US20110118208A1 - Thiazolyl-Dihydro-Indazoles - Google Patents

Thiazolyl-Dihydro-Indazoles Download PDF

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US20110118208A1
US20110118208A1 US12/921,588 US92158809A US2011118208A1 US 20110118208 A1 US20110118208 A1 US 20110118208A1 US 92158809 A US92158809 A US 92158809A US 2011118208 A1 US2011118208 A1 US 2011118208A1
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Darryl McConnell
Maria Impagnatiello
Dirk Kessler
Oliver Kraemer
Siegfried Schneider
Lars van der VEEN
Ulrike Weyer-Czernilofsky
Tobias Wunberg
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Boehringer Ingelheim International GmbH
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Definitions

  • the present invention relates to new thiazolyl-dihydro-indazoles of general formula (1)
  • a number of protein kinases have already proved to be suitable target molecules for therapeutic intervention in a variety of indications, e.g. cancer and inflammatory and autoimmune diseases. Since a high percentage of the genes involved in the development of cancer which have been identified thus far encode kinases, these enzymes are attractive target molecules for the therapy of cancer in particular.
  • Phosphatidylinositol-3-kinases are a subfamily of the lipid kinases which catalyse the transfer of a phosphate group to the 3′-position of the inositol ring of phosphoinositides.
  • PI3-kinases play an important role in numerous cell processes such as e.g. cell growth and differentiation processes, the control of cytoskeletal changes and the regulation of intracellular transport processes.
  • cell growth and differentiation processes e.g. cell growth and differentiation processes
  • cytoskeletal changes e.g. cell growth and differentiation processes
  • intracellular transport processes e.g. cell growth and differentiation processes
  • PI3-kinases can be divided into different categories.
  • compounds of general formula (1) act as inhibitors of specific cell cycle kinases.
  • the compounds according to the invention may be used for example for the treatment of diseases connected with the activity of specific cell cycle kinases and characterised by excessive or abnormal cell proliferation.
  • the present invention relates to compounds of general formula (1)
  • R 1 is selected from among —NHR c , —NHC(O)R c , —NHC(O)OR c , —NHC(O)NR c R c , —NHC(O)N(R g )OR c and —NHC(O)SR c , and
  • R 2 denotes hydrogen or a group selected from among C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C 6-10 aryl, C 7-16 arylalkyl and 5-10 membered heteroaryl, optionally substituted by one or more identical or different R 4 and
  • R 3 denotes a 6 membered heteroaryl, substituted by one or more identical or different R a and/or R b , or
  • R 3 denotes a 8-10 membered heteroaryl, optionally substituted by one or more identical or different R e and/or R f , and
  • each R 4 denotes a group selected from among R a , R b and R a substituted by one or more identical or different R b and/or R c ;
  • each R a independently of one another denotes a group optionally substituted by one or more identical or different R b and/or R c , selected from among C 1-6 alkyl, 2-6 membered heteroalkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 4-16 cycloalkylalkyl, C 6-10 aryl, C 7-16 arylalkyl, 5-12 membered heteroaryl, 6-18 membered heteroarylalkyl, 3-14 membered heterocycloalkyl and 4-14 membered heterocycloalkylalkyl,
  • each R b denotes a suitable group and is selected independently of one another from among ⁇ O, —OR', C 1-3 haloalkyloxy, —OCF 3 , ⁇ S, —SR c , ⁇ NR c , ⁇ NOR c , ⁇ NNR c R c , ⁇ NN(R g )C(O)NR c R c , —NR c R c , —ONR c R c , —N(OR c )R c , —N(R g )NR c R c , halogen, —CF 3 , —CN, —NC, —OCN, —SCN, —NO, —NO 2 , ⁇ N 2 , —N 3 , —S(O)R c , —S(O)OR c , —S(O) 2 R c , —S(O) 2 OR c , —
  • R 3 is a radical selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl, optionally substituted by one or more R 4 .
  • a further aspect of the invention are compounds of general formular (1), wherein R 3 is pyridyl.
  • a further aspect of the invention are compounds of general formular (1), wherein R 3 is substituted by a residue selected from the group consisting of halogen, —CN, —OR', —NR c R c and C 1-6 alkyl optionally substituted by R b .
  • a further aspect of the invention are compounds of general formular (1), wherein R 1 is —NHC(O)R c .
  • a further aspect of the invention are compounds of general formular (1), wherein R 1 is —NHC(O)CH 3 .
  • a further aspect of the invention are compounds of general formular (1)—or the pharmaceutically active salts thereof—for use as a medicament.
  • a further aspect of the invention are compounds of general formular (1)—or the pharmacologically effective salts thereof, for preparing a medicament with an antiproliferative activity.
  • a further aspect of the invention is a pharmaceutical preparation, containing as active substance one or more compounds of general formula (1) or the physiologically acceptable salts thereof optionally in conjunction with conventional excipients and/or carriers.
  • a further aspect of the invention is the use of a compound of general formula (1) for preparing a pharmaceutical composition for the treatment and/or prevention of cancer, infections, inflammatory and autoimmune diseases.
  • a further aspect of the invention is a pharmaceutical preparation comprising a compound of general formula (1) and at least one other cytostatic or cytotoxic active substance, different from formula (1), optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.
  • alkyl substituents are meant in each case saturated, unsaturated, straight-chain or branched aliphatic hydrocarbon groups (alkyl group) and this includes both saturated alkyl groups and unsaturated alkenyl and alkynyl groups.
  • Alkenyl substituents are in each case straight-chain or branched, unsaturated alkyl groups, which have at least one double bond.
  • alkynyl substituents are meant in each case straight-chain or branched, unsaturated alkyl groups, which have at least one triple bond.
  • heteroalkyl refers to groups which can be derived from alkyl as defined above in its broadest sense by replacing one or more of the groups —CH 3 in the hydrocarbon chains independently of one another by the groups —OH, —SH or —NH 2 , one or more of the groups —CH 2 — independently of one another by the groups —O—, —S— or —NH—, one or more of the groups
  • heteroalkyl is made up of the sub-groups of saturated hydrocarbon chains with hetero-atom(s), heteroalkenyl and hetero-alkynyl, while further subdivision into straight-chain (unbranched) and branched may be carried out. If a heteroalkyl is supposed to be substituted, the substitution may take place independently of one another, in each case mono- or polysubstituted, at all the hydrogen-carrying oxygen, sulphur, nitrogen and/or carbon atoms. Heteroalkyl itself may be linked to the molecule as substituent both through a carbon atom and through a heteroatom.
  • dimethylaminomethyl dimethylaminoethyl (1-dimethylaminoethyl; 2-dimethyl-aminoethyl); dimethylaminopropyl (1-dimethylaminopropyl, 2-dimethylaminopropyl, 3-dimethylaminopropyl); diethylaminomethyl; diethylaminoethyl (1-diethylaminoethyl, 2-diethylaminoethyl); diethylaminopropyl (1-diethylaminopropyl, 2-diethylamino-propyl, 3-diethylaminopropyl); diisopropylaminoethyl (1-diisopropylaminoethyl, 2-di-isopropylaminoethyl); bis-2-methoxyethylamino; [2-(dimethylamino-ethyl)
  • Haloalkyl relates to alkyl groups, wherein one or more hydrogen atoms are replaced by halogen atoms.
  • Haloalkyl includes both saturated alkyl groups and unsaturated alkenyl and alkynyl groups, such as for example —CF 3 , —CHF 2 , —CH 2 F, —CF 2 CF 3 ,—CHFCF 3 , —CH 2 CF 3 , —CF 2 CH 3 , —CHFCH 3 , —CF 2 CF 2 CF 3 , —CF 2 CH 2 CH 3 , —CF ⁇ CF 2 , —CCl ⁇ CH 2 , —CBr ⁇ CH 2 , —Cl ⁇ CH 2 , —C ⁇ C—CF 3 , —CHFCH 2 CH 3 and —CHFCH 2 CF 3 .
  • Halogen refers to fluorine, chlorine, bromine and/or iodine atoms.
  • cycloalkyl is meant a mono or bicyclic ring, while the ring system may be a saturated ring or, however, an unsaturated, non-aromatic ring, which may optionally also contain double bonds, such as for example cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, norbornyl and norbornenyl.
  • Cycloalkylalkyl includes a non-cyclic alkyl group wherein a hydrogen atom bound to a carbon atom, usually to a terminal C atom, is replaced by a cycloalkyl group.
  • Aryl relates to monocyclic or bicyclic aromatic rings with 6-10 carbon atoms such as phenyl and naphthyl, for example.
  • Arylalkyl includes a non-cyclic alkyl group wherein a hydrogen atom bound to a carbon atom, usually to a terminal C atom, is replaced by an aryl group.
  • heteroaryl mono- or bicyclic aromatic rings, which instead of one or more carbon atoms contain one or more, identical or different hetero atoms, such as e.g. nitrogen, sulphur or oxygen atoms.
  • heteroaryl mono- or bicyclic aromatic rings, which instead of one or more carbon atoms contain one or more, identical or different hetero atoms, such as e.g. nitrogen, sulphur or oxygen atoms.
  • heteroaryl mono- or bicyclic aromatic rings, which instead of one or more carbon atoms contain one or more, identical or different hetero atoms, such as e.g. nitrogen, sulphur or oxygen atoms.
  • heteroaryl include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,
  • bicyclic heteroaryl groups are indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl and benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, indolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetrahydrofuryl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyr
  • Heteroarylalkyl encompasses a non-cyclic alkyl group wherein a hydrogen atom bound to a carbon atom, usually to a terminal C atom, is replaced by a heteroaryl group.
  • Heterocycloalkyl relates to saturated or unsaturated, non-aromatic mono-, bicyclic or bridged bicyclic rings comprising 3-12 carbon atoms, which instead of one or more carbon atoms carry heteroatoms, such as nitrogen, oxygen or sulphur.
  • heterocyloalkyl groups are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thiomorpholinyl-S,S-dioxide, tetrahydropyranyl, tetrahydrothienyl, homothiomorpholinyl-S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidin
  • Heterocycloalkylalkyl relates to a non-cyclic alkyl group wherein a hydrogen atom bound to a carbon atom, usually to a terminal C atom, is replaced by a heterocycloalkyl group.
  • the monoketone is added to dry THF (e.g. 10 mmol in 90 mL solvent) and the suspension is cooled to ⁇ 78° C. under inert atmosphere. LiHMDS (3.4 eq.) is slowly added to the reaction mixture so that the reaction temperature is kept below ⁇ 60° C. After completion of the addition, a solution of the acid chloride (1.2 eq.) in dry THF (about 2-2.5 M) is added slowly. The reaction mixture is stirred overnight allowing it to warm to RT. For the work-up the mixture is cooled to ⁇ 20° C.
  • the monoketone (1.0 eq.) is dissolved in DMSO (1 M solution) and NaOtBu or sodium tert.-pentoxide (3.0 eq.) is slowly added.
  • the reaction mixture is stirred for 30 min at room temperature before the ester (1.1 eq.) is added slowly. After completion of the addition the mixture is stirred for 4 h at RT, poured on ice and neutralized with saturated ammonium chloride solution. The precipitate is filtered off, washed with water dried under vacuum at 40° C. overnight. Alternatively, the solvent is evaporated after completion of the reaction and the crude product may be used for the next step without further purification.
  • Carboxylic acid (1.0 eq.) is dissolved in CH 2 Cl 2 , CDI (1.0 eq.) is added and the reaction mixture is stirred at RT over night. The solvent is removed in vacuo and the crude product is used without further purification.
  • a 1 M solution of LiHMDS (3 eq.) in THF is diluted with THF and the resulting solution is cooled to ⁇ 10° C. under inert atmosphere.
  • the monoketone (1.0 eq.) is added in small portions so that the reaction temperature is kept below ⁇ 10° C.
  • a solution of the active ester (2.0 eq.) in THF is added slowly.
  • the reaction mixture is stirred over night allowing it to warm to RT.
  • the reaction is quenched with a saturated solution of NH 4 Cl in water and the aqueous phase is extracted twice with CH 2 Cl 2 .
  • the combined organic layers are dried over MgSO 4 , filtered and the solvent is removed under reduced pressure.
  • the product is purified by RP-chromatography.
  • the o-fluoropyridine and an excess of the amine are dissolved in EtOH or iPrOH/THF (0.1-0.2 M) and the mixture is heated in the microwave at 100° C. for 30-60 min or alternatively at RT without heating (the reaction is typically monitored by LC-MS until all starting material has reacted). After completion of the reaction the solvent is removed in vacuo and the product is either purified by chromatography (NP with MeOH/DCM or RP with ACN/H 2 O) or used without further purification.
  • the title compound is obtained from 500 mg (1.5 mmol) A-01 and 5.0 mL of a 2 M solution of dimethylamine in THF (10 mmol). The reaction is performed in EtOH according to the general procedure A4. The product is purified by NP-chromatography. Yield 205 mg.
  • the title compound is obtained from 160 mg (0.39 mmol, ⁇ 81% purity) A-01 and 410 ⁇ L (3.90 mmol) tert-butylamine.
  • the reaction is performed in EtOH according to the general procedure A4.
  • the crude product is used without further purification. Yield: 157 mg.
  • the title compound is obtained from 160 mg (0.39 mmol, about 81% purity) A-01 and 270 ⁇ L (3.90 mmol) cyclopropylamine.
  • the reaction is performed in EtOH according to the general procedure A4.
  • the crude product is used without further purification. Yield: 168 mg.
  • the title compound is obtained from 160 mg (0.39 mmol, about 81% purity) A-01 and 290 ⁇ L (3.87 mmol) allylamine according to the general procedure A4. The reaction is performed in EtOH. The crude product is used without further purification. Yield: 177 mg.
  • the title compound is obtained from 160 mg (0.39 mmol, about 81% purity) A-01 and 335 ⁇ L (3.89 mmol) isopropylamine.
  • the reaction is performed in EtOH according to the general procedure A4.
  • the crude product is used without further purification. Yield: 179 mg.
  • the title compound is obtained from 27.0 g (72.90 mmol, about 90% purity) A-01 and 27 mL (319.7 mmol) of a solution of methylamine in water.
  • the reaction is performed in a 1:1 mixture of THF and iPrOH according to the general procedure A4.
  • a large portion of the solvent is removed under reduced pressure, the formed precipitate is filtered off and washed with a small amount of iPrOH as well as water. Yield: 17.8 g.
  • the title compound is obtained from 1.0 g (3.00 mmol) A-01 and 1.56 mL (14.1 mmol) N,N-dimethylethylendiamine.
  • the reaction is performed in a 1:1 mixture of THF and iPrOH according to the general procedure A4.
  • the solvent is removed under reduced pressure, the residue taken up with water, extracted with CH 2 Cl 2 , the organic phase dried over MgSO 4 , filtered and the solvent removed in vacuo. Yield: 1.49 g.
  • the title compound is obtained from 1.0 g (3.0 mmol) A-01 and 1.22 mL (14.1 mmol) 2-methoxyethylamine.
  • the reaction is performed in a 1:1 mixture of THF and iPrOH according to the general procedure A4.
  • the solvent is removed under reduced pressure, the residue treated with water.
  • the precipitate is filtered off, washed twice with water and dried. Yield: 1.03 g.
  • the title compound is obtained from 25.0 g (67.50 mmol, about 90% purity) A-01 and 25 mL (314 mmol) of a solution of ethylamine in water.
  • the reaction is performed in a 1:1 mixture of THF and iPrOH according to the general procedure A4.
  • For the work-up a large portion of the solvent is removed under reduced pressure, water is added and the formed precipitate is filtered off.
  • the product is washed twice with both iPrOH and water. Yield: 20.2 g.
  • the title compound is obtained from 3.46 g (9.96 mmol) N-[6-(6-fluoro-5-methyl-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzothiazol-2-yl]-acetamide (made in analogy to A-01) and 3.46 mL (43.5 mmol) of a solution of ethylamine in water.
  • the reaction is performed in a 1:1 mixture of THF and iPrOH according to the general procedure A4.
  • the crude product is used without further purification. Yield: 2.1 g.
  • the title compound is obtained by reacting 3.34 g (15.9 mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 6.60 g (31.8 mmol) (6-chloro-pyridin-3-yl)-imidazol-1-yl-methanone according to the general procedure A3.
  • the product is purified by RP-HPLC (gradient 5-70% ACN, 25 min, 60 mL/min). Yield: 570 mg.
  • the title compound is obtained by reacting 500 mg (2.38 mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 909 mg (4.76 mmol) (5-fluoro-pyridin-3-yl)-imidazol-1-yl-methanone according to the general procedure A3.
  • the reaction is quenched with 4 N HCl in dioxane prior to the addition of phosphate buffer (pH 6-7).
  • the crude product obtained after extraction is used without further purification. Yield: 800 mg.
  • the title compound is obtained by reacting 786 mg (3.74 mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 1.40 g (7.48 mmol) of (5-methyl-pyridin-3-yl)-imidazol-1-yl-methanone according to the general procedure A3 ( ⁇ 60° C.).
  • the reaction is quenched with HCl in ether (pH 3) before CH 2 Cl 2 and phosphate buffer (28.1 g NaH 2 PO 4 ⁇ 2 H 2 O, 106.8 g NaHPO 4 ⁇ 2 H 2 O, 500 mL H 2 O) are added.
  • the product is purified by RP-HPLC (gradient 5-80% ACN, 40 min). Yield: 439 mg.
  • the title compound is obtained by reacting 21.0 g (210 mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 19.0 g (115 mmol) of 6-ethyl-nicotinic acid ethyl ester according to the general procedure A2. Yield: 26.4 g.
  • the title compound is obtained by reacting 3.36 g (16.0 mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 6.50 g (32.0 mmol) of the (6-methoxy-pyridin-3-yl)-imidazol-1-yl-methanone according to the general procedure A3.
  • the reaction is quenched with saturated NH 4 Cl solution prior to extraction.
  • the product is purified by RP-chromatography (gradient: 5-70% ACN, 25 min, 60 mL/min). Yield: 860 mg.
  • the title compound is obtained by reacting 5.00 g (23.8 mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 4.71 g (28.5 mmol) of 5,6-dimethylnicotinic acid methylester according to the general procedure A2.
  • the product is purified by NP-HPLC (gradient DCM/MeOH 99:1-80:20, 20 min, 60 mL/min). Yield: 917 mg.
  • the title compound is obtained by reacting 1.67 g (7.95 mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 2.66 g (23.9 mmol) imidazol-1-yl-quinolin-3-yl-methanone according to the general procedure A3.
  • a precipitate is formed during the reaction and is filtered off without quenching, washed with THF, dissolved in a mixture of saturated NaHCO 3 -solution and CH 2 Cl 2 .
  • the water phase is extracted with CH 2 Cl 2 , the combined organic phases are dried over MgSO 4 , filtered, and the solvent is removed under reduced pressure. The remaining solid is treated with diethylether, filtered off and dried. Yield: 1.12 g.
  • the title compound is obtained by reacting 1.91 g (9.08 mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 2.70 g (13.6 mmol) (6-cyano-pyridin-3-yl)-imidazol-1-yl-methanone according to the general procedure A3.
  • the reaction is quenched by adding saturated NaHCO 3 -solution.
  • the water phase is extracted with CH 2 Cl 2 , the combined organic phases are dried over MgSO 4 , filtered, and the solvent is removed under reduced pressure.
  • the product is purified by RP-HPLC (gradient 5-80% ACN, 30 min, 60 mL/min). Yield: 149 mg.
  • the title compound is obtained by reacting 3.82 g (18.2 mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 6.80 g (36.3 mmol) (6-methyl-pyrid-3-yl)-imidazol-1-yl-methanone according to the general procedure A3.
  • the reaction is quenched by adding saturated NH 4 Cl-solution.
  • the water phase is extracted with CH 2 Cl 2 , the combined organic phases are dried over MgSO 4 , filtered, and the solvent is removed under reduced pressure.
  • the product is purified by RP-HPLC (gradient 5-70% ACN, 25 min, 60 mL/min). Yield: 4.68 g.
  • the title compound is obtained by reacting 12.7 g (56.3 mmol) (7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-carbamic acid methyl ester and 13.7 g (73.2 mmol) (6-methyl-pyrid-3-yl)-imidazol-1-yl-methanone according to the general procedure A3.
  • the product precipitates during the reaction, is filtered off and distributed between saturated NaHCO 3 solution and ethyl acetate.
  • the organic phase is dried over MgSO 4 , filtered and the solvent removed under reduced pressure.
  • the crude product is treated with diethylether, filtered and dried. Yield: 13.3 g.
  • the title compound is obtained by reacting 4.10 g (18.3 mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-propionamide and 6.79 g (36.0 mmol) (6-methyl-pyrid-3-yl)-imidazol-1-yl-methanone according to the general procedure A3. After the complete addition a dark, sticky gum has formed. The THF is decanted of and the gum is dissolved in a saturated solution of NaHCO 3 in water. The mixture is extracted with CH 2 Cl 2 , the organic phases are washed with water and brine, dried on MgSO 4 and concentrated in vacuo. The residue is triturated with diethylether and ACN. Yield: 1.50 g.
  • the title compound is obtained from 2.10 g (11.2 mmol) 2-chloro-5,6-dihydro-4H-benzothiazol-7-one and 1.83 g (11.4 mmol) 6-fluoronicotinic acid chloride according to general procedure A1.
  • the crude product is taken up in DMSO, water and ACN are added. A precipitate is formed, filtered off and washed with water. Yield: 1.20 g.
  • the title compound is obtained from 2.70 g (7.73 mmol) [7-hydroxy-6-(6-fluoro-pyridine-3-carbonyl)-4,5-dihydro-benzothiazol-2-yl]-carbamic acid methyl ester (which was made in analogy to A-01) and 2.7 mL (32.0 mmol) of a solution of methylamine in water.
  • the reaction is performed in a 1:1 mixture of THF and iPrOH according to the general procedure A4.
  • the solvent is removed under reduced pressure, the precipitate is filtered and washed with iPrOH. Yield: 2.31 g.
  • a solution of 200 mg (0.64 mmol) A-26 in THF is cooled to 0° C.
  • a solution of methylamine in THF (1.6 mL, 2 M) is added and the mixture is stirred at 0° C. for 2 h and at RT for 2 h.
  • 50 ⁇ L (0.72 mmol) cyclopropylamine are added and the mixture is stirred at RT for 18 h.
  • the solvent is removed under reduced pressure.
  • the crude product is used for the next step without further purification.
  • the title compound is obtained from 100 mg (0.32 mmol) A-26, 160 ⁇ L of a 2 M solution of methylamine in THF and 800 ⁇ L (1.60 mmol) of a 2 M solution of ethylamine in THF as outline for A-29.
  • the product is purified by RP-HPLC. Yield: 33 mg.
  • A-31) Azetidine-1-carboxylic acid [7-hydroxy-6-(6-methyl-pyridine-3-carbonyl)-4,5-dihydro-benzothiazol-2-yl]-amide
  • the title compound is obtained from 12.0 g (46.8 mmol) (7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-thiocarbamic acid S-ethyl ester and 8.22 g (51.1 mmol) 6-fluoro-nicotinic acid chloride according to general procedure A1.
  • the reaction is quenched with 25 mL 2 M hydrochloric acid and 100 mL phosphate buffer (pH 6).
  • the crude product obtained after the extraction is treated with TBME. Yield: 18.5 g.
  • the title compound is obtained from 1.50 g (3.95 mmol) A-32 and 1.50 mL (19.8 mmol) of a solution of methylamine in water according to the general procedure A4.
  • the reaction is performed in THF/iPrOH. After removal of the solvent in vacuo the remaining solid is treated with TBME. Yield 1.47 g.
  • the title compound is obtained from 18.5 g (48.8 mmol) A-32 and 20.0 mL (247 mmol) of a solution of ethylamine in water according to the general procedure A4. The reaction is performed in THF/iPrOH at RT. Yield: 19.8 g.
  • 6-Chloro-nicotinic acid methyl ester (60 g, 0.35 mol) is taken up in 500 mL 2 M ethyl-amine in THF and stirred at 100° C. in a sealed tube for 16 h. The reaction mixture is cooled to RT and the solvents are removed under reduced pressure. The residue is poured on ice and stirred for 15 min. The precipitate is filtered off, washed with water and dried in vacuo.
  • the dried 6-ethylamino-nicotinic acid methyl ester (30 g, 0.17 mol) is dissolved in 150 mL DCM and triethylamine (29 mL, 0.20 mol), DMAP (4.0 g, 33 mmol) and BOC anhydride (100 mL, 0.42 mol) are added successively at 0° C.
  • the reaction mixture is allowed to warm up to RT and stirred for 16 h.
  • To the reaction mixture 100 mL of 10% citric acid in water is added and the reaction mixture is stirred for 10 min.
  • the organic phase is separated, dried over Na 2 SO 4 and concentrated under reduced pressure. Yield: 60 g.
  • the crude 6-(tert-butoxycarbonyl-ethyl-amino)-nicotinic acid methyl ester is taken up in 100 mL dioxane and a solution of lithium hydroxide monohydrate (13.5 g, 0.32 mol) in 100 mL water is added and the reaction mixture is stirred at RT for 4 h.
  • the dioxane is removed from the reaction mixture under reduced pressure, water is added and the reaction mixture is acidified to pH 6 with a solution of 10% citric acid in water.
  • the formed precipitate is filtered off and dried in vacuo. Yield: 36 g.
  • A-36a (6.40 g, 24.0 mmol) is taken up in 150 mL DCE, 1-chloro-N,N-2-trimethylpropenyl-amine (6.42 mL, 48.1 mmol) is added and the reaction mixture is stirred overnight at RT.
  • the reaction mixture is concentrated under reduced pressure and the crude product is used in the next step without purification.
  • A-36 is synthesized according to general procedure A1 starting from 3.8 g (15 mmol) A-36c and 6.8 g (24 mmol) A-36b. Yield: 1.23 g.
  • 6-Amino-nicotinic acid methyl ester (13.7 g, 90.0 mmol), triethyl amine (12.5 mL, 90.0 mmol) and DMAP (3.30 g, 27.0 mmol) are taken up in 200 mL DCM and a solution of di-tert-butyl dicarbonate (41.3 g, 189 mmol) in 40 mL DCM is added drop wise. The reaction mixture is stirred overnight at RT. An aqueous 5% KHSO 4 solution is added and the reaction mixture is extracted with DCM. The combined organic phases are washed with an aqueous 50% saturated KHCO 3 solution, dried over MgSO 4 and concentrated under reduced pressure. Yield: 34.9 g.
  • A-38a (5.00 g, 14.8 mmol) is dried by azeotropic distillation with toluene and then taken up in 20 mL dry THF and cooled to 0° C.
  • 1-Chloro-N,N-2-trimethylpropenyl-amine (3.95 g, 30.0 mmol) is added drop wise and the reaction mixture is stirred at RT for 3 h.
  • the reaction mixture is concentrated under reduced pressure and the crude product is used in the next step without purification.
  • A-38 is synthesized according to general procedure A1 starting from 8.0 g (38 mmol) N-(7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide and 21.7 g (61 mmol) A-38b. Yield: 10.9 g.
  • Example A-39 is prepared analogously to example A-37 starting from 0.30 g (0.95 mmol) A-37a, 0.21 mL (1.4 mmol) DBU and 0.48 g (2.4 mmol) 1-imidazol-1-yl-3-(1-methyl-1H-imidazol-2-yl)-propan-1-one. Yield: 66 mg.
  • Example A-40 is prepared analogously to example A-37 starting from 0.30 g (0.95 mmol) A-37a, 0.21 mL (1.4 mmol) DBU and 0.57 g (2.4 mmol) (2-imidazol-1-yl-2-oxo-ethyl)-methyl-carbamic acid tert-butyl ester. Yield: 0.16 g.
  • Example A-41 is prepared analogously to example A-37 starting from 0.30 g (0.95 mmol) A-37a, 0.21 mL (1.4 mmol) DBU and 0.53 g (2.4 mmol) (2-imidazol-1-yl-2-oxo-ethyl)-carbamic acid tert-butyl ester. Yield: 0.19 g.
  • Example A-42 is prepared analogously to example A-37 starting from 0.30 g (0.95 mmol) A-37a, 0.21 mL (1.4 mmol) DBU and 0.36 g (2.4 mmol) 2-dimethylamino-1-imidazol-1-yl-ethanone. Yield: 0.20 g.
  • Example A-44 is prepared analogously to example A-43 starting from 0.30 g (1.0 mmol) A-27, 0.42 g (2.6 mmol) CDI, 0.31 mL (2.1 mmol) DBU and 0.50 mL (5.2 mmol) tetrahydrofurfuryl alcohol. Yield: 0.14 g.
  • Example A-45 is prepared analogously to example A-43 starting from 0.30 g (1.0 mmol) A-27, 0.42 g (2.6 mmol) CDI, 0.31 mL (2.1 mmol) DBU and 0.50 mL (5.2 mmol) (tetrahydro-furan-3-yl)-methanol. Yield: 83 mg.
  • Example A-46 is synthesized according to general procedure A1 starting from 0.20 g (2.5 g, 10 mmol) A-46a and 6.0 g (17 mmol) A-38b. Yield: 2.5 g.
  • A-47a is prepared analogously to example A-37a starting from 4.0 g (7.6 mmol) A-38. Yield: 2.7 g.
  • Example A-47 is prepared analogously to example A-37 starting from 2.0 g (6.9 mmol) A-47a, 2.1 mL (14 mmol) DBU and 3.1 g (17 mmol) 4-dimethylamino-1-imidazol-1-yl-butan-1-one. Yield: 1.9 g.
  • A-51) 1-(2-Dimethylamino-ethyl)-3-[6-(6-ethylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzothiazol-2-yl]-urea
  • A-52) 1-[6-(6-Ethylamino-pyridine-3-carbonyl)-7-hydroxy-4,5-dihydro-benzothiazol-2-yl]-3-(2-methoxy-ethyl)-urea
  • B-02a (2.0 g, 10.3 mmol) is dissolved in 120 mL MeOH and 10% palladium on coal (200 mg) is added. The reaction mixture is stirred for 2 h under an atmosphere of 4 bar hydrogen. The reaction mixture is filtered and concentrated in vacuo. Yield: 1.69 g.
  • B-03a (27.7 g, 91.1 mmol) is dissolved in 300 mL toluene, degassed and added under argon atmosphere dropwise to a mixture of benzophenone hydrazone (18.8 g, 95.8 mmol), sodium tert-butoxide (13.1 g, 136 mmol), BINAP (2.0 g, 3.21 mmol) and palladium(II) acetate (400 mg, 1.78 mmol).
  • the reaction mixture is warmed to 100° C. and stirred for 2 h. Active charcoal is added and reaction mixture is filtered over Celite. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography (silica gel, 0-10% MeOH in DCM) followed by trituration with MeOH. Yield: 27.6 g.
  • the compound is prepared according to WO 2007/113246.
  • B-06a (5.8 g, 24.2 mmol) is dissolved in 60 mL THF and cooled to 0° C. Borane dimethylsulfide complex (9.18 mL, 121 mmol) is added and the reaction mixture is warmed to RT. The reaction mixture is stirred overnight at reflux temperature. Additional borane dimethyl sulfide complex (9.18 mL, 121 mmol) is added and the reaction mixture is stirred for another 20 h at reflux temperature. The reaction mixture is cooled to RT, 40 mL MeOH and 12 mL conc. HCl are added and the reaction mixture is stirred overnight at 80° C.
  • B-06c is prepared analogously to B-03b starting from B-06b (3.5 g, 16.5 mmol), benzophenone hydrazone (3.24 g, 16.5 mmol), sodium tert-butoxide (2.38 g, 24.8 mmol), (2-biphenyl)-di-tert-butylphosphine (246 mg, 0.825 mmol) and palladium(II) acetate (111 mg, 0.495 mmol). Yield: 1.25 g.
  • B-06 is prepared analogously to B-03 starting from B-06c (1.55 g, 4.73 mmol). Yield: 620 mg.
  • B-07b is prepared analogously to B-03b starting from B-07a (77.6 g, 362 mmol), benzophenone hydrazone (71.0 g, 362 mmol), sodium tert-pentoxide (59.8 g, 543 mmol), BINAP (5.12 mg, 8.20 mmol) and palladium(II)acetate (1.38 g, 6.16 mmol). Yield: 122 g. The product is purified by treatment with active coal in n-propanol.
  • B-07 is prepared analogously to B-03 starting from B-07b (122 g, 362 mmol). Yield: 57.6 g.
  • B-08 is prepared analogously to B-05 starting from 4-aminophenethyl alcohol (7.3 g, 53.2 mmol), sodium nitrite (3.7 g, 53.6 mmol) and tin(II) chloride dihydrate (50.0 g, 222 mmol). Yield: 3.70 g.
  • B-09b is prepared analogously to B-03b starting from B-09a (3.0 g, 10.9 mmol), benzophenone hydrazone (2.15 g, 10.9 mmol), sodium tert-butoxide (1.58 g, 16.4 mmol), (2-biphenyl)-di-tert-butylphosphine (135 mg, 0.438 mmol) and palladium(II)acetate (49 mg, 0.22 mmol). Yield: 2.40 g.
  • B-09 is prepared analogously to B-03 starting from B-09b (2.40 g, 6.16 mmol). Yield: 1.64 g.
  • B-10d is prepared analogously to B-03b starting from B-10c (1.35 g, 5.62 mmol) benzophenone hydrazone (1.10 g, 5.62 g), sodium tert-butoxide (0.81 g, 8.4 mmol), (2-biphenyl)di-tert-butyl phosphine (84 mg, 0.28 mmol) and paldium(II) acetate (38 mg, 0.17 mmol). Yield: 1.20 g.
  • B-10 is prepared analogously to B-03 starting from B-10d (1.20 g, 3.38 mmol). Yield: 0.42 g.
  • B-012 is prepared analogously to B-05 starting from 3-methylsulfonylaniline hydrochloride (2.50 g, 11.4 mmol), sodium nitrite (1.18 g, 17.1 mmol) and tin(II)chloride dihydrate (14.9 g, 66.0 mmol).
  • the product is purified by precipitation from ethyl acetate with cyclohexane. Yield: 1.08 g.
  • B-15c is prepared analogously to B-14a starting from 4-formylphenylboronic acid (3.52 g, 23.5 mmol), di-tert-butylazodicarboxylate (5.95 g, 25.8 mmol) and copper(II) acetate (230 mg, 1.27 mmol).
  • the product is purified by flash chromatography (silica gel, 0-60% ethyl acetate in cyclohexane).Yield: 7.50 g.
  • B-15d is prepared analogously to B-14b starting from B-15c (3.96 g, 11.8 mmol) and B-15b (1.50 g, 11.8 mmol).
  • the product is purified by preparative RP-HPLC (5-98% ACN in water). Yield: 4.25 g.
  • B-15 is prepared analogously to B-14 starting from B-15d (4.25 g, 10.4 mmol) and 4 M HCl in dioxane (25.9 mL, 104 mmol). Yield: 2.90 g.
  • B-16a is prepared analogously to B-15a starting from N-hydroxyphthalimide (5.0 g, 30.7 mmol), potassium carbonate (4.24 g, 30.7 mmol) and N-(2-chloroethyl)morpholine hydrochloride (6.27 g, 33.7 mmol). The product is isolated as the hydrochloride.
  • B-16b is prepared analogously to B-15b starting from B-16a (4.22 g, 15.3 mmol) and ethanolamine (1.01 mL, 16.8 mmol). Yield: 1.31 g.
  • B-16c is prepared analogously to B-14a starting from B-16b (1.31 g, 7.17 mmol) and B-15c (2.41 g, 7.17 mmol).
  • the product is purified by preparative RP-HPLC (5-98% ACN in water) Yield: 1.48 g.
  • B-17a is prepared analogously to B-14a starting from 3,5-difluoro-4-formylboronic acid (5.0 g, 26.9 mmol), di-tert-butylazocarboxylate (6.81 g, 29.6 mmol) and copper(II) acetate (488 mg, 2.69 mmol). Yield: 9.93 g.
  • B-17b is prepared analogously to B-14b starting from B-17a (1.46 g, 3.92 mmol) and B-15b (500 mg, 3.92 mmol).
  • the product is purified by preparative RP-HPLC (5-98% ACN in water). Yield: 700 mg.
  • B-17 is prepared analogously to B-14 starting from B-17b (700 mg, 1.57 mmol) and 4 M HCl in dioxane (3.93 mL, 15.7 mmol). Yield: 263 mg.
  • B-18a is prepared analogously to B-14a starting from 2,3-difluoro-4-formylboronic acid (5.0 g, 26.9 mmol), di-tert-butylazodicarboxylate (6.81 g, 29.6 mmol) and copper(II) acetate (488 mg, 2.69 mmol). Yield: 9.70 g.
  • B-18b is prepared analogously to B-14b starting from B-18a (1.46 g, 3.92 mmol) and B-15b (500 mg, 3.92 mmol).
  • the product is purified by preparative RP-HPLC (5-98% ACN in water). Yield: 840 mg.
  • B-18 is prepared analogously to B-14 starting from B-18b (840 mg, 1.89 mmol) and 4 M HCl in dioxane (4.72 ml, 18.9 mmol). Yield: 276 mg.
  • B-20a is prepared analogously to B-19a starting from 3-pentanone (1.23 mL, 11.6 mmol) and tert-butylcarbazate (1.53 g, 11.6 mmol). Yield: 2.26 g.
  • B-20b was prepared analogously to B-19b starting from B-20a (2.26 g, 11.3 mmol) and sodium cyanoborohydride (709 mg, 11.3 mmol). Yield: 1.68 g.
  • B-20 is prepared analogously to B-19 starting from B-20b (1.68 g, 8.31 mmol) and 4 M hydrochloric acid in dioxane (10.4 ml, 41.5 mmol). Yield: 1.20 g.
  • B-21a is prepared analogously to B-19a starting from isobutyraldehyde (1.26 mL, 13.9 mmol) and tert-butylcarbazate (1.83 g, 13.9 mmol). Yield: 2.56 g.
  • B-21b is prepared analogously to B-19b starting from B-21a (2.56 g, 13.7 mmol) and sodium cyanoborohydride (864 mg, 13.7 mmol). Yield: 1.97 g.
  • B-21 is prepared analogously to B-19 starting from B-21b (1.97 g, 10.5 mmol) and 4 M HCl in dioxane (13.1 mL, 52.3 mmol). Yield: 1.30 g.
  • B-22a was prepared analogously to B-19a starting from tetrahydro-4H-pyran-4-one (923 ⁇ L, 9.99 mmol) and tert-butylcarbazate (1.32 g, 9.99 mmol). Yield: 2.15 g.
  • B-22b is prepared analogously to B-19b starting from B-22a (2.15 g, 10.0 mmol) and sodium cyanoborohydride (631 mg, 10.0 mmol). Yield: 1.57 g.
  • B-22 is prepared analogously to B-19 starting from B-22b (1.57 g, 7.26 mmol) and 4 M HCl in dioxane (9.07 ml, 36.3 mmol). Yield: 1.10 g.
  • B-23a is prepared analogously to B-19a starting from methacroleine (1.18 ml, 14.3 mmol) and tert-butylcarbazate (1.89 g, 14.3 mmol). Yield: 2.61 g.
  • B-23b is prepared analogously to B-19b starting from B-23a (2.61 g, 14.2 mmol) and sodium cyanoborohydride (890 mg, 14.2 mmol). Yield: 1.88 g.
  • B-23 is prepared analogously to B-19 starting from B-23b (1.88 g, 10.1 mmol) and 4 M HCl in dioxane (12.6 mL, 50.5 mmol). Yield: 1.14 g.
  • B-25a is prepared analogously to B-24b starting from B-24a (2.34 g, 13.6 mmol), potassium hydroxide (991 mg, 17.7 mmol), tetrabutylammonium hydrogensulfate (461 mg, 1.36 mmol) and propargyl chloride (70% in toluene, 1.8 mL, 16.3 mmol). Yield: 1.99 g.
  • B-25 is prepared analogously to B-24 starting from B-25a (1.99 g, 9.64 mmol) and 2 M aqueous HCl (9.46 mL, 18.9 mmol). Yield: 1.03 g.
  • B-28a is prepared analogously to B-27c starting from B-27b (10.0 g, 46.4 mmol), potassium carbonate (4.0 g, 29.0 mmol) and propargyl bromide (80% in toluene, 5.26 mL, 48.8 mmol). Yield: 12.4 g.
  • B-28 is prepared analogously to B27 starting from B-28 a (12.4 g, approximately 46.4 mmol) and 4 M hydrochloric acid in dioxane (61.3 ml, 245 mmol). Yield: 9.30 g.
  • B-29b is prepared analogously to B-27b starting from B-29a (18.0 g, 71.1 mmol) and sodium cyanoborohydride (4.47 g, 71.1 mmol). Yield: 17.2 g.
  • B-34 is prepared analogously to B-05 starting from B-34b (21.5 g, 108 mmol), sodium nitrite (7.75 g, 110 mmol) and tin(II) chloride dihydrate (104 g, 453 mmol).
  • the product is lyophilized from dioxane. Yield: 19.3 g.
  • B-35a is prepared analogously to B-14a starting from 3-(N,N-dimethylsulphonamido)-benzeneboronic acid (1.0 g, 4.37 mmol), di-tert-butylazodicarboxylate (1.11 g, 4.83 mmol) and copper(II) acetate (79 mg, 0.44 mmol).
  • the product is purified by preparative RP-HPLC (5-98% ACN in water). Yield: 1.15 g.
  • B-35 is prepared analogously to B-14 starting from B-35a (1.15 g, 2.77 mmol) and 4 M HCl in dioxane (6.92 ml, 27.8 mmol). Yield: 527 mg.
  • B-36a is prepared analogously to B-14a starting from 3-(trifluoromethoxy)benzeneboronic acid (1.0 g, 4.86 mmol), di-tert-butylazodicarboxylate (1.23 g, 5.34 mmol) and copper(II) acetate (88 mg, 0.49 mmol).
  • the product is purified by preparative RP-HPLC (5-98% ACN in water). Yield: 1.26 g.
  • B-36 is prepared analogously to B-14 starting from B-36a (1.26 g, 3.21 mmol) and 4 M HCl in dioxane (8.03 ml, 32.1 mmol). Yield: 557 mg.
  • B-37a is prepared analogously to B-14a starting from 3-(1H-pyrazol-1-yl)phenylboronic acid (800 mg, 4.26 mmol), di-tert-butylazodicarboxylate (1.08 g, 4.68 mmol) and copper(II) acetate (77 mg, 0.43 mmol). Yield: 1.17 g.
  • B-37 is prepared analogously to B-14 starting from B-37a (1.17 g, 3.13 mmol) and 4 M HCl in dioxane (7.81 mL, 31.3 mmol). Yield: 518 mg.
  • Examples C-01 to C-118 can be synthesized according to one of the following general procedures.
  • the appropriate hydrazine and diketone required for synthesis can be deduced from the table of examples.
  • the appropriate diketone (1 eq.) and the appropriate hydrazine or hydrazine hydrochloride (1 eq.) are added to acetic acid and allowed to stir at RT for 24 h.
  • the acetic acid is removed under reduced pressure, the resulting crude material is dissolved in NMP and purified using RP-LC/MS (ACN:H 2 O-ammonium hydrogen carbonate pH 9.3).
  • the resulting product fractions are collected and the solvent removed via freeze-drying to yield the desired product.
  • the appropriate diketone (1 eq.) and the appropriate hydrazine or hydrazine hydrochloride (5-10 eq.) are added to acetic acid and heated to 85° C.-160° C. for 1-6 h in the microwave.
  • the acetic acid is removed under reduced pressure, the resulting crude material dissolved in NMP and purified using RP-LC/MS (ACN:H 2 O-TFA pH 1).
  • the resulting product fractions recollected and the solvent removed via freeze-drying to yield the desired product.
  • the appropriate diketone (1 eq.) and the appropriate hydrazine hydrochloride (1 eq.) are added to EtOH and heated to 100° C.-140° C. for 15-60 min in the microwave.
  • the EtOH is removed under reduced pressure, the resulting crude material dissolved in NMP and purified using RP-LC/MS (ACN:H 2 O-TFA pH 1).
  • the resulting product fractions are collected and the solvent removed via freeze-drying to yield the desired product.
  • the appropriate diketone (1 eq.) and the appropriate hydrazine or hydrazine hydrochloride (1.3 eq.) are added to acetic acid and allowed to stir at 70° C. for 2 d.
  • the acetic acid is removed under reduced pressure, the resulting crude material is dissolved in DMSO/TFA and purified using RP-LC/MS.
  • the resulting product fractions are collected and the solvent is removed via freeze-drying to yield the desired product.
  • the reaction mixture is filtered over celite and the solvent is evaporated under reduced pressure.
  • the residue is taken up in ACN.
  • the solid material is filtered off and dried at 60° C. yielding 3.94 g D-01.
  • the reaction mixture is filtered over silica and the solvent is evaporated under reduced pressure.
  • the residue is taken up in ACN and the solid material is filtered off and dried at 60° C. yielding 5.34 g D-02.
  • D-23 is made in analoguously to D-25
  • D-30 can be synthesized in analoguously to D-14.
  • E-13 and E-14 are prepared in a procedure analogous to example E-12. If the compounds did not precipitate in sufficient purity they are purified by prep. HPLC-MS.
  • E-20 to E-26 are prepared with a procedure analogous to example E-19.
  • Example E-28 is prepared analogous to example E-27.
  • E-29 and E-31 are prepared with a procedure analogous to example E-30.
  • Cyclopropylcarboxylic acid (0.12 g), diisopropylethyl amine (0.12 g) and TBTU (0.44 g) are dissolved in DCM (1 mL) and allowed to react at 30° C. for 30 min.
  • a solution of intermediate D-17 (150 mg) in NMP (1 mL) is then added dropwise to reaction mixture which is then heated at 90° C. for 4 h.
  • MeOH (1 mL) and 1 drop of HCL (conc.) is then added and the mixture stirred for 10 min at RT.
  • the reaction mixture is filtered and purified using RP-LC/MS (ACN:H 2 O-ammonium hydrogen carbonate pH 9.3). Yield: 70 mg.
  • the reaction mixture is purified using RP-LC/MS (ACN:H 2 O-formic acid pH 2-3). Yield: 20 mg.
  • the reaction mixture is purified using RP-LC/MS (ACN:H 2 O-ammonium hydrogen carbonate pH 9.3). Yield: 30 mg.
  • the reaction mixture is purified using RP-LC/MS (ACN:H 2 O-ammonium hydrogen carbonate pH 9.3). Yield: 26 mg.
  • the reaction mixture is purified using RP-LC/MS (ACN:H 2 O-ammonium hydrogen carbonate pH 9.3). Yield: 8 mg.
  • E-50 250 mg is dissolved in THF (15 mL) and placed under an atmosphere of argon. A methyllithium solution (1.5 M, 2.6 mL) is then added over 1 min and the reaction mixture stirred at RT for a further 1 h. Saturated ammonium chloride solution (1 mL) is added and the THF is removed under reduced pressure. The resulting material is dissolved in DMSO (1.8 mL) and water (0.2 mL) and purified using RP-LC/MS (ACN:H 2 O-TFA pH 1). Yield: 12 mg.
  • Examples F-01 to F-20 can be synthesized according to one of the following general procedures.
  • the appropriate acid or acid chloride required for synthesis can be deduced from the table of examples. Boc-groups are removed with HCl (5-10 eq.) by stirring overnight in dioxane at 40° C.
  • Example D-17 (1 eq.) is taken up in NMP and sonicated until all material is dissolved. DMAP (0.1 eq.), DIPEA (5 eq.) and acid chloride (5 eq.) are added and the reaction mixture is stirred for 1 h at RT. The reaction mixture is poured in water and extracted with DCM. The organic phases are concentrated under reduced pressure and the product is purified by flash column chromatography (silica gel, 0-20% MeOH in DCM).
  • the combined organic phase are washed with an aqueous 1% citric acid solution and brine, dried on magnesium sulfate and concentrated under reduced pressure.
  • the product is purified by flash column chromatography (silica gel, 0-20% MeOH in DCM).
  • Examples G-01 to G-05 can be synthesized according to the following general procedure. The appropriate amine required for synthesis can be deduced from the table of examples.
  • Example F-20 (1 eq.) is taken up in NMP, DIPEA (2 eq.) and amine (3 eq.) are added and the reaction mixture is stirred overnight at RT.
  • the reaction mixture is poured in water, extracted with DCM and the organic phase is loaded on a SCX column.
  • the column is washed with DCM and methanol and the product is eluted with a mixture of DCM and 7N ammonia in methanol.
  • the product is further purified by flash column chromatography (silica gel, 0-20% methanol in DCM).
  • Examples H-01 to H-14 can be synthesized according to the following general procedure. The appropriate amine or alcohol required for synthesis can be deduced from the table of examples.
  • Example D-17 (1 eq.), DBU (2 eq.) and CDI (2.5 eq.) are taken up in acetonitrile and stirred at 100° C. overnight. Amine or alcohol (5 eq.) is added and the reaction mixture is stirred again overnight at 100° C. The reaction mixture is concentrated under reduced pressure and the product is purified by HPLC (C-18, 2-98% acetonitrile in water).
  • Examples J-01 to J-02 can be synthesized according to the following general procedure.
  • the appropriate example C can be deduced from the table of examples.
  • DAD Diode Array Detector
  • the test is based on measurement of cellular DNA content via fluorescent dye binding. Because cellular DNA content is highly regulated, it is closely proportional to cell number. The extent of proliferation is determined by comparing cell counts for samples treated with drugs with untreated controls.
  • PC3 human prostate carcinoma cell line
  • PC3 human prostate carcinoma cell line
  • the test substances are diluted stepwise and added to the cells such that the total volume is 200 ⁇ L/well.
  • Cells to which diluent, but not substance, is added serve as controls.
  • the medium is replaced by 100 ⁇ L/well dye-binding solution and the cells are incubated at 37° C. in the dark for a further 60 min.
  • excitation takes place at a wavelength of 485 nm and the emission is measured at 530 nm.
  • EC 50 values are calculated using the GraphPad Prism program.
  • P-AKT levels in PC3 cells are detected by cell-based ELISA.
  • Cells are cultured in 96-well plates and treated with serial dilutions of test substances for 2 h. Cells to which diluent, but not substance, is added serve as controls. Subsequently, the cells are fixed rapidly to preserve protein modifications. Each well is then incubated with a primary antibody specific for Ser473-phosphorylated AKT. Subsequent incubation with secondary HRP-conjugated antibody and developing solution provides a colorimetric readout at 450 nm. EC 50 values are calculated using the GraphPad Prism program.
  • the substances of the present invention are PI3 kinase inhibitors.
  • the novel compounds of the general formula (1) and their isomers and their physiologically tolerated salts are suitable for treating diseases which are characterized by excessive or anomalous cell proliferation.
  • diseases include, for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammation and autoimmune diseases (e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing); bacterial, fungal and/or parasitic infections; leukaemias, lymphomas and solid tumours; skin diseases (e.g. psoriasis); bone diseases; cardiovascular diseases (e.g. restenosis and hypertrophy).
  • the compounds are useful for protecting proliferating cells (e.g. hair cells, intestinal cells, blood cells and progenitor cells) from DNA damage due to irradiation, UV treatment and/or cytostatic treatment (Davis et al., 2001).
  • cancers may be treated with compounds according to the invention, without being restricted thereto:
  • brain tumours such as for example acoustic neurinoma, astrocytomas such as fibrillary, protoplasmic, gemistocytary, anaplastic, pilocytic astrocytomas, glioblastoma, gliosarcoma, pleomorphic xanthoastrocytoma, subependymal large-cell giant cell astrocytoma and desmoplastic infantile astrocytoma; brain lymphomas, brain metastases, hypophyseal tumour such as prolactinoma, hypophyseal incidentaloma, HGH (human growth hormone) producing adenoma and corticotrophic adenoma, craniopharyngiomas, medulloblastoma, meningeoma and oligodendroglioma; nerve tumours such as for example tumours of the vegetative nervous system such as neuroblastoma, ganglioneuroma, paraganglioma (phe
  • novel compounds can be used for the prevention or short-term or long-term treatment of the abovementioned diseases including, where appropriate, in combination with other state-of-the-art compounds such as other anti-tumour substances, cytotoxic substances, cell proliferation inhibitors, antiangiogenic substances, steroids or antibodies.
  • other state-of-the-art compounds such as other anti-tumour substances, cytotoxic substances, cell proliferation inhibitors, antiangiogenic substances, steroids or antibodies.
  • the compounds of the general formula (1) can be used on their own or in combination with other active compounds according to the invention and, where appropriate, in combination with other pharmacologically active compounds as well.
  • Chemotherapeutic agents which can be administered in combination with the compounds according to the invention include, without being restricted thereto, hormones, hormone analogs and antihormones (e.g.
  • tamoxifen toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone and octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane and atamestane), LHRH agonists and antagonists (e.g.
  • goserelin acetate and luprolide inhibitors of growth factors (growth factors such as platelet-derived growth factor and hepatocyte growth factor, examples of inhibitors are growth factor antibodies, growth factor receptor antibodies and tyrosine kinase inhibitors, such as gefitinib, imatinib, lapatinib, Erbitux® and trastuzumab); antimetabolites (e.g.
  • antifolates such as methotrexate and raltitrexed, pyrimidine analogs such as 5-fluorouracil, capecitabine and gemcitabine, purine and adenosine analogs such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine and fludarabine); antitumour antibiotics (e.g. anthracyclines, such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin C, bleomycin, dactinomycin, plicamycin and streptozocin); platinum derivatives (e.g.
  • cisplatin, oxaliplatin and carboplatin e.g. estramustine, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazine, cyclophosphamide, ifosfamide and temozolomide, nitrosoureas such as carmustine and lomustine and thiotepa); antimitotic agents (e.g. vinca alkaloids such as vinblastine, vindesine, vinorelbine and vincristine; and taxans such as paclitaxel and docetaxel); topoisomerase inhibitors (e.g.
  • epipodophyllo-toxins such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan and mitoxantrone) and various chemotherapeutic agents such as amifostin, anagrelide, clodronate, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotan, pamidronate and porfimer.
  • epipodophyllo-toxins such as etoposide and etopophos, teniposide, amsacrine, topotecan, irinotecan and mitoxantrone
  • various chemotherapeutic agents such as amifostin, anagrelide, clodronate, filgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole
  • suitable forms for use are tablets, capsules, suppositories, solutions, in particular solutions for injection (s.c., i.v., i.m.) and infusion, syrups, emulsions or dispersible powders.
  • the proportion of the pharmaceutically active compound(s) should in each case be in the range of 0.1-90% by weight, preferably 0.5-50% by weight, of the total composition, that is in quantities which are sufficient to achieve the dosage range which is specified below. If necessary, the doses mentioned can be given several times a day.
  • Appropriate tablets can be obtained, for example, by mixing the active compound(s) with known auxiliary substances, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrants, such as maize starch or alginic acid, binders, such as starch or gelatine, lubricants, such as magnesium stearate or talc, and/or agents for achieving a depot effect, such as carboxymethyl cellulose, cellulose acetate phthalate or polyvinyl acetate.
  • the tablets can also comprise several layers.
  • sugar-coated tablets can be produced by coating cores, which have been prepared in analogy with tablets, with agents which are customarily used in sugar coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also comprise several layers in order to achieve a depot effect or to avoid incompatibilities.
  • the sugar coating can also comprise several layers in order to achieve a depot effect, with it being possible to use the auxiliary substances which are mentioned above in the case of the tablets.
  • Syrups of the active compounds or active compound combinations according to the invention can additionally comprise a sweetening agent, such as saccharine, cyclamate, glycerol or sugar as well as a taste-improving agent, e.g. flavouring agents such as vanillin or orange extract. They can also comprise suspension aids or thickeners, such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols and ethylene oxide, or protectants such as p-hydroxybenzoates.
  • a sweetening agent such as saccharine, cyclamate, glycerol or sugar
  • a taste-improving agent e.g. flavouring agents such as vanillin or orange extract.
  • suspension aids or thickeners such as sodium carboxymethyl cellulose, wetting agents, for example condensation products of fatty alcohols and ethylene oxide, or protectants such as p-hydroxybenzoates.
  • Injection and infusion solutions are produced in a customary manner, e.g. while adding isotonizing agents, preservatives, such as p-hydroxybenzoates, or stabilizers, such as alkali metal salts of ethylenediaminetetraacetic acid, where appropriate using emulsifiers and/or dispersants, with it being possible, for example, to employ, where appropriate, organic solvents as solubilizing agents or auxiliary solvents when using water as diluent, and aliquoted into injection bottles or ampoules or infusion bottles.
  • the capsules which comprise one or more active compounds or active compound combinations, can, for example, be produced by mixing the active compounds with inert carriers, such as lactose or sorbitol, and encapsulating the mixture in gelatine capsules.
  • inert carriers such as lactose or sorbitol
  • Suitable suppositories can be produced, for example, by mixing with excipients which are envisaged for this purpose, such as neutral fats or polyethylene glycol, or their derivatives.
  • Auxiliary substances which may be mentioned by way of example are water, pharmaceutically unobjectionable organic solvents, such as paraffins (e.g. petroleum fractions), oils of vegetable origin (e.g. groundnut oil or sesame oil), monofunctional or poly-functional alcohols (e.g. EtOH or glycerol), carrier substances such as natural mineral powders (e.g. kaolins, argillaceous earths, talc and chalk), synthetic mineral powders (e.g. highly disperse silicic acid and silicates), sugars (e.g. cane sugar, lactose and grape sugar), emulsifiers (e.g.
  • paraffins e.g. petroleum fractions
  • oils of vegetable origin e.g. groundnut oil or sesame oil
  • monofunctional or poly-functional alcohols e.g. EtOH or glycerol
  • carrier substances such as natural mineral powders (e.g. kaolins, argillaceous earths, talc and chalk),
  • lignin sulphite waste liquors, methyl cellulose, starch and polyvinyl-pyrrolidone
  • glidants e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate.
  • the tablets can naturally also comprise, in addition to the abovementioned carrier substances, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with a variety of further substances such as starch, preferably potato starch, gelatine and the like. It is furthermore also possible to use glidants, such as magnesium stearate, sodium lauryl sulphate and talc, for the tableting.
  • glidants such as magnesium stearate, sodium lauryl sulphate and talc, for the tableting.
  • a variety of taste improvers or dyes can also be added to the active compounds in addition to the abovementioned auxiliary substances.
  • the finely ground active compound, lactose and a part of the maize starch are mixed with each other.
  • the mixture is sieved, after which it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
  • the granular material, the remainder of the maize starch and the magnesium stearate are sieved and mixed with each other.
  • the mixture is pressed into tablets of suitable shape and size.
  • the active compound is dissolved, either at its intrinsic pH or, where appropriate, at pH 5.5-6.5, in water after which sodium chloride is added as isotonizing agent.
  • the resulting solution is rendered pyrogen-free by filtration and the filtrate is aliquoted, under aseptic conditions, into ampoules, which are then sterilized and sealed by melting.
  • the ampoules contain 5 mg, 25 mg and 50 mg of active compound.
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