WO2012001020A1 - Novel tetrahydroquinoline derivatives - Google Patents

Novel tetrahydroquinoline derivatives Download PDF

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Publication number
WO2012001020A1
WO2012001020A1 PCT/EP2011/060864 EP2011060864W WO2012001020A1 WO 2012001020 A1 WO2012001020 A1 WO 2012001020A1 EP 2011060864 W EP2011060864 W EP 2011060864W WO 2012001020 A1 WO2012001020 A1 WO 2012001020A1
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Prior art keywords
phenyl
carboxylic acid
fluoro
spiro
tetrahydroquinoline
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PCT/EP2011/060864
Other languages
French (fr)
Inventor
Li Chen
Lichun Feng
Yun He
Mengwei Huang
Yongfu Liu
Hongying Yun
Mingwei Zhou
Original Assignee
F. Hoffmann-La Roche Ag
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Filing date
Publication date
Application filed by F. Hoffmann-La Roche Ag filed Critical F. Hoffmann-La Roche Ag
Priority to MX2012014647A priority Critical patent/MX2012014647A/en
Priority to ES11730935.1T priority patent/ES2479718T3/en
Priority to BR112012033599A priority patent/BR112012033599A2/en
Priority to JP2013517259A priority patent/JP2013534928A/en
Priority to RU2013102031/04A priority patent/RU2013102031A/en
Priority to EP11730935.1A priority patent/EP2588458B1/en
Priority to KR1020137002692A priority patent/KR20130088843A/en
Priority to CA2803478A priority patent/CA2803478A1/en
Priority to CN201180032842XA priority patent/CN102958919A/en
Publication of WO2012001020A1 publication Critical patent/WO2012001020A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the invention relates to compounds which are activators of AMP-activated protein kinase (AMPK) and which are useful in the treatment or prophylaxis of diseases that are related to AMPK regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes and cancers.
  • AMPK AMP-activated protein kinase
  • the invention relates in particular to a compound of formula (I)
  • a 1 is absent or -CH 2 -; A is nitrogen or -CH-; A 3 is absent or -C(CH 3 ) 2 -; P Ss hydroxyl or NR n R 12 ;
  • R 2" and R3 J are independently selected from alkyl, alkenyl and phenyl; or R 2 and R3 together with the carbon atom to which they are attached form
  • R 4 , R 5 , R 6 , R 7 and R 8 are independently selected from hydrogen, alkyl, alkoxy, halogen, alkylsulfonyl, morpholinyl, piperazinyl and alkylpiperazinyl;
  • R 9 is hydrogen, alkyl, benzyl or alkylaminocarbonyl
  • R 10 is hydrogen or halogen;
  • R 1 ⁇ 1 and R 1 1 2" are independently selected from hydrogen, alkyl, cycloalkyl,
  • morpholinyl piperazinyl, alkylpiperazinyl, alkylsulfonylpiperazinyl, alkylhydroxypyrrolidinyl or hydroxyalkylpyrrolidinyl; or a pharmaceutically acceptable salt or ester thereof.
  • the invention also relates to a process for the manufacture of these novel compounds and medicaments containing them.
  • the compounds of the invention have activation effect on AMP (adenosine monophosphate)-activated protein kinase, which results in lowered blood glucose and lipid levels.
  • AMP adenosine monophosphate
  • AMPK regulation diseases that are related to AMPK regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes, and cancers.
  • Obesity and type 2 diabetes, hypertension and cardiovascular disease are diseases that feature serious disturbances in glucose or lipid metabolism that severely affect the health and quality of life of affected individuals.
  • cancer metabolism is known to be different from normal cellular metabolism. The increasing prevalence of these diseases makes finding new drug targets for treating these syndromes an urgent task.
  • AMP-activated protein kinase acts as a cellular energy sensor and regulator. It is activated by an increase in the cellular AMP:ATP ratio induced by metabolic stress, hormone and nutrient signals and other cellular mechanisms such as phosphorylation and protein-protein interaction. Once activated, AMPK switches on catabolic pathways that generate ATP and switches off ATP-consuming anabolic pathways by acute regulation of the activity of key enzymes in metabolism and chronic regulation of the expression of pivotal transcription factors (Hardie, DG. Nature reviews 8 (2007b), 774-785; Woods, A et al. Molecular and cellular biology 20 (2000), 6704-6711).
  • Adiponectin stimulates glucose uptake and fatty acid oxidation in vitro by activation of AMPK. Furthermore, it exerts its hypoglycemic effect by decreasing PEPCK and G6Pase expression, whereas the administration of dominant negative al adenovirus reverses the effect in vivo (Yamauchi, T et al. Nature medicine 8 (2002), 1288-1295).
  • AMPK a potential target for treating metabolic syndrome
  • Rosiglitazone is traditionally considered to be a PPARy agonist and exerts its antidiabetic effects through differentiation of adipocytes (Semple, RK et al. The Journal of clinical investigation 116 (2006), 581-589). Recent findings indicate that AMPK may be involved in the antidiabetic effects of rosiglitazone (Brunmair, B et al. The Journal of biological chemistry 277 (2002), 25226-25232; Kadowaki, T et al. The Journal of clinical investigation 116(2006), 1784-1792).
  • metformin an existing antidiabetic agent without a defined mechanism of action
  • recent studies demonstrate that it could activate AMPK in vitro and in vivo by inhibiting complex I (El-Mir, MY et al. The Journal of biological chemistry 275 (2000), 223-228; Owen, MR et al. The Biochemical journal 348 Pt 3 (2000), 607-614; Zhou, G et al. The Journal of clinical investigation 108 (2001), 1167-1174), and the hypoglycemic effect could be blocked completely by knockout of its upstream kinase LKB1, confirming the key role of AMPK in mediating the antidiabetic effect of metformin (Shaw, RJ et al. Science (New York) N.Y. 310 (2005), 1642-1646).
  • alkyl signifies a saturated, linear or branched chain alkyl group containing 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl and tert-butyl.
  • Preferred "alkyl” groups are methyl, ethyl, isopropyl and tert-butyl.
  • alkenyl alone or in combination, signifies an alkyl group as defined above wherein one or more carbon-carbon single bond is replaced by a carbon-carbon double bond.
  • alkenyl are ethenyl, propenyl, n-butenyl and i-butenyl.
  • Preferred alkenyl groups are ethenyl, propenyl and i-propenyl.
  • alkoxy signifies a group alkyl-O-, wherein the "alkyl” is as defined above; for example methoxy, ethoxy, propoxy, isopropoxy, w-butoxy, j-butoxy, 2-butoxy and i-butoxy.
  • Preferred alkoxy groups are methoxy and ethoxy and more preferably methoxy.
  • cycloalkyl refers to a saturated carbon ring containing from 3 to 7 carbon atoms, preferably from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Preferred cycloalkyl groups are cyclopropyl, cyclopentyl and cyclohexyl.
  • halogen means fluorine, chlorine, bromine or iodine. Halogen is preferably fluorine, chlorine or bromine.
  • halophenyl means phenyl substituted by halogen.
  • carboxyl alone or in combination, refers to the group -COOH.
  • carbonyl alone or in combination, refers to the group -C(O)-.
  • amino alone or in combination, refers to primary (-NH 2 -), secondary (-NH-) or tertiary amino (-N-).
  • hydroxy alone or in combination, refers to the group -OH.
  • sulfonyl alone or in combination, refers to the group -S(0) 2 -.
  • the compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts.
  • pharmaceutically acceptable salt refers to conventional acid-addition salts or base-addition salts that retain the biological
  • Acid- addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid
  • organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like.
  • Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide.
  • the chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et. al. organic Process Research & Development 2000, 4, 427-435; or in Ansel, H., et. al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457.
  • “Pharmaceutically acceptable esters” means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as
  • esters methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters.
  • any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention.
  • Preferred are the methyl and ethyl esters of the compounds of formula (I).
  • a 1 is absent. In another embodiment, A 1 is -CH 2 -. In another particular embodiment of the invention, A is nitrogen. In a further embodiment of the invention, A is -CH-.
  • a 3 is absent.
  • a 3 can also be -C(CH) 3 - in a particular embodiment of the compound of formula (I).
  • R 1 can be hydroxyl. In antother particular embodiment of the invention, R 1 is NR U NR 12 .
  • the invention relates also to a compound of formula (I) wherein R 2 and R 3 together with the carbon atom to which they are attached form cycloalkyl.
  • the invention relates to a compound of formula (I) wherein R 2 and R 3 are independently selected from methyl, ethyl, ethenyl and phenyl, or R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl, cyclopentyl or cyclohexyl.
  • a compound of formula (I) wherein R 4 is hydrogen, alkyl, alkoxy, halogen or alkylsulfonyl is also an object of the invention.
  • the invention relates also in particular is a compound of formula (I) wherein R 4 is hydrogen, methyl, fluoro, chloro, bromo or methylsulfonyl.
  • a compound of formula (I) wherein R 5 is hydrogen, alkyl, alkoxy, halogen, alkylsulfonyl, morpholinyl, piperazinyl or alkylpiperazinyl is also a particular embodiment of the invention. Furthermore, the invention relates to a compound of formula (I) wherein R 5 is hydrogen, chloro, or morpholinyl.
  • a compound of formula (I) wherein R 6 is hydrogen or halogen is a further particular object of the invention. Moreover, the invention is directed in particular to formula (I) wherein R 6 is hydrogen or fluoro.
  • a compound of formula (I) wherein R is hydrogen, halogen, alkylsulfonyl or morpholinyl is an object of the invention.
  • the invention relates to a compound of formula (I) wherein R is hydrogen, fluoro, chloro, bromo or methylsulfonyl.
  • R is hydrogen or alkyl
  • the invention relates to a compound of formula (I) wherein R is hydrogen or methyl.
  • a compound of formula (I) wherein R 9 is hydrogen, pentyl, dimethylaminocarbonyl or benzyl is a further object of the invention.
  • a compound of formula (I) wherein R 10 is hydrogen or chloro is also an object of the invention.
  • a compound of formula (I) wherein R 11 and R 12 are independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl and alkylpiperidinyl is an object of the invention.
  • alkylsulfonylpiperazinyl is another object of the invention.
  • this invention relates to a compound of formula (I) wherein R 11 and R 12 are independently selected from hydrogen, methyl, propyl, dihydroxybutyl, cyclopropyl, cyclobutyl, methylpiperidinyl and hydroxyethyl or R 11 and R 12 together with the nitrogen atom to which they are attached form morpholinyl, piperazinyl, methylpiperazinyl or methylsulfonylpiperazinyl.
  • the invention relates in particular to a compound of formula (I) wherein R 11 and R 12 are independently selected from hydrogen, methyl, propyl, dihydroxybutyl, cyclopropyl, cyclobutyl, methylpiperidinyl and hydroxyethyl.
  • the invention also relates to a compound of formula (I) wherein R 11 and R 12 together with the nitrogen atom to which they are attached form morpholinyl, piperazinyl, methylpiperazinyl or methylsulfonylpiperazinyl.
  • the compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds are provided in the schemes below and in the examples. In the following schemes, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , A 1 ,
  • a 2 , and A 3 are as defined above unless otherwise indicated.
  • X is halogen.
  • DMSO dimethylsulfoxide gram h or hr: hour hrs: hours
  • HATU o-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
  • R 2 and R 3 together with the carbon atom to which they are attached form cycloalkyl.
  • the compound of formula la can be prepared according to Scheme 1.
  • the aniline III reacts with the aldehyde IV to generate the imine V.
  • the imine V reacts with the methylene-cycloalkene VI to afford the tetrahydroquinoline VII.
  • Hydrolysis of the tetrahydroquinoline VII affords la.
  • the imine V can be prepared by a condensation reaction of the substituted aniline III and the substituted aldehyde IV in an organic solvent such as toluene, methanol or ethanol and a mixture thereof, at a temperature between 80 and 140 °C for 2 to 16 hours.
  • an organic solvent such as toluene, methanol or ethanol and a mixture thereof
  • the compound VII can be prepared from the imine V and the methylene-cycloalkene VI.
  • This Diels-Alder reaction can be carried out in the presence of a Lewis acid such as ytterbium(ni) trifluoromethanesulfonate (Yb(OTf) 3 ), scandium(III)
  • La(OTf) indium(in) trifluoromethanesulfonate (In(OTf) ), indium trichloride (InCl 3 ), or boron trifluoride diethyl etherate (BF 3 Et 2 0), or a protic acid such as trifluoroacetic acid (TFA) or /7-toluenesulfonic acid, in a solvent such as acetonitrile, dichloromethane, tetrahydrofuran, nitromethane, N,N-dimethylformamide, 2,2,2-trifluoroethanol or a mixture thereof, at a temperature between 25 and 100 °C for several hours (reference: Kiselyov, A. S.
  • Hydrolysis of the methyl ester VII to the resulting product la can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature or refluxed for several hours.
  • an aqueous inorganic base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide
  • a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature or refluxed for several hours.
  • R 2 and R 3 together with the carbon atom to which they are attached form cycloalkyl.
  • the compound of formula lb and Ic can be prepared according to Scheme 2.
  • the compound of formula VIII can be synthesized as illustrated in Scheme 1. VIII is functionalized by copper-catalyzed Ullmann coupling reaction, followed by hydrolysis of the methyl ester to produce the compounds lb and Ic.
  • the Ullmann coupling reaction as outlined in the Scheme 2 can be carried out in the presence of a copper source such as copper(I) iodide (Cul) or copper(II)
  • trifluoromethanesulfonate and a ligand such as 2,2'-bipyridine, proline, N,N'-dimethyl glycine or ethylene glycol, in the presence of a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert- butoxide or potassium ie/t-butoxide.
  • a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert- butoxide or potassium ie/t-butoxide.
  • the reaction can be carried out in a suitable solvent such as 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrolidinone at a temperature between 100 and 180 °C for 15 to 60 minutes under microwave irradiation.
  • the reactions can be carried out without the use of a microwave at a heated temperature such as 130 °C for a longer reaction time (reference: Ley, S. V. et al., Angew. Chem. Int. Ed. 42 (2003) 5400).
  • Hydrolysis of the methyl esters X and XI to the resulting products lb and Ic can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature or refluxed for several hours.
  • an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature or refluxed for several hours.
  • R 2 and R 3 together with the carbon atom to which they are attached form cycloalkyl
  • a 3 is absent;R 9 is alkyl, benzyl or alkylaminocarbonyl.
  • the compound of formula Id can be prepared according to Scheme 3.
  • the compound of formula VII can be synthesized as illustrated in Scheme 1. VII is functionalized by acylation, alkylation or benzylation with tetrahydro-quinoline-l-yl group, followed by hydrolysis of the methyl ester to produce the compound Id.
  • Acylation, alkylation or benzylation of tetrahydro-quinoline-l-yl group of formula XII can be easily accomplished using methods well known to someone skilled in the art.
  • the reaction is typically carried out in the presence of a base such as triethylamine, pyridine, sodium methoxide, sodium ie/t-butoxide, potassium ie/t-butoxide, sodium hydride or dimethyl-pyridin-4-yl-amine in a suitable inert solvent such as dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran or a mixtures thereof, at room temperature for several hours.
  • a base such as triethylamine, pyridine, sodium methoxide, sodium ie/t-butoxide, potassium ie/t-butoxide, sodium hydride or dimethyl-pyridin-4-yl-amine
  • a suitable inert solvent such as dichlorome
  • Hydrolysis of the methyl esters can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1,4-dioxane, tetrahydrofuran or a mixtures thereof at room temperature or refluxed for several hours.
  • an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a solvent such as methanol, 1,4-dioxane, tetrahydrofuran or a mixtures thereof at room temperature or refluxed for several hours.
  • R 2 and R 3 are independently selected from alkyl, alkenyl and phenyl.
  • the compound of formula Ie can be prepared according to Scheme 4. This approach is based on three-component aza-Diels-Alder reactions using a Lewis acid or protic acid as the catalyst. The substituted aniline XIII, substituted aldehyde IV and substituted ethylene XIV are used in this reaction to afford XV. The corresponding acid Ie can be afforded through hydrolysis of the methyl ester XV. In the method outlined in Scheme 4, the compound XV can be prepared by a three- component condensation of substituted aniline XIII, substituted aldehyde IV, and substituted ethylene XIV.
  • This reaction can be carried out successfully in the presence of a Lewis acid such as ytterbium(III) trifluoromethanesulfonate (Yb(OTf>3), scandium(III) trifluoromethanesulfonate (Sc(OTf) 3 ), lanthanum(III) trifluoromethanesulfonate
  • a Lewis acid such as ytterbium(III) trifluoromethanesulfonate (Yb(OTf>3), scandium(III) trifluoromethanesulfonate (Sc(OTf) 3 ), lanthanum(III) trifluoromethanesulfonate
  • La(OTf) 3 indium(in) trifluoromethanesulfonate (In(OTf) 3 ), indium trichloride (InCl 3 ) or boron trifluoride diethyl etherate (BF Et 2 0) or a pro tic acid such as trifluoroacetic acid (TFA) or /7-toluenesulfonic acid, in aqueous or anhydrous conditions such as acetonitrile, dichloromethane, tetrahydrofuran, nitromethane, N,N-dimethylformamide, 2,2,2- trifluoroethanol, water or a mixture thereof, at a temperature between 25 and 100 °C for several hours (reference: Kiselyov, A. S. et al., Tetrahedron 54 (1998) 5089).
  • Hydrolysis of the methyl ester XV to the resulting product Ie can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1,4-dioxane, tetrahydrofuran or a mixture thereof at room temperature or refluxed for several hours.
  • an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a solvent such as methanol, 1,4-dioxane, tetrahydrofuran or a mixture thereof at room temperature or refluxed for several hours.
  • R 2 and R 3 are alkyl
  • R 5 is morpholinyl, piperazinyl or alkylpiperazinyl.
  • the compound of formula If can be prepared according to Scheme 5.
  • the compound of formula XVI can be synthesized as illustrated in Scheme 4.
  • XVI is functionalized by copper-catalyzed Ullmann coupling reaction with amine such as morpholine, piperazine or N-methyl-piperazine or sodium methanesulfinate, followed by hydrolysis of the methyl ester to produce the compound If.
  • the Ullmann coupling reaction as outlined in the Scheme 5 can be carried out in the presence of a copper source such as copper(I) iodide (Cul) or copper(II)
  • trifluoromethanesulfonate and a ligand such as 2,2'-bipyridine, proline, N,N'-dimethyl glycine or ethylene glycol, in the presence of a suitable base such as triethylamine, potassium carbonate or cesium carbonate.
  • a suitable solvent such as 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N- methylpyrolidinone at a temperature between 100 and 180 °C for 15 to 60 minutes under microwave irradiation.
  • the reactions can be carried out without the use of a microwave at high temperature such as 130 °C for a longer reaction time (reference: Ley, S. V. et al., Angew. Chem. Int. Ed. 42 (2003) 5400).
  • Hydrolysis of the methyl ester XVII to the resulting product If can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1,4-dioxane, tetrahydrofuran or a mixture thereof at room temperature or refluxed for several hours.
  • an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a solvent such as methanol, 1,4-dioxane, tetrahydrofuran or a mixture thereof at room temperature or refluxed for several hours.
  • a 3 is absent; R 4 , R 5 , R 6 , R 7 , R 8 are independently selected from hydrogen and halogen; R 9 is alkyl.
  • a 3 is absent; R 4 , R 5 , R 6 , R 7 , R 8 are independently selected from hydrogen and halogen; R is alkyl.
  • the compounds of formula Ig, Ih, Ii and Ij can be prepared according to Scheme 6.
  • the imine XIX can be prepared from 5-amino- pyridine-2-carbonitrile XVIII and substituted aldehyde IV.
  • the compound Ig can be prepared from imine XIX and 2-methyl-buta-l,3-diene XX through Diels- Alder reactions. This Diels-Alder reaction can be carried out successfully in the presence of a Lewis acid such as ytterbium(ni) trifluoromethanesulfonate (Yb(OTf) 3 ), scandium(III)
  • a Lewis acid such as ytterbium(ni) trifluoromethanesulfonate (Yb(OTf) 3 ), scandium(III)
  • La(OTf) indium(in) trifluoromethanesulfonate (In(OTf) ), indium trichloride (InCl 3 ) or boron trifluoride diethyl etherate (BF 3 Et 2 0) or a pro tic acid such as trifluoroacetic acid (TFA) or /7-toluenesulfonic acid, in a solvent such as acetonitrile, dichloromethane, tetrahydrofuran, nitromethane, N,N-dimethylformamide, 2,2,2-trifluoroethanol, water or a mixture thereof, at a temperature between 25 and 100 °C for several hours (reference: Kiselyov, A. S. et al., Tetrahedron 54 (1998) 5089).
  • Methanolysis of the nitrile Ig can provide the corresponding methyl ester XXI.
  • the reaction can be carried out in the presence of a catalyst such as hydrochloride, concentrated sulfuric acid, chlorotrimethylsilane or thionyl chloride in methanol, at a temperature between room temperature and 90 °C for several hours.
  • a catalyst such as hydrochloride, concentrated sulfuric acid, chlorotrimethylsilane or thionyl chloride in methanol, at a temperature between room temperature and 90 °C for several hours.
  • Hydrolysis of the methyl ester XXI (Route A) to the resulting product Ih can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1,4-dioxane,
  • reaction is typically carried out under 10% palladium on active carbon in a suitable solvent such as methanol, ethanol, tetrahydrofuran, water or a mixture thereof at room temperature or reflux of the solvent for several hours.
  • Hydrogenation of the vinyl compound XXI (Route B) can be accomplished using methods well known to someone skilled in the art.
  • the reaction typically is carried out under 10% palladium on active carbon in a suitable solvent such as methanol, ethanol, tetrahydrofuran, water or a mixture thereof at room temperature or reflux of the solvent for several hours.
  • a suitable inert solvent such as dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran or mixtures thereof
  • Hydrolysis of the methyl ester XXII to the resulting product Ij can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1,4-dioxane, tetrahydrofuran or a mixture thereof at room temperature or refluxed for several hours.
  • an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a solvent such as methanol, 1,4-dioxane, tetrahydrofuran or a mixture thereof at room temperature or refluxed for several hours.
  • the compound of formula Ik can be synthesized as illustrated in Scheme 7, starting from the one compound selected from la to Ij, which can be prepared according to Schemes 1-6.
  • Conversion of the acids la to Ij to the corresponding amide Ik with suitable amines XXIII can be easily accomplished using methods well known to someone skilled in the art.
  • the reaction is typically carried out in the presence of a coupling reagent such as dicyclohexyl carbodiimide (DCC), benzotriazol-l-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBop), o-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), o(lH-benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or l-ethyl-3-(3'-dimethylamino)carbodiimide hydrochloride salt (EDCI), in the presence
  • the reaction can be carried out in a solvent such as dichloromethane or N,N- dimethylformamide at room temperature for several hours (reference: Montalbetti, C. A. G. N. et al., Tetrahedron 61 (2005) 10827).
  • the invention also relates to a process for the preparation of a compound of formula (I) comprising one of the following steps:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , A 1 , A 2 and A 3 are defined above and R 11 is alkyl.
  • R 11 is preferably methyl.
  • the base can be for example independently selected form lithium hydroxide, sodium hydroxide or potassium hydroxide.
  • the coupling reagent can be for example dicyclohexyl carbodiimide (DCC), benzotriazol-l-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBop), o-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU),
  • DCC dicyclohexyl carbodiimide
  • PyBop benzotriazol-l-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate
  • HATU o-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • HBTU 0- (lH-benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or
  • Step (i) can be carried out in the presence or absence of hydroxybenzotriazole (HOBt), in the presence of a base such as triethylamine or N,N-diisopropyl ethylamine or N,N-dimethylaminopyridine (DMAP).
  • HOBt hydroxybenzotriazole
  • DMAP N,N-dimethylaminopyridine
  • the invention also relates to a compound of formula (I) for use as therapeutically active substance.
  • the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier.
  • the use of a compound of formula (I) for the preparation of medicaments useful in the treatment or prophylaxis diseases that are related to AMPK regulation is an object of the invention.
  • the invention relates in particular to the use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes, in particular type 2 diabetes.
  • Said medicaments e.g. in the form of pharmaceutical preparations, can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions.
  • the administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions with an effective amount of a compound as defined above.
  • the above-mentioned pharmaceutical composition can be obtained by processing the compounds according to this invention with pharmaceutically inert inorganic or organic carriers.
  • Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers (or excipients) for tablets, coated tablets, dragees and hard gelatine capsules.
  • Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules.
  • Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
  • Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
  • the pharmaceutical composition can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage depends on various factors such as manner of administration, species, age and/or individual state of health.
  • the doses to be administered daily are about 5-400 mg/kg, preferably about 10-100 mg/kg, and can be taken singly or distributed over several administrations.
  • a compound of formula (I) when manufactured according to the above process is also an object of the invention.
  • the invention also relates to a method for the treatment or prophylaxis of diseases that are related to AMPK regulation, which method comprises administering an effective amount of a compound of formula (I).
  • the invention further relates to a method for the treatment or prophylaxis of obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes, in particular type 2 diabetes, which method comprises administering an effective amount of a compound of formula (I).
  • the invention also relates to a compound of formula (I) for the preparation of medicaments useful in the treatment of cancers that are related to AMPK regulation.
  • the invention provides a method for the treatment of cancers that are related to AMPK regulation, which method comprises administering an effective amount of a compound of formula (I).
  • Acidic condition A: 0.1% formic acid in H 2 0; B: 0.1% formic acid in acetonitrile;
  • Basic condition A: 0.01% NH 3 H 2 0 in H 2 0; B: acetonitrile;
  • reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3) and washed with brine (100 mL) and then dried over anhydrous Na 2 S0 4 .
  • the solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30 - 60% ethyl acetate in petroleum ether) to afford 2-(5-fluoro-2- methanesulfonyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid methyl ester ( 160 mg, 41.1%) as a white solid.
  • 6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[l,5]naphthyridine-2- carbonitrile (327 mg, 1 mmol) was dissolved in MeOH (30 mL, saturated with HC1 gas) and stirred at 75 °C overnight. The mixture was cooled to room temperature, poured into saturate NaHC0 3 solution (150 mL) carefully, and extracted with ethyl acetate (50 mL x 3). The organic layers were washed with brine (10 mL), dried over anhydrous Na 2 S0 4 and concentrated in vacuo.
  • 6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro-[l,5]naphthyridine- 2-carboxylic acid methyl ester The mixture solution of 6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid methyl ester (360 mg, 1 mmol) and 10% palladium on active carbon (120 mg) in methanol (50 mL) was stirred at room temperature under hydrogen (14 psi) for 8 hours.
  • 6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid methyl ester To a 0 °C solution of 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid methyl ester (200 mg, 0.5 mmol) in N,N- dimethylformamide (5 mL) was added a 60% dispersion of sodium hydride in mineral oil (44 mg, 1.1 mmol) portionwise.
  • Recombinant human AMPK ⁇ , 2 ⁇ 1 ⁇ 1 or AMPK a subunit truncations ccl(l-335), l(l-394) and 2(l-394) were constructed, expressed and purified as described previously (Pang, T., Zhang, Z.S., Gu, M., Qiu, B.Y., Yu, L.F., Cao, P.R., Shao, W., Su, M.B., Li, J.Y., Nan, F.J., and Li, J. (2008).
  • Rat liver AMPK heterotrimer enzyme was obtained from Upstate (Billerica, MA, U.S.A.).
  • SPA reactions were performed in 96-well plates at a final volume of 50 ⁇ ⁇ containing 20 mM Tris-HCl pH 7.5, 5 mM MgCl 2 , 1 mM DTT, 2 ⁇ biotin-SAMS, 2 ⁇ ATP,0.2 ⁇ /well [ ⁇ - 33 ⁇ ] ⁇ , and various amount of activator. Reactions were initiated by the addition of 50 nM recombinant AMPK proteins to the reaction solutions and incubated at 30 °C for 2 hours.
  • EC50 effective concentration of the activator
  • Seleceted compounds of formula (I) have the following EC50, obtained by using the foregoing Scintillation Proximity Assay.
  • Example 57 2.36
  • Example 58 3.74
  • a compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet
  • a compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:

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Abstract

A compound of formula (I) or a pharmaceutically acceptable salt or ester thereof, wherein A1 to A3 and R1 to R10 have the significance given in claim 1, can be used as AMPK activators.

Description

NOVEL TETRAHYDROQUINOLINE DERIVATIVES
The invention relates to compounds which are activators of AMP-activated protein kinase (AMPK) and which are useful in the treatment or prophylaxis of diseases that are related to AMPK regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes and cancers.
The invention relates in particular to a compound of formula (I)
Figure imgf000002_0001
wherein
A1 is absent or -CH2-; A is nitrogen or -CH-; A3 is absent or -C(CH3)2-; P Ss hydroxyl or NRnR12;
R 2" and R3J are independently selected from alkyl, alkenyl and phenyl; or R 2 and R3 together with the carbon atom to which they are attached form
cycloalkyl;
FZ/DP/05.05.2011 R4, R5, R6, R7 and R8 are independently selected from hydrogen, alkyl, alkoxy, halogen, alkylsulfonyl, morpholinyl, piperazinyl and alkylpiperazinyl;
R9 is hydrogen, alkyl, benzyl or alkylaminocarbonyl;
R10 is hydrogen or halogen; R 1^ 1 and R 112" are independently selected from hydrogen, alkyl, cycloalkyl,
hydroxyalkyl, oxetanyl, alkylpiperidinyl, 1,1-dioxothiomorpholinylalkyl or benzylpiperidinyl ;
or R 11 and R 12 together with the nitrogen atom to which they are attached form
morpholinyl, piperazinyl, alkylpiperazinyl, alkylsulfonylpiperazinyl, alkylhydroxypyrrolidinyl or hydroxyalkylpyrrolidinyl; or a pharmaceutically acceptable salt or ester thereof.
The invention also relates to a process for the manufacture of these novel compounds and medicaments containing them. The compounds of the invention have activation effect on AMP (adenosine monophosphate)-activated protein kinase, which results in lowered blood glucose and lipid levels. The invention thus also concerns the use of such
compounds for the treatment or prophylaxis of diseases that are related to AMPK regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes, and cancers.
Obesity and type 2 diabetes, hypertension and cardiovascular disease are diseases that feature serious disturbances in glucose or lipid metabolism that severely affect the health and quality of life of affected individuals. In addition, cancer metabolism is known to be different from normal cellular metabolism. The increasing prevalence of these diseases makes finding new drug targets for treating these syndromes an urgent task.
AMP-activated protein kinase acts as a cellular energy sensor and regulator. It is activated by an increase in the cellular AMP:ATP ratio induced by metabolic stress, hormone and nutrient signals and other cellular mechanisms such as phosphorylation and protein-protein interaction. Once activated, AMPK switches on catabolic pathways that generate ATP and switches off ATP-consuming anabolic pathways by acute regulation of the activity of key enzymes in metabolism and chronic regulation of the expression of pivotal transcription factors (Hardie, DG. Nature reviews 8 (2007b), 774-785; Woods, A et al. Molecular and cellular biology 20 (2000), 6704-6711). The growing evidence of AMPK regulatory effects on glucose and lipid metabolism makes it a potential drug target for treatment of diabetes, metabolic syndrome and cancer (Carling, D. Trends Biochem Sci 29(2004), 18-24; Hardie, DG. Annual review of pharmacology and toxicology 47 (2007a), 185-210; Kahn, BB et al. Cell metabolism 1 (2005), 15-25; Long, YC et al. The Journal of clinical investigation 116 (2006), 1776-1783).
At the physiological level, this concept has been supported by two adipokines, leptin and adiponectin, both of which exert excellent effects on glucose and lipid metabolism (Friedman, JM and Halaas, JL. Nature 395 (1998), 763-770; Muoio, DM et al. Diabetes 46 (1997), 1360-1363; Yamauchi, T et al. Nature medicine 7 (2001), 941-946). Recent studies suggest that leptin and adiponectin exert their antidiabetic effects by activating AMPK. Leptin stimulates muscle fatty acid oxidation by activating AMPK directly and through a hypothalamic-adrenergic pathway (Minokoshi, Y et al. Nature 415 (2002), 339-343). Adiponectin stimulates glucose uptake and fatty acid oxidation in vitro by activation of AMPK. Furthermore, it exerts its hypoglycemic effect by decreasing PEPCK and G6Pase expression, whereas the administration of dominant negative al adenovirus reverses the effect in vivo (Yamauchi, T et al. Nature medicine 8 (2002), 1288-1295).
At the pharmacological level, the concept of AMPK as a potential target for treating metabolic syndrome has been further supported by the discovery of two major classes of existing antidiabetic drugs: thiazolidinediones (rosiglitazone, troglitazone and
pioglitazone) and biguanides (metformin and phenformin) activate AMPK in cultured cells and in vivo. Rosiglitazone is traditionally considered to be a PPARy agonist and exerts its antidiabetic effects through differentiation of adipocytes (Semple, RK et al. The Journal of clinical investigation 116 (2006), 581-589). Recent findings indicate that AMPK may be involved in the antidiabetic effects of rosiglitazone (Brunmair, B et al. The Journal of biological chemistry 277 (2002), 25226-25232; Kadowaki, T et al. The Journal of clinical investigation 116(2006), 1784-1792). In the case of metformin, an existing antidiabetic agent without a defined mechanism of action, recent studies demonstrate that it could activate AMPK in vitro and in vivo by inhibiting complex I (El-Mir, MY et al. The Journal of biological chemistry 275 (2000), 223-228; Owen, MR et al. The Biochemical journal 348 Pt 3 (2000), 607-614; Zhou, G et al. The Journal of clinical investigation 108 (2001), 1167-1174), and the hypoglycemic effect could be blocked completely by knockout of its upstream kinase LKB1, confirming the key role of AMPK in mediating the antidiabetic effect of metformin (Shaw, RJ et al. Science (New York) N.Y. 310 (2005), 1642-1646).
Most recently, Cool and coworkers have identified a small direct AMPK activator, A-769662, which exerts antidiabetic effects in vivo (Cool, B et al. Cell metabolism 3 (2006), 403-416). Li's laboratory has also identified a small AMPK activator, PTl, which activates the inactive forms of AMPK 2398 and l3g4 with micromolar activity and exerts some cellular effects (Pang, T et al. The Journal of biological chemistry 283 (2008), 16051-16060). It has been found that the compounds of the present invention are potent AMPK activators. The compounds of the invention are therefore useful in the treatment or prophylaxis of diseases that are related to AMPK regulation, such as obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes and cancers.
As used herein, the term "alkyl", alone or in combination, signifies a saturated, linear or branched chain alkyl group containing 1 to 8, preferably 1 to 6, more preferably 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1-butyl, 2-butyl and tert-butyl. Preferred "alkyl" groups are methyl, ethyl, isopropyl and tert-butyl.
The term "alkenyl", alone or in combination, signifies an alkyl group as defined above wherein one or more carbon-carbon single bond is replaced by a carbon-carbon double bond. Examples of alkenyl are ethenyl, propenyl, n-butenyl and i-butenyl.
Preferred alkenyl groups are ethenyl, propenyl and i-propenyl.
The term "alkoxy", alone or in combination, signifies a group alkyl-O-, wherein the "alkyl" is as defined above; for example methoxy, ethoxy, propoxy, isopropoxy, w-butoxy, j-butoxy, 2-butoxy and i-butoxy. Preferred alkoxy groups are methoxy and ethoxy and more preferably methoxy.
The term "cycloalkyl", alone or in combination, refers to a saturated carbon ring containing from 3 to 7 carbon atoms, preferably from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Preferred cycloalkyl groups are cyclopropyl, cyclopentyl and cyclohexyl The term "halogen" means fluorine, chlorine, bromine or iodine. Halogen is preferably fluorine, chlorine or bromine. The term "halophenyl" means phenyl substituted by halogen.
The term "carboxyl", alone or in combination, refers to the group -COOH.
The term "carbonyl", alone or in combination, refers to the group -C(O)-.
The term "amino", alone or in combination, refers to primary (-NH2-), secondary (-NH-) or tertiary amino (-N-).
The term "hydroxy", alone or in combination, refers to the group -OH.
The term "sulfonyl", alone or in combination, refers to the group -S(0)2-.
The compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to conventional acid-addition salts or base-addition salts that retain the biological
effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid- addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et. al. organic Process Research & Development 2000, 4, 427-435; or in Ansel, H., et. al., In: Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th ed. (1995), pp. 196 and 1456-1457. Preferred are the sodium salts of the compounds of formula (I).
"Pharmaceutically acceptable esters" means that compounds of general formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compounds in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives, such as
methoxymethyl esters, methylthiomethyl esters and pivaloyloxymethyl esters.
Additionally, any physiologically acceptable equivalents of the compounds of general formula (I), similar to the metabolically labile esters, which are capable of producing the parent compounds of general formula (I) in vivo, are within the scope of this invention. Preferred are the methyl and ethyl esters of the compounds of formula (I).
In a particular embodiment of the invention, A1 is absent. In another embodiment, A1 is -CH2-. In another particular embodiment of the invention, A is nitrogen. In a further embodiment of the invention, A is -CH-.
Still in a particular embodiment of the invention, A 3 is absent. A 3 can also be -C(CH)3- in a particular embodiment of the compound of formula (I).
R1 can be hydroxyl. In antother particular embodiment of the invention, R1 is NRUNR12.
The compound of formula (I) wherein R 2 and R 3 are independently selected from alkyl, alkenyl and phenyl is a particular embodiment of the invention.
The invention relates also to a compound of formula (I) wherein R 2 and R 3 together with the carbon atom to which they are attached form cycloalkyl. In particular, the invention relates to a compound of formula (I) wherein R 2 and R 3 are independently selected from methyl, ethyl, ethenyl and phenyl, or R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl, cyclopentyl or cyclohexyl.
The compound of formula (I) wherein R 2 and R 3 are independently selected from methyl, ethyl, ethenyl and phenyl is an embodiment of the invention.
The compound of formula (I) wherein R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl, cyclopentyl or cyclohexyl is another
embodiment of the invention.
A compound of formula (I) wherein R4 is hydrogen, alkyl, alkoxy, halogen or alkylsulfonyl is also an object of the invention.
The invention relates also in particular is a compound of formula (I) wherein R4 is hydrogen, methyl, fluoro, chloro, bromo or methylsulfonyl.
A compound of formula (I) wherein R5 is hydrogen, alkyl, alkoxy, halogen, alkylsulfonyl, morpholinyl, piperazinyl or alkylpiperazinyl is also a particular embodiment of the invention. Furthermore, the invention relates to a compound of formula (I) wherein R5 is hydrogen, chloro, or morpholinyl.
A compound of formula (I) wherein R6 is hydrogen or halogen is a further particular object of the invention. Moreover, the invention is directed in particular to formula (I) wherein R6 is hydrogen or fluoro.
A compound of formula (I) wherein R is hydrogen, halogen, alkylsulfonyl or morpholinyl is an object of the invention.
Furthermore, the invention relates to a compound of formula (I) wherein R is hydrogen, fluoro, chloro, bromo or methylsulfonyl.
In a particular embodiment of the invention, R is hydrogen or alkyl.
In particular, the invention relates to a compound of formula (I) wherein R is hydrogen or methyl.
A compound of formula (I) wherein R9 is hydrogen, pentyl, dimethylaminocarbonyl or benzyl is a further object of the invention.
A compound of formula (I) wherein R10 is hydrogen or chloro is also an object of the invention.
Furthermore, a compound of formula (I) wherein R 11 and R 12 are independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl and alkylpiperidinyl, or R11 and R 12 together with the nitrogen atom to which they are attached form morpholinyl, piperazinyl, alkylpiperazinyl or alkylsulfonylpiperazinyl, is an object of the invention.
A compound of formula (I) wherein R 11 and R 12 are independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl and alkylpiperidinyl is an object of the invention.
A compound of formula (I) wherein R 11 and R 12 together with the nitrogen atom to which they are attached form morpholinyl, piperazinyl, alkylpiperazinyl or
alkylsulfonylpiperazinyl is another object of the invention.
Furthermore, this invention relates to a compound of formula (I) wherein R 11 and R 12 are independently selected from hydrogen, methyl, propyl, dihydroxybutyl, cyclopropyl, cyclobutyl, methylpiperidinyl and hydroxyethyl or R 11 and R 12 together with the nitrogen atom to which they are attached form morpholinyl, piperazinyl, methylpiperazinyl or methylsulfonylpiperazinyl.
The invention relates in particular to a compound of formula (I) wherein R 11 and R 12 are independently selected from hydrogen, methyl, propyl, dihydroxybutyl, cyclopropyl, cyclobutyl, methylpiperidinyl and hydroxyethyl.
The invention also relates to a compound of formula (I) wherein R 11 and R 12 together with the nitrogen atom to which they are attached form morpholinyl, piperazinyl, methylpiperazinyl or methylsulfonylpiperazinyl.
Particular compounds of formula (I) according to the invention can be selected from
2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'- ,2',3',4'-tetrahydroquinoline)-6- carboxylic acid;
2-(5-Bromo-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(3,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(3-Methanesulfonyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(3-Fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclohexane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid; 2-(5-Fluoro-2-methanesulfonyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(2,5-Dimethanesulfonyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(2,5-Dichloro-phenyl)-l-dimethylcarbamoyl-spiro(cyclopropane-l,4'- ,2',3',4'- tetrahydroquinoline)-6-carboxylic acid;
1 -Benzyl-2-(2,5-dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(2,5-Dichloro-phenyl)-4,4-dimethyl- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid;
4,4-Dimethyl-2-(l-methyl-l-phenyl-ethyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid;
7-Chloro-2-(5-chloro-2-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid;
[2-(5-Chloro-2-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6-yl]-acetic acid;
2-(3-Chloro-4-fluoro-phenyl)-4-methyl-4- vinyl- l,2,3,4-tetrahydro-quinoline-6-carboxylic acid;
2-(3-Chloro-4-fluoro-phenyl)-4-methyl-4-phenyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid;
2-(5-Fluoro-2-isopropoxy-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid;
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid;
2-[3-(4-Isopropyl-piperazin-l-yl)-phenyl]-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid;
4,4-Dimethyl-2-(3-piperazin-l-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid;
6-(3-Chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[l,5]naphthyridine-2- carboxylic acid;
6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro-[l,5]naphthyridine-2- carboxylic acid; 6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid;
2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'- ,2',3',4'-tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'- ,2',3',4'-tetrahydroquinoline)-6- carboxylic acid dimethylamide;
[2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6- yl] -morpholin-4-yl-methanone;
[2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6- yl] -(4-methyl-piperazin- 1 -yl)-methanone;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6- yl] -morpholin-4-yl-methanone;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid isopropylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid dimethylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
2-(5-Bromo-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclopropylamide;
2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid methylamide;
2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
[2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6-yl] - morpholin-4-yl-methanone; 2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid isopropylamide;
[2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6-yl] -(4- methanesulfonyl-piperazin- 1 -yl)-methanone;
2-(3,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
[2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6- yl] -morpholin-4-yl-methanone;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid dimethylamide;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid isopropylamide;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6- yl] -piperazin- 1 -yl-methanone;
2-(2-Bromo-4-fluoro-6-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid methylamide;
4,4-Dimethyl-2-(l-methyl-l-phenyl-ethyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid dimethylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid dimethylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclopropylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid (l-methyl-piperidin-4-yl)-amide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide; 2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid methylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid (2-hydroxy-ethyl)-amide;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6- yl] -morpholin-4-yl-methanone;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6- yl] -(4-methyl-piperazin- 1 -yl)-methanone;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid oxetan-3-ylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid isopropylamide;
2-(2,5-Dichloro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
2-(3-Fluoro-phenyl)-spiro(cyclopentane-l,4'- ,2',3',4'-tetrahydroquinoline)-6-carboxylic acid cyclobutylamide;
2-(3-Morpholin-4-yl-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid methylamide;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid dimethylamide;
2-(2,5-Dichloro-phenyl)-4,4-dimethyl- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid cyclobutylamide ;
2-(5-Chloro-2-fluoro-phenyl)-4,4-dimethyl- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid cyclobutylamide ;
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2-hydroxy- 1 -hydroxymethyl- 1 -methyl-ethyl)-amide; 2- (3-Chloro-4-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro-[l,5]naphthyridine-2- carboxylic acid cyclobutylamide;
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid isopropylamide;
N-[2-(l,l-dioxidothiomorpholin-4-yl)ethyl]-4,4-dimethyl-2-[3-(morpholin-4-yl)pheny l,2,3,4-tetrahydroquinoline-6-carboxamide;
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2,3-dihydroxy-propyl)-amide;
N-[2-(l,l-dioxidothiomorpholin-4-yl)ethyl]-4,4-dimethyl-2-{3-[4-(propan-2-yl)piperazin- 1 -yl]phenyl } - 1 ,2,3,4-tetrahydroquinoline-6-carboxamide;
N-[2-( 1 , 1 -dioxidothiomorpholin-4-yl)ethyl] -4,4-dimethyl-2-(2-phenylpropan-2-yl)- l,2,3,4-tetrahydroquinoline-6-carboxamide;
[4,4-Dimethyl-2-(l-methyl-l-phenyl-ethyl)-l,2,3,4-tetrahydro-quinolin-6-yl]-morphom^ yl-methanone;
[4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinolin-6-yl]-(3-hydroxy-
3- methyl-pyrrolidin- 1 -yl)-methanone;
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2-hydroxy- 1 -hydroxymethyl-ethyl)-amide;
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2-hydroxy-ethyl)-amide;
[2-(3-Fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6-yl]-(3- hydroxy-3-methyl-pyrrolidin- 1 -yl)-methanone;
[2-(3-Fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6-yl]- morpholin-4-yl-methanone;
[4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinolin-6-yl]-morpho yl-methanone; 2-(3-Fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6-yl]-[3- ( 1 -hydroxy- 1 -methyl-ethyl)-pyrrolidin- 1 -yl] -methanone;
2-(5-Fluoro-2-isopropoxy-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid cyclobutylamide;
2-(5-Fluoro-2-isopropoxy-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2-hydroxy- 1 -hydroxymethyl-ethyl)-amide;
[2-(5-Fluoro-2-isopropoxy-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6-yl]-(3- hydroxy-3-methyl-pyrrolidin- 1 -yl)-methanone;
2-(3-Chloro-4-fluoro-phenyl)-4,4-dimethyl- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid ( 1 -benzyl-piperidin-4-yl)-amide;
2-(3-Fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid (2-hydroxy-ethyl)-amide; and
[4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinolin-6-yl]-[3-(l- hydroxy- 1 -methyl-ethyl)-pyrrolidin- 1 -yl] -methanone.
Further particular compounds of formula (I) can be selected from
2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'- ,2',3',4'-tetrahydroquinoline)-6- carboxylic acid;
2-(5-Bromo-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(3-Fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclohexane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid; 2-(5-Fluoro-2-methanesulfonyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(2,5-Dichloro-phenyl)-l-dimethylcarbamoyl-spiro(cyclopropane-l,4'- ,2',3',4'- tetrahydroquinoline)-6-carboxylic acid;
1 -Benzyl-2-(2,5-dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
7-Chloro-2-(5-chloro-2-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid;
[2-(5-Chloro-2-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6-yl]-acetic acid;
2-(3-Chloro-4-fluoro-phenyl)-4-methyl-4- vinyl- l,2,3,4-tetrahydro-quinoline-6-carboxylic acid;
2-(3-Chloro-4-fluoro-phenyl)-4-methyl-4-phenyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid;
6-(3-Chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[l,5]naphthyridine-2- carboxylic acid;
6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro-[l,5]naphthyridine-2- carboxylic acid;
6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid;
[2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6- yl] -morpholin-4-yl-methanone;
[2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6- yl] -(4-methyl-piperazin- 1 -yl)-methanone;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6- yl] -morpholin-4-yl-methanone;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid dimethylamide;
2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid methylamide; 2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
[2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6-yl] - morpholin-4-yl-methanone;
[2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6-yl] -(4- methanesulfonyl-piperazin- 1 -yl)-methanone;
[2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6- yl] -morpholin-4-yl-methanone;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid dimethylamide;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6- yl] -piperazin- 1 -yl-methanone;
2-(2-Bromo-4-fluoro-6-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid methylamide;
4,4-Dimethyl-2-(l-methyl-l-phenyl-ethyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid dimethylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid dimethylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclopropylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid (l-methyl-piperidin-4-yl)-amide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid methylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid (2-hydroxy-ethyl)-amide; [2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6- yl] -morpholin-4-yl-methanone;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinolin)-6- yl] -(4-methyl-piperazin- 1 -yl)-methanone;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid isopropylamide;
2-(3-Fluoro-phenyl)-spiro(cyclopentane-l,4'- ,2',3',4'-tetrahydroquinoline)-6-carboxylic acid cyclobutylamide;
2-(3-Morpholin-4-yl-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid methylamide;
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2-hydroxy- 1 -hydroxymethyl- 1 -methyl-ethyl)-amide; and
2-(3-Chloro-4-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide.
The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds are provided in the schemes below and in the examples. In the following schemes, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, A1,
A 2 , and A 3 are as defined above unless otherwise indicated. X is halogen.
The following abbreviations are used in the present specification.
Abbreviations: d: day or days
DMSO: dimethylsulfoxide gram h or hr: hour hrs: hours
HATU: o-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium
hexafluoropho sphate HPLC: high performance liquid chromatography
Hz: hertz
mg: milligram
min: minute or minutes
mL: milliliter
mmol: millimole
mM: millimole per liter
MS(ESI): mass spectroscopy (electron spray ionization)
MW: molecular weight
r.t. or R.T.: room temperature
quant. quantitative
μg: microgram
μL·: microliter
μΜ: micro mole per liter
Scheme 1
Figure imgf000020_0001
R2 and R3 together with the carbon atom to which they are attached form cycloalkyl.
The compound of formula la can be prepared according to Scheme 1. The aniline III reacts with the aldehyde IV to generate the imine V. The imine V reacts with the methylene-cycloalkene VI to afford the tetrahydroquinoline VII. Hydrolysis of the tetrahydroquinoline VII affords la.
In the method outlined in Scheme 1, the imine V can be prepared by a condensation reaction of the substituted aniline III and the substituted aldehyde IV in an organic solvent such as toluene, methanol or ethanol and a mixture thereof, at a temperature between 80 and 140 °C for 2 to 16 hours.
The compound VII can be prepared from the imine V and the methylene-cycloalkene VI. This Diels-Alder reaction can be carried out in the presence of a Lewis acid such as ytterbium(ni) trifluoromethanesulfonate (Yb(OTf)3), scandium(III)
trifluoromethanesulfonate (Sc(OTf)3), lanthanum(III) trifluoromethanesulfonate
(La(OTf) ), indium(in) trifluoromethanesulfonate (In(OTf) ), indium trichloride (InCl3), or boron trifluoride diethyl etherate (BF3 Et20), or a protic acid such as trifluoroacetic acid (TFA) or /7-toluenesulfonic acid, in a solvent such as acetonitrile, dichloromethane, tetrahydrofuran, nitromethane, N,N-dimethylformamide, 2,2,2-trifluoroethanol or a mixture thereof, at a temperature between 25 and 100 °C for several hours (reference: Kiselyov, A. S. et al., Tetrahedron 54 (1998) 5089). Hydrolysis of the methyl ester VII to the resulting product la can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature or refluxed for several hours.
Scheme 2
Figure imgf000021_0001
R2 and R3 together with the carbon atom to which they are attached form cycloalkyl.
The compound of formula lb and Ic can be prepared according to Scheme 2. In this process, the compound of formula VIII can be synthesized as illustrated in Scheme 1. VIII is functionalized by copper-catalyzed Ullmann coupling reaction, followed by hydrolysis of the methyl ester to produce the compounds lb and Ic.
The Ullmann coupling reaction as outlined in the Scheme 2 can be carried out in the presence of a copper source such as copper(I) iodide (Cul) or copper(II)
trifluoromethanesulfonate and a ligand such as 2,2'-bipyridine, proline, N,N'-dimethyl glycine or ethylene glycol, in the presence of a suitable base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, sodium tert- butoxide or potassium ie/t-butoxide. The reaction can be carried out in a suitable solvent such as 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N-methylpyrolidinone at a temperature between 100 and 180 °C for 15 to 60 minutes under microwave irradiation. Alternatively, the reactions can be carried out without the use of a microwave at a heated temperature such as 130 °C for a longer reaction time (reference: Ley, S. V. et al., Angew. Chem. Int. Ed. 42 (2003) 5400).
Hydrolysis of the methyl esters X and XI to the resulting products lb and Ic can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1,4-dioxane or tetrahydrofuran at room temperature or refluxed for several hours.
Scheme 3
Figure imgf000022_0001
Id
R2 and R3 together with the carbon atom to which they are attached form cycloalkyl;
A3 is absent;R9 is alkyl, benzyl or alkylaminocarbonyl. The compound of formula Id can be prepared according to Scheme 3. In this process, the compound of formula VII can be synthesized as illustrated in Scheme 1. VII is functionalized by acylation, alkylation or benzylation with tetrahydro-quinoline-l-yl group, followed by hydrolysis of the methyl ester to produce the compound Id.
Acylation, alkylation or benzylation of tetrahydro-quinoline-l-yl group of formula XII can be easily accomplished using methods well known to someone skilled in the art. The reaction is typically carried out in the presence of a base such as triethylamine, pyridine, sodium methoxide, sodium ie/t-butoxide, potassium ie/t-butoxide, sodium hydride or dimethyl-pyridin-4-yl-amine in a suitable inert solvent such as dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran or a mixtures thereof, at room temperature for several hours.
Hydrolysis of the methyl esters can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1,4-dioxane, tetrahydrofuran or a mixtures thereof at room temperature or refluxed for several hours.
Scheme 4
Figure imgf000023_0001
R2 and R3 are independently selected from alkyl, alkenyl and phenyl. The compound of formula Ie can be prepared according to Scheme 4. This approach is based on three-component aza-Diels-Alder reactions using a Lewis acid or protic acid as the catalyst. The substituted aniline XIII, substituted aldehyde IV and substituted ethylene XIV are used in this reaction to afford XV. The corresponding acid Ie can be afforded through hydrolysis of the methyl ester XV. In the method outlined in Scheme 4, the compound XV can be prepared by a three- component condensation of substituted aniline XIII, substituted aldehyde IV, and substituted ethylene XIV. This reaction can be carried out successfully in the presence of a Lewis acid such as ytterbium(III) trifluoromethanesulfonate (Yb(OTf>3), scandium(III) trifluoromethanesulfonate (Sc(OTf)3), lanthanum(III) trifluoromethanesulfonate
(La(OTf)3), indium(in) trifluoromethanesulfonate (In(OTf)3), indium trichloride (InCl3) or boron trifluoride diethyl etherate (BF Et20) or a pro tic acid such as trifluoroacetic acid (TFA) or /7-toluenesulfonic acid, in aqueous or anhydrous conditions such as acetonitrile, dichloromethane, tetrahydrofuran, nitromethane, N,N-dimethylformamide, 2,2,2- trifluoroethanol, water or a mixture thereof, at a temperature between 25 and 100 °C for several hours (reference: Kiselyov, A. S. et al., Tetrahedron 54 (1998) 5089).
Hydrolysis of the methyl ester XV to the resulting product Ie can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1,4-dioxane, tetrahydrofuran or a mixture thereof at room temperature or refluxed for several hours.
Scheme 5
Figure imgf000024_0001
R2 and R3 are alkyl;
R5 is morpholinyl, piperazinyl or alkylpiperazinyl.
The compound of formula If can be prepared according to Scheme 5. In this process, the compound of formula XVI can be synthesized as illustrated in Scheme 4. XVI is functionalized by copper-catalyzed Ullmann coupling reaction with amine such as morpholine, piperazine or N-methyl-piperazine or sodium methanesulfinate, followed by hydrolysis of the methyl ester to produce the compound If. The Ullmann coupling reaction as outlined in the Scheme 5 can be carried out in the presence of a copper source such as copper(I) iodide (Cul) or copper(II)
trifluoromethanesulfonate and a ligand such as 2,2'-bipyridine, proline, N,N'-dimethyl glycine or ethylene glycol, in the presence of a suitable base such as triethylamine, potassium carbonate or cesium carbonate. The reaction can be carried out in a suitable solvent such as 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide or N- methylpyrolidinone at a temperature between 100 and 180 °C for 15 to 60 minutes under microwave irradiation. Alternatively, the reactions can be carried out without the use of a microwave at high temperature such as 130 °C for a longer reaction time (reference: Ley, S. V. et al., Angew. Chem. Int. Ed. 42 (2003) 5400).
Hydrolysis of the methyl ester XVII to the resulting product If can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1,4-dioxane, tetrahydrofuran or a mixture thereof at room temperature or refluxed for several hours.
Scheme 6
Figure imgf000025_0001
Figure imgf000026_0001
A3 is absent; R4, R5, R6, R7, R8 are independently selected from hydrogen and halogen; R9 is alkyl.
A3 is absent; R4, R5, R6, R7, R8 are independently selected from hydrogen and halogen; R is alkyl. The compounds of formula Ig, Ih, Ii and Ij can be prepared according to Scheme 6.
This approach is based on two-component Diels-Alder reactions using a Lewis acid or protic acid as the catalyst. Condensation of the compound of XVIII and substituted aldehyde IV generates imine XIX. Imine XIX and 2-methyl-buta-l,3-diene XX are used in this reaction to afford Ig. The corresponding methyl ester XXI can be formed by methanolysis of nitrile Ig, followed by hydrolysis of the methyl ester (Route A) to produce the compound Ih. Reduction of the vinyl compound Ih to the corresponding derivative Ii can be accomplished using methods well known to someone skilled in the art. The corresponding acid Ij can be prepared through hydrogenation of compound XXI (Route B), followed by acylation and hydrolysis of the methyl ester XXII.
In the method outlined in Scheme 6, the imine XIX can be prepared from 5-amino- pyridine-2-carbonitrile XVIII and substituted aldehyde IV. The compound Ig can be prepared from imine XIX and 2-methyl-buta-l,3-diene XX through Diels- Alder reactions. This Diels-Alder reaction can be carried out successfully in the presence of a Lewis acid such as ytterbium(ni) trifluoromethanesulfonate (Yb(OTf)3), scandium(III)
trifluoromethanesulfonate (Sc(OTf)3), lanthanum(III) trifluoromethanesulfonate
(La(OTf) ), indium(in) trifluoromethanesulfonate (In(OTf) ), indium trichloride (InCl3) or boron trifluoride diethyl etherate (BF3 Et20) or a pro tic acid such as trifluoroacetic acid (TFA) or /7-toluenesulfonic acid, in a solvent such as acetonitrile, dichloromethane, tetrahydrofuran, nitromethane, N,N-dimethylformamide, 2,2,2-trifluoroethanol, water or a mixture thereof, at a temperature between 25 and 100 °C for several hours (reference: Kiselyov, A. S. et al., Tetrahedron 54 (1998) 5089).
Methanolysis of the nitrile Ig can provide the corresponding methyl ester XXI. The reaction can be carried out in the presence of a catalyst such as hydrochloride, concentrated sulfuric acid, chlorotrimethylsilane or thionyl chloride in methanol, at a temperature between room temperature and 90 °C for several hours.
Hydrolysis of the methyl ester XXI (Route A) to the resulting product Ih can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1,4-dioxane,
tetrahydrofuran or a mixture thereof at room temperature or refluxed for several hours.
Hydrogenation of the vinyl compound Ih to the corresponding Ii can be
accomplished using methods well known to someone skilled in the art. The reaction is typically carried out under 10% palladium on active carbon in a suitable solvent such as methanol, ethanol, tetrahydrofuran, water or a mixture thereof at room temperature or reflux of the solvent for several hours. Hydrogenation of the vinyl compound XXI (Route B) can be accomplished using methods well known to someone skilled in the art. The reaction typically is carried out under 10% palladium on active carbon in a suitable solvent such as methanol, ethanol, tetrahydrofuran, water or a mixture thereof at room temperature or reflux of the solvent for several hours.
Acylation, alkylation or benzylation of the tetrahydro-quinoline-l-yl group of formula XXII can be easily accomplished using methods well known to someone skilled in the art. The reaction is typically carried out in the presence of a base such as
triethylamine, pyridine, sodium methoxide, sodium ie/t-butoxide, potassium ie/t-butoxide, sodium hydride or dimethyl-pyridin-4-yl-amine in a suitable inert solvent such as dichloromethane, acetonitrile, 1,4-dioxane, tetrahydrofuran or mixtures thereof, at room temperature for several hours.
Hydrolysis of the methyl ester XXII to the resulting product Ij can be carried out in the presence of an aqueous inorganic base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a solvent such as methanol, 1,4-dioxane, tetrahydrofuran or a mixture thereof at room temperature or refluxed for several hours.
Scheme 7
Figure imgf000028_0001
The compound of formula Ik can be synthesized as illustrated in Scheme 7, starting from the one compound selected from la to Ij, which can be prepared according to Schemes 1-6.
Conversion of the acids la to Ij to the corresponding amide Ik with suitable amines XXIII can be easily accomplished using methods well known to someone skilled in the art. The reaction is typically carried out in the presence of a coupling reagent such as dicyclohexyl carbodiimide (DCC), benzotriazol-l-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBop), o-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), o(lH-benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or l-ethyl-3-(3'-dimethylamino)carbodiimide hydrochloride salt (EDCI), in the presence or absence of hydroxybenzotriazole (HOBt), in the presence of a base such as triethylamine or N,N-diisopropyl ethylamine or N,N-dimethylaminopyridine (DMAP). The reaction can be carried out in a solvent such as dichloromethane or N,N- dimethylformamide at room temperature for several hours (reference: Montalbetti, C. A. G. N. et al., Tetrahedron 61 (2005) 10827).
The invention also relates to a process for the preparation of a compound of formula (I) comprising one of the following steps:
(a) the reaction of a compound of formula (A)
Figure imgf000029_0001
in the presence of a base; or
(b) the reaction of a compound of formula (B)
Figure imgf000030_0001
in the presence of a coupling agent and a base; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, A1, A2 and A3 are defined above and R11 is alkyl. R11 is preferably methyl.
In step (a), the base can be for example independently selected form lithium hydroxide, sodium hydroxide or potassium hydroxide.
In step (b), the coupling reagent can be for example dicyclohexyl carbodiimide (DCC), benzotriazol-l-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBop), o-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU),
0- (lH-benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) or
1- ethyl-3-(3'-dimethylamino)carbodiimide hydrochloride salt (EDCI). Step (i) can be carried out in the presence or absence of hydroxybenzotriazole (HOBt), in the presence of a base such as triethylamine or N,N-diisopropyl ethylamine or N,N-dimethylaminopyridine (DMAP).
The invention also relates to a compound of formula (I) for use as therapeutically active substance.
The invention also relates to a pharmaceutical composition comprising a compound of formula (I) and a therapeutically inert carrier.
The use of a compound of formula (I) for the preparation of medicaments useful in the treatment or prophylaxis diseases that are related to AMPK regulation is an object of the invention. The invention relates in particular to the use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes, in particular type 2 diabetes.
Said medicaments, e.g. in the form of pharmaceutical preparations, can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in the form of injection solutions with an effective amount of a compound as defined above.
The above-mentioned pharmaceutical composition can be obtained by processing the compounds according to this invention with pharmaceutically inert inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers (or excipients) for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like. The pharmaceutical composition can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
The dosage depends on various factors such as manner of administration, species, age and/or individual state of health. The doses to be administered daily are about 5-400 mg/kg, preferably about 10-100 mg/kg, and can be taken singly or distributed over several administrations.
A compound of formula (I) when manufactured according to the above process is also an object of the invention. Furthermore, the invention also relates to a method for the treatment or prophylaxis of diseases that are related to AMPK regulation, which method comprises administering an effective amount of a compound of formula (I). The invention further relates to a method for the treatment or prophylaxis of obesity, dyslipidemia, hyperglycemia, type 1 or type 2 diabetes, in particular type 2 diabetes, which method comprises administering an effective amount of a compound of formula (I).
Furthermore, the invention also relates to a compound of formula (I) for the preparation of medicaments useful in the treatment of cancers that are related to AMPK regulation. The invention provides a method for the treatment of cancers that are related to AMPK regulation, which method comprises administering an effective amount of a compound of formula (I).
The invention will be illustrated by the following examples which have no limiting character. Unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in organic chemistry.
Examples
Materials and instrumentation
Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and the Quad 12/25 Cartridge module, ii) ISCO combi-flash chromatography instrument. Silica gel Brand and pore size: i) KP-SIL 60 A, particle size: 40-60 μΜ; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400.
Intermediates and final compounds were purified by preparative HPLC on reversed phase column using X BridgeTM Perp C18 (5 μιη, OBDTM 30 x 100 mm) column or SunFire™ Perp C18 (5 μηι, OBD™ 30 x 100 mm) column.
LC/MS spectra were obtained using a MicroMass Plateform LC (Waters™ alliance 2795- ZQ2000). Standard LC/MS conditions were as follows (running time 6 min):
Acidic condition: A: 0.1% formic acid in H20; B: 0.1% formic acid in acetonitrile; Basic condition: A: 0.01% NH3 H20 in H20; B: acetonitrile;
Neutral condition: A: H20; B: acetonitrile.
Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion-(M+H)+.
The microwave assisted reactions were carried out in a Biotage Initiator Sixty. NMR Spectra were obtained using Brake Avance 400MHz.
All reactions involving air-sensitive reagents were performed under an argon atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.
Example 1 2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid
Figure imgf000034_0001
4-[(5-Fluoro-2-methyl-benzylidene)-amino]-benzoic acid methyl
A mixture of 4-aminobenzoic acid methyl ester (10.8 g, 71.4 mmol), 5-fluoro-2- methylbenzaldehyde (10.0 g, 72.4 mmol) and p-toluenesulfonic acid (271.8 mg, 1.4 mmol) in toluene (150 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4- [(5-fluoro-2-methyl-benzylidene)-amino] -benzoic acid methyl (16.0 g, 82.6%) as a light yellow solid. MS (ESI+) [(M+H)+] 272.0.
2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid methyl ester
To a stirred solution 4-[(5-fluoro-2-methyl-benzylidene)-amino]-benzoic acid methyl (2.7 g, 10 mmol) in MeCN (6 mL) were added methylene-cyclopropane (2.8 mL, 40 mol) and scandium(in) trifluoromethanesulfonate (Sc(OTf)3) (980 mg, 2 mmol). The resulting mixture was stirred at 80 °C for 16 hours in sealed tube. The mixture was extracted with diethyl ether (80 mL) and washed with water (100 mL) and brine (100 mL) and then dried over anhydrous Na2S04. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 0 -10% ethyl acetate in petroleum ether) to afford 2-(5-fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'- ,2',3',4'- tetrahydroquinoline)-6-carboxylic acid methyl ester (1.2 g, 37%) as a light yellow solid. MS (ESI+) [(M+H)+] 326.2.
2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid
To a solution of 2-(5-fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'- ,2',3',4'- tetrahydroquinoline)-6-carboxylic acid methyl ester (800 mg, 2.5 mmol) in tetrahydrofuran (4 mL) and methanol (4 mL) was added 3 N sodium hydroxide (2 mL). The reaction mixture was stirred at 80 °C for 6 hours, and then diluted with water (10 mL), extracted with diethyl ether (20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL x 3). The combined organic layers were dried over anhydrous Na2S04 The solvent was removed in vacuo and purified by preparative HPLC to afford 2-(5-fluoro-2-methyl- phenyl)-spiro(cyclopropane-l,4'- ,2',3',4'-tetrahydroquinoline)-6-carboxylic acid (650 mg, 85%) as a light yellow powder. MS (ESI+) [(M+H)+] 312.3.
Example 2
2-(5-Bromo-2-fluoro-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid
Figure imgf000035_0001
The title compound was prepared in analogy to example 1 starting from 5-Bromo-2-fluoro- benzaldehyde. MS (ESI+) [(M+H)+] 376.0, 378.0.
Example 3
2-(2,5-Dichloro-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'-tetrahydroquinoline)-6- carboxylic acid
Figure imgf000035_0002
The title compound was prepared in analogy to example 1 starting from 2,5-dichloro- benzaldehyde. MS (ESI+) [(M+H)+] 348.1.
Example 4 2-(3,5-Dichloro-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'-tetrahydroquinoline)-6- carboxylic acid
Figure imgf000036_0001
The title compound was prepared in analogy to example 1 starting from 3,5-dichloro- benzaldehyde. MS (ESI+) [(M+H)+] 348.1.
Example 5
2-(5- Chloro-2-fluoro-phenyl) -spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinoline)-6-carboxylic acid
Figure imgf000036_0002
The title compound was prepared in analogy to example 1 starting from 5-chloro-2-fluoro- benzaldehyde. MS (ESI+) [(M+H)+] 332.2.
Example 6
2-(3-Methanesulf onyl-phenyl) -spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinoline)-6-carboxylic acid
Figure imgf000036_0003
The title compound was prepared in analogy to example 1 starting from 3- Methanesulfonyl-benzaldehyde. MS (ESI+) [(M+H)+] 358.1.
Example 7
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid
Figure imgf000037_0001
The title compound was prepared in analogy to example 1 starting from 2-bromo-5-fluoro- benzaldehyde. MS (ESI+) [(M+H)+] 376.0, 378.0.
Example 8 2-(3-Fluoro-phenyl) -spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' -tetrahydroquinoline) -6- carboxylic acid
Figure imgf000037_0002
The title compound was prepared in analogy to example 1 starting from 3-fluoro- benzaldehyde. MS (ESI+) [(M+H)+] 298.2. Example 9
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclohexane-l,4'-l',2',3',4'-tetrahydroquinoline)- 6-carboxylic acid
Figure imgf000037_0003
The title compound was prepared in analogy to example 1 starting from 2-bromo-5-fluoro- benzaldehyde. MS (ESI+) [(M+H)+] 418.0, 420.0.
Example 10
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid
Figure imgf000038_0001
The title compound was prepared in analogy to example 1 starting from 2-bromo-5-fluoro- benzaldehyde. MS (ESI+) [(M+H)+] 404.0, 406.0.
Example 11 2-(5-Fluoro-2-methanesulf onyl-phenyl) -spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinoline)-6-carboxylic acid
Figure imgf000038_0002
2-(5-Fluoro-2-methanesulf onyl-phenyl) -spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinoline)-6-carboxylic acid methyl ester 2-(2,5-Dimethanesulfonyl-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid methyl ester
The mixture of 2-(2-bromo-5-fluoro-phenyl)-spiro(cyclopropane-l,4'- ,2',3',4'- tetrahydroquinoline)-6-carboxylic acid methyl ester (390 mg, 1 mmol) (prepared as in example 1 starting from 2-bromo-5-fluoro-benzaldehyde), Cul (60 mg, 0.3 mmol), L- proline (70 mg, 0.6 mmol) and methanesulfinic acid, sodium salt (510 mg, 5 mmol) in DMSO (5 mL) was stirred at 120 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3) and washed with brine (100 mL) and then dried over anhydrous Na2S04. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30 - 60% ethyl acetate in petroleum ether) to afford 2-(5-fluoro-2- methanesulfonyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid methyl ester ( 160 mg, 41.1%) as a white solid. MS (ESI+) [(M+H)+] 390. And side-product 2-(2,5-dimethanesulfonyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid methyl ester (120 mg, 30%) was also obtained as a white solid. MS (ESI+) [(M+H)+] 450.2.
2- (5-Fluoro-2-methanesulf onyl-phenyl) -spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinoline)-6-carboxylic acid To a solution of 2-(5-fluoro-2-methanesulfonyl-phenyl)-spiro(cyclopropane-l,4'- l',2',3',4'-tetrahydroquinoline)-6-carboxylic acid methyl ester (100 mg, 0.3 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 3 N sodium hydroxide (1 mL). The reaction mixture was stirred at 80 °C for 6 hours, and then diluted with water (10 mL), extracted with diethyl ether (20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL x 3), and the combined organics were dried over anhydrous Na2S04 The solvent was removed in vacuo and purified by preparative HPLC to afford 2-(5-fluoro-2- methanesulfonyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid (35 mg, 35.9%) as a yellow foam. MS (ESI+) [(M+H)+] 376.1. Example 12
2-(2,5-Dimethanesulfonyl-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid
Figure imgf000039_0001
The title compound was prepared as a white powder in analogy to Example 11 starting from 2-(2,5-dimethanesulfonyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid methyl ester. MS (ESI+) [(M+H)+] 436.2.
Example 13
2-(2,5-Dichloro-phenyl)- 1 -dimethylcarbamoyl-spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinoline)-6-carboxylic acid
Figure imgf000040_0001
2-(2,5-Dichloro-phenyl)- 1 -dimethylcarbamoyl-spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinoline)-6-carboxylic acid methyl ester
To a 0 °C solution of 2-(2,5-dichloro-phenyl)-spiro(cyclopropane-l,4'- ,2',3',4'- tetrahydroquinoline)-6-carboxylic acid methyl ester as prepared according to Example 1 (200 mg, 0.6 mmol) in N,N-dimethylformamide (5 mL) was added a 60% dispersion of sodium hydride in mineral oil (44 mg, 1.1 mmol) portionwise. The mixture was stirred at 0 °C for 30 min and then dimethylcarbamoyl chloride (177 mg, 1.6 mmol) was added to above mixture dropwise at 0 °C. The mixture was stirred at 0 °C for 3 hours and then extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The yellowish residue was purified by ISCO combi-flash chromatography (gradient elution, 5% ethyl acetate/hexane) to afford 2-(2,5-dichloro- phenyl)- 1 -dimethylcarbamoyl-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid methyl ester (100 mg, 42.2%) as a yellow oil. MS (ESf ) [(M+H)+] 433.0. 2-(2,5-Dichloro-phenyl)- 1 -dimethylcarbamoyl-spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinoline)-6-carboxylic acid
To a solution of 2-(2,5-dichloro-phenyl)-l-dimethylcarbamoyl-spiro(cyclopropane-l,4'- l',2',3',4'-tetrahydroquinoline)-6-carboxylic acid methyl ester (50 mg, 0.1 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 3 N sodium hydroxide (0.5 mL). The reaction mixture was stirred at 80 °C for 4 hours, and then diluted with water (10 mL), extracted with diethyl ether (20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL x 3), and the combined organics were dried over anhydrous Na2S04 The solvent was removed in vacuo and purified by preparative HPLC to afford 2-(2,5-dichloro-phenyl)- 1 -dimethylcarbamoyl- spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid (25 mg, 35.9%) as a white foam. MS (ESI+) [(M+H)+] 419.2.
Example 14 l-Benzyl-2-(2,5-dichloro-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid
Figure imgf000041_0001
The title compound was prepared as a yellow foam in analogy to Example 13 starting from 2-(2,5-dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid methyl ester prepared according to Example 1. MS (ESI+) [(M+H)+] 438.1.
Example 15
2-(2,5-Dichloro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid
Figure imgf000041_0002
2-(2,5-Dichloro^henyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester
To a stirred solution of 4-aminobenzoic acid methyl ester (1.5 g, 10 mmol) and 2,5- dichloro-benzaldehyde (1.8 g, 10 mmol) in MeCN (5 mL) were added isobutene (2.1 mL, 30 mmol) and ytterbium(III) trifluoromethanesulfonate (Yb(OTf)3) (1.3 g, 2 mmol). The resulting mixture was stirred at 80 °C for 18 hours in sealed tube. The mixture was diluted with water (50 mL), extracted with diethyl ether (50 mL x 3). The extracts were washed with water (100 mL) and brine (100 mL) and then dried over anhydrous Na2S04. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 0 -10% ethyl acetate in petroleum ether) to 2-(2,5- dichloro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.8 g, 50%) as a light yellow solid (reference: Kiselyov, A. S. et al., Tetrahedron 54 (1998) 5089): MS (ESI+) [(M+H)+] 364.2. 2-(2,5-Dichloro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid
To a solution of 2-(2,5-dichloro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid methyl ester (1.0 g, 2.8 mmol) in tetrahydrofuran (8 mL) and methanol (8 mL) was added 3N sodium hydroxide (5 mL). The reaction mixture was stirred at 80 °C for 4 hours, and then diluted with water (10 mL), extracted with diethyl ether (20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated
hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL x 3), and the combined organics were dried over anhydrous Na2S04 The solvent was removed in vacuo and purified by preparative HPLC to afford 2-(2,5-dichloro-phenyl)-4,4-dimethyl- 1,2,3,4- tetrahydro-quinoline-6-carboxylic acid (600 mg, 61.4%) as a yellow foam. MS (ESI+) [(M+H)+] 350.1.
Example 16
4,4-Dimethyl-2-(l-methyl-l^henyl-ethyl)-l,23,4 etrahydro-quinoline-6-carboxylic acid
Figure imgf000042_0001
The title compound was prepared in analogy to example 15 starting from 2-methyl-2- phenyl-propionaldehyde. MS (ESI+) [(M+H)+] 324.1.
Example 17
7-Chloro-2-(5-chloro-2-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline carboxylic acid
Figure imgf000042_0002
The title compound was prepared in analogy to example 15 starting from 5-chloro-2- fluoro-benzaldehyde. MS (ESI+) [(M+H)+] 368.2.
Example 18
[2-(5-Chloro-2-fluoro^henyl)-4,4-dimethyl-l,2,3,4 etrahydro-quinolin-6-yl]-acetic acid
Figure imgf000043_0001
The title compound was prepared in analogy to example 15 starting from 5-chloro-2- fluoro-benzaldehyde. MS (ESI+) [(M+H)+] 348.2.
Example 19 2-(3-Chloro-4-fluoro-phenyl)-4-methyl-4-vinyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid
Figure imgf000043_0002
The title compound was prepared in analogy to example 15 starting from 3-chloro-4- fluoro-benzaldehyde. MS (ESI+) [(M+H)+] 346.2. Example 20
2-(3-Chloro-4-fluoro-phenyl)-4-methyl-4-phenyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid
Figure imgf000043_0003
The title compound was prepared in analogy to example 15 starting from 3-chloro-4- fluoro-benzaldehyde. MS (ESI+) [(M+H)+] 396.2.
Example 21
2-(5-Fluoro-2-isopropoxy-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid
Figure imgf000044_0001
The title compound was prepared in analogy to example 15 starting from 5-fluoro-2- isopropoxy-benzaldehyde. MS (ESI+) [(M+H)+] 358.1.
Example 22 4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid
Figure imgf000044_0002
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester The mixture of 4,4-dimethyl-2-(3-bromo-phenyl)-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid methyl ester as prepared according to Example 1 (374 mg, 1 mmol), Cul (60 mg, 0.3 mmol), L-proline (70 mg, 0.6 mmol) and morpholine (440 mg, 5 mmol) in DMSO (5 mL) was stirred at 120 °C for 16 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL x 3) and washed with brine (100 mL) and then dried over anhydrous Na2S04. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 30 - 60% ethyl acetate in petroleum ether) to afford 4,4-dimethyl-2-(3- morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (200 mg, 52.6%) as a white solid. MS (ESI+) [(M+H)+] 381.1.
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,23,4-tetrahydro-quinoline-6-carboxylic acid To a solution of 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid methyl ester (100 mg, 0.3 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 3 N sodium hydroxide (1 mL). The reaction mixture was stirred at 80 °C for 6 hours, and then diluted with water (10 mL), extracted with diethyl ether (20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL x 3); and the combined organics were dried over anhydrous Na2S04 The solvent was removed in vacuo and purified by preparative HPLC to afford 4,4-dimethyl-2-(3-morpholin-4-yl-phenyl)- 1,2,3,4- tetrahydro-quinoline-6-carboxylic acid (50 mg, 52%) as a yellow foam. MS (ESI+)
[(M+H)+] 367.2. Example 23
2- [3- (4-Isopropyl-piperazin- 1 -yl) -phenyl] -4,4-dimethyl- 1 ,2,3,4-tetrahydro- quinoline- 6-carboxylic acid
Figure imgf000045_0001
The title compound was prepared in analogy to example 22 starting from 2-(3-bromo- phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester. MS
(ESI+) [(M+H)+] 408.1.
Example 24
4,4-Dimethyl-2- (3-piperazin- 1 -yl-phenyl) - 1 ,2,3,4-tetrahydro- quinoline-6-carboxylic acid
Figure imgf000046_0001
The title compound was prepared in analogy to example 22 starting from 2-(3-bromo- phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester. MS (ESI+) [(M+H)+] 366.1.
Example 25
6-(3-Chloro-4-fluoro^henyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[l,5]naphthyridine- 2-carboxylic acid
Figure imgf000046_0002
5- [(3-Chloro-4-fluoro-benzylidene)-amino]-pyridine-2-carbonitrile A mixture of 5-amino-2-cyanopyridine (2.86 g, 24 mmol), 3-chloro-4-fluoro-benzaldehyde (3.79 g, 24 mmol) and p-toluenesulfonic acid (92 mg, 0.5 mmol) in toluene (150 mL) was heated to reflux for 12 hours. Then the reaction mixture was cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 5-[(3- chloro-4-fluoro-benzylidene)-amino]-pyridine-2-carbonitrile (5.8 g, 93.6%) as a light yellow solid. MS (ESI+) [(M+H)+] 260.1.
6- (3-Chloro-4-fluoro^henyl)-8-methyl-8-vinyl-5,6,7,8 etrahydro-[l,5]naphthyridine- 2-carbonitrile
To a stirred solution 5-[(3-chloro-4-fluoro-benzylidene)-amino]-pyridine-2-carbonitrile (3.7 g, 14.3 mmol) in MeCN (36 mL) were added isoprene (5.8 mL, 57.1 mol) and scandium(in) trifluoromethanesulfonate (Sc(OTf)3) (1.4 g, 2.9 mmol). The resulting mixture was stirred at 80 °C for 16 hours in sealed tube. The mixture was extracted with diethyl ether (80 mL) and washed with water (100 mL) and brine (100 mL) and then dried over anhydrous Na2S04. The solvent was removed in vacuo and the residue was purified by ISCO combi-flash chromatography (gradient elution, 0 - 20% ethyl acetate in petroleum ether) to afford 6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carbonitrile (0.25 g, 5.5%) as white powder. MS (ESI+) [(M+H)+] 328.2. 6-(3-Chloro-4-fluoro^henyl)-8-methyl-8-vinyl-5,6,7,8 etrahydro-[l,5]naphthyridine- 2-carboxylic acid methyl ester
6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[l,5]naphthyridine-2- carbonitrile (327 mg, 1 mmol) was dissolved in MeOH (30 mL, saturated with HC1 gas) and stirred at 75 °C overnight. The mixture was cooled to room temperature, poured into saturate NaHC03 solution (150 mL) carefully, and extracted with ethyl acetate (50 mL x 3). The organic layers were washed with brine (10 mL), dried over anhydrous Na2S04 and concentrated in vacuo. The residue was purified by ISCO combi-flash chromatography (gradient elution, 0 - 35% ethyl acetate in petroleum ether) to give 6-(3-chloro-4-fluoro- phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[l,5]naphthyridine-2-carboxylic acid methyl ester (310 mg, 86%) as a yellow solid. MS (ESI+) [(M+H)+] 361.2.
6-(3-Chloro-4-fluoro^henyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[l,5]naphthyridine- 2-carboxylic acid
To a solution of 6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid methyl ester (300 mg, 0.8 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 3 N sodium hydroxide (1 mL). The reaction mixture was stirred at room temperature for 16 hours, and then diluted with water (10 mL), extracted with diethyl ether (20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL x 3), and the combined organics were dried over anhydrous Na2S04 The solvent was removed in vacuo and purified by preparative HPLC to afford 6-(3-chloro-4-fluoro- phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro-[l,5]naphthyridine-2-carboxylic acid (180 mg, 62.7%) as a yellow oil. MS (ESI+) [(M+H)+] 347.2.
Example 26
6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro-[l,5]naphthyridine- 2-carboxylic acid
Figure imgf000048_0001
The mixture solution of 6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid (100 mg, 0.3 mmol) and 10% palladium on active carbon (30 mg) in methanol (50 mL) was stirred at room temperature under hydrogen (14 psi) for 8 hours. The catalyst was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo and purified by preparative HPLC to afford 6-(3-chloro-4- fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro-[ 1 ,5]naphthyridine-2-carboxylic acid (30 mg, 30%) as a yellow oil. MS (ESI+) [(M+H)+] 349.2.
Example 27 6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid
Figure imgf000048_0002
6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro-[l,5]naphthyridine- 2-carboxylic acid methyl ester The mixture solution of 6-(3-chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid methyl ester (360 mg, 1 mmol) and 10% palladium on active carbon (120 mg) in methanol (50 mL) was stirred at room temperature under hydrogen (14 psi) for 8 hours. The catalyst was filtered off and washed with ethyl acetate. The filtrate was concentrated in vacuo to afford 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8- methyl-5,6,7,8-tetrahydro-[l,5]naphthyridine-2-carboxylic acid methyl ester (360 mg, quant.) as a yellow oil. MS (ESI+) [(M+H)+] 363.2.
6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid methyl ester To a 0 °C solution of 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid methyl ester (200 mg, 0.5 mmol) in N,N- dimethylformamide (5 mL) was added a 60% dispersion of sodium hydride in mineral oil (44 mg, 1.1 mmol) portionwise. The mixture was stirred at 0 °C for 30 min and then 1- iodo-3-methyl-butane (327 mg, 1.6 mmol) was added to above mixture dropwise at 0 °C. The mixture was stirred at 0 °C for 3 hours and then extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The yellowish residue was purified by ISCO combi-flash chromatography (gradient elution, 0 - 5% ethyl acetate/hexane) to afford 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl- butyl)-5,6,7,8-tetrahydro-[l,5]naphthyridine-2-carboxylic acid methyl ester (160 mg, 67.5%) as a yellow oil. MS (ESI+) [(M+H)+] 433.1.
6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid
To a solution of 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8- tetrahydro-[l,5]naphthyridine-2-carboxylic acid methyl ester (100 mg, 0.2 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 3 N sodium hydroxide (1 mL). The reaction mixture was stirred at room temperature for 16 hours, and then diluted with water (10 mL), extracted with diethyl ether (20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL x 3), and the combined organics were dried over anhydrous Na2S04
The solvent was removed in vacuo and purified by preparative HPLC to afford 6-(3- chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid (30 mg, 31.3%) as a yellow oil. MS (ESf ) [(M+H)+] 419.1. Example 28
2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid cyclobutylamide
Figure imgf000050_0001
A solution of 2-(5-fluoro-2-methyl-phenyl)-spiro(cyclopropane- l,4'- ,2' ,3' ,4'- tetrahydroquinoline)-6-carboxylic acid (311 mg, 1 mmol), cyclobutylamine (213 mg, 3 mmol), o-(7-azabenzotriazol- 1-yl)— N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (760 mg, 2 mmol) and N,N-diisopropyl ethylamine (386 mg, 3 mmol) in N, N- dimethylformamide (3 mL) was stirred at room temperature for 12 hours under a nitrogen atmosphere. Purification by preparative HPLC affords 2-(5-fluoro-2-methyl-phenyl)- spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid
cyclobutylamide (112 mg, 31.3%) as a yellow powder. (ESf ) [(M+H)+] 365.1. Example 29
2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid dimethylamide
Figure imgf000050_0002
The title compound was prepared in analogy to example 28 starting from 2-(5-fluoro-2- methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 339.2.
Example 30
[2-(5-Fluoro-2-methyl-phenyl) -spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinolin)-6-yl]-morpholin-4-yl-methanone
Figure imgf000050_0003
The title compound was prepared in analogy to example 28 starting from 2-(5-fluoro-2- methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 381.2.
Example 31 [2-(5-Fluoro-2-methyl-phenyl) -spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinolin)-6-yl]-(4-methyl-piperazin-l-yl)-methanone
Figure imgf000051_0001
The title compound was prepared in analogy to example 28 starting from 2-(5-fluoro-2- methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS. (ESI+) [(M+H)+] 394.2.
Example 32
[2-(2-Bromo-5-fluoro-phenyl) -spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinolin)-6-yl]-morpholin-4-yl-methanone
Figure imgf000051_0002
The title compound was prepared in analogy to example 28 starting from 2-(5-fluoro-2- bromo-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 445.2, 447.1.
Example 33
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid isopropylamide
Figure imgf000052_0001
The title compound was prepared in analogy to example 28 starting from 2-(5-fluoro-2- bromo-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 417.2, 419.1.
Example 34
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid dimethylamide
Figure imgf000052_0002
The title compound was prepared in analogy to example 28 starting from 2-(5-fluoro-2- bromo-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 403.2, 405.1.
Example 35
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid cyclobutylamide
Figure imgf000052_0003
The title compound was prepared in analogy to example 28 starting from 2-(5-fluoro-2- bromo-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 429.2, 431.1.
Example 36 2-(5-Bromo-2-fluoro-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid cyclobutylamide
Figure imgf000053_0001
The title compound was prepared in analogy to example 28 starting from 2-(5-bromo-2- fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 429.2, 431.1.
Example 37
2-(2,5-Dichloro^henyl)-spiro(cyclopropane-l,4'-l',2',3',4'-tetrahydroquinoline)-6- carboxylic acid cyclopropylamide
Figure imgf000053_0002
The title compound was prepared in analogy to example 28 starting from 2-(2,5-dichloro- phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS . (ESI+) [(M+H)+] 387.2.
Example 38
2-(2,5-Dichloro-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'-tetrahydroquinoline)-6- carboxylic acid methylamide
Figure imgf000053_0003
The title compound was prepared in analogy to example 28 starting from 2-(2,5-dichloro- phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 361.2.
Example 39 2-(2,5-Dichloro-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'-tetrahydroquinoline)-6- carboxylic acid cyclobutylamide
Figure imgf000054_0001
The title compound was prepared in analogy to example 28 starting from 2-(2,5-dichloro- phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 401.2.
Example 40
[2-(2,5-Dichloro-phenyl) -spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' -tetrahydroquinolin) -6- yl]-morpholin-4-yl-methanone
Figure imgf000054_0002
The title compound was prepared in analogy to example 28 starting from 2-(2,5-dichloro- phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 417.2.
Example 41
2-(2,5-Dichloro-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'-tetrahydroquinoline)-6- carboxylic acid isopropylamide
Figure imgf000055_0001
The title compound was prepared in analogy to example 28 starting from 2-(2,5-dichloro- phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 389.2.
Example 42
[2-(2,5-Dichloro-phenyl) -spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' -tetrahydroquinolin) -6- yl]-(4-methanesulfonyl-piperazin-l-yl)-methanone
Figure imgf000055_0002
The title compound was prepared in analogy to example 28 starting from 2-(2,5-dichloro- phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 494.2.
Example 43
2-(3,5-Dichloro^henyl)-spiro(cyclopropane-l,4'-l',2',3',4'-tetrahydroquinoline)-6- carboxylic acid cyclobutylamide
Figure imgf000055_0003
The title compound was prepared in analogy to example 28 starting from 2-(3,5-dichloro- phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 401.2.
Example 44 [2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinolin)-6-yl]-morpholin-4-yl-methanone
Figure imgf000056_0001
The title compound was prepared in analogy to example 28 starting from 2-(5-chloro-2- fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 401.2.
Example 45
2-(5- Chloro-2-fluoro-phenyl) -spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinoline)-6-carboxylic acid dimethylamide
Figure imgf000056_0002
The title compound was prepared in analogy to example 28 starting from 2-(5-chloro-2- fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 359.1.
Example 46
2-(5- Chloro-2-fluoro-phenyl) -spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinoline)-6-carboxylic acid cyclobutylamide
Figure imgf000056_0003
The title compound was prepared in analogy to example 28 starting from 2-(5-chloro-2- fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 385.3.
Example 47 2-(5- Chloro-2-fluoro-phenyl) -spiro(cyclopropane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinoline)-6-carboxylic acid isopropylamide
Figure imgf000057_0001
The title compound was prepared in analogy to example 28 starting from 2-(5-chloro-2- fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 373.2.
Example 48
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'-tetrahydroquinolin)- 6-yl]-piperazin-l-yl-methanone
Figure imgf000057_0002
The title compound was prepared in analogy to example 28 starting from 2-(2-bromo-5- fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 444.1, 446.1.
Example 49
2-(2-Bromo-4-fluoro-6-methyl-phenyl)-spiro(cyclopropane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid methylamide
Figure imgf000058_0001
The title compound was prepared in analogy to example 28 starting from 2-(2-bromo-4- fluoro-6-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid. MS (ESI+) [(M+H)+] 403.0, 405.0.
Example 50
4,4-Dimethyl-2-(l-methyl-l^henyl-ethyl)-l,23,4 etrahydro-quinoline-6-carboxylic acid dimethylamide
Figure imgf000058_0002
The title compound was prepared in analogy to example 28 starting from 4,4-dmethyl-2- (l-methyl-l-phenyl-ethyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 351.2.
Example 51
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid dimethylamide
Figure imgf000058_0003
The title compound was prepared in analogy to example 28 starting from 2-(2-bromo-5- fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 431.0, 433.0.
Example 52 2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid cyclopropylamide
Figure imgf000059_0001
The title compound was prepared in analogy to example 28 starting from 2-(2-bromo-5- fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS. (ESI+) [(M+H)+] 443.0, 445.0.
Example 53
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid (l-methyl-piperidin-4-yl)-amide
Figure imgf000059_0002
The title compound was prepared in analogy to example 28 starting from 2-(2-bromo-5- fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 500.1, 502.1.
Example 54 2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid cyclobutylamide
Figure imgf000059_0003
The title compound was prepared in analogy to example 28 starting from 2-(2-bromo-5- fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 457.0, 459.0.
Example 55 2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid methylamide
Figure imgf000060_0001
The title compound was prepared in analogy to example 28 starting from 2-(2-bromo-5- fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 417.0, 419.0.
Example 56
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid (2-hydroxy-ethyl)-amide
Figure imgf000060_0002
The title compound was prepared in analogy to example 28 starting from 2-(2-bromo-5- fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 447.0, 449.0.
Example 57
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane-l,4'-l',2',3',4'-tetrahydroquinolin)- 6-yl]-morpholin-4-yl-methanone
Figure imgf000061_0001
The title compound was prepared in analogy to example 28 starting from 2-(2-bromo-5- fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 473.0, 475.0. Example 58
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane-l,4'-l',2',3',4'-tetrahydroquinolin)- 6-yl]-(4-methyl-piperazin-l-yl)-methanone
Figure imgf000061_0002
The title compound was prepared in analogy to example 28 starting from 2-(2-bromo-5- fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 486.0, 488.0.
Example 59
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid oxetan-3-ylamide
Figure imgf000061_0003
The title compound was prepared in analogy to example 28 starting from 2-(2-bromo-5- fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 459.0, 461.0.
Example 60 2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane-l,4'-l',2',3',4'- tetrahydroquinoline)-6-carboxylic acid isopropylamide
Figure imgf000062_0001
The title compound was prepared in analogy to example 28 starting from 2-(2-bromo-5- fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 445.0, 447.0.
Example 61
2-(2,5-Dichloro^henyl)-spiro(cyclopentane-l,4'-l',2',3',4'-tetrahydroquinoline)-6- carboxylic acid cyclobutylamide
Figure imgf000062_0002
The title compound was prepared in analogy to example 28 starting from 2-(2,5-dichloro- phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 429.1.
Example 62
2-(3-Fluoro-phenyl)-spiro(cyclopentane-l,4'-l',2',3',4'-tetrahydroquinoline)-6- carboxylic acid cyclobutylamide
Figure imgf000063_0001
The title compound was prepared in analogy to example 28 starting from 2-(3-fluoro- phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 379.2.
Example 63
2-(3-Morpholin-4-yl^henyl)-spiro(cyclopentane-l,4'-1^2 3',4'-tetrahydroquinoline)- 6-carboxylic acid methylamide
Figure imgf000063_0002
The title compound was prepared in analogy to example 28 starting from 2-(3-morpholin- 4-yl-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 406.1.
Example 64
2-(5- Chloro-2-fluoro-phenyl) -spiro(cyclopentane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinoline)-6-carboxylic acid cyclobutylamide
Figure imgf000063_0003
The title compound was prepared in analogy to example 28 starting from 2-(5-chloro-2- fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 413.3.
Example 65 2-(5- Chloro-2-fluoro-phenyl) -spiro(cyclopentane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinoline)-6-carboxylic acid dimethylamide
Figure imgf000064_0001
The title compound was prepared in analogy to example 28 starting from 2-(5-chloro-2- fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 387.1.
Example 66
2-(2,5-Dichloro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid cyclobutylamide
Figure imgf000064_0002
The title compound was prepared in analogy to example 28 starting from 2-(2,5-dichloro- phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 403.3.
Example 67 2-(5-Chloro-2-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid cyclobutylamide
Figure imgf000064_0003
The title compound was prepared in analogy to example 28 starting from 2-(5-chloro-2- fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 387.2.
Example 68 4,4-Dimethyl-2-(3-morpholin-4-yl^henyl)-l,23,4 etrahydro-quinoline-6-carboxylic acid (2-hydroxy-l-hydroxymethyl-l-methyl-ethyl)-amide
Figure imgf000065_0001
The title compound was prepared in analogy to example 28 starting from 4,4-dimethyl-2- (3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 454.1.
Example 69
2-(3- Chloro-4-fluoro-phenyl) -spiro(cyclopentane- 1 ,4 ' - 1 ' ,2 ' ,3 ' ,4 ' - tetrahydroquinoline)-6-carboxylic acid cyclobutylamide
Figure imgf000065_0002
The title compound was prepared in analogy to example 28 starting from 2-(3-chloro-4- fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6-carboxylic acid. MS (ESI+) [(M+H)+] 413.3.
Example 70
6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro-[l,5]naphthyridine- 2-carboxylic acid cyclobutylamide
Figure imgf000066_0001
The title compound was prepared in analogy to example 28 starting from 6-(3-chloro-4- fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro-[l,5]naphthyridine-2-carboxylic acid. MS (ESI+) [(M+H)+] 402.1.
Example 71
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,23,4-tetrahydro-quinoline-6-carboxylic acid isopropylamide
Figure imgf000066_0002
The title compound was prepared in analogy to example 28 starting from 4,4-dimethyl-2- (3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 408.2.
Example 72
N-[2-(l,l-dioxidothiomorpholin-4-yl)ethyl]-4,4-dimethyl-2-[3-(morpholin-4- yl)phenyl]-l,2,3,4-tetrahydroquinoline-6-carboxamide
Figure imgf000066_0003
The title compound was prepared in analogy to example 28 starting from 4,4-dimethyl-2 (3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 527.1.
Example 73 4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2,3-dihydroxy-propyl)-amide
Figure imgf000067_0001
The title compound was prepared in analogy to example 28 starting from 4,4-dimethyl-2- (3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 440.1. Example 74
N-[2-(l,l-dioxidothiomorpholin-4-yl)ethyl]-4,4-dimethyl-2-{3-[4-(propan-2- yl)piperazin-l-yl]phenyl}-l,2,3,4-tetrahydroquinoline-6-carboxamide
Figure imgf000067_0002
The title compound was prepared in analogy to example 28 starting from 2-[3-(4- isopropyl-piperazin-l-yl)-phenyl]-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 568.1.
Example 75
N-[2-(l,l-dioxidothiomorpholin-4-yl)ethyl]-4,4-dimethyl-2-(2-phenylpropan-2-yl)- l,2,3,4-tetrahydroquinoline-6-carboxamide
Figure imgf000067_0003
The title compound was prepared in analogy to example 28 starting from 4,4-dimethyl-2- (l-methyl-l-phenyl-ethyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 484.3.
Example 76 [4,4-Dimethyl-2-(l-methyl-l-phenyl-ethyl)-l,2,3,4-tetrahydro-quinolin-6-yl]- morpholin-4-yl-methanone
Figure imgf000068_0001
The title compound was prepared in analogy to example 28 starting from 4,4-dimethyl-2- (l-methyl-l-phenyl-ethyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 393.1.
Example 77
[4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinolin-6-yl]-(3- hydroxy-3-methyl-pyrrolidin-l-yl)-methanone
Figure imgf000068_0002
The title compound was prepared in analogy to example 28 starting from 4,4-dimethyl-2- (3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 450.1.
Example 78
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2-hydroxy-l-hydroxymethyl-ethyl)-amide
Figure imgf000068_0003
The title compound was prepared in analogy to example 28 starting from 4,4-dimethyl-2- (3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 440.2.
Example 79 4,4-Dimethyl-2-(3-morpholin-4-yl^henyl)-l,23,4 etrahydro-quinoline-6-carboxylic acid (2-hydroxy-ethyl)-amide
Figure imgf000069_0001
The title compound was prepared in analogy to example 28 starting from 4,4-dimethyl-2- (3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 410.1.
Example 80
[2-(3-Fluoro-5-morpholin-4-yl^henyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6- yl]-(3-hydroxy-3-methyl-pyrrolidin-l-yl)-methanone
Figure imgf000069_0002
The title compound was prepared in analogy to example 28 starting from 2-(3-fluoro-5- morpholin-4-yl-phenyl)-4,4-dimethyl- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 468.3.
Example 81
[2-(3-Fluoro-5-morpholin-4-yl^henyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6- yl]-morpholin-4-yl-methanone
Figure imgf000070_0001
The title compound was prepared in analogy to example 28 starting from 2-(3-fluoro-5- morpholin-4-yl-phenyl)-4,4-dimethyl- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 454.2.
Example 82
[4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinolin-6-yl]- morpholin-4-yl-methanone
Figure imgf000070_0002
The title compound was prepared in analogy to example 28 starting from 4,4-dimethyl-2- (3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 436.1.
Example 83
2-(3-Fluoro-5-morpholin-4-yl^henyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6-yl]- [3-(l-hydroxy-l-methyl-ethyl)-pyrrolidin-l-yl]-methanone
Figure imgf000070_0003
The title compound was prepared in analogy to example 28 starting from 2-(3-fluoro-5- morpholin-4-yl-phenyl)-4,4-dimethyl- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 496.2. Example 84
2-(5-Fluoro-2-isopropoxy-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid cyclobutylamide
Figure imgf000071_0001
The title compound was prepared in analogy to example 28 starting from 2-(5-fluoro-2- isopropoxy-phenyl)-4,4-dimethyl- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 411.2.
Example 85
2-(5-Fluoro-2-isopropoxy-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid (2-hydroxy-l-hydroxymethyl-ethyl)-amide
Figure imgf000071_0002
The title compound was prepared in analogy to example 28 starting from 2-(5-fluoro-2- isopropoxy-phenyl)-4,4-dimethyl- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 431.1.
Example 86
[2-(5-Fluoro-2-isopropoxy-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6-yl]-(3- hydroxy-3-methyl-pyrrolidin-l-yl)-methanone
Figure imgf000072_0001
The title compound was prepared in analogy to example 28 starting from 2-(5-fluoro-2- isopropoxy-phenyl)-4,4-dimethyl- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 441.3.
Example 87
2-(3-Chloro-4-fluoro^henyl)-4,4-dimethyl-l,23,4 etrahydro-quinoline-6-carboxylic acid (l-benzyl-piperidin-4-yl)-amide
Figure imgf000072_0002
The title compound was prepared in analogy to example 28 starting from 2-(3-chloro-4- fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 506.2.
Example 88
2-(3-Fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid (2-hydroxy-ethyl)-amide
Figure imgf000072_0003
The title compound was prepared in analogy to example 28 starting from 2-(3-fluoro-5- morpholin-4-yl-phenyl)-4,4-dimethyl- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+) [(M+H)+] 428.1. Example 89
[4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinolin-6-yl]-[3-(l- hydroxy-l-methyl-ethyl)-pyrrolidin-l-yl]-methanone
Figure imgf000073_0001
The title compound was prepared in analogy to example 28 starting from 4,4-dimethyl-2- (3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid. MS (ESI+)
[(M+H)+] 478.1.
Example 90
Scintillation Proximity Assay Preparation of Enzymes
Recombinant human AMPK ΐβΐγΐ, 2β1γ1 or AMPK a subunit truncations ccl(l-335), l(l-394) and 2(l-394) were constructed, expressed and purified as described previously (Pang, T., Zhang, Z.S., Gu, M., Qiu, B.Y., Yu, L.F., Cao, P.R., Shao, W., Su, M.B., Li, J.Y., Nan, F.J., and Li, J. (2008). Rat liver AMPK heterotrimer enzyme was obtained from Upstate (Billerica, MA, U.S.A.).
Scintillation Proximity Assay
Before the Scintillation Proximity Assay (SPA) assay, 200 nM recombinant AMPK proteins ( ΐβΐγΐ, οώβΐγΐ, l(l-335), al(l-394) or o 2(l-394)) were fully
phosphorylated as described previously (Pang et al., 2008). SPA reactions were performed in 96-well plates at a final volume of 50 μΐ^ containing 20 mM Tris-HCl pH 7.5, 5 mM MgCl2, 1 mM DTT, 2 μΜ biotin-SAMS, 2 μΜ ATP,0.2 μα/well [γ-33Ρ]ΑΤΡ, and various amount of activator. Reactions were initiated by the addition of 50 nM recombinant AMPK proteins to the reaction solutions and incubated at 30 °C for 2 hours. After that, reactions were terminated by the addition of 40 μΐ^ stop solution containing 80 μg streptavidin-coated SPA beads per well, 50 mM ED TA, 0.1% Triton X-100 in PBS, pH 7.5 and incubated for 1 hour. Finally, a 160 μΐ^ suspension solution containing 2.4 M CsCl, 50 mM EDTA, and 0.1% Triton X-100 in PBS (pH 7.5) was added to the reaction solution to suspend SPA beads completely. SPA signals were determined with a Wallac MicroBeta plate counter (PerkinElmer) 30 min later for calculation of the amount of product formed. The amount of products formed in 2 hour was plotted against activator concentrations to determine the effective concentration of the activator (EC50) required for 50% of maximal enzyme activity. Compounds as described above have EC50 values between 0.5 μΜ and 50 μΜ, preferred compounds have EC50 values between 0.5 μΜ and 10 μΜ, particularly preferred compounds have EC50 values between 0.5 μΜ and 1 μΜ.
Seleceted compounds of formula (I) have the following EC50, obtained by using the foregoing Scintillation Proximity Assay.
Example No. EC50 (μΜ)
Example 1 2.07
Example 2 3.21
Example 3 6.12
Example 4 13.22
Example 5 1.24
Example6 7.41
Example 7 2.29
Example 8 4.44
Example 9 1.68
Example 10 3.48 Example 11 4.96
Example 12 5.92
Example 13 2.63
Example 14 3.76
Example 15 7.6
Example 16 8.61
Example 17 4.54
Example 18 4.58
Example 19 2.13
Example 20 3.31
Example 22 5.35
Example 23 7.02
Example 25 4.83
Example 26 2.1
Example 27 1.49
Example 28 11.36
Example 30 2.47
Example 31 2.58
Example 32 1.24
Example 33 13.58
Example 34 2.71
Example 35 6.88 Example 36 5.63
Example 37 13.91
Example 38 2.38
Example 39 4.95
Example 40 3.69
Example 41 5.17
Example 42 3.77
Example 43 5.86
Example 44 3.02
Example 45 1.76
Example 46 7.62
Example 47 11.41
Example 48 2.1
Example 49 3.23
Example 50 2.87
Example 51 3.58
Example 52 4.84
Example 53 1.38
Example 54 2.61
Example 55 3.7
Example 56 3.38
Example 57 2.36 Example 58 3.74
Example 59 11.35
Example 60 4.41
Example 61 5.98
Example 62 1.59
Example 63 2.37
Example 64 7.68
Example 66 5.53
Example 67 15.06
Example 68 1.56
Example 69 4.18
Example 70 9.17
Example A
A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of tablets of the following composition: Per tablet
Active ingredient 200 mg
Microcrystalline cellulose 155 mg
Corn starch 25 mg
Talc 25 mg
Hydroxypropylmethylcellulo se 20 mg
Total 425 mg Example B
A compound of formula (I) can be used in a manner known per se as the active ingredient for the production of capsules of the following composition:
Per capsule Active ingredient 100.0 mg
Corn starch 20.0 mg
Lactose 95.0 mg
Talc 4.5 mg
Magnesium stearate 0.5 mg
Total 220.0 mg

Claims

A compound of formula (I)
Figure imgf000079_0001
wherein
A1 is absent or -CH2-; A is nitrogen or -CH-; A3 is absent or -C(CH3)2-; R s hydroxyl or NRnR12;
R 2" and R 3J are independently selected from alkyl, alkenyl and phenyl; or R 2 and R 3 together with the carbon atom to which they are attached form cycloalkyl;
R4, R5, R6, R7 and R8 are independently selected from hydrogen, alkyl, alkoxy, halogen, alkylsulfonyl, morpholinyl, piperazinyl and alkylpiperazinyl;
R9 is hydrogen, alkyl, benzyl or alkylaminocarbonyl;
R10 is hydrogen or halogen;
R 11 and R 112" are independently selected from hydrogen, alkyl, cycloalkyl,
hydroxyalkyl, oxetanyl, alkylpiperidinyl, 1,1-dioxothiomorpholinylalkyl benzylpiperidinyl ; or R 11 and R 12 together with the nitrogen atom to which they are attached form morpholinyl, piperazinyl, alkylpiperazinyl, alkylsulfonylpiperazinyl, alkylhydroxypyrrolidinyl or hydroxyalkylpyrrolidinyl; or a pharmaceutically acceptable salt or ester thereof.
2. A compound according to claim 1, wherein R 2 and R 3 are independently selected from methyl, ethyl, ethenyl and phenyl, or R 2 and R 3 together with the carbon atom to which they are attached form cyclopropyl, cyclopentyl or cyclohexyl.
3. A compound according to claim 1 or 2, wherein R4 is hydrogen, alkyl, alkoxy,
halogen or alkylsulfonyl.
4. A compound according to any one of claims 1 to 3, wherein R4 is hydrogen, methyl, fluoro, chloro, bromo or methylsulfonyl.
5. A compound according to any one of claims 1 to 4, wherein R5 is hydrogen, alkyl, alkoxy, halogen, alkylsulfonyl, morpholinyl, piperazinyl or alkylpiperazinyl.
6. A compound according to any one of claims 1 to 5, wherein R5 is hydrogen, chloro, or morpholinyl.
7. A compound according to any one of claims 1 to 6, wherein R6 is hydrogen or
halogen.
8. A compound according to any one of claims 1 to 7, wherein R6 is hydrogen or fluoro.
9. A compound according to any one of claims 1 to 8, wherein R is hydrogen, halogen, alkylsulfonyl or morpholinyl.
10. A compound according to any one of claims 1 to 9, wherein R is hydrogen, fluoro, chloro, bromo or methylsulfonyl.
11. A compound according to any one of claims 1 to 10, wherein R is hydrogen or alkyl.
12. A compound according to any one of claims 1 to 11, wherein R is hydrogen or
methyl.
13. A compound according to any one of claims 1 to 12, wherein R9 is hydrogen, pentyl, dimethylaminocarbonyl or benzyl.
14. A compound according to any one of claims 1 to 13, wherein R10 is hydrogen or chloro.
15. A compound according to any one of claims 1 to 14, wherein R 11 and R 12 are
independently selected from hydrogen, alkyl, cycloalkyl, hydroxyalkyl and alkylpiperidinyl, or R 11 and R 12 together with the nitrogen atom to which they are attached form morpholinyl, piperazinyl, alkylpiperazinyl or alkylsulfonylpiperazinyl.
16. A compound according to any one of claims 1 to 15, wherein R 11 and R 12 are
independently selected from hydrogen, methyl, propyl, dihydroxybutyl, cyclopropyl, cyclobutyl, methylpiperidinyl and hydroxyethyl or R 11 and R 12 together with the nitrogen atom to which they are attached form morpholinyl, piperazinyl,
methylpiperazinyl or methylsulfonylpiperazinyl.
17. A compound according to any one of claims 1 to 16 selected from
2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(5-Bromo-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(2, 5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(3, 5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(3-Methanesulfonyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(3-Fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclohexane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline) -6-carboxylic acid;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid; 2-(5-Fluoro-2-methanesulfonyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(2,5-Dimethanesulfonyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(2,5-Dichloro-phenyl)-l-dimethylcarbamoyl-spiro(cyclopropane-l,4'- ,2',3',4'- tetrahydroquinoline)-6-carboxylic acid;
1 -Benzyl-2-(2,5-dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(2,5-Dichloro-phenyl)-4,4-dimethyl- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid;
4,4-Dimethyl-2-(l-methyl-l-phenyl-ethyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid;
7-Chloro-2-(5-chloro-2-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid;
[2-(5-Chloro-2-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6-yl]-acetic acid;
2-(3-Chloro-4-fluoro-phenyl)-4-methyl-4- vinyl- l,2,3,4-tetrahydro-quinoline-6- carboxylic acid;
2-(3-Chloro-4-fluoro-phenyl)-4-methyl-4-phenyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid;
2-(5-Fluoro-2-isopropoxy-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid;
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid;
2-[3-(4-Isopropyl-piperazin-l-yl)-phenyl]-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline- 6-carboxylic acid;
4,4-Dimethyl-2-(3-piperazin-l-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid;
6-(3-Chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid; 6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid;
6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8- tetrahydro-[ 1 ,5]naphthyridine-2-carboxylic acid;
2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid cyclobutylamide;
2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid dimethylamide;
[2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinolin)-6-yl]-morpholin-4-yl-methanone;
[2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinolin)-6-yl] -(4-methyl-piperazin- 1 -yl)-methanone;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinolin)-6-yl]-morpholin-4-yl-methanone;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid isopropylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid dimethylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid cyclobutylamide;
2-(5-Bromo-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid cyclobutylamide;
2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6 carboxylic acid cyclopropylamide;
2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6 carboxylic acid methylamide;
2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6 carboxylic acid cyclobutylamide; [2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3' ,4' -tetrahydroquinolin)-6- yl] -morpholin-4-yl-methanone;
2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid isopropylamide;
[2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3' ,4' -tetrahydroquinolin)-6- yl] -(4-methanesulfonyl-piperazin- 1 -yl)-methanone;
2-(3,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
[2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinolin)-6-yl]-morpholin-4-yl-methanone;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid dimethylamide;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid cyclobutylamide;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid isopropylamide;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinolin)-6-yl] -piperazin- 1 -yl-methanone;
2-(2-Bromo-4-fluoro-6-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid methylamide;
4,4-Dimethyl-2-(l-methyl-l-phenyl-ethyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid dimethylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid dimethylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid cyclopropylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid ( 1 -methyl-piperidin-4-yl)-amide; 2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid cyclobutylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid methylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid (2-hydroxy-ethyl)-amide;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinolin)-6-yl]-morpholin-4-yl-methanone;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinolin)-6-yl] -(4-methyl-piperazin- 1 -yl)-methanone;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid oxetan-3-ylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid isopropylamide;
2-(2,5-Dichloro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
2-(3-Fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
2-(3-Morpholin-4-yl-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid methylamide;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid cyclobutylamide;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid dimethylamide;
2-(2,5-Dichloro-phenyl)-4,4-dimethyl- 1 ,2,3,4-tetrahydro-quinoline-6-carboxylic acid cyclobutylamide ;
2-(5-Chloro-2-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid cyclobutylamide; 4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2-hydroxy- 1 -hydroxymethyl- 1 -methyl-ethyl)-amide;
2-(3-Chloro-4-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid cyclobutylamide;
6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid cyclobutylamide;
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid isopropylamide;
N-[2-(l,l-dioxidothiomorpholin-4-yl)ethyl]-4,4-dimethyl-2-[3-(morpholin-4- yl)phenyl] - 1 ,2,3 ,4-tetrahydroquinoline-6-carboxamide; ;
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2,3 -dihydroxy-propyl)- amide ;
N-[2-(l,l-dioxidothiomorpholin-4-yl)ethyl]-4,4-dimethyl-2-{3-[4-(propan-2- yl)piperazin- 1 -yl]phenyl } - 1 ,2,3,4-tetrahydroquinoline-6-carboxamide;
N-[2-(l,l-dioxidothiomorpholin-4-yl)ethyl]-4,4-dimethyl-2-(2-phenylpropan-2-yl)- l,2,3,4-tetrahydroquinoline-6-carboxamide;
[4,4-Dimethyl-2- ( 1 -methyl- 1 -phenyl-ethyl)- 1 ,2,3 ,4-tetrahydro-quinolin-6-yl] - morpholin-4-yl-methanone;
[4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinolin-6-yl]-(3- hydroxy-3-methyl-pyrrolidin- 1 -yl)-methanone;
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2-hydroxy- 1 -hydroxymethyl-ethyl)-amide;
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2-hydroxy-ethyl)-amide;
[2-(3-Fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6- yl] -(3-hydroxy-3-methyl-pyrrolidin- 1 -yl)-methanone;
[2-(3-Fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6- yl] -morpholin-4-yl-methanone; [4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinolin-6-yl]- morpholin-4-yl-methanone;
2-(3-Fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6- yl] -[3-( 1 -hydroxy- 1 -methyl-ethyl)-pyrrolidin- 1 -yl] -methanone;
2-(5-Fluoro-2-isopropoxy-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid cyclobutylamide;
2-(5-Fluoro-2-isopropoxy-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid (2-hydroxy-l-hydroxymethyl-ethyl)-amide;
[2-(5-Fluoro-2-isopropoxy-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6-yl]- (3-hydroxy-3-methyl-pyrrolidin- 1 -yl)-methanone;
2-(3-Chloro-4-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid ( 1 -benzyl-piperidin-4-yl)-amide;
2-(3-Fluoro-5-morpholin-4-yl-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid (2-hydroxy-ethyl)-amide; and
[4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinolin-6-yl]-[3-(l- hydroxy- 1 -methyl-ethyl)-pyrrolidin- 1 -yl] -methanone.
18. A compound according to any one of claims 1 to 17 selected from
2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(5-Bromo-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(3-Fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclohexane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid; 2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(5-Fluoro-2-methanesulfonyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
2-(2,5-Dichloro-phenyl)-l-dimethylcarbamoyl-spiro(cyclopropane-l,4'- ,2',3',4'- tetrahydroquinoline)-6-carboxylic acid;
1 -Benzyl-2-(2,5-dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid;
7-Chloro-2-(5-chloro-2-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid;
[2-(5-Chloro-2-fluoro-phenyl)-4,4-dimethyl-l,2,3,4-tetrahydro-quinolin-6-yl]-acetic acid;
2-(3-Chloro-4-fluoro-phenyl)-4-methyl-4- vinyl- l,2,3,4-tetrahydro-quinoline-6- carboxylic acid;
2-(3-Chloro-4-fluoro-phenyl)-4-methyl-4-phenyl-l,2,3,4-tetrahydro-quinoline-6- carboxylic acid;
6-(3-Chloro-4-fluoro-phenyl)-8-methyl-8-vinyl-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid;
6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5,6,7,8-tetrahydro- [l,5]naphthyridine-2-carboxylic acid;
6-(3-Chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8- tetrahydro-[ 1 ,5]naphthyridine-2-carboxylic acid;
[2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinolin)-6-yl]-morpholin-4-yl-methanone;
[2-(5-Fluoro-2-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinolin)-6-yl] -(4-methyl-piperazin- 1 -yl)-methanone;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinolin)-6-yl]-morpholin-4-yl-methanone; 2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid dimethylamide;
2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid methylamide;
2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
[2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3' ,4' -tetrahydroquinolin)-6- yl] -morpholin-4-yl-methanone;
[2-(2,5-Dichloro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3' ,4' -tetrahydroquinolin)-6- yl] -(4-methanesulfonyl-piperazin- 1 -yl)-methanone;
[2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinolin)-6-yl]-morpholin-4-yl-methanone;
2-(5-Chloro-2-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid dimethylamide;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinolin)-6-yl] -piperazin- 1 -yl-methanone;
2-(2-Bromo-4-fluoro-6-methyl-phenyl)-spiro(cyclopropane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid methylamide;
4,4-Dimethyl-2-(l-methyl-l-phenyl-ethyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid dimethylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid dimethylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid cyclopropylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid ( 1 -methyl-piperidin-4-yl)-amide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid cyclobutylamide; 2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid methylamide;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid (2-hydroxy-ethyl)-amide;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinolin)-6-yl]-morpholin-4-yl-methanone;
[2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinolin)-6-yl] -(4-methyl-piperazin- 1 -yl)-methanone;
2-(2-Bromo-5-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid isopropylamide;
2-(3-Fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' -tetrahydroquinoline)-6- carboxylic acid cyclobutylamide;
2-(3-Morpholin-4-yl-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid methylamide;
4,4-Dimethyl-2-(3-morpholin-4-yl-phenyl)-l,2,3,4-tetrahydro-quinoline-6-carboxylic acid (2-hydroxy-l-hydroxymethyl-l-methyl-ethyl)-amide; and
2-(3-Chloro-4-fluoro-phenyl)-spiro(cyclopentane- 1 ,4' - 1 ' ,2' ,3 ' ,4' - tetrahydroquinoline)-6-carboxylic acid cyclobutylamide.
19. A process for the preparation of a compound of formula (I) according to any one of claims 1 to 18 comprising one of the following steps:
(a) the reaction of a compound of formula (A)
Figure imgf000090_0001
(A) in the presence of a base; or
(b) the reaction of a compound of formula (B)
Figure imgf000091_0001
in the presence of a coupling agent and a base; wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, A1, A2 and A3 are defined as in any one of claims 1 to 16 and R11 is alkyl.
20. A compound according to any one of claims 1 to 18, when manufactured according to a process of claim 19.
21. A compound according to any one of claims 1 to 18 for use as therapeutically active substance.
22. A compound according to any one of claims 1 to 18 for use in the treatment or prophylaxis of obesity, hyperglycemia or type 2 diabetes.
23. A pharmaceutical composition comprising a compound in accordance with any one of claims 1 to 18 and a therapeutically inert carrier.
24. The use of a compound according to any one of claims 1 to 18 for the preparation of a medicament for the treatment or prophylaxis of obesity, hyperglycemia or type 2 diabetes.
25. The use of a compound according to any one of claims 1 to 18 for the treatment or prophylaxis of obesity, hyperglycemia or type 2 diabetes. 25. A method for the treatment or prophylaxis of obesity, hyperglycemia or type 2
diabetes which method comprises administering an effective amount of a compound as defined in any one of claims 1 to 18.
26. The invention as hereinbefore described.
***
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