WO2013098373A1 - New azetidine derivatives, pharmaceutical compositions and uses thereof - Google Patents

New azetidine derivatives, pharmaceutical compositions and uses thereof Download PDF

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Publication number
WO2013098373A1
WO2013098373A1 PCT/EP2012/077025 EP2012077025W WO2013098373A1 WO 2013098373 A1 WO2013098373 A1 WO 2013098373A1 EP 2012077025 W EP2012077025 W EP 2012077025W WO 2013098373 A1 WO2013098373 A1 WO 2013098373A1
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alkyl
group
heterocyclyl
cycloalkyl
heteroaryl
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PCT/EP2012/077025
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French (fr)
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Bernd Nosse
Martin Fleck
Gerald Juergen Roth
Niklas Heine
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Boehringer Ingelheim International Gmbh
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Priority to EP12813885.6A priority Critical patent/EP2797885B1/en
Priority to JP2014549478A priority patent/JP6130398B2/en
Publication of WO2013098373A1 publication Critical patent/WO2013098373A1/en

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Definitions

  • This invention relates to new compounds, in particular piperidine 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.
  • 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.
  • 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; DB Savage, KF Petersen, Gl 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.
  • malonyl-CoA is also described to act centrally to control food intake, and may play an important role in controlling insul in secretion from the pancreas (GD Lopaschuk, JR Ussher, JS Jaswal. Pharmacol Rev. 2010;62(2):237- 64; D Saggerson Annu Rev Nutr. 2008;28:253-72), further coordinating the regulation of intermediary metabolism.
  • 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 (SJ Wakil and LA Abu-Elheiga, J . Lipid Res. 2009. 50: S1 38-S143; L. Tong, HJ Harwood Jr. Journal of Cellular Biochemistry 99:1476-1488, 2006).
  • 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, HJ Harwood Jr. Journal of Cellular Biochemistry 99: 1476-1 488 , 2006 ; Corbett JW, Harwood J H J r. , Recent Pat Cardiovasc Drug Discov. 2007 Nov;2(3):162-80).
  • NASH nonalcoholic steatohepatitis
  • ACC inhibitors are also considered as interesting drugs for the treatment of type 1 diabetes.
  • 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, DF Liao, D Cao Front Biosci 2010; 2:515-26).
  • ACC1 associates with and is regulated by the breast cancer susceptibility gene 1 (BRCA1 ).
  • BRCA1 breast cancer susceptibility gene 1
  • ketone bodies can provide neuroprotective effects in models of Parkinson's disease, AD, hypoxia, ischemia, amyotrophic lateral sclerosis and glioma (LC Costantini, LJ Barr, JL Vogel, ST Henderson BMC Neurosci. 2008, 9 Suppl 2:S16) and improved cognitive scores in Alzheimers Diseases patients (MA Reger, ST Henderson, C Hale, B Cholerton, LD Baker, GS Watson, K Hydea, D Chapmana, S Craft Neurobiology of Aging 25 (2004) 31 1-314).
  • 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.
  • HCMV and influenza A divergent enveloped viruses
  • 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.
  • ACC inhibitors acting on key enzymes in the fatty acid metabolism have the potential to be antiviral drugs.
  • 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.
  • the present invention provides a compound of general formula (I)
  • Ar 1 is selected from the group Ar 1 -G1 consisting of:
  • R A is selected from the group R A -G1 consisting of :
  • R 1 is selected from the group R 1 -G1 consisting of:
  • Ar 2 is selected from the group Ar 2 -G1 consisting of:
  • R 2a and R 2b are each independently selected from the group R 2 -G1 consisting of:
  • R 3 is selected from the group R 3 -G1 consisting of: H and Ci -4 -alkyl;
  • R 4 is selected from the group R 4 -G1 consisting of:
  • each alkyl group may be optionally substituted with one R 5 ; is selected from the group R N2 -G1 consisting of:
  • each alkyl may be optionally substituted with one or more F- atoms and/ or with a substituent selected from OH, Ci-3-alkyl-O- and CN; and wherein two substituents R 5 attached to an aryl or heteroaryl group may be linked to each other and form a C 2 -5-alkylene bridging group in which one or two -CH 2 -groups may be replaced by a group independently of each other selected from O, S, NH and N(Ci -4
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • the group Ar 1 is preferably selected from the group Ar 1 -G1 as defined hereinbefore and hereinafter.
  • Ar 1 -G2 In one embodiment the group Ar 1 is selected from the group Ar 1 -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 R A .
  • the group Ar 1 is selected from the group Ar 1 -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 R A .
  • the group Ar 1 is selected from the group Ar 1 -G3a consisting of: phenylene and pyridinylene, which may be substituted with one or two R A .
  • the group Ar 1 is selected from the group Ar 1 -G3b consisting of: phenylene, which may be substituted with one or two R A .
  • group Ar 1 is selected from the group Ar 1 -G4 consisting of:
  • each of the before mentioned groups is optionally substituted with one or two substituents R A .
  • group Ar 1 is selected from the group Ar 1 -G4a consisting of:
  • the roup Ar 1 is selected from the group Ar 1 -G5 consisting of:
  • group Ar 1 is selected from the group Ar 1 -G5a consisting of:
  • group Ar 1 is selected from the group Ar 1 -G6 consisting of:
  • group Ar 1 is selected from the group Ar 1 -G7 consisting of:
  • the group Ar 1 is selected from the group Ar 1 -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 R 1 .
  • group Ar 1 is selected from the group Ar 1 -G9 consisting of:
  • the group R A is preferably selected from the group R A -G1 as defined hereinbefore and hereinafter.
  • the group R A is selected from the group R A -G3 consisting of: H, F, CI, CN, OH, Ci.s-alkyI and Ci -3 -alkyl-O-.
  • the group R A is selected from the group R A -G4 consisting of: H, F, CI, CN, -CH 3 and -OCH 3 .
  • the group R A is selected from the group R A -G5 consisting of: F and CI.
  • the group R 1 is preferably selected from the group R 1 -G1 as defined hereinbefore and hereinafter.
  • the group R 1 is selected from the group R 1 -G2 consisting of: H, OH, Ci -4 -alkyl, Ci -4 -alkyl-O-, C3-7-cycloalkyl, C3-7-cycloalkyl-O-, tetrahydrofuranyl- O-, C 3- 7-cycloalkyl-Ci -3 -alkyl-O-, H 2 N-, (Ci -4 -alkyl)NH-, (Ci -4 -alkyl) 2 N-, C 3-7 -cycloalkyl- NH- , C 3- 7-cycloalkyl-N(Ci -4 -alkyl)-, phenyl, phenyl-Ci -3 -alkyl-, phenyl-Ci -3 -alkyl-O-, piperidinyl, morpholinyl, pyrrolidinyl and pyrrolyl, wherein each alkyl and cycloal
  • the group R 1 is selected from the group R 1 -G3 consisting of: H, Ci -4 -alkyl, Ci -4 -alkyl-O-, C3-6-cycloalkyl, C3-6-cycloalkyl-O-, tetrahydrofuranyl-O-, C 3- 6-cycloalkyl-CH 2 -O-, (Ci -4 -alkyl)NH-, (Ci -4 -alkyl) 2 N-, phenyl, benzyl, phenyl-CH 2 -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 CH 3 .
  • the group R 1 is selected from the group R 1 -G4 consisting of: Ci -4 -alkyl, Ci -4 -alkyl-O-, C3-5-cycloalkyl, C3-5-cycloalkyl-O-, tetrahydrofuranyl-O-, C3-5- cycloalkyl-CH 2 -O-, (Ci -4 -alkyl) 2 N-, phenyl, benzyl, phenyl-CH 2 -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 CH 3 .
  • the group R 1 is selected from the group R 1 -G4a consisting of: Ci-4-alkyl-O-, C 3-5 -cycloalkyl-O-, C 3-5 -cycloalkyl-CH 2 -O-, wherein each alkyl and cycloalkyl may be optionally substituted with one to three F atoms.
  • the group R 1 is selected from the group R 1 -G4b consisting of: Ci -4 -alkyl, Ci -4 -alkyl-O-, Cs-5-cycloalkyl, Cs-5-cycloalkyl-O-, tetrahydrofuranyl-O-, cyclopropyl-CH 2 -O-, (Ci -4 -alkyl) 2 N-, piperidinyl, pyrrolidinyl and morpholinyl, wherein each alkyl and cycloalkyl is optionally substituted with one to three F atoms or one OH or -O-CH3, and wherein piperidinyl is optionally substituted with one CH 3 .
  • the group R 1 is selected from the group R 1 -G4c consisting of: Ci -4 -alkyl-O-, cyclopropyl-CH 2 -O- and tetrahydrofuranyl-O-, wherein each alkyl and the cyclopropyl groups are optionally substituted with one to three F atoms.
  • group R 1 is selected from the group R 1 -G5a consisting of:
  • the group R 1 is selected from the group R 1 -G5b consisting of: -N(CH 3 ) 2 , -CHF 2 and -C(CH 3 ) 3 .
  • group R 1 is selected from the group R 1 -G5c consisting of:
  • the group R 1 is selected from the group R 1 -G6 consisting of: CH3CH2-O- and cyclopropyl-CH 2 -O-, wherein the ethyl and cycloalkyl may be optionally substituted with one to three F atoms.
  • the group R 1 is selected from the group R 1 -G6a consisting of: CH3CH2-O- and cyclopropyl-CH 2 -O-.
  • group R 1 is selected from the group R 1 -G6b consisting of: CH3CH2-O- .
  • Ar 2 is selected from the group R 1 -G6b consisting of: CH3CH2-O- .
  • the group Ar 2 is preferably selected from the group Ar 2 -G1 as defined hereinbefore and hereinafter.
  • the group Ar 2 is selected from the group Ar 2 -G2 consisting of: phenylene and pyridinylene, which may be optionally substituted with one or two substituents R A .
  • the group Ar 2 is selected from the group Ar 2 -G2a consisting of: phenylene.
  • group Ar 2 is selected from the group Ar 2 -G3 consisting of: wherein the before mentioned group may be optionally substituted with one substituent R A .
  • group Ar 2 is selected from the group Ar 2 -G3a consisting of:
  • the groups R 2a and R 2b are each preferably selected from the group R 2 -G1 defined hereinbefore and hereinafter.
  • R 2 -G2 In another embodiment the groups R 2a and R 2b are each independently selected from the group R 2 -G2 consisting of: H and CH 3 .
  • the groups R 2a and R 2b are selected from the group R 2 -G3 consisting of: R 2a being H, and R 2b being CH 3 .
  • the group R 3 is preferably selected from the group R 3 -G1 as defined hereinbefore and hereinafter.
  • the group R 3 is selected from the group R 3 -G2 consisting of: H and CH 3 .
  • group R 3 is selected from the group R 3 -G3 consisting of: H.
  • the group R 4 is preferably selected from the group R 4 -G1 as defined hereinbefore and hereinafter.
  • the group R 4 is selected from the group R 4 -G3 consisting of: H, Ci -4 -alkyl, C3-6-cycloalkyl, C 4- 6-cycloalkenyl, C3-6-cycloalkyl-Ci-3-alkyl-, C 2 -6-alkenyl, C 2 -6-alkynyl, Ci-6-alkyl-O-, R N1 R N2 N-, heterocyclyl, heterocyclyl-Ci-3-alkyl-, phenyl, phenyl-Ci-3-alkyl-, heteroaryl and heteroaryl-Ci-3-alkyl-, wherein R N1 is selected from the group consisting of: H and Chalky!; and wherein R N2 is selected from the group consisting of: H, Ci -4 -alkyl, C3- 7-cycloalkyl and heteroaryl; and wherein in each cycloalkyi and heterocyclyl a -CH 2 -group may optionally be
  • the group R 4 is selected from the group R 4 -G4 consisting of: -CH3, -CH2OH, -CH2OCH3, -CH2OCH2CH3, -CH(OH)(CH 3 ), -CH2CH3,
  • group R 4 is selected from the group R 4 -G6 consisting of: methyl.
  • the group R 5 is preferably selected from the group R 5 -G1 as defined hereinbefore and hereinafter.
  • the group R 5 is selected from the group R 5 -G5 consisting of: F and CH 3 .
  • the group R N1 is preferably selected from the group R N1 -G1 as defined hereinbefore and hereinafter.
  • group R N1 is selected from the group R N1 -G2 consisting of:
  • each alkyi group may be optionally substituted with one CN.
  • the group R N1 is selected from the group R N1 -G3 consisting of: H, CH 3 and -CH 2 CN.
  • the group R N1 is selected from the group R N1 -G4 consisting of: H and CH 3 . pN2.
  • the group R is preferably selected from the group R -G1 as defined hereinbefore and hereinafter.
  • R N2 is selected from the group R N2 -G2 consisting of: H, Ci -4 -alkyl, C 3-7 -cycloalkyl and heteroaryl.
  • R N2 -G3 :
  • the group R N2 is selected from the group R N2 -G3 consisting of: H, Ci-3-alkyl, cyclopropyl, pyridinyl and pyrimidinyl.
  • the group R is selected from the group R -G3a consisting of: Ci-3-alkyl, cyclopropyl, pyridinyl and pyrimidinyl.
  • Preferred embodiments of the above formulae (1.1 ) to (I.5) according to the present invention are set forth in the following table, wherein each group Ar 1 , R 1 and R 4 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:
  • a preferred embodiment of the present invention concerns those compounds of general formula (I), wherein Ar 1 is selected from the roup Ar 1 -G4a consisting 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 R 1 , and in addition each of the before mentioned groups is optionally substituted with one or two F or CI atoms;
  • R 1 is selected from the group R 1 -G4 consisting of:
  • Ar 2 is selected from the group Ar 2 -G3a consisting of:
  • R ⁇ a is H
  • R 2b is CH 3 ;
  • R 3 is H
  • a more preferred embodiment of the present invention concerns those compounds of general formula (I), wherein Ar 1 is selected from the group Ar 1 -G5 consisting of:
  • R 1 is selected from the roup R 1 -G5a consisting of:
  • R 1 is -OCH 2 CH 3 ;
  • Ar 2 is selected from the group Ar 2 -G3a consisting of:
  • R a is H
  • R 2b is CH 3 ;
  • R 3 is H
  • R 4 is selected from the group R 4 -G5 consisting of:
  • 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 CI, 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.
  • Z is a leaving group which for example denotes mesylate or tosylate.
  • 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.
  • coupling reagents such as e.g. TBTU, HATU or CDI.
  • acid chlorides (R 4 COCI) can be directly coupled with the respective amines (VI).
  • Compounds of general formula (la) 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.
  • coupling reagents such as CDI, CDT or 4- nitrophenyl chloroformate.
  • carbamoyl chlorides (IX) or isocyanates (X) can be used as coupling partners for amines (VI).
  • heteroaryls wherein X is a leaving group and for example denotes CI or Br.
  • halogenides (XI) with alcohols (XII) can be used, wherein X for example denotes CI or Br.
  • compound(s) according to this invention 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.
  • treatment and “treating” embraces both preventative, i.e. prophylactic, or therapeutic, i.e. curative and/or palliative, treatment.
  • 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.
  • 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.
  • treatment and “treating” comprise prophylactic treatment, i.e. a treatment of patients at risk to develop a condition mentioned hereinbefore, thus reducing said risk.
  • this invention refers to patients requiring treatment, it relates primarily to treatment in mammals, in particular humans.
  • terapéuticaally 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.
  • modulated refers to the inhibition of acetyl-CoA carboxylase(s) (ACC) with one or more compounds of the present invention.
  • mediated 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.
  • substituted 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.
  • Ci-6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
  • the last named subgroup is the radical attachment point, for example, the substituent "aryl-Ci-3-alkyl-" means an aryl group which is bound to a Ci-3-alkyl- group, the latter of which is bound to the core or to the group to which the substituent is attached.
  • 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.
  • 3-carboxypropyl-group represents the following substituent:
  • the asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
  • each X, Y and Z group is optionally substituted with
  • 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.
  • R ex denotes H, Ci-3-alkyl, C3-6- cycloalkyl, C3-6-cycloalkyl-Ci-3-alkyl or Ci-3-alkyl-O-, wherein each alkyl group is optionally substituted with one or more L ex .” or the like means that in each of the beforementioned groups which comprise the term alkyl, i.e. in each of the groups Ci- 3-alkyl, C3-6-cycloalkyl-Ci-3-alkyl and Ci-3-alkyl-O-, the alkyl moiety may be substituted with L ex as defined.
  • bicyclic includes spirocyclic.
  • 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
  • phrases "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.
  • 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.
  • 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.
  • halogen generally denotes fluorine, chlorine, bromine and iodine.
  • n is an integer from 1 to n, either alone or in
  • Ci -5 -alkyl embraces the radicals H 3 C-, H 3 C-CH 2 -, H 3 C-CH 2 -CH 2 -, H 3 C-CH(CH 3 )-, H 3 C-CH2-CH 2 -CH 2 -, H 3 C-CH 2 -CH(CH 3 )-, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-C(CH 3 ) 2 -, H 3 C-CH 2 -CH 2 -CH 2 -CH 2 -, H 3 C-CH 2 -CH 2 -CH(CH 3 )-, H 3 C-CH 2 -CH(CH 3 )-, H 3 C-CH 2 -CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -, H 3 C-CH(CH 3 )-CH 2 -,
  • 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.
  • Ci -4 -alkylene includes -(CH 2 )-, -(CH 2 -CH 2 )-, -(CH(CH 3 ))-, -(CH 2 -CH 2 -CH 2 )-, -(C(CH 3 ) 2 )-, - (CH(CH 2 CH 3 ))-, -(CH(CH 3 )-CH 2 )-, -(CH 2 -CH(CH 3 ))-, -(CH 2 -CH 2 -CH 2 -CH 2 )-, -(CH 2 - CH 2 -CH(CH 3 ))-, -(CH(CH 3 )-CH 2 -CH 2 )-, -(CH 2 -CH(CH 3 )-CH 2 )-, -(CH 2 -CH(CH 3 )-CH 2 )-, -(CH 2 -C(CH 3 ) 2 )-, -(C (CH 3 ) 2 -CH 2
  • C 2-n -alkenyl is used for a group as defined in the definition for "Ci -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.
  • C 2-n -alkenylene is used for a group as defined in the definition for
  • Ci-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.
  • C 2-n -alkynyl is used for a group as defined in the definition for "Ci -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.
  • C 2 -3-alkynyl includes -C ⁇ CH, -C ⁇ C-CH 3 , -CH 2 -C ⁇ CH .
  • C 2-n -alkynylene is used for a group as defined in the definition for
  • Ci-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.
  • C 2 -3- alkynylene includes -C ⁇ C-, -C ⁇ C-CH 2 -, -CH 2 -C ⁇ C-.
  • 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 is preferably nonaromatic.
  • the 3 to n C atoms form one or two rings.
  • the rings may be attached to each other via a single bond or may be fused or may form a spirocydic or bridged ring system.
  • C3-io-carbocyclyl includes C3-io-cylcoalkyl, C3-io-cycloalkenyl,
  • C3 -n -carbocyclyl denotes C3 -n -cylcoalkyl, in particular C3-7-cycloalkyl.
  • C3 -n -cycloalkyl wherein n is an integer 4 to n, either alone or in
  • the cyclic group may be mono-, bi-, tri- or spirocydic, most preferably monocyclic.
  • Examples of such cycloalkyi groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclododecyl, bicyclo[3.2.1 .]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl, etc.
  • 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.
  • C3 -7 -cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl and cycloheptatrienyl.
  • aryl 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.
  • heterocyclyl is intended to include all the possible isomeric forms.
  • heterocydyl 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:
  • heteroaryl is intended to include all the possible isomeric forms.
  • 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:
  • fluorinated alkyl groups are fluoromethyl, difluoromethyl and trifluoromethyl.
  • Preferred fluorinated alkoxy resp. alkyl-O- groups are fluoromethoxy, difluoromethoxy and trifluoromethoxy
  • 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.
  • 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.
  • DMSO dimethyl sulfoxide
  • 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 KHCO 3 , 10 mM MgCI 2 , 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 200 ⁇ 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').
  • %CTL (S(compound)-S('LOW'))/(S('HIGH')- S('LOW')) * 100.
  • Compounds will give values between 100%CTL (no inhibition) and 0%CTL (complete inhibition).
  • the compounds of general formula (I) according to the invention for example have IC 5 0 values below 10000 nM, particularly below 1000 nM, preferably below 300 nM.
  • 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.
  • the present invention relates to a compound of general formula (I) as a 5 medicament.
  • 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 D patient, preferably in a human.
  • 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, 5 preferably a human, in need of such treatment a therapeutically effective amount of a compound of the present invention, or a pharmaceutical composition thereof.
  • acetyl-CoA carboxylases embrace metabolic and/or cardiovascular and/or neurodegenerative diseases or conditions.
  • 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 ishyperglycemia, metabolic syndrome, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic
  • retinopathy 5 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-
  • 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.
  • visceral anterior obesity
  • NAFLD nonalcoholic fatty liver disease
  • obesity related disorders such as for example weight gain or weight maintenance.
  • BMI body mass index
  • Overweight is typically defined as a BMI of 25-29.9 kg/m 2
  • obesity is typically defined as a BMI of 30 kg/m 2 or greater.
  • the compounds of the present invention are particularly suitable for treating, inclduing 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
  • 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
  • Atherosclerosis coronary heart disease, cerebrovascular disorders, diabetes mellitus, metabolic syndrome, obesity, insulin resistance and/or cardiovascular disorders.
  • D compounds of the present invention may be suitable for treating eating disorders
  • 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.
  • inhibitors of acetyl-CoA carboxylases 5 embrace but are not limited to:
  • disorders of fatty acid metabolism and glucose utilization disorders disorders in which insulin resistance is involved;
  • D B hepatic disorders and conditions related thereto, including:
  • NASH steatohepatitis
  • alcoholic hepatitis acute fatty liver, fatty liver of pregnancy, drug-induced hepatitis, iron storage diseases, hepatic fibrosis, hepatic cirrhosis, hepatoma, viral hepatitis;
  • apoCII or apoE deficiency familial histiocytic reticulosis, lipoprotein lipase deficiency, hyperlipoproteinemias, 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;
  • - 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),
  • coronary sclerosis including angina pectoris or myocardial infarction
  • stroke ischemic
  • stroke transient ischemic attack
  • - 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
  • Alzheimer's disease including Alzheimer's disease, multiple sclerosis, D Parkinson's disease, epilepsy,
  • erythemato-squamous dermatoses such as, for example, psoriasis
  • - 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,
  • - 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 (W), 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
  • 5 - skin cancer such as, for example, basal-cell carcinomas, melanomas or
  • PCOS polycystic ovary syndrome
  • L 5 - lupus erythematosus (LE) or inflammatory rheumatic disorders such as, for example rheumatoid arthritis,
  • ARDS acute respiratory distress syndrome
  • lipid myopathis such as carnitine palmitoyltransferase I or II deficiency
  • 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 5 will be administered at dosages and in a manner which allows a therapeutically
  • Suitable preparations for administering the compounds of formula (I) will be apparent D 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.
  • excipients for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants.
  • the tablets may also consist of several layers.
  • the compounds of the invention may further be combined with one or more, preferably one additional therapeutic agent.
  • the additional therapeutic agent is selected from the group of therapeutic agents useful in 5 the treatment of diseases or conditions associated with metabolic diseases or
  • diabetes mellitus a condition such as for example diabetes mellitus, obesity, diabetic complications, hypertension, hyperlipidemia.
  • a compound of the invention may be combined with one or more additional D therapeutic agents selected from the group consisting of anti-obesity agents
  • agents which lower blood glucose include appetite suppressants, agents which lower blood glucose, anti-diabetic agents, agents for treating dyslipidemias, such as lipid lowering agents, antihypertensive 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 1 1 beta-hydroxy steroid dehydrogenase-1 5 (1 1 beta-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 D antagonists, lipase inhibitors, anorectic agents, neuropeptide-Y antagonists (e.g., NPY Y5 antagonists), ⁇ 3-36 (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 5 O-Acyltransferase) inhibitors, histamine 3 antagonists or inverse agonists,
  • leptin the OB protein
  • leptin analogs leptin agonist
  • MTP/ApoB inhibitors e.g., gut-selective MTP inhibitors
  • opioid antagonists e.g., opioid antagonists, orexin antagonists, and the like.
  • Preferred anti-obesity agents for use in the combination aspects of the present D 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 1 1 beta-hydroxy steroid dehydrogenase-1 (1 1 beta-HSD type 1 ) inhibitors, phosphodiesterase (PDE) 10 inhibitors, diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitors, sulfonylureas (e.g., acetohexamide, chlorpropamide, diabinese,
  • PDE phosphodiesterase
  • DGAT diacylglycerol acyltransferase
  • sulfonylureas e.g., acetohexamide, chlorpropamide, diabinese
  • glibenclamide glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone,
  • D 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
  • 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, voglibo
  • 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 e.g., glucagon-like peptide 1 (GLP-1 ) agonists (e.g., ByettaTM, exendin-3 and exendin-4), GLP-1 receptor and
  • PTP-1 B protein tyrosine phosphatase-1 B inhibitors
  • 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 GPR1 19 agonists
  • GPR40 agonists TGR5
  • D 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.
  • Ghrelin O-Acyltransferase Ghrelin O-Acyltransferase
  • fatty acid oxidation inhibitors A2 antagonists
  • JNK c-jun amino-terminal kinase
  • 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, 1 1 beta-hydroxy steroid
  • dehydrogenase-1 (1 1 beta-HSD type 1 ) inhibitors and DPP-IV inhibitors e.g.
  • 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 5 and/or a diet.
  • 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 D 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.
  • 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 5 compound of the present invention in combination with a therapeutically effective amount of one or more additional therapeutic agents described in hereinbefore and hereinafter,
  • D 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- 5 called kit-of-parts.
  • 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 D together with one or more inert carriers and/or diluents.
  • 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
  • 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
  • D invention relates to an agricultural composition
  • an agricultural composition comprising a compound of the
  • 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.
  • ambient temperature and “room temperature” are used interchangeably and designate a temperature of about 20 °C.
  • Example I.2 The following compounds are prepared analogously to Example 1.1 : Example I.2
  • Example IV.2 The following compound is prepared analogously to Example IV.1 : 5 Example IV.2
  • Example V.2 The following compound is prepared analogously to Example V.1 : Example V.2
  • step b no column chromatography was conducted and the desired product obtained as a HCI-salt.
  • Reagent in step a) 4-benzyloxy-1 H-pyhdin-2-one; DMSO is used as solvent and reaction conditions are 2 days at 70 °C.
  • step b no column chromatography was conducted and the desired product was obtained as a HCI-salt.
  • step b) HCI in methanol was used for deprotection and no column chromatography was conducted. The desired product was obtained as a HCI-salt.
  • Example XI.2 The following compound is prepared analogously to Example XI.1 : Example XI.2
  • Example 7.2 is prepared analogously to 7.1 .
  • (Sj-Cyclopropanecarboxylic acid [1 -(4- bromo-phenyl)-ethyl]-amide (I.2) is used as starting material .
  • Example 8.2 is prepared analogously to 8.1 .
  • (S)-1 H-Pyrazole-4-carboxylic acid [1 -(4- bromo-phenyl)-ethyl]-amide (I.5) is used as starting material .
  • Example 8.3 is prepared analogously to 8.1 .
  • (S)-[1 -(4-Bromo-phenyl)-ethyl]-carbamic acid terf-butyl ester (I.3) and 3-(4-cyclopropylmethoxy-phenoxy)-azetidine (IX.1 ) are used as starting materials and the reaction temperature is 45 °C.
  • 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 .
  • C 2 6H 2 9FN 4 O 4 S (M 512.6 g/mol)
  • Example 8.5 is prepared analogously to 8.1 .
  • 3-(4-Benzyloxy-phenoxy)-azetidine and ( , Sj-/V-[1 -(4-bromo-phenyl)-ethyl]-acetamide (1.1 ) are used as starting materials. Reaction conditions are stirring for 2 days at 30 °C.
  • Example 8.6 is prepared analogously to 8.1 .
  • (A/-[1 -(6-Bromo-pyridin-3-yl)-ethyl]- acetamide (1.4) and 3-(4-ethoxy-phenoxy)-azetidine are used as starting materials.
  • C2oH 2 5N 3 O3 (M 355.4 g/mol)
  • Example 8.7 is prepared analogously to 8.1 .
  • 2-(Azetidin-3-yloxy)-4-benzyloxy- pyridine (IX.3) and (S)-/V-[1 -(4-bromo-phenyl)-ethyl]-acetamide (1.1 ) are used as D starting materials.
  • Example 8.8 is prepared analogously to 8.1 .
  • 2-(Azetidin-3-yloxy)-5-trifluoromethyl- pyridine and (S)-/V-[1 -(4-bromo-phenyl)-ethyl]-acetamide (1.1 ) are used as starting materials. Reaction conditions are stirring for 12 h at 50 °C.
  • Example 13.2 is prepared analogously to 13.1 . 4-Bromo-2-pyrrolidin-1 -yl-pyrimidine is used as starting material.
  • Example 14.2 is prepared analogously to 14.1 . 6-Trifluoromethyl-pyridin-2-ol is used as starting material .
  • Example 14.2 is prepared analogously to 14.1 .
  • 2-Methyl-pyrimidin-4-ol is used as starting material .

Abstract

The invention relates to new azetidine derivatives of the formula (I) to their use as medicaments, to methods for their therapeutic use and to pharmaceutical compositions containing them.

Description

New azetidine derivatives, pharmaceutical compositions and uses thereof Field of the invention
This invention relates to new compounds, in particular piperidine 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; DB Savage, KF Petersen, Gl 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 insul in secretion from the pancreas (GD Lopaschuk, JR Ussher, JS 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 (SJ Wakil and LA Abu-Elheiga, J . Lipid Res. 2009. 50: S1 38-S143; L. Tong, HJ 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, HJ Harwood Jr. Journal of Cellular Biochemistry 99: 1476-1 488 , 2006 ; Corbett JW, Harwood J H J r. , Recent Pat Cardiovasc Drug Discov. 2007 Nov;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, Bl Freedmann, JS Parks, PA Antinozzi, SC Elbein, LM 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, Bl Freedmann, JS Parks, PA Antinozzi, SC Elbein, LM 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 (IE Schauer, JK Snell-Bergeon, BC Bergman, DM Maahs, A Kretowski, RH Eckel, M Rewers Diabetes 201 1 ;60:306-14; P Ebeling, B Essen-Gustavsson, JA Tuominen and VA Koivisto Diabetologia 41 : 1 1 1 -1 15; KJ Nadeau, JG Regensteiner, TA Bauer, MS Brown,JL Dorosz, A Hull, P Zeitler, B Draznin, JEB. 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, DF 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 in h ibited g rowth and induced apoptosis in d ifferent types of cancer cel l s . 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, DF Liao, D Cao Front Biosci 2010; 2:515-26).
Furthermore in central nervous system d isorders includ ing but not l im ited to Alzheimer's disease, Parkinson disease and epilepsy, impairements in neuronal energy metabol ism have been described (Ogawa M, Fu kuyama H , Ouch i 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 (ST Henderson Neurotherapeutics, 2008, 5:470-480; LC Costantini, LJ Barr, JL Vogel, ST Henderson BMC Neurosci. 2008, 9 Suppl 2:S16; KW Barahano, AL 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 (LC Costantini, LJ Barr, JL Vogel, ST Henderson BMC Neurosci. 2008, 9 Suppl 2:S16) and improved cognitive scores in Alzheimers Diseases patients (MA Reger, ST Henderson, C Hale, B Cholerton, LD Baker, GS Watson, K Hydea, D Chapmana, S Craft Neurobiology of Aging 25 (2004) 31 1-314). The end resu lt of increased ketone levels is an improvement in mitochondrial efficiency and reduction in the generation of reactive oxygen species (for reviews see LC Costantini, LJ Barr, JL Vogel, ST Henderson BMC Neurosci. 2008, 9 Suppl 2:S1 6; KW Barahano, AL 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, HJ 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, BD Bennett, A Parikh, XJ Feng, J McArdle, HA Rabitz, T Shenk, JD Rabinowitz. Nat Biotechnol. 2008;26:1 179-86). 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)
Figure imgf000007_0001
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(Ci-4- alkyl)-, wherein the alkylene bridge may optionally be substituted by one or two Ci-3-alkyl groups;
RA is selected from the group RA-G1 consisting of :
H, F, CI, Br, I, CN, OH, -NO2, Ci-4-alkyl, C2-4-alkenyl, Ci-4-alkyl-O-, Ci-4-alkyl- C(=O)-, H2N-, H2N-C(=O)-, H2N-S(=O)2-, HO-C(=O)-, Ci-4-alkyl-O-C(=O)-, phenyl and phenyl-Ci-3-alkyl, wherein in each NH2-group, one or both hydrogen atoms may independently be replaced by Ci-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, Ci-e-alkyl, Ci-6-alkyl-O-, C3-7-cycloalkyl, C3-7-cycloalkyl-O-, C3-7- cycloalkyl-Ci-3-alkyl-O-, H2N-, (Ci-4-alkyl)NH-, (Ci-4-alkyl)2N-, C3-7-cycloalkyl- NH-, C3-7-cycloalkyl-N(Ci-4-alkyl)-, C3-7-cycloalkyl-Ci-3-alkyl-NH-, (C3-7- cycloalkyl-Ci-3-alkyl)-N(Ci-4-alkyl)-, Ci-4-alkyl-C(=O)-, Ci-4-alkyl-S(=O)2-, HO- C(=O)-, Ci-4-alkyl-O-C(=O)-, H2N-C(=O)-, (Ci-4-alkyl)HN-C(=O)-, (Ci-4- alkyl)2N-C(=O)-, aryl, aryl-Ci-3-alkyl-, aryl-Ci-3-alkyl-O-, heterocyclyl, heterocyclyl-O-, heterocyclyl-Ci-3-alkyl-O-, heteroaryl, heteroaryl-Ci-3-alkyl- and heteroaryl-Ci-3-alkyl-O-, wherein each alkyl and cycloalkyi may be optionally substituted with one or more substituents selected from F, OH and Ci-4-alkyl-O-, and wherein each heterocyclyl is optionally substituted with one or more Ci-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 Ci-3-alkyl;
R3 is selected from the group R3-G1 consisting of: H and Ci-4-alkyl; and
R4 is selected from the group R4-G1 consisting of:
H, Ci-6-alkyl, C3-io-carbocyclyl, C3-io-carbocyclyl-Ci-3-alkyl-, C2-6-alkenyl, C2-6- alkynyl, Ci-6-alkyl-O-, RN1RN2N-, heterocyclyl, heterocyclyl-Ci-3-alkyl, aryl, aryl-Ci-3-alkyl, heteroaryl and heteroaryl-Ci-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 is selected from the group RN1-G1 consisting of:
H and Ci-4-alkyl; wherein each alkyl group may be optionally substituted with one R5; is selected from the group RN2-G1 consisting of:
H, Ci-4-alkyl, C3-io-carbocyclyl, C3-io-carbocyclyl-Ci-3-alkyl, C2-6-alkenyl, C2-6- alkynyl, heterocyclyl, heterocyclyl-Ci-3-alkyl, aryl, aryl-Ci-3-alkyl, heteroaryl and heteroaryl-Ci-3-alkyl, wherein each aryl, heteroaryl, carbocyclyl and heterocyclyl may be optionally substituted with one or more Ci-4-alkyl, aryl, aryl-Ci-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 is selected from the group R5-G1 consisting of:
F, CI, Br, CN, OH, Ci-4-alkyl-, Ci-4-alkyl-O-, Ci-4-alkyl-S-, Ci-4-alkyl-S(=O)2-, H2N-, (Ci-4-alkyl)NH-, (Ci-4-alkyl)2N-, Ci-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, Ci-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(Ci-4- alkyl)-, wherein the C2-5-alkylene bridging group is optionally substituted by one or two Ci-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 RA.
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 RA.
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:
Figure imgf000014_0001
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:
Figure imgf000014_0002
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 CI atoms. Ar1-G5:
In another embodiment the roup 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 CI.
Ar1-G5a:
In another embodiment the group Ar1 is selected from the group Ar1-G5a consisting of:
Figure imgf000015_0002
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:
Figure imgf000015_0003
Ar1-G7:
In another embodiment the group Ar1 is selected from the group Ar1-G7 consisting of:
Figure imgf000016_0001
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:
Figure imgf000016_0002
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:
Figure imgf000016_0003
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-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, CI, Br, CN, OH, -NO2, Ci-4-alkyl, Ci-4-alkyl-O-, H2N-, Ci-6-alkyl-O-C(=O)-, phenyl and phenyl-CH2-, wherein in each NH2-group, one or both hydrogen atoms may independently be replaced by Ci-4-alkyl.
RA-G3:
In another embodiment the group RA is selected from the group RA-G3 consisting of: H, F, CI, CN, OH, Ci.s-alkyI and Ci-3-alkyl-O-.
RA-G4:
In another embodiment the group RA is selected from the group RA-G4 consisting of: H, F, CI, CN, -CH3 and -OCH3.
RA-G5:
In another embodiment the group RA is selected from the group RA-G5 consisting of: F and CI.
El
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, Ci-4-alkyl, Ci-4-alkyl-O-, C3-7-cycloalkyl, C3-7-cycloalkyl-O-, tetrahydrofuranyl- O-, C3-7-cycloalkyl-Ci-3-alkyl-O-, H2N-, (Ci-4-alkyl)NH-, (Ci-4-alkyl)2N-, C3-7-cycloalkyl- NH- , C3-7-cycloalkyl-N(Ci-4-alkyl)-, phenyl, phenyl-Ci-3-alkyl-, phenyl-Ci-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 Ci-4-alkyl-O-, and wherein piperidinyl is optionally substituted with one or two Ci-3-alkyl. R1-G3:
In another embodiment the group R1 is selected from the group R1-G3 consisting of: H, Ci-4-alkyl, Ci-4-alkyl-O-, C3-6-cycloalkyl, C3-6-cycloalkyl-O-, tetrahydrofuranyl-O-, C3-6-cycloalkyl-CH2-O-, (Ci-4-alkyl)NH-, (Ci-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: Ci-4-alkyl, Ci-4-alkyl-O-, C3-5-cycloalkyl, C3-5-cycloalkyl-O-, tetrahydrofuranyl-O-, C3-5- cycloalkyl-CH2-O-, (Ci-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: Ci-4-alkyl-O-, 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: Ci-4-alkyl, Ci-4-alkyl-O-, Cs-5-cycloalkyl, Cs-5-cycloalkyl-O-, tetrahydrofuranyl-O-, cyclopropyl-CH2-O-, (Ci-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-CH3, 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: Ci-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 gro nsisting of:
H, -CH3, -CF3, -OCH3, -OCF3,
Figure imgf000019_0001
Figure imgf000019_0002
R1-G5a:
In another embodiment the group R1 is selected from the group R1-G5a consisting of:
Figure imgf000020_0001
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:
Figure imgf000020_0002
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:
Ai^-GI :
The group Ar2 is preferably selected from the group Ar2-G1 as defined hereinbefore and hereinafter.
Ar2^:
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.
Ar^a:
In another embodiment the group Ar2 is selected from the group Ar2-G2a consisting of: phenylene.
Ar2^:
In another embodiment the group Ar2 is selected from the group Ar2-G3 consisting of:
Figure imgf000021_0001
wherein the before mentioned group may be optionally substituted with one substituent RA.
Ai^-GSa:
In another embodiment the group Ar2 is selected from the group Ar2-G3a consisting of:
Figure imgf000021_0002
FT1 and R ,2b
R2-G1 :
The groups R2a and R2b are each preferably selected from the group R2-G1 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.
E
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.
E i
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, Ci-4-alkyl, C3-7-cycloalkyl, C4-7-cycloalkenyl, C3-7-cycloalkyl-Ci-3-alkyl, C2-6-alkenyl, C2-6-alkynyl, Ci-6-alkyl-O-, RN1RN2N-, heterocyclyl, heterocyclyl-Ci-3-alkyl, phenyl, phenyl-Ci-3-alkyl, heteroaryl and heteroaryl-Ci-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, Ci-4-alkyl, C3-6-cycloalkyl, C4-6-cycloalkenyl, C3-6-cycloalkyl-Ci-3-alkyl-, C2-6-alkenyl, C2-6-alkynyl, Ci-6-alkyl-O-, RN1RN2N-, heterocyclyl, heterocyclyl-Ci-3-alkyl-, phenyl, phenyl-Ci-3-alkyl-, heteroaryl and heteroaryl-Ci-3-alkyl-, wherein RN1 is selected from the group consisting of: H and Chalky!; and wherein RN2 is selected from the group consisting of: H, Ci-4-alkyl, C3- 7-cycloalkyl and heteroaryl; and wherein in each cycloalkyi and heterocyclyl a -CH2-group may optionally be replaced by -C(=O)-, and wherein each alkyl, cycloalkyi, heterocyclyl, aryl and heteroaryl group may be optionally substituted with one to three substituents independently selected from the group consisting of: F, CI, CN, OH, CF3, Ci-3-alkyl, -O-(Ci-3-alkyl) and -NH-(C=O)-Ci-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: Ci-4-alkyl, Cs-5-cycloalkyl, cyclopentenyl, C3-5-cycloalkyl-CH2-, C3-5-alkenyl, C3-6- alkynyl, Ci-4-alkyl-O-, RN1 RN2N-, 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, Ci-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: CI, 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,
Figure imgf000025_0001
-25-
Figure imgf000026_0001
R4-G5:
In another embodiment the group R4 is selected from the group R4-G5 consisting of: - -CH2CH3, -CH2-CH=CH2, -CF2-CH3, -CH2-CF3, -N(CH3)2,
Figure imgf000027_0001
R4-G6:
In another embodiment the group R4 is selected from the group R4-G6 consisting of: methyl.
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, CI, Br, CN, OH, Ci-4-alkyl-, Ci-4-alkyl-O- and Ci-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, CI, CN, OH, CF3, Ci-3-alkyl, -O-(Ci-3-alkyl) and -NH-(C=O)-Ci-3-alkyl.
R5-G4: In another embodiment the group R5 is selected from the group R5-G4 consisting of: F, CI, CN, OH, CF3,CH3, -O-CH3 and -NH-(C=0)-CH3.
R5-G5:
In another embodiment the group R5 is selected from the group R5-G5 consisting of: F and CH3.
)N1.
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 Ci-3-alkyl, wherein each alkyi group may be optionally substituted with one CN.
RN1-G3:
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. pN2.
The group R is preferably selected from the group R -G1 as defined hereinbefore and hereinafter.
RN2-G2:
In another embodiment the group RN2 is selected from the group RN2-G2 consisting of: H, Ci-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, Ci-3-alkyl, cyclopropyl, pyridinyl and pyrimidinyl.
In another embodiment the group R is selected from the group R -G3a consisting of: Ci-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
R1 Ar1 RA Ar2 R2b R3 R4 ment
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 Embodi R2a and
R1 Ar1 RA Ar2 R2b R3 R4 ment
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 Embodi R2a and
R1 Ar1 RA Ar2 R2b R3 R4 ment
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 (1.1 ) to (1.5), wherein any tautomers and stereoisomers, solvates, hydrates and salts thereof, in particular the pharmaceutically acceptable salts thereof, are encompassed.
Figure imgf000031_0001
Figure imgf000032_0001
wherein in each of the above formulae (1.1 ) to (1.5), the groups Ar1, R1 and R4 are defined as hereinbefore and hereinafter.
Preferred embodiments of the above formulae (1.1 ) 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¬
ForbodiAr1 RA R1 R4
mula
ment
E-A (1.1 ) Ar1-G3 RA-G5 R1-G3 R4-G3
E-B (1.1 ) Ar1-G3 RA-G5 R1-G4 R4-G3a
E-C (1.1 ) Ar1-G3b RA-G5 R1-G4 R4-G3
E-D (1.1 ) Ar1-G3b RA-G5 R1-G4a R4-G3
E-E (1.1 ) Ar1-G3b RA-G5 R1-G5 R4-G3
E-F (1.1 ) Ar1-G3b RA-G5 R1-G5a R4-G3
E-G (1.1 ) Ar1-G3b RA-G5 R1-G6 R4-G3
E-H (1.1 ) Ar1-G3b RA-G5 R1-G6b R4-G3
E-l (1.1 ) Ar1-G3b RA-G5 R1-G4 R4-G3a
E-J (1.1 ) Ar1-G3b RA-G5 R1-G4 R4-G4 Em¬
ForbodiAr1 R1 R4
mula
ment
E-K (1.1 ) Ar1-G3b RA-G5 R1-G4 R4-G5
E-L (1.1 ) Ar1-G3b RA-G5 R1-G4 R4-G6
E-M (1.1 a) Ar1-G3a RA-G5 R1-G4 R4-G5
E-N (1.1 a) Ar1-G3a RA-G5 R1-G6b R4-G4
E-O (1.1 b) Ar1-G3a RA-G5 R1-G4 R4-G5
E-P (1.1 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 (l.2a) — — — R4-G2
E-V (l.2a) — — — R4-G3
E-W (l.2a) — — — R4-G3a
E-X (l.2a) — — — R4-G4
E-Y (l.2a) — — — R4-G5
E-Z (I.3) — — R1-G4b R4-G6
E-Aa (I.3) — — R1-G5b R4-G6
CH3 or
E-Ab (I.4) — — R1-G4c
*
E-Ac (I.4) — — R1-G5c R4-G6
CH3,
E-Ad (I.5) — — or 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 roup Ar1-G4a consisting of:
Figure imgf000034_0001
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 CI atoms;
R1 is selected from the group R1-G4 consisting of:
Ci-4-alkyl, Ci-4-alkyl-O-, C3-5-cycloalkyl, C3-5-cycloalkyl-O-, tetrahydrofuranyl-O-, C3-5- cycloalkyl-CH2-O-, (Ci-4-alkyl)2N-, phenyl, benzyl, phenyl-CH2-O-, piperidinyl, morpholinyl, pyrrol idinyl 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:
Figure imgf000034_0002
R^a is H;
R2b is CH3;
R3 is H; and
R4 is selected from the group R4-G3a consisting of: Ci-4-alkyl, Cs-s-cycloalkyl, cyclopentenyl, C3-5-cycloalkyl-CH2-, C3-5-alkenyl, C3-6- alkynyl, Ci-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, Ci-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, cydoalkyi, 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: CI, 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:
Figure imgf000036_0001
which are each optionally substituted with one or two substituents independently selected from F and CI;
R1 is selected from the roup R1-G5a consisting of:
Figure imgf000036_0002
preferably, R1 is -OCH2CH3;
Ar2 is selected from the group Ar2-G3a consisting of:
Figure imgf000036_0003
R a 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,
Figure imgf000036_0004
Figure imgf000037_0001
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.
Figure imgf000037_0002
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 CI, Br, I or OTf (triflate).
Figure imgf000038_0001
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.
Figure imgf000038_0002
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 (R4COCI) can be directly coupled with the respective amines (VI).
Figure imgf000038_0003
Compounds of general formula (la) 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).
Figure imgf000039_0001
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 CI or Br.
Alternatively palladium-mediated Buchwald-type reactions of (hetero)aryl
halogenides (XI) with alcohols (XII) can be used, wherein X for example denotes CI or Br.
Figure imgf000039_0002
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 CI.
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, Ci-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-Ci-3-alkyl-" means an aryl group which is bound to a Ci-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:
Figure imgf000041_0001
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 followin groups:
Figure imgf000041_0002
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, Ci-3-alkyl, C3-6- cycloalkyl, C3-6-cycloalkyl-Ci-3-alkyl or Ci-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 Ci- 3-alkyl, C3-6-cycloalkyl-Ci-3-alkyl and Ci-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 "Ci-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 Ci-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 "Ci-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 Ci-4-alkylene includes -(CH2)-, -(CH2-CH2)-, -(CH(CH3))-, -(CH2-CH2-CH2)-, -(C(CH3)2)-, - (CH(CH2CH3))-, -(CH(CH3)-CH2)-, -(CH2-CH(CH3))-, -(CH2-CH2-CH2-CH2)-, -(CH2- CH2-CH(CH3))-, -(CH(CH3)-CH2-CH2)-, -(CH2-CH(CH3)-CH2)-, -(CH2-C(CH3)2)-, -(C (CH3)2-CH2)-, -(CH(CH3)-CH(CH3))-, -(CH2-CH(CH2CH3))-, -(CH(CH2CH3)-CH2)-, -(CH(CH2CH2CH3))- , -(CHCH(CH3) 2)- and -C(CH3)(CH2CH3)-.
The term "C2-n-alkenyl", is used for a group as defined in the definition for "Ci-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
"Ci-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 "Ci-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
"Ci-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 spirocydic or bridged ring system. For example the term C3-io-carbocyclyl includes C3-io-cylcoalkyl, C3-io-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 spirocydic, most preferably monocyclic. Examples of such cycloalkyi 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)r 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)r 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, pyrrol id inonyl, piperidinonyl, piperazinonyl, morpholinonyl. Thus, the term "heterocydyl" 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:
Figure imgf000046_0001
Figure imgf000046_0002
-46 -
Figure imgf000047_0001
Figure imgf000048_0001
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:
Figure imgf000049_0001
Figure imgf000050_0001
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 MgCI2, 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 200μΜ 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 IC5o 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)AD))))).
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 (μΜ) 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 ICso [μΜ] 1.35 0.40 1.70 1.10
1.1 2.59 1.36 1.61 1.71 0.71
1.2 0.15 1.37 0.17 1.72 1.19
1.3 1.04 1.38 0.78 1.73 0.16
1.4 0.17 1.39 2.25 1.74 0.41
1.5 0.12 1.40 6.43 1.75 0.41
1.6 0.28 1.41 1.07 1.76 1.00
1.7 0.17 1.42 1.70 1.77 1.04
1.8 0.55 1.43 0.32 1.78 0.36
1.9 0.46 1.44 0.61 1.79 1.72
1.10 3.19 1.45 2.01 1.80 1.06
1.11 0.21 1.46 1.73 1.81 2.33
1.12 0.23 1.47 1.33 1.82 0.27
1.13 0.48 1.48 3.35 1.83 0.59
1.14 0.07 1.49 1.47 1.84 0.73
1.15 2.56 1.50 1.06 1.85 0.23
1.16 0.11 1.51 0.07 1.86 0.05
1.17 0.28 1.52 0.97 1.87 0.20
1.18 0.34 1.53 0.07 1.88 0.10
1.19 0.59 1.54 0.54 1.89 0.12
1.20 0.33 1.55 0.44 1.90 0.09
1.21 0.48 1.56 0.11 1.91 0.75
1.22 0.45 1.57 1.30 2.1 1.53
1.23 1.47 1.58 3.90 2.2 0.79
1.24 0.22 1.59 2.06 2.3 0.82
1.25 0.21 1.60 0.32 2.4 0.29
1.26 1.23 1.61 1.44 2.5 0.18
1.27 1.95 1.62 2.50 2.6 0.04
1.28 1.01 1.63 0.93 2.7 0.07
1.29 1.16 1.64 2.19 3.1 0.06
1.30 0.74 1.65 0.80 4.1 3.41
1.31 1.75 1.66 0.55 4.2 1.54
1.32 0.05 1.67 1.29 4.3 1.00
1.33 2.52 1.68 1.52 4.4 1.61
1.34 2.06 1.69 3.15 4.5 5.57 4.6 1.46 10.1 1.28 10.30 1.56
4.7 2.31 10.2 0.78 10.31 0.30
4.8 1.39 10.3 0.91 10.32 0.73
11.1 0.08
4.9 0.86 10.4 0.28
11.2 0.27
4.10 3.10 10.5 0.64 11.3 0.06
4.11 2.37 10.6 0.33 11.4 0.08
4.12 1.61 10.7 0.20 11.5 0.10
11.6 0.15
4.13 0.37 10.8 0.74
11.7 0.23
4.14 3.45 10.9 0.86 12.1 0.81
4.15 0.07 10.10 0.12 12.2 1.38
12.3 0.73
4.16 0.28 10.11 0.10
12.4 0.22
4.17 1.13 10.12 0.79 12.5 0.53
5.1 0.34 10.13 0.32 12.6 0.09
6.1 0.26 10.14 0.61 12.7 0.31
12.8 1.75
7.1 0.12 10.15 0.95
12.9 0.49
7.2 2.42 10.16 2.23 12.10 0.45
8.1 0.25 10.17 0.11 12.11 0.33
12.12 0.10
8.2 2.98 10.18 0.56
12.13 0.18
8.3 1.37 10.19 0.14 12.14 0.22
8.4 0.11 10.20 4.40 12.15 0.83
8.5 0.14 10.21 3.99 12.16 0.38
12.17 0.05
8.6 0.17 10.22 1.27
12.18 0.65
8.7 2.24 10.23 0.13 12.19 0.23
8.8 0.81 10.24 2.26 13.1 0.35
13.2 0.06
9.1 0.07 10.25 3.37
14.1 0.38
9.2 0.09 10.26 0.37 14.2 0.06
9.3 0.05 10.27 0.17 14.3 0.98
9.4 0.04 10.28 2.08 15.1 0.91
16.1 0.13
9.5 0.04 10.29 0.57
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 5 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 D 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, 5 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.
D
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 ishyperglycemia, metabolic syndrome, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic
5 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-
D 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 5 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.
D According to another aspect the compounds of the present invention are particularly suitable for treating, inclduing 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
5 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).
D 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
5 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 D 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 5 embrace but are not limited to:
A. disorders of fatty acid metabolism and glucose utilization disorders; disorders in which insulin resistance is involved;
D 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;
5
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 releated to mucous membrane fatty acid
D composition;
D. primary hypertriglyceridemia or secondary hypertriglyceridemias following
familial histiocytic reticulosis, lipoprotein lipase deficiency, hyperlipoproteinemias, apolipoprotein deficiency (e.g. apoCII or apoE deficiency);
5
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 D 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,
5 - chronic inflammatory bowel diseases such as, for example, Crohn's disease and ulcerative colitis,
- pancreatitis,
- sinusitis,
- retinopathy, ischemic retinopathy,
D - 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
5 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, D 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,
5 - 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,
D - 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 (W), 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,
5 - 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;
D - high blood pressure,
- polycystic ovary syndrome (PCOS),
- asthma,
- cystic fibrosis,
- osteoarthritis,
5 - lupus erythematosus (LE) or inflammatory rheumatic disorders such as, for example rheumatoid arthritis,
- vasculitis,
- wasting (cachexia),
- gout,
D - ischemia/reperfusion syndrome,
- acute respiratory distress syndrome (ARDS),
- viral diseases and infections,
- lipodystrophy and lipodystrophic conditions, also for treating adverse drug effect;
5 - myophathies and lipid myopathis (such as carnitine palmitoyltransferase I or II deficiency);
H. formation of muscles and a lean body or muscle mass formation.
D 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 5 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 D 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.
5
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.
D
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 5 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 D 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, antihypertensive 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 1 1 beta-hydroxy steroid dehydrogenase-1 5 (1 1 beta-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 D antagonists, lipase inhibitors, anorectic agents, neuropeptide-Y antagonists (e.g., NPY Y5 antagonists), ΡΥγ3-36 (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 5 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 D 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.
5 Suitable anti-diabetic agents include sodium-glucose co-transporter (SGLT)
inhibitors, 1 1 beta-hydroxy steroid dehydrogenase-1 (1 1 beta-HSD type 1 ) inhibitors, phosphodiesterase (PDE) 10 inhibitors, diacylglycerol acyltransferase (DGAT) 1 or 2 inhibitors, sulfonylureas (e.g., acetohexamide, chlorpropamide, diabinese,
glibenclamide, glipizide, glyburide, glimepiride, gliclazide, glipentide, gliquidone,
D 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., Byetta™, exendin-3 and exendin-4), GLP-1 receptor and
5 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, GPR1 19 agonists, GPR40 agonists, TGR5
D 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.
5
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, 1 1 beta-hydroxy steroid
dehydrogenase-1 (1 1 beta-HSD type 1 ) inhibitors and DPP-IV inhibitors (e.g.
D 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 5 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 D 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 5 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
D 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- 5 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 D 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
5 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
D 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, 1 H-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 teff-butoxycarbonyl
CDI Λ/,/V-carbonyldiimidazole
CDT 1 ,1 '-carbonyldi(1 ,2,4-triazole)
Cul copper(l) iodide
DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
DCM dichloromethane
DIPEA Λ/,/V-diisopropylethylamine
DMA Λ/,/V-dimethylacetamide
DMF N, Ν-ό i methylforma mide
EtOAc ethyl acetate
FA formic acid
MeOH methanol
NMP A/-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-(1 H-benzotriazol-1 -yl)-1 ,1 ,3,3- tetramethyluronium tetrafluoroborate HPLC methods Method A1
Figure imgf000064_0002
Method B1
Figure imgf000064_0003
Method C1
Figure imgf000064_0001
Method D1
Figure imgf000065_0002
Method E1
Figure imgf000065_0003
Method G1
Figure imgf000065_0001
Method H1
Figure imgf000066_0002
Method 11
Figure imgf000066_0003
Method J1
Figure imgf000066_0004
Method K1
Figure imgf000066_0001
Method L1
Figure imgf000067_0003
Method N1
Figure imgf000067_0001
Method 01
Figure imgf000067_0002
Method P1
Figure imgf000068_0002
Method R1
Figure imgf000068_0003
Method S1
Figure imgf000068_0001
Method T1
Figure imgf000069_0002
Method U1
Figure imgf000069_0003
Method U3
Figure imgf000069_0001
Method V1
Figure imgf000070_0003
Preparation of Starting Compounds
Example I
Example 1.1
,Sj-/V-[1 -(4-Bromo-phenyl)-ethyl]-acetamide
Figure imgf000070_0001
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.
Ci0Hi2BrNO (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 1.1 : Example I.2
-Cyclopropanecarboxylic acid [1 -(4-bromo-phenyl)-ethyl]-amide
Figure imgf000070_0002
Reagent: cyclopropylcarbonyl chloride
Ci2Hi4BrNO (M = 268.2 g/mol), ESI-MS: 268/270 [M+H]+ Rt (HPLC): 2.76 min (method B1 )
Example I.3
-[1 -(4-Bromo-phenyl)-ethyl]-carbamic acid terf-butyl ester
Figure imgf000071_0001
Reagent: di-terf-butyldicarbonate
Ci3Hi8BrNO2 (M = 300.2 g/mol), ESI-MS: 300/302 [M+H]+
Rf (TLC): 0.56 (silica gel, DCM:methanol 98:2)
D Example I.4
-[1 -(6-Bromo-pyridin-3-yl)-ethyl]-acetamide
Figure imgf000071_0002
Reagents: acetic anhydride and 1 -(6-bromo-pyridin-3-yl)-ethyl
C9HnBrN2O (M = 243.1 g/mol), ESI-MS: 243/245 [M+H]+
Rt (HPLC): 1 .94 min (method D1 )
Example I.5
-1 H-Pyrazole-4-carboxylic acid [1 -(4-bromo-phenyl)-ethyl]-amide
Figure imgf000071_0003
D 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.
Ci2Hi2BrN3O (M = 294.1 g/mol), ESI-MS: 294 [M+H]+
Rt (HPLC): 1 .23 min (method E1 )
5
The following compound is prepared analogously to Example 1.5:
Example I.6
(S)-2-Acetylamino-4-methyl-thiazole-5-carboxylic acid [1 -(4-bromo-phenyl)-ethyl]- D amide
Figure imgf000072_0001
Reagent: 2-acetylamino-4-methyl-thiazole-5-carboxylic acid
Ci5Hi6BrN3O2S (M = 382.3 g/mol), ESI-MS: 382/384 [M+H]+
Rt (HPLC): 0.97 min (method F1 )
Example II
Example 11.1
-3-[1 -(4-Bromo-phenyl)-ethyl]-1 ,1 -dimethyl-urea
Figure imgf000072_0002
D 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 (2x) and water (1 x). The organic layer is dried over
5 magnesium sulphate and the solvent is removed by evaporation to yield the desired product.
CnHi5BrN2O (M = 271 .2 g/mol), ESI-MS: 271/273 [M+H]+ Rt (HPLC): 1 .68 min (method C1 )
Example III
Example III.1
(, -/V-[1 -(4-lodo-phenyl)-ethyl]-acetamide
Figure imgf000073_0001
9.01 g (47.3 mmol) Cul are added to a mixture of 1 14.6 g (473.3 mmol) (S)-N-^ -( - bromo-phenyl)-ethyl]-acetamide (1.1 ), 283.8 g (1 .893 mmol) sodium iodide and 10.43 g (1 1 8.3 mmol) Λ/,/V -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 (2x) and the combined organic layers are washed with water (2x) 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)-/V-(1 -{4-[3-(feri-Butyl-dimethyl-silanyloxy)-azetidin-1 -yl]-phenyl}-ethyl)-acetamide
Figure imgf000073_0002
A mixture of 3.0 g (12.4 mmol) (S)-/V-[1 -(4-bromo-phenyl)-ethyl]-acetamide (1.1 ), 2.3 g (12.4 mmol) 3-(tert-butyl-dimethyl-silanyloxy)-azetidine (US2008/214520A1 ), 4.9 g (97%, 49.6 mmol) NaOfBu, 1 .48 g (4.96 mmol) 2-(di-terf-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.
C19H32N2O2S1 (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 : 5 Example IV.2
(Sj-Cyclopropanecarboxylic acid (1 -{4-[3-(terf-butyl-dimethyl-silanyloxy)-azetidin-1 - -phenyl}-ethyl)-amide
Figure imgf000074_0001
Reagent: I.2
D C2i H34N2O2Si (M = 374.6 g/mol), ESI-MS: 375 [M+H]+
Rt (HPLC): 1 .34 min (method F1 )
Example V
Example V.1
5 -/V-{1 -[4-(3-Hydroxy-azetidin-1 -yl)-phenyl]-ethyl}-acetamide
Figure imgf000074_0002
2.6 g (7.46 mmol) (,S)-A/-(1 -{4-[3-(feri-Butyl-dimethyl-silanyloxy)-azetidin-1 -yl]-phenyl}- ethyl)-acetamide (IV.1 ) are added to 20 mL TH F and the mixture is cooled to 5 °C. 14.9 mL (14.9 mmol) tetrabutylammonium fluoride (1 N in THF) are added and the D mixture is al lowed 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.
C13H 18N2O2 (M = 234.3 g/mol), ESI-MS: 235 [M+H]+
Rt (HPLC): 1 .12 min (method H1 )
5
The following compound is prepared analogously to Example V.1 : Example V.2
(Sj-Cyclopropanecarboxylic acid {1 -[4-(3-hydroxy-azetidin-1 -yl)-phenyl]-ethyl}-amide
Figure imgf000075_0001
Reagent: IV.2
C15H20N2O2 (M = 260.3 g/mol), ESI-MS: 261 [M+H]+
Rt (HPLC): 1 .33 m in (method H1 )
Example VI
Example VI.1
, -/V-(1 -{4-[3-(4-Hydroxy-phenoxy)-azetidin-1 -yl]-phenyl}-ethyl)-acetamide
Figure imgf000075_0002
1 .3 g (3.12 mmol) (,S)-A/-(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 1 2 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 11 )
Example VII
Example VII.1
2-Acetylamino-4-phenyl-thiazole-5-carboxylic acid
Figure imgf000075_0003
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 HCI 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
5 -Acetylamino-oxazole-4-carboxylic acid
Figure imgf000076_0001
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 anyhdride are stirred for 2 d at rt. The mixture is concentrated in D 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. 5 HCI 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
D Example IX.1
-(4-Cyclopropylmethoxy-phenoxy)-azetidine
Figure imgf000076_0002
a) 3-(4-Cyclopropylmethoxy-phenoxy)-azetidine-1 -carboxylic acid terf-butyl ester A mixture of 2.6 g (10.4 mmol) 3-methanesulfonyloxy-azetidine-1 -carboxylic acid tert- 5 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 (2x). 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.
Ci8H25NO4 (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 terf-butyl ester in 15 mL 1 ,4-dioxane is added 12.8 mL (16.0 mmol) HCI 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 (2x). 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.
C13H 17NO2 (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
Figure imgf000077_0001
Reagent in step a): 4-ethoxy-2-fluoro-phenol (US20090286812A1 )
In step b no column chromatography was conducted and the desired product obtained as a HCI-salt.
CiiHi4FNO2 (M = 21 1 .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
Figure imgf000077_0002
Reagent in step a): 4-benzyloxy-1 H-pyhdin-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 HCI-salt.
C15H 16N2O2 (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
Figure imgf000078_0001
Reagent in step a): 4-(2-methoxy-ethoxy)-phenol
In step b) HCI in methanol was used for deprotection and no column chromatography was conducted. The desired product was obtained as a HCI-salt.
C12H 17NO3 (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
Figure imgf000078_0002
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 terf-butyl ester (1.3) in 80 mL 1 ,4-dioxane under an argon atmosphere are added 8.6 g (87.1 mmol) KOfBu, 0.65 g (2.18 mmol) 2-(di- terf-butylphosphino)biphenyl and 1 .0 g (1 .09 mmol) tris-(dibenzylideneacetone)- dipalladium(O). The mixture is stirred for 2 h at 1 20 °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 % N eluent B: MeOH) to yield the desired product.
Ci9H24N2O2 (M = 312.4 g/mol), ESI-MS: 296 [M+H-NH3]+
Rt (HPLC): 1 .19 min (method J1 )
Example X.2
(' -1 -{4-[3-(4-Cyclopropylmethoxy-phenoxy)-azetidin-1 -yl]-phenyl}-ethylamine
Figure imgf000079_0001
a) (1 -{4-[3-(4-Cyclopropylmethoxy-phenoxy)-azetidin-1 -yl]-phenyl}-ethyl)-carbamic
D acid terf-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 terf-butyl ester (1.3), 1 .6 g (16.4 mmol) NaOfBu, 0.49 g (1 .64 mmol) 2-(di-terf-butylphosphino)biphenyl and 0.38 g (0.41 mmol) tris-(dibenzylideneacetone)-dipalladium(0) are added under an argon
5 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.
C26H3 N2O4 (M = 438.6 g/mol), ESI-MS: 439 [M+H]+
Rt (HPLC): 1 .62 min (method K1 )
D 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 terf-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.
5 C2iH26N2O2 (M = 338.4 g/mol), ESI-MS: 339 [M+H]+
Rt (HPLC): 2.19 min (method H1 )
Example XI
Example XI.1 ,S /V-(1 -{4-[3-(2-Fluoro-pyridin-4-yloxy)-azetidin-1 -yl]-phenyl}-ethyl)-ac^^
Figure imgf000080_0001
1 .0 g (4.3 mmol) ('Sj-/\/-{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]+
Figure imgf000080_0002
The following compound is prepared analogously to Example XI.1 : Example XI.2
(Sj-Cyclopropanecarboxylic acid (1 -{4-[3-(2-fluoro-pyridin-4-yloxy)-azetidin-1 -yl]- phenyl}-ethyl)-amide
Figure imgf000080_0003
Reagent: V.2
C20H22FN3O2 (M = 355.4 g/mol), ESI-MS: 356 [M+H]+
Figure imgf000080_0004
Example XII
Example XII.1
2-Bromo-6-(2,2-difluoro-cyclopropylmethoxy)-pyridine
Figure imgf000080_0005
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 5 (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)
D Preparation of Final Compounds
Example 1
Example 1 .1
(Sj-l -Methyl-cyclobutanecarboxylic acid (1 -{4-[3-(4-ethoxy-phenoxy)-azetid
phenyl}-ethyl)-amide
Figure imgf000081_0001
To 0.01 1 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)- D 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 )
5 The following compounds of general formula (1 -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
D vacuo:
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Example 2
Example 2.1
('Sj-2,5-Dimethyl-furan-3-carboxylic acid (1 -{4-[3-(4-ethoxy-phenoxy)-azetidin-1 -yl]- phenyl}-ethyl)-amide
Figure imgf000089_0001
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.
C26H3oN2O4 (M = 434.5 g/mol), ESI-MS: 435 [M+H]+
Rt (HPLC): 1 .90 m in (method M1 )
The following compounds of general formula (1 -1 ) are prepared analogously to Example 2.1 , the educts used being shown in the column headed Έ 1 " and "E 2":
Figure imgf000089_0002
Figure imgf000090_0001
Example 3
Example 3.1
(,S -/V-(1 -{4-[3-(4-Ethoxy-phenoxy)-azetidin-1 -yl]-phenyl}-ethyl)-2,2,2-trifluoro- acetamide
Figure imgf000090_0002
To 0.094 g (0.30 mmol) ('Sj-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.
C21 H23 F3 N2O3 (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
Figure imgf000090_0003
0.03 mL (0.20 mmol) DBU and 0.033 g (0.20 mmol) CDT are added to 0.01 Og (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) (Sj-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.
C2 H27N5O3 (M = 433.5 g/mol), ESI-MS: 434 [M+H]+
Rt (HPLC): 1 .79 min (method L1 )
The following compounds of general formula (1 -1 ) are prepared analogously to Example 4.1 , the educts used being shown in the column headed Έ 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.
Figure imgf000091_0001
Figure imgf000092_0001
Example 5
Example 5.1
('S 4-(1-{4-[3-(4-Ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamino)-5H-furan-2-
Figure imgf000093_0001
To 0.040 g (0.13 mmol) ('Sj-1 -{4-[3-(4-ethoxy-phenoxy)-azetidin-1 -yl]-phenyl}- ethylamine (X.1 ) in 1 .5 mL THF are added 54 μΙ_ (0.38 mmol) TEA and 0.021 g (0.13 mmol ) 4-bromo-2(5H)-fu ranone. The m ixtu re is stirred for 1 2 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 .1 1 min (method F1 ) Example 6
Example 6.1
,S)-/V-(1 -{4-[3-(4-teri-Butyl-phenoxy)-azetidin-1 -yl]-phenyl}-ethyl)-acetamide
Figure imgf000093_0002
Under an argon atmosphere a mixture of 0.28 g (0.97 mmol) (S)-/V-[1 -(4-iodo- phenyl)-ethyl]-acetamide (111.1 ), 0.20 g (0.98 mmol) 3-(4-terf-butyl-phenoxy)- azetidine, 0.0093 g (0.049 mmol) Cu l, 0.41 g (1 .95 mmol) K3PO4 and 0.1 2 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%, 2x). The aq. layer is extracted with ethyl acetate (1 x) 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.
C23H3oN2O2 (M = 366.5 g/mol), ESI-MS: 367 [M+H]+
Rt (HPLC): 2.28 min (method H1 ) Example 7
Example 7.1
(,S)-/V-(1 -{4-[3-(4-Ethoxy-2-fluoro-phenoxy)-azetidin-1 -yl]-phenyl}-ethyl)-acetamide
Figure imgf000094_0001
Under an argon atmosphere a mixture of 0.078 g (0.32 mmol) (,S)-/V-[1 -(4-bromo- phenyl)-ethyl]-acetamide (1.1 ), 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
5 mmol) palladium(ll) acetate, 0.0077 g (0.016 mmol) 2-dicyclohexylphosphine-2',4',6'- tri-isopropyl-1 , 1 '-biphenyl (X-Phos) in 1 .5 mL tol uene and 0.5 m L terf-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 H PLC (Gemin iCI 8, acetone/water (+0.3% NH OH)) to yield the desired product.
D C21 H25FN2O3 (M = 372.4 g/mol), ESI-MS: 373 [M+H]+
Rt (HPLC): 1 .1 1 min (method F1 )
Example 7.2
(Sj-Cyclopropanecarboxylic acid (1 -{4-[3-(4-ethoxy-2-fluoro-phenoxy)-azetid phenyl}-ethyl)-amide
Figure imgf000094_0002
Example 7.2 is prepared analogously to 7.1 . (Sj-Cyclopropanecarboxylic acid [1 -(4- bromo-phenyl)-ethyl]-amide (I.2) is used as starting material .
C23H27FN2O3 (M = 398.5 g/mol), ESI-MS: 399 [M+H]+
D 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-
5 urea
Figure imgf000095_0001
Under an argon atmosphere a mixture of 0.080 g (0.295 mmol) (S)-3-[1 -(4-bromo- phenyl)-ethyl]-1 ,1 -dimethyl-urea (11.1 ), 0.073 g (0.295 mmol) 3-(4-ethoxy-2-fluoro- phenoxy)-azetidine (IX.2), 0.1 17 g (97%, 1 .18 mmol) NaOfBu, 0.0035 g (0.1 18 mmol) 5 2-(di-terf-butylphosphino)biphenyl, 0.027 g (0.0295 mmol) tris-(dibenzylideneaceton)- dipalladium(O) 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.
D C22H28FN3O3 (M = 401 .5 g/mol), ESI-MS: 402 [M+H]+
Rt (HPLC): 1 .65 min (method Q1 )
Example 8.2
('S)-1 /-/-Pyrazole-4-carboxylic acid (1 -{4-[3-(4-ethoxy-2-fluoro-phenoxy)-azetid phenyl}-ethyl)-amide
Figure imgf000095_0002
Example 8.2 is prepared analogously to 8.1 . (S)-1 H-Pyrazole-4-carboxylic acid [1 -(4- bromo-phenyl)-ethyl]-amide (I.5) is used as starting material .
C23H25FN4O3 (M = 424.5 g/mol), ESI-MS: 425 [M+H]+
D Rt (HPLC): 1 .62 min (method Q1 )
Example 8.3
('S)-(1 -{4-[3-(4-Cyclopropylmethoxy-phenoxy)-azetidin-1 -yl]-phenyl}-ethyl)-carbamic acid terf-butyl ester
Figure imgf000096_0001
Example 8.3 is prepared analogously to 8.1 . (S)-[1 -(4-Bromo-phenyl)-ethyl]-carbamic acid terf-butyl ester (I.3) and 3-(4-cyclopropylmethoxy-phenoxy)-azetidine (IX.1 ) are used as starting materials and the reaction temperature is 45 °C.
C26H3 N2O4 (M = 438.6.4 g/mol), ESI-MS: 439 [M+H]+
Rt (HPLC): 2.53 min (method H1 )
Example 8.4
CS)-2-Acetylamino-4-methyl-thiazole-5-carboxylic acid (1 -{4-[3-(4-ethoxy-2-fluoro- phenoxy)-azetidin-1 -yl]-phenyl}-ethyl)-amide
Figure imgf000096_0002
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)-/V-(1 -{4-[3-(4-Benzyloxy-phenoxy)-azetidin-1 -yl]-phenyl}-ethyl)-acetamide
Figure imgf000096_0003
Example 8.5 is prepared analogously to 8.1 . 3-(4-Benzyloxy-phenoxy)-azetidine and (,Sj-/V-[1 -(4-bromo-phenyl)-ethyl]-acetamide (1.1 ) 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]+
5 Rt (HPLC): 2.17 min (method H1 )
Example 8.6
A/-(1 -{6-[3-(4-Ethoxy-phenoxy)-azetidin-1 -yl]-pyridin-3-yl}-ethyl)-acetamide
Figure imgf000097_0001
D Example 8.6 is prepared analogously to 8.1 . (A/-[1 -(6-Bromo-pyridin-3-yl)-ethyl]- acetamide (1.4) and 3-(4-ethoxy-phenoxy)-azetidine are used as starting materials. C2oH25N3O3 (M = 355.4 g/mol), ESI-MS: 356 [M+H]+
Rt (HPLC): 1 .47 min (method Q1 )
5 Example 8.7
(,S)-/V-(1 -{4-[3-(4-Benzyloxy-pyhdin-2-yloxy)-azetidin-1 -yl]-phenyl}-ethyl)-acetamide
Figure imgf000097_0002
Example 8.7 is prepared analogously to 8.1 . 2-(Azetidin-3-yloxy)-4-benzyloxy- pyridine (IX.3) and (S)-/V-[1 -(4-bromo-phenyl)-ethyl]-acetamide (1.1 ) are used as D starting materials.
C25H27N3O3 (M = 417.5 g/mol), ESI-MS: 418 [M+H]+
Rt (HPLC): 1 .20 min (method F1 )
Example 8.8
5 (S)-/V-(1 -{4-[3-(5-Trifluoromethyl-pyridin-2-yloxy)-azetidin-1 -yl]-phenyl}-ethyl)- acetamide
Figure imgf000098_0001
Example 8.8 is prepared analogously to 8.1 . 2-(Azetidin-3-yloxy)-5-trifluoromethyl- pyridine and (S)-/V-[1 -(4-bromo-phenyl)-ethyl]-acetamide (1.1 ) are used as starting materials. Reaction conditions are stirring for 12 h at 50 °C.
5 C19H20F3N3O2 (M = 379.4 g/mol), ESI-MS: 380 [M+H]+
Rt (HPLC): 1 .14 min (method F1 )
Example 9
Example 9.1
D -N-C\ -{4-[3-(4-lsopropoxy-phenoxy)-azetidin-1 -yl]-phenyl}-ethyl)-acetamide
Figure imgf000098_0002
To 0.050g (0.15 mmol) Sj-A/'il ^-tS^-hydroxy-phenoxyJ-azetidin-l -yll-phenyl}- ethyl)-acetamide (VI .1 ) in 1 .0 ml_ DMF are added 0.053 g (0.38 mmol) potassium carbonate and 1 7.2 μΙ_ (0.18 mmol) 2-bromopropane. The mixture is stirred for 12 h 5 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 )
D The following compounds of general formula (1 -1 ) are prepared analogously to Example 9.1 , the educts used being shown in the column headed Έ 1 " and "E 2".
Figure imgf000098_0003
Figure imgf000099_0001
Example 10
Example 10.1
'SJ-/V-(1 -{4-[3-(2,3-Difluoro-4-methyl-phenoxy)-azetidin-1 -yl]-phenyl}-eth
Figure imgf000099_0002
To 0.023 g (0.10 mmol) (S)-/V-{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 (0.1 0 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 (2x). 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 Έ 1" and "E 2".
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Example 11
Example 1 1 .1
('SJ-/V-(1 -{4-[3-(2-Cyclopropylmethoxy-pyridin-4-yloxy)-azetidin-1 -yl]-phenyl}-ethyl)^ acetamide
Figure imgf000102_0002
To 55 mg (0.17 mmol) (,S)-/V-(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]+
Figure imgf000103_0001
The following compounds of general formula (1 -1 ) are prepared analogously to Example 1 1 .1 , the educts used being shown in the column headed Έ 1 " and "E 2".
Figure imgf000103_0002
Example 12
Example 12.1
(,S /V-{1 -[4-(3-{6-[(2-Hydroxy-2-methyl-propyl)-methyl-amino]-pyridin-2-yloxy}- zetidin-1 -yl)-phenyl]-ethyl}-acetamide
Figure imgf000104_0001
23 mg (0.10 mmol) (,Sj-/V-{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) NaOfBu 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(ll). 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(ll) 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 Έ 1 " and "E 2".
Figure imgf000104_0002
Figure imgf000105_0001
Figure imgf000106_0001
Example 13
Example 13.1
(S)-/V-(1 -{4-[3-(2-Morpholin-4-yl-pyrimidin-4-yloxy)-azetidin-1 -yl]-phenyl}-ethyl)- acetamide
Figure imgf000106_0002
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)-/V-{1 -[4-(3-hydroxy-azetidin-1 -yl)-phenyl]-ethyl}- acetamide (V.1 ) in DMF (1 .0 m L). 20 mg (0.45 mmol , 55% in m ineral 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, acetronithle/H2O (+0.1 % NH4OH)) to yield the desired product.
C21 H27N5O3 (M = 397.5 g/mol), ESI-MS: 398 [M+H]+
Rt (HPLC): 0.66 (T1 )
Example 13.2
(S)-/V-(1 -{4-[3-(2-Pyrrolidin-1 -yl-pyrimidin-4-yloxy)-azetidin-1 -yl]-phenyl}-ethyl)- acetamide
Figure imgf000106_0003
Example 13.2 is prepared analogously to 13.1 . 4-Bromo-2-pyrrolidin-1 -yl-pyrimidine is used as starting material.
C21 H27N5O2 (M = 381 .5 g/mol), ESI-MS: 382 [M+H]+
Rt (HPLC): 0.69 min (T1 ) Example 14
Example 14.1
,S /V-(1 -{4-[3-(6-Methoxy-pyridin-2-yloxy)-azetidin-1 -yl]-phenyl}-ethyl)-acetamid
Figure imgf000107_0001
To 13 mg (0.10 mmol) 6-methoxy-pyridin-2-ol in THF (1 .0 mL) is added 23 mg (0.10 mmol) (,S)-/V-{1 -[4-(3-hydroxy-azetidin-1 -yl)-phenyl]-ethyl}-acetamide (V.1 ) in THF (1 .0 mL). 29 mg (0.1 1 mmol) triphenylphosphine and 25 mg (0.1 1 mmol) di-terf-butyl azodicarboxylate are added and the mixture is stirred for 3 h at 60 °C. Another
D portion of 29 mg (0.1 1 mmol) triphenylphosphine and 25 mg (0.1 1 mmol) di-terf-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, acetronithle/H2O (+0.1 % NH4OH)) to yield the desired product.
C19H23N3O3 (M = 341 .4 g/mol), ESI-MS: 342 [M+H]+
5 Rt (HPLC): 1 .05 (T1 )
Example 14.2
,S)-/V-(1 -{4-[3-(6-Methoxy-pyhdin-2-yloxy)-azetidin-1 -yl]-phenyl}-ethyl)-acetamide
Figure imgf000107_0002
D 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]+
Figure imgf000107_0003
5 Example 14.3
('S /V-(1 -{4-[3-(2-Methyl-pyrimidin-4-yloxy)-azetidin-1 -yl]-phenyl}-ethyl)-acetamide
Figure imgf000108_0001
Example 14.2 is prepared analogously to 14.1 . 2-Methyl-pyrimidin-4-ol is used as starting material .
Ci8H22N4O2 (M = 326.4 g/mol), ESI-MS: 327 [M+H]+
5 Rt (HPLC): 0.61 min (T1 )
Example 15
Example 15.1
A/-(1 -{4-[3-(4-Cyclopropylmethoxy-phenoxy)-azetidin-1 -yl]-phenyl}-1 -methyl-ethyl)- D acetamide
Figure imgf000108_0002
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) A/-[1 -(4-bromo- phenyl)-1 -methyl-ethyl]-acetamide, 63 mg (0.64 mmol) NaOfBu, 19 mg (0.064 mmol)
5 2-(di-terf-butylphosphino)biphenyl and 15 mg (0.016 mmol) tris-(dibenzylidene- acetone)-dipalladium(O). 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, acetronithle/H2O (+0.15% HCOOH)) to yield the desired product.
C2 H3oN2O3 (M = 394.5 g/mol), ESI-MS: 395 [M+H]+
D 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)- 5 phenoxy]-azetidin-1 -yl}-phenyl)-ethyl]-amide
Figure imgf000109_0001
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 (1.6), 45 mg (0.06 mmol) chloro(2-dicyclohexylphosphino-2',4',6'-tri-/'so- propyl-1 ,1 '-biphenyl)[2-(2-aminoethyl)phenyl]palladium(ll) and 150 mg (1 .56 mmol) NaOfBu 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

Patent Claims:
1 . A compound of formula I
Figure imgf000110_0001
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(Ci-4- alkyl)-, wherein the alkylene bridge may optionally be substituted by one or two Ci-3-alkyl groups; is selected from a group consisting of :
H, F, CI, Br, I, CN, OH, -NO2, Ci-4-alkyl, C2-4-alkenyl, Ci-4-alkyl-O-, Ci-4-alkyl- C(=O)-, H2N-, H2N-C(=O)-, H2N-S(=O)2-, HO-C(=O)-, Ci-4-alkyl-O-C(=O)-, phenyl and phenyl-Ci-3-alkyl, wherein in each NH2-group, one or both hydrogen atoms may independently be replaced by Ci-4-alkyl; wherein each alkyl and cycloalkyi may be optionally substituted with one or more F atoms; is selected from a group consisting of:
H, OH, Ci-e-alkyl, Ci-6-alkyl-O-, C3-7-cycloalkyl, C3-7-cycloalkyl-O-, C3-7- cycloalkyl-Ci-3-alkyl-O-, H2N-, (Ci-4-alkyl)NH-, (Ci-4-alkyl)2N-, C3-7-cycloalkyl- NH-, C3-7-cycloalkyl-N(Ci-4-alkyl)-, C3-7-cycloalkyl-Ci-3-alkyl-NH-, (C3-7- cycloalkyl-Ci-3-alkyl)-N(Ci-4-alkyl)-, Ci-4-alkyl-C(=O)-, Ci-4-alkyl-S(=O)2-, HO- C(=0)-, Ci-4-alkyl-0-C(=0)-, H2N-C(=O)-, (Ci-4-alkyl)HN-C(=O)-, (C1-4- alkyl)2N-C(=O)-, aryl, aryl-Ci-3-alkyl-, aryl-Ci-3-alkyl-O-, heterocyclyl, heterocyclyl-O-, heterocyclyl-Ci-3-alkyl-O-, heteroaryl, heteroaryl-Ci-3-alkyl- and heteroaryl-Ci-3-alkyl-O-, wherein each alkyl and cycloalkyi may be optionally substituted with one or more substituents selected from F, OH and Ci-4-alkyl-O-, and wherein each heterocyclyl is optionally substituted with one or more Ci-3-alkyl; is selected from a group consisting of:
Figure imgf000111_0001
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; and R2b are each independently selected from a group consisting of:
H and Ci-3-alkyl; is selected from a group consisting of: H and Ci-4-alkyl; and is selected from a group consisting of:
H, Ci-6-alkyl, C3-io-carbocyclyl, C3-io-carbocyclyl-Ci-3-alkyl-, C2-6-alkenyl, C2-6- alkynyl, Ci-6-alkyl-O-, RN 1 RN2N-, heterocyclyl, heterocyclyl-Ci-3-alkyl, aryl, aryl-Ci-3-alkyl, heteroaryl and heteroaryl-Ci-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 is selected from a group consisting of:
H and Ci-4-alkyl;
5. wherein each alkyl group may be optionally substituted with one R1 is selected from a group consisting of:
H, Ci-4-alkyl, C3-io-carbocyclyl, C3-io-carbocyclyl-Ci-3-alkyl, C2-6-alkenyl, C2-6- alkynyl, heterocyclyl, heterocyclyl-Ci-3-alkyl, aryl, aryl-Ci-3-alkyl, heteroaryl and heteroaryl-Ci-3-alkyl, wherein each carbocyclyl and heterocyclyl may be optionally substituted with one or more Ci-4-alkyl, aryl or aryl-Ci-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 is selected from a group consisting of:
F, CI, Br, CN, OH, Ci-4-alkyl-, Ci-4-alkyl-O-, Ci-4-alkyl-S-, Ci-4-alkyl-S(=O)2-, H2N-, (Ci-4-alkyl)NH-, (Ci-4-alkyl)2N-, Ci-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, Ci-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(Ci-4- alkyl)-, wherein the C2-5-alkylene bridging group is optionally be substituted by one or two Ci-3-alkyl groups or F atoms; including any tautomers and stereoisomers thereof, or a 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 or 2, wherein
Figure imgf000113_0001
4. A compound according to any of the previous claims, wherein Ar1 is selected from a group 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 RA.
5. A compound according to any of the previous claims, wherein RA is F or CI.
6. A compound according to any of the previous claims, wherein R1 is selected from a group consisting of:
H, Ci-4-alkyl, Ci-4-alkyl-O-, C3-6-cycloalkyl, C3-6-cycloalkyl-O-, tetrahydrofuranyl-O-, C3-6-cycloalkyl-CH2-O-, (Ci-4-alkyl)NH-, (Ci-4-alkyl)2N-, phenyl, benzyl, phenyl-CH2-O- , piperidinyl, morpholinyl, pyrrolidinyl and pyrrolyl, wherein each alkyl and cydoalkyi 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.
7. A compound according to any of the previous claims, wherein
R4 is selected from a group consisting of:
H, Ci-4-alkyl, C3-6-cycloalkyl, C4-6-cycloalkenyl, C3-6-cycloalkyl-Ci-3-alkyl-, C2-6
C2-6-alkynyl, Ci-6-alkyl-O-, RN1RN2N-, heterocyclyl, heterocyclyl-Ci-3-alkyl-, ph phenyl-Ci-3-alkyl-, heteroaryl and heteroaryl-Ci-3-alkyl-, wherein RN1 is selected from the group consisting of: H and Chalky!; and wherein RN2 is selected from the group consisting of: H, Ci-4-alkyl, C3- 7-cycloalkyl and heteroaryl; and wherein in each cydoalkyi and heterocyclyl a -CH2-group may optionally be replaced by -C(=O)-, and wherein each alkyl, cydoalkyi, heterocyclyl, aryl and heteroaryl group may be optionally substituted with one to three substituents independently selected from the group consisting of: F, CI, CN, OH, CF3, Ci-3-alkyl, -O-(Ci-3-alkyl) and -NH-(C=O)-Ci-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 roup consisting of:
Figure imgf000115_0001
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 CI atoms;
R1 is selected from a group consisting of:
Ci-4-alkyl, Ci-4-alkyl-O-, C3-5-cycloalkyl, C3-5-cycloalkyl-O-, tetrahydrofuranyl-O-, C3-5- cycloalkyl-CH2-O-, (Ci-4-alkyl)2N-, phenyl, benzyl, phenyl-CH2-O-, piperidinyl, morpholinyl, pyrrol idinyl 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;
Figure imgf000115_0002
R^a is H;
R2b is CH3;
R3 is H; and R4 is selected from a group consisting of:
Ci-4-alkyl, Cs-5-cycloalkyl, cyclopentenyl, C3-5-cycloalkyl-CH2-, C3-5-alkenyl, C3-6- alkynyl, Ci-4-alkyl-O-, RN1 RN2N-, 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, Ci-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, cydoalkyi, 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: CI, 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 salt thereof.
9. A compound according to claim 1 , wherein
Ar is selected from a group consisting of:
Figure imgf000116_0001
which are each optionally substituted with one or two substituents independently selected from F and CI;
R1 is selected from a roup consisting of:
Figure imgf000117_0001
R^a is H;
R2b is CH3;
R3 is H; and
R4 is selected from a group consisting of:
- -CH2CH3, -CH2-CH=CH2, -CF2-CH3, -CH2-CF3, -N(CH3)2,
Figure imgf000117_0002
or a pharmceutically acceptable salt thereof.
10. A compound according to claim 8 or 9, wherein
Figure imgf000118_0001
1 1 . A pharmaceutically acceptable salt of a compound according to any of claims 1 to 10.
12. A compound according to any of claims 1 to 1 1 for use in the treatment of obesity or type 2 diabetes.
13. A pharmaceutical composition comprising a compound according to any one of the claims 1 to 10 or a pharmaceutically acceptable salt thereof, optionally together with one or more inert carriers and/or diluents.
14. 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 according to one or more of the claims 1 to 10 or a
pharmaceutically acceptable salt thereof is administered to the patient.
15. A pharmaceutical composition comprising one or more compounds according to one or more of the claims 1 to 10 or a pharmaceutically acceptable salt thereof and one or more additional therapeutic agents, optionally together with one or more inert carriers and/or diluents.
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