2,2-Difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}cycloheptanecarboxylic acid

The title compound was synthesized in analogy to example 454.

LC/MS (Method LC4): Rt = 1.38 min. m/z = 476.36 [MH⁺]

Example 456

219

Cis-1 -{[2,2-Difluoro-7-(2-m-tolyl-ethoxy)-benzo[1,3]dioxole-5-carbonyl]-amino}-4-ethylcyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 454.

LC/MS (Method LC4): Rt = 1.42 min. m/z = 490.38 [MH⁺]

Example 457

1-[(6-Methoxy-3'-oxetan-3-yl-biphenyl-3-carbonyl)-amino]-cycloheptanecarboxylic acid

Step 1: 3-(3-Bromo-phenyl)-oxetane

4.7g of 3-bromophenylboronic acid, 219mg of Nil₂, 4.3g of sodium bis(trimethylsilyl)amide, and 106mg of trans-2-aminocyclohexanol hydrochloride were added to 14ml of anhydrous 2propanol and oxygen removed by passing argon through the mixture for 10 minutes. Then, a solution of 2.2g of 3-iodo-oxetane in 1ml of anhydrous 2-propanol was added and the mixture kept at 80°C under microwave irradiation for 50 minutes. The mixture was then evaporated, distributed between 100ml of water and 100ml of EA, and the aqueous layer extracted twice using 20ml of EA each. The organic layer was then dried using MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP 1:4 yielded 1.4g ofthe title compound, colorless oil. R_f (EA/HEP 1:4) = 0.27

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Step 2: 6-Methoxy-3'-oxetan-3-yl-biphenyl-3-carboxylic acid methyl ester

1.3g of 3-(3-bromo-phenyl)-oxetane, 1.3g of 2-methoxy-5-methoxycarbonylphenylboronic acid, 1.3g of Na₂CO₃, 69mg of palladium(ll)acetate, and 160mg of triphenylphosphine were combined and 15ml of DMF and 1ml of water added. The mixture was stirred at 100°C for 1h and then allowed to cool to room température. 100ml of EA were then added and washed three times using 30ml of water each. The organic layer was then dried using MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP 1:3 yielded 1.3g ofthe title compound, colorless oil.

Step 3: 6-Methoxy-3'-oxetan-3-yl-biphenyl-3-carboxylic acid

The title compound was synthesized from 6-methoxy-3'-oxetan-3-yl-biphenyl-3-carboxylic acid methyl ester in analogy to example 443, step 5.

Step 4: 1-[(6-Methoxy-3'-oxetan-3-yl-biphenyl-3-carbonyl)-amino]-cycloheptanecarboxylic acid methyl ester

The title compound was synthesized from 6-Methoxy-3'-oxetan-3-yl-biphenyl-3-carboxylic acid and 1-amino-cycloheptanecarboxylic acid methyl ester in analogy to example 126, step 4. R_f (EA/HEP 1:1) = 0.13

Step 5: 1-[(6-Methoxy-3'-oxetan-3-yl-biphenyl-3-carbonyl)-amino]-cycloheptanecarboxylic acid The title compound has been synthesized from 1-[(6-Methoxy-3'-oxetan-3-yl-biphenyl-3carbonyl)-amino]-cycloheptanecarboxylic acid methyl ester in analogy to example 442, step 5. LC/MS (Method LC4): Rt = 1.21 min. m/z = 424.35 [MH⁺]

Example 458 Cis-4-Ethyl-1-[(6-methoxy-3'-oxetan-3-yl-biphenyl-3-carbonyl)-amino]-cyclohexanecarboxylic acid

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The title compound has been synthesized in analogy to example 457. LC/MS (Method LC4): Rt = 1.26 min. m/z = 438.36 [MIT]

Example 459

1-[(6-Methoxy-3'-oxetan-3-yl-biphenyl-3-carbonyl)-amino]-4-trifluoromethylcyclohexanecarboxylic acid

The title compound has been synthesized in analogy to example 457. LC/MS (Method LC4): Rt = 1.22 min. m/z = 478.34 [MIT]

Example 460 1-{4-Methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-4-trifluoromethyl15 cyclohexanecarboxylic acid

222

Step 1: 3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-benzeneboronic acid

50.0g of [2-(3-Bromo-phenyl)-ethoxy]-tert-butyl-dimethyl-silane was dissolved using 500ml of anhydrous THF and 64.6ml of a 2.7M solution of n-butyllithium in n-heptane added dropwise at 70°C. The reaction mixture was then stirred at -70°C for 1h. 40.2ml of triisopropylborate was then added dropwise at -70°C and stirring was continued for 30 minutes at -70°C. The mixture was then allowed to warm to -20°C and 500ml of water added. The reaction mixture was then allowed to warm to room température and extracted three times using 300ml of CH₂CI₂ each. The organic layer was then dried using MgSO₄ and evaporated to yield 43.6g of the title compound, used without further purification.

Step 2: tert-Butyl-dimethyl-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-silane

18.3g of 3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-benzeneboronic acid, 510mg of Nil₂, 19.9g of sodium bis(trimethylsilyl)amide, and 250mg of trans-2-aminocyclohexanol hydrochloride were added to 14.0ml of 2-propanol and the mixture was stirred for 10 minutes at room température. Then, a solution of 10.0g of 3-lodo-oxetane in 6.0ml of 2-propanol was added and the reaction mixture kept at 80°C under microwave irradiation for 30 minutes. The reaction mixture was then poured into 100ml of a saturated aqueous NaHCO₃-solution and extracted three times using 100ml of EA each. The organic layer was then dried using MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP (gradient) yielded 22.0g of the title compound, colorless oil.

Step 3: 2-(3-Oxetan-3-yl-phenyl)-ethanol

9.0g of tert-Butyl-dimethyl-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-silane were dissolved using 200ml of anhydrous THF and 92ml of a 1M solution of tetra-n-butylammonium fluoride in THF added at room température. The reaction mixture was stirred at room température for 3h and then poured into 500ml of a saturated aqueous NaHCO₃-solution and extracted three times using 300ml of

223

EA each. The organic layer was then dried using MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP (gradient) yielded 4.9g ofthe title compound, colorless oil.

Step 4: ToIuene-4-sulfonic acid 2-(3-oxetan-3-yl-phenyl)-ethyl ester

4.9g of 2-(3-Oxetan-3-yl-phenyl)-ethanol were dissolved using 30ml of CH₂CI₂ and 9.5ml of pyridine added. Then, 6.3g of p-toluenesulfonyl chloride was added at 0°C and the reaction mixture stirred for 6h at room température. The reaction mixture was then evaporated, redissolved using 100ml of EA and washed using 100ml of a saturated aqueous NaHCO₃solution. The aqueous layer was then extracted twice using 100ml of EA each. The combined organic layer was then dried using MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP 1:1 yielded 2.0g ofthe title compound, colorless oil.

Step 5: 3-Acetoxy-4-methoxy-benzoic acid

17.0g of 3-Hydroxy-4-methoxy-benzoic acid were added to 51.6g of acetic ahydride and the mixture stirred at 140°C for 3h. The mixture was then allowed to cool to 100°C, 50ml of water added dropwise and the température kept at 100°C. Then, 200ml of water were added and the mixture was stirred at 100°C for 30 minutes. The mixture was then cooled and stirred at 0°C for 1h. The product was then isolated by filtration, washed with 50ml of water and dried under reduced pressure to yield 18.8g ofthe title compound thatwas used withoutfurther purification.

Step 6: 1-(3-Acetoxy-4-methoxy-benzoylamino)-4-trifluoromethyl-cyclohexanecarboxylic acid methyl ester

80.3mg of 3-Acetoxy-4-methoxy-benzoic acid were combined with 1ml of CH₂CI₂, 3pl of DMF added and 0.57ml of a 2M solution of oxalyl chloride in CH₂CI₂ added dropwise under stirring at room température. Stirring was continued until the évolution of gas ceased. Then, the reaction mixture was evaporated, 5ml of CH₂CI₂ added and again evaporated. The residue (crude acid chloride) was then dissolved using 2ml of CH₂CI₂ and added dropwise to an intensely stirred mixture of 100mg of 1-Amino-4-trifluoromethyl-cyclohexanecarboxylic acid methyl ester, 5ml of EA, and 10ml of a saturated aqueous NaHCO₃-solution at 0°C. Stirring was continued for 1h at room température. Then, the organic layer was separated and the aqueous layer was extracted twice using 15ml of EA each. The organic layer was then dried using MgSO₄ and evaporated to yield 105mg ofthe title compound that was used without further purification.

Step 7: 1-(3-Hydroxy~4-methoxy-benzoylamino)-4-trifluoromethyl-cyclohexanecarboxylic acid methyl ester

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105mg of 1-(3-Acetoxy-4-methoxy-benzoylamino)-4-trifluoromethyl-cyclohexanecarboxylic acid methyl ester and 7.0mg of K₂CO₃ were stirred in 4ml of anhydrous methanol for 1h at room température. Then, 10.4mg of K₂CO₃ were added and stirring was continued for 2h at room température. 10ml of EA and 10ml of a 1N aqueous HCI-solution were then added. The layers were separated and the aqueous layer was extracted twice using 10ml of EA each. The combined organic layers were washed twice using 10 ml of a saturated aqueous NaHCO₃solution, once using 10ml of a 1N aqueous HCI-solution, and once using a 10 ml ofa saturated aqueous NaCI-solution. The organic layer was then dried using MgSO₄ and evaporated to yield 60mg ofthe title compound that was used without further purification.

Step 8: 1 -{4-Methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-4-trifluoromethylcyclohexanecarboxylic acid methyl ester

60mg of 1-(3-Hydroxy-4-methoxy-benzoylamino)-4-trifluoromethyl-cyclohexanecarboxylic acid methyl ester, 53mg of toluene-4-sulfonic acid 2-(3-oxetan-3-yl-phenyl)-ethyl ester, and 66mg of K₂CO₃ were added to 3ml of DMF and the mixture was stirred for 8h at 40°C. Then, 27mg of toluene-4-sulfonic acid 2-(3-oxetan-3-yl-phenyl)-ethyl ester were added and stirring was continued for 8h at 40°C. Then, 10ml of EA and 15ml of a half-saturated aqueous NaCI-solution were added. The layers were separated and the aqueous layer was extracted twice using 10ml of EA each. The combined organic layer was then dried using MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP 1:1 yielded 77mg ofthe title compound, amorphous solid.

Step 9: 1 -{4-Methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-4-trifluoromethylcyclohexanecarboxylic acid

77mg of 1-{4-Methoxy-3-[2-(3-oxetan-3-yl-phenyl)-ethoxy]-benzoylamino}-4-trifluoromethylcyclohexanecarboxylic acid methyl ester were dissolved using 3.5ml of methanol and 173μΙ of a 1M aqueous solution of NaOH added. The mixture was stirred at 60°C for 8h. The mixture was then poured into 10ml of water and acidified to pH = 5 using 5% aqueous NaHSO₄-solution. The mixture was then extracted three times using 15ml of EA each. The organic layer was then dried using MgSO₄ and evaporated.

LC/MS (Method LC4): Rt = 1.23 min. m/z = 522.29 [MH⁺]

Example 461 Cis-1-{[5-(3-Chloro-4-methoxy-phenyl)-pyridine-3-carbonyl]-amino}-4-ethylcyclohexanecarboxylic acid

225

Step 1: 5-(3-Chloro-4-methoxy-phenyl)-nicotinic acid methyl ester

6.5g of 3-chloro-4-methoxyphenylboronic acid, 5.0g of methyl 5-bromonicotinate, 1.3g of tetrakis(triphenyiphosphine)pailadium(0), and 22.6g of Cs₂CO₃ were stirred in 325ml of DMF and 65ml of water for 3h at 45°C. The reaction mixture was then poured into 750ml of water and extracted three times using 300ml of EA each. The combined organic layers were then washed twice using 150ml of water each. The organic layer was then dried using MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP (gradient) yielded 2.4g ofthetitle compound, colorless oil.

Step 2: 5-(3-Chloro-4-methoxy-phenyl)-nicotinic acid 5-(3-Chloro-4-methoxy-phenyl)-nicotinic acid methyl ester was saponified in analogy to example 460, step 9.

Step 3: 1 -{[5-(3-Chloro-4-methoxy-phenyl)-pyridine-3-carbonyl]-amino}-4-ethylcyclohexanecarboxylic acid methyl ester

The title compound was synthesized from 5-(3-Chloro-4-methoxy-phenyl)-nicotinic acid and 1Amino-4-ethyl-cyclohexanecarboxylic acid methyl ester in analogy to example 126, step 4.

Step 4: Cis-1 -{[5-(3-Chloro-4-methoxy-phenyl)-pyridine-3-carbonyl]-amino}-4-ethylcyclohexanecarboxylic acid

The title compound has been synthesized in analogy to example 460, step 9.

LC/MS (Method LC4): Rt = 1.17 min. m/z = 417.09 [MH⁺]

Example 462

Cis-4-Ethyl-1-[4-(2-methanesulfonyl-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]cyclohexanecarboxylic acid

226

Step 1: 3-Hydroxy-4-iodo-benzoic acid methyl ester

37.0g of methyl 4-amino-3-hydroxybenzoate were stirred in 200ml of water and 200g of ice and 300ml of a saturated aqueous HCI-solution added. Stirring was continued for 5 minutes. A solution of 16.8g NaNO₂ was then added drop-wise at 0°C and the mixture was stirred at 0°C for 10 minutes. The resulting solution was then added portion-wise to a solution 73.5g Kl in 300ml of water at 25°C. Stirring was continued for 1h at 25°C-30°C. The reaction mixture was the extracted three times using 200ml of EA each. The organic layer was then washed successively once using 100ml of a 1M aqueous HCI-solution, once using 100ml of a saturated aqueous Na₂S0₃-solution, and three times using 100ml of a saturated aqueous NaHCO₃solution each. The organic layer was then dried using MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP 1:2 yielded 37.0g ofthe title compound, colorless oil.

R_f (EA/HEP 1:2) = 0.34

Step 2: 4-lodo-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester

10.0g of 3-Hydroxy-4-iodo-benzoic acid methyl ester, 14.3g of 1-(2-bromo-ethyl)-3-methylbenzene, and 10.0g of K₂CO₃ were stirred in anhydrous DMF at 80°C for 10h. Then, 14.3g of 1(2-bromo-ethyl)-3-methyl-benzene, and 10.0g of K₂CO₃ were added and stirring was continued at 80°C for 10h. 400ml of EA were then added and the mixture was washed twice using 200ml of water each. The organic layer was then dried using MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP (gradient) yielded 11.5g ofthe title compound, colorless oil.

Step 3: 4-((E)-2-Methanesulfonyl-vinyl)-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester 500mg of 4-lodo-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester, 200mg of methyl vinyl sulfone, 115mg of tri-o-tolylphosphine, and 43mg of palladium(ll) acetate were stirred in 4ml of acetonitrile and 1.5ml of diisopropylethylamin for 2h at 82°C. The reaction mixture was allowed to cool to room température. 10ml of EA were then added and the mixture was washed successively twice using 5ml of water each and twice using 5ml of a saturated aqueous

227

Na₂CO₃-solution. The organic layer was then dried using MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP 1:2 yielded 270mg ofthe title compound. R_f (EA/HEP 1:2) = 0.17

Step 4: 4-(2-Methanesulfonyl-ethyl)-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester

250mg of 4-((E)-2-Methanesulfonyl-vinyl)-3-(2-m-tolyl-ethoxy)-benzoic acid methyl ester were dissolved using 10ml of méthanol and hydrogenated under an 1.5 bar atmosphère of hydrogen using 50mg of Pd/C (10%, 50% water) for 30 minutes. The catalyst was then removed by filtration and the solution evaporated to yield 250mg ofthe title compound thatwas used without further purification.

Step 5: 4-(2-Methanesulfonyl-ethyl)-3-(2-m-tolyl-ethoxy)-benzoic acid

The title compound was synthesized in analogy to example 443, step 5.

Step 6: cis-4-Ethyl-1 -[4-(2-methanesulfonyl-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]cyclohexanecarboxylic acid methyl ester

The title compound was synthesized from 4-(2-Methanesulfonyl-ethyl)-3-(2-m-tolyl-ethoxy)benzoic acid and 1-Amino-4-ethyl-cyclohexanecarboxylic acid methyl ester in analogy to example 126, step 4.

Step 7: cis-4-Ethy 1-1 -[4-(2-methanesulfonyl-ethyl)-3-(2-m-tolyl-ethoxy)-benzoylamino]cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 443, step 5.

LC/MS (Method LC4): Rt = 1.32 min. m/z = 516.39 [MH⁺]

Example 463

Cis-1-([7-(3-Chloro-4-methoxy-phenyl)-2,2-difluoro-benzo[1,3]dioxole-5-carbonyl]-amino}-4ethyl-cyclohexanecarboxylic acid

228

Step 1: 7-(3-Chloro-4-methoxy-phenyl)-2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid methyl ester

1.9g of 7-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2,2-difluoro-benzo[1,3]dioxole-5-carboxy!ic acid methyl ester (example YY, step 4), 1.5g of 4-bromo-2-chloro-1-methoxybenzene, 152mg of triphenylphosphine, 65mg of palladium(ll) acetate, and 2.4g of K₂CO₃ were stirred in 30ml of DMF and 3ml of water under an argon atmosphère at 100°C for 4h. 200ml of water were then added and the mixture was extracted three times using 100ml of EA each. The organic layer was then dried using MgSO₄ and evaporated. Chromatography on silica gel using EA/HEP 1:5 yielded 330mg ofthe title compound, colorless oil. R_f (EA/HEP 1:5) = 0.29

Step 2: 7-(3-Chloro-4-methoxy-phenyl)-2,2-difluoro-benzo[1,3]dioxole-5-carboxylic acid

The title compound was synthesized in analogy to example 442, step 5.

Step 3: cis-1-{[7-(3-Chloro-4-methoxy-phenyl)-2,2-difluoro-benzo[1,3]dioxole-5-carbonyl]amino}-4-ethyl-cyclohexanecarboxylic acid methyl ester

The title compound was synthesized form 7-(3-Chloro-4-methoxy-phenyl)-2,2-difluorobenzo[1,3]dioxole-5-carboxylic acid and cis-1-amino-4-ethyl-cyclohexanecarboxylic acid methyl ester in analogy to example 126, step 4.

Step 4: Cis-1 -{[7-(3-Chloro-4-methoxy-phenyl)-2,2-difluoro-benzo[1,3]dioxole-5-carbonyl]amino}-4-ethyl-cyclohexanecarboxylic acid

The title compound was synthesized in analogy to example 442, step 5.

LC/MS (Method LC4): Rt = 1.42 min. m/z = 496.28 [MH⁺]

Pharmacological tests

229

A) Détermination of Edg-2 receptor inhibition by fluorescence imaging plate reader (FLIPR) measurements

The inhibition ofthe Edg-2 receptor (LPA-ι receptor) by the compounds ofthe invention was quantified by the inhibitory effect on the LPA-mediated calcium libération in a cell-based calcium fluorescence assay by use of Chinese hamster ovarian (CHO) cells in which the human Edg-2 receptor was stably overexpressed (Flp-ln system, Invitrogen). In order to enforce G-Protein coupling and to direct signaling towards Ca²⁺ libération, the overexpressed receptor additionally had a C-terminal sequence of a modified G-protein (G_aj4qj4) (WO 02/04665). Changes in intracellular calcium were determined by fluorescence measurement with the calcium-sensitive dye fluo-4 (Invitrogen) in a fluorescence imaging plate reader (FLIPR, Molecular Dynamics).

CHO cells stably overexpressing the human Edg-2 receptor were seeded (40.000 per well) in black clear-bottomed poly-D-lysine-coated 96 well plates (Becton Dickinson, Biocoat cellware) approximately 18-24 h prior to the experiments. Cells were grown in an incubator at 37 °C, 5 % carbon dioxide and 95 % humidity in cell culture media based on F-12 glutamax media (Gibco, #31765) supplemented with 1 % (vol/vol) penicilline/streptomycine (PAN, #P06-07100), 10 % (vol/vol) fêtai calf sérum (FCS, PAA, #A15-151) and hygromycin B (Invitrogen, #10687-010) 300 mg/l (final concentrations).

Prior to the FLIPR experiment, cells were loaded with fluo-4 acetoxymethyl ester (fluo-4 AM, Invitrogen, #F14202) for 60 min in an incubator at 37 °C, 5 % carbon dioxide and 95 % humidity in dye-loading buffer consisting of Hanks' Balanced Sait Solution (HBSS, Invitrogen, #14065049) supplemented with fluo-4 AM at 2 μΜ (ail data given for final concentration), Pluronic® F-127 0.05 % (vol/vol) (Invitrogen, #P-3000MP), HEPES 20 mM (Gibco, #15630), probenecid 2.5 mM (Sigma, #P-8761) and bovine sérum albumin 0.05 % (BSA, Sigma, #A6003), adjusted to pH 7.5 with sodium hydroxide. During cell loading, fluo-4 AM is cleaved by intracellular esterase resulting in trapping of the dye fluo-4 within the cells. Loading was terminated by washing of the cells in a cell washer (Tecan Power washer) three times with the buffer specified afore but without fluo-4 AM and BSA. This latter buffer was also used as the buffer in the subséquent cell fluorescence measurements.

The dye-loaded and washed cells were pre-incubated for approximately 5 min with various concentrations ofthe test compound added as a solution in DMSO (0.3 % vol/vol maximum final

230 concentration of DMSO), or with DMSO in the respective concentration only (positive control). Subséquent addition of LPA (18:1, 1-oleoyl-sn-glycerol 3-phosphate; 100 nM final concentration) leads to libération of intracellular calcium from internai stores resulting in a large transient increase of the fluo-4 fluorescence signal which was monitored over approximately 3 min. The percent inhibition caused by the test compound was determined from the maximum fluorescence response after LPA addition to cells pre-incubated with the compound as compared to the maximum fluorescence response after LPA addition to cells pre-incubated with DMSO only. Ail fluorescence values were corrected for the baseline fluorescence values obtained with cells which were pre-incubated with DMSO only and were not treated with LPA (baseline control). Ail measurements were performed in triplicate. From the percent inhibitions the inhibitory concentration IC₅₀ was determined.

Inhibitory concentrations IC₅₀ of various example compounds are given in table 23, wherein a dénotés an IC₅₀ of less than 0.1 μΜ, b dénotés an IC_So between 0.1 μΜ and 1 μΜ, and c dénotés an IC₅₀ between 1 μΜ and 30 μΜ.

Table 23. Inhibitory concentrations IC₅₀for inhibition ofthe Edg-2 receptor

Example	IC50
1	b
2	a
3	a
4	b
5	a
6	b
7	a
8	a
9	a
10	a
11	b
12	b
13	a
14	b
15	c
16	a
17	a

Example	IC50
18	b
19	b
20	a
21	b
22	a
23	b
24	b
25	c
26	a
27	a
28	a
29	a
30	a
31	a
32	c
33	a
34	c

231

Example	IC50
35	c
36	b
37	c
38	b
39	c
40	b
41	a
43	a
44	b
45	b
46	a
47	a
48	c
49	c
50	a
51	a
52	c
53	b
54	a
55	b
56	a
57	a
58	c
59	a
60	b
61	b
62	a
63	a
64	b
65	a
66	b
66	b
67	b

Example	IC50
67	c
68	a
69	b
70	a
71	a
72	a
73	c
74	a
75	a
76	a
77	a
78	b
79	a
80	a
81	a
82	a
83	a
84	c
85	a
86	c
87	c
88	a
89	c
90	a
91	a
92	c
93	c
94	b
95	b
96	a
97	a
98	a
99	a

232

Example	IC50
100	a
103	b
104	b
105	b
106	c
107	a
108	a
109	a
110	a
111	a
112	a
113	b
114	b
115	c
116	c
117	c
118	c
119	a
121	b
122	a
123	a
124	b
125	a
126	a
127	a
128	b
129	b
130	a
131	a
132	a
133	a
134	a
205	a

Example	IC50
206	a
207	a
208	a
299	a
300	a
301	a
302	a
303	a
304	a
305	a
306	a
307	a
308	a
309	a
310	a
311	a
312	b
313	a
314	a
315	a
316	a
317	a
318	a
319	a
320	a
326	a
327	a
328	b
329	a
330	c
331	a
332	a
333	a

233

Example	IC50
334	b
351	a
352	a
355	a
356	a
357	a
358	a
359	a
360	a
361	a
362	a
363	b
364	a
365	b
366	b
367	b
368	b
369	b
370	a
371	b
372	b
373	b
374	a
375	a
376	a
377	a
378	a
379	a
380	a
381	a
382	a
383	a
384	a

Example	IC50
385	a
386	a
387	a
388	a
389	a
390	a
391	a
392	a
393	a
394	a
395	a
396	a
397	a
398	a
399	a
400	a
401	a
402	a
403	a
404	a
405	a
406	b
407	a
408	b
409	a
410	a
411	a
412	a
413	a
414	a
415	a
416	a
417	a

234

Example	IC50
418	a
419	a
420	b
421	b
422	b
423	a
424	a
425	b
426	b
427	b
428	a
429	b
430	b
431	b
432	b
433	a
434	b
435	b
436	b
437	a
438	a
439	b
440	b

Example	IC50
441	c
442	a
443	b
444	b
445	a
446	a
447	a
448	a
449	b
450	a
451	a
452	b
453	a
454	a
455	a
456	a
457	b
458	a
459	a
460	b
461	a
462	b
463	a

B) In vivo antihypertrophic and renoprotective activity

The in vivo pharmacological activity ofthe compounds ofthe invention can be investigated, for example, in the model of DOCA-salt sensitive rats with unilatéral nephrectomy. Briefly, in this model unilatéral nephrectomy ofthe left kidney (UNX) is performed on Sprague Dawley rats of 150 g to 200 g of body weight. After the operation as well as at the beginning of each of the following weeks 30 mg/kg of body weight of DOCA (desoxycorticosterone acetate) are administered to the rats by subcutaneous injection. The nephrectomized rats treated with DOCA are supplied with drinking water containing 1 % of sodium chloride (UNX/DOCA rats). The UNX/DOCA rats develop high blood pressure, endothélial dysfunction, myocardial hypertrophy

235 and fibrosis as well as rénal dysfunction. In the test group (UNX/DOCA Test) and the placebo group (UNX/DOCA Placebo), which consist of randomized UNX/DOCA rats, the rats are treated orally by gavage in two part administrations at 6 a.m. and 6 p.m. with the daily dose of the test compound (for example 10 mg/kg of body weight dissolved in vehicle) or with vehicle only, respectively. In a control group (control), which consists of animais which hâve not been subjected to UNX and DOCA administration, the animais receive normal drinking water and are treated with vehicle only. After five weeks of treatment, systolic blood pressure (SBP) and heart rate (HR) are measured non-invasively via the tail cuff method. For détermination of albuminuria and créatinine, 24 h urine is collected on metabolic cages. Endothélial function is assessed in excised rings ofthe thoracic aorta as described previously (W. Linz et al., JRAAS (Journal of the renin-angiotensin-aldosterone system) 7 (2006), 155-161). As a measure of myocardial hypertrophy and fibrosis, heart weight, left ventricular weight and the relation of hydroxyproline and proline are determined in excised hearts.

Claims (12)

1. We claim:

   1. A compound of formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable sait thereof, wherein ring A is a 3-membered to 12-membered monocyclic, bicyclic or spirocyclic ring which comprises 0, 1 or 2 identical or different hetero ring members chosen from the sériés consisting of N, N(R°), O, S, S(O) and S(O)₂, and which is saturated or comprises 1 double bond, provided that ring A is not a bicyclo[3.1.0]hexane or bicyclo[3.2.0]heptane ring carrying the groups N(R²⁰) and C(O)-R⁵⁰ in its position 3, and not an octahydropentalene, octahydroindene or decahydroazulene ring carrying the groups N(R²⁰) and C(O)-R⁵⁰ in its position 2, wherein ring A is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the sériés consisting of halogen, R¹, R², (C2-C6)-alkenyl, HO-, R¹-O-, phenyl-(C-iC4)-alkyl-O-, R¹-C(O)-O-, R¹-S(O)2-O-, R¹-S(O)m-, H_ZN-, R¹-NH-, R¹-N(R¹)-, R¹-C(O)-NH-, R¹C(O)-N(R¹)-, R¹-S(O)2-NH-, R¹-S(O)2-N(R¹)-, R¹-C(O)-, HO-C(O)-, R¹-O-C(O)-, H2N-C(O)-, r¹NH-C(O)-, R¹-N(R¹)-C(O)-, H2N-S(O)₂-, R¹-NH-S(O)2-, R¹-N(R¹)-S(O)2-, F₅S-, NC-, oxo and methylene;

   Y is chosen from the sériés consisting of N(R¹⁰), S, O, C(R¹²)=C(R¹³), N=C(R¹⁴) and C(R¹⁵)=N;

   Z is chosen from the sériés consisting of N and C(R¹⁶);

   R° is chosen from the sériés consisting of hydrogen and R¹;

   R¹ is chosen from the sériés consisting of (CrC₆)-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)cycloalkyl-ÎCi-C^-alkyl-;

   R² is (C_rC₄)-alkyl which is substituted by one or more identical or different substituents chosen from the sériés consisting of HO- and (C_rC₄)-alkyl-O-;

   237

   R¹⁰ is chosen from the sériés consisting of hydrogen and R¹¹;

   R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸ are, independently of each other group R¹¹, R³⁰, R³³, R³⁵, R⁵⁴, R⁵⁵, R⁵⁷ and R⁵⁸, chosen from the sériés consisting of (C^-CsJ-alkyf, (C₂-C₆)-alkenyl, (C₂C₆)-alkynyl, (C3-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C-rC₄)-alkyl- which are ail optionally substituted by one or more identical or different substituents R⁷⁰;

   R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ are independently of each other chosen from the sériés consisting of hydrogen, halogen, (C-i-C^-alkyl, HOqCfC^-alkyl-, (C-i-C₄)-alkyl-O-, (CrC^-alkyl-SCO)™-, H₂N-, (CrCD-alkyl-NH-, (C₁-C₄)-alkyl-N((C₁-C₄)-alkyl)-, (CrC₄)-alkyl-C(O)- and NC-, or R¹³ or R¹⁴, together with the one of the groups R²¹ and R²² which is not the group of the formula II, forms a chain consisting of 3 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members chosen from the sériés consisting of N(R¹⁷), O and S, but two hetero chain members cannot be présent in adjacent positions, and the other chain members are identical or different groups C(R¹⁸)(R¹⁸);

   R¹⁷ and R²⁵ are independently of each other chosen from the sériés consisting of hydrogen and (C_rC₄)-alkyl;

   R¹⁸, independently of each other group R¹⁸, is chosen from the sériés consisting of hydrogen, fluorine and (CrC^-alkyl, ortwo ofthe groups R¹⁸ bonded to the same carbon atom, together with the carbon atom carrying them, form a 3-membered to 6-membered cycloalkane ring which is optionally substituted by one more identical or different substituents chosen from the sériés consisting of fluorine and (CrC^-alkyl;

   R²⁰ is chosen from the sériés consisting of hydrogen and (C₁-C₄)-alkyl;

   one ofthe groups R²¹ and R²² is a group ofthe formula II

   R²⁴-R²³- Il and the other of the groups R²¹ and R²² is chosen from the sériés consisting of hydrogen, halogen, R³⁰, HO-, R³⁰-O-, R³⁰-C(O)-O-, R³⁰-S(O)2-O-, R³⁰-S(O)m-, H₂N-, R³⁰-NH-, R³⁰-N(R³⁰)-, R³⁰-C(O)-NH-, R^3D-C(O)-N(R⁷¹)-, R³⁰-S(O)2-NH-, R³⁰-S(O)2-N(R⁷¹)-, R³⁰-C(O)-, HO-C(O)-, r³⁰-oC(O)-, HZN-C(O)-, R³⁰-NH-C(O)-, R³⁰-N(R³⁰)-C(O)-, H2N-S(O)₂-, R³⁰-NH-S(O)₂-, R³⁰-N(R³⁰)17884

   238

   S(O)₂-, NC-, O₂N- and Het¹, or together with R¹³ or R¹⁴ forms a chain as specified in the définition of R¹³ and R¹⁴;

   R²³ is a direct bond or a chain consisting of 1 to 5 chain members of which 0, 1 or 2 chain members are identical or different hetero chain members chosen from the sériés consisting of N(R²⁵), O, S, S(O) and S(O)₂, but two hetero chain members can be présent in adjacent positions only if one of them is chosen from the sériés consisting of S(O) and S(O)₂ and the other is chosen from the sériés consisting of N(R²⁵), O and S, and the other chain members are identical or different groups C(R²⁶)(R²⁶);

   R²⁴ is a 3-membered to 10-membered, monocyclic or bicyclic ring, which is saturated and contains 0 or 1 hetero ring members, or is unsaturated and contains 0, 1 or 2 identical or different hetero ring members, wherein the hetero ring members are chosen from the sériés consisting of N, N(R³²), O, S, S(O) and S(O)2, and wherein the ring is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the sériés consisting of halogen, R³³, oxetanyl, HO-, R³³-O-, R³³-C(O)-O-, R³³-S(O)2-O-, R³³-S(O)m-, H2N-, R³³-NH-, R³³-N(R³³)-, R³³-C(O)-NH-, R³³-C(O)-N(R⁷¹)-, R³³-S(O)2-NH-, R³³-S(O)2-N(R⁷¹)-, H2N-S(O)₂-NH-, R³³-NH-S(O)2-NH-, R³³-N(R³³)-S(O)2-NH-, H₂N-S(O)₂-N(R⁷¹)-, R³³-NH-S(O)2N(R⁷¹)-, R³³-N(R³³)-S(O)2-N(R⁷¹)-, R³³-C(O)-, HO-C(O)-, R³³-O-C(O)-, H2N-C(O)-, R³³-NH-C(O)-, R³³-N(R³³)-C(O)-, H2N-S(O)₂-, R³³-NH-S(O)2-, R³³-N(R³³)-S(O)2-, NC-, O₂N- and oxo ;

   R²⁶, independently of each other group R²⁶, is chosen from the sériés consisting of hydrogen, fluorine, (C1-C4)-alkyl and HO-, or two groups R²⁶ bonded to the same carbon atom together are oxo, ortwo ofthe groups R²⁶ or one group R²⁵ and one group R²⁶, togetherwith the comprised chain members, form a 3-membered to 7-membered monocyclic ring which is saturated and contains 0, 1 or 2 identical or different hetero ring members chosen from the sériés consisting of N, N(R³⁴), O, S, S(O) and S(O)2, which ring is optionally substituted on ring carbon atoms by one more identical or different substituents chosen from the sériés consisting of fluorine and (C_rC₄)-alkyl;

   R³² and R³⁴ are independently of each other chosen from the sériés consisting of hydrogen, R³⁵, R³⁵-S(O)₂-, R³⁵-C(O)-, R³⁵-O-C(O)- and phenyl;

   R⁵⁰ is chosen from the sériés consisting of R⁵¹-O- and R⁵²-N(R⁵³)-;

   R⁵¹ is chosen from the sériés consisting of hydrogen and R⁵⁴;

   239

   R⁵² is chosen from the sériés consisting of hydrogen, R⁵⁵, NC- and R⁵⁶-S(O)₂-;

   R⁵³ is chosen from the sériés consisting of hydrogen and R⁵⁷;

   R⁵⁶ is chosen from the sériés consisting of R⁵⁸ and phenyl;

   R⁶⁰, independently of each other group R⁶⁰, is chosen from the sériés consisting of hydrogen and (Ci-C₄)-alkyl;

   R⁷⁰ is chosen from the sériés consisting of HO-, R⁷¹-O-, R⁷¹-C(O)-O-, R⁷¹-S(O)m-, H2N-, R⁷¹-NH-, R⁷¹-N(R⁷¹)-, R⁷¹-C(O)-NH-, R⁷¹-C(O)-N(R⁷¹)-, R⁷¹-S(O)2-NH-, R⁷¹-S(O)2-N(R⁷¹)-, HO-C(O)-, R⁷¹O-C(O)-, H2N-C(O)-, R⁷¹-NH-C(O)-, R⁷¹-N(R⁷¹)-C(O)-, HzN-S(O)2-, R⁷¹-NH-S(O)2-, R⁷¹-N(R⁷¹)S(O)₂- and oxo;

   R⁷¹, independently of each other group R⁷¹, is chosen from (Ci-C₄)-alkyl, (C3-C₄)-cycloalkyl and (C₃-C4)-cycloalkyl-(C₁-C₂)-alkyl-;

   Het¹ is a monocyclic 4-membered to 7-membered heterocyclic ring which comprises 1 or 2 identical or different hetero ring members chosen from the sériés consisting of N, N(R⁶⁰), O, S, S(O) and S(O)₂, which ring is saturated and is optionally substituted by one or more identical or different substituents chosen from the sériés consisting of fluorine and (CrC^-alkyl;

   m, independently of each other number m, is an integer chosen from the sériés consisting of 0,

   1 and 2;

   phenyl, independently of each other group phenyl, is optionally substituted by one or more identical or different substituents chosen from the sériés consisting of halogen, (Ci-C₄)-alkyl, (C₁-C₄)-alkyl-O- and NC-, unless specified otherwise;

   cycloalkyl, independently of each other group cycloalkyl, and independently of any other substituents on cycloalkyl, is optionally substituted by one or more identical or different substituents chosen from fluorine and (C-i-C₄)-alkyl;

   240 alkyl, alkenyl and alkynyl, independently of each other group alkyl, alkenyl and alkynyl, and independently of any other substituents on alkyl, alkenyl and alkynyl, is optionally substituted by one or more fluorine substituents;

   provided that the compound ofthe formula I is not 1-[(biphenyl-4-carbonyl)-amino]cyclohexanecarboxylic acid, 1 -[4-(2-pyrrolidin-1 -yl-ethoxy)-benzoylamino]cyclohexanecarboxylic acid, 1 -[4-(2-piperidin-1 -yl-ethoxy)-benzoylamino]-cyclohexanecarboxylic acid, 1-[4-(2-oxo-pyrrolidin-1-yl)-benzoylamino]-cyclohexanecarboxylic acid, 1-{[4-(2-oxopyrrolidin-1-yl)-furan-2-carbonyl]-amino}-cyclohexanecarboxylic acid, 1-[(2',3-dichloro-biphenyl4-carbonyl)-amino]-cycloheptanecarboxylic acid, 1-(4-(4,6-dimethyl-pyrimidin-2-ylsulfanyl)benzoylamino]-cyclopentanecarboxylic acid ethyl ester, 1-[4-(4-oxo-piperidin-1 -yl)benzoylamino]-cyclopropanecarboxylic acid methyl ester or 1-[2-chloro-4-(3-hydroxybenzylcarbamoyl)-benzoylamino]-cyclopropanecarboxylic acid.
2. 2. A compound ofthe formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable sait thereof, as claimed in claim 1, wherein ring A is a 3-membered to 8-membered monocyclic ring which comprises 0 or 1 hetero ring members chosen from the sériés consisting of O, S, S(O) and S(O)₂, and which is saturated, wherein ring A is optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the sériés consisting of halogen, R¹, R², (C2-C6)-alkenyl, HO-, R¹-O-, phenyl-(CrC₄)-alkyl-O-, R¹-C(O)-O-, R¹-S(O)2-O-, HO-C(O)-, R¹-O-C(O)-, H2N-C(O)-, R¹NH-C(O)-, R¹-N(R¹)-C(O)- and oxo.
3. 3. A compound ofthe formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable sait thereof, as claimed in any one or more of claims 1 and 2, wherein ring A is a cyclohexane ring or cycloheptane ring which is optionally substituted by one or more identical or different substituents chosen from the sériés consisting of halogen, R¹, R², (C2-C6)-alkenyl, HO-, R¹-O-, phenyl-(C-i-C4)-alkyl-O-, R¹-C(O)-O-, R¹-S(O)2O-, HO-C(O)-, R¹-O-C(O)-, H2N-C(O)-, R¹-NH-C(O)-, R¹-N(R¹)-C(O)- and oxo.
4. 4. A compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable sait thereof, as claimed in any one or more of claims 1 to 3, wherein

   Y is chosen from the sériés consisting of C(R¹²)=C(R¹³) and C(R¹⁵)=N;

   Z is C(R¹⁶).

   241
5. 5. A compound ofthe formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable sait thereof, as claimed in any one or more of claims 1 to 4, wherein

   R²¹ is chosen from the sériés consisting of hydrogen, halogen, (Ci-C₄)-alkyl, HO-(C₁-C₄)-alkyl-, (CrC^-alkyl-O-CCrC^-alkyl-, (Ci-C₄)-alkyl-O-, HO-iCrC^-alkyl-O-, (CrC^-alkyl-O-iCrC^alkyl-O-, (C₁-C₄)-alkyl-S(O)_m-, (Ci-C₄)-alkyl-C(O)-, NC- and Het¹, or together with R¹³ or R¹⁴ forms a chain as specified in the définition of R¹³ and R¹⁴;

   R²² is a group of the formula II

   R²⁴-R²³- Il

   R²³ is a direct bond or a chain consisting of 2, 3 or 4 chain members of which 0 or 1 chain members are hetero chain members chosen from the sériés consisting of N(R²⁵), O, S, S(O) and S(O)₂, and the other chain members are identical or different groups C(R²⁶)(R²⁶).
6. 6. A compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable sait thereof, as claimed in any one or more of claims 1 to 5, wherein

   R²⁴ is a 3-membered to 7-membered monocyclic ring or a 7-membered to 10-membered bicyclic ring, which rings are saturated and contain 0 or 1 hetero ring members, or are unsaturated and contain 0, 1 or 2 identical or different hetero ring members chosen from the sériés consisting of N, N(R³²), O, S, S(O) and S(O)2, and which rings are optionally substituted on ring carbon atoms by one or more identical or different substituents chosen from the sériés consisting of halogen, R³³, oxetanyl, HO-, R³³-O-, R³³-S(O)m-, H₂N-, R³³-NH-, R³³-N(R³³)-, R³³-C(O)-NH-, R³³C(O)-N(R⁷¹)-, R³³-S(O)₂-NH-, R³³-S(O)2-N(R⁷¹)-, H2N-S(O)₂-NH-, R³³-NH-S(O)₂-NH-, R³³-N(R³³)S(O)2-NH-, H2N-S(O)2-N(R⁷¹)-, R³³-NH-S(O)2-N(R⁷¹)-, R³³-N(R³³)-S(O)2-N(R⁷¹)-, HO-C(O)-, r³³O-C(O)-, H2N-C(O)-, R³³-NH-C(O)-, R³³-N(R³³)-C(O)-, NC- and oxo;

   R³² is chosen from the sériés consisting of hydrogen, R³⁵, R³⁵-C(O)-, R³⁵-O-C(O)- and phenyl.
7. 7. A compound of the formula I, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a physiologically acceptable sait thereof, as claimed in any one or more of claims 1 to 6, wherein

   242 ring A is a cyclohexane ring or a cycloheptane ring which is optionally substituted by one or two identical or different substituents chosen from the sériés consisting of halogen, (C_rC₄)-alkyl and (C_rC₄)-alkyl-O-;

   Y is chosen from the sériés consisting of C(R¹²)=C(R¹³) and C(R¹⁵)=N;

   Z is C(R¹⁶);

   R¹², R¹³, R¹⁵ and R¹⁶ are independently of each other chosen from the sériés consisting of hydrogen, halogen, (C1-C4)-alkyl; or R¹³ forms together with R²¹ a chain which is chosen from the sériés consisting of-O- C(R¹⁸)(R¹⁸)-O-, -CH2-CH2-CH2, -CH2-O-CH₂-, -CH₂-CH₂-CH₂-CH₂- and -O-C(R¹⁸)(R¹⁸)- C(R¹⁸)(R¹⁸)-O;

   R¹⁸ is chosen from the sériés consisting of hydrogen or fluorine;

   R²¹ is chosen from the sériés consisting of hydrogen, halogen, (CrC^-alkyl, HO-(C₁-C₄)-alkyl-, (C_rC₄)-alkyl-O-, (C_rC₄)-alkyl-C(O)-, (C_rC₄)-alkyl-O-(C_rC₄)alkyl-, HO-(C_rC₄)-alkyl-O-, (C_rC₄)alkyl-O-(Ci-C₄)-alkyl-O-, NC- and oxetanyl, or together with R¹³ forms a chain as specified in the définition of R¹³;

   R²² is a group oftheformula II

   R²⁴-R²³- Il

   R²³ is a direct bond or a chain consisting of 2, 3 or 4 chain members of which 0 or 1 chain members are hetero chain members chosen from the sériés consisting of O and S, and the other chain members are identical or different groups C(R²⁶)(R²⁶);

   R²⁴ is a benzene ring which is optionally substituted by one or more identical or different substituents chosen from the sériés consisting of halogen, R³³, oxetanyl, HO-, R³³-O-, R³³-S(O)m-, H2N-, R³³-NH-, R³³-N(R³³)-, R³³-C(O)-NH-, R³³-S(O)2-NH-, HO-C(O)-, R³³-O-C(O)-, H₂N-C(O)-, R³³-NH-C(O)-, R³³-N(R³³)-C(O)- and NC-;

   R²⁶, independently of each other group R²⁶, is chosen from the sériés consisting of hydrogen, fluorine, (C_rC₄)-alkyl, ortwo ofthe groups R²⁸ which are bonded to the same carbon atom in

   243 the chain, together with the carbon atom carrying them, form a cyclopropane ring or an oxetane ring;

   R³³, independently of each other group R³³, is chosen from the sériés consisting of (CrC^-alkyl, (C₃-C₇)-cycloalkyl and (C₃-C₇)-cycloalkyl-(C₁-C₂)-alkyl-, which are ail optionally substituted by one or more identical or different substituents R⁷⁰;

   R⁵⁰ is chosen from the sériés consisting of R⁵¹0- and R⁵²(R⁵³)N-;

   R⁵¹, R⁵² and R⁵³ are independently of each other chosen from the sériés consisting of hydrogen and (CrC₄)-alkyl;

   R⁷⁰ is chosen from the sériés consisting of HO- and R⁷¹-O-;

   R⁷¹ is (C_rC₄)-alkyl;

   m, independently of each other number m, is an integer chosen from the sériés consisting of 0 and 2;

   cycloalkyl, independently of each other group cycloalkyl, and independently of any other substituents on cycloalkyl, is optionally substituted by one or more identical or different substituents chosen from fluorine and (C_rC₄)-alkyl;

   alkyl, independently of each other group alkyl, and independently of any other substituents on alkyl, is optionally substituted by one or more fluorine substituents.
8. 8. A compound according to claim 1, which is: trans-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methylcyclohexanecarboxylic acid, cis-1-[(5-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-4methyl-cyclohexanecarboxylic acid, trans-1-[(5-{2-[3-(2-Hydroxy-ethyl)-phenyl]-ethoxy}-6-methoxy-pyridine-3-carbonyl)-amino]-4methyl-cyclohexanecarboxylic acid, cis-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}cyciohexanecarboxylic acid,

   244 cis-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid, trans-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid, trans-4-Ethyl-1-{[6-methoxy-5-(3-trifluoromethyl-phenyl)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid, cis-1-{[5-(3-Chloro-4-methoxy-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-methylcyclohexanecarboxylic acid, trans-1-{[5-(3-Chloro-4-methoxy-phenyl)-6-methoxy-pyridine-3-carbonyl]-amino}-4-methylcyclohexanecarboxylic acid, cis-1-[(3'-Chloro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-ethyl-cyclohexanecarboxylic acid, trans-1-[(3'-Chloro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-ethyl-cyclohexanecarboxylic acid, trans-4-Ethyl~1-[(6-methoxy-5-phenethyloxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylic acid, cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-methylcyclohexanecarboxylic acid, cis-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-ethylcyclohexanecarboxylic acid, cis-4-Ethyl-1-[(6-methoxy~5-phenethyloxy-pyridine-3-carbonyl)-amino]-cyclohexanecarboxylic acid, trans-4-Ethyl-1-{[6-(2-hydroxy-ethoxy)-3'-trifluoromethyl-biphenyl-3-carbonyl]-amino}cyclohexanecarboxylic acid, trans-1-({5-[2-(3-Chloro-phenyl)-ethoxy]-6-methoxy-pyridine-3-carbonyl}-amino)-4-ethylcyclohexanecarboxylic acid, trans-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-4-ethylcyclohexanecarboxylic acid, cis-1-[3-[2-(3-Chloro-phenyl)-ethoxy]-4-(2-hydroxy-ethoxy)-benzoylamino]-4-ethylcyclohexanecarboxylic acid, Trans-1-[(3'-Chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-methylcyclohexanecarboxylic acid, Cis-1-[(3'-chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-ethylcyclohexanecarboxylic acid,

   Cis-1-[(3'-Chloro-5-fluoro-6,4'-dimethoxy-biphenyl-3-carbonyl)-amino]-4-trifluoromethylcyclohexanecarboxylic acid, or

   245 cis-4-Ethyl-1-{[6-(2-hydroxy-ethoxy)-5-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-amino}cyclohexanecarboxylic acid, in any of their stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, and their physiologically acceptable salts.
9. 9. A process for the préparation of a compound of the formula I or a physiologically acceptable sait thereof as claimed in any one or more of claims 1 to 8, comprising reacting a compound of the formula lll with a compound of the formula IV, wherein the ring A and the groups Y, Z, R²⁰ to R²² and R⁵⁰ in the compounds of the formulae lll and IV are defined as in the compounds of the formula I and additionally functional groups can be présent in protected form or in the form of a precursor group, and the group G in the compound of the formula IV is HO-, (CrCAalkyl-O- or halogen.
10. 10. A compound of the formula I as claimed in any one or more of claims 1 to 8 or a physiologically acceptable sait thereof for use as a pharmaceutical.
11. 11. A pharmaceutical composition, which comprises at least one compound of the formula I as claimed in any one or more of claims 1 to 8 or a physiologically acceptable sait thereof and a pharmaceutically acceptable carrier.
12. 12. Use of a compound of the formula I as claimed in any one or more of claims 1 to 8 or a physiologically acceptable sait thereof for the manufacture of a médicament for the treatment of cardiovascular diseases, heart failure, cardiomyopathy, myocardial infarction, myocardial remodeling, vascular remodeling, hypertension, atherosclerosis, peripheral arterial occlusive disease, restenosis, thrombosis, vascular permeability disorders, inflammatory diseases, rheumatoid arthritis, osteoarthritis, rénal diseases, rénal papillary necrosis, rénal failure, pulmonary diseases, chronic obstructive pulmonary disease, asthma, acute respiratory dystress

    246 syndrome, immunological diseases, allergie diseases, tumor growth, metastasis, metabolic diseases, fibrotic diseases, pulmonary fibrosis, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, rénal fibrosis, liver fibrosis, fibrosing skin conditions, psoriasis, pain, pruritus, retinal ischemia/reperfusion damage, macular degeneration, psychiatrie disorders, neurodegenerative 5 diseases, cérébral nerve disorders, peripheral nerve disorders, endocrinie disorders, hyperthyroidism, scarring disorders or would healing disorders, or for cardioprotection or renoprotection.