# Patent

## Title
Azetidine derivatives

## Abstract

Azetidine derivatives of which the following is exemplary




    
    
        and their use in the treatment of obesity, diabetes or dyslipidemia.

## Background
FIELD OF THE INVENTION
This invention relates to new compounds, in particular azetidine derivatives, to processes for preparing such compounds, to their use as inhibitors of acetyl-CoA carboxylase(s), to methods for their therapeutic use, in particular in diseases and conditions mediated by the inhibition of acetyl-CoA carboxylase(s), and to pharmaceutical compositions comprising them.
BACKGROUND OF THE INVENTION
Obesity is a major public health issue not only for the EU, USA, Japan but also for the world in general. It is associated with a number of serious diseases including diabetes, dyslipidemia, hypertension, cardiovascular and cerebrovascular diseases. Although the underlying mechanisms are not yet fully understood, the impairement of insulin action in target tissues by accumulation of excess lipids is generally regarded as a key mechanism linking obesity to secondary pathologies (G. Wolf, Nutrition Reviews Vol. 66(10):597-600; D B Savage, K F Petersen, G I Shulman, Physiol Rev. 2007; 87:507-520). Therefore, understanding of cellular lipid metabolism in insulin target tissues is crucial in order to elucidate the development of diseases associated with obesity.
A central event in lipid metabolism is the generation of malonyl-CoA via carboxylation of acetyl-CoA by the two mammalian ACC isoforms ACC1 (ACC-alpha, also termed ACCA) and ACC2 (ACC-beta, also designated ACCB) (Saggerson D. Annu Rev Nutr. 2008; 28:253-72). The malonyl-CoA generated is used for de novo fatty acid synthesis and acts as inhibitor of CPT-1, thereby regulating mitochondrial fatty acid oxidation. Furthermore, malonyl-CoA is also described to act centrally to control food intake, and may play an important role in controlling insulin secretion from the pancreas (G D Lopaschuk, J R Ussher, J S Jaswal. Pharmacol Rev. 2010; 62(2):237-64; D Saggerson Annu Rev Nutr. 2008; 28:253-72), further coordinating the regulation of intermediary metabolism.
Therefore ACC1 and ACC2 have been shown to be major regulators of fatty acid metabolism and are presently considered as an attractive target to regulate the human diseases of obesity, diabetes and cardiovascular complications (S J Wakil and L A Abu-Elheiga, J. Lipid Res. 2009. 50: S138-S143; L. Tong, H J Harwood Jr. Journal of Cellular Biochemistry 99:1476-1488, 2006).
As a result of its unique position in intermediary metabolism, inhibition of ACC offers the ability to inhibit de novo fatty acid production in lipogenic tissues (liver and adipose) while at the same time stimulating fatty acid oxidation in oxidative tissues (liver, heart, and skeletal muscle) and therefore offers an attractive modality for favorably affecting, in a concerted manner, a multitude of cardiovascular risk factors associated with obesity, diabetes, insulin resistance, nonalcoholic steatohepatitis (NASH) and the metabolic syndrome (L. Tong, H J Harwood Jr. Journal of Cellular Biochemistry 99:1476-1488, 2006; Corbett J W, Harwood J H Jr., Recent Pat Cardiovasc Drug Discov. 2007 November; 2(3):162-80).
Furthermore recent data show that cellular toxicity mediated by lipids (lipotoxicity) is implicated in the susceptibitlity to diabetes associated nephropathy (for review see M Murea, B I Freedmann, J S Parks, P A Antinozzi, S C Elbein, L M Ma; Clin J Am Soc Nephrol. 2010; 5:2373-9). A large-scale genome-wide association study in japanese patients identified single nucleotide polymorphism in the ACC2 gene (ACACB) associated with diabetic nephropathy risk which was replicated in nine independent cohorts. In the kidney, dysregulation of fatty acid metabolism leading to increased fatty acid levels is believed to lead to glomerular and tubular dysfunction (M Murea, B I Freedmann, J S Parks, P A Antinozzi, S C Elbein, L M Ma; Clin J Am Soc Nephrol. 2010; 5:2373-9). Therefore inhibitors targeting ACC as key molecule involved in lipid oxidation have the potential to be beneficial for favorably affecting diabetic nephropathy.
Additionally, insulin resistance, deregulated lipid metabolism, lipotoxicity and increased intramuscular lipids have also been described to play a role in type 1 diabetes (I E Schauer, J K Snell-Bergeon, B C Bergman, D M Maahs, A Kretowski, R H Eckel, M Rewers Diabetes 2011; 60:306-14; P Ebeling, B Essén-Gustavsson, J A Tuominen and V A Koivisto Diabetologia 41: 111-115; K J Nadeau, J G Regensteiner, T A Bauer, M S Brown, J L Dorosz, A Hull, P Zeitler, B Draznin, J E B. Reusch J Clin Endocrinol Metab, 2010, 95:513-521). Therefore ACC inhibitors are also considered as interesting drugs for the treatment of type 1 diabetes.
In addition ACC inhibitors also have the potential to intervene in the progression of diseases that result from the rapid growth of malignant cells or invading organisms that are dependent on endogenous lipid synthesis to sustain their rapid proliferation. De novo lipogenesis is known to be required for growth of many tumor cells and ACC up-regulation has been recognized in multiple human cancers, promoting lipogenesis to meet the need of cancer cells for rapid growth and proliferation (C Wang, S Rajput, K Watabe, D F Liao, D Cao Front Biosci 2010; 2:515-26). This is further demonstrated in studies using ACC inhibitors which induced growth arrest and selective cytotoxicity in cancer cells and by RNA interference-mediated knock-down of ACC which inhibited growth and induced apoptosis in different types of cancer cells. Furthermore, ACC1 associates with and is regulated by the breast cancer susceptibility gene 1 (BRCA1). Commonly occurring BRCA1 mutations lead to ACC1 activation and breast cancer susceptibility (C Wang, S Rajput, K Watabe, D F Liao, D Cao Front Biosci 2010; 2:515-26).
Furthermore in central nervous system disorders including but not limited to Alzheimer's disease, Parkinson disease and epilepsy, impairements in neuronal energy metabolism have been described (Ogawa M, Fukuyama H, Ouchi Y, Yamauchi H, Kimura J, J Neurol Sci. 1996; 139(1):78-82). Interventions targeting this metabolic defect may prove beneficial to the patients. One promising intervention is therefore to provide the glucose-compromised neuronscerebral brain neurons with ketone bodies as an alternative substrate (S T Henderson Neurotherapeutics, 2008, 5:470-480; L C Costantini, L J Barr, J L Vogel, S T Henderson BMC Neurosci. 2008, 9 Suppl 2:S16; K W Barañano, A L Hartman. Curr Treat Options Neurol. 2008; 10:410-9). ACC inhibition leading to increased fatty acid oxidation may thereby result in increases in the blood levels of ketone bodies thereby providing an alternative energy substrate for the brain.
Preclinical and clinical evidence indicates that ketone bodies can provide neuroprotective effects in models of Parkinson's disease, AD, hypoxia, ischemia, amyotrophic lateral sclerosis and glioma (L C Costantini, L J Barr, J L Vogel, S T Henderson BMC Neurosci. 2008, 9 Suppl 2:S16) and improved cognitive scores in Alzheimers Diseases patients (M A Reger, S T Henderson, C Hale, B Cholerton, L D Baker, G S Watson, K Hydea, D Chapmana, S Craft Neurobiology of Aging 25 (2004) 311-314). The end result of increased ketone levels is an improvement in mitochondrial efficiency and reduction in the generation of reactive oxygen species (for reviews see L C Costantini, L J Barr, J L Vogel, S T Henderson BMC Neurosci. 2008, 9 Suppl 2:S16; K W Barañano, A L Hartman. Curr Treat Options Neurol. 2008; 10:410-9).
Furthermore, the potential of ACC inhibitors as antifungal agents and as antibacterial agents is well documented (L. Tong, H J Harwood Jr. Journal of Cellular Biochemistry 99:1476-1488, 2006). In addition, ACC inhibitors can be used to combat viral infections. It was discovered recently that viruses rely on the metabolic network of their cellular hosts to provide energy and building blocks for viral replication (Munger J, B D Bennett, A Parikh, X J Feng, J McArdle, H A Rabitz, T Shenk, J D Rabinowitz. Nat Biotechnol. 2008; 26:1179-86). A flux measurement approach to quantify changes in metabolic activity induced by human cytomegalovirus (HCMV) elucidated that infection with HCMV markedly changed fluxes through much of the central carbon metabolism, including glycolysis, tricarboxylic acid cycle and fatty acid biosynthesis. Pharmacological inhibition of fatty acid biosynthesis suppressed the replication of two divergent enveloped viruses (HCMV and influenza A) indicating that fatty acid synthesis is essential for the replication. These examples show that acetyl-CoA fluxes and de novo fatty acid biosynthesis are critical to viral survival and propagation as the newly synthesized fatty acids and phospholipids are important for formation of viral envelopes. Changing the metabolic flux influences the absolute quantity of phospholipid available, the chemical composition and physical properties of the envelope negatively affect viral growth and replication. Hence, ACC inhibitors acting on key enzymes in the fatty acid metabolism, have the potential to be antiviral drugs.
AIM OF THE PRESENT INVENTION
The aim of the present invention is to provide new compounds, in particular new azetidine derivatives, which are active with regard to acetyl-CoA carboxylase(s).
Another aim of the present invention is to provide new compounds, in particular new azetidine derivatives, which are active with regard to ACC2.
A further aim of the present invention is to provide new compounds, in particular new azetidine derivatives, which have an inhibitory effect on acetyl-CoA carboxylase(s) in vitro and/or in vivo and possess suitable pharmacological and pharmacokinetic properties to use them as medicaments.
A further aim of the present invention is to provide new compounds, in particular new azetidine derivatives, which have an inhibitory effect on ACC2 in vitro and/or in vivo and possess suitable pharmacological and pharmacokinetic properties to use them as medicaments.
A further aim of the present invention is to provide effective ACC inhibitors, in particular for the treatment of metabolic disorders, for example of obesity and/or diabetes.
A further aim of the present invention is to provide methods for treating a disease or condition mediated by the inhibition of acetyl-CoA carboxylase(s) in a patient.
A further aim of the present invention is to provide a pharmaceutical composition comprising at least one compound according to the invention.
A further aim of the present invention is to provide a combination of at least one compound according to the invention with one or more additional therapeutic agents.
A further aim of the present invention is to provide methods for the synthesis of the new compounds, in particular azetidine derivatives.
A further aim of the present invention is to provide starting and/or intermediate compounds suitable in methods for the synthesis of the new compounds.
Further aims of the present invention become apparent to the one skilled in the art by the description hereinbefore and in the following and by the examples.
OBJECT OF THE INVENTION
Within the scope of the present invention it has now surprisingly been found that the new compounds of general formula (I) as described hereinafter exhibit an inhibiting activity with regard to acetyl-CoA carboxylase(s).
According to another aspect of the present invention it has been found that the new compounds of general formula (I) as described hereinafter exhibit an inhibiting activity with regard to ACC2.
In a first aspect the present invention provides a compound of general formula (I)




wherein

    Ar1 is selected from the group Ar1-G1 consisting of:
    
        6- to 10-membered arylene and 5- to 10-membered heteroarylene all of which may be optionally substituted with one or more substituents RA, wherein R1 and RA linked to adjacent C-atoms of Ar1 may be connected with each other and together form a C3-5-alkylene bridging group in which 1, 2 or 3-CH2-groups may be replaced by O, C(═O), S, S(═O), S(═O)2, NH or N(C1-4-alkyl)-, wherein the alkylene bridge may optionally be substituted by one or two C1-3-alkyl groups;
    
    
    RA is selected from the group RA-G1 consisting of:
    
        H, F, Cl, Br, I, CN, OH, —NO2, C1-4-alkyl, C2-4-alkenyl, C1-4-alkyl-O—, C1-4-alkyl-C(═O)—, H2N—, H2N—C(═O)—, H2N—S(═O)2—, HO—C(═O)—, C1-4-alkyl-O—C(═O)—, phenyl and phenyl-C1-3-alkyl,
        
            wherein in each NH2-group, one or both hydrogen atoms may independently be replaced by C1-4-alkyl;
            wherein each alkyl and cycloalkyl may be optionally substituted with one or more F atoms;
        
        
    
    
    R1 is selected from the group R1-G1 consisting of:
    
        H, OH, C1-6-alkyl, C1-6-alkyl-O—, C3-7-cycloalkyl, C3-7-cycloalkyl-O—, C3-7-cycloalkyl-C1-3-alkyl-O—, H2N—, (C1-4-alkyl)NH—, (C1-4-alkyl)2N—, C3-7-cycloalkyl-NH—, C3-7-cycloalkyl-N(C1-4-alkyl)-, C3-7-cycloalkyl-C1-3-alkyl-NH—, (C3-7cycloalkyl-C1-3-alkyl)-N(C1-4-alkyl)-, C1-4-alkyl-C(═O)—, C1-4-alkyl-S(═O)2—, HO—C(═O)—, C1-4-alkyl-O—C(═O)—, H2N—C(═O)—, (C1-4-alkyl)HN—C(═O)—, (C1-4-alkyl)2N—C(═O)—, aryl, aryl-C1-3-alkyl-, aryl-C1-3-alkyl-O, heterocyclyl, heterocyclyl-O—, heterocyclyl-C1-3-alkyl-O—, heteroaryl, heteroaryl-C1-3-alkyl- and heteroaryl-C1-3-alkyl-O—,
        
            wherein each alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from F, OH and C1-4-alkyl-O—, and
            wherein each heterocyclyl is optionally substituted with one or more C1-3-alkyl;
        
        
    
    
    Ar2 is selected from the group Ar2-G1 consisting of:
    
        phenylene and a 5- or 6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, or S,
        
            wherein all of the before mentioned groups may be optionally substituted with one or more substituents RA;
        
        
    
    
    R2a and R2b are each independently selected from the group R2-G1 consisting of:
    
        H and C1-3-alkyl;
    
    
    R3 is selected from the group R3-G1 consisting of: H and C1-4-alkyl; and
    R4 is selected from the group R4-G1 consisting of:
    
        H, C1-6-alkyl, C3-10-carbocyclyl, C3-10-carbocyclyl-C1-3-alkyl-, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkyl-O—, RN1RN2N—, heterocyclyl, heterocyclyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heteroaryl and heteroaryl-C1-3-alkyl,
        
            wherein in each carbocyclyl and heterocyclyl a —CH2-group may optionally be replaced by —C(═O)—, and
            wherein each alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group may be optionally substituted with one or more substituents independently selected from the group R5; while
        
        
    
    
    RN1 is selected from the group RN1-G1 consisting of:
    
        H and C1-4-alkyl;
        
            wherein each alkyl group may be optionally substituted with one R5;
        
        
    
    
    RN2 is selected from the group RN2-G1 consisting of:
    
        H, C1-4-alkyl, C3-10-carbocyclyl, C3-10-carbocyclyl-C1-3-alkyl, C2-6-alkenyl, C2-6-alkynyl, heterocyclyl, heterocyclyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heteroaryl and heteroaryl-C1-3-alkyl,
        
            wherein each aryl, heteroaryl, carbocyclyl and heterocyclyl may be optionally substituted with one or more C1-4-alkyl, aryl, aryl-C1-3-alkyl- or F atom, and
            wherein in each carbocyclyl and heterocyclyl a CH2-group may optionally be replaced by —C(═O)—; and
            with the provision that there is at least one CH2-group between any double or triple bond of the alkenyl and alkynyl groups and the nitrogen atom to which they are attached; and
        
        
    
    
    R5 is selected from the group R5-G1 consisting of:
    
        F, Cl, Br, CN, OH, C1-4-alkyl-, C1-4-alkyl-O—, C1-4-alkyl-S—, C1-4-alkyl-S(═O)2—, H2N—, (C1-4-alkyl)NH—, (C1-4-alkyl)2N—, C1-4-alkyl-(C═O)—NH—, heterocyclyl and aryl,
        
            wherein each alkyl may be optionally substituted with one or more F-atoms and/or with a substituent selected from OH, C1-3-alkyl-O— and CN; and
            wherein two substituents R5 attached to an aryl or heteroaryl group may be linked to each other and form a C2-5-alkylene bridging group in which one or two —CH2-groups may be replaced by a group independently of each other selected from O, S, NH and N(C1-4-alkyl)-, wherein the C2-5-alkylene bridging group is optionally substituted by one or two C1-3-alkyl groups or F atoms;

including any tautomers and stereoisomers thereof,

or a salt thereof

or a solvate or hydrate thereof.

        
        
    
    


In a further aspect the present invention relates to processes for preparing a compound of general formula (I) and to new intermediate compounds in these processes.
A further aspect of the invention relates to a salt of the compounds of general formula (I) according to this invention, in particular to a pharmaceutically acceptable salt thereof.
In a further aspect this invention relates to a pharmaceutical composition, comprising one or more compounds of general formula (I) or one or more pharmaceutically acceptable salts thereof according to the invention, optionally together with one or more inert carriers and/or diluents.
In a further aspect this invention relates to a method for treating diseases or conditions which are mediated by inhibiting the activity of acetyl-CoA carboxylase(s) in a patient in need thereof characterized in that a compound of general formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient.
According to another aspect of the invention, there is provided a method for treating a metabolic disease or disorder in a patient in need thereof characterized in that a compound of general formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient.
According to another aspect of the invention, there is provided a method for treating a cardiovascular disease or disorder in a patient in need thereof characterized in that a compound of general formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient.
According to another aspect of the invention, there is provided a method for treating a neurodegenerative disease or disorder or for treating a disease or disorder of the central nervous system in a patient in need thereof characterized in that a compound of general formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient.
According to another aspect of the invention, there is provided a method for treating a cancer, a malignant disorder or a neoplasia in a patient in need thereof characterized in that a compound of general formula (I) or a pharmaceutically acceptable salt thereof is administered to the patient.
According to another aspect of the invention, there is provided the use of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for a therapeutic method as described hereinbefore and hereinafter.
According to another aspect of the invention, there is provided a compound of the general formula (I) or a pharmaceutically acceptable salt thereof for a therapeutic method as described hereinbefore and hereinafter.
In a further aspect this invention relates to a method for treating a disease or condition mediated by the inhibition of acetyl-CoA carboxylase(s) in a patient that includes the step of administering to the patient in need of such treatment a therapeutically effective amount of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more additional therapeutic agents.
In a further aspect this invention relates to a use of a compound of the general formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more additional therapeutic agents for the treatment or prevention of diseases or conditions which are mediated by the inhibition of acetyl-CoA carboxylase(s).
In a further aspect this invention relates to a pharmaceutical composition which comprises a compound according to general formula (I) or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents, optionally together with one or more inert carriers and/or diluents.
Other aspects of the invention become apparent to the one skilled in the art from the specification and the experimental part as described hereinbefore and hereinafter.


DETAILED DESCRIPTION
Unless otherwise stated, the groups, residues, and substituents, particularly Ar1, Ar2, RA, R1, R2a, R2b, R3, R4, are defined as above and hereinafter. If residues, substituents, or groups occur several times in a compound, as for example RA, RN1, RN2 or R5, they may have the same or different meanings. Some preferred meanings of individual groups and substituents of the compounds according to the invention will be given hereinafter. Any and each of these definitions may be combined with each other.
Ar1:
Ar1-G1:
The group Ar1 is preferably selected from the group Ar1-G1 as defined hereinbefore and hereinafter.
Ar1-G2:
In one embodiment the group Ar1 is selected from the group Ar1-G2 consisting of: phenylene, naphthylene, pyridylene, pyrimidinylene, pyridazinylene, pyrazinylene, quinolinylene, indanylene, benzofuranylene, benzothiophenylene, benzo[1,3]dioxolylene, 2,3-dihydro-benzo[1,4]dioxinylene and 3,4-dihydro-2H-benzo[b][1,4]dioxepinylene,

    
    
        wherein the before mentioned bicyclic groups preferably are linked to the ring of the core structure of the formula (I) via an aromatic or heteroaromatic ring of the bicyclic group, and
        wherein all of the before mentioned groups may be optionally substituted with one or more substituents

Ar1-G3:

    
    


In another embodiment the group Ar1 is selected from the group Ar1-G3 consisting of: phenylene, pyridinylene, pyrimidinylene, benzofuranylene and benzo[1,3]dioxolylene,

    
    
        wherein each of the beforementioned groups may be substituted with one or two substituents

Ar1-G3a:

    
    


In another embodiment the group Ar1 is selected from the group Ar1-G3a consisting of: phenylene and pyridinylene, which may be substituted with one or two RA.
Ar1-G3b:
In another embodiment the group Ar1 is selected from the group Ar1-G3b consisting of: phenylene, which may be substituted with one or two RA.
Ar1-G4:
In another embodiment the group Ar1 is selected from the group Ar1-G4 consisting of:




wherein the asterisk to the right side of each group indicates the bond which is connected to the azetidine ring of the core structure of the formula (I), and the asterisk to the left side of each group indicates the bond which is connected to a substituent R1, and in addition each of the before mentioned groups is optionally substituted with one or two substituents RA.

Ar1-G4a:

In another embodiment the group Ar1 is selected from the group Ar1-G4a consisting of:




wherein the asterisk to the right side of each group indicates the bond which is connected to the azetidine ring of the core structure of the formula (I), and the asterisk to the left side of each group indicates the bond which is connected to a substituent R1, and in addition each of the before mentioned groups is optionally substituted with one or two F or Cl atoms.

Ar1-G5:

In another embodiment the group Ar1 is selected from the group Ar1-G5 consisting of:




which are each optionally substituted with one or two substituents independently selected from F and Cl.

Ar1-G5a:

In another embodiment the group Ar1 is selected from the group Ar1-G5a consisting of:




wherein the asterisk to the right side of the cyclic group indicates the bond which is connected to the azetidine ring of the core structure of the formula (I), and if existing the asterisk to the left side of the cyclic group indicates the bond which is connected to a substituent R1.

Ar1-G6:

In another embodiment the group Ar1 is selected from the group Ar1-G6 consisting of:




Ar1-G7:

In another embodiment the group Ar1 is selected from the group Ar1-G7 consisting of:




wherein the asterisk to the right-hand side indicates the bond which is connected to the azetidine ring of the core structure of the formula (I), and the asterisk to the left-hand side indicates the bond which is connected to a substituent R1.

Ar1-G8:

In another embodiment the group Ar1 is selected from the group Ar1-G8 consisting of:




wherein the asterisk to the right-hand side indicates the bond which is connected to the azetidine ring of the core structure of the formula (I), and the asterisk to the left-hand side indicates the bond which is connected to a substituent R1.

Ar1-G9:

In another embodiment the group Ar1 is selected from the group Ar1-G9 consisting of:




wherein the asterisk to the right-hand side indicates the bond which is connected to the azetidine ring of the core structure of the formula (I), and the asterisk to the left-hand side indicates the bond which is connected to a substituent R1.

RA:

RA-G1:

The group RA is preferably selected from the group RA-G1 as defined hereinbefore and hereinafter.
RA-G2:
In another embodiment the group RA is selected from the group RA-G2 consisting of: H, F, Cl, Br, CN, OH, —NO2, C1-4-alkyl, C1-4-alkyl-O—, H2N—, C1-6-alkyl-O—C(═O)—, phenyl and phenyl-CH2—,

    
    
        wherein in each NH2-group, one or both hydrogen atoms may independently be replaced by C1-4-alkyl.

RA-G3:

    
    


In another embodiment the group RA is selected from the group RA-G3 consisting of: H, F, Cl, CN, OH, C1-3-alkyl and C1-3-alkyl-O—.
RA-G4:
In another embodiment the group RA is selected from the group RA-G4 consisting of: H, F, Cl, CN, —CH3 and —OCH3.
RA-G5:
In another embodiment the group RA is selected from the group RA-G5 consisting of: F and Cl.
R1 
R1-G1:
The group R1 is preferably selected from the group R1-G1 as defined hereinbefore and hereinafter.
R1-G2:
In another embodiment the group R1 is selected from the group R1-G2 consisting of: H, OH, C1-4-alkyl, C1-4-alkyl-O—, C3-7-cycloalkyl, C3-7-cycloalkyl-O—, tetrahydrofuranyl-O—, C3-7-cycloalkyl-C1-3-alkyl-O—, H2N—, (C1-4-alkyl)NH—, (C1-4-alkyl)2N—, C3-7-cycloalkyl-NH—, C3-7-cycloalkyl-N(C1-4-alkyl)-, phenyl, phenyl-C1-3-alkyl-, phenyl-C1-3-alkyl-O—, piperidinyl, morpholinyl, pyrrolidinyl and pyrrolyl,

    
    
        wherein each alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from F, OH and C1-4-alkyl-O—, and
        wherein piperidinyl is optionally substituted with one or two C1-3-alkyl.

R1-G3:

    
    


In another embodiment the group R1 is selected from the group R1-G3 consisting of: H, C1-4-alkyl, C1-4-alkyl-O—, C3-6-cycloalkyl, C3-6-cycloalkyl-O—, tetrahydrofuranyl-O—, C3-6-cycloalkyl-CH2—O—, (C1-4-alkyl)NH—, (C1-4-alkyl)2N—, phenyl, benzyl, phenyl-CH2—O—, piperidinyl, morpholinyl, pyrrolidinyl and pyrrolyl,

    
    
        wherein each alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from F, OH and —O—CH3, and
        wherein piperidinyl is optionally substituted with one or two CH3.

R1-G4:

    
    


In another embodiment the group R1 is selected from the group R1-G4 consisting of: C1-4-alkyl, C1-4-alkyl-O—, C3-5-cycloalkyl, C3-5-cycloalkyl-O—, tetrahydrofuranyl-O—, C3-5-cycloalkyl-CH2—O—, (C1-4-alkyl)2N—, phenyl, benzyl, phenyl-CH2—O—, piperidinyl, morpholinyl, pyrrolidinyl and pyrrolyl,

    
    
        wherein each alkyl and cycloalkyl may be optionally substituted with one to three F atoms or one OH or —O—CH3, and
        wherein piperidinyl is optionally substituted with one CH3.

R1-G4a:

    
    


In another embodiment the group R1 is selected from the group R1-G4a consisting of: C3-5-cycloalkyl-O—, C3-5-cycloalkyl-CH2—O—,

    
    
        wherein each alkyl and cycloalkyl may be optionally substituted with one to three F atoms.

R1-G4b:

    
    


In another embodiment the group R1 is selected from the group R1-G4b consisting of: C1-4alkyl, C1-4alkyl-O—, C3-5-cycloalkyl, C3-5-cycloalkyl-O—, tetrahydrofuranyl-O—, cyclopropyl-CH2—O—, (C1-4-alkyl)2N—, piperidinyl, pyrrolidinyl and morpholinyl,

    
    
        wherein each alkyl and cycloalkyl is optionally substituted with one to three F atoms or one OH or —O—OH3, and
        wherein piperidinyl is optionally substituted with one CH3.

R1-G4c:

    
    


In another embodiment the group R1 is selected from the group R1-G4c consisting of: C1-4-alkyl-O—, cyclopropyl-CH2—O— and tetrahydrofuranyl-O—,

    
    
        wherein each alkyl and the cyclopropyl groups are optionally substituted with one to three F atoms.

R1-G5:

    
    


In another embodiment the group R1 is selected from the group R1-G5 consisting of:




R1-G5a:

In another embodiment the group R1 is selected from the group R1-G5a consisting of:




R1-G5b:

In another embodiment the group R1 is selected from the group R1-G5b consisting of: —N(CH3)2, —CHF2 and —C(CH3)3.
R1-G5c:
In another embodiment the group R1 is selected from the group R1-G5c consisting of:




R1-G6:

In another embodiment the group R1 is selected from the group R1-G6 consisting of: CH3CH2—O— and cyclopropyl-CH2—O—,

    
    
        wherein the ethyl and cycloalkyl may be optionally substituted with one to three F atoms.

R1-G6a:

    
    


In another embodiment the group R1 is selected from the group R1-G6a consisting of: CH3CH2—O— and cyclopropyl-CH2—O—.
R1-G6b:
In another embodiment the group R1 is selected from the group R1-G6b consisting of: CH3CH2—O—.
Ar2:
Ar2-G1:
The group Ar2 is preferably selected from the group Ar2-G1 as defined hereinbefore and hereinafter.
Ar2-G2:
In another embodiment the group Ar2 is selected from the group Ar2-G2 consisting of: phenylene and pyridinylene, which may be optionally substituted with one or two substituents RA.
Ar2-G2a:
In another embodiment the group Ar2 is selected from the group Ar2-G2a consisting of: phenylene.
Ar2-G3:
In another embodiment the group Ar2 is selected from the group Ar2-G3 consisting of:




wherein the before mentioned group may be optionally substituted with one substituent RA.

Ar2-G3a:

In another embodiment the group Ar2 is selected from the group Ar2-G3a consisting of:




R2a and R2b 

R2-G1:

The groups R2a and R2b are each preferably selected from the group R2-G1 as defined hereinbefore and hereinafter.
R2-G2:
In another embodiment the groups R2a and R2b are each independently selected from the group R2-G2 consisting of: H and CH3.
R2-G3:
In another embodiment the groups R2a and R2b are selected from the group R2-G3 consisting of: R2a being H, and R2b being CH3.
R3 
R3-G1:
The group R3 is preferably selected from the group R3-G1 as defined hereinbefore and hereinafter.
R3-G2:
In another embodiment the group R3 is selected from the group R3-G2 consisting of: H and CH3.
R3-G3:
In another embodiment the group R3 is selected from the group R3-G3 consisting of: H.
R4:
R4-G1:
The group R4 is preferably selected from the group R4-G1 as defined hereinbefore and hereinafter.
R4-G2:
In one embodiment the group R4 is selected from the group R4-G2 consisting of: H, C1-4-alkyl, C3-7-cycloalkyl, C4-7-cycloalkenyl, C3-7-cycloalkyl-C1-3-alkyl, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkyl-O—, RN1RN2N—, heterocyclyl, heterocyclyl-C1-3-alkyl, phenyl, phenyl-C1-3-alkyl, heteroaryl and heteroaryl-C1-3-alkyl,

    
    
        wherein in each carbocyclyl and heterocyclyl a —CH2-group may optionally be replaced by —C(═O)—, and
        wherein each alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group may be optionally substituted with one or more substituents independently selected from the group R5.

R4-G3:

    
    


In one embodiment the group R4 is selected from the group R4-G3 consisting of: H, C1-4-alkyl, C3-6-cycloalkyl, C4-6-cycloalkenyl, C3-6-cycloalkyl-C1-3-alkyl-, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkyl-O—, RN1RN2N—, heterocyclyl, heterocyclyl-C1-3-alkyl-, phenyl, phenyl-C1-3-alkyl-, heteroaryl and heteroaryl-C1-3-alkyl-,

    
    
        wherein RN1 is selected from the group consisting of: H and C1-3-alkyl; and
        wherein RN2 is selected from the group consisting of: H, C1-4-alkyl, C3-7-cycloalkyl and heteroaryl; and
        wherein in each cycloalkyl and heterocyclyl a —CH2-group may optionally be replaced by —C(═O)—, and
        wherein each alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group may be optionally substituted with one to three substituents independently selected from the group consisting of: F, Cl, CN, OH, CF3, C1-3-alkyl, —O—(C1-3-alkyl) and —NH—(C═O)—C1-3-alkyl; and
        wherein each heterocyclyl is selected from the group consisting of: azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl and 3H-pyrimidin-4-onyl; and
        wherein each heteroaryl is selected from the group consisting of: pyrrolyl, furanyl, furazanyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl.

R4-G3a:

    
    


In one embodiment the group R4 is selected from the group R4-G3a consisting of: C1-4-alkyl, C3-5-cycloalkyl, cyclopentenyl, C3-5-cycloalkyl-CH2—, C3-5-alkenyl, C3-6-alkynyl, C1-4-alkyl-O—, RN1NR2N—, heterocyclyl, phenyl, heteroaryl and heteroaryl-CH2—,

    
    
        wherein RN1 is selected from the group consisting of: H and CH3; and
        wherein RN2 is selected from the group consisting of: H, C1-3-alkyl, cyclopropyl, pyridinyl and pyrimidinyl; and
        wherein in each heterocyclyl a —CH2-group may optionally be replaced by —C(═O)—, and
        wherein each alkyl, cycloalkyl, heterocyclyl and heteroaryl group may be optionally substituted with one to three F atoms and/or with one or two substituents independently selected from the group consisting of: Cl, CN, OH, CF3, CH3, —O—CH3 and —NH—(C═O)—CH3; and
        wherein each heterocyclyl is selected from the group consisting of: azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl and 3H-pyrimidin-4-onyl; and
        wherein each heteroaryl is selected from the group consisting of: pyrrolyl, furanyl, furazanyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl and pyrimidinyl.

R4-G4:

    
    


In another embodiment the group R4 is selected from the group R4-G4 consisting of: —CH3, —CH2OH, —CH2OCH3, —CH2OCH2CH3, —CH(OH)(CH3), —CH2CH3, —CH2CH2CH2CH3, —CH(CH3)2, —C(CH3)2(OH), —CH2—CH═CH2, —CH2F, —CHF2, —CF3, —CH2CN, —CHF—CH3, —CF2—CH3, —CH2—CF3, —CF(CH3)2, —NH(CH3), —N(CH3)2, —NH(C2H5), —N(CH3)(C2H5), —N(CH3)(iPr), —O—C(CH3)3,







R4-G5:

In another embodiment the group R4 is selected from the group R4-G5 consisting of: —CH3, —CH2CH3, —CH2—CH═CH2, —CF2—CH3, —CH2—CF3, —N(CH3)2,




R4-G6:

In another embodiment the group R4 is selected from the group R4-G6 consisting of: methyl.
R5:
R5-G1:
The group R5 is preferably selected from the group R5-G1 as defined hereinbefore and hereinafter.
R5-G2:
In another embodiment the group R5 is selected from the group R5-G2 consisting of: F, Cl, Br, CN, OH, C1-4-alkyl-, C1-4-alkyl-O— and C1-4-alkyl-(C═O)—NH—,

    
    
        wherein each alkyl may be optionally substituted with one to three F-atoms.

R5-G3:

    
    


In another embodiment the group R5 is selected from the group R5-G3 consisting of: F, Cl, CN, OH, CF3, C1-3-alkyl, —O—(C1-3-alkyl) and —NH—(C═O)—C1-3-alkyl.
R5-G4:
In another embodiment the group R5 is selected from the group R5-G4 consisting of: F, Cl, CN, OH, CF3, CH3, —O—CH3 and —NH—(C═O)—CH3.
R5-G5:
In another embodiment the group R5 is selected from the group R5-G5 consisting of: F and CH3.
RN1:
RN1-G1:
The group RN1 is preferably selected from the group RN1-G1 as defined hereinbefore and hereinafter.
RN1-G2:
In another embodiment the group RN1 is selected from the group RN1-G2 consisting of:
H and C1-3-alkyl, wherein each alkyl group may be optionally substituted with one CN.
In another embodiment the group RN1 is selected from the group RN1-G3 consisting of: H, CH3 and —CH2CN.
RN1-G4:
In another embodiment the group RN1 is selected from the group RN1-G4 consisting of: H and CH3.
RN2:
RN2-G1:
The group RN2 is preferably selected from the group RN2-G1 as defined hereinbefore and hereinafter.
RN2-G2:
In another embodiment the group RN2 is selected from the group RN2-G2 consisting of: H, C1-4-alkyl, C3-7-cycloalkyl and heteroaryl.
RN2-G3:
In another embodiment the group RN2 is selected from the group RN2-G3 consisting of: H, C1-3-alkyl, cyclopropyl, pyridinyl and pyrimidinyl.
RN2-G3a:
In another embodiment the group RN2 is selected from the group RN2-G3a consisting of: C1-3-alkyl, cyclopropyl, pyridinyl and pyrimidinyl.
Examples of preferred subgeneric embodiments according to the present invention are set forth in the following table, wherein each substituent group of each embodiment is defined according to the definitions set forth hereinbefore and wherein all other substituents of the formula (I) are defined according to the definitions set forth hereinbefore:

















Embodi-




R2a and




ment
R1
Ar1
RA
Ar2
R2b
R3
R4






















E-1
R1-G1
Ar1-G1 
RA-G1 
Ar2-G1
R2-G1
R3-G1
R4-G1


E-2
R1-G1 
Ar1-G2
RA-G2
Ar2-G2
R2-G2
R3-G2
R4-G1


E-3
R1-G2
Ar1-G2
RA-G3 
Ar2-G2
R2-G2
R3-G2
R4-G2


E-4
R1-G2
Ar1-G3
RA-G3
Ar2-G2
R2-G2
R3-G2
R4-G1


E-5
R1-G3
Ar1-G3
RA-G4
Ar2-G2
R2-G2
R3-G2 
R4-G1


E-6
R1-G2
Ar1-G3
RA-G3
Ar2-G2
R2-G3
R3-G3
R4-G2


E-7
R1-G3 
Ar1-G3
RA-G4
Ar2-G2
R2-G3
R3-G3
R4-G2


E-8
R1-G3
Ar1-G3
RA-G4
Ar2-G2a
R2-G3
R3-G3
R4-G3


E-9
R1-G4
Ar1-G3a
RA-G4
Ar2-G2a
R2-G3
R3-G3
R4-G3a


E-10
R1-G6a
Ar1-G3a
RA-G4
Ar2-G2a
R2-G3
R3-G3
R4-G3a


E-11
R1-G3
Ar1-G3a
RA-G4
Ar2-G2a
R2-G3
R3-G3
R4-G4


E-12
R1-G4 
Ar1-G3a
RA-G4
Ar2-G2a
R2-G3
R3-G3
R4-G5


E-13
R1-G4
Ar1-G3a
RA-G4
Ar2-G3
R2-G3
R3-G3
R4-G6


E-14
R1-G4a 
Ar1-G3a
RA-G5
Ar2-G3a
R2-G3
R3-G3 
R4-G3a


E-15
R1-G4a 
Ar1-G3a
RA-G5
Ar2-G3a
R2-G3
R3-G3
R4-G4


E-16 
R1-G4a
Ar1-G3a
RA-G5
Ar2-G3a
R2-G3
R3-G3
R4-G5


E-17
R1-G5
Ar1-G3a
RA-G5
Ar2-G3a
R2-G3
R3-G3
R4-G3a


E-18
R1-G6a
Ar1-G3a
RA-G5
Ar2-G3a
R2-G3
R3-G3
R4-G3a


E-19
R1-G5
Ar1-G3a
RA-G5
Ar2-G3a 
R2-G3
R3-G3
R4-G4


E-20
R1-G5
Ar1-G3a
RA-G5
Ar2-G3a
R2-G3
R3-G3
R4-G5


E-21
R1-G4
Ar1-G5
—
Ar2-G3a
R2-G3
R3-G3
R4-G3


E-22
R1-G4
Ar1-G5
—
Ar2-G3a
R2-G3 
R3-G3
R4-G3a


E-23
R1-G4 
Ar1-G5
—
Ar2-G3a
R2-G3
R3-G3
R4-G4


E-24 
R1-G6a
Ar1-G5
—
Ar2-G3a
R2-G3
R3-G3
R4-G4


E-25
R1-G4
Ar1-G5 
—
Ar2-G3a
R2-G3
R3-G3
R4-G5


E-26
R1-G5
Ar1-G5
—
Ar2-G3a
R2-G3
R3-G3
R4-G3


E-27
R1-G5 
Ar1-G5
—
Ar2-G3a
R2-G3
R3-G3
R4-G3a


E-28
R1-G5
Ar1-G5
—
Ar2-G3a
R2-G3
R3-G3
R4-G4


E-29
R1-G5
Ar1-G5
—
Ar2-G3a
R2-G3
R3-G3
R4-G5


E-30
R1-G4
Ar1-G5a
—
Ar2-G3a
R2-G3
R3-G3 
R4-G3a


E-31
R1-G4
Ar1-G5a
—
Ar2-G3a
R2-G3
R3-G3
R4-G4


E-32
R1-G4
Ar1-G5a
—
Ar2-G3a
R2-G3
R3-G3
R4-G5


E-33
R1-G5
Ar1-G5a
—
Ar2-G3a
R2-G3
R3-G3
R4-G3a


E-34
R1-G5
Ar1-G5a
—
Ar2-G3a
R2-G3 
R3-G3 
R4-G4


E-35
R1-G5
Ar1-G5a
—
Ar2-G3a
R2-G3 
R3-G3
R4-G5


E-36
R1-G5a
Ar1-G5a 
—
Ar2-G3a
R2-G3
R3-G3
R4-G3a


E-37 
R1-G5a
Ar1-G5a
—
Ar2-G3a
R2-G3
R3-G3
R4-G4


E-38 
R1-G5a
Ar1-G5a
—
Ar2-G3a
R2-G3
R3-G3 
R4-G5


E-39 
R1-G6b
Ar1-G6
—
Ar2-G3a
R2-G3
R3-G3
R4-G3a


E-40 
R1-G6b
Ar1-G6
—
Ar2-G3a
R2-G3
R3-G3
R4-G4


E-41
R1-G6b
Ar1-G6
—
Ar2-G3a
R2-G3
R3-G3
R4-G5


E-42
R1-G6a
Ar1-G6
—
Ar2-G3a
R2-G3
R3-G3
R4-G4









The following preferred embodiments of compounds of the formula (I) are described using generic formulae (I.1) to (I.5), wherein any tautomers and stereoisomers, solvates, hydrates and salts thereof, in particular the pharmaceutically acceptable salts thereof, are encompassed.













(I.1)






 


(I.1a)






 


(I.1b)






 


(I.2)






 


(I.2a)






 


(I.3)






 


(I.4)






 


(I.5)













wherein in each of the above formulae (I.1) to (I.5), the groups Ar1, R1 and R4 are defined as hereinbefore and hereinafter.

Preferred embodiments of the above formulae (I.1) to (I.5) according to the present invention are set forth in the following table, wherein each group Ar1, R1 and R4 of each embodiment is defined according to the definitions set forth hereinbefore and wherein all other substituents of the formula (I) are defined according to the definitions set forth hereinbefor. Preferred embodiments include:















Em-







bodi-
For-






ment
mula
Ar1
RA
R1
R4







E-A
(I.1)
Ar1-G3
RA-G5
R1-G3
R4-G3


E-B
(I.1)
Ar1-G3
RA-G5
R1-G4
R4-G3a


E-C
(I.1)
Ar1-G3b
RA-G5
R1-G4
R4-G3


E-D
(I.1)
Ar1-G3b
RA-G5
R1-G4a
R4-G3


E-E
(I.1)
Ar1-G3b
RA-G5
R1-G5
R4-G3


E-F
(I.1)
Ar1-G3b
RA-G5
R1-G5a
R4-G3


E-G
(I.1)
Ar1-G3b
RA-G5
R1-G6
R4-G3


E-H
(I.1)
Ar1-G3b
RA-G5
R1-G6b
R4-G3


E-I
(I.1)
Ar1-G3b
RA-G5
R1-G4
R4-G3a


E-J
(I.1)
Ar1-G3b
RA-G5
R1-G4
R4-G4


E-K
(I.1)
Ar1-G3b
RA-G5
R1-G4
R4-G5


E-L
(I.1)
Ar1-G3b
RA-G5
R1-G4
R4-G6


E-M
(I.1a)
Ar1-G3a
RA-G5
R1-G4
R4-G5


E-N
(I.1a)
Ar1-G3a
RA-G5
R1-G6b
R4-G4


E-O
(I.1b)
Ar1-G3a
RA-G5
R1-G4
R4-G5


E-P
(I.1 b)
Ar1-G3a
RA-G5
R1-G6b
R4-G4


E-Q
(I.2)
—
—
R1-G3
R4-G4


E-R
(I.2)
—
—
R1-G5
R4-G4


E-S
(I.2)
—
—
R1-G4
R4-G5


E-T
(I.2)
—
—
R1-G4a
R4-G6


E-U
(I.2a)
—
—
—
R4-G2


E-V
(I.2a)
—
—
—
R4-G3


E-W
(I.2a)
—
—
—
R4-G3a


E-X
(I.2a)
—
—
—
R4-G4


E-Y
(I.2a)
—
—
—
R4-G5


E-Z
(I.3)
—
—
R1-G4b
R4-G6


E-Aa
(I.3)
—
—
R1-G5b
R4-G6


 


E-Ab
(I.4)
—
—
R1-G4c
CH3 or 





 


E-Ac
(I.4)
—
—
R1-G5c
R4-G6


 


E-Ad
(I.5)
—
—
CH3, 



R4-G6









including any tautomers and stereoisomers, solvates, hydrates and salts thereof, in particular the pharmaceutically acceptable salts thereof.

A preferred embodiment of the present invention concerns those compounds of general formula (I), wherein
Ar1 is selected from the group Ar1-G4a consisting of:




wherein the asterisk to the right side of each group indicates the bond which is connected to the azetidine ring of the core structure of the formula (I), and the asterisk to the left side of each group indicates the bond which is connected to a substituent R1, and in addition each of the before mentioned groups is optionally substituted with one or two F or Cl atoms;

R1 is selected from the group R1-G4 consisting of:

C1-4-alkyl, C1-4-alkyl-O—, C3-5-cycloalkyl, C3-5-cycloalkyl-O—, tetrahydrofuranyl-O—, C3-5-cycloalkyl-CH2—O—, (C1-4-alkyl)2N—, phenyl, benzyl, phenyl-CH2—O—, piperidinyl, morpholinyl, pyrrolidinyl and pyrrolyl,

    
    
        wherein each alkyl and cycloalkyl may be optionally substituted with one to three F atoms or one OH or —O—CH3, and
        wherein piperidinyl is optionally substituted with one CH3;

Ar2 is selected from the group Ar2-G3a consisting of:

    
    






R2a is H;

R2b is CH3;

R3 is H; and

R4 is selected from the group R4-G3a consisting of:

C1-4-alkyl, C3-5-cycloalkyl, cyclopentenyl, C3-5-cycloalkyl-CH2—, C3-5-alkenyl, C3-6-alkynyl, C1-4-alkyl-O—, RN1RN2N—, heterocyclyl, phenyl, heteroaryl and heteroaryl-CH2—,

    
    
        wherein RN1 is selected from the group consisting of: H and CH3; and
        wherein RN2 is selected from the group consisting of: H, C1-3-alkyl, cyclopropyl, pyridinyl and pyrimidinyl; and
        wherein in each heterocyclyl a —CH2-group may optionally be replaced by —C(═O)—, and
        wherein each alkyl, cycloalkyl, heterocyclyl and heteroaryl group may be optionally substituted with one to three F atoms and/or with one or two substituents independently selected from the group consisting of: Cl, CN, OH, CF3, CH3, —O—CH3 and —NH—(C═O)—CH3; and
        wherein each heterocyclyl is selected from the group consisting of: azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl and 3H-pyrimidin-4-onyl; and
        wherein each heteroaryl is selected from the group consisting of: pyrrolyl, furanyl, furazanyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl and pyrimidinyl;

including any tautomers and stereoisomers thereof,

or a salt thereof

or a solvate or hydrate thereof.

    
    


A more preferred embodiment of the present invention concerns those compounds of general formula (I), wherein
Ar1 is selected from the group Ar1-G5 consisting of:




    
    
        which are each optionally substituted with one or two substituents independently selected from F and Cl;

R1 is selected from the group R1-G5a consisting of:

    
    






preferably, R1 is —OCH2CH3;

Ar2 is selected from the group Ar2-G3a consisting of:





R2a is H;

R2b is CH3;

R3 is H; and

R4 is selected from the group R4-G5 consisting of:

—CH3, —CH2CH3, —CH2—CH═CH2, —CF2—CH3, —CH2—CF3, —N(CH3)2,





including any tautomers and stereoisomers thereof,

or a salt thereof

or a solvate or hydrate thereof.

Particularly preferred compounds, including their tautomers and stereoisomers, the salts thereof, or any solvates or hydrates thereof, are described in the experimental section hereinafter.
Synthesis Schemes
The compounds according to the invention may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis. Preferably the compounds are obtained analogously to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section.




Compounds of general formula (I) may be prepared by palladium-mediated Buchwald reactions or copper-mediated Ullmann reactions of aryl halogenides or aryl triflates (III) with azetidines (II) wherein Z is a leaving group which for example denotes Cl, Br, I or OTf (triflate).




Compounds of general formula (I) may alternatively be prepared by nucleophilic substitution reactions of aryl/hetaryl alcohols (IV) with mesylated or tosylated hydroxyazetidines (V), wherein Z is a leaving group which for example denotes mesylate or tosylate. Alternatively Mitsunobu-type reactions using the free alcohols (Z═H) can be used.




Compounds of general formula (I) may be prepared by amide coupling reactions of amines (VI) with carboxylic acids (VII) mediated by coupling reagents such as e.g. TBTU, HATU or CDI. Alternatively acid chlorides (R4COCl) can be directly coupled with the respective amines (VI).




Compounds of general formula (Ia) may be prepared by urea formation reactions of amines (VI) with amines (VIII) mediated by coupling reagents such as CDI, CDT or 4-nitrophenyl chloroformate. Alternatively carbamoyl chlorides (IX) or isocyanates (X) can be used as coupling partners for amines (VI).




Compounds of general formula (I) may alternatively be prepared by either nucleophilic substitution reactions of alcohols (XII) with halogen substituted heteroaryls (XI), wherein X is a leaving group and for example denotes Cl or Br. Alternatively palladium-mediated Buchwald-type reactions of (hetero)aryl halogenides (XI) with alcohols (XII) can be used, wherein X for example denotes Cl or Br.




Compounds of general formula (I) may alternatively be prepared by either nucleophilic substitution reactions of alcohols (XIII) with halogen substituted heteroaryls (XIV), wherein X is a leaving group and for example denotes F or Cl.
Terms and Definitions
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
The terms “compound(s) according to this invention”, “compound(s) of formula (I)”, “compound(s) of the invention” and the like denote the compounds of the formula (I) according to the present invention including their tautomers, stereoisomers and mixtures thereof and the salts thereof, in particular the pharmaceutically acceptable salts thereof, and the solvates and hydrates of such compounds, including the solvates and hydrates of such tautomers, stereoisomers and salts thereof.
The terms “treatment” and “treating” embraces both preventative, i.e. prophylactic, or therapeutic, i.e. curative and/or palliative, treatment. Thus the terms “treatment” and “treating” comprise therapeutic treatment of patients having already developed said condition, in particular in manifest form. Therapeutic treatment may be symptomatic treatment in order to relieve the symptoms of the specific indication or causal treatment in order to reverse or partially reverse the conditions of the indication or to stop or slow down progression of the disease. Thus the compositions and methods of the present invention may be used for instance as therapeutic treatment over a period of time as well as for chronic therapy. In addition the terms “treatment” and “treating” comprise prophylactic treatment, i.e. a treatment of patients at risk to develop a condition mentioned hereinbefore, thus reducing said risk.
When this invention refers to patients requiring treatment, it relates primarily to treatment in mammals, in particular humans.
The term “therapeutically effective amount” means an amount of a compound of the present invention that (i) treats or prevents the particular disease or condition, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of the particular disease or condition described herein.
The terms “modulated” or “modulating”, or “modulate(s)”, as used herein, unless otherwise indicated, refers to the inhibition of acetyl-CoA carboxylase(s) (ACC) with one or more compounds of the present invention.
The terms “mediated” or “mediating” or “mediate”, as used herein, unless otherwise indicated, refers to the (i) treatment, including prevention the particular disease or condition, (ii) attenuation, amelioration, or elimination of one or more symptoms of the particular disease or condition, or (iii) prevention or delay of the onset of one or more symptoms of the particular disease or condition described herein.
The term “substituted” as used herein, means that any one or more hydrogens on the designated atom, radical or moiety is replaced with a selection from the indicated group, provided that the atom's normal valence is not exceeded, and that the substitution results in an acceptably stable compound.
In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, C1-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent “aryl-C1-3-alkyl-” means an aryl group which is bound to a C1-3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
In case a compound of the present invention is depicted in form of a chemical name and as a formula in case of any discrepancy the formula shall prevail.
An asterisk is may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
The numeration of the atoms of a substituent starts with the atom which is closest to the core or to the group to which the substituent is attached.
For example, the term “3-carboxypropyl-group” represents the following substituent:




wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or “cyclopropylmethyl-” group represent the following groups:





The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
In a definition of a group the term “wherein each X, Y and Z group is optionally substituted with” and the like denotes that each group X, each group Y and each group Z either each as a separate group or each as part of a composed group may be substituted as defined. For example a definition “Rex denotes H, C1-3-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-C1-3-alkyl or C1-3-alkyl-O—, wherein each alkyl group is optionally substituted with one or more Lex.” or the like means that in each of the beforementioned groups which comprise the term alkyl, i.e. in each of the groups C1-3-alkyl, C3-6-cycloalkyl-C1-3-alkyl and C1-3-alkyl-O—, the alkyl moiety may be substituted with Lex as defined.
In the following the term bicyclic includes spirocyclic.
Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc. . . . ) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention also comprise a part of the invention.
The term halogen generally denotes fluorine, chlorine, bromine and iodine.
The term “C1-n-alkyl”, wherein n is an integer from 1 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C1-5-alkyl embraces the radicals H3C—, H3C—CH2—, H3C—CH2—CH2—, H3C—CH(CH3)—, H3C—CH2—CH2—CH2—, H3C—CH2—CH(CH3)—, H3C—CH(CH3)—CH2—, H3C—C(CH3)2—, H3C—CH2—CH2—CH2—CH2—, H3C—CH2—CH2—CH(CH3)—, H3C—CH2—CH(CH3)—CH2—, H3C—CH(CH3)—CH2—CH2—, H3C—CH2—C(CH3)2—, H3C—C(CH3)2—CH2—, H3C—CH(CH3)—CH(CH3)— and H3C—CH2—CH(CH2CH3)—.
The term “C1-n-alkylene” wherein n is an integer 1 to n, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms. For example the term C1-4-alkylene includes —(CH2)—, —(CH2—CH2)—, —(CH(CH3))—, —(CH2—CH2—CH2)—, —(C(CH3)2)—, —(CH(CH2CH2CH3))—, —(CH(CH3)—CH2)—, —(CH2—CH(CH3))—, —(CH2—CH2—CH2—CH2)—, —(CH2—CH2—CH(CH3))—, —(CH(CH3)—CH2—CH2)—, —(CH2—CH(CH3)—CH2)—, —(CH2—C(CH3)2)—, —(C (CH3)2—CH2)—, —(CH(CH3)—CH(CH3))—, —(CH2—CH(CH2CH3))—, —(CH(CH2CH3)—CH2)—, —(CH(CH2CH2CH3))—, —(CHCH(CH3)2)— and —C(CH3)(CH2CH3)—.
The term “C2-n-alkenyl”, is used for a group as defined in the definition for “C1-n-alkyl” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond. For example the term C2-3-alkenyl includes —CH═CH2, —CH═CH—CH3, —CH2—CH═CH2.
The term “C2-n-alkenylene” is used for a group as defined in the definition for “C1-n-alkylene” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond. For example the term C2-3-alkenylene includes —CH═CH—, —CH═CH—CH2—, —CH2—CH═CH—.
The term “C2-n-alkynyl”, is used for a group as defined in the definition for “C1-n-alkyl” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond. For example the term C2-3-alkynyl includes —C≡CH, —C≡C—CH3, —CH2—C≡CH.
The term “C2-n-alkynylene” is used for a group as defined in the definition for “C1-n-alkylene” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond. For example the term C2-3-alkynylene includes —C≡C—, —C≡C—CH2—, —CH2—C≡C—.
The term “C3-n-carbocyclyl” as used either alone or in combination with another radical, denotes a monocyclic, bicyclic or tricyclic, saturated or unsaturated hydrocarbon radical with 3 to n C atoms. The hydrocarbon radical is preferably nonaromatic. Preferably the 3 to n C atoms form one or two rings. In case of a bicyclic or tricyclic ring system the rings may be attached to each other via a single bond or may be fused or may form a spirocyclic or bridged ring system. For example the term C3-10-carbocyclyl includes C3-10-cylcoalkyl, C3-10-cycloalkenyl, octahydropentalenyl, octahydroindenyl, decahydronaphthyl, indanyl, tetrahydronaphthyl. Most preferably the term C3-n-carbocyclyl denotes C3-n-cylcoalkyl, in particular C3-7-cycloalkyl.
The term “C3-n-cycloalkyl”, wherein n is an integer 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. The cyclic group may be mono-, bi-, tri- or spirocyclic, most preferably monocyclic. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.
The term “C3-n-cycloalkenyl”, wherein n is an integer 3 to n, either alone or in combination with another radical, denotes a cyclic, unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to n C atoms, at least two of which are bonded to each other by a double bond. For example the term C3-7-cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl and cycloheptatrienyl.
The term “aryl” as used herein, either alone or in combination with another radical, denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl. More preferably the term “aryl” as used herein, either alone or in combination with another radical, denotes phenyl or naphthyl, most preferably phenyl.
The term “heterocyclyl” means a saturated or unsaturated mono-, bi-, tri- or spirocarbocyclic, preferably mono-, bi- or spirocyclic-ring system containing one or more heteroatoms selected from N, O or S(O), with r=0, 1 or 2, which in addition may have a carbonyl group. More preferably the term “heterocyclyl” as used herein, either alone or in combination with another radical, means a saturated or unsaturated, even more preferably a saturated mono-, bi- or spirocyclic-ring system containing 1, 2, 3 or 4 heteroatoms selected from N, O or S(O), with r=0, 1 or 2 which in addition may have a carbonyl group. The term “heterocyclyl” is intended to include all the possible isomeric forms. Examples of such groups include aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, azepanyl, piperazinyl, morpholinyl, tetrahydrofuranonyl, tetrahydropyranonyl, pyrrolidinonyl, piperidinonyl, piperazinonyl, morpholinonyl.
Thus, the term “heterocyclyl” includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:




The term “heteroaryl” means a mono- or polycyclic, preferably mono- or bicyclic-ring system containing one or more heteroatoms selected from N, O or S(O)r with r=0, 1 or 2 wherein at least one of the heteroatoms is part of an aromatic ring, and wherein said ring system may have a carbonyl group. More preferably the term “heteroaryl” as used herein, either alone or in combination with another radical, means a mono- or bicyclic-ring system containing 1, 2, 3 or 4 heteroatoms selected from N, O or S(O)r with r=0, 1 or 2 wherein at least one of the heteroatoms is part of an aromatic ring, and wherein said ring system may have a carbonyl group. The term “heteroaryl” is intended to include all the possible isomeric forms.
Thus, the term “heteroaryl” includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:







All rests and substituents as defined hereinbefore and hereinafter may be substituted with one or more F atoms. Preferred fluorinated alkyl groups are fluoromethyl, difluoromethyl and trifluoromethyl. Preferred fluorinated alkoxy resp. alkyl-O— groups are fluoromethoxy, difluoromethoxy and trifluoromethoxy
Many of the terms given above may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.
Pharmacological Activity
The activity of the compounds of the invention may be demonstrated using the following ACC2 assay:
Spectrophotometric 384 Well Assay
Malonyl CoA formation by acetyl CoA carboxylases is stoichometrically linked to the consumption of ATP. ACC2 activity is measured in a NADH-linked kinetic method measuring ADP generated during the ACC reaction using a coupled lactate dehydrogenase/pyruvate kinase reaction.
For biological testing, a human ACC2 construct which lacks the 128 amino acids at the N-terminus for increased solubility (nt 385-6966 in Genbank entry AJ575592) is cloned. The protein is then expressed in insect cells using a baculoviral expression system. Protein purification is performed by anion exchange.
All compounds are dissolved in dimethyl sulfoxide (DMSO) to a concentration of 10 mM.
Assay reactions are then carried out in 384-well plates, with hACC2 in an appropriate dilution and at final assay concentrations (f.c.) of 100 mM Tris (pH 7.5), 10 mM trisodium citrate, 25 mM KHCO3, 10 mM MgCl2, 0.5 mg/ml BSA, 3.75 mM reduced L-glutathione, 15 U/ml lactate dehydrogenase, 0.5 mM phosphoenolpyruvate, 15 U/ml pyruvate kinase, compounds at different concentrations at final DMSO concentrations of 1%.
The enzymatic reaction is then started by addition of a mixture of NADH, acetyl Coenzyme A (both 2000 f.c.) and ATP (500 uM f.c.). The decrease of the optical density (slope S) is then determined at 25° C. at a wavelength of 340 nm over 15 minutes in a spectrophotometric reader.
Each assay microtiter plate contains wells with vehicle instead of compound as controls for the non-inhibited enzyme (100% CTL; ‘HIGH’) and wells without acetyl-CoA as controls for non-specific NADH degradation (0% CTL; ‘LOW’).
The slope S is used for calculation of % CTL=(S(compound)−S(‘LOW’))/(S(‘HIGH’)−S(‘LOW’))100. Compounds will give values between 100% CTL (no inhibition) and 0% CTL (complete inhibition).
For IC50 value determination, the sample slope in the presence of the test compound after subtraction of the low controls (S(compound)−S(‘LOW’)) are used.
An IC50 value is derived from the compound slopes at different dosages after subtraction of the low controls (S(compound)−S(‘LOW’)) by non-linear regression curve fitting (equation y=(A+((B−A)/(1+((C/x)^D))))).
The compounds of general formula (I) according to the invention for example have IC50 values below 10000 nM, particularly below 1000 nM, preferably below 300 nM.
In the following table the activity expressed as IC50 (μM) of compounds according to the invention is presented wherein the IC50 values are determined in the ACC2 assay as described hereinbefore. The term “Ex.” refers to the example numbers according to the following experimental section.














Example
IC50 [μM]



















1.1
2.59



1.2
0.15



1.3
1.04



1.4
0.17



1.5
0.12



1.6
0.28



1.7
0.17



1.8
0.55



1.9
0.46



1.10
3.19



1.11
0.21



1.12
0.23



1.13
0.48



1.14
0.07



1.15
2.56



1.16
0.11



1.17
0.28



1.18
0.34



1.19
0.59



1.20
0.33



1.21
0.48



1.22
0.45



1.23
1.47



1.24
0.22



1.25
0.21



1.26
1.23



1.27
1.95



1.28
1.01



1.29
1.16



1.30
0.74



1.31
1.75



1.32
0.05



1.33
2.52



1.34
2.06



1.35
0.40



1.36
1.61



1.37
0.17



1.38
0.78



1.39
2.25



1.40
6.43



1.41
1.07



1.42
1.70



1.43
0.32



1.44
0.61



1.45
2.01



1.46
1.73



1.47
1.33



1.48
3.35



1.49
1.47



1.50
1.06



1.51
0.07



1.52
0.97



1.53
0.07



1.54
0.54



1.55
0.44



1.56
0.11



1.57
1.30



1.58
3.90



1.59
2.06



1.60
0.32



1.61
1.44



1.62
2.50



1.63
0.93



1.64
2.19



1.65
0.80



1.66
0.55



1.67
1.29



1.68
1.52



1.69
3.15



1.70
1.10



1.71
0.71



1.72
1.19



1.73
0.16



1.74
0.41



1.75
0.41



1.76
1.00



1.77
1.04



1.78
0.36



1.79
1.72



1.80
1.06



1.81
2.33



1.82
0.27



1.83
0.59



1.84
0.73



1.85
0.23



1.86
0.05



1.87
0.20



1.88
0.10



1.89
0.12



1.90
0.09



1.91
0.75



2.1
1.53



2.2
0.79



2.3
0.82



2.4
0.29



2.5
0.18



2.6
0.04



2.7
0.07



3.1
0.06



4.1
3.41



4.2
1.54



4.3
1.00



4.4
1.61



4.5
5.57



4.6
1.46



4.7
2.31



4.8
1.39



4.9
0.86



4.10
3.10



4.11
2.37



4.12
1.61



4.13
0.37



4.14
3.45



4.15
0.07



4.16
0.28



4.17
1.13



5.1
0.34



6.1
0.26



7.1
0.12



7.2
2.42



8.1
0.25



8.2
2.98



8.3
1.37



8.4
0.11



8.5
0.14



8.6
0.17



8.7
2.24



8.8
0.81



9.1
0.07



9.2
0.09



9.3
0.05



9.4
0.04



9.5
0.04



10.1 
1.28



10.2 
0.78



10.3 
0.91



10.4 
0.28



10.5 
0.64



10.6 
0.33



10.7 
0.20



10.8 
0.74



10.9 
0.86



10.10
0.12



10.11
0.10



10.12
0.79



10.13
0.32



10.14
0.61



10.15
0.95



10.16
2.23



10.17
0.11



10.18
0.56



10.19
0.14



10.20
4.40



10.21
3.99



10.22
1.27



10.23
0.13



10.24
2.26



10.25
3.37



10.26
0.37



10.27
0.17



10.28
2.08



10.29 
0.57



10.30 
1.56



10.31 
0.30



10.32 
0.73



11.1
0.08



11.2
0.27



11.3
0.06



11.4
0.08



11.5
0.10



11.6
0.15



11.7
0.23



12.1
0.81



12.2
1.38



12.3
0.73



12.4
0.22



12.5
0.53



12.6
0.09



12.7
0.31



12.8
1.75



12.9
0.49



12.10 
0.45



12.11 
0.33



12.12 
0.10



12.13 
0.18



12.14 
0.22



12.15 
0.83



12.16 
0.38



12.17 
0.05



12.18 
0.65



12.19 
0.23



13.1
0.35



13.2
0.06



14.1
0.38



14.2
0.06



14.3
0.98



15.1
0.91



16.1
0.13










In view of their ability to inhibit the enzyme(s) acetyl-CoA carboxylase, the compounds of general formula (I) according to the invention and the corresponding salts thereof are theoretically suitable for the treatment, including preventative treatment of all those diseases or conditions which may be affected or which are mediated by the inhibition of the enzyme(s) acetyl-CoA carboxylase, in particular ACC2, activity.
Accordingly, the present invention relates to a compound of general formula (I) as a medicament.
Furthermore, the present invention relates to the use of a compound of general formula (I) for the treatment and/or prevention of diseases or conditions which are mediated by the inhibition of acetyl-CoA carboxylase(s), in particular ACC2, in a patient, preferably in a human.
In yet another aspect the present invention relates a method for treating, including preventing a disease or condition mediated by the inhibition of acetyl-CoA carboxylase(s) in a mammal that includes the step of administering to a patient, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the present invention, or a pharmaceutical composition thereof.
Diseases and conditions mediated by inhibitors of acetyl-CoA carboxylases embrace metabolic and/or cardiovascular and/or neurodegenerative diseases or conditions.
According to one aspect the compounds of the present invention are particularly suitable for treating diabetes mellitus, in particular Type 2 diabetes, Type 1 diabetes, and diabetes-related diseases, such as is hyperglycemia, metabolic syndrome, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, dyslipidemia, hypertension, hyperinsulinemia, and insulin resistance syndrome, hepatic insulin resistance, including complications such as macro- and microvascular disorders, including thromboses, hypercoagulable and prothrombotic states (arterial and venous), high blood pressure, coronary artery disease and heart failure, increased abdominal girth, hypercoagulability, hyperuricemia, micro-albuminemia.
According to another aspect the compounds of the present invention are particularly suitable for treating overweight, obesity, including visceral (abdominal) obesity, nonalcoholic fatty liver disease (NAFLD) and obesity related disorders, such as for example weight gain or weight maintenance.
Obesity and overweight are generally defined by body mass index (BMI), which is correlated with total body fat and estimates the relative risk of disease. BMI is calculated by weight in kilograms divided by height in meters squared (kg/m2). Overweight is typically defined as a BMI of 25-29.9 kg/m2, and obesity is typically defined as a BMI of 30 kg/m2 or greater.
According to another aspect the compounds of the present invention are particularly suitable for treating, including preventing, or delaying the progression or onset of diabetes or diabetes-related disorders including Type 1 (insulin-dependent diabetes mellitus, also referred to as “IDDM”) and Type 2 (noninsulin-dependent diabetes mellitus, also referred to as “NIDDM”) diabetes, impaired glucose tolerance, insulin resistance, hyperglycemia, pancreatic beta cell degeneration and diabetic complications (such as macro- and microvascular disorders, atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, nephropathy, hypertension, neuropathy, and retinopathy).
In addition the compounds of the present invention are suitable for treating dyslipidemias in general and more specifically elevated lipid concentrations in the blood and in tissues, dysregulation of LDL, HDL and VLDL, in particular high plasma triglyceride concentrations, high postprandial plasma triglyceride concentrations, low HDL cholesterol concentration, low apoA lipoprotein concentrations, high LDL cholesterol concentrations, high apoB lipoprotein concentrations, including atherosclerosis, coronary heart disease, cerebrovascular disorders, diabetes mellitus, metabolic syndrome, obesity, insulin resistance and/or cardiovascular disorders.
ACC inhibition may lead to a centrally stimulating effect on food intake. Therefore compounds of the present invention may be suitable for treating eating disorders such as anorexia nervosa.
In addition the compounds of the present invention may provide neuroprotective effects in patients with Parkinson's disease, Alzheimer's disease, hypoxia, ischemia, amyotrophic lateral sclerosis or glioma and may improve cognitive scores in Alzheimer's diseases patients.
Further diseases and conditions mediated by inhibitors of acetyl-CoA carboxylases embrace but are not limited to:

    A. disorders of fatty acid metabolism and glucose utilization disorders; disorders in which insulin resistance is involved;
    B. hepatic disorders and conditions related thereto, including:
    
        fatty liver, hepatic steatosis, non-alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis, acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, iron storage diseases, hepatic fibrosis, hepatic cirrhosis, hepatoma, viral hepatitis;
    
    
    C. skin disorders and conditions and those associated with polyunsaturated fatty acids, such as
    
        eczema, acne, sebaceous gland diseases, psoriasis, keloid scar formation or prevention, other diseases related to mucous membrane fatty acid composition;
    
    
    D. primary hypertriglyceridemia or secondary hypertriglyceridemias following familial histiocytic reticulosis, lipoprotein lipase deficiency, hyperlipo-proteinemias, apolipoprotein deficiency (e.g. apoCII or apoE deficiency);
    E. diseases or conditions related to neoplastic cellular proliferation, for example benign or malignant tumors, cancer, neoplasias, metastases, carcinogenesis;
    F. diseases or conditions related to neurological, psychiatric or immune disorders or conditions;
    G. other diseases or conditions in which inflammatory reactions, cell differentiation and/or other ACC-mediated aspects may for example be involved are:
    
        atherosclerosis such as, for example (but not restricted thereto), coronary sclerosis including angina pectoris or myocardial infarction, stroke, ischemic, stroke and transient ischemic attack (TIA),
        peripheral occlusive disease,
        vascular restenosis or reocclusion,
        chronic inflammatory bowel diseases such as, for example, Crohn's disease and ulcerative colitis,
        pancreatitis,
        sinusitis,
        retinopathy, ischemic retinopathy,
        adipose cell tumors,
        lipomatous carcinomas such as, for example, liposarcomas,
        solid tumors and neoplasms such as, for example (but not restricted thereto), carcinomas of the gastrointestinal tract, of the liver, of the biliary tract and of the pancreas, endocrine tumors, carcinomas of the lungs, of the kidneys and the urinary tract, of the genital tract, prostate carcinomas, breast cancer (in particular breast cancer with BRCA1 mutations), etc.,
        tumors in which ACC is up regulated,
        acute and chronic myeloproliferative disorders and lymphomas, angiogenesis
        neurodegenerative disorders including Alzheimer's disease, multiple sclerosis, Parkinson's disease, epilepsy,
        erythemato-squamous dermatoses such as, for example, psoriasis,
        acne vulgaris,
        other skin disorders and dermatological conditions which are modulated by PPAR,
        eczemas and neurodermatitis,
        dermatitis such as, for example, seborrheic dermatitis or photodermatitis,
        keratitis and keratoses such as, for example, seborrheic keratoses, senile keratoses, actinic keratoses, photo-induced keratoses or keratosis follicularis,
        keloids and keloid prophylaxis,
        bacterial infections,
        fungal infections,
        warts, including condylomata or condylomata acuminata
        viral infections such as, for example, human hepatitis B virus (HBV), hepatitis C virus (HCV), West Nile virus (WNV) or Dengue virus, human Immunodeficiency virus (HIV), poxvirus and Vaccinia virus (VV), HCMV, influenza A, human papilloma viral (HPV). venereal papillomata, viral warts such as, for example, molluscum contagiosum, leukoplakia,
        papular dermatoses such as, for example, lichen planus,
        skin cancer such as, for example, basal-cell carcinomas, melanomas or cutaneous T-cell lymphomas,
        localized benign epidermal tumors such as, for example, keratoderma, epidermal naevi,
        chilblains;
        high blood pressure,
        polycystic ovary syndrome (PCOS),
        asthma,
        cystic fibrosis,
        osteoarthritis,
        lupus erythematosus (LE) or inflammatory rheumatic disorders such as, for example rheumatoid arthritis,
        vasculitis,
        wasting (cachexia),
        gout,
        ischemia/reperfusion syndrome,
        acute respiratory distress syndrome (ARDS),
        viral diseases and infections,
        lipodystrophy and lipodystrophic conditions, also for treating adverse drug effect;
        myophathies and lipid myopathis (such as carnitine palmitoyltransferase I or II deficiency);
    
    
    H. formation of muscles and a lean body or muscle mass formation.


The dose range of the compounds of general formula (I) applicable per day is usually from 0.001 to 10 mg per kg body weight of the patient, preferably from 0.01 to 8 mg per kg body weight of the patient. Each dosage unit may conveniently contain 0.1 to 1000 mg of the active substance, preferably it contains between 0.5 to 500 mg of the active substance.
The actual therapeutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a therapeutically effective amount to be delivered based upon patient's unique condition.
Pharmaceutical Compositions
Suitable preparations for administering the compounds of formula (I) will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc. The content of the pharmaceutically active compound(s) is advantageously in the range from 0.1 to 90 wt.-%, for example from 1 to 70 wt.-% of the composition as a whole.
Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula (I) with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants. The tablets may also consist of several layers.
Combination Therapy
The compounds of the invention may further be combined with one or more, preferably one additional therapeutic agent. According to one embodiment the additional therapeutic agent is selected from the group of therapeutic agents useful in the treatment of diseases or conditions associated with metabolic diseases or conditions such as for example diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia.
Therefore a compound of the invention may be combined with one or more additional therapeutic agents selected from the group consisting of anti-obesity agents (including appetite suppressants), agents which lower blood glucose, anti-diabetic agents, agents for treating dyslipidemias, such as lipid lowering agents, anti-hypertensive agents, antiatherosclerotic agents, anti-inflammatory active ingredients, agents for the treatment of malignant tumors, antithrombotic agents, agents for the treatment of heart failure and agents for the treatment of complications caused by diabetes or associated with diabetes.
Suitable anti-obesity agents include 11beta-hydroxy steroid dehydrogenase-1 (11beta-HSD type 1) inhibitors, stearoyl-CoA desaturase-1 (SCD-1) inhibitors, MCR-4 agonists, cholecystokinin-A (CCK-A) agonists, monoamine reuptake inhibitors, sympathomimetic agents, beta3 adrenergic agonists, dopamine agonists, melanocyte-stimulating hormone analogs, 5HT2c agonists, melanin concentrating hormone antagonists, leptin (the OB protein), leptin analogs, leptin agonists, galanin antagonists, lipase inhibitors, anorectic agents, neuropeptide-Y antagonists (e.g., NPY Y5 antagonists), PYY3-36 (including analogs thereof), thyromimetic agents, dehydroepiandrosterone or an analog thereof, glucocorticoid agonists or antagonists, orexin antagonists, glucagon-like peptide-1 agonists, ciliary neurotrophic factors, human agouti-related protein (AGRP) inhibitors, ghrelin antagonists, GOAT (Ghrelin O-Acyltransferase) inhibitors, histamine 3 antagonists or inverse agonists, neuromedin U agonists, MTP/ApoB inhibitors (e.g., gut-selective MTP inhibitors), opioid antagonists, orexin antagonists, and the like.
Preferred anti-obesity agents for use in the combination aspects of the present invention include gut-selective MTP inhibitors CCKa agonists, 5HT2c agonists, MCR4 agonists, lipase inhibitors, opioid antagonists, oleoyl-estrone, obinepitide, pramlintide (Symlin®), tesofensine (NS2330), leptin, liraglutide, bromocriptine, orlistat, exenatide (Byetta®), AOD-9604 (CAS No. 221231-10-3) and sibutramine.
Suitable anti-diabetic agents include sodium-glucose co-transporter (SGLT) inhibitors, 11beta-hydroxy steroid dehydrogenase-1 (11beta-HSD type 1) inhibitors, phosphodiesterase (PDE) 10 inhibitors, diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitors, sulfonylureas (e.g., acetohexamide, chiorpropamide, diabinese, glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone, glisolamide, tolazamide, and tolbutamide), meglitinides, an alpha-amylase inhibitors (e.g., tendamistat, trestatin and AL-3688), alpha-glucoside hydrolase inhibitors (e.g., acarbose), alpha-glucosidase inhibitors (e.g., adiposine, camiglibose, emiglitate, miglitol, voglibose, pradimicin-Q, and salbostatin), PPAR gamma agonists (e.g., balaglitazone, ciglitazone, darglitazone, englitazone, isaglitazone, pioglitazone, rosiglitazone and troglitazone), PPAR alpha/gamma agonists (e.g., CLX-0940, GW-1536, GW-20 1929, GW-2433, KRP-297, L-796449, LR-90, MK-0767 and SB-219994), biguanides (e.g., metformin), GLP-1 derivatives, glucagon-like peptide 1 (GLP-1) agonists (e.g., ByettaTM, exendin-3 and exendin-4), GLP-1 receptor and glucagon receptor co-agonists, glucagon receptor antagonists, GIP receptor antagonists, protein tyrosine phosphatase-1 B (PTP-1 B) inhibitors (e.g., trodusquemine, hyrtiosal extract), SIRT-1 activators (e.g. reservatrol), dipeptidyl peptidease IV (DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, linagliptin and saxagliptin), insulin secretagogues, GPR119 agonists, GPR40 agonists, TGR5 agonists, MNK2 inhibitors, GOAT (Ghrelin O-Acyltransferase) inhibitors, fatty acid oxidation inhibitors, A2 antagonists, c-jun amino-terminal kinase (JNK) inhibitors, insulins, insulin derivatives, fast acting insulins, inhalable insulins, oral insulins, insulin mimetics, glycogen phosphorylase inhibitors, VPAC2 receptor agonists and glucokinase activators.
Preferred anti-diabetic agents are metformin, glucagon-like peptide 1 (GLP-1) agonists (e.g., ByettaTM), GLP-1 receptor and glucagon receptor co-agonists, sodium-glucose co-transporter (SGLT) inhibitors, 11beta-hydroxy steroid dehydrogenase-1 (11beta-HSD type 1) inhibitors and DPP-IV inhibitors (e.g. sitagliptin, vildagliptin, alogliptin, linagliptin and saxagliptin).
Preferably, compounds of the present invention and/or pharmaceutical compositions comprising a compound of the present invention optionally in combination with one or more additional therapeutic agents are administered in conjunction with exercise and/or a diet.
Therefore, in another aspect, this invention relates to the use of a compound according to the invention in combination with one or more additional therapeutic agents described hereinbefore and hereinafter for the treatment or prevention of diseases or conditions which may be affected or which are mediated by the inhibition of the acetyl-CoA carboxylase(s), in particular ACC2, in particular diseases or conditions as described hereinbefore and hereinafter.
In yet another aspect the present invention relates a method for treating, including preventing a disease or condition mediated by the inhibition of acetyl-CoA carboxylase(s) in a patient that includes the step of administering to the patient, preferably a human, in need of such treatment a therapeutically effective amount of a compound of the present invention in combination with a therapeutically effective amount of one or more additional therapeutic agents described in hereinbefore and hereinafter,
The use of the compound according to the invention in combination with the additional therapeutic agent may take place simultaneously or at staggered times.
The compound according to the invention and the one or more additional therapeutic agents may both be present together in one formulation, for example a tablet or capsule, or separately in two identical or different formulations, for example as a so-called kit-of-parts.
Consequently, in another aspect, this invention relates to a pharmaceutical composition which comprises a compound according to the invention and one or more additional therapeutic agents described hereinbefore and hereinafter, optionally together with one or more inert carriers and/or diluents.
Further aspects of the invention include the use of a compound according to the invention or a salt thereof as a crop protection agent to combat and/or prevent fungal infestations, or to control other pests such as weeds, insects, or acarids that are harmful to crops. Another aspect of the invention relates to the use of a compound according to the invention or a salt thereof for controlling and/or preventing plant pathogenic microorganisms, for example plant pathogenic fungi. Therefore one aspect of the invention is a compound according to the formula (I) or a salt thereof for use as a fungicide, insecticide, acaricide and/or herbicide. Another aspect of the invention relates to an agricultural composition comprising a compound of the present invention together with one or more suitable carriers. Another aspect of the invention relates to an agricultural composition comprising a compound of the present invention in combination with at least one additional fungicide and/or systemically acquired resistance inducer together with one or more suitable carriers.
EXAMPLES
The Examples that follow are intended to illustrate the present invention without restricting it. The terms “ambient temperature” and “room temperature” are used interchangeably and designate a temperature of about 20° C.
Preliminary Remarks:
As a rule, 1H-NMR and/or mass spectra have been obtained for the compounds prepared. The Rf values are determined using Merck silica gel 60 F254 plates and UV light at 254 nm.
Experimental Part
The following abbreviations are used above and hereinafter:
















aq.
aqueous



ACN
acetonitrile



Boc
tert-butoxycarbonyl



CDI
N,N-carbonyldiimidazole



CDT
1,1′-carbonyldi(1,2,4-triazole)



Cul
copper(I) iodide



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



DCM
dichloromethane



DIPEA
N,N-diisopropylethylamine



DMA
N,N-dimethylacetamide



DMF
N,N-dimethylformamide



EtOAc
ethyl acetate



FA
formic acid



MeOH
methanol



NMP
N-methyl-2-pyrrolidone



PE
petroleum ether



RP
reversed phase



rt
room temperature (about 20° C.)



sat.
saturated



TEA
triethylamine



TFA
trifluoroacetic acid



THF
tetrahydrofuran



TBTU
2-(1H-benzotriazol-1-yl)-1,1,3,3-




tetramethyluronium tetrafluoroborate










HPLC Methods

Method A1











Analytical Column: XBridge C18, 3 × 30 mm, 2.5 μm (Waters)











time 
Vol % H2O incl.
Vol % 
Flow 
Temperature


[min]
0.1% NH4OH]
methanol
[mL/min]
[° C.]














0.0
95
5
2.2
60


0.30
95
5
2.2
60


1.50
0
100
2.2
60


1.55
0
100
2.9
60


1.70
0
100
2.9
60









Method B1











Analytical Column: X-terra MS C18 (Waters) 2.5 μm; 4.6 × 30 mm











time
Vol % H2O 
Vol % acetonitrile
Flow
Temperature 


[min]
(incl. 0.1% FA]
(incl. 0.1% FA)
[mL/min]
[° C.]














0.0
95
5
1.0
rt


0.1
95
5
1.0
rt


3.1
2
98
1.0
rt


4.5
2
98
1.0
rt


5.0
95
5
1.0
rt









Method C1











Analytical Column: XBridge C18 (Waters) 2.5 μm, 3.0 × 30 mm











time
Vol % H2O
Vol % methanol
Flow
Temperature


[min]
(incl. 0.2% NH4OH)
(incl. 3% water)
[mL/min]
[° C.]














0.0
95
5
1.3
40


0.2
95
5
1.3
40


2.2
5
95
1.3
40


2.3
5
95
1.3
40


2.4
0
100
1.3
40


2.6
0
100
1.3
40









Method D1











Analytical Column: Waters X-BridgeTM C18, 50 × 2.1 mm, 3.5 μm











time
Vol % H2O
Vol % ACN (incl.
Flow
Temperature


(min)
(incl. 0.1% FA)
0.1% FA)
[mL/min]
[° C.]














0.0
95
5
0.8
35


3.5
2
98
0.8
35


6.0
2
98
0.8
35









Method E1











Analytical Column: Sunfire C18, 4,6 × 30 mm, 3.5 μm (Waters)











time
Vol % H2O
Vol % methanol
Flow
Temperature


[min]
(incl 0.1% TFA)
(incl. 0.1% TFA]
[mL/min]
[° C.]














0.0
95
5
4
60


0.15
95
5
4
60


1.7
0
100
4
60


2.25
0
100
4
60









Method F1











Analytical Column XBridge C18, 3 × 30 mm, 2.5 μm (Waters)











time 
Vol % [H2O, 
Vol % 
Flow
Temperature 


[min]
0.2% NH4OH]
methanol
[mL/min]
[° C.]














0.0
95
5
2.2
60


0.05
95
5
2.2
60


1.40
0
100
2.2
60


1.80
0
100
2.2
60









Method G1











Analytical Column Sunfire C18_3 × 30 mm, 2.5 μm













Time 
Vol % H2O
Vol % 
Flow
Temp 



[min]
(incl. 0.1% TFA]
methanol 
[ml/min]
[° C.]

















0.0
95.0
5.0
2.2
60.0



0.05
95.0
5.0
2.2
60.0



1.4
0.0
100.0
2.2
60.0



1.8
0.0
100.0
2.2
60.0










Method H1











Analytical Column: Waters X-BridgeTM C18, 3.0 × 30 mm, 2.5 μm











time
Vol % H2O
Vol % 
Flow
Temperature


[min]
(incl. 0.2% NH4OH]
methanol
[mL/min]
[° C.]














0.0
95
5
1.3
40


0.2
95
5
1.3
40


2.2
5
95
1.3
40


2.3
5
95
1.3
40


2.4
0
100
1.3
40


2.6
0
100
1.3
40









Method I1











Analytical Column: StableBond C18_3.0 × 30 mm, 1.8 μm











time
Vol % H2O
Vol %
Flow
Temperature


[min]
(incl. 0.1% TFA] 
methanol
[mL/min]
[° C.]














0.0
95.0
5.0
2.2
60.0


0.05
95.0
5.0
2.2
60.0


1.4
0.0
100.0
2.2
60.0


1.8
0.0
100.0
2.2
60.0









Method J1











Analytical Column: XBridge 


C18, 3 × 30 mm, 2.5 μm (Waters)














Vol % H2O
Vol % metha-

Temp-



time
(incl. 0.1% 
nol (incl.
Flow 
erature 



[min]
TFA)
0.1% TFA)
[mL/min]
[° C.]

















0.0
95
5
2.2
60



0.3
95
5
2.2
60



1.5
0
100
2.2
60



1.55
0
100
2.9
60



1.7
0
100
2.9
60










Method K1











Analytical Column: Waters X-BridgeTM 


C18, 3.0 × 30 mm, 2.5 μm











time
Vol % H2O (incl.
Vol % 
Flow
Temp-


[min]
0.2% NH4OH)
methanol
[mL/min]
erature [° C.]














0.0
95
5
1.3
40


1.0
10
90
1.3
40


2.2
10
90
1.3
40


2.3
0
100
1.3
40


2.5
0
100
1.3
40









Method L1











Analytical Column: Sunfire 


C18_4.6 × 50 mm, 3.5μm











time 
Vol % H2O (incl.
Vol % 
Flow
Tempera-


[min]
0.1% TFA]
methanol
[mL/min]
ture [° C.]














0.0
80.0
20.0
2.0
60.0


1.7
0.0
100.0
2.0
60.0


2.5
0.0
100.0
2.0
60.0


2.6
80.0
20.0
2.0
60.0









Method M1











Analytical Column: XBridge 


C18_4.6 × 50 mm, 3.5 μm











time
Vol % H2O (incl. 
Vol %
Flow
Tempera-


[min]
0.1% NH4OH)
methanol
[mL/min]
ture [° C.]














0.0
80.0
20.0
2.0
60.0


1.7
0.0
100.0
2.0
60.0


2.5
0.0
100.0
2.0
60.0


2.6
80.0
20.0
2.0
60.0









Method N1











Analytical Column: Ascentis Express 


C18_2.1 × 50 mm, 2.7 μm













time
Vol % H2O (incl. 
Vol % 
Flow
Tempera-



[min]
0.1% TFA]
ACN
[mL/min]
ture [° C.]

















0.0
95.0
5.0
1.5
60.0



0.7
1.0
99.0
1.5
60.0



0.8
1.0
99.0
1.5
60.0



0.81
95.0
5.0
1.5
60.0










Method O1











Analytical Column: Sunfire 


C18_4.6 × 30 mm, 2.5 μm











time
Vol % H2O (incl.
Vol % 
Flow 
Tempera-


[min]
0.1% TFA]
methanol
[mL/min]
ture [° C.]














0.0
95.0
5.0
4.0
60.0


0.05
95.0
5.0
3.0
60.0


2.05
0.0
100.0
3.0
60.0


2.1
0.0
100.0
4.5
60.0


2.4
0.0
100.0
4.5
60.0









Method P1











Analytical Column: XBridge 


C18_4.6 × 50 mm, 3.5 μm











time
Vol % H2O (incl. 
Vol % 
Flow
Tempera-


[min]
0.1% NH4OH)
methanol
[mL/min]
ture [° C.]














0.0
80.0
20.0
2.0
60.0


1.7
0.0
100.0
2.0
60.0


2.5
0.0
100.0
2.0
60.0









Method Q1











Analytical Column: XBridge 


C18_4.6 × 30 mm, 3.5 μm











time
Vol % H2O (incl. 
Vol %
Flow 
Tempera-


[min]
0.1% NH4OH)
methanol
[mL/min]
ture [° C.]














0.0
95.0
5.0
4.0
60.0


0.15
95.0
5.0
4.0
60.0


1.7
0.0
100.0
4.0
60.0


2.1
0.0
100.0
4.0
60.0









Method R1











Analytical Column: XBridge 


C18_4.6 × 50 mm, 3.5 μm











time
Vol % H2O (incl.
Vol %
Flow
Tempera-


[min]
0.1% NH4OH)
methanol
[mL/min]
ture [° C.]














0.0
95.0
5.0
1.5
40.0


2.0
0.0
100.0
1.5
40.0









Method S1











Analytical Column: StableBond 


C18_3.0 × 30 mm, 1.8 μm











time 
Vol % H2O (incl.
Vol % 
Flow
Tempera-


[min]
0.1% TFA)
methanol
[mL/min]
ture [° C.]














0.0
95.0
5.0
2.2
60.0


0.05
95.0
5.0
2.2
60.0


1.4
0.0
100.0
2.2
60.0


1.8
0.0
100.0
2.2
60.0









Method T1











Analytical Column: SunFire 


C18_4.6 × 30 mm, 3.5 μm













Vol % 





time 
acetonitrile (incl.
Flow 
Tempera-



[min]
0.1% TFA)
[mL/min]
ture [° C.]
















0.0
2.0
2.5
60.0



1.5
100.0
2.5
60.0



1.8
100.0
2.5
60.0










Method U1











Analytical Column: XBridge 


C18_3.0 × 30 mm, 2.5 μm











time
Vol % H2O (incl. 
Vol % 
Flow
Tempera-


[min]
0.1% NH4OH)
acetonitrile
[mL/min]
ture [° C.]














0.0
97.0
3.0
2.2
60.0


0.2
97.0
3.0
2.2
60.0


1.2
0.0
100.0
2.2
60.0


1.25
0.0
100.0
3.0
60.0


1.4
0.0
100.0
3.0
60.0









Method U2











Analytical Column: Sunfire 


C18_3.0 × 30 mm, 2.5 μm











time
Vol % H2O
Vol %
Flow
Tempera-


[min]
(incl. 0.1% TFA)
acetonitrile
[mL/min]
ture [° C.]














0.0
97.0
3.0
2.2
60.0


0.2
97.0
3.0
2.2
60.0


1.2
0.0
100.0
2.2
60.0


1.25
0.0
100.0
3.0
60.0


1.4
0.0
100.0
3.0
60.0









Method U3











Analytical Column: StableBond 


C18_3.0 × 30 mm, 1.8 μm











time
Vol % H2O (incl.
Vol %
Flow
Tempera-


[min]
0.1% TFA)
acetonitrile
[mL/min]
ture [° C.]














0.0
97.0
3.0
2.2
60.0


0.2
97.0
3.0
2.2
60.0


1.2
0.0
100.0
2.2
60.0


1.25
0.0
100.0
3.0
60.0


1.4
0.0
100.0
3.0
60.0









Method V1











Analytical Column: Sunfire 


C18_3.0 × 30 mm, 2.5 μm











time
Vol % H2O (incl.
Vol % 
Flow
Tempera-


[min]
0.1% TFA)
methanol
[mL/min]
ture [° C.]














0.0
95.0
5.0
1.8
60.0


0.25
95.0
5.0
1.8
60.0


1.7
0.0
100.0
1.8
60.0


1.75
0.0
100.0
2.5
60.0


1.9
0.0
100.0
2.5
60.0









Preparation of Starting Compounds
Example I
Example I.1
(S)—N-[1-(4-Bromo-phenyl)-ethyl]-acetamide




23.6 mL (250 mmol) acetic anhydride are added to 50.0 g (250 mmol) (S)-1-(4-bromophenyl)-ethylamine in 200 mL DCM while keeping the reaction temperature below 30° C. Stirring is continued for 12 h at rt. After that time, saturated NaHCO3-solution is added. The organic layer is separated, washed with water, dried over magnesium sulphate and the solvent is removed by evaporation.
C10H12BrNO (M=242.1 g/mol), ESI-MS: 242/244 [M+H]+
Rt (HPLC): 1.03 min (method A1)
The following compounds are prepared analogously to Example I.1:
Example I.2
(S)-Cyclopropanecarboxylic acid [1-(4-bromo-phenyl)-ethyl]amide




Reagent: cyclopropylcarbonyl chloride
C12H14BrNO (M=268.2 g/mol), ESI-MS: 268/270 [M+H]+
Rt (HPLC): 2.76 min (method B1)
Example I.3
(S)-[1-(4-Bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester




Reagent: di-tert-butyldicarbonate
C13H18BrNO2 (M=300.2 g/mol), ESI-MS: 300/302 [M+H]+
Rf (TLC): 0.56 (silica gel, DCM:methanol 98:2)
Example I.4
N-[1-(6-Bromo-pyridin-3-yl)-ethyl]acetamide




Reagents: acetic anhydride and 1-(6-bromo-pyridin-3-yl)-ethylamine
C9H11BrN2O (M=243.1 g/mol), ESI-MS: 243/245 [M+H]+
Rt (HPLC): 1.94 min (method D1)
Example I.5
(S)-1H-Pyrazole-4-carboxylic acid [1-(4-bromo-phenyl)-ethyl]amide




To 5.0 g (44.6 mmol) 4-pyrazolecarboxylic acid in 100 mL DMF 15.2 mL (89.2 mmol) DIPEA and 15.7 g (49.1 mmol) TBTU are added and the mixture is stirred for 10 min at rt. Subsequently 8.9 g (44.6 mmol) (S)-1-(4-bromophenyl)ethylamine are added and stirring is continued over night. The mixture is poured on water and is extracted with ethyl acetate. The combined organic layers are dried over sodium sulphate and the solvent is removed in vacuo. The residue is triturated with DCM to yield the desired product.
C12H12BrN3O (M=294.1 g/mol), ESI-MS: 294 [M+H]+
Rt (HPLC): 1.23 min (method E1)
The following compound is prepared analogously to Example I.5:
Example I.6
(S)-2-Acetylamino-4-methyl-thiazole-5-carboxylic acid [1-(4-bromo-phenyl)-ethyl]-amide




Reagent: 2-acetylamino-4-methyl-thiazole-5-carboxylic acid
C15H16BrN3O2S (M=382.3 g/mol), ESI-MS: 382/384 [M+H]+
Rt (HPLC): 0.97 min (method F1)
Example II
Example II.1
(S)-3-[1-(4-Bromo-phenyl)-ethyl]-1,1-dimethyl-urea




17.2 g (105 mmol) CDT are added to a mixture of 20.0 g (100 mmol) (S)-1-(4-bromophenyl)-ethylamine and 17.6 mL (125 mmol) TEA in 300 mL DCM at 0° C. Stirring is continued for 2 h at 5° C. 13.5 g (300 mmol) dimethylamine are added and the mixture is allowed to warm to rt. DCM is added and the organic layer is washed with 1 N KHSO4 solution (2×) and water (1×). The organic layer is dried over magnesium sulphate and the solvent is removed by evaporation to yield the desired product.
C11H15BrN2O (M=271.2 g/mol), ESI-MS: 271/273 [M+H]+
Rt (HPLC): 1.68 min (method C1)
Example III
Example III.1
(S)—N-[1-(4-Iodo-phenyl)-ethyl]acetamide




9.01 g (47.3 mmol) CuI are added to a mixture of 114.6 g (473.3 mmol) (S)—N-[1-(4-bromo-phenyl)-ethyl]acetamide (I.1), 283.8 g (1.893 mmol) sodium iodide and 10.43 g (118.3 mmol) N,N′-dimethylethylendiamine in 1.3 L 1,4-dioxane. The mixture is stirred for 60 h at 120° C. After that time, the solvent is evaporated, the residue is suspended in 2 L DCM and poured into a mixture of ice (1 kg), ammonia (1 L) and water (2 L). The organic layer is separated, the aq. layer is washed with DCM (2×) and the combined organic layers are washed with water (2×) and dried over sodium sulphate. The solvent is evaporated and the residue is washed with diethyl ether.
C10H12INO (M=289.1 g/mol), ESI-MS: 290 [M+H]+
Rf (TLC): 0.57 (silica gel, DCM:methanol 9:1)
Example IV
Example IV.1
(S)—N-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




A mixture of 3.0 g (12.4 mmol) (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1), 2.3 g (12.4 mmol) 3-(tert-butyl-dimethyl-silanyloxy)-azetidine (US2008/214520A1), 4.9 g (97%, 49.6 mmol) NaOtBu, 1.48 g (4.96 mmol) 2-(di-tert-butylphosphino)biphenyl and 1.1 g (1.24 mmol) tris-(dibenzylideneacetone)-dipalladium(0) in 30 mL 1,4-dioxane is stirred for 45 min under microwave irradiation at 80° C. After cooling water and MeOH are added, the mixture is filtered, concentrated in vacuo and directly purified by HPLC (column: XbridgeC18; eluent A: water+0.3% NH4OH, eluent B: MeOH) to yield the desired product.
C19H32N2O2Si (M=348.6 g/mol), ESI-MS: 349 [M+H]+
Rt (HPLC): 0.88 min (method G1)
The following compound is prepared analogously to Example IV.1:
Example IV.2
(S)-Cyclopropanecarboxylic acid (1-{4-[3-(tert-butyl-dimethyl-silanyloxy)-azetidin-1-yl]-phenyl}-ethyl)-amide




Reagent: I.2
C21H34N2O2Si (M=374.6 g/mol), ESI-MS: 375 [M+H]+
Rt (HPLC): 1.34 min (method F1)
Example V
Example V.1
(S)—N-{1-[4-(3-Hydroxy-azetidin-1-yl)-phenyl]ethyl}-acetamide




2.6 g (7.46 mmol) (S)—N-(1-{4-[3-(tert-Butyl-dimethyl-silanyloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide (IV.1) are added to 20 mL THF and the mixture is cooled to 5° C. 14.9 mL (14.9 mmol) tetrabutylammonium fluoride (1 N in THF) are added and the mixture is allowed to warm to rt. Stirring is continued for 1 h and the solvent is removed in vacuo. The residue is purified by column chromatography (silica gel; DCM:MeOH; gradient 9:1→8:2) to yield the desired product.
C13H18N2O2 (M=234.3 g/mol), ESI-MS: 235 [M+H]+
Rt (HPLC): 1.12 min (method H1)
The following compound is prepared analogously to Example V.1:
Example V.2
(S)-Cyclopropanecarboxylic acid {1-[4-(3-hydroxy-azetidin-1-yl)-phenyl]ethyl}-amide




Reagent: IV.2
C15H20N2O2 (M=260.3 g/mol), ESI-MS: 261 [M+H]+
Rt (HPLC): 1.33 min (method H1)
Example VI
Example VI.1
(S)—N-(1-{4-[3-(4-Hydroxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




1.3 g (3.12 mmol) (S)—N-(1-{4-[3-(4-Benzyloxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide (Ex. 8.5) and 130 mg Pd/C (10%) in 50 mL MeOH are hydrogenated at 3 bar and 50° C. for 12 h. The mixture is filtered and concentrated in vacuo. The residue is titurated with diisopropyl ether to yield the desired product.
C19H22N2O3 (M=326.4 g/mol), ESI-MS: 327 [M+H]+
Rt (HPLC): 0.96 min (method I1)
Example VII
Example VII.1
2-Acetylamino-4-phenyl-thiazole-5-carboxylic acid




To 2.2 g (7.62 mmol) 2-acetylamino-4-phenyl-thiazole-5-carboxylic acid ethyl ester in 10 mL water is added 5 mL 4N NaOH and the mixture is allowed to stand at rt for 12 h. 1 g LiOH is added and the mixture is allowed to stand at rt for 2 h. The mixture is neutralized with aq. 2 N HCl solution and the precipitate is collected and washed with water and ACN to yield the desired product.
C12H10N2O3S (M=262.3 g/mol), ESI-MS: 263 [M+H]+
Example VIII
Example VIII.1
2-Acetylamino-oxazole-4-carboxylic acid




a) 2-Acetylamino-oxazole-4-carboxylic acid ethyl ester
1.0 g (6.40 mmol) 2-Amino-oxazole-4-carboxylic acid ethyl ester and 9.1 mL (96.3 mmol) acetic acid anhydride are stirred for 2 d at rt. The mixture is concentrated in vacuo to yield the desired product which is used without further purification.
b) 2-Acetylamino-oxazole-4-carboxylic acid
1.3 g (6.60 mmol) 2-Acetylamino-oxazole-4-carboxylic acid ethyl ester is added to 33 mL ethanol. 0.55 g (13.2 mmol) LiOH monohydrate is added and the mixture is stirred for 12 h at rt. The mixture is concentrated in vacuo, acidified by means of aq. HCl solution and the precipitate is collected and washed with cold water to yield the desired product.
C6H6N2O4 (M=170.1 g/mol), ESI-MS: 171 [M+H]+
Example XI
Example IX.1
3-(4-Cyclopropylmethoxy-phenoxy)-azetidine




a) 3-(4-Cyclopropylmethoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester
A mixture of 2.6 g (10.4 mmol) 3-methanesulfonyloxy-azetidine-1-carboxylic acid tert-butyl ester, 1.7 g (10.4 mmol) 4-cyclopropylmethoxy-phenol and 6.7 g (20.7 mmol) Cs2CO3 in 60 mL DMF is stirred for 12 h at 80° C. Water is added and the mixture is extracted with ethyl acetate (2×). The combined organic layers are washed with NaHCO3 solution and are dried over MgSO4. The solvent is evaporated and the residue is purified by column chromatography (silica gel; PE/ethyl acetate; gradient 9:1→8:2) to yield the desired product.
C18H25NO4 (M=319.4 g/mol), ESI-MS: 320 [M+H]+
Rt (HPLC): 2.46 min (method H1)
b) 3-(4-Cyclopropylmethoxy-phenoxy)-azetidine
To 1.7 g (5.32 mmol) 3-(4-cyclopropylmethoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester in 15 mL 1,4-dioxane is added 12.8 mL (16.0 mmol) HCl in dioxane (1.25 mol/L) and the mixture is stirred for 2 h at rt. 1 N NaOH solution is added until the mixture is slightly basic followed by extraction with DCM (2×). The combined organic layers are washed and dried over MgSO4. The solvent is evaporated and the residue is purified by column chromatography (silica gel; DCM/MeOH; gradient 9:1→7:3) to yield the desired product.
C13H17NO2 (M=219.3 g/mol), ESI-MS: 220 [M+H]+
Rt (HPLC): 1.79 min (method H1)
The following compounds are prepared analogously to Example IX.1:
Example IX.2
3-(4-Ethoxy-2-fluoro-phenoxy)-azetidine




Reagent in step a): 4-ethoxy-2-fluoro-phenol (US20090286812A1)
In step b no column chromatography was conducted and the desired product was obtained as a HCl-salt.
C11H14FNO2 (M=211.2 g/mol), ESI-MS: 212 [M+H]+
Rt (HPLC): 0.85 min (method F1)
Example IX.3
2-(Azetidin-3-yloxy)-4-benzyloxy-pyridine




Reagent in step a): 4-benzyloxy-1H-pyridin-2-one; DMSO is used as solvent and reaction conditions are 2 days at 70° C.
In step b no column chromatography was conducted and the desired product was obtained as a HCl-salt.
C15H16N2O2 (M=256.3 g/mol), ESI-MS: 257 [M+H]+
Rt (HPLC): 1.01 min (method F1)
Example IX.4
3-[4-(2-Methoxy-ethoxy)-phenoxy]-azetidine




Reagent in step a): 4-(2-methoxy-ethoxy)-phenol
In step b) HCl in methanol was used for deprotection and no column chromatography was conducted. The desired product was obtained as a HCl-salt.
C12H17NO3 (M=223.3 g/mol), ESI-MS: 224 [M+H]+
Rt (HPLC): 0.65 min (S1)
Example X
Example X.1
(S)-1-{4-[3-(4-Ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine




To 5.0 g (21.8 mmol) 3-(4-ethoxy-phenoxy)-azetidine and 6.5 g (21.8 mmol) (S)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.3) in 80 mL 1,4-dioxane under an argon atmosphere are added 8.6 g (87.1 mmol) KOtBu, 0.65 g (2.18 mmol) 2-(di-tert-butylphosphino)biphenyl and 1.0 g (1.09 mmol) tris-(dibenzylideneacetone)-dipalladium(0). The mixture is stirred for 2 h at 120° C. Subsequently 200 mL MeOH and 5 mL water are added and the mixture is filtered and concentrated in vacuo. The residue is taken up in ethyl acetate and is washed with water. The organic layer is concentrated and the residue is purified by HPLC (eluent A: water+0.1% NH4OH, eluent B: MeOH) to yield the desired product.
C19H24N2O2 (M=312.4 g/mol), ESI-MS: 296 [M+H—NH3]+
Rt (HPLC): 1.19 min (method J1)
Example X.2
(S)-1-{4-[3-(4-Cyclopropylmethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine




a) (1-{4-[3-(4-Cyclopropylmethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-carbamic acid tert-butyl ester
To 0.9 g (4.1 mmol) 3-(4-cyclopropylmethoxy-phenoxy)-azetidine (IX.1), 1.2 g (4.1 mmol) (S)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (I.3), 1.6 g (16.4 mmol) NaOtBu, 0.49 g (1.64 mmol) 2-(di-tert-butylphosphino)biphenyl and 0.38 g (0.41 mmol) tris-(dibenzylideneacetone)-dipalladium(0) are added under an argon atmosphere 25 mL 1,4-dioxane. The mixture is stirred for 12 h at 45° C. The mixture is filtered, washed with MeOH and concentrated. The residue is purified by HPLC (silica gel; PE/ethyl acetate; gradient 9:1→1:1) to yield the desired product.
C26H34N2O4 (M=438.6 g/mol), ESI-MS: 439 [M+H]+
Rt (HPLC): 1.62 min (method K1)
b) (S)-1-{4-[3-(4-Cyclopropylmethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine
130 mg (0.30 mmol) (1-{4-[3-(4-cyclopropylmethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-carbamic acid tert-butyl ester are added to 2 mL DCM and the mixture is cooled to 0° C. 0.03 mL TFA is added and stirring is continued for 1 h at 0° C. The solution as such is used directly for subsequent reactions.
C21H26N2O2 (M=338.4 g/mol), ESI-MS: 339 [M+H]+
Rt (HPLC): 2.19 min (method H1)
Example XI
Example XI.1
(S)—N-(1-{4-[3-(2-Fluoro-pyridin-4-yloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




1.0 g (4.3 mmol) (S)—N-{1-[4-(3-Hydroxy-azetidin-1-yl)-phenyl]-ethyl}-acetamide (V.1), 0.6 g (5.2 mmol) 2,4-difluoropyridine and 2.0 g (6.2 mmol) cesium carbonate are combined in 40 mL DMF and the mixture is stirred for 12 h at 80° C. Water is added and the mixture is extracted twice with ethylacetate. After concentration in vacuo the residue is purified by chromatography (silica; ethylacetate) to yield the desired product.
C18H20FN3O2 (M=329.4 g/mol), ESI-MS: 330 [M+H]+
Rt (HPLC): 0.89 min (U3)
The following compound is prepared analogously to Example XI.1:
Example XI.2
(S)-Cyclopropanecarboxylic acid (1-{4-[3-(2-fluoro-pyridin-4-yloxy)-azetidin-1-yl]-phenyl}-ethyl)-amide




Reagent: V.2
C20H22FN3O2 (M=355.4 g/mol), ESI-MS: 356 [M+H]+
Rt (HPLC): 0.95 min (U3)
Example XII
Example XII.1
2-Bromo-6-(2,2-difluoro-cyclopropylmethoxy)-pyridine




To 307 mg (2.84 mmol) (2,2-difluorocyclopropyl)methanol in 1,4-dioxane (10 mL) is added 69 mg (2.84 mmol) sodium hydride and 500 mg (2.84 mmol) 2-bromo-6-fluoropyridine. The mixture is stirred for 2 h at 90° C. Water and DMF are added and the mixture is filtered and concentrated in vacuo. The residue is purified by HPLC (C18 RP Sunfire, acetonitrile/water (+0.1% TFA)) to yield the desired product.
C9H8BrF2NO (M=264.1 g/mol), ESI-MS: 264 [M+H]+
Rt (HPLC): 0.97 min (U2)
Preparation of Final Compounds
Example 1
Example 1.1
(S)-1-Methyl-cyclobutanecarboxylic acid (1-{4-[3-(4-ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-amide




To 0.011 g (0.10 mmol) 1-methyl-cyclobutanecarboxylic acid in 1 mL DMF are added 0.035 mL (0.20 mmol) DIPEA and 0.032 g (49.1 mmol) TBTU. The mixture is stirred for 15 min at rt. Subsequently 0.031 g (0.10 mmol) (S)-1-{4-[3-(4-ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine (X.1) are added and stirring is continued for 12 h at rt. The mixture is directly purified by HPLC to yield the desired product.
C25H32N2O3 (M=408.5 g/mol), ESI-MS: 409 [M+H]+
Rt (HPLC): 1.93 min (method L1)
The following compounds of general formula (I-1) are prepared analogously to Example 1.1, the educts used being shown in the column headed “E 1” and “E 2”. Alternatively to purification by means of HPLC the products can also be obtained by adding K2CO3 solution (3 mol/L) to the reaction mixture prior to filtration through basic aluminum oxide followed by washing with DMF/MeOH (9:1) and concentration in vacuo:










(1-1)








 



















Rt







ESI-MS
HPLC [min]


Ex.
R1—Ar1
R4
E 1
E 2
[m/z]
(method)





1.1












X.1
409 [M + H]+
1.93 (L1)


 


1.2












X.1
369 [M + H]+
1.82 (L1)


 


1.3












X.1
385 [M + H]+
1.84 (L1)


 


1.4












X.1
381 [M + H]+
1.83 (L1)


 


1.5












X.1
383 [M + H]+
1.86 (L1)


 


1.6












X.1
383 [M + H]+
1.87 (L1)


 


1.7












X.1
395 [M + H]+
1.89 (L1)


 


1.8












X.1
409 [M + H]+
1.94 (L1)


 


1.9












X.1
395 [M + H]+
1.89 (L1)


 


1.10












X.1
397 [M + H]+
1.81 (L1)


 


1.11












X.1
407 [M + H]+
1.76 (L1)


 


1.12












X.1
395 [M + H]+
1.90 (L1)


 


1.13












X.1
421 [M + H]+
1.42 (L1)


 


1.14












X.1
422 [M + H]+
1.86 (L1)


 


1.15












X.1
395 [M + H]+
1.88 (L1)


 


1.16












X.1
373 [M + H]+
1.81 (L1)


 


1.17












X.1
401 [M + H]+
1.92 (L1)


 


1.18












X.1
406 [M + H]+
1.88 (L1)


 


1.19












X.1
425 [M + H]+
1.85 (L1)


 


1.20












X.1
408 [M + H]+
1.85 (L1)


 


1.21












X.1
421 [M + H]+
1.78 (L1)


 


1.22












X.1
433 [M + H]+
1.76 (L1)


 


1.23












X.1
411 [M + H]+
1.81 (L1)


 


1.24












X.1
413 [M + H]+
1.88 (L1)


 


1.25












X.1
407 [M + H]+
1.86 (L1)


 


1.26












X.1
418 [M + H]+
1.70 (L1)


 


1.27












X.1
418 [M + H]+
1.74 (L1)


 


1.28












X.1
371 [M + H]+
1.75 (L1)


 


1.29












X.1
407 [M + H]+
1.73 (M1)


 


1.30












X.1
437 [M + H]+
1.75 (M1)


 


1.31












X.1
435 [M + H]+
1.80 (M1)


 


1.32












X.1
495 [M + H]+
1.71 (M1)


 


1.33












X.1
421 [M + H]+
1.75 (M1)


 


1.34












X.1
421 [M + H]+
1.73 (M1)


 


1.35












X.1
422 [M + H]+
1.78 (M1)


 


1.36












X.1
408 [M + H]+
1.80 (M1)


 


1.37












X.1
408 [M + H]+
1.74 (M1)


 


1.38












X.1
438 [M + H]+
1.78 (M1)


 


1.39












X.1
436 [M + H]+
1.79 (M1)


 


1.40












X.1
413 [M + H]+
1.89 (M1)


 


1.41












X.1
438 [M + H]+
1.80 (M1)


 


1.42












X.1
421 [M + H]+
1.86 (M1)


 


1.43












X.1
387 [M + H]+
0.66 (N1)


 


1.44












X.1
481 [M + H]+
0.64 (N1)


 


1.45












X.1
435 [M + H]+
0.64 (N1)


 


1.46












X.1
438 [M + H]+
0.64 (N1)


 


1.47












X.1
421 [M + H]+
0.62 (N1)


 


1.48












X.1
472 [M + H]+
0.65 (N1)


 


1.49












X.1
420 [M + H]+
0.64 (N1)


 


1.50












X.1
452 [M + H]+
0.66 (N1)


 


1.51












X.1
407 [M + H]+
0.66 (N1)


 


1.52












X.1
432 [M + H]+
0.62 (N1)


 


1.53












X.1
405 [M + H]+
0.66 (N1)


 


1.54












X.1
436 [M + H]+
0.65 (N1)


 


1.55












X.1
440 [M + H]+
0.63 (N1)


 


1.57












X.1
424 [M + H]+
0.63 (N1)


 


1.58












X.1
448 [M + H]+
0.64 (N1)


 


1.59












X.1
424 [M + H]+
0.63 (N1)


 


1.60












X.1
481 [M + H]+
0.64 (N1)


 


1.61












X.1
422 [M + H]+
0.63 (N1)


 


1.62












X.1
399 [M + H]+
0.66 (N1)


 


1.63












X.1
407 [M + H]+
0.68 (N1)


 


1.64












X.1
432 [M + H]+
0.62 (N1)


 


1.65












X.1
397 [M + H]+
0.66 (N1)


 


1.66












X.1
557 [M + H]+
0.68 (N1)


 


1.67












X.1
399 [M + H]+
0.64 (N1)


 


1.68












X.1
408 [M + H]+
0.66 (N1)


 


1.69












X.1
488 [M + H]+
0.64 (N1)


 


1.70












X.1
411 [M + H]+
0.64 (N1)


 


1.71












X.1
397 [M + H]+
0.66 (N1)


 


1.72












X.1
465 [M + H]+
0.63 (N1)


 


1.73












X.1
391 [M + H]+
0.65 (N1)


 


1.74












X.1
449 [M + H]+
0.68 (N1)


 


1.75












X.1
423 [M + H]+
0.65 (N1)


 


1.76












X.1
452 [M + H]+
0.66 (N1)


 


1.77












X.1
393 [M + H]+
0.65 (N1)


 


1.78












X.1
475 [M + H]+
0.63 (N1)


 


1.79












X.1
385 [M + H]+
0.63 (N1)


 


1.80












X.1
394 [M + H]+
0.63 (N1)


 


1.81












X.1
432 [M + H]+
0.62 (N1)


 


1.82












X.1
394 [M + H]+
0.64 (N1)


 


1.83












X.1
380 [M + H]+
0.64 (N1)


 


1.84












X.1
409 [M + H]+
0.64 (N1)


 


1.85












X.1
424 [M + H]+
2.01 (O1)


 


1.86












X.2
433 [M + H]+
2.11 (H1)


 


1.87












X.2
406 [M + H]+
2.17 (H1)


 


1.88












X.2
395 [M + H]+
2.04 (H1)


 


1.89












X.2
421 [M + H]+
2.14 (H1)


 


1.90












X.2
450 [M + H]+
2.04 (H1)


 


1.91












X.2
394 [M + H]+
1.47 (V1)









Example 2
Example 2.1
(S)-2,5-Dimethyl-furan-3-carboxylic acid (1-{4-[3-(4-ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-amide




To 0.015 g (0.10 mmol) 2,5-dimethyl-furan-3-carbonyl chloride in 1 mL DCM is added a mixture of 0.031 g (0.10 mmol) (S)-1-{4-[3-(4-ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine (X.1) and 0.010 g (0.10 mmol) TEA in 0.5 mL DCM. The mixture is stirred for 12 h at rt. The solvent is removed in vacuo and the residue is purified by HPLC to yield the desired product.
C26H30N2O4 (M=434.5 g/mol), ESI-MS: 435 [M+H]+
Rt (HPLC): 1.90 min (method M1)
The following compounds of general formula (I-1) are prepared analogously to Example 2.1, the educts used being shown in the column headed “E 1” and “E 2”:










(1-1)








 



















Rt







ESI-MS
HPLC [min]


Ex.
R1—Ar1
R4
E 1
E 2
[m/z]
(method)





2.1












X.1
435 [M + H]+
1.90 (M1)


 


2.2












X.1
421 [M + H]+
1.77 (M1)


 


2.3












X.1
421 [M + H]+
1.83 (M1)


 


2.4












X.1
408 [M + H]+
1.77 (M1)


 


2.5












X.1
422 [M + H]+
1.30 (J1)


 


2.6












X.2
381 [M + H]+
2.13 (H1)


 


2.7












X.2
407 [M + H]+
2.16 (H1)









Example 3
Example 3.1
(S)—N-(1-{4-[3-(4-Ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-2,2,2-trifluoro-acetamide




To 0.094 g (0.30 mmol) (S)-1-{4-[3-(4-ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine (X.1) in 10 mL DCM are added 0.063 g (0.30 mmol) trifluoroacetic anhydride and the mixture is stirred for 30 min at rt. After concentration in vacuo the residue is purified by HPLC (C18 RP Sunfire, MeOH/water (+0.1% TFA)) to yield the desired product.
C21H23F3N2O3 (M=408.4 g/mol), ESI-MS: 409 [M+H]+
Rt (HPLC): 0.87 min (method J1)
Example 4
Example 4.1
(S)-1-(1-{4-[3-(4-Ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-3-pyrimidin-4-yl-urea




0.03 mL (0.20 mmol) DBU and 0.033 g (0.20 mmol) CDT are added to 0.010 g (0.10 mmol) 4-aminopyrimidine in 1.0 mL 1,4-dioxane. The mixture is stirred for 5 min at rt followed by addition of 0.048 g (0.092 mmol) (S)-1-{4-[3-(4-ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine (X.1) in 1.0 mL 1,4-dioxane. The mixture is stirred for 12 h at rt and subsequently concentrated in vacuo. The residue is purified by HPLC (XBridge, ACN/water (+0.1% NH4OH)) to yield the desired product.
C24H27N5O3 (M=433.5 g/mol), ESI-MS: 434 [M+H]+
Rt (HPLC): 1.79 min (method L1)
The following compounds of general formula (I-1) are prepared analogously to Example 4.1, the educts used being shown in the column headed “E 1” and “E 2”. In case of non-aromatic amines as reagents the order of addition is reverted so that X.1 is reacted with CDT prior to the addition of the amine “E-1”. Alternatively DCM can be used as solvent and TEA can be used as a base instead of dioxane and DBU.










(1-1)








 



















Rt







ESI-MS
HPLC [min]


Ex.
R1—Ar1
R4
E 1
E 2
[m/z]
(method)





4.1












X.1
434 [M + H]+
1.79 (L1)


 


4.2












X.1
384 [M + H]+
1.86 (P1)


 


4.3












X.1
370 [M + H]+
1.83 (P1)


 


4.4












X.1
412 [M + H]+
1.78 (P1)


 


4.5












X.1
424 [M + H]+
1.97 (P1)


 


4.6












X.1
426 [M + H]+
1.83 (P1)


 


4.7












X.1
422 [M + H]+
1.88 (P1)


 


4.8












X.1
428 [M + H]+
1.91 (P1)


 


4.9












X1
398 [M + H]+
1.91 (P1)


 


4.10












X.1
412 [M + H]+
1.95 (P1)


 


4.11












X.1
396 [M + H]+
1.86 (P1)


 


4.12












X.1
435 [M + H]+
1.89 (P1)


 


4.13












X.1
447 [M + H]+
1.87 (P1)


 


4.14












X.1
410 [M + H]+
1.98 (P1)


 


4.15












X.2
410 [M + H]+
2.15 (H1)


 


4.16












X.2
410 [M + H]+
2.03 (H1)


 


4.17












X.2
436 [M + H]+
2.14 (H1)









Example 5
Example 5.1
(S)-4-(1-{4-[3-(4-Ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamino)-5H-furan-2-one




To 0.040 g (0.13 mmol) (S)-1-{4-[3-(4-ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine (X.1) in 1.5 mL THF are added 54 μL (0.38 mmol) TEA and 0.021 g (0.13 mmol) 4-bromo-2(5H)-furanone. The mixture is stirred for 12 h at 80° C. After concentration in vacuo the residue is purified by HPLC (SunfireC18, MeOH/water (+0.3% formic acid)) to yield the desired product.
C23H26N2O4 (M=394.5 g/mol), ESI-MS: 395 [M+H]+
Rt (HPLC): 1.11 min (method F1)
Example 6
Example 6.1
(S)—N-(1-{4-[3-(4-tert-Butyl-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




Under an argon atmosphere a mixture of 0.28 g (0.97 mmol) (S)—N-[1-(4-iodo-phenyl)-ethyl]-acetamide (III.1), 0.20 g (0.98 mmol) 3-(4-tert-butyl-phenoxy)-azetidine, 0.0093 g (0.049 mmol) CuI, 0.41 g (1.95 mmol) K3PO4 and 0.12 g (1.95 mmol) ethyleneglycol in 1.0 mL isopropanol is stirred for 12 h at 80° C. 100 mL Ethyl acetate are added and the mixture is washed with ammonia solution (5%, 2×). The aq. layer is extracted with ethyl acetate (1×) and the combined organic layers are dried (MgSO4) and concentrated in vacuo. The residue is purified by HPLC (XBridge, MeOH/water (+0.3% NH4OH)) to yield the desired product.
C23H30N2O2 (M=366.5 g/mol), ESI-MS: 367 [M+H]+
Rt (HPLC): 2.28 min (method H1)
Example 7
Example 7.1
(S)—N-(1-{4-[3-(4-Ethoxy-2-fluoro-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




Under an argon atmosphere a mixture of 0.078 g (0.32 mmol) (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1), 0.080 g (0.32 mmol) 3-(4-ethoxy-2-fluoro-phenoxy)-azetidine (see US20090286812), 0.26 g (0.081 mmol) Cs2CO3, 0.0036 g (0.016 mmol) palladium(II) acetate, 0.0077 g (0.016 mmol) 2-dicyclohexylphosphine-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (X-Phos) in 1.5 mL toluene and 0.5 mL tert-butanol is stirred for 12 h at 120° C. Few water and methanol is added, the mixture is filtered and concentrated in vacuo. The residue is purified by HPLC (GeminiCl8, acetone/water (+0.3% NH4OH)) to yield the desired product.
C21H25FN2O3 (M=372.4 g/mol), ESI-MS: 373 [M+H]+
Rt (HPLC): 1.11 min (method F1)
Example 7.2
(S)-Cyclopropanecarboxylic acid (1-{4-[3-(4-ethoxy-2-fluoro-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-amide




Example 7.2 is prepared analogously to 7.1. (S)-Cyclopropanecarboxylic acid [1-(4-bromo-phenyl)-ethyl]-amide (1.2) is used as starting material.
C23H27FN2O3 (M=398.5 g/mol), ESI-MS: 399 [M+H]+
Rt (HPLC): 1.15 min (method F1)
Example 8
Example 8.1
(S)-3-(1-{4-[3-(4-Ethoxy-2-fluoro-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-1,1-dimethyl-urea




Under an argon atmosphere a mixture of 0.080 g (0.295 mmol) (S)-3-[1-(4-bromo-phenyl)-ethyl]-1,1-dimethyl-urea (II.1), 0.073 g (0.295 mmol) 3-(4-ethoxy-2-fluoro-phenoxy)-azetidine (IX.2), 0.117 g (97%, 1.18 mmol) NaOtBu, 0.0035 g (0.118 mmol) 2-(di-tert-butylphosphino)biphenyl, 0.027 g (0.0295 mmol) tris-(dibenzylideneaceton)-dipalladium(0) in 1.5 mL 1,4-dioxane is stirred for 3 h at 80° C. Few water and methanol is added, the mixture is filtered and concentrated in vacuo. The residue is purified by HPLC (GeminiC18, methanol/water (+0.3% NH4OH)) to yield the desired product.
C22H28FN3O3 (M=401.5 g/mol), ESI-MS: 402 [M+H]+
Rt (HPLC): 1.65 min (method Q1)
Example 8.2
(S)-1H-Pyrazole-4-carboxylic acid (1-{4-[3-(4-ethoxy-2-fluoro-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-amide




Example 8.2 is prepared analogously to 8.1. (S)-1H-Pyrazole-4-carboxylic acid [1-(4-bromo-phenyl)-ethyl]-amide (1.5) is used as starting material.
C23H25FN4O3 (M=424.5 g/mol), ESI-MS: 425 [M+H]+
Rt (HPLC): 1.62 min (method Q1)
Example 8.3
(S)-(1-{4-[3-(4-Cyclopropylmethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-carbamic acid tert-butyl ester




Example 8.3 is prepared analogously to 8.1. (S)-[1-(4-Bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (1.3) and 3-(4-cyclopropylmethoxy-phenoxy)-azetidine (IX.1) are used as starting materials and the reaction temperature is 45° C.
C26H34N2O4 (M=438.6.4 g/mol), ESI-MS: 439 [M+H]+
Rt (HPLC): 2.53 min (method H1)
Example 8.4
(S)-2-Acetylamino-4-methyl-thiazole-5-carboxylic acid (1-{4-[3-(4-ethoxy-2-fluoro-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-amide




Example 8.4 is prepared analogously to 8.1. (S)-2-Acetylamino-4-methyl-thiazole-5-carboxylic acid [1-(4-bromo-phenyl)-ethyl]amide (1.6) is used as starting material.
C26H29FN4O4S (M=512.6 g/mol), ESI-MS: 513 [M+H]+
Rt (HPLC): 1.16 min (method F1)
Example 8.5
(S)—N-(1-{4-[3-(4-Benzyloxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




Example 8.5 is prepared analogously to 8.1. 3-(4-Benzyloxy-phenoxy)-azetidine and (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1) are used as starting materials. Reaction conditions are stirring for 2 days at 30° C.
C26H28N2O3 (M=416.5 g/mol), ESI-MS: 417 [M+H]+
Rt (HPLC): 2.17 min (method H1)
Example 8.6
N-(1-{6-[3-(4-Ethoxy-phenoxy)-azetidin-1-yl]-pyridin-3-yl}-ethyl)-acetamide




Example 8.6 is prepared analogously to 8.1. (N-[1-(6-Bromo-pyridin-3-yl)-ethyl]-acetamide (I.4) and 3-(4-ethoxy-phenoxy)-azetidine are used as starting materials.
C20H25N3O3 (M=355.4 g/mol), ESI-MS: 356 [M+H]+
Rt (HPLC): 1.47 min (method Q1)
Example 8.7
(S)—N-(1-{4-[3-(4-Benzyloxy-pyridin-2-yloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




Example 8.7 is prepared analogously to 8.1. 2-(Azetidin-3-yloxy)-4-benzyloxy-pyridine (IX.3) and (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1) are used as starting materials.
C25H27N3O3 (M=417.5 g/mol), ESI-MS: 418 [M+H]+
Rt (HPLC): 1.20 min (method F1)
Example 8.8
(S)—N-(1-{4-[3-(5-Trifluoromethyl-pyridin-2-yloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




Example 8.8 is prepared analogously to 8.1. 2-(Azetidin-3-yloxy)-5-trifluoromethyl-pyridine and (S)—N-[1-(4-bromo-phenyl)-ethyl]-acetamide (I.1) are used as starting materials. Reaction conditions are stirring for 12 h at 50° C.
C19H20F3N3O2 (M=379.4 g/mol), ESI-MS: 380 [M+H]+
Rt (HPLC): 1.14 min (method F1)
Example 9
Example 9.1
(S)—N-(1-{4-[3-(4-Isopropoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




To 0.050 g (0.15 mmol) (S)—N-(1-{4-[3-(4-hydroxy-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide (VI.1) in 1.0 mL DMF are added 0.053 g (0.38 mmol) potassium carbonate and 17.2 μL (0.18 mmol) 2-bromopropane. The mixture is stirred for 12 h at 80° C. After cooling the mixture is directly purified by HPLC (XBridge, MeOH/water (+0.3% NH4OH)) to yield the desired product.
C22H28N2O3 (M=368.5 g/mol), ESI-MS: 369 [M+H]+
Rt (HPLC): 2.04 min (method H1)
The following compounds of general formula (1-1) are prepared analogously to Example 9.1, the educts used being shown in the column headed “E 1” and “E 2”.










(1-1)








 



















Rt







ESI-MS
HPLC [min]


Ex.
R1—Ar1
R4
E 1
E 2
[m/z]
(method)





9.1












VI.1
369 [M + H]+
2.04 (H1)


 


9.2












VI.1
355 [M + H]+
1.98 (H1)


 


9.3












VI.1
369 [M + H]+
2.10 (H1)


 


9.4












VI.1
381 [M + H]+
2.11 (H1)


 


9.5












VI.1
417 [M + H]+
2.13 (H1)









Example 10
Example 10.1
(S)—N-(1-{4-[3-(2,3-Difluoro-4-methyl-phenoxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




To 0.023 g (0.10 mmol) (S)—N-{1-[4-(3-hydroxy-azetidin-1-yl)-phenyl]-ethyl}-acetamide (V.1) in 5 mL THF are added 0.017 mL (0.12 mmol) TEA and the mixture is cooled to 0° C. 0.008 mL (0.10 mmol) methanesulfonyl chloride are added dropwise and the mixture is stirred for 2 h at 0° C. Water is added and the aq. phase is extracted with ethyl acetate (2×). The combined organic layers are dried (MgSO4) and concentrated. The residue is taken up in 1.0 mL DMA and is added to a mixture of 0.014 g (0.12 mmol) 2,3-difluoro-4-methylphenol and 0.039 g (0.12 mmol) Cs2CO3 in 1.0 mL DMA. The resulting mixture is stirred for 12 h at 100° C. After cooling the mixture is directly purified by HPLC (MeOH/water (+0.1% NH4OH)) to yield the desired product.
C20H22F2N2O2 (M=360.4 g/mol), ESI-MS: 361 [M+H]+
Rt (HPLC): 1.96 min (method L1)
The following compounds of general formula (1-1) are prepared analogously to Example 10.1, the educts used being shown in the column headed “E 1” and “E 2”.










(1-1)








 



















Rt







ESI-MS
HPLC [min]


Ex.
R1—Ar1
R4
E 1
E 2
[m/z]
(method)





10.1












V.1
361 [M + H]+
1.96 (L1)


 


10.2












V.1
395 [M + H]+
1.94 (L1)


 


10.3












V.1
410 [M + H]+
200 (L1)


 


10.4












V.1
359 [M + H]+
1.79 (L1)


 


10.5












V.1
383 [M + H]+
1.92 (L1)


 


10.6












V.1
391 [M + H]+
1.94 (L1)


 


10.7












V.1
391 [M + H]+
1.90 (L1)


 


10.8












V.1
342 [M + H]+
1.68 (L1)


 


10.9












V.1
529 [M + H]+
2.04 (L1)


 


10.10












V.1
367 [M + H]+
2.09 (L1)


 


10.11












V.1
365 [M + H]+
1.94 (L1)


 


10.12












V.1
311 [M + H]+
1.83 (L1)


 


10.13












V.1
355 [M + H]+
1.79 (L1)


 


10.14












V.1
325 [M + H]+
1.92 (L1)


 


10.15












V.1
325 [M + H]+
1.94 (L1)


 


10.16












V.1
363 [M + H]+
1.95 (L1)


 


10.17












V.1
397 [M + H]+
1.94 (L1)


 


10.18












V.1
377 [M + H]+
1.84 (L1)


 


10.19












V.1
385 [M + H]+
1.72 (L1)


 


10.20












V.2
421 [M + H]+
1.99 (L1)


 


10.21












V.2
385 [M + H]+
1.87 (L1)


 


10.22












V.2
409 [M + H]+
1.97 (L1)


 


10.23












V.2
417 [M + H]+
1.98 (L1)


 


10.24












V.2
417 [M + H]+
1.95 (L1)


 


10.25












V.2
368 [M + H]+
1.76 (L1)


 


10.26












V.2
393 [M + H]+
2.11 (L1)


 


10.27












V.2
391 [M + H]+
1.99 (L1)


 


10.28












V.2
381 [M + H]+
1.85 (L1)


 


10.29












V.1
375 [M + H]+
2.62 (O1)


 


10.30












V2
417 [M + H]+
2.70 (R1)


 


10.31












V.1
391 [M + H]+
2.66 (R1)


 


10.32












V.1
342 [M + H]+
1.68 (L1)









Example 11
Example 11.1
(S)—N-(1-{4-[3-(2-Cyclopropylmethoxy-pyridin-4-yloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




To 55 mg (0.17 mmol) (S)—N-(1-{4-[3-(2-Fluoro-pyridin-4-yloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide (XI.1) in 5 mL 1,4-dioxane is added 0.14 mL (1.73 mmol) cyclopropanemethanol. 38 mg (0.95 mmol, 60% suspension in mineral oil) NaH is added and the mixture is stirred for 15 h at 130° C. After concentration in vacuo the residue is purified by chormotography (silica, ethylacetate) to yield the desired product.
C22H27N3O3 (M=381.5 g/mol), ESI-MS: 382 [M+H]+
Rt (HPLC): 0.85 min (U3)
The following compounds of general formula (1-1) are prepared analogously to Example 11.1, the educts used being shown in the column headed “E 1” and “E 2”.










(1-1)








 



















Rt







ESI-MS
HPLC [min]


Ex.
R1—Ar1
R4
E 1
E 2
[m/z]
(method)





11.1












XI.1
382 [M + H]+
0.85 (U3)


 


11.2












XI.1
398 [M + H]+
0.80 (U3)


 


11.3












XI.1
384 [M + H]+
0.88 (U3)


 


11.4












XI.1
368 [M + H]+
0.83 (U3)


 


11.5












XI.1
418 [M + H]+
0.93 (U3)


 


11.6












XI.1
392 [M + H]+
0.95 (U3)


 


11.7












XI.2
410 [M + H]+
0.94 (U3)


 


11.8












XI.1
392 [M + H]+
0.95 (U3)









Example 12
Example 12.1
(S)—N-{1-[4-(3-{6-[(2-Hydroxy-2-methyl-propyl)-methyl-amino]-pyridin-2-yloxy}-azetidin-1-yl)-phenyl]ethyl}-acetamide




23 mg (0.10 mmol) (S)—N-{1-[4-(3-Hydroxy-azetidin-1-yl)-phenyl]ethyl}-acetamide (V.1) in 1,4-dioxane (2.0 mL) is added to 31 mg (0.12 mmol) 1-[(6-bromo-pyridin-2-yl)-methyl-amino]-2-methyl-propan-2-ol. 38 mg (0.40 mmol) NaOtBu is added followed by 7.4 mg (0.01 mmol) chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II). The mixture is stirred for 12 h at 50° C. 7.8 mg (0.01 mmol) chloro(2-dicyclohexylphosphino-2′,4′,6′-triisoporpyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) is added and the mixture is stirred for 12 h at 100° C. After cooling to room temperature water (0.5 mL) and DMF (2.0 mL) are added and the mixture is filtered and concentrated. The residue is purified by HPLC (acetonitrile/water (+0.1% NH4OH)) to yield the desired product.
C23H32N4O3 (M=412.5 g/mol), ESI-MS: 413 [M+H]+
Rt (HPLC): 0.90 min (T1)
The following compounds of general formula (1-1) are prepared analogously to Example 12.1, the educts used being shown in the column headed “E 1” and “E 2”.










(1-1)








 



















Rt







ESI-MS
HPLC [min]


Ex.
R1—Ar1
R4
E 1
E 2
[m/z]
(method)





12.1












V.1
413 [M + H]+
0.90 (T1)


 


12.2












V.1
382 [M + H]+
1.24 (T1)


 


12.3












V.1
370 [M + H]+
1.27 (T1)


 


12.4












V.1
409 [M + H]+
1.28 (T1)


 


12.5












V.1
326 [M + H]+
0.53 (T1)


 


12.6












V.1
355 [M + H]+
0.97 (T1)


 


12.7












V.1
382 [M + H]+
1.29 (T1)


 


12.8












V.1
398 [M + H]+
1.05 (T1)


 


12.9












V.1
370 [M + H]+
1.24 (T1)


 


12.10












V.1
352 [M + H]+
1.16 (T1)


 


12.11












V.1
340 [M + H]+
0.57 (T1)


 


12.12












V.1
362 [M + H]+
1.09 (T1)


 


12.13












V.1
380 [M + H]+
1.31 (T1)


 


12.14












V.1
366 [M + H]+
1.21 (T1)


 


12.15












V.1
397 [M + H]+
1.02 (T1)


 


12.16












V.1
356 [M + H]+
0.92 (U1)


 


12.17












V.1
368 [M + H]+
1.03 (U1)


 


12.18












V.1
418 [M + H]+
0.96 (U1)


 


12.19












V.1
354 [M + H]+
0.56 (U2)









Example 13
Example 13.1
(S)—N-(1-{4-[3-(2-Morpholin-4-yl-pyrimidin-4-yloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




To 30 mg (0.15 mmol) 4-(4-chloro-pyrimidin-2-yl)-morpholine in DMF (1.0 mL) is added 30 mg (0.13 mmol) (S)—N-{1-[4-(3-hydroxy-azetidin-1-yl)-phenyl]-ethyl}-acetamide (V.1) in DMF (1.0 mL). 20 mg (0.45 mmol, 55% in mineral oil) NaH is added and the mixture is stirred for 12 h at room temperature. Water is added, the mixture is concentrated in vacuo and the residue is purified by HPLC (XBridge, acetronitrile/H2O (+0.1% NH4OH)) to yield the desired product.
C21H27N5O3 (M=397.5 g/mol), ESI-MS: 398 [M+H]+
Rt (HPLC): 0.66 (T1)
Example 13.2
(S)—N-(1-{4-[3-(2-Pyrrolidin-1-yl-pyrimidin-4-yloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




Example 13.2 is prepared analogously to 13.1. 4-Bromo-2-pyrrolidin-1-yl-pyrimidine is used as starting material.
C21H27N5O2 (M=381.5 g/mol), ESI-MS: 382 [M+H]+
Rt (HPLC): 0.69 min (T1)
Example 14
Example 14.1
(S)—N-(1-{4-[3-(6-Methoxy-pyridin-2-yloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




To 13 mg (0.10 mmol) 6-methoxy-pyridin-2-ol in THF (1.0 mL) is added 23 mg (0.10 mmol) (S)—N-{1-[4-(3-hydroxy-azetidin-1-yl)-phenyl]-ethyl}-acetamide (V.1) in THF (1.0 mL). 29 mg (0.11 mmol) triphenylphosphine and 25 mg (0.11 mmol) di-tert-butyl azodicarboxylate are added and the mixture is stirred for 3 h at 60° C. Another portion of 29 mg (0.11 mmol) triphenylphosphine and 25 mg (0.11 mmol) di-tert-butyl azodicarboxylate are added and stirring is continued for 2 h at 60° C. The mixture is concentrated in vacuo and the residue is purified by HPLC (XBridge, acetronitrile/H2O (+0.1% NH4OH)) to yield the desired product.
C19H23N3O3 (M=341.4 g/mol), ESI-MS: 342 [M+H]+
Rt (HPLC): 1.05 (T1)
Example 14.2
(S)—N-(1-{4-[3-(6-Methoxy-pyridin-2-yloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




Example 14.2 is prepared analogously to 14.1. 6-Trifluoromethyl-pyridin-2-ol is used as starting material.
C19H20F3N3O2 (M=379.4 g/mol), ESI-MS: 380 [M+H]+
Rt (HPLC): 1.18 min (T1)
Example 14.3
(S)—N-(1-{4-[3-(2-Methyl-pyrimidin-4-yloxy)-azetidin-1-yl]-phenyl}-ethyl)-acetamide




Example 14.2 is prepared analogously to 14.1. 2-Methyl-pyrimidin-4-ol is used as starting material.
C18H22N4O2 (M=326.4 g/mol), ESI-MS: 327 [M+H]+
Rt (HPLC): 0.61 min (T1)
Example 15
Example 15.1
N-(1-{4-[3-(4-Cyclopropylmethoxy-phenoxy)-azetidin-1-yl]-phenyl}-1-methyl-ethyl)-acetamide




To 35 mg (0.16 mmol) 3-(4-cyclopropylmethoxy-phenoxy)-azetidine (IX.1) in THF (2.0 mL) are added under an argon atmosphere 41 mg (0.16 mmol) N-[1-(4-bromo-phenyl)-1-methyl-ethyl]-acetamide, 63 mg (0.64 mmol) NaOtBu, 19 mg (0.064 mmol) 2-(di-tert-butylphosphino)biphenyl and 15 mg (0.016 mmol) tris-(dibenzylidene-acetone)-dipalladium(0). The mixture is stirred for 12 h at 45° C. The mixture is filtered and concentrated in vacuo. The residue is purified by HPLC (Zorbax, acetronitrile/H2O (+0.15% HCOOH)) to yield the desired product.
C24H30N2O3 (M=394.5 g/mol), ESI-MS: 395 [M+H]+
Rt (HPLC): 2.38 (H1)
Example 16
Example 16.1
(S)-2-Acetylamino-4-methyl-thiazole-5-carboxylic acid [1-(4-{3-[4-(2-methoxy-ethoxy)-phenoxy]-azetidin-1-yl}-phenyl)-ethyl]-amide




100 mg (0.39 mmol) 3-[4-(2-Methoxy-ethoxy)-phenoxy]-azetidine (IX.4), 165 mg (0.43 mmol) (S)-2-acetylamino-4-methyl-thiazole-5-carboxylic acid [1-(4-bromo-phenyl)-ethyl]-amide (I.6), 45 mg (0.06 mmol) chloro(2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) and 150 mg (1.56 mmol) NaOtBu are combined under an argon atmosphere and 1,4-dioxane (4.0 mL) is added. The mixture is stirred for 12 h at 45° C. Some water and methanol are added and the mixture is filtered and purified by HPLC (Zorbax, acetronitrile/H2O (+0.1% TFA)) to yield the desired product.
C27H32N4O5S (M=524.6 g/mol), ESI-MS: 525 [M+H]+
Rt (HPLC): 1.24 (S1)

## Claims

1. A compound of the formula I




wherein
Ar1 is selected from a group consisting of:
6- to 10-membered arylene and 5- to 10-membered heteroarylene all of which may be optionally substituted with one or more substituents RA,
wherein R1 and RA linked to adjacent C-atoms of Ar1 may be connected with each other and together form a C3-5-alkylene bridging group in which 1, 2 or 3-CH2-groups may be replaced by O, C(═O), S, S(═O), S(═O)2, NH or N(C1-4-alkyl)-, wherein the alkylene bridge may optionally be substituted by one or two C1-3-alkyl groups;

RA is selected from a group consisting of:
H, F, Cl, Br, I, CN, OH, —NO2, C1-4-alkyl, C2-4-alkenyl, C1-4-alkyl-O—, C1-4alkyl-C(═O)—, H2N—, H2N—C(═O)—, H2N—S(═O)2—, HO—C(═O)—, C1-4-alkyl-O—C(═O)—, phenyl and phenyl-C1-3-alkyl,
wherein in each NH2-group, one or both hydrogen atoms may independently be replaced by C1-4-alkyl;
wherein each alkyl may be optionally substituted with one or more F atoms;


R1 is selected from a group consisting of:
H, OH, C1-6-alkyl, C1-6-alkyl-O—, C3-7-cycloalkyl, C3-7-cycloalkyl-O—, C3-7-cycloalkyl-C1-3-alkyl-O—, H2N—, (C1-4-alkyl)NH—, (C1-4-alkyl)2N—, C3-7-cycloalkyl-NH—, C3-7-cycloalkyl-N(C1-4-alkyl)-, C3-7-cycloalkyl-C1-3-alkyl-NH—, (C3-7-cycloalkyl-C1-3-alkyl)-N(C1-4-alkyl)-, C1-4-alkyl-C(═O)—, C1-4-alkyl-S(═O)2—, HO—C(═O)—, C1-4-alkyl-O—C(═O)—, H2N—C(═O)—, (C1-4-alkyl)HN—C(═O)—, (C1-4-alkyl)2N—C(═O)—, aryl, aryl-C1-3-alkyl-, aryl-C1-3-alkyl-O—, heterocyclyl, heterocyclyl-O—, heterocyclyl-C1-3-alkyl-O—, heteroaryl, heteroaryl-C1-3-alkyl- and heteroaryl-C1-3-alkyl-O—,
wherein each alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of F, OH and C1-4-alkyl-O-—, and
wherein each heterocyclyl is optionally substituted with one or more C1-3-alkyl;


Ar2 is selected from a group consisting of:
phenylene and a 5- or 6-membered monocyclic heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O, or S,
wherein Ar2 may be optionally substituted with one or more substituents RA;


R2a and R2b are each independently selected from a group consisting of:
H and C1-3-alkyl;

R3 is selected from a group consisting of: H and C1-4-alkyl; and
R4 is selected from a group consisting of:
H, C1-6-alkyl, C3-10-carbocyclyl, C3-10-carbocyclyl-C1-3-alkyl-, C2-6-alkenyl, O2-6-alkynyl, C1-6-alkyl-O—, RN1R2NN—, heterocyclyl, heterocyclyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heteroaryl and heteroaryl-C1-3-alkyl,
wherein in each carbocyclyl and heterocyclyl a —CH2-group may optionally be replaced by —C(═O)—, and
wherein each alkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group may be optionally substituted with one or more substituents independently selected from the group R5;


RN1 is selected from a group consisting of:
H and C1-4-alkyl;
wherein each alkyl group may be optionally substituted with one R5;


RN2 is selected from a group consisting of:
H, C1-4-alkyl, C3-10-carbocyclyl, C3-10-carbocyclyl-C1-3-alkyl, C2-6-alkenyl, C2-6-alkynyl, heterocyclyl, heterocyclyl-C1-3-alkyl, aryl, aryl-C1-3-alkyl, heteroaryl and heteroaryl-C1-3-alkyl,
wherein each carbocyclyl and heterocyclyl may be optionally substituted with one or more C1-4-alkyl, aryl or aryl-C1-3-alkyl-, and
wherein in each carbocyclyl and heterocyclyl a CH2-group may optionally be replaced by —C(═O)—; and
with the provision that there is at least one CH2-group between any double or triple bond of the alkenyl and alkynyl groups and the nitrogen atom to which they are attached and


R5 is selected from a group consisting of:
F, Cl, Br, CN, OH, C1-4-alkyl-, C1-4-alkyl-O—, C1-4-alkyl-S—, C1-4-alkyl-S(═O)2—, H2N—, (C1-4-alkyl)NH—, (C1-4-alkyl)2N—, C1-4-alkyl-(C═O)—NH—, heterocyclyl and aryl,
wherein each alkyl may be optionally substituted with one or more F-atoms and/or with a substituent selected from OH, C1-3-alkyl-O— and CN; and
wherein two substituents R5 attached to an aryl or heteroaryl group may be linked to each other and form a O2-5-alkylene bridging group in which one or two —CH2-groups may be replaced by a group independently of each other selected from the group consisting of O, S, NH, and N(C1-4-alkyl)-, wherein the C2-5-alkylene bridging group is optionally be substituted by one or two C1-3-alkyl groups or F atoms;


or a tautomer or pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, wherein
R2a is H;
R2b is CH3; and
R3 is H.

3. A compound according to claim 1, wherein
Ar2 is

4. A compound according to claim 1, wherein Ar1 is selected from a group consisting of:
phenylene, pyridinylene, pyrimidinylene, benzofuranylene and benzo[1,3]dioxolylene,
wherein Ar1 may be substituted with one or two substituents RA.

5. A compound according to claim 1, wherein RA is F or Cl.

6. A compound according to claim 1, wherein R1 is selected from a group consisting of:
H, C1-4-alkyl, C1-4alkyl-O—, C3-6-cycloalkyl, C3-6-cycloalkyl-O—, tetrahydrofuranyl-O—, C3-6-cycloalkyl-CH2—O—, (C1-4-alkyl)NH—, (C1-4-alkyl)2N—, phenyl, benzyl, phenyl-CH2—O—, piperidinyl, morpholinyl, pyrrolidinyl and pyrrolyl,
wherein each alkyl and cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of F, OH, and —O—CH3, and
wherein piperidinyl is optionally substituted with one or two CH3.

7. A compound according to claim 1, wherein
R4 is selected from a group consisting of:
H, C1-4-alkyl, C3-6-cycloalkyl, C4-6-cycloalkenyl, C3-6-cycloalkyl-C1-3-alkyl-, C2-6-alkenyl, C2-6-alkynyl, C1-6-alkyl-O—, RN1RN2N—, heterocyclyl, heterocyclyl-C1-3-alkyl-, phenyl, phenyl-C1-3-alkyl-, heteroaryl and heteroaryl-C1-3-alkyl-,
wherein RN1 is selected from the group consisting of: H and C1-3-alkyl; and
wherein RN2 is selected from the group consisting of: H, C1-4-alkyl, C3-7-cycloalkyl and heteroaryl; and
wherein in each cycloalkyl and heterocyclyl a —CH2-group may optionally be replaced by —C(═O)—, and
wherein each alkyl, cycloalkyl, heterocyclyl, phenyl and heteroaryl group may be optionally substituted with one to three substituents independently selected from the group consisting of: F, Cl, CN, OH, CF3, C1-3-alkyl, —O—(C1-3-alkyl) and —NH—(C═O)—C1-3-alkyl; and
wherein each heterocyclyl is selected from the group consisting of: azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, morpholinyl and 3H-pyrimidin-4-onyl; and
wherein each heteroaryl is selected from the group consisting of: pyrrolyl, furanyl, furazanyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl.

8. A compound according to claim 1, wherein
Ar1 is selected from a group consisting of:




wherein the asterisk to the right side of each group indicates the bond which is connected to the O-azetidine ring of the core structure of the formula (I), and the asterisk to the left side of each group indicates the bond which is connected to a substituent R1, and Ar1 is optionally additionally substituted with one or two F or Cl atoms;
R1 is selected from a group consisting of:
C1-4-alkyl, C1-4-alkyl-O—, C3-5-cycloalkyl, C3-5-cycloalkyl-O—, tetrahydrofuranyl-O—, C3-5-cycloalkyl-CH2—O—, (C1-4-alkyl)2N—, phenyl, benzyl, phenyl-CH2—O—, piperidinyl, morpholinyl, pyrrolidinyl and pyrrolyl,
wherein each alkyl and cycloalkyl may be optionally substituted with one to three F atoms or one OH or —O—CH3, and
wherein piperidinyl is optionally substituted with one CH3;

Ar2 is




R2a is H;
R2b is CH3;
R3 is H; and
R4 is selected from a group consisting of:
C1-4-alkyl, C3-5-cycloalkyl, cyclopentenyl, C3-5-cycloalkyl-CH2—, C3-5-alkenyl, C3-6-alkynyl, C1-4-alkyl-O, RN1RN2N—, heterocyclyl, phenyl, heteroaryl and heteroaryl-CH2—,
wherein RN1 is selected from the group consisting of: H and CH3; and
wherein RN2 is selected from the group consisting of: H, cyclopropyl, pyridinyl and pyrimidinyl; and
wherein in each heterocyclyl a —CH2-group may optionally be replaced by —C(═O)—, and
wherein each alkyl, cycloalkyl, heterocyclyl and heteroaryl group may be optionally substituted with one to three F atoms and/or with one or two substituents independently selected from the group consisting of: Cl, CN, OH, CF3, CH3, —O—CH3 and —NH—(C═O)—CH3; and
wherein each heterocyclyl is selected from the group consisting of: azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl and 3H-pyrimidin-4-onyl; and
wherein each heteroaryl is selected from the group consisting of: pyrrolyl, furanyl, furazanyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl and pyrimidinyl;

or a pharmaceutically acceptable salt thereof.

9. A compound according to claim 1, wherein
Ar1 is selected from a group consisting of:





which are each optionally substituted with one or two substituents independently selected from F and Cl;

R1 is selected from a group consisting of:




R2a is H;
R2b is CH3;
R3 is H; and
R4 is selected from a group consisting of:
—CH3, —CH2CH3, —CH2—CH═CH2, —CF2—CH3, —CH2—CF3, —N(CH3)2,




or a pharmaceutically acceptable salt thereof.

10. A compound according to claim 8 or 9, wherein
R1 is —OCH2CH3.

11. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

12. method for treating obesity, diabetes or dyslipidemia in a patient suffering from one of said conditions which method comprises administering to said patient a therapeutically effective amount of a compound according to claim 1.