WO2010007116A2 - New chemical compounds - Google Patents

New chemical compounds Download PDF

Info

Publication number
WO2010007116A2
WO2010007116A2 PCT/EP2009/059114 EP2009059114W WO2010007116A2 WO 2010007116 A2 WO2010007116 A2 WO 2010007116A2 EP 2009059114 W EP2009059114 W EP 2009059114W WO 2010007116 A2 WO2010007116 A2 WO 2010007116A2
Authority
WO
WIPO (PCT)
Prior art keywords
oxo
carboxamide
methyl
prop
dihydropyridine
Prior art date
Application number
PCT/EP2009/059114
Other languages
French (fr)
Other versions
WO2010007116A3 (en
Inventor
Harald Engelhardt
Guido Boehmelt
Christiane Kofink
Daniel Kuhn
Darryl Mcconnell
Heinz Stadtmueller
Original Assignee
Boehringer Ingelheim International Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International Gmbh filed Critical Boehringer Ingelheim International Gmbh
Priority to US13/054,245 priority Critical patent/US8637549B2/en
Priority to EP09780675.6A priority patent/EP2321299B1/en
Priority to CA2729990A priority patent/CA2729990A1/en
Priority to JP2011517923A priority patent/JP5612573B2/en
Publication of WO2010007116A2 publication Critical patent/WO2010007116A2/en
Publication of WO2010007116A3 publication Critical patent/WO2010007116A3/en

Links

Classifications

    • 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
    • C07D401/12—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 chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to new compounds of general formula (1)
  • Substituted pyridinonecarboxylic acid amides are described in WO 2008/005457 as inhibitors of PDKl.
  • the aim of the present invention is to discover new active substances which can be used for the prevention and/or treatment of diseases characterised by excessive or abnormal cell proliferation.
  • compounds of general formula (1) wherein the groups R 4 to R 7 and the units W, L, Q a and Q H have the meanings given hereinafter act as inhibitors of specific signal enzymes which are involved in controlling cell proliferation.
  • the compounds according to the invention may be used for example for the treatment of diseases connected with the activity of these signal enzymes and characterised by excessive or abnormal cell proliferation.
  • the present invention therefore relates to compounds of general formula (1)
  • Q a is a ring system optionally substituted by one or more, identical or different R a and/or R b , selected from among C 3 _iocycloalkyl, C ⁇ -ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
  • W is selected from among -CR 1 R 2 -, -NR 3 -, and -O-;
  • R 1 and R 2 independently of one another are selected from among R a and R b ,
  • R 3 denotes R a ;
  • the group Q a -W- is not an unsubstituted or substituted benzyl
  • R 4 denotes hydrogen or Ci_ 6 -alkyl
  • R 5 , R 6 and R 7 independently of one another are selected from among R a and R b ;
  • L denotes the group -L 1 -L 2 -L 3 -, wherein L 1 binds to the unit -NR 4 - and L 3 binds to the ring system Q H ;
  • L 1 , L 2 and L 3 are selected independently of one another from among Ci_ 6 alkylene, 2-6 membered heteroalkylene, Ci- ⁇ haloalkylene, C3_iocycloalkylene, C ⁇ -ioarylene, 5-12 membered heteroarylene, 3-14 membered heterocycloalkylene, while all the above-mentioned bivalent units may each optionally be substituted independently of one another by one or more, identical or different R a and/or R b ,
  • L 1 1 , T 1/ 2 and L 3 each independently of one another denotes a bond, while at least one of the units L 1 , L 2 or L 3 must be other than a bond;
  • the ring system Q H is selected from among
  • ring systems Q H may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by R a and/or R b ,
  • R 8 denotes R a
  • R 9 denotes a group R al and R 10 denotes a group R ! a2
  • R 10 denotes a 5-12 membered heteroaryl or 5-14 membered heterocycloalkyl, optionally substituted by one or more, identical or different R a and/or R b ,
  • R 11 denotes a group R a3 ;
  • R al denotes a group optionally substituted by one or more, identical or different R b and/or R c selected from among Ci_ 6 alkyl, Ci_ 6 haloalkyl, 2-6 membered heteroalkyl,
  • R a2 is hydrogen or a group optionally substituted by one or more identical or different R b and/or R c , selected from among Ci_ 6 alkyl, Ci- ⁇ haloalkyl, 2-6 membered heteroalkyl, C 3 _iocycloalkyl, C ⁇ -ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, or a suitable substituent, selected from among -CN, -C(O)R C , -C(O)OR C , -C(O)NR C R C , -C(O)SR C , -C(O)NR g NR c R c and -C(O)NR g OR c ;
  • R a3 is a group optionally substituted by one or more identical or different R b and/or R c , selected from among Ci_ 6 alkyl, Ci- ⁇ haloalkyl, 2-6 membered heteroalkyl, C 3 _iocycloalkyl, C ⁇ -ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, or a suitable substituent, selected from among -OR C and -NR C R C ;
  • each R a independently of one another is hydrogen or a group optionally substituted by one or more identical or different R b and/or R c , selected from among Ci_ 6 alkyl, 2-6 membered heteroalkyl, Ci- ⁇ haloalkyl, C 3 -iocycloalkyl, C ⁇ -ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl; each R b denotes a suitable substituent and each is selected independently of one another from among -OR C , -NR C R C , halogen, -CN, -NO 2 , -C(O)R C , -C(O)OR C , -C(O)NR C R C , -OC(O)R C , -OC(O)OR C , -OC(O)NR C R C , -S(O) 2 R C , -S(O) 2 OR 0 , -S(O) 2 NR C R
  • each R c independently of one another is hydrogen or a group optionally substituted by one or more identical or different R d and/or R e , selected from among Ci_ 6 alkyl, 2-6 membered heteroalkyl, Ci- ⁇ haloalkyl, C 3 _iocycloalkyl, C ⁇ -ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
  • each R d is a suitable substituent and each is selected independently of one another from among -OR e , -NR e R e , halogen, -CN, -NO 2 , -C(O)R e , -C(O)OR e , -C(0)NR e R e , -OC(O)R e , -OC(O)OR e , -0C(0)NR e R e , -S(O) 2 R 6 , -S(O) 2 OR 6 , -S(O) 2 NR e R e , -NR g C(O)R e , -NR g C(0)0R e , -NR g C(O)NR e R e , -NR g S(O) 2 R e , -NR g S(O) 2 OR e and -NR g S(0) 2 NR e R e , and the bivalent substituent
  • each R e independently of one another is hydrogen or a group optionally substituted by one or more identical or different R f and/or R g , selected from among Ci_ 6 alkyl, 2-6 membered heteroalkyl, Ci- ⁇ haloalkyl, C 3 -iocycloalkyl, C ⁇ -ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
  • each R g independently of one another is hydrogen or a group optionally substituted by one or more identical or different R h , selected from among Ci_ 6 alkyl, 2-6 membered heteroalkyl, Ci- ⁇ haloalkyl, C 3 _iocycloalkyl, C ⁇ -ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, and
  • each R h independently of one another is selected from among hydrogen, Ci_ 6 alkyl, 2-6 membered heteroalkyl, Ci- ⁇ haloalkyl, Cs-iocycloalkyLC ⁇ -ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl
  • Q a is a ring system optionally substituted by one or more identical or different R a and/or R b , selected from among C ⁇ -ioaryl and 5-12 membered heteroaryl, and
  • R a and R b are as hereinbefore defined.
  • Q a is a ring system optionally substituted by one or more identical or different R a and/or R b , selected from among phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, ind
  • R a and R b are as hereinbefore defined.
  • the invention in another aspect (A3) relates to compounds (1), wherein Q a is a ring system optionally substituted by one or more identical or different R a and/or R b , selected from among phenyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrimidyl and pyridyl, and
  • R a and R b are as hereinbefore defined.
  • the invention relates to compounds (1), wherein Q a is a ring system optionally substituted by one or more identical or different R a and/or R b , selected from among phenyl and pyridyl, and R a and R b are as hereinbefore defined.
  • R hl is in each case selected independently of one another from among hydrogen, Ci_ 6 alkyl, 2-6 membered heteroalkyl and Ci- ⁇ haloalkyl.
  • the invention relates to compounds (1), wherein the ring system Q a may be substituted by up to three identical or different substituents, selected from among methyl, trifluoromethyl, -OCH 3 , -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , fluorine, chlorine and bromine.
  • W is selected from among -NH-, -N(Ci_ 6 alkyl)-, -CH 2 -, -CH(Ci_ 6 alkyl)-, -C(Ci_ 6 alkyl) 2 - and -O- .
  • the invention in another aspect (C2) the invention relates to compounds (1), wherein W is selected from among -CH 2 -, -CH(CH 3 )-, -NH- and -N(CH 3 )-.
  • the invention in another aspect (C3) the invention relates to compounds (1), wherein W is selected from among -CH 2 - and -CH(CH 3 )-.
  • the invention relates to compounds (1), wherein Q a denotes phenyl, while this phenyl may be substituted by one or more identical or different substituents, selected from among Ci_ 6 alkyl, Ci_ 6 haloalkyl, -OR hl , -NR hl R hl , halogen, -CN, -C(O)R hl , -C(O)OR hl , -C(O)NR hl R hl , -S(O) 2 NR hl R hl , -NR hl C(O)R hl , -NR hl C(O)OR hl , -NR hl C(O)NR hl R hl and -NR hl S(O) 2 R hl ,
  • R hl is selected in each case independently of one another from among hydrogen, Ci_ 6 alkyl, 2-6 membered heteroalkyl and Ci_ 6 haloalkyl, and
  • W is selected from among -NH-, -N(Ci_ 6 alkyl)- and -O-.
  • Q a is selected from among furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrimidyl and pyridyl, while the ring system Q a may be substituted by one or more, identical or different substituents, selected from among Ci_ 6 alkyl, Ci_ 6 haloalkyl, -OR hl , -NR hl R hl , halogen, -CN, -C(O)R hl , -C(O)OR hl , -C(O)NR hl R hl , -S(O) 2 NR hl R hl , -NR hl C(O)R hl , -NR hl C(O)OR hl , -NR hl C(O)NR hl R hl and -NR hl S(O) 2 R hl
  • R hl is selected independently of one another in each case from among hydrogen, Ci_ 6 alkyl, 2-6 membered heteroalkyl and Ci_ 6 haloalkyl, and
  • W is selected from among -NH-, -N(Ci_ 6 alkyl)-, -CH 2 -, -CH(Ci_ 6 alkyl)-, -C(Ci_ 6 alkyl) 2 - and -O- .
  • the invention relates to compounds (1), wherein Q a denotes phenyl, while this phenyl may be substituted by up to three identical or different substituents, selected independently of one another from among methyl, trifluoromethyl, -OCH 3 , -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , fluorine, chlorine and bromine, and
  • W is selected from among -NH-, -N(Ci_ 6 alkyl)- and -O-.
  • the invention in another aspect (D28) relates to compounds (1), wherein Q a is selected from among furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrimidyl and pyridyl, while the ring system Q a may be substituted by up to three identical or different substituents, selected independently of one another from among methyl, trifluoromethyl, -OCH 3 , -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , fluorine, chlorine and bromine, and
  • W is selected from among -NH-, -N(Ci_ 6 alkyl)-, -CH 2 -, -CH(Ci_ 6 alkyl), -C(Ci_ 6 alkyl) 2 - and -O-.
  • the invention relates to compounds (1), wherein Q a denotes phenyl, while this phenyl may be substituted by up to three identical or different substituents, selected independently of one another from among methyl, trifluoromethyl, -OCH 3 , -NH 2 ,
  • W is selected from among -NH- and -N(CH 3 )-.
  • Q a is selected from among furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrimidyl and pyridyl, while the ring system Q a may be substituted by up to three identical or different substituents, selected independently of one another from among methyl, trifluoromethyl, -OCH 3 , -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , fluorine, chlorine and bromine, may be substituted, and
  • W is selected from among -CH 2 -, -CH(CH 3 )-, -NH- and -N(CH 3 )-.
  • D31 the invention relates to compounds (1), wherein
  • Q a is selected from among furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrimidyl and pyridyl, while the ring system Q a may be substituted by up to three identical or different substituents, selected independently of one another from among methyl, trifluoromethyl, -OCH 3 ,
  • W is selected from among -CH 2 - and -CH(CH 3 )-.
  • the invention relates to compounds (1), wherein Q a denotes pyridyl, while this pyridyl may be substituted by up to three identical or different substituents, selected independently of one another from among methyl, trifluoromethyl, -OCH 3 , -NH 2 , -NH(CH 3 ), -N(CH 3 ) 2 , fluorine, chlorine and bromine, and
  • W is selected from among -CH 2 - and -CH(CH 3 )-.
  • R 5 , R 6 and R 7 independently of one another are selected from among hydrogen, Ci_ 6 alkyl, Ci_ 6 haloalkyl, -OR h2 , -NR h2 R h2 , halogen, -CN, -C(O)R h2 , -C(O)OR h2 , -C(O)NR h2 R h2 , -S(O) 2 NR h2 R h2 , -NR h2 C(O)R h2 , -NR h2 C(O)OR h2 , -NR h2 C(O)NR h2 R h2 and -NR h2 S(O) 2 R h2 and
  • R h2 is selected independently of one another in each case from among hydrogen, Ci_ 6 alkyl, 2-6 membered heteroalkyl and Ci_ 6 haloalkyl.
  • the invention relates to compounds (1), wherein R 5 , R 6 and R 7 in each case denotes hydrogen.
  • the invention relates to compounds (1), wherein L is selected from among
  • the bivalent units L shown bind on the right to the ring system Q H and on the left to the amide nitrogen -NR .4 - according to formula (1) and may optionally each be substituted independently of one another by one or more identical or different R and/or R >b and R a and R b are as hereinbefore defined.
  • the invention in another aspect (G2) relates to compounds (1), wherein L is selected from among L-I to L-47 and L-53 to L-56, the bivalent units L bind on the right to the ring system Q H and on the left to the amide nitrogen -NR 4 - according to formula (1) and may optionally each be substituted independently of one another by one or more identical or different R a and/or R b and
  • R a and R b are as hereinbefore defined.
  • the invention relates to compounds (1), wherein L is selected from among
  • the bivalent units L shown bind on the right to the ring system Q H and on the left to the amide nitrogen -NR 4 - according to formula (1);
  • p denotes O or 1 ;
  • R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 and R 39 is selected in each case independently of one another from among R a and R b , and
  • R 40 denotes R a ;
  • R 15 and R 17 are each selected independently of one another from among R a and R b , R 14 and R 16 together with the carbon atoms to which they are bound form a
  • C3_7Cycloalkylene or a 3-7 membered heterocycloalkylene while the above-mentioned ring systems may optionally each be substituted independently of one another by one or more identical or different R a and/or R b ; or
  • R 19 and R 21 are each selected independently of one another from among R a and R b , R 18 and R 20 together with the carbon atoms to which they are bound form a
  • C3_7Cycloalkylene or a 3-7 membered heterocycloalkylene while the above-mentioned ring systems may optionally each be substituted independently of one another by one or more identical or different R a and/or R b ; or R 23 and R 24 are each selected independently of one another from among R a and R b ,
  • R 22 and R 25 together with the carbon atoms to which they are bound form an unsaturated C ⁇ cycloalkylene or an unsaturated 4-7 membered heterocycloalkylene, while the above-mentioned ring systems may optionally each be substituted independently of one another by one or more identical or different R a and/or R b ; or
  • R 30 , R 31 , R 33 and R 35 are each selected independently of one another from among R a and R b ,
  • R 32 and R 35 together with the carbon atoms to which they are bound form a C3_7Cycloalkylene or a 3-7 membered heterocycloalkylene, while the above-mentioned ring systems may optionally each be substituted independently of one another by one or more identical or different R a and/or R b ; or
  • R 37 , R 38 and R 39 are each selected independently of one another from among R a and R b ,
  • R 36 and R 40 together with the atoms to which they are bound form a 3-7 membered heterocycloalkylene, while this heterocycloalkylene may optionally be substituted independently of one another in each case by one or more identical or different R a and/or R b ; or
  • R 36 , R 37 and R 39 are each selected independently of one another from among R a and R b ,
  • R 38 and R 40 together with the atoms to which they are bound form a 3-7 membered heterocycloalkylene, while this heterocycloalkylene may optionally be substituted independently of one another in each case by one or more identical or different R a and/or R b ; and
  • R a and R b are as hereinbefore defined.
  • the invention relates to compounds (1), wherein L is selected from among '
  • the bivalent units L shown bind on the right to the ring system Q H and on the left to the amide nitrogen -NR 4 - according to formula (1);
  • p denotes 0 or 1 ;
  • R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 22 , R 23 , R 24 , R 25 , R 36 , R 37 , R 38 and R 39 are each selected independently of one another from among R a and R b , and
  • R 40 denotes R a ;
  • R 37 , R 38 and R 39 are each selected independently of one another from among R a and R b ,
  • R 36 and R 40 together with the atoms to which they are bound form a 3-7 membered heterocycloalkylene, while this heterocycloalkylene may optionally be substituted independently of one another in each case by one or more identical or different R a and/or R b ; or
  • R 36 , R 37 and R 39 are each selected independently of one another from among R a and R b ,
  • R 38 and R 40 together with the atoms to which they are bound form a 3-7 membered heterocycloalkylene, while this heterocycloalkylene may optionally be substituted independently of one another in each case by one or more identical or different R a and/or R b ; and
  • R a and R b are as hereinbefore defined.
  • the invention relates to compounds (1), wherein L is selected from among
  • the invention relates to compounds (1), wherein L is selected from among
  • the invention relates to compounds (1), wherein L is selected from among
  • the ring systems Q H shown may each optionally be substituted independently of one another at one or more hydrogen-carrying carbon atom(s) by R a and/or R b and
  • R a and R b are as hereinbefore defined.
  • R al is a group optionally substituted by one or more identical or different R b and/or R c , selected from among C ⁇ -ioaryl and 5-12 membered heteroaryl;
  • R a2 is selected from among hydrogen, Ci_ 6 alkyl, Ci- ⁇ haloalkyl, C 3 _iocycloalkyl,
  • R b and R c are as hereinbefore defined.
  • the invention relates to compounds (1) with the structural aspect H2, wherein R al is a group optionally substituted by one or more identical or different R b and/or R c , selected from among phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4- oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-thiadia
  • R b and R c are as hereinbefore defined.
  • R al is a group optionally substituted by one or more identical or different R b and/or R c , selected from among pyrrolyl, pyrazolyl and imidazolyl, and
  • R b and R c are as hereinbefore defined.
  • R a2 is hydrogen, methyl or ethyl.
  • the invention relates to compounds (1) with one of the structural aspects Hl to H5, wherein
  • R al is substituted by one or more, identical or different R bl and/or R cl ;
  • each R bl is a suitable substituent and is selected in each case independently of one another from among -OR C , -SR C , -NR C R C , halogen, -CN, -NO 2 , -C(O)R C , -C(O)OR C , -C(O)NR C R C , -OC(O)R C , -OC(O)OR C , -OC(O)NR C R C , -S(O) 2 R C , -S(O) 2 OR 0 , -S(O) 2 NR C R C , -NR g C(O)R c , -NR g C(O)OR c , -NR g C(0)NR c R c , -NR g S(O) 2 R c ,
  • each R cl independently denotes a group optionally substituted by one or more identical or different R d and/or R e , selected from among Ci_ 6 alkyl, 2-6 membered heteroalkyl, Ci- ⁇ haloalkyl, Cs-iocycloalkyl, C ⁇ -ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, and
  • R c , R d , R e and R g are as hereinbefore defined.
  • R al and R a3 are selected independently of one another from among -NHR c2 or
  • R a2 is selected from among hydrogen, methyl and ethyl
  • R c2 is selected from among phenyl, pyridyl, pyrimidyl, piperidyl, cyclohexyl and benzyl, all the above-mentioned groups optionally being substituted by one or more identical or different R d and/or R e and
  • R d and R e are as hereinbefore defined.
  • Q H is selected from among
  • the ring systems Q H shown may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by R a and/or R b and
  • R 8 , R a and R b are as hereinbefore defined.
  • the invention relates to compounds (1), wherein
  • Q H is selected from among
  • the ring systems Q H shown may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by R a and/or R b and
  • R 8 , R a and R b are as hereinbefore defined.
  • Q H is selected from among
  • the ring systems Q H shown may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by R a and/or R b ,
  • R 8 denotes R c and
  • R a , R b and R c are as hereinbefore defined.
  • the invention relates to compounds (1), wherein
  • Q H is selected from among , while
  • R 41 is selected from among hydrogen, halogen, methyl, ethyl, trifluoromethyl and methoxy,
  • R 42 is selected from among hydrogen, R a and R b ,
  • R 43 denotes hydrogen or R a ,
  • R 8 denotes R c and
  • R a , R b and R c are as hereinbefore defined.
  • Q H is selected from among
  • R 41 is selected from among hydrogen, halogen, methyl, ethyl, trifluoromethyl and methoxy,
  • R 42 is selected from among hydrogen, R a and R b ,
  • R 43 denotes hydrogen or R a ,
  • R 44 is selected from among R d and R e ,
  • R a , R b ,R d and R e are as hereinbefore defined.
  • the invention relates to compounds (1), wherein Q H is selected from among
  • R 8 denotes a phenyl, optionally substituted by one or more, identical or different R b and/or R c , and
  • R b and R c are as hereinbefore defined.
  • the ring systems Q H shown may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by R a and/or R b and
  • R a and R b are as hereinbefore defined.
  • the invention relates to compounds (1), wherein Q H is selected from among
  • R ,45 independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different R b and/or R c , selected from among C 3 _ 7 Cycloalkyl, phenyl, 5-10 membered heteroaryl, particularly lH-benzimidazolyl, lH-indolyl, pyrrolyl, imidazolyl or pyrazolyl, and 3-10 membered heterocycloalkyl, and
  • R b and R c are as hereinbefore defined.
  • the invention relates to compounds (1), wherein Q H is selected from among
  • the ring systems Q H shown may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by R a and/or R b and
  • R a and R b are as hereinbefore defined.
  • R 46 and R 47 in each case independently of one another denote hydrogen or a group optionally substituted by one or more, identical or different R b and/or R c , selected from among C 3 _ 7 Cycloalkyl, phenyl, 5-10 membered heteroaryl, particularly pyridyl, and 3-10 membered heterocycloalkyl,
  • R 48 denotes R c
  • R b and R c are as hereinbefore defined.
  • R 49 is selected from among R d and R e , r denotes 0, 1, 2 or 3 and
  • R d and R e are as hereinbefore defined.
  • the invention relates to compounds (1), wherein Q H is selected from among
  • Q H -5a Q H -5b QH-6a the above mentioned ring systems Q H may each optionally be substituted independently of one another at one or more hydrogen-carrying carbon atom(s) by R a and/or R b and
  • R a and R b are as hereinbefore defined.
  • Q H may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by a substituent selected from among -NH 2 , -NH(Ci_ 6 alkyl), -N(Ci_ 6 alkyl) 2 , -Ci_ 6 alkylene-OH, halogen, -C(O)OH, -C(O)NH 2 , -C(O)NH(Ci_ 6 alkyl), -C(O)N(Ci_ 6 alkyl) 2 , -Ci_ 6 alkylene-NH 2 , heteroaryl, phenyl, -C(O)NH- Ci_ 6 alkylene-O-Ci_ 6 alkyl, -Ci_ 6 alkylene-NH(Ci_ 6 alkyl), -CN, -OCi_ 6 alkyl,
  • Q H is selected from among
  • R ,50 is selected from among R and R e and R d and R e are as hereinbefore defined.
  • the invention relates to compounds selected from among 1-1 l-[(6-chloropyridin-3-yl)methyl]-N- ⁇ (2E)-3-[(3Z)-3-(lH-imidazol-5- ylmethylidene)-2-oxo-2,3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl ⁇ -2-oxo- 1 ,2- dihy dropyridine-3 -carboxamide
  • 11-12 1 -[(6-chloropyridin-3-yl)methyl]-JV- ⁇ 3-[2-( ⁇ 4-[(dimethylamino)methyl]phenyl ⁇ - amino)-5-fluoroquinazolin-6-yl]prop-2-yn- 1 -yl ⁇ -2-oxo- 1 ,2-dihydropyridine-3- carboxamide; 11-13 N- ⁇ 3-[5-methyl-2- ⁇ [4-(morpholin-4-yl)phenyl]amino ⁇ -7-oxo-8-(propane-2-yl)-7.8- dihydropyrido [2,3- ⁇ T]pyrimidin-6-yl]prop-2-yn- 1 -yl ⁇ -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-di- hydropyridine-3-carboxamide;
  • III-3 N-[(2E)-3- ⁇ 4-[5-amino-3-(phenylamino)- IH- 1 ,2,4-triazol- 1 -yl]-5-methoxypyrimi- din-2-yl ⁇ prop-2-en- 1 -yl]-2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3- carboxamide;
  • III-6 N-( ⁇ 5-[5-amino-3-( ⁇ 4-[(dimethylamino)methyl]phenyl ⁇ amino)- IH- 1 ,2,4-triazol- 1 - yl]-lH-pyrrolo[3.2- ⁇ ]pyridin-2-yl ⁇ methyl)-2-oxo-l-(pyridin-3-ylmethyl)-l,2-dihydropyri- dine-3 -carboxamide; III-7 N-( ⁇ 5-[5-amino-3-( ⁇ 4-[(dimethylamino)methyl]phenyl ⁇ amino)- IH- 1 ,2,4-triazol- 1 - yl]- 1 -methyl- lH-pyrrolo[3.2- ⁇ ]pyridin-2-yl ⁇ methyl)-2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-di- hydropyridine-3-carboxamide;
  • III-9 N- ⁇ 2-[6-(5-amino-3- ⁇ [4-(4-methylpiperazin- 1 -yl)phenyl] amino ⁇ - IH- 1 ,2,4-triazol- 1 -yl)pyridin-2-yl] ethyl ⁇ -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3- carboxamide; III-10 N-(I- ⁇ 4-[5-amino-3-( ⁇ 4-[(dimethylamino)methyl]phenyl ⁇ amino)- IH- 1 ,2,4-triazol- 1 -yl]pyrimidin-2-yl ⁇ ethyl)-2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3- carboxamide;
  • the invention relates to compounds - or the pharmacologically acceptable salts thereof- of general formula (1) as pharmaceutical compositions. In another aspect the invention relates to compounds - or the pharmacologically acceptable salts thereof - of general formula (1) for the treatment and/or prevention of cancer, infections, inflammations and autoimmune diseases.
  • the invention relates to compounds - or the pharmacologically acceptable salts thereof- of general formula (1) for the treatment and/or prevention of cancer.
  • the invention relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (1) or the pharmacologically acceptable salts thereof, optionally in combination with conventional excipients and/or carriers.
  • the invention in another aspect relates to a pharmaceutical preparation comprising a compound of general formula (1), while the compounds (1) may optionally also be in the form of the tautomers, racemates, enantiomers, diastereomers, mixtures thereof or as the respective pharmacologically acceptable salts of all the above-mentioned forms, and at least one other cytostatic or cytotoxic active substance different from formula (1).
  • heteroalkyl refers to the total atomic number of all the ring members or chain members or the total of all the ring and chain members.
  • Alkyl is made up of the sub-groups saturated hydrocarbon chains and unsaturated hydrocarbon chains, while the latter may be further subdivided into hydrocarbon chains with a double bond (alkenyl) and hydrocarbon chains with a triple bond (alkynyl). Alkenyl contains at least one double bond, alkynyl at least one triple bond.
  • a hydrocarbon chain should have both at least one double bond and at least one triple bond, by definition it belongs to the alkynyl sub-group. All the above-mentioned sub-groups may be further subdivided into straight-chain (unbranched) and branched. If an alkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying carbon atoms. Examples of individual sub-groups are listed below.
  • -butyl (1.1-dimethylethyl); n-pentyl; 1- methylbutyl; 1-ethylpropyl; isopentyl (3-methylbutyl); neopentyl (2,2-dimethyl-propyl); n-hexyl; 2,3-dimethylbutyl; 2,2-dimethylbutyl; 3,3-dimethylbutyl; 2-methyl-pentyl; 3- methylpentyl; n-heptyl; 2-methylhexyl; 3-methylhexyl; 2,2-dimethylpentyl; 2,3- dimethylpentyl; 2,4-dimethylpentyl; 3,3-dimethylpentyl; 2,2,3-trimethylbutyl; 3-ethylpentyl; n-octyl; n-nonyl; n-decyl etc.
  • butadienyl pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl etc. unless otherwise stated are meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and two double bonds, including all the isomeric forms, also (Z)/(E)-isomers, where applicable.
  • propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc. unless otherwise stated are meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and a triple bond, including all the isomeric forms.
  • alkylene can also be derived.
  • Alkylene unlike alkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from an alkyl.
  • Corresponding groups are for example -CH3 and -CH 2 , -CH2CH3 and -CH 2 CH 2 or >CHCH3 etc. For all the subgroups of alkyl there are correspondences for alkylene.
  • heteroatoms oxygen, nitrogen and sulphur atoms.
  • heteroalkyl is made up of the sub-groups saturated hydrocarbon chains with heteroatom(s), heteroalkenyl and heteroalkynyl, and it may be further subdivided into straight-chain (unbranched) and branched. If a heteroalkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying oxygen, sulphur, nitrogen and/or carbon atoms. Heteroalkyl itself as a substituent may be attached to the molecule both through a carbon atom and through a heteroatom.
  • dimethylamino methyl dimethylaminoethyl (1- dimethylaminoethyl; 2-dimethyl- aminoethyl); dimethylaminopropyl (1-dimethylaminopropyl, 2-dimethylaminopropyl, 3-dimethylaminopropyl); diethylamino methyl; diethylaminoethyl (1-diethylaminoethyl, 2- diethylaminoethyl); diethylaminopropyl (1-diethylaminopropyl, 2- diethylamino -propyl, 3- diethylaminopropyl); diisopropylamino ethyl (1-diisopropylaminoethyl, 2-di- isopropylaminoethyl); bis-2-methoxyethylamino; [2-(dimethylamino-ethyl)-e
  • heteroalkylene can also be derived.
  • Heteroalkylene unlike heteroalkyl is bivalent and requires two bonding partners.
  • the second valency is produced by removing a hydrogen atom from a heteroalkyl.
  • Corresponding groups are for example -CH 2 NH 2 and -CH 2 NH or >CHNH 2 , - NHCH 3 and >NCH 3 or -NHCH 2 , -CH 2 OCH 3 and -CH 2 OCH 2 or >CHOCH 3 etc.
  • Haloalkyl is derived from alkyl as hereinbefore defined in its broadest sense, by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different.
  • a direct result of the indirect definition/derivation from alkyl is that haloalkyl is made up of the sub-groups saturated hydrohalogen chains, haloalkenyl and haloalkynyl, and it may be further subdivided into straight-chain (unbranched) and branched. If a haloalkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying carbon atoms. Typical examples are listed below:
  • haloalkylene can also be derived.
  • Haloalkylene unlike haloalkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a haloalkyl.
  • Corresponding groups are for example -CH 2 F and -CHF, -CHFCH 2 F and -CHFCHF or >CFCH 2 F etc. For all the subgroups of haloalkyl there are correspondences for haloalkylene.
  • Halogen encompasses fluorine, chlorine, bromine and/or iodine atoms.
  • Cycloalkyl is made up of the sub-groups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spirohydrocarbon rings, while each sub-group may be further subdivided into saturated and unsaturated (cycloalkenyl).
  • unsaturated is meant that there is at least one double bond in the ring system, but no aromatic system is formed.
  • bicyclic hydrocarbon rings two rings are linked such that they share at least two carbon atoms.
  • spirohydrocarbon rings one carbon atom (spiroatom) is shared by two rings. If a cycloalkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying carbon atoms.
  • Cycloalkyl itself as a substituent may be attached to the molecule through any suitable position of the ring system.
  • the following individual sub-groups are listed by way of example: monocyclic hydrocarbon rings, saturated: cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl etc. monocyclic hydrocarbon rings, unsaturated:
  • cycloprop-1-enyl cycloprop-2-enyl; cyclobut-1-enyl; cyclobut-2-enyl; cyclopent-1-enyl; cyclopent-2-enyl; cyclopent-3-enyl; cyclohex-1-enyl; cyclohex-2-enyl; cyclohex-3-enyl; cyclohept-1-enyl; cyclohept-2-enyl; cyclohept-3-enyl; cyclohept-4-enyl; cyclobuta-1,3- dienyl; cyclopenta-l,4-dienyl; cyclopenta-l,3-dienyl; cyclopenta-2,4-dienyl; cyclohexa- 1,3-dienyl; cyclohexa-l,5-dienyl; cyclohexa-2,4-dienyl; cyclohe
  • bicyclic hydrocarbon rings saturated and unsaturated: bicyclo[2.2.0]hexyl; bicyclo[3.2.0]heptyl; bicyclo[3.2.1]octyl; bicyclo[2.2.2]octyl; bicyclo[4.3.0]nonyl (octahydroindenyl); bicyclo[4.4.0]decyl (decahydronaphthalene); bicyclo[2.2.1]heptyl (norbornyl); (bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl); bicyclo[2.2.1]hept-2-enyl (norbornenyl); bicyclo[4.1.0]heptyl (norcaranyl); bicyclo- [3.1.1]heptyl (pinanyl) etc.
  • spirohydrocarbon rings saturated and unsaturated: spiro[2.5]octyl, spiro[3.3]heptyl, spiro[4.5]dec-2-ene, etc.
  • cycloalkylene can also be derived.
  • Cycloalkylene unlike cycloalkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a
  • cycloalkyl cycloalkyl.
  • Corresponding groups are for example cyclohexyl and or
  • Cycloalkylalkyl refers to the combination of the alkyl in question, as hereinbefore defined, with cycloalkyl, both in their widest sense.
  • cycloalkylalkyl may also be regarded as a combination of cycloalkyl with alkylene.
  • cycloalkylalkyl is obtained by first linking an alkyl as substituent directly with the molecule and then substituting with a cycloalkyl.
  • the linking of alkyl and cycloalkyl may be carried out in both groups using carbon atoms that are suitable for this purpose.
  • the respective subgroups of alkyl (alkylene) and cycloalkyl are also included in the combination of the two groups.
  • Aryl denotes mono-, bi- or tricyclic carbon rings with at least one aromatic ring. If an aryl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon atoms, independently of one another. Aryl itself may be linked to the molecule as substituent via any suitable position of the ring system.
  • Typical examples are listed below: phenyl, naphthyl, indanyl (2,3-dihydroindenyl), 1,2,3,4-tetrahydronaphthyl; fluorenyl, etc. If the free valency of an aryl is saturated off, an aromatic group is obtained.
  • arylene can also be derived.
  • Arylene unlike aryl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from an aryl.
  • Corresponding groups are for
  • Arylalkyl denotes the combination of the groups alkyl and aryl as hereinbefore defined, in each case in their broadest sense.
  • arylalkyl may also be regarded as a combination of aryl with alkylene.
  • arylalkyl is obtained by first linking an alkyl as substituent directly to the molecule and substituting it with an aryl group. The alkyl and aryl may be linked in both groups via any carbon atoms suitable for this purpose.
  • the respective sub-groups of alkyl (alkylene) and aryl are also included in the combination of the two groups.
  • Heteroaryl denotes monocyclic aromatic rings or poly cyclic rings with at least one aromatic ring, which, compared with corresponding aryl or cycloalkyl, contain instead of one or more carbon atoms one or more identical or different heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, while the resulting group must be chemically stable.
  • the prerequisite for the presence of heteroaryl is a heteroatom and an aromatic system, although it need not necessarily be a heteroaromatic system.
  • heteroaryl may according to the definition be a heteroaryl.
  • heteroaryl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon and/or nitrogen atoms, independently of one another. Heteroaryl itself as substituent may be linked to the molecule via any suitable position of the ring system, both carbon and nitrogen. Typical examples are listed below.
  • heteroarylene can also be derived.
  • Heteroarylene unlike heteroaryl is bivalent and requires two bonding partners.
  • Formally the second valency is produced by removing a hydrogen atom from a heteroaryl.
  • Corresponding groups are for example pyrrolyl and or or
  • Heteroarylalkyl denotes the combination of the alkyl in question as hereinbefore defined with heteroaryl, both in their broadest sense.
  • heteroarylalkyl may also be regarded as a combination of heteroaryl with alkylene.
  • Formally heteroarylalkyl is obtained by first linking an alkyl as substituent directly with the molecule and then substituting it with a heteroaryl. The linking of the alkyl and heteroaryl may be achieved on the alkyl side via any carbon atoms suitable for this purpose and on the heteroaryl side via any carbon or nitrogen atoms suitable for this purpose.
  • the respective sub-groups of alkyl (alkylene) and heteroaryl are also included in the combination of the two groups.
  • Heteroatoms may simultaneously be present in all the possible oxidation stages (sulphur -> sulphoxide -SO-, sulphone -SO 2 -; nitrogen -> N- oxide). It is immediately apparent from the indirect definition/derivation from cycloalkyl that heterocycloalkyl is made up of the sub-groups monocyclic hetero-rings, bicyclic hetero-rings and spirohetero-rings, while each sub-group can also be further subdivided into saturated and unsaturated (heterocycloalkenyl).
  • unsaturated means that in the ring system in question there is at least one double bond, but no aromatic system is formed.
  • bicyclic hetero-rings two rings are linked such that they have at least two atoms in common.
  • one carbon atom spiroatom
  • the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon and/or nitrogen atoms, independently of one another.
  • Heterocycloalkyl itself as substituent may be linked to the molecule via any suitable position of the ring system.
  • monocyclic heterorings saturated and unsaturated: tetrahydrofuryl; pyrrolidinyl; pyrrolinyl; imidazolidinyl; thiazolidinyl; imidazolinyl; pyrazolidinyl; pyrazolinyl; piperidinyl; piperazinyl; oxiranyl; aziridinyl; azetidinyl; 1,4- dioxanyl; azepanyl; diazepanyl; morpholinyl; thiomorpholinyl; homomorpholinyl; homopiperidinyl; homopiperazinyl; homothiomorpholinyl; thiomorpholinyl-iS'-oxide; thiomorpholinyl- ⁇ -dioxide; 1,3-dioxolanyl; tetrahydropyranyl; tetrahydrothiopyranyl
  • spiro -heterorings saturated and unsaturated: l,4-dioxa-spiro[4.5]decyl; l-oxa-3.8-diaza-spiro[4.5]decyl; and 2,6-diaza-spiro[3.3]heptyl; 2,7-diaza-spiro[4.4]nonyl; 2,6-diaza-spiro[3.4]octyl; 3,9-diaza-spiro[5.5]undecyl; 2,8- diaza-spiro[4.5]decyl etc.
  • heterocycloalkylene can also be derived.
  • Heterocycloalkylene unlike heterocycloalkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a heterocycloalkyl.
  • Corresponding groups are for example piperidinyl and
  • Heterocycloalkylalkyl denotes the combination of the alkyl in question as hereinbefore defined with heterocycloalkyl, both in their broadest sense.
  • heterocycloalkylalkyl may also be regarded as a combination of heterocycloalkyl with alkylene.
  • Formally heterocycloalkyl is obtained by first linking an alkyl as substituent directly with the molecule and then substituting it with a heterocycloalkyl. The linking of the alkyl and heterocycloalkyl may be achieved on the alkyl side via any carbon atoms suitable for this purpose and on the heterocycloalkyl side via any carbon or nitrogen atoms suitable for this purpose.
  • the respective sub-groups of alkyl and heterocycloalkyl are also included in the combination of the two groups.
  • substituted By is substituted is meant that a hydrogen atom that is bound directly to the atom under consideration is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms) mono- or polysubstitution may take place at an atom.
  • substitution by a bivalent substituent may only take place at ring systems and requires exchange for two geminal hydrogen atoms, i.e. hydrogen atoms that are bound to the same carbon atom saturated before the substitution. Substitution by a bivalent substituent is therefore only possible at the group -CH 2 - or sulphur atoms of a ring system.
  • suitable substituent denotes a substituent which on the one hand is suitable on account of its valency and on the other hand leads to a system with chemical stability.
  • Groups or substituents are frequently selected from among alternative groups/ substituents with a corresponding group designation (e.g. R a , R b etc). If a group of this kind is used repeatedly to define a compound according to the invention in different parts of the molecule, it should always be borne in mind that the respective uses are to be regarded as being totally independent of one another.
  • HPLC preparative high pressure chromatography
  • Waters named: Sunfire C 18, 5 ⁇ m, 30 x 100 mm Part.No. 186002572; X-Bridge C 18, 5 ⁇ m, 30 x 100 mm Part.No. 186002982
  • analytical HPLC reaction control
  • Agilent named: Zorbax Extend C18, 3.5 ⁇ m, 2.1 x 50 mm, Part.No. 735700-902
  • Zorbax SB-C8 3.5 ⁇ m, 2.1 x 50 mm, Part.No. 871700-906
  • Phenomenex named: Mercury Gemini C 18, 3 ⁇ m, 2 x 20 mm, Part.No. 00M-4439-B0-CE.
  • HPLC 333 and 334 Pumps column: Waters Sunfire C 18, 5 ⁇ m, 30 x 100 mm Part.No. 186002572 eluant: A: H 2 O + 0.2 % HCOOH; B: acetonitrile (HPLC grade) + 0.2 % HCOOH detection: UV/Vis-155 flow: 50 mL/min gradient: 0.00 min: 5 % B
  • MS Agilent LC/MSD SL column: WatersXBridge Cl 8 2.1 x 50mm, 5.0 ⁇ m eluant: A: 5 mM NH 4 HCO 3 /20 mM NH 3 in H 2 O; B: acetonitrile (HPLC grade) detection: MS: Positive and negative mode mass range: 105 - 1200 m/z flow: 1.20 mL/min column temp.: 35 0 C gradient: 0.01 min: 5 % B
  • MS Agilent LC/MSD column: Waters Sunfire, 21 x 50 mm, 3.5 ⁇ m eluant: A: H 2 O + 1 % HCOOH; B: acetonitrile (HPLC grade) detection: MS: Positive and negative mode; UV: 254 as well as 210 nm mass range: 100 - 750 m/z flow: 1.00 mL/min (0.9 mL H 2 O/MeCN, 0.I mL formic acid buffer) column temp.: 35 0 C gradient: 0.1 min: 5 % B
  • the compounds according to the invention are prepared by the methods of synthesis described hereinafter, in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention, without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to the published methods of synthesis.
  • a key intermediate in the synthesis of compounds (1) according to the invention are the pyridinonecarboxylic acids A.l.
  • compounds (1) are obtained directly by amide coupling with amines A.2, while A.1 is activated by coupling reagents such as for example DCC, DIC, TBTU, HATU, EDC or the like. Carrying out this reaction requires aminic synthesis components A.2 which contain both the linker unit L and the grouping Q H .
  • synthesis components A.2 may also be coupled, by means of which first of all a precursor Q H* of the final grouping Q H is introduced.
  • the intermediate Cl obtained is then reacted in later steps to obtain compounds (1) (cf. Reaction scheme C).
  • reaction scheme A-2 The synthesis of the components A.2/A.2 * proceeds via the incorporation of the ring system Q H(A) into the amines A.3 or A.5 provided with protective groups, while Q H(A) is introduced in the form of the activated species A.4/A.4 * or A.6/A.6 * (Reaction scheme A-2).
  • These are simple reactions of substitution between nucleophils or electrophils activated by electron-attracting and -pushing groups, or transition metal-catalysed cross- coupling reactions, e.g. the BUCHWALD-HARTWIG, SUZUKI, KUMADA, STILLE, NEGISHI, HECK or SONOGASHIRA reaction.
  • Electron-pushing groups EDG are, in particular, boric acid and boric acid ester derivatives -B(OH) 2 Z-B(ORZ) 2 , -MgHaI, -ZnHaI and -SnR'3, but this term may also include hydrogen. Suitable groups R' are known to the skilled man.
  • the activating groups act as leaving groups in all the types of reaction mentioned above. After the reaction of A.3 with A.4/A.4 * or A.5 with A.6/A.6 * the product obtained still contains the protective group PG (intermediate product A.2-PG or A.2 * -PG), which is cleaved in order to obtain A.2/A.2 * . Any of the amino protecting groups common in organic synthesis may be used as the protective group PG.
  • a component A.2 * may also be converted into a component A.2, the final grouping Q H being formed from the grouping Q H* .
  • EDG electron-repelling group, e.g.. -B(OH) 2 /-B(OR ' ) 2 , -MgHaI, -ZnHaI, SnR ' 3 or hydrogen
  • compounds (1) according to the invention may also be synthesised stepwise (Reaction scheme A-3).
  • reaction scheme A-3 first of all an amine A.7 or A.8, which in each case contains only the linker unit L, is coupled to the carboxylic acid A.1 (-> A.9 or A.10) and only then is the grouping Q H introduced via the components A.4 or A.6.
  • the linking of the linker unit L and the grouping Q H are carried out from a chemical-method point of view analogously to that described under Reaction scheme A-2.
  • the amide coupling in the first reaction step is assisted by coupling reagents such as for example DCC, DIC, TBTU, HATU, EDC or the like.
  • the compounds (1) which may be obtained directly or stepwise according to the foregoing reaction schemes may optionally be modified by associated synthesis steps (e.g. Substitutions, acylations etc.) to obtain further compounds according to the invention (1).
  • reaction scheme A-4 In a departure from the cases shown in reaction schemes A-I to A-3 the incorporation of the grouping Q H or a corresponding precursor Q H* may also be carried out by amide coupling, esterification, carbamate or urea formation (Reaction scheme A-4).
  • linker fragment L 3 in the target compounds (1) is selected from among -C(O)O-, -C(O)NR 8 -, -OS(O) 2 -, -OS(O) 2 NR 8 -, -OC(O)-, -OC(O)O-, -OC(O)NR 8 -, -S(O) 2 O-, -S(O) 2 NR 8 -, -NR 8 C(O)-, -NR 8 C(O)O-, -NR 8 C(O)NR 8 -, -NR 8 S(O) 2 -, -NR 8 S(O) 2 O- and -NR 8 S(O) 2 NR 8 -.
  • one of the groups R * or R ** of the components A.11, A.12/ A.12 or A.13 is an optionally activated carbon, sulphone, sulphur or carbonic acid function, while an alcohol or amine, is present as the other group in each case.
  • the method of synthesising pyridinonecarboxylic acids A.1 depends on the bridge unit W that joins together the ring systems Q a and Q b :
  • the grouping Q a -CR 1 R 2 - may be incorporated by nucleophilic substitution at component B.2, which is activated by an electron-attracting leaving group LG, e.g. a halogen, triflate or mesylate.
  • LG e.g. a halogen, triflate or mesylate.
  • B.I is optionally deprotonated for this purpose by the addition of a base.
  • the synthesis of a pyridinone ring system is carried out starting from malonic acid diester derivatives B.3.
  • the derivatives used are di- or trielectrophils, which cyclise during the reaction with amines, hydroxylamines or hydrazines B.4. It is not absolutely essential for a leaving group LG to be present in compounds B.3.
  • an electrophilic carbon activated by a leaving group an electrophilic carbonylcarbon is also possible.
  • EDG electron-repelling group, e.g.. -B(OH) 2 /-B(OR ' ) 2 , -MgHaI, -ZnHaI, SnR ' 3 or hydrogen
  • the ring systems Q H -la to Q H -lk shown may each optionally be substituted independently of one another at one or more hydrogen-carrying carbon atom(s) by R a and/or R b .
  • Embodiments Q H -la to Q H -lk or more especially Q H -la.l to Q H -la.6 for example can be synthesised via the following key intermediates Q H* -la.l to Q H* -la.3 (prepared on the basis of Q H -la, also analogously for Q H -lb to Q H -lk)
  • A.12 (R ** -Q H ) or A.12 * (R ** -Q H* ) may be used, while the activating substituents EWG and EDG or the linker fragment R ** are located at Q H /Q H* in such a way that their position corresponds to the later linkage point to the linker unit L.
  • EWG and EDG or the linker fragment R ** are located at Q H /Q H* in such a way that their position corresponds to the later linkage point to the linker unit L.
  • ring systems Q H may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by R a and/or R b , while R 8 , B, R a and R b are as hereinbefore defined.
  • linker unit L which may be incorporated or synthesised according to methods described in reaction schemes A-I to A-4 and reaction scheme C are as follows (the notation in each case being such that the bond to the amide nitrogen -NR 4 - is shown on the left and the bond to the ring system Q H is shown on the right):
  • linkers L in compounds according to the invention (1) are selected from among L-I, L-2, L-2a, L-2b, L-2c, L-2d, L-2e, L-2f, L-2g, L-2h, L-2i, L-2j, L-2k, L-3, L-3a, L-3b, L-3c, L-3d, L-3e, L-3f, L-3g, L-3h, L-3i, L-3j, L-3k, L-31, L-3m, L-3n, L- 3o, L-3p, L-3q, L-3r, L-3s, L-3t, L-4, L-5, L-5a, L-5b, L-5c, L-6, L-7, L-8, L-9, L-IO, L-Il, L-12, L-13, L-14, L-15, L-16, L-16a, L-16b, L-16c, L-16d, L-16e; L-16f, L-16g, L-16h, L-16i, L-17, L-18, L-19, L-20, L-21
  • Amine B.4a (200 mg, 1.0 mmol) is taken up in 1.6 mL 2-butanol and combined with the malonic acid diester derivative B.3a (142 mg, 1.0 mmol), which is taken up in 0.4 mL 2- butanol, at 5°C.
  • the mixture is stirred for 1 h at 20 0 C, diluted with another 5 mL 2-butanol and refluxed for 48 h with stirring.
  • the reaction solution is combined with 0.5 mL 2 N aqueous sodium hydroxide solution and 0.5 mL 2 N methanolic sodium hydroxide solution and stirred for 2 h at 20 0 C.
  • the reaction mixture is acidified with 1 N aqueous hydrochloric acid and extracted with DCM.
  • carboxylic acids A.1 may also be synthesised from B.3a and the corresponding amines B.4 analogously to the synthesis of A. Ia:
  • 2,6-Dibromoquinazoline A.4 * a (200 mg, 0.697 mmol) and aniline (97 mg, 1.045 mmol) are taken up in 1 rnL dioxane and combined with dioxanic HCl (174 ⁇ L, 4 mmol/mL).
  • A.4c may also be prepared from A.4 * a and 4-dimethylaminomethyl- phenylamine.
  • A.4 * a 4-dimethylaminomethyl- phenylamine.
  • structurally diverse anilines may be reacted with A.4 * a in this way.
  • A.4d-PG (2.50 g, 8.51 mmol) is taken up in 80 mL THF and cooled to -78°C under an argon atmosphere.
  • LDA dissolved in cyclohexane (8.5 mL, 12.75 mmol) is added to this mixture within 15 min.
  • iodine (2.38 g, 9.36 mmol)
  • the reaction mixture is combined with 10 mL of a 1 N hydrochloric acid solution and stirred for 1 h at 20 0 C.
  • A.4g-PG or A.4h is prepared according to WO 2007/117607:
  • 2-amino-5-bromo-3-methoxybenzoic acid (20.0 g, 81.30 mmol) is suspended in 250 mL THF, cooled to 0 0 C and combined with borane-THF complex (315 mL, 0.315 mol). The reaction mixture is stirred for 5 d at 20 0 C and then combined with 10 mL EtOH, stirred for 15 min and then stirred into 250 mL water. The mixture is extracted 3x with DCM, the combined organic phases are dried and the solvent is eliminated in vacuo. The crude product is suspended in DCM and extracted 2x with 400 mL 1 N hydrochloric acid.
  • Triphenylphosphine (577 mg, 2.20 mmol), di-tert-butylazodicarboxylate (506 mg, 2.20 mmol) and tert-butyl 4-hydroxy-piperidine-l-carboxylate (1.32 g, 6.62 mmol) are taken up in 6 mL THF, stirred for 15 min at 20 0 C and then combined with 6-bromo-2- chloro-quinazolin-8-ol (1.16 g, 4.45 mmol). After stirring for 24 h at 20 0 C the mixture is diluted with MeOH, the solvent is eliminated in vacuo, the crude product is purified by RP-chromatography (method prep.
  • HPLCl 20 % acetonitrile to 90 % in 6 min
  • 6-bromo-2-chloro-5-fluoro-quinazoline is prepared analogously to WO 2007/117607 or to the above-mentioned synthesis of 6-bromo-2-chloro-8-methoxy-quinazoline starting from 2-amino-5-bromo-6-fluoro-benzonitrile.
  • l-(2,4-dichloro-pyrimidin-5-yl)-ethanone (10 g, 0.052 mol), sodium hydrogen carbonate (19.35 g, 0.058 mol) and isopropylamine (5 mL, 0.058 mol) are taken up in 35 mL THF and 200 mL cyclohexane and stirred for 2 h at 20 0 C.
  • the reaction solution is filtered through silica gel, the solvent is eliminated in vacuo and l-(2-chloro-4-isopropylamino- pyrimidin-5-yl)-ethanone (HPLC-MS: t Re t.
  • A.41 is prepared as described in WO 2008/008821.
  • 2,6-dichloro-3-nitro-pyridine (2.5 g, 12.9 mmol) is taken up in a solvent mixture of THF and NMP (5:1, 13 mL), combined with two spatula tips of silicon carbide and CuCN (2.3 g, 26.0 mmol) and heated to 180 0 C in the microwave reactor for 45 min. Then the solid obtained is suspended in H 2 O, extracted with ethyl acetate, washed with NaCl-sln., the organic phase is dried on MgSO 4 , the solvent is eliminated in vacuo and 6-chloro-3- nitro-pyridine-2-carbonitrile (HPLC-MS: t Ret .
  • 3-amino-6-chloro-pyridine-2-carboxylic acid amide (94 mg, 0.55 mmol) is taken up in cone. HCl (0.5 mL) and heated to 110 0 C for 5 h. Then the solvent is removed and 3- amino-6-chloro-pyridine-2-carboxylic acid is obtained.
  • 3-amino-6-chloro-pyridine-2-carboxylic acid (95 mg, 0.55 mmol) is taken up in THF (1 mL) and combined with BH 3 -THF complex (2.2 mL, 2.2mmol, 1 M in THF). The reaction mixture is stirred for 2 d at 20 0 C. The reaction is ended with dilute HCl and H 2 O, then neutralised with NaHCO 3 , extracted with EtOAc, the organic phase is dried on MgSO 4 , the solvent is eliminated in vacuo and (3-amino-6-chloro-pyridin-2-yl)-methanol is obtained (HPLC-MS: t Re t.
  • 3-amino-6-chloro-pyridine-2-carbaldehyde (3.2 g, 13.0 mmol) is mixed thoroughly with urea (7.8 g, 130 mmol) and heated to 180 0 C in the preheated oil bath for 3 h. Then the reaction mixture is suspended in H 2 O, the precipitate is filtered off and 6-chloro-3H- pyrido[3,2-d]pyrimidin-2-one is obtained.
  • Compounds A.4n, A.4o and A.4p may be prepared analogously to A.4m starting from the corresponding carboxylic acids.
  • 2-Amino-5-chloro-nicotinic acid is used for A.4n, while 3-amino-6-chloro-pyrazine-2-carboxylic acid is used for A.4o.
  • Bromoindolinone A.4 * p (3.433 g, 16.19 mmol), A.3a (5.0 g, 19.43 mmol), palladium(II)- acetate (363 mg, 1.619 mmol), tri-o-tolylphosphine (986 mg, 3.24 mmol) and H ⁇ nig base (5.771 mL, 34.0 mmol) are suspended in 15 mL acetonitrile and stirred for 2 h at 90 0 C. The reaction mixture is stirred into 0.1 N hydrochloric acid, extracted with DCM, the organic phase is dried and the solvent is eliminated in vacuo.
  • A.3a may also be coupled with A.4c to form A.2b under analogous reaction conditions.
  • Boc-protective group on A.2c-PG and A.2 * d-PG may be eliminated in TFA/DCM (I h, RT) and A.2c or A.2 * d is then obtained.
  • A.3b may also be reacted with A.4 p to form A.2 e-PG and after the Boc protective group has been cleaved A.2 e is obtained.
  • A.2 * d-PG (100 mg, 0.21 mmol) is taken up in MeOH/dioxane (1 mL, 1 :1), combined with Boc-pyrrole-2-boric acid (50 mg, 0.24 mmol), K 2 CO 3 (0.32 mL, 0.63 mmol, 2 M in H 2 O) and Pd(PPh 3 )4 (12 mg, 10 mol%) and heated to 80 0 C for 20 min in the microwave reactor. The reaction mixture is filtered off, purified by column chromatography (CH 3 CN/H 2 O, 15 % auf 98 %) and the A.2e provided with two Boc protective groups is obtained.
  • A.4f-PG (30 mg, 0.081 mmol) and 4-aminomethyl-phenylamine A.3c (20 mg, 0.164 mmol) are taken up in 0.3 mL NMP and combined with dioxanic HCl (81 ⁇ L, 4 mmol/mL).
  • A.4c 200 mg, 0.56 mmol
  • A.3d 115 mg, 0.572 mmol
  • palladium(II)-acetate 14 mg, 0.063 mmol
  • tri-o-tolylphosphine 37 mg, 0.122 mmol
  • H ⁇ nig base 0.2 mL, 1.214 mmol
  • the reaction mixture is stirred into 0.1 N hydrochloric acid, extracted with DCM, the organic phase is dried and the solvent is eliminated in vacuo.
  • the residue is purified by RP-chromatography (method prep. HPLC2; 5 % acetonitrile to 65 % in 12 min).
  • the phthalimide-protected intermediate product thus obtained is taken up in 3 mL EtOH, combined with hydrazine hydrate (70 ⁇ L, 1.41 mmol) and stirred for 3 h at 50 0 C.
  • A.3e is then coupled with A.4c to form A.2i, the reaction conditions being those used in the synthesis of A.2h from A.3d and A.4c (see above).
  • A.4c 50 mg, 0.14 mmol
  • A.3f 78 mg, 0.419 mmol
  • Pd 2 dba 3 13 mg, 0.014 mmol
  • X-Phos 20 mg, 0.042 mmol
  • caesium carbonate 182 mg, 0.559 mmol
  • A.21 400 mg, 1.43 mmol
  • benzenesulphonyl chloride (272 ⁇ L, 2.13 mmol)
  • DMAP 18 mg, 0.15 mmol
  • H ⁇ nig base 350 ⁇ L, 2.17 mmol
  • Carboxylic acid A.5a (71 mg, 0.376 mmol), HATU (214 mg, 0.564 mmol) and triethylamine (364 ⁇ L, 2.256 mmol) are suspended in 0.5 mL DMF and stirred for 5 min at 20 0 C. Then A.6a (101 mg, 0.451 mmol) is added and the mixture is stirred for 60 min at 20 0 C. It is combined with semi-saturated sodium hydrogen carbonate solution and DCM, the organic phase is separated off and the solvent is eliminated in vacuo. The residue is taken up in 5 mL DCM, combined with 5 mL trifluoroacetic acid and stirred for 4 h at 20 0 C.
  • A.9c may also be prepared analogously to A.9b from A.la and allylamine.
  • the carboxylic acid A.la (233 mg, 0.528 mmol), HATU (201 mg, 0.528 mmol) and triethylamine (146 ⁇ L, 1.16 mmol) are suspended in 1 mL DMF and stirred for 5 min at
  • Example compounds 1-2 to 1-27 are prepared analogously to 1-1, by reacting the corresponding carboxylic acid A.I first of all with component A.2 * a and then with pyrrole- or imidazole-carbaldehydes C.2.
  • Amide A.9a (64.6 mg, 0.178 mmol), azaindole A.4s-PG (50 mg, 0.148 mmol), palladium DPPF (16 mg, 0.020 mmol) and caesium carbonate solution (72 ⁇ L, 5 mmol/mL) are suspended in 720 ⁇ L of a mixture consisting of THF/NMP (2:1) and stirred for 1 h at 100 0 C.
  • the reaction mixture is diluted with water, extracted with DCM, the organic phase is dried and the solvent is eliminated in vacuo.
  • the residue is suspended in 4 mL methanol and 1 mL water and combined with potassium carbonate (93 mg, 0.676 mmol).
  • Example compounds III-3 to III- 18 are synthesised stepwise analogously to IH-I or III-2 by SUZUKI, SONOGASHIRA or HECK cross-coupling.
  • the components A.9a, A.9b, A.9c or analogues thereof are reacted with components A.4.
  • all the Example compounds may be synthesised by synthesising corresponding amino components A.2 and coupling with carboxylic acids A.l.
  • Example compounds III-2 to III-42 (Table 3) are synthesised analogously to the synthesis of IH-I described hereinbefore, by synthesising corresponding amino components A.2 and coupling them with carboxylic acids A.l.
  • Example compounds IV-2 and IV-3 may be prepared (Table 4).
  • Compounds of general formula (1) are characterised by their many possible applications in the therapeutic field. Particular mention should be made of those applications in which the inhibition of specific signal enzymes, particularly the inhibiting effect on the proliferation of cultivated human tumour cells but also on the proliferation of other cells such as endothelial cells, for example, are involved.
  • the activity of the compounds according to the invention on the kinase PDKl which inhibits the signal transduction pathway is determined in an in vitro kinase assay with recombinant Iy prepared protein:
  • Recombinant human PDKl enzyme (aa 52-556) linked at its N-terminal end to HiS 6 is isolated from baculo virus-infected insect cells. Purified enzyme may be obtained for example from the University of Dundee, Scotland. The following components are combined in a well of a 96-well round-based dish (Messrs. Greiner bio-one, No. 650101):
  • PDKtide KTFCGTPEYLAPEVRREPRILSEEEQEM- FRDFDYIADWC
  • PDKl and PDKtide are together diluted accordingly in assay buffer; PDKtide is present in this mixture as an 83.3 ⁇ M solution.
  • the reaction is started by adding the ATP solution and the mixture is incubated for 30 min at ambient temperature; at the start of the reaction the dishes are shaken gently.
  • the reaction is stopped by the addition of 50 ⁇ L/well 125 mM phosphoric acid (H3PO4) and incubated for about 20 min at ambient temperature.
  • the precipitate is transferred by harvesting onto filter plates (96-well microtitre filter plate: UniFilter GF/C; Messrs Perkin Elmer; No. 6005174), then washed 6 times with 50 mM H 3 PO 4 and dried at 60 0 C. Then the plate is stuck down with sealing tape, 25 ⁇ L/well of scintillation solution (Microscint 0; Messrs. Perkin Elmer; No. 6013611) are added and the amount of P33 precipitated is measured using the Wallac Betacounter. The measured data are evaluated using Graphpad Prism software.
  • a shortened PDKl enzyme (aa 51-359; Q66A mutation) is used that carries in the N-terminal position a HiS 6 tag that is cleaved during purification. ( ⁇ PH-PDK1).
  • the reaction is started by adding the ATP solution and the mixture is incubated for 120 min at ambient temperature; at the start of the reaction the dishes are shaken gently.
  • the reaction is stopped by the addition of 50 ⁇ L/well of 500 mM phosphoric acid (H 3 PO 4 ) and incubated for about 20 min at ambient temperature.
  • the precipitate is transferred by harvesting onto filter plates (96-well microtitre filter plate: UniFilter GF/C; Messrs Perkin Elmer; No. 6005174), then washed 6 times with 50 mM H 3 PO 4 and dried at 60 0 C. Then the plate is stuck down with sealing tape, 25 ⁇ L/well of scintillation solution (Microscint 0; Messrs. Perkin Elmer; No. 6013611) are added and the amount of P33 precipitated is measured using the Wallac Betacounter. The measured data are evaluated using Graphpad Prism software.
  • PDKl Kinase Assay III Another PDKl assay was developed which by comparison with PDKl assay 1 additionally contains Tween 20:
  • HiS 6 -PDKl (aa 52-556) 3.33 ng/well) and PDKtide (KTFCGTPEYLAPEVRRE PRILSEEEQEMFRDFDYIADWC), synthesised by Pepceuticals Limited, Nottingham, United Kingdom; 25 ⁇ M final concentration); HiS 6 -PDKl and PDKtide are together diluted accordingly in assay buffer (50 mM tris pH 7.5, 0.05 % ⁇ -mercaptoethanol, 10 mM Mg-acetate); PDKtide is present in this mixture as an 83.3 ⁇ M solution. These 30 ⁇ L are routinely incubated for 30 min at RT.
  • the reaction is started by adding the ATP solution and the mixture is incubated for 90 min at ambient temperature; at the start of the reaction the dishes are shaken gently.
  • the reaction is stopped by the addition of 50 ⁇ L/well of 500 mM phosphoric acid (H3PO4) and incubated for about 20 min at ambient temperature.
  • the precipitate is transferred by harvesting onto filter plates (96-well microtitre filter plate: UniFilter GF/C; Messrs Perkin Elmer; No. 6005174), then washed 6 times with 50 mM H 3 PO 4 and dried at 6O 0 C. Then the plate is stuck down with sealing tape, 25 ⁇ L/well of scintillation solution (Microscint 0; Messrs. Perkin Elmer; No.
  • Compounds (1) according to the invention generally exhibit good to very good inhibition in at least one of the PDKl assays described hereinbefore, i.e. for example an IC50 value of less than 1 ⁇ mol/L, less than 0.25 ⁇ mol/L.
  • Table 5 shows the %CTL values of the compound examples at a concentration of 10 ⁇ M. A value of 100 % indicates that there is no total inhibition with a value of 0%.
  • the %CTL values indicate the residual activity of the enzyme after the addition of the inhibitory compound in the solvent DMSO in relation to the enzyme activity in the solvent DMSO without the addition of a compound (control). The majority of the values were determined using the PDKl kinase assay III described hereinbefore. The values marked with an asterisk ( ) were determined using the PDKl kinase assay II described hereinbefore.
  • the antiproliferative activity of the compounds according to the invention is determined in the proliferation test on cultivated human tumour cells and/or in a cell cycle analysis, for example on HCTl 16 or PC-3 tumour cells:
  • HCTl 16 Inhibition of proliferation on cultivated human tumour cells
  • HCTl 16 cells of the colon carcinoma line HCTl 16 (obtained from American Type Culture Collection (ATCC)) are cultivated in McCoy medium (Gibco) and 10% foetal calf serum (Gibco) and harvested in the log growth phase. Then the HCTl 16 cells are placed in 96-well flat bottomed plates (Falcon) at a density of 1000 cells per well in McCoy medium and incubated overnight in an incubator (at 37°C and 5 % CO 2 ). The active substances are added to the cells in various concentrations (dissolved in DMSO; DMSO final concentration: 0.1%).
  • AlamarBlue reagent (AccuMed International) are added to each well, and the cells are incubated for a further 5-7 hours. After incubation the colour change of the AlamarBlue reagent is determined in a Wallac Microbeta fluorescence spectrophotometer EC50 values are calculated by means of Standard Levenburg Marquard algorithms (GraphPadPrizm).
  • the cells are cultivated in Ham's F12K (Gibco) and 10% foetal calf serum (Gibco) and harvested in the log growth phase. Then the PC-3 cells are placed in 96-well plates (Costar) at a density of 2000 cells per well and incubated overnight in an incubator (at 37°C and 5 % CO 2 ), while on each plate 16 wells are used as controls (8 wells with cells to which only DMSO solution has been added (should yield 30 - 50% maximum value of reduced AlamarBlue), 4 wells containing only medium (medium control, after the addition of oxidised AlamarBlue reagent the background signal is obtained) and 4 wells where again only medium is added (after the addition of reduced AlamarBlue reagent it acts as a maximum value)).
  • ATCC American Type Culture Collection
  • the active substances are added to the cells in various concentrations (dissolved in DMSO; DMSO final concentration: 0.2%) (in each case as a double or triple measurement). After 5 days' incubation 20 ⁇ l AlamarBlue reagent (Serotec) are added to each well, and the cells are incubated for a further 5-7 hours. As a control, 20 ⁇ l reduced AlamarBlue reagent is added to each of 4 wells (AlamarBlue reagent which is autoclaved for 30 min). After incubation the colour change of the AlamarBlue reagent in the individual wells is determined in a SpectraMax Photometer (Molecular Devices) (extinction 530 nm, emission 590 nm, 5 sec measuring time).
  • SpectraMax Photometer Molecular Devices
  • the amount of AlamarBlue reagent reacted represents the metabolic activity of the cells.
  • the relative cell activity is calculated in relation to the control (PC-3 cells without inhibitor) and the active substance concentration which inhibits the cell activity by 50% (EC50) is derived.
  • the values are calculated from the average of two or three individual measurements.
  • Many of the compounds according to the invention cause inhibition of proliferation by interfering with intracellular signal transduction pathways which are important for cell survival, predominantly, but not exclusively, in cells which have become dependent on these signal pathways during their development. Inhibition of these pathways induces arrest in corresponding cells in the Gl phase of the cell cyle and/or apoptosis, i.e. cell responses that can be analysed using Cellomics Array Scan or FACS analysis (see below).
  • the compounds according to the invention are also tested accordingly on other tumour cells.
  • these compounds are effective on carcinomas of all kinds of tissue (e.g. Gliomas (U87MG; U373MG), sarcoma (e.g. MES-SA; SK-UT-IB), breast (MDA- MB468), colon (HCTl 16), lung (NCIH460, NCI-H520), melanoma (MALME-3M; C32), prostate (DU- 145), ovary (SKO V-3)] and could be used in indications of this kind, particularly in indications which have activating changes in the PI3K-AKT-PDK1 signal pathway.
  • Compounds (1) according to the invention generally demonstrate good activity in cell assays of this kind, i.e. for example an EC50 value in the PC-3 or HCTl 16 proliferation test of less than 10 ⁇ mol/L, very often less than 2 ⁇ mol/L.
  • PI Propidium iodide binds stoichiometrically to double-stranded DNA, and is thus suitable for determining the proportion of cells in the Gl, S, and G2/M phase of the cell cycle on the basis of the cellular DNA content.
  • Cells in the GO and Gl phase have a diploid DNA content (2N), whereas cells in the G2 or mitosis phase have a 4N DNA content.
  • PI staining for example, 1.0 x 10 6 PC-3 or HCTl 16 cells are seeded onto a 75 cm 2 cell culture flask, and after 24 h either 0.1 % DMSO is added as control or the substance is added in various concentrations (in 0.1% DMSO). The cells are incubated for 42 h with the substance or with DMSO. Then the cells are detached with trypsin and centrifuged. The cell pellet is washed with buffered saline solution (PBS) and the cells are then fixed with 80% ethanol at -20 0 C for at least 2 h.
  • PBS buffered saline solution
  • the cells are permeabilised with Triton X-IOO (Sigma; 0.25% in PBS) on ice for 5 min, then washed with PBS and incubated with a mixture of PBS and anti-cyclin Bl (FITC conjugated) antibody for 30 min at RT.
  • This step is optional, but helps improve the identification of cells in the G2/M phase as these specifically express cyclin Bl.
  • the suspension is washed with PBS and the pellet is incubated in a solution of PI (Sigma; 10 ⁇ g/ml)and RNAse (Serva; lmg/mLl) in the ratio 9:1 for at least 20 min in the dark.
  • the DNA measurement is carried out in a Becton Dickinson FACScalibur, with an argon laser (500 mW, emission 488 nm); data are obtained and evaluated using the DNA Cell Quest Programme (BD).
  • PC-3 cells are cultivated in Ham's F12K (Gibco) and 10% foetal calf serum (Gibco) and harvested in the log growth phase. Then the PC-3 cells are placed in 96-well plates [FALCON black/clear bottom (#353948)] in a density of 3000 cells per well and incubated overnight in an incubator (at 37°C and 5 % CO 2 ). The active substances are added to the cells in various concentrations (dissolved in DMSO; DMSO final concentration: 0.1%).
  • the medium is suction filtered, the cells are fixed for 10 min with 4% formaldehyde solution and Triton X-IOO (1 :200 in PBS) at ambient temperature and simultaneously permeabilised, and then washed twice with a 0.3% BSA solution (Calbiochem). Then the DNA is stained by the addition of 50 ⁇ L/well of 4',6-diamidino- 2-phenylindole (DAPI; Molecular Probes) in a final concentration of 300 nM for 1 h at RT, in the dark.
  • DAPI 4',6-diamidino- 2-phenylindole
  • Compounds (1) according to the invention generally induce Gl arrest in PC-3 cells, for example, at concentrations of less than 30 ⁇ mol/L, often less than 5 ⁇ mol/L. In HCTl 16 or MALME-3M cells they generally induce apoptosis at similar or lower concentrations.
  • the substances of the present invention bring about cellular inhibition of PDKl -substrates.
  • the latter are Phospho-Thr308/AKT, Phospho-Ser221,227/RSK, or phosphorylation sites on p70S6 kinase (Thr229).
  • the cells are treated with substance for e.g. 2 h, lysed and analysed by Western Blot and/or BioPlex analysis for phosphoproteins of this kind.
  • Commercially obtainable phospho-specific antibodies against the above-mentioned phosphorylation sites are used.
  • the compounds of general formula (1) according to the invention are suitable for treating diseases characterised by excessive or abnormal cell proliferation or by aberrant activation of the phosphatidylinositol-3-kinase (PBK)-PDKl-AKT signal pathway.
  • PBK phosphatidylinositol-3-kinase
  • Such diseases include for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory 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 (e.g. carcinomas and sarcomas), skin diseases (e.g. psoriasis); diseases based on hyperplasia which are characterised by an increase in the number of cells (e.g. fibroblasts, hepatocytes, bones and bone marrow cells, cartilage or smooth muscle cells or epithelial cells (e.g.
  • viral infections e.g. HIV and Kaposi's sarcoma
  • inflammatory and autoimmune diseases e.g. colitis, arthritis, Alzheimer's disease, glomerulonephritis and wound healing
  • bacterial, fungal and/or parasitic infections e.g. colitis, arthritis, Alzheimer's
  • endometrial hyperplasia bone diseases and cardiovascular diseases (e.g. restenosis and hypertrophy). They are also suitable for protecting proliferating cells (e.g. hair, intestinal, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and/or cytostatic treatment.
  • proliferating cells e.g. hair, intestinal, blood and progenitor cells
  • brain tumours such as for example acoustic neurinoma, astrocytomas such as pilocytic astrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma and glioblastoma, brain lymphomas, brain metastases, hypophyseal tumour such as prolactinoma, HGH (human growth hormone) producing tumour and ACTH producing tumour (adrenocorticotropic hormone), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours (neoplasms) such as for example tumours of the vegetative nervous system such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (pheochromocytoma, chromaff ⁇ nom
  • astrocytomas such as pilocytic astrocytomas, fibrillary
  • the new compounds may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy or other "state-of-the-art" compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies.
  • radiotherapy or other "state-of-the-art” compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies.
  • the compounds of general formula (1) may be used on their own or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances.
  • Chemo therapeutic agents which may be administered in combination with the compounds according to the invention, include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g., tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, flu
  • anastrozole anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane
  • LHRH agonists and antagonists e.g. goserelin acetate, luprolide
  • inhibitors of growth factors growth factors such as for example "platelet derived growth factor” and “hepatocyte growth factor”
  • inhibitors are for example "growth factor” antibodies, “growth factor receptor” antibodies and tyrosinekinase inhibitors, such as for example cetuximab, gefitinib, imatinib, lapatinib and trastuzumab
  • antimetabolites e.g.
  • antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5- fluorouracil, capecitabin and gemcitabin, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine); antitumour antibiotics (e.g. anthracyclins such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g.
  • Cisplatin, oxaliplatin, carboplatin alkylation agents (e.g. Estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (e.g.
  • epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron) and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, f ⁇ lgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porf ⁇ mer.
  • epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron
  • chemotherapeutic agents such as amifostin, anagrelid, clodronat, f ⁇ lgrastin, interferon alpha, leucovorin, rituximab, procarbazine,
  • Suitable preparations include for example tablets, capsules, suppositories, solutions - particularly solutions for injection (s.c, i.v., i.m.) and infusion - elixirs, emulsions or dispersible powders.
  • the content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below.
  • the doses specified may, if necessary, be given several times a day.
  • Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • excipients for example inert dilu
  • Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core may also consist of a number of layers.
  • the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
  • Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
  • a sweetener such as saccharine, cyclamate, glycerol or sugar
  • a flavour enhancer e.g. a flavouring such as vanillin or orange extract.
  • suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
  • Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsif ⁇ ers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.
  • Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
  • Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
  • Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g.
  • pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly disper
  • lignin e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone
  • lubricants e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate.
  • the preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route.
  • the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like.
  • lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process.
  • the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
  • solutions of the active substances with suitable liquid carriers may be used.
  • the dosage for intravenous use is from 1 - 1000 mg per hour, preferably between 5 and
  • the finely ground active substance, lactose and some of the corn starch are mixed together.
  • the mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried.
  • the granules, the remaining corn starch and the magnesium stearate are screened and mixed together.
  • the mixture is compressed to produce tablets of suitable shape and size.
  • the finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened.
  • the sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
  • the active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic.
  • the solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion.
  • the ampoules contain 5 mg, 25 mg and 50 mg of active substance.

Abstract

The present invention encompasses compounds of general formula (1) while the groups R4 to R7 and the units W, L, Qa and QH are defined as in claim 1, which are suitable for the treatment of diseases characterised by excessive or abnormal cell proliferation, and their use as medicaments having the above-mentioned properties.

Description

NEW CHEMICAL COMPOUNDS
The present invention relates to new compounds of general formula (1)
Figure imgf000002_0001
(1)
wherein the groups R4 to R7 and the units W, L, Qa and QH have the meanings given in the claims and specification, as well as the tautomers, racemates, enantiomers, diastereomers, mixtures and the salts of all these forms, and their use as medicaments with an antiproliferative activity.
Background to the invention
Substituted pyridinonecarboxylic acid amides are described in WO 2008/005457 as inhibitors of PDKl.
The aim of the present invention is to discover new active substances which can be used for the prevention and/or treatment of diseases characterised by excessive or abnormal cell proliferation.
Detailed description of the invention
It has now been found that, surprisingly, compounds of general formula (1), wherein the groups R4 to R7 and the units W, L, Qa and QH have the meanings given hereinafter act as inhibitors of specific signal enzymes which are involved in controlling cell proliferation. Thus, the compounds according to the invention may be used for example for the treatment of diseases connected with the activity of these signal enzymes and characterised by excessive or abnormal cell proliferation. The present invention therefore relates to compounds of general formula (1)
Figure imgf000003_0001
C) , while:
Qa is a ring system optionally substituted by one or more, identical or different Ra and/or Rb, selected from among C3_iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
W is selected from among -CR1R2-, -NR3-, and -O-;
R1 and R2 independently of one another are selected from among Ra and Rb,
R3 denotes Ra;
the group Qa-W- is not an unsubstituted or substituted benzyl;
R4 denotes hydrogen or Ci_6-alkyl;
R5, R6 and R7 independently of one another are selected from among Ra and Rb;
L denotes the group -L1-L2-L3-, wherein L1 binds to the unit -NR4- and L3 binds to the ring system QH;
L1, L2 and L3 are selected independently of one another from among Ci_6alkylene, 2-6 membered heteroalkylene, Ci-βhaloalkylene, C3_iocycloalkylene, Cβ-ioarylene, 5-12 membered heteroarylene, 3-14 membered heterocycloalkylene, while all the above-mentioned bivalent units may each optionally be substituted independently of one another by one or more, identical or different Ra and/or Rb,
-O-, -S-, -NRg-, -N(0Rg)-, -C(O)-, -C(O)O-, -C(O)NR8-, -OS(O)2-, -OS(O)2NR8-, -OC(O)-, -OC(O)O-, -OC(O)NR8-, -S(O)2-, -S(O)2O-, -S(O)2NR8-, -NR8C(O)-,
-NR8C(O)O-, -NR8C(O)NR8-, -NR8S(O)2-, -NR8S(O)2O- and -NR8S(O)2NR8-, and/or
L 11, T 1/ 2 and L3 each independently of one another denotes a bond, while at least one of the units L1, L2 or L3 must be other than a bond;
the ring system QH is selected from among
Figure imgf000004_0001
QH-1a QH-1b QH-1c QH-1d QH-1e
Figure imgf000004_0002
QH-If QH-1g QH-1h QH-Ii QH-Ij QH-Ik
Figure imgf000004_0003
QH-2a QH-2a.1 QH-2b QH-2b.1 QH-2C QH-2C.1
Figure imgf000004_0004
QH-2d QH-2d.1 QH-2e QH-2f QH-2g QH-2h
Figure imgf000004_0005
QH-3a QH-3b QH-3c QH-3d QH-3e
Figure imgf000004_0006
QH-4a QH-4b QH-4c QH-4d QH-4e
Figure imgf000005_0001
QH-5a QH-5b QH-6a QH-6b QH-6c QH-6d
Figure imgf000005_0002
QH-7a QH-7b QH-7c QH-7d QH-8a QH-8b
Figure imgf000005_0003
QH-9a QH-9b QH-9c QH-9d
Figure imgf000005_0004
QH-10a QH-10b QH-IOc QH-10d QH-10e
Figure imgf000005_0005
QH-11a QH-11b QH-12a QH-12b
Figure imgf000005_0006
QH-13 QH-14 QH-15 , while
the above mentioned ring systems QH may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by Ra and/or Rb,
R8 denotes Ra,
B denotes =CR9R10 or =NRπ,
R9 denotes a group Ral and R10 denotes a group R! a2
or =CR9R10 denotes a 5-12 membered heteroaryl or 5-14 membered heterocycloalkyl, optionally substituted by one or more, identical or different Ra and/or Rb,
R11 denotes a group Ra3;
Ral denotes a group optionally substituted by one or more, identical or different Rb and/or Rc selected from among Ci_6alkyl, Ci_6haloalkyl, 2-6 membered heteroalkyl,
C3_iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, or a suitable substituent, selected from among -ORC, -SRC, -NRCRC, -ONRCRC, -N(ORC)RC, -NRgNRcRc, -NRgC(O)Rc, -NRgC(O)ORc, -NRgC(O)NRcRc, -NRgC(O)NRgNRcRc, -NRgC(NRg)Rc, -NRgC(NRg)ORc, -NRgC(NRg)NRcRc, -NRgC(NORg)Rc, -NRgS(O)2Rc, -NRgNRgC(O)Rc, -NRgNRgC(O)NRcRc and -NRgNRgC(NRg)Rc;
Ra2 is hydrogen or a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among Ci_6alkyl, Ci-βhaloalkyl, 2-6 membered heteroalkyl, C3_iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, or a suitable substituent, selected from among -CN, -C(O)RC, -C(O)ORC, -C(O)NRCRC, -C(O)SRC, -C(O)NRgNRcRc and -C(O)NRgORc;
Ra3 is a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among Ci_6alkyl, Ci-βhaloalkyl, 2-6 membered heteroalkyl, C3_iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, or a suitable substituent, selected from among -ORC and -NRCRC;
each Ra independently of one another is hydrogen or a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among Ci_6alkyl, 2-6 membered heteroalkyl, Ci-βhaloalkyl, C3-iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl; each Rb denotes a suitable substituent and each is selected independently of one another from among -ORC, -NRCRC, halogen, -CN, -NO2, -C(O)RC, -C(O)ORC, -C(O)NRCRC, -OC(O)RC, -OC(O)ORC, -OC(O)NRCRC, -S(O)2RC, -S(O)2OR0, -S(O)2NRCRC, -NRgC(O)Rc, -NRgC(O)ORc, -NRgC(0)NRcRc, -NRgS(O)2Rc, -NRgS(O)2ORc and -NRgS(O)2NRcRc, and the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring systems;
each Rc independently of one another is hydrogen or a group optionally substituted by one or more identical or different Rd and/or Re, selected from among Ci_6alkyl, 2-6 membered heteroalkyl, Ci-βhaloalkyl, C3_iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
each Rd is a suitable substituent and each is selected independently of one another from among -ORe, -NReRe, halogen, -CN, -NO2, -C(O)Re, -C(O)ORe, -C(0)NReRe, -OC(O)Re, -OC(O)ORe, -0C(0)NReRe, -S(O)2R6, -S(O)2OR6, -S(O)2NReRe, -NRgC(O)Re, -NRgC(0)0Re, -NRgC(O)NReRe, -NRgS(O)2Re, -NRgS(O)2ORe and -NRgS(0)2NReRe, and the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring systems;
each Re independently of one another is hydrogen or a group optionally substituted by one or more identical or different Rf and/or Rg, selected from among Ci_6alkyl, 2-6 membered heteroalkyl, Ci-βhaloalkyl, C3-iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
each Rf is a suitable substituent and each is selected independently of one another from among -0Rg, -NRgRg, halogen, -CN, -NO2, -C(O)Rg, -C(O)OR8, -C(O)NR8R8, -OC(O)R8, -OC(O)OR8, -OC(O)NR8R8, -S(O)2R8, -S(O)2OR8, -S(O)2NR8R8, -NRhC(0)R8, -NRhC(0)0R8, -NR11C(O)NR8R8, -NR11S(O)2R8, -NR11S(O)2OR8 and -NR11S(O)2NR8R8, and the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring systems;
each Rg independently of one another is hydrogen or a group optionally substituted by one or more identical or different Rh, selected from among Ci_6alkyl, 2-6 membered heteroalkyl, Ci-βhaloalkyl, C3_iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, and
each Rh independently of one another is selected from among hydrogen, Ci_6alkyl, 2-6 membered heteroalkyl, Ci-βhaloalkyl, Cs-iocycloalkyLCβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl
In one aspect (Al) the invention relates to compounds (1), wherein
Qa is a ring system optionally substituted by one or more identical or different Ra and/or Rb, selected from among Cβ-ioaryl and 5-12 membered heteroaryl, and
Ra and Rb are as hereinbefore defined.
In another aspect (A2) the invention relates to compounds (1), wherein
Qa is a ring system optionally substituted by one or more identical or different Ra and/or Rb, selected from among phenyl, naphthyl, indanyl, 1,2,3,4-tetrahydronaphthyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, triazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl and quinolinyl, and
Ra and Rb are as hereinbefore defined.
In another aspect (A3) the invention relates to compounds (1), wherein Qa is a ring system optionally substituted by one or more identical or different Ra and/or Rb, selected from among phenyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrimidyl and pyridyl, and
Ra and Rb are as hereinbefore defined.
In another aspect (A4) the invention relates to compounds (1), wherein Qa is a ring system optionally substituted by one or more identical or different Ra and/or Rb, selected from among phenyl and pyridyl, and Ra and Rb are as hereinbefore defined.
In another aspect (Bl) the invention relates to compounds (1), wherein the ring system Qa may be substituted by one or more identical or different substituents, selected from among Ci_6alkyl, Ci_6haloalkyl, -ORhl, -NRhlRhl, halogen, -CN, -C(O)Rhl, -C(O)ORhl, -C(O)NRhlRhl, -S(O)2NRhlRhl, -NRhlC(O)Rhl, -NRhlC(O)ORhl, -NRhlC(O)NRhlRhl, -NRhlS(O)2Rhl and =0, while the latter may only be a substituent in non-aromatic ring systems, and
Rhl is in each case selected independently of one another from among hydrogen, Ci_6alkyl, 2-6 membered heteroalkyl and Ci-βhaloalkyl.
In another aspect (B2) the invention relates to compounds (1), wherein the ring system Qa may be substituted by up to three identical or different substituents, selected from among methyl, trifluoromethyl, -OCH3, -NH2, -NH(CH3), -N(CH3)2, fluorine, chlorine and bromine.
In another aspect (Cl) the invention relates to compounds (1), wherein
W is selected from among -NH-, -N(Ci_6alkyl)-, -CH2-, -CH(Ci_6alkyl)-, -C(Ci_6alkyl)2- and -O- .
In another aspect (C2) the invention relates to compounds (1), wherein W is selected from among -CH2-, -CH(CH3)-, -NH- and -N(CH3)-.
In another aspect (C3) the invention relates to compounds (1), wherein W is selected from among -CH2- and -CH(CH3)-.
The above-mentioned structural aspects Al to A4, Bl, B2 and Cl to C3 may be permuted with one another as desired to form 24 different combinations ABC (= D) which characterise the partial range Qa-W of compounds (1) according to the invention. All these embodiments (Dl to D24) are expressly included, while those compounds in which the group Qa-W- denotes an unsubstituted or substituted benzyl are not included;
In another aspect (D25) the invention relates to compounds (1), wherein Qa denotes phenyl, while this phenyl may be substituted by one or more identical or different substituents, selected from among Ci_6alkyl, Ci_6haloalkyl, -ORhl, -NRhlRhl, halogen, -CN, -C(O)Rhl, -C(O)ORhl, -C(O)NRhlRhl, -S(O)2NRhlRhl, -NRhlC(O)Rhl, -NRhlC(O)ORhl, -NRhlC(O)NRhlRhl and -NRhlS(O)2Rhl,
Rhl is selected in each case independently of one another from among hydrogen, Ci_6alkyl, 2-6 membered heteroalkyl and Ci_6haloalkyl, and
W is selected from among -NH-, -N(Ci_6alkyl)- and -O-.
In another aspect (D26) the invention relates to compounds (1), wherein
Qa is selected from among furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrimidyl and pyridyl, while the ring system Qa may be substituted by one or more, identical or different substituents, selected from among Ci_6alkyl, Ci_6haloalkyl, -ORhl, -NRhlRhl, halogen, -CN, -C(O)Rhl, -C(O)ORhl, -C(O)NRhlRhl, -S(O)2NRhlRhl, -NRhlC(O)Rhl, -NRhlC(O)ORhl, -NRhlC(O)NRhlRhl and -NRhlS(O)2Rhl,
Rhl is selected independently of one another in each case from among hydrogen, Ci_6alkyl, 2-6 membered heteroalkyl and Ci_6haloalkyl, and
W is selected from among -NH-, -N(Ci_6alkyl)-, -CH2-, -CH(Ci_6alkyl)-, -C(Ci_6alkyl)2- and -O- .
In another aspect (D27) the invention relates to compounds (1), wherein Qa denotes phenyl, while this phenyl may be substituted by up to three identical or different substituents, selected independently of one another from among methyl, trifluoromethyl, -OCH3, -NH2, -NH(CH3), -N(CH3)2, fluorine, chlorine and bromine, and
W is selected from among -NH-, -N(Ci_6alkyl)- and -O-.
In another aspect (D28) the invention relates to compounds (1), wherein Qa is selected from among furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrimidyl and pyridyl, while the ring system Qa may be substituted by up to three identical or different substituents, selected independently of one another from among methyl, trifluoromethyl, -OCH3, -NH2, -NH(CH3), -N(CH3)2, fluorine, chlorine and bromine, and
W is selected from among -NH-, -N(Ci_6alkyl)-, -CH2-, -CH(Ci_6alkyl), -C(Ci_6alkyl)2- and -O-.
In another aspect (D29) the invention relates to compounds (1), wherein Qa denotes phenyl, while this phenyl may be substituted by up to three identical or different substituents, selected independently of one another from among methyl, trifluoromethyl, -OCH3, -NH2,
-NH(CH3), -N(CH3)2, fluorine, chlorine and bromine, may be substituted, and
W is selected from among -NH- and -N(CH3)-.
In another aspect (D30) the invention relates to compounds (1), wherein
Qa is selected from among furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrimidyl and pyridyl, while the ring system Qa may be substituted by up to three identical or different substituents, selected independently of one another from among methyl, trifluoromethyl, -OCH3, -NH2, -NH(CH3), -N(CH3)2, fluorine, chlorine and bromine, may be substituted, and
W is selected from among -CH2-, -CH(CH3)-, -NH- and -N(CH3)-. In another aspect (D31) the invention relates to compounds (1), wherein
Qa is selected from among furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrimidyl and pyridyl, while the ring system Qa may be substituted by up to three identical or different substituents, selected independently of one another from among methyl, trifluoromethyl, -OCH3,
-NH2, -NH(CH3), -N(CH3)2, fluorine, chlorine and bromine, and
W is selected from among -CH2- and -CH(CH3)-.
In another aspect (D32) the invention relates to compounds (1), wherein Qa denotes pyridyl, while this pyridyl may be substituted by up to three identical or different substituents, selected independently of one another from among methyl, trifluoromethyl, -OCH3, -NH2, -NH(CH3), -N(CH3)2, fluorine, chlorine and bromine, and
W is selected from among -CH2- and -CH(CH3)-.
In another aspect (El) the invention relates to compounds (1), wherein R4 denotes hydrogen.
In another aspect (Fl) the invention relates to compounds (1), wherein
R5, R6 and R7 independently of one another are selected from among hydrogen, Ci_6alkyl, Ci_6haloalkyl, -ORh2, -NRh2Rh2, halogen, -CN, -C(O)Rh2, -C(O)ORh2, -C(O)NRh2Rh2, -S(O)2NRh2Rh2, -NRh2C(O)Rh2, -NRh2C(O)ORh2, -NRh2C(O)NRh2Rh2 and -NRh2S(O)2Rh2 and
Rh2 is selected independently of one another in each case from among hydrogen, Ci_6alkyl, 2-6 membered heteroalkyl and Ci_6haloalkyl.
In another aspect (F2) the invention relates to compounds (1), wherein R5, R6 and R7 in each case denotes hydrogen. In another aspect (Gl) the invention relates to compounds (1), wherein L is selected from among
Figure imgf000013_0001
L-1 L-2 L-3 L-4 L-5 L-6
Figure imgf000013_0002
L-7 L-8 L-9 L-10 L-11 L-12
Figure imgf000013_0003
L-13 L-14 L-15 L-16 L-17
Figure imgf000013_0004
L-18 L-19 L-20 L-21 L-22 L-23
Figure imgf000013_0005
L-24 L-25 L-26 L-27 L-28 L-29
Figure imgf000013_0006
L-30 L-31 L-32 L-33 L-34 L-35
Figure imgf000013_0007
L-36 L-37 L-38 L-39 L-40
Figure imgf000013_0008
L-41 L-42 L-43 L-44 L-45 L-46
Figure imgf000014_0001
L-47 L-48 L-49 L-50 L-51
Figure imgf000014_0002
L-52 L-53 L-54 L-55 L-56
the bivalent units L shown bind on the right to the ring system QH and on the left to the amide nitrogen -NR .4 - according to formula (1) and may optionally each be substituted independently of one another by one or more identical or different R and/or R >b and Ra and Rb are as hereinbefore defined.
In another aspect (G2) the invention relates to compounds (1), wherein L is selected from among L-I to L-47 and L-53 to L-56, the bivalent units L bind on the right to the ring system QH and on the left to the amide nitrogen -NR4- according to formula (1) and may optionally each be substituted independently of one another by one or more identical or different Ra and/or Rb and
Ra and Rb are as hereinbefore defined.
In another aspect (G3) the invention relates to compounds (1), wherein L is selected from among
Figure imgf000015_0001
L-V L-Vl L-VII , while
the bivalent units L shown bind on the right to the ring system QH and on the left to the amide nitrogen -NR4- according to formula (1);
p denotes O or 1 ;
„12 „13 „14 „15 „16 „17 „18 „19 „20 „21 „22 „23 „24 „25 „26 „27 „28 „29 R. , R. , R. , R. , R. , R. , R. , R. , R. , R. , R. , R. , R. , R. , R. , R. , R. , R. ,
R30, R31, R32, R33, R34, R35, R36, R37, R38 and R39 is selected in each case independently of one another from among Ra and Rb, and
R40 denotes Ra; or
R15 and R17 are each selected independently of one another from among Ra and Rb, R14 and R16 together with the carbon atoms to which they are bound form a
C3_7Cycloalkylene or a 3-7 membered heterocycloalkylene, while the above-mentioned ring systems may optionally each be substituted independently of one another by one or more identical or different Ra and/or Rb; or
R19 and R21 are each selected independently of one another from among Ra and Rb, R18 and R20 together with the carbon atoms to which they are bound form a
C3_7Cycloalkylene or a 3-7 membered heterocycloalkylene, while the above-mentioned ring systems may optionally each be substituted independently of one another by one or more identical or different Ra and/or Rb; or R23 and R24 are each selected independently of one another from among Ra and Rb,
R22 and R25 together with the carbon atoms to which they are bound form an unsaturated C^cycloalkylene or an unsaturated 4-7 membered heterocycloalkylene, while the above-mentioned ring systems may optionally each be substituted independently of one another by one or more identical or different Ra and/or Rb; or
R30, R31, R33 and R35 are each selected independently of one another from among Ra and Rb,
R32 and R35 together with the carbon atoms to which they are bound form a C3_7Cycloalkylene or a 3-7 membered heterocycloalkylene, while the above-mentioned ring systems may optionally each be substituted independently of one another by one or more identical or different Ra and/or Rb; or
R37, R38 and R39 are each selected independently of one another from among Ra and Rb,
R36 and R40 together with the atoms to which they are bound form a 3-7 membered heterocycloalkylene, while this heterocycloalkylene may optionally be substituted independently of one another in each case by one or more identical or different Ra and/or Rb; or
R36, R37 and R39 are each selected independently of one another from among Ra and Rb,
R38 and R40 together with the atoms to which they are bound form a 3-7 membered heterocycloalkylene, while this heterocycloalkylene may optionally be substituted independently of one another in each case by one or more identical or different Ra and/or Rb; and
Ra and Rb are as hereinbefore defined.
In another aspect (G4) the invention relates to compounds (1), wherein L is selected from among '
Figure imgf000017_0001
L-I L-Il L-IV L-VII , while
the bivalent units L shown bind on the right to the ring system QH and on the left to the amide nitrogen -NR4- according to formula (1);
p denotes 0 or 1 ;
R12, R13, R14, R15, R16, R17, R22, R23, R24, R25, R36, R37, R38 and R39 are each selected independently of one another from among Ra and Rb, and
R40 denotes Ra; or
R37, R38 and R39 are each selected independently of one another from among Ra and Rb,
R36 and R40 together with the atoms to which they are bound form a 3-7 membered heterocycloalkylene, while this heterocycloalkylene may optionally be substituted independently of one another in each case by one or more identical or different Ra and/or Rb; or
R36, R37 and R39 are each selected independently of one another from among Ra and Rb,
R38 and R40 together with the atoms to which they are bound form a 3-7 membered heterocycloalkylene, while this heterocycloalkylene may optionally be substituted independently of one another in each case by one or more identical or different Ra and/or Rb; and
Ra and Rb are as hereinbefore defined.
In another aspect (G5) the invention relates to compounds (1), wherein L is selected from among
Figure imgf000018_0001
L-12 L-29 L-29a L-29b L-29c L-29d
Figure imgf000018_0002
0e^
L-29e L-29f L-29g L-29h L-29i L-29J
Figure imgf000018_0003
L -29k L-29I L-29m L-29n L-29o L-29p
Figure imgf000018_0004
L-29q L-29r L-29s L-29t L-29u
Figure imgf000018_0005
L-30 L-36 L-42 L-42a L-49
Figure imgf000018_0006
L-50 L-51
and the bivalent units L shown bind on the right to the ring system QH and on the left to the amide nitrogen -NR4- according to formula (1).
In another aspect (G6) the invention relates to compounds (1), wherein L is selected from among
Figure imgf000019_0001
L-12 L-36 L-36 L-49 L-50 L-51
and the bivalent units L shown bind on the right to the ring system QH and on the left to the amide nitrogen -NR4- according to formula (1).
In another aspect (G7) the invention relates to compounds (1), wherein L is selected from among
Figure imgf000019_0002
and the bivalent units L shown bind on the right to the ring system QH and on the left to the amide nitrogen -NR4- according to formula (1).
In another aspect (Hl) the invention relates to compounds (1), wherein QH is selected from among
Figure imgf000020_0001
QH-1a QH-1c QH-1e
Figure imgf000020_0002
QH-1f QH-1h QH-1i QH-1k
the ring systems QH shown may each optionally be substituted independently of one another at one or more hydrogen-carrying carbon atom(s) by Ra and/or Rb and
B, Ra and Rb are as hereinbefore defined.
In another aspect (H2) the invention relates to compounds (1) with the structural aspect Hl, wherein
B denotes =CRalRa2;
Ral is a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among Cβ-ioaryl and 5-12 membered heteroaryl; Ra2 is selected from among hydrogen, Ci_6alkyl, Ci-βhaloalkyl, C3_iocycloalkyl,
Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl and
Rb and Rc are as hereinbefore defined.
In another aspect (H3) the invention relates to compounds (1) with the structural aspect H2, wherein Ral is a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4- oxadiazolyl, 1,2,3,4-oxatriazolyl, 1,2,3,5-oxatriazolyl, 1,2,3-thiadiazolyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3,4-thiatriazolyl, 1,2,3,5- thiatriazolyl, tetrazolyl, indolyl, isoindolyl, azaindolyl, benzothienyl, benzofuryl, 4,5,6,7- tetrahydro-lH-indolyl, l,4,5,6-tetrahydro-cyclopenta[δ]pyrrolyl and l-benzopyran-4-on-yl, and
Rb and Rc are as hereinbefore defined.
In another aspect (Η4) the invention relates to compounds (1) with the structural aspect H3, wherein
Ral is a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among pyrrolyl, pyrazolyl and imidazolyl, and
Rb and Rc are as hereinbefore defined.
In another aspect (H5) the invention relates to compounds (1) with one of the structural aspects Hl to H4, wherein
Ra2 is hydrogen, methyl or ethyl.
In another aspect (H6) the invention relates to compounds (1) with one of the structural aspects Hl to H5, wherein
Ral is substituted by one or more, identical or different Rbl and/or Rcl;
each Rbl is a suitable substituent and is selected in each case independently of one another from among -ORC, -SRC, -NRCRC, halogen, -CN, -NO2, -C(O)RC, -C(O)ORC, -C(O)NRCRC, -OC(O)RC, -OC(O)ORC, -OC(O)NRCRC, -S(O)2RC, -S(O)2OR0, -S(O)2NRCRC, -NRgC(O)Rc, -NRgC(O)ORc, -NRgC(0)NRcRc, -NRgS(O)2Rc,
-NRgS(O)2ORc and -NRgS(O)2NRcRc and the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring systems; each Rcl independently denotes a group optionally substituted by one or more identical or different Rd and/or Re, selected from among Ci_6alkyl, 2-6 membered heteroalkyl, Ci-βhaloalkyl, Cs-iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, and
Rc, Rd, Re and Rg are as hereinbefore defined.
In another aspect (H7) the invention relates to compounds (1), wherein B denotes =CRalRa2 or =NRa3;
Ral and Ra3 are selected independently of one another from among -NHRc2 or
Figure imgf000022_0001
Ra2 is selected from among hydrogen, methyl and ethyl;
Rc2 is selected from among phenyl, pyridyl, pyrimidyl, piperidyl, cyclohexyl and benzyl, all the above-mentioned groups optionally being substituted by one or more identical or different Rd and/or Re and
Rd and Re are as hereinbefore defined.
In another aspect (H8) the invention relates to compounds (1), wherein
QH is selected from among
Figure imgf000022_0002
QH-2a QH-2a.1 QH-2e QH-2g
Figure imgf000022_0003
QH-2h QH-2i QH-2j QH-2k
the ring systems QH shown may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by Ra and/or Rb and
R8, Ra and Rb are as hereinbefore defined. In another aspect (H9) the invention relates to compounds (1), wherein
QH is selected from among
Figure imgf000023_0001
QH-2a QH-2a.1 QH-2e QH-2i
the ring systems QH shown may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by Ra and/or Rb and
R8, Ra and Rb are as hereinbefore defined.
In another aspect (HlO) the invention relates to compounds (1), wherein
QH is selected from among
Figure imgf000023_0002
QH-2a.1
the ring systems QH shown may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by Ra and/or Rb,
R8 denotes Rc and
Ra, Rb and Rc are as hereinbefore defined.
In another aspect (HIl) the invention relates to compounds (1), wherein
QH is selected from among
Figure imgf000024_0001
, while
R41 is selected from among hydrogen, halogen, methyl, ethyl, trifluoromethyl and methoxy,
R42 is selected from among hydrogen, Ra and Rb,
R43 denotes hydrogen or Ra,
R8 denotes Rc and
Ra, Rb and Rc are as hereinbefore defined.
In another aspect (H12) the invention relates to compounds (1), wherein
QH is selected from among
and
Figure imgf000024_0002
Figure imgf000024_0003
> while
R41 is selected from among hydrogen, halogen, methyl, ethyl, trifluoromethyl and methoxy,
R42 is selected from among hydrogen, Ra and Rb,
R43 denotes hydrogen or Ra,
R44 is selected from among Rd and Re,
q denotes 0, 1, 2 or 3 and Ra, Rb,Rd and Re are as hereinbefore defined.
In another aspect (H13) the invention relates to compounds (1), wherein QH is selected from among
Figure imgf000025_0001
R8 denotes a phenyl, optionally substituted by one or more, identical or different Rb and/or Rc, and
Rb and Rc are as hereinbefore defined.
In another aspect (H14) the invention relates to compounds (1), wherein QH is selected from among
Figure imgf000025_0002
QH-3a QH-3c QH-3e
the ring systems QH shown may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by Ra and/or Rb and
Ra and Rb are as hereinbefore defined.
In another aspect (H15) the invention relates to compounds (1), wherein QH is selected from among
Figure imgf000026_0001
R ,45 independently of one another denotes hydrogen or a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among C3_7Cycloalkyl, phenyl, 5-10 membered heteroaryl, particularly lH-benzimidazolyl, lH-indolyl, pyrrolyl, imidazolyl or pyrazolyl, and 3-10 membered heterocycloalkyl, and
Rb and Rc are as hereinbefore defined.
In another aspect (Η16) the invention relates to compounds (1), wherein QH is selected from among
Figure imgf000026_0002
QH-4a QH-4b QH-4c QH-4d QH-4e
the ring systems QH shown may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by Ra and/or Rb and
Ra and Rb are as hereinbefore defined.
In another aspect (H17) the invention relates to compounds (1), wherein QH is selected from among
Figure imgf000026_0003
R46 and R47 in each case independently of one another denote hydrogen or a group optionally substituted by one or more, identical or different Rb and/or Rc, selected from among C3_7Cycloalkyl, phenyl, 5-10 membered heteroaryl, particularly pyridyl, and 3-10 membered heterocycloalkyl,
R48 denotes Rc and
Rb and Rc are as hereinbefore defined.
In another aspect (H18) the invention relates to compounds (1), wherein
QH denotes
Figure imgf000027_0001
)r
R49 is selected from among Rd and Re, r denotes 0, 1, 2 or 3 and
Rd and Re are as hereinbefore defined.
In another aspect (H19) the invention relates to compounds (1), wherein QH is selected from among
Figure imgf000027_0002
QH-4a QH"4b QH-4c QH.4CJ
QH-4e
Figure imgf000027_0003
QH-5a QH-5b QH-6a the above mentioned ring systems QH may each optionally be substituted independently of one another at one or more hydrogen-carrying carbon atom(s) by Ra and/or Rb and
Ra and Rb are as hereinbefore defined.
In another aspect (H20) the invention relates to compounds (1) with the structural aspect Hl 9, wherein
QH may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by a substituent selected from among -NH2, -NH(Ci_6alkyl), -N(Ci_6alkyl)2, -Ci_6alkylene-OH, halogen, -C(O)OH, -C(O)NH2, -C(O)NH(Ci_6alkyl), -C(O)N(Ci_6alkyl)2, -Ci_6alkylene-NH2, heteroaryl, phenyl, -C(O)NH- Ci_6alkylene-O-Ci_6alkyl, -Ci_6alkylene-NH(Ci_6alkyl), -CN, -OCi_6alkyl,
-C(O)morpholinyl, -Ci_6alkylene-N(Ci_6alkyl)2, -C(O)piperazinyl, Ci_6alkyl, -CF3, -C(0)NH(C3-iocycloalkyl) and -OH.
In another aspect (H21) the invention relates to compounds (1), wherein
QH is selected from among
Figure imgf000028_0001
R ,50 is selected from among R and Re and Rd and Re are as hereinbefore defined.
All the above listed structural aspects D, E, F, G and H relating to different molecular parts of the compounds according to the invention (1) may be combined with one another in any desired permutation to form combinations DEFGH, resulting in preferred compounds (1). Each combination DEFGH represents and defines individual embodiments or generic partial quantities of compounds according to the invention. Each individual embodiment or partial quantity fixed by this combination is expressly included and forms part of the subject-matter of the invention.
In another aspect the invention relates to compounds selected from among 1-1 l-[(6-chloropyridin-3-yl)methyl]-N-{(2E)-3-[(3Z)-3-(lH-imidazol-5- ylmethylidene)-2-oxo-2,3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 ,2- dihy dropyridine-3 -carboxamide
1-2 l-[(6-chloropyridin-3-yl)methyl]-2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2- ylmethylidene)-2,3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} - 1 ,2-dihydropyridine-3- carboxamide;
1-3 l-[(6-chloropyridin-3-yl)methyl]-N-{(2E)-3-[(3Z)-3-{[4-(3-{[2-(dimethylamino)- ethyl] carbamoyl} phenyl)- lH-pyrrol-2-yl]methylidene} -2-oxo-2,3-dihydro- lH-indol-6- yl]prop-2-en- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3-carboxamide;
1-4 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-5 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(pyridin-4-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-6 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(pyridin-2-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide; 1-7 N-{(2E)-3-[(3Z)-3-(lH-imidazol-5-ylmethylidene)-2-oxo-2,3-dihydro-lH-indol-6- yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-8 N-{(2E)-3-[(3Z)-3-(lH-imidazol-5-ylmethylidene)-2-oxo-2,3-dihydro-lH-indol-6- yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-4-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-9 N-{(2E)-3-[(3Z)-3-(lH-imidazol-5-ylmethylidene)-2-oxo-2,3-dihydro-lH-indol-6- yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-2-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-10 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(pyrimidin-5-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-11 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(pyrimidin-4-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-12 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(pyrimidin-2-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide; 1-13 l-(cyclohexylmethyl)-2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2- ylmethylidene)-2,3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} - 1 ,2-dihydropyridine-3- carboxamide;
1-14 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1 ,2-dihydropyridine-3- carboxamide;
1-15 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(pyridazin-4-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-16 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(phenylamino)- 1 ,2-dihydropyridine-3-carboxamide; 1-17 l-[methyl(phenyl)amino]-2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2- ylmethylidene)-2,3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} - 1 ,2-dihydropyridine-3- carboxamide;
1-18 l-[(3,4-difluorophenyl)amino]-2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2- ylmethylidene)-2,3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} - 1 ,2-dihydropyridine-3- carboxamide;
1-19 l-[(3,4-difluorophenyl)(methyl)amino]-2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol- 2-ylmethylidene)-2,3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} - 1 ,2-dihydropyridine-3- carboxamide; 1-20 N- {(2£)-3-[(3Z)-3- {6-[(dimethylamino)methyl]-3,4-dihydroquinazolin-2(lH)-yli- den} -2-0X0-2, 3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2- dihy dropyridine-3 -carboxamide;
1-21 JV-[(2£)-3-{(3Z)-3-[({4- [(dimethylamino)methyl]phenyl} amino)(phenyl)methylidene]-2-oxo-2,3-dihydro- IH- indol-6-yl}prop-2-en- 1 -yl]-2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihy dropyridine-3 - carboxamide;
1-22 N- {(2£)-3-[(3Z)-3-(2- {4-[(dimethylamino)methyl]phenyl}hydrazinyliden)-2-oxo- 2, 3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} -2-oxo-l -(pyridin-3-ylmethyl)- 1 ,2-dihydropy- ridine-3-carboxamide;
1-23 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(quinoline-2(lH)-yliden)-2,3-dihydro-lH-indol-6- yl]prop-2-en- 1 -yl} - 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-24 N-{(2E)-3-[(3Z)-3-(lH-imidazol-5-ylmethylidene)-2-oxo-2,3-dihydro-lH-indol-6- yl]prop-2-en- 1 -yl} - 1 -[(6-methylpyridin-3-yl)methyl] -2-oxo- 1 ,2-dihy dropyridine-3 - carboxamide;
1-25 l-(cyclohexylmethyl)-N-{(2E)-3-[(3Z)-3-(lH-imidazol-5-ylmethylidene)-2-oxo- 2, 3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} -2-oxo-l ,2-dihydropyridine-3-carboxamide;
1-26 N-{(2E)-3-[(3Z)-3-(lH-imidazol-5-ylmethylidene)-2-oxo-2,3-dihydro-lH-indol-6- yl]prop-2-en- 1 -yl} - 1 -[(1 -methyl- lH-imidazol-5-yl)methyl]-2-oxo- 1 ,2-dihy dropyridine-3 - carboxamide;
1-27 N-{(2E)-3-[(3Z)-3-(lH-imidazol-5-ylmethylidene)-2-oxo-2,3-dihydro-lH-indol-6- yl]prop-2-en- 1 -yl} - 1 -[(1 -methyl- lH-imidazol-4-yl)methyl]-2-oxo- 1 ,2-dihy dropyridine-3 - carboxamide;
II-l 2-oxo- l-(pyridin-3-ylmethyl)-Λ/-[3-(lH-pyrrolo[2,3-b]pyridin-3-yl)benzyl]- 1,2- dihy dropyridine-3 -carboxamide;
II-2 2-oxo-N- {3-[2-(phenylamino)quinazolin-6-yl]prop-2-yn- 1 -yl} - 1 -(pyridin-3- ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
II-3 l-[(6-chloropyridin-3-yl)methyl]-2-oxo-N-[3-(lH-pyrrolo[2,3-b]pyridin-3- yl)benzyl]- 1 ,2-dihydropyridine-3-carboxamide;
II-4 1 -[(6-chloropyridin-3-yl)methyl]-2-oxo-Λ/- {3-[2-(phenylamino)quinazolin-6- yl]prop-2-yn- 1 -yl} - 1 ,2-dihydropyridine-3-carboxamide;
II-5 N- {3-[2-( {4-[(dimethylamino)methyl]phenyl} amino)quinazolin-6-yl]prop-2-yn- 1 - yl}-2-oxo-l-(pyridin-3-ylmethyl)-l,2-dihydropyridine-3-carboxamide;
II-6 N- {3-[2-( {4-[(dimethylamino)methyl]phenyl} amino)quinazolin-6-yl]prop-2-yn- 1 - yl}-2-oxo-l-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-l,2-dihydropyridine-3- carboxamide;
II-7 Λ/-{3-[2-({3-fluoro-4-[(l-methylpiperidin-4-yl)amino]phenyl}amino)quinazolin-6- yl]prop-2-yn- 1 -yl} -2-oxo- 1 - { [6-(trifluoromethyl)pyridin-3-yl]methyl} - 1 ,2-dihydropyri- dine-3 -carboxamide;
II-8 Λ/-{3-[2-({4-[methyl(l-methylpiperidin-4-yl)amino]phenyl}amino)quinazolin-6- yl]prop-2-yn- 1 -yl} -2-oxo- 1 - { [6-(trifluoromethyl)pyridin-3-yl]methyl} - 1 ,2-dihydropyri- dine-3 -carboxamide; II-9 Λ/-{3-[8-(3-aminopropoxy)-2-{[4-(morpholin-4-yl)phenyl]amino}quinazolin-6- yl]prop-2-yn- 1 -yl} -2-oxo- l-(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
II- 10 N- {3 - [8-(3-aminopropoxy)-2- { [4-(morpholin-4-yl)phenyl] amino } quinazo lin-6- yl]prop-2-yn- 1 -yl} - 1 -[(6-chlorpyridin-3-yl)methyl]-2-oxo- 1 ,2-dihydropyridine-3- carboxamide; H-Il N- {3-[2-( {4-[(dimethylamino)methyl]phenyl} amino)-5-fluoroquinazolin-6-yl]prop- 2-yn- 1 -yl} -2-oxo- l-(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
11-12 1 -[(6-chloropyridin-3-yl)methyl]-JV- {3-[2-( {4-[(dimethylamino)methyl]phenyl} - amino)-5-fluoroquinazolin-6-yl]prop-2-yn- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3- carboxamide; 11-13 N-{3-[5-methyl-2-{[4-(morpholin-4-yl)phenyl]amino}-7-oxo-8-(propane-2-yl)-7.8- dihydropyrido [2,3-ύT]pyrimidin-6-yl]prop-2-yn- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-di- hydropyridine-3-carboxamide;
11-14 l-[(6-chloropyridin-3-yl)methyl]-N-{3-[5-methyl-2-{[4-(morpholin-4-yl)phenyl]- amino} -7-oxo-8-(propane-2-yl)-7.8-dihydropyrido[2,3-(i]pyrimidin-6-yl]prop-2-yn-l-yl}- 2-oxo- 1 ,2-dihydropyridine-3-carboxamide;
II- 15 N- {3 - [2-( {4- [(dimethylamino)methyl]phenyl} amino)pyrido [3 ,4-<i]pyrimidin-6- yl]prop-2-yn- 1 -yl} -2-oxo- l-(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide; 11-16 1 -[(6-chloropyridin-3-yl)methyl]-JV- {3-[2-( {4-[(dimethylamino)methyl]phenyl} - amino)pyrido [3 ,4-<i]pyrimidin-6-yl]prop-2-yn- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
11-17 Λ/-{3-[2-({4-[(dimethylamino)methyl]phenyl}amino)pyrido[2,3-(i]pyrimidin-6- yl]prop-2-yn- 1 -yl} -2-oxo- l-(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide; 11-18 1 -[(6-chloropyridin-3-yl)methyl]-N- {3-[2-( {4-[(dimethylamino)methyl]phenyl} - amino)pyrido[2,3- J]pyrimidin-6-yl]prop-2-yn- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
IH-I 2-OXO-JV- {(2£)-3-[2-(phenylamino)quinazolin-6-yl]prop-2-en- 1 -yl} - 1 -(pyridin-3- ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide; III-2 l-[(6-chloropyridin-3-yl)methyl]-2-oxo-Λ/-{(2E)-3-[2-(phenylamino)quinazolin-6- yl]prop-2-en- 1 -yl} - 1 ,2-dihydropyridine-3-carboxamide;
III-3 N-[(2E)-3- {4-[5-amino-3-(phenylamino)- IH- 1 ,2,4-triazol- 1 -yl]-5-methoxypyrimi- din-2-yl}prop-2-en- 1 -yl]-2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3- carboxamide; III-4 N- {(2E)-3-[4-(5-amino-3- {[4-(4-methylpiperazin- 1 -yl)phenyl] amino} - IH- 1 ,2,4- triazol- 1 -yl)-5-methoxypyrimidin-2-yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2- dihy dropyridine-3 -carboxamide;
III-5 N-[(2E)-3- {4-[5-amino-3-(phenylamino)- IH- 1 ,2,4-triazol- 1 -yl]-5-methoxy-6-(pi- peridin-3-ylamino)pyrimidin-2-yl}prop-2-en- 1 -yl]-2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-di- hydropyridine-3-carboxamide;
III-6 N-( {5-[5-amino-3-( {4-[(dimethylamino)methyl]phenyl} amino)- IH- 1 ,2,4-triazol- 1 - yl]-lH-pyrrolo[3.2-δ]pyridin-2-yl}methyl)-2-oxo-l-(pyridin-3-ylmethyl)-l,2-dihydropyri- dine-3 -carboxamide; III-7 N-( {5-[5-amino-3-( {4-[(dimethylamino)methyl]phenyl} amino)- IH- 1 ,2,4-triazol- 1 - yl]- 1 -methyl- lH-pyrrolo[3.2-δ]pyridin-2-yl}methyl)-2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-di- hydropyridine-3-carboxamide;
III-8 N-(I- {6-[5-amino-3-( {4-[(dimethylamino)methyl]phenyl} amino)- IH- 1 ,2,4-triazol- 1 -yl]pyridin-2-yl} ethyl)-2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3- carboxamide;
III-9 N- {2-[6-(5-amino-3- {[4-(4-methylpiperazin- 1 -yl)phenyl] amino} - IH- 1 ,2,4-triazol- 1 -yl)pyridin-2-yl] ethyl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3- carboxamide; III-10 N-(I- {4-[5-amino-3-( {4-[(dimethylamino)methyl]phenyl} amino)- IH- 1 ,2,4-triazol- 1 -yl]pyrimidin-2-yl} ethyl)-2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3- carboxamide;
III-l 1 N- {2-[4-(5-amino-3- {[4-(4-methylpiperazin- 1 -yl)phenyl] amino} - IH- 1 ,2,4-triazol- 1 -yl)pyrimidin-2-yl]ethyl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3- carboxamide;
111-12 N- {(2E)-3-[2-( {4-[(dimethylamino)methyl]phenyl} amino)quinazolin-6-yl]prop-2- en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
111-13 1 -[(6-chloropyridin-3-yl)methyl]-JV- {(2E)-3-[2-( {4-[(dimethylamino)methyl]- phenyl}amino)quinazolin-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3-carboxamide; 111-14 Λ/-{(2E)-3-[2-({3-fluoro-4-[(l-methylpiperidin-4-yl)amino]phenyl}amino)quinazo- lin-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 - { [6-(trifluoromethyl)pyridin-3-yl]methyl} - 1 ,2-dihydro- pyridine-3-carboxamide;
111-15 N-{(2E)-3-[2-({4-[methyl(l-methylpiperidin-4-yl)amino]phenyl}amino)quinazolin- 6-yl]prop-2-en- 1 -yl} -2-oxo- 1 - { [6-(trifluoromethyl)pyridin-3-yl]methyl} - 1 ,2-dihydropyri- dine-3 -carboxamide;
111-16 N- {(2E)-3-[2-( {4-[(dimethylamino)methyl]phenyl} amino)quinazolin-6-yl]prop-2- en- 1 -yl} -2-oxo- 1 - {[6-(trifluoromethyl)pyridin-3-yl]methyl} - 1 ,2-dihydropyridine-3- carboxamide; III- 17 N- {(2E)-3 - [8-(3 -aminopropoxy)-2- { [4-(morpho lin-4-yl)phenyl]amino } quinazo lin- 6-yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
III- 18 N- {(2E)-3 - [8-(3 -aminopropoxy)-2- { [4-(morpho lin-4-yl)phenyl]amino } quinazo lin- 6-yl]prop-2-en- 1 -yl} - 1 -[(6-chlorpyridin-3-yl)methyl] -2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
111-19 N- {(2E)-3-[2-( {4-[(dimethylamino)methyl]phenyl} amino)-5-fluoroquinazolin-6- yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
111-20 1 -[(6-chloropyridin-3-yl)methyl]-N- {(2E)-3-[2-( {4-[(dimethylamino)methyl]- phenyl}amino)-5-fluoroquinazolin-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
111-21 N-{(2E)-3-[5-methyl-2-{[4-(morpholin-4-yl)phenyl]amino}-7-oxo-8-(propane-2- yl)-7.8-dihydropyrido[2,3-d]pyrimidin-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- l,2-dihydropyridine-3-carboxamide;
111-22 l-[(6-chloropyridin-3-yl)methyl]-N-{(2E)-3-[5-methyl-2-{[4-(morpholin-4-yl)- phenyl]amino}-7-oxo-8-(propane-2-yl)-7.8-dihydropyrido[2,3-J]pyrimidin-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3-carboxamide;
111-23 Λ/-{(2E)-3-[2-({4-[(dimethylamino)methyl]phenyl}amino)pyrido[3,4-(i]pyrimidin- 6-yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
111-24 1 -[(6-chloropyridin-3-yl)methyl]-N- {(2E)-3-[2-( {4-[(dimethylamino)methyl]- phenyl} amino)pyrido [3 ,4-<i]pyrimidin-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
111-25 N-{(2E)-3-[2-({4-[(dimethylamino)methyl]phenyl}amino)pyrido[2,3-ύf]pyrimidin- 6-yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
111-26 1 -[(6-chloropyridin-3-yl)methyl]-N- {(2E)-3-[2-( {4-[(dimethylamino)methyl]- phenyl} amino)pyrido[2,3- J]pyrimidin-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
111-27 2-oxo-l-(pyridin-3-ylmethyl)-N-{(2E)-3-[3-(lH-pyrrol-2-yl)-lH-indazol-6-yl]prop- 2-en- 1 -yl} - 1 ,2-dihydropyridine-3-carboxamide; 111-28 l-[(6-chloropyridin-3-yl)methyl]-2-oxo-N-{(2E)-3-[3-(lH-pyrrol-2-yl)-lH-indazol- 6-yl]prop-2-en- 1 -yl} - 1 ,2-dihydropyridine-3-carboxamide;
111-29 2-oxo-l-(pyridin-3-ylmethyl)-N-{3-[3-(lH-pyrrol-2-yl)-lH-indazol-6-yl]prop-2-yn- 1 -yl} - 1 ,2-dihydropyridine-3-carboxamide; 111-30 l-[(6-chloropyridin-3-yl)methyl]-2-oxo-N-{3-[3-(lH-pyrrol-2-yl)-lH-indazol-6- yl]prop-2-yn- 1 -yl} - 1 ,2-dihydropyridine-3-carboxamide;
111-31 N-[(2E)-3-(3- {4-[(dimethylamino)methyl]phenyl} - lH-indazol-6-yl)prop-2-en- 1 - yl]-2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
111-32 1 -[(6-chloropyridin-3-yl)methyl]-N-[(2E)-3-(3- {4-[(dimethylamino)methyl]- phenyl} - lH-indazol-6-yl)prop-2-en- 1 -yl]-2-oxo- 1 ,2-dihydropyridine-3-carboxamide;
111-33 N-[3-(3- {4-[(dimethylamino)methyl]phenyl} - lH-indazol-6-yl)prop-2-yn- 1 -yl]-2- oxo-l-(pyridin-3-ylmethyl)-l,2-dihydropyridine-3-carboxamide;
111-34 1 -[(6-chloropyridin-3-yl)methyl]-N-[3-(3- {4-[(dimethylamino)methyl]phenyl} - IH- indazol-6-yl)prop-2-yn- 1 -yl]-2-oxo- 1 ,2-dihydropyridine-3-carboxamide; 111-35 N- { 1 -[2-( {4-[(dimethylamino)methyl]phenyl} amino)quinazolin-6-yl]pyrrolidin-3- yl} -2-oxo- 1 -(pyridin-3 -ylmethyl)- 1 ,2-dihydropyridine-3 -carboxamide;
111-36 1 -[(6-chloropyridin-3-yl)methyl]-JV- { 1 -[2-( {4-[(dimethylamino)methyl]phenyl} - amino)quinazolin-6-yl]pyrrolidin-3-yl} -2-oxo- 1 ,2-dihydropyridine-3 -carboxamide;
IV-I N-{3-[3-(lH-indole-2-yl)-4.6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl]-3-oxopro- pyl} -2-oxo- l-(pyridin-3-ylmethyl)-l,2-dihydropyridine-3-carboxamide;
IV-2 l-[(6-chloropyridin-3-yl)methyl]-N-{3-[3-(lH-indol-2-yl)-4.6-dihydropyrrolo[3,4- c]pyrazol-5(lH)-yl]-3-oxopropyl} -2-oxo- l,2-dihydropyridine-3-carboxamide;
IV-3 N- {3-[3-( {[4-(4-methylpiperazin- 1 -yl)phenyl]carbonyl} amino)-4.6-dihydro- pyrrolo[3,4-c]pyrazol-5(lH)-yl]-3-oxopropyl}-2-oxo-l-(pyridin-3-ylmethyl)-l,2-dihydro- pyridine-3-carboxamide;
In another aspect the invention relates to compounds - or the pharmacologically acceptable salts thereof- of general formula (1) as pharmaceutical compositions. In another aspect the invention relates to compounds - or the pharmacologically acceptable salts thereof - of general formula (1) for the treatment and/or prevention of cancer, infections, inflammations and autoimmune diseases.
In another aspect the invention relates to compounds - or the pharmacologically acceptable salts thereof- of general formula (1) for the treatment and/or prevention of cancer.
In another aspect the invention relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (1) or the pharmacologically acceptable salts thereof, optionally in combination with conventional excipients and/or carriers.
In another aspect the invention relates to a pharmaceutical preparation comprising a compound of general formula (1), while the compounds (1) may optionally also be in the form of the tautomers, racemates, enantiomers, diastereomers, mixtures thereof or as the respective pharmacologically acceptable salts of all the above-mentioned forms, and at least one other cytostatic or cytotoxic active substance different from formula (1).
Definitions
As used herein, the following definitions apply, unless stated otherwise:
The use of the prefix Cx-y, where x and y in each case denote a natural number (x < y), indicates that the chain or cyclic structure or combination of chain and cyclic structure referred to and mentioned in direction connection may consist in total of a maximum of y and a minimum of x carbon atoms.
The information as to the number of members in groups containing one or more heteroatom(s) (heteroalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl) refers to the total atomic number of all the ring members or chain members or the total of all the ring and chain members. Alkyl is made up of the sub-groups saturated hydrocarbon chains and unsaturated hydrocarbon chains, while the latter may be further subdivided into hydrocarbon chains with a double bond (alkenyl) and hydrocarbon chains with a triple bond (alkynyl). Alkenyl contains at least one double bond, alkynyl at least one triple bond. If a hydrocarbon chain should have both at least one double bond and at least one triple bond, by definition it belongs to the alkynyl sub-group. All the above-mentioned sub-groups may be further subdivided into straight-chain (unbranched) and branched. If an alkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying carbon atoms. Examples of individual sub-groups are listed below.
Straight-chain (unbranched) or branched, saturated hydrocarbon chains: methyl; ethyl; /? -propyl; isopropyl (1-methylethyl); n-butyl; 1-methylpropyl; isobutyl (2-methylpropyl); sec. -butyl (1-methylpropyl); tert. -butyl (1.1-dimethylethyl); n-pentyl; 1- methylbutyl; 1-ethylpropyl; isopentyl (3-methylbutyl); neopentyl (2,2-dimethyl-propyl); n-hexyl; 2,3-dimethylbutyl; 2,2-dimethylbutyl; 3,3-dimethylbutyl; 2-methyl-pentyl; 3- methylpentyl; n-heptyl; 2-methylhexyl; 3-methylhexyl; 2,2-dimethylpentyl; 2,3- dimethylpentyl; 2,4-dimethylpentyl; 3,3-dimethylpentyl; 2,2,3-trimethylbutyl; 3-ethylpentyl; n-octyl; n-nonyl; n-decyl etc.
straight-chained (unbranched) or branched alkenyl: vinyl (ethenyl); prop-1-enyl; allyl (prop-2-enyl); isopropenyl; but-1-enyl; but-2-enyl; but- 3-enyl; 2-methyl-prop-2-enyl; 2-methyl-prop-l-enyl; l-methyl-prop-2-enyl; 1 -methyl- prop- 1-enyl; 1-methylidenepropyl; pent- 1-enyl; pent-2-enyl; pent-3-enyl; pent-4-enyl; 3- methyl-but-3-enyl; 3-methyl-but-2-enyl; 3 -methyl-but- 1-enyl; hex- 1-enyl; hex-2-enyl; hex- 3-enyl; hex-4-enyl; hex-5-enyl; 2,3-dimethyl-but-3-enyl; 2,3-dimethyl-but-2-enyl; 2- methylidene-3-methylbutyl; 2,3-dimethyl-but- 1-enyl; hexa-l,3-dienyl; hexa-l,4-dienyl; penta-l,4-dienyl; penta-l,3-dienyl; buta-l,3-dienyl; 2,3-dimethylbuta-l,3-diene etc. straight-chain (unbranched) or branched alkynyl: ethynyl; prop-1-ynyl; prop-2-ynyl; but-1-ynyl; but-2-ynyl; but-3-ynyl; l-methyl-prop-2- ynyl etc. By the terms propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl etc. unless otherwise stated are meant saturated hydrocarbon groups with the corresponding number of carbon atoms, including all the isomeric forms.
By the terms propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl etc. unless otherwise stated are meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and a double bond, including all the isomeric forms, also [Z)I[E)- isomers, where applicable.
By the terms butadienyl, pentadienyl, hexadienyl, heptadienyl, octadienyl, nonadienyl, decadienyl etc. unless otherwise stated are meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and two double bonds, including all the isomeric forms, also (Z)/(E)-isomers, where applicable.
By the terms propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl etc. unless otherwise stated are meant unsaturated hydrocarbon groups with the corresponding number of carbon atoms and a triple bond, including all the isomeric forms.
From alkyl as hereinbefore defined and its subgroups the term alkylene can also be derived. Alkylene unlike alkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from an alkyl. Corresponding groups are for example -CH3 and -CH2, -CH2CH3 and -CH2CH2 or >CHCH3 etc. For all the subgroups of alkyl there are correspondences for alkylene.
By heteroatoms are meant oxygen, nitrogen and sulphur atoms.
By the term heteroalkyl are meant groups which are derived from the alkyl as hereinbefore defined in its widest sense by replacing, in the hydrocarbon chains, one or more of the groups -CH3 independently of one another by the groups -OH, -SH or -NH2, one or more of the groups -CH2- independently of one another by the groups -O-, -S- or -NH- , one or more of the groups >CH- by the group >N, one or more of the groups =CH- by the group =N, one or more of the groups =CH2 by the group =NH or one or more of the groups ≡CH by the group ≡N, while a total of not more than three heteroatoms may be present in one heteroalkyl, there must be at least one carbon atom between two oxygen atoms and between two sulphur atoms or between one oxygen and one sulphur atom and the group as a whole must have chemical stability.
A direct result of the indirect definition/derivation from alkyl is that heteroalkyl is made up of the sub-groups saturated hydrocarbon chains with heteroatom(s), heteroalkenyl and heteroalkynyl, and it may be further subdivided into straight-chain (unbranched) and branched. If a heteroalkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying oxygen, sulphur, nitrogen and/or carbon atoms. Heteroalkyl itself as a substituent may be attached to the molecule both through a carbon atom and through a heteroatom.
The following are listed by way of example: dimethylamino methyl; dimethylaminoethyl (1- dimethylaminoethyl; 2-dimethyl- aminoethyl); dimethylaminopropyl (1-dimethylaminopropyl, 2-dimethylaminopropyl, 3-dimethylaminopropyl); diethylamino methyl; diethylaminoethyl (1-diethylaminoethyl, 2- diethylaminoethyl); diethylaminopropyl (1-diethylaminopropyl, 2- diethylamino -propyl, 3- diethylaminopropyl); diisopropylamino ethyl (1-diisopropylaminoethyl, 2-di- isopropylaminoethyl); bis-2-methoxyethylamino; [2-(dimethylamino-ethyl)-ethyl-amino]- methyl; 3-[2-(dimethylamino-ethyl)-ethyl-amino]-propyl; hydroxymethyl; 2-hydroxy- ethyl; 3-hydroxypropyl; methoxy; ethoxy; propoxy; methoxymethyl; 2-methoxyethyl etc.
From heteroalkyl as hereinbefore defined and its subgroups the term heteroalkylene can also be derived. Heteroalkylene unlike heteroalkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a heteroalkyl. Corresponding groups are for example -CH2NH2 and -CH2NH or >CHNH2, - NHCH3 and >NCH3 or -NHCH2, -CH2OCH3 and -CH2OCH2 or >CHOCH3 etc. For all the subgroups of heteroalkyl there are correspondences for heteroalkylene.
Haloalkyl is derived from alkyl as hereinbefore defined in its broadest sense, by replacing one or more hydrogen atoms of the hydrocarbon chain independently of one another by halogen atoms, which may be identical or different. A direct result of the indirect definition/derivation from alkyl is that haloalkyl is made up of the sub-groups saturated hydrohalogen chains, haloalkenyl and haloalkynyl, and it may be further subdivided into straight-chain (unbranched) and branched. If a haloalkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying carbon atoms. Typical examples are listed below:
-CF3; -CHF2; -CH2F; -CF2CF3; -CHFCF3; -CH2CF3; -CF2CH3; -CHFCH3; -CF2CF2CF3; -CF2CH2CH3; -CF=CF2; -CCl=CH2; -CBr=CH2; -CI=CH2; -C=C-CF3; -CHFCH2CH3; -CHFCH2CF3 etc.
From haloalkyl as hereinbefore defined and its subgroups the term haloalkylene can also be derived. Haloalkylene unlike haloalkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a haloalkyl. Corresponding groups are for example -CH2F and -CHF, -CHFCH2F and -CHFCHF or >CFCH2F etc. For all the subgroups of haloalkyl there are correspondences for haloalkylene.
Halogen encompasses fluorine, chlorine, bromine and/or iodine atoms.
Cycloalkyl is made up of the sub-groups monocyclic hydrocarbon rings, bicyclic hydrocarbon rings and spirohydrocarbon rings, while each sub-group may be further subdivided into saturated and unsaturated (cycloalkenyl). By unsaturated is meant that there is at least one double bond in the ring system, but no aromatic system is formed. In bicyclic hydrocarbon rings two rings are linked such that they share at least two carbon atoms. In spirohydrocarbon rings one carbon atom (spiroatom) is shared by two rings. If a cycloalkyl is substituted, it may be mono- or polysubstituted independently of one another at all the hydrogen-carrying carbon atoms. Cycloalkyl itself as a substituent may be attached to the molecule through any suitable position of the ring system. The following individual sub-groups are listed by way of example: monocyclic hydrocarbon rings, saturated: cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl; cycloheptyl etc. monocyclic hydrocarbon rings, unsaturated:
cycloprop-1-enyl; cycloprop-2-enyl; cyclobut-1-enyl; cyclobut-2-enyl; cyclopent-1-enyl; cyclopent-2-enyl; cyclopent-3-enyl; cyclohex-1-enyl; cyclohex-2-enyl; cyclohex-3-enyl; cyclohept-1-enyl; cyclohept-2-enyl; cyclohept-3-enyl; cyclohept-4-enyl; cyclobuta-1,3- dienyl; cyclopenta-l,4-dienyl; cyclopenta-l,3-dienyl; cyclopenta-2,4-dienyl; cyclohexa- 1,3-dienyl; cyclohexa-l,5-dienyl; cyclohexa-2,4-dienyl; cyclohexa-l,4-dienyl; cyclohexa- 2,5-dienyl etc.
bicyclic hydrocarbon rings (saturated and unsaturated): bicyclo[2.2.0]hexyl; bicyclo[3.2.0]heptyl; bicyclo[3.2.1]octyl; bicyclo[2.2.2]octyl; bicyclo[4.3.0]nonyl (octahydroindenyl); bicyclo[4.4.0]decyl (decahydronaphthalene); bicyclo[2.2.1]heptyl (norbornyl); (bicyclo[2.2.1]hepta-2,5-dienyl (norborna-2,5-dienyl); bicyclo[2.2.1]hept-2-enyl (norbornenyl); bicyclo[4.1.0]heptyl (norcaranyl); bicyclo- [3.1.1]heptyl (pinanyl) etc.
spirohydrocarbon rings (saturated and unsaturated): spiro[2.5]octyl, spiro[3.3]heptyl, spiro[4.5]dec-2-ene, etc.
If the free valency of a cycloalkyl is saturated off, an alicyclic ring is obtained.
From cycloalkyl as hereinbefore defined and its subgroups the term cycloalkylene can also be derived. Cycloalkylene unlike cycloalkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a
cycloalkyl. Corresponding groups are for example cyclohexyl and or
Figure imgf000042_0001
or , cyclopentenyl and or or or
etc. For all the subgroups of cycloalkyl there are correspondences for cycloalkylene.
Cycloalkylalkyl refers to the combination of the alkyl in question, as hereinbefore defined, with cycloalkyl, both in their widest sense. Alternatively cycloalkylalkyl may also be regarded as a combination of cycloalkyl with alkylene. Formally, cycloalkylalkyl is obtained by first linking an alkyl as substituent directly with the molecule and then substituting with a cycloalkyl. The linking of alkyl and cycloalkyl may be carried out in both groups using carbon atoms that are suitable for this purpose. The respective subgroups of alkyl (alkylene) and cycloalkyl are also included in the combination of the two groups.
Aryl denotes mono-, bi- or tricyclic carbon rings with at least one aromatic ring. If an aryl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon atoms, independently of one another. Aryl itself may be linked to the molecule as substituent via any suitable position of the ring system.
Typical examples are listed below: phenyl, naphthyl, indanyl (2,3-dihydroindenyl), 1,2,3,4-tetrahydronaphthyl; fluorenyl, etc. If the free valency of an aryl is saturated off, an aromatic group is obtained.
From aryl as hereinbefore defined the term arylene can also be derived. Arylene unlike aryl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from an aryl. Corresponding groups are for
example phenyl and
Figure imgf000043_0001
or or , naphthyl and
or or etc. For all the subgroups of aryl there are correspondences for arylene. Arylalkyl denotes the combination of the groups alkyl and aryl as hereinbefore defined, in each case in their broadest sense. Alternatively arylalkyl may also be regarded as a combination of aryl with alkylene. Formally, arylalkyl is obtained by first linking an alkyl as substituent directly to the molecule and substituting it with an aryl group. The alkyl and aryl may be linked in both groups via any carbon atoms suitable for this purpose. The respective sub-groups of alkyl (alkylene) and aryl are also included in the combination of the two groups.
Typical examples are listed below: benzyl; 1-phenylethyl; 2-phenylethyl; phenylvinyl; phenylallyl etc. Heteroaryl denotes monocyclic aromatic rings or poly cyclic rings with at least one aromatic ring, which, compared with corresponding aryl or cycloalkyl, contain instead of one or more carbon atoms one or more identical or different heteroatoms, selected independently of one another from among nitrogen, sulphur and oxygen, while the resulting group must be chemically stable. The prerequisite for the presence of heteroaryl is a heteroatom and an aromatic system, although it need not necessarily be a heteroaromatic system. Thus 2,3-dihydro-lH-indol-6-yl
Figure imgf000044_0001
may according to the definition be a heteroaryl.
If a heteroaryl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon and/or nitrogen atoms, independently of one another. Heteroaryl itself as substituent may be linked to the molecule via any suitable position of the ring system, both carbon and nitrogen. Typical examples are listed below. monocyclic heteroaryls: furyl; thienyl; pyrrolyl; oxazolyl; thiazolyl; isoxazolyl; isothiazolyl; pyrazolyl; imidazolyl; triazolyl; tetrazolyl; oxadiazolyl; thiadiazolyl; pyridyl; pyrimidyl; pyridazinyl; pyrazinyl; triazinyl; pyridyl-JV-oxide; pyrrolyl-JV-oxide; pyrimidinyl-JV-oxide; pyridazinyl-JV-oxide; pyrazinyl-JV-oxide; imidazolyl-iV-oxide; isoxazolyl-iV-oxide; oxazolyl-iV-oxide; thiazolyl- iV-oxide; oxadiazolyl-iV-oxide; thiadiazolyl-iV-oxide; triazolyl-iV-oxide; tetrazolyl-iV-oxide etc.
polvcvclic heteroaryls indolyl; isoindolyl; benzofuryl; benzothienyl; benzoxazolyl; benzothiazolyl; benz- isoxazolyl; dihydroindolyl; benzisothiazolyl; benzimidazolyl; indazolyl; isoquinolinyl; quinolinyl; quinoxalinyl; cinnolinyl; phthalazinyl; quinazolinyl; benzotriazinyl; indoli- zinyl; oxazolopyridyl; imidazopyridyl; naphthyridinyl; indolinyl; isochromanyl; chromanyl; tetrahydroisoquinolinyl; isoindolinyl; isobenzotetrahydrofuryl; isobenzotetra- hydrothienyl; isobenzothienyl; benzoxazolyl; pyridopyridyl; benzotetrahydrofuryl; benzotetrahydro-thienyl; purinyl; benzodioxolyl; phenoxazinyl; phenothiazinyl; pteridinyl; benzothiazolyl; imidazopyridyl; imidazothiazolyl; dihydrobenzisoxazinyl; benzisoxazinyl; benzoxazinyl; dihydrobenzisothiazinyl; benzopyranyl; benzothiopyranyl; coumarinyl; isocoumarinyl; chromonyl; chromanonyl; tetrahydroquinolinyl; dihydroquinolinyl; dihydroquinolinonyl; dihydroisoquinolinonyl; dihydrocoumarinyl; dihydroisocoumarinyl; isoindolinonyl; benzodioxanyl; benzoxazolinonyl; quinolinyl-JV-oxide; indolyl-iV-oxide; indolinyl- JV-oxide; isoquinolyl-iV-oxide; quinazolinyl-N-oxide; quinoxalinyl-N-oxide; phthalazinyl-N-oxide; indolizinyl-JV-oxide; indazolyl-N-oxide; benzothiazolyl-N-oxide; benzimidazolyl-N-oxide; benzothiopyranyl-^-oxide and benzothiopyranyl-^, 5*-dioxide etc. If the free valency of a heteroaryl is saturated off, a heteroaromatic group is obtained.
From heteroaryl as hereinbefore defined the term heteroarylene can also be derived. Heteroarylene unlike heteroaryl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a heteroaryl.
Corresponding groups are for example pyrrolyl and
Figure imgf000045_0001
or or
Figure imgf000045_0003
or 2,3-dihydro-lH-indolyl and
Figure imgf000045_0002
Figure imgf000046_0001
For all the subgroups of heteroaryl there are correspondences for heteroarylene.
Heteroarylalkyl denotes the combination of the alkyl in question as hereinbefore defined with heteroaryl, both in their broadest sense. Alternatively heteroarylalkyl may also be regarded as a combination of heteroaryl with alkylene. Formally heteroarylalkyl is obtained by first linking an alkyl as substituent directly with the molecule and then substituting it with a heteroaryl. The linking of the alkyl and heteroaryl may be achieved on the alkyl side via any carbon atoms suitable for this purpose and on the heteroaryl side via any carbon or nitrogen atoms suitable for this purpose. The respective sub-groups of alkyl (alkylene) and heteroaryl are also included in the combination of the two groups.
By the term heterocycloalkyl are meant groups which are derived from the cycloalkyl as hereinbefore defined if in the hydrocarbon rings one or more of the groups -CH2- are replaced independently of one another by the groups -O, -S or -NH or one or more of the groups =CH- are replaced by the group =N-, while not more than five heteroatoms may be present in total, there must be at least one carbon atom between two oxygen atoms and between two sulphur atoms or between one oxygen and one sulphur atom and the group as a whole must be chemically stable. Heteroatoms may simultaneously be present in all the possible oxidation stages (sulphur -> sulphoxide -SO-, sulphone -SO2-; nitrogen -> N- oxide). It is immediately apparent from the indirect definition/derivation from cycloalkyl that heterocycloalkyl is made up of the sub-groups monocyclic hetero-rings, bicyclic hetero-rings and spirohetero-rings, while each sub-group can also be further subdivided into saturated and unsaturated (heterocycloalkenyl). The term unsaturated means that in the ring system in question there is at least one double bond, but no aromatic system is formed. In bicyclic hetero-rings two rings are linked such that they have at least two atoms in common. In spirohetero-rings one carbon atom (spiroatom) is shared by two rings. If a heterocycloalkyl is substituted, the substitution may be mono- or polysubstitution in each case, at all the hydrogen-carrying carbon and/or nitrogen atoms, independently of one another. Heterocycloalkyl itself as substituent may be linked to the molecule via any suitable position of the ring system.
Typical examples of individual sub-groups are listed below. monocyclic heterorings (saturated and unsaturated) : tetrahydrofuryl; pyrrolidinyl; pyrrolinyl; imidazolidinyl; thiazolidinyl; imidazolinyl; pyrazolidinyl; pyrazolinyl; piperidinyl; piperazinyl; oxiranyl; aziridinyl; azetidinyl; 1,4- dioxanyl; azepanyl; diazepanyl; morpholinyl; thiomorpholinyl; homomorpholinyl; homopiperidinyl; homopiperazinyl; homothiomorpholinyl; thiomorpholinyl-iS'-oxide; thiomorpholinyl-^^-dioxide; 1,3-dioxolanyl; tetrahydropyranyl; tetrahydrothiopyranyl; [l,4]-oxazepanyl; tetrahydrothienyl; homothiomorpholinyl-^^-dioxide; oxazolidinonyl; dihydropyrazolyl; dihydropyrrolyl; dihydropyrazinyl; dihydropyridyl; dihydro- pyrimidinyl; dihydrofuryl; dihydropyranyl; tetrahydrothienyl-iS'-oxide; tetrahydrothienyl- S, S-dioxide; ho mo thiomorpholinyl-iS'-oxide; 2,3-dihydroazet; 2H-pyrrolyl; 4H-pyranyl; 1 ,4-dihydropyridinyl etc.
bicvclic heterorings (saturated and unsaturated):
8-azabicyclo[3.2.1]octyl; 8-azabicyclo[5.1.0]octyl; 2-oxa-5-azabicyclo[2.2.1]heptyl; 8-oxa-3-aza-bicyclo[3.2.1]octyl; 3,8-diaza-bicyclo[3.2.1]octyl; 2,5-diaza-bicyclo- [2.2.1]heptyl; l-aza-bicyclo[2.2.2]octyl; 3,8-diaza-bicyclo[3.2.1]octyl; 3,9-diaza- bicyclo[4.2.1]nonyl; 2,6-diaza-bicyclo[3.2.2]nonyl etc.
spiro -heterorings (saturated and unsaturated): l,4-dioxa-spiro[4.5]decyl; l-oxa-3.8-diaza-spiro[4.5]decyl; and 2,6-diaza-spiro[3.3]heptyl; 2,7-diaza-spiro[4.4]nonyl; 2,6-diaza-spiro[3.4]octyl; 3,9-diaza-spiro[5.5]undecyl; 2,8- diaza-spiro[4.5]decyl etc.
If the free valency of a heterocycloalkyl is saturated off, then a heterocyclic ring is obtained.
From heterocycloalkyl as hereinbefore defined the term heterocycloalkylene can also be derived. Heterocycloalkylene unlike heterocycloalkyl is bivalent and requires two bonding partners. Formally the second valency is produced by removing a hydrogen atom from a heterocycloalkyl. Corresponding groups are for example piperidinyl and
Figure imgf000048_0001
or or , 2,3-dihydro-lH-pyrrolyl and or
Figure imgf000048_0002
etc. For all the subgroups of heterocycloalkyl there are correspondences for heterocycloalkylene.
Heterocycloalkylalkyl denotes the combination of the alkyl in question as hereinbefore defined with heterocycloalkyl, both in their broadest sense. Alternatively heterocycloalkylalkyl may also be regarded as a combination of heterocycloalkyl with alkylene. Formally heterocycloalkyl is obtained by first linking an alkyl as substituent directly with the molecule and then substituting it with a heterocycloalkyl. The linking of the alkyl and heterocycloalkyl may be achieved on the alkyl side via any carbon atoms suitable for this purpose and on the heterocycloalkyl side via any carbon or nitrogen atoms suitable for this purpose. The respective sub-groups of alkyl and heterocycloalkyl are also included in the combination of the two groups.
By is substituted is meant that a hydrogen atom that is bound directly to the atom under consideration is replaced by another atom or another group of atoms (substituent). Depending on the starting conditions (number of hydrogen atoms) mono- or polysubstitution may take place at an atom.
Bivalent substituents such as for example =S, =NR, =NOR, =NNRR, =NN(R)C(O)NRR, =N2 or the like may only be substituents at carbon atoms, while the bivalent substituent =0 may also be a substituent of sulphur. Generally speaking, substitution by a bivalent substituent may only take place at ring systems and requires exchange for two geminal hydrogen atoms, i.e. hydrogen atoms that are bound to the same carbon atom saturated before the substitution. Substitution by a bivalent substituent is therefore only possible at the group -CH2- or sulphur atoms of a ring system.
In addition to this, the term "suitable substituent" denotes a substituent which on the one hand is suitable on account of its valency and on the other hand leads to a system with chemical stability.
The following are some abbreviated notations and their structural correspondences:
CH< or >CH- ->
=C< or >C=
N=>
-N= or =N- -ϊ
"N
>N- or -N< ^
If for example in the sequence the member B were to correspond to the structural detail -N=, this is to be understood as both A-N C an(j A-N=c .
If for example in the sequence Bγ D c the member A were to correspond to the structural detail >C=
Bγc Bγc Bγc this is to be understood as being D , D or D
In a diagram such as for example
Figure imgf000049_0001
the dotted line indicates that the ring system may be attached to the molecule via the carbon 1 or 2, i.e. is equivalent to the following diagram
Figure imgf000050_0001
Figure imgf000050_0002
Groups or substituents are frequently selected from among alternative groups/ substituents with a corresponding group designation (e.g. Ra, Rb etc). If a group of this kind is used repeatedly to define a compound according to the invention in different parts of the molecule, it should always be borne in mind that the respective uses are to be regarded as being totally independent of one another.
List of abbreviations
Figure imgf000050_0003
Figure imgf000051_0001
Figure imgf000052_0001
Features and advantages of the present invention will become apparent from the following detailed Examples, which illustrate the fundamentals of the invention by way of example, without restricting its scope:
Preparation of the compounds according to the invention
General
Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon). Microwave reactions are carried out in an initiator made by Biotage or in an Explorer made by CEM in sealed containers (preferably 2, 5 or 20 mL), preferably with stirring.
Chromatography The thin layer chromatography is carried out on ready-made TLC silica gel 60 plates on glass (with fluorescence indicator F-254) made by Merck.
The preparative high pressure chromatography (HPLC) is carried out using columns made by Waters (named: Sunfire C 18, 5 μm, 30 x 100 mm Part.No. 186002572; X-Bridge C 18, 5 μm, 30 x 100 mm Part.No. 186002982), the analytical HPLC (reaction control) using columns made by Agilent (named: Zorbax Extend C18, 3.5 μm, 2.1 x 50 mm, Part.No. 735700-902; Zorbax SB-C8, 3.5 μm, 2.1 x 50 mm, Part.No. 871700-906) and Phenomenex (named: Mercury Gemini C 18, 3 μm, 2 x 20 mm, Part.No. 00M-4439-B0-CE).
HPLC mass spectroscopy/UV spectrometry
The retention times/MS-ESI+ for characterising the examples are obtained using an HPLC- MS apparatus (high performance liquid chromatography with mass detector) made by Agilent. Compounds that elute at the injection peak have the retention time tRet. = 0.00.
HPLC-methods
Preparative prep. HPLCl: HPLC: 333 and 334 Pumps column: Waters X-Bridge C 18, 5 μm, 30 x 100 mm Part.No. 186002982 eluant: A: 10 mM NH4HCO3 in H2O; B: acetonitrile (HPLC grade) detection: UV/Vis-155 flow: 50 mL/min gradient: 0.00 min: 5 % B
3.00 - 15.00 min: variable (see individual methods) 15.00 - 17.00 min: 100 % B prep. HPLC2:
HPLC: 333 and 334 Pumps column: Waters Sunfire C 18, 5 μm, 30 x 100 mm Part.No. 186002572 eluant: A: H2O + 0.2 % HCOOH; B: acetonitrile (HPLC grade) + 0.2 % HCOOH detection: UV/Vis-155 flow: 50 mL/min gradient: 0.00 min: 5 % B
3.00 - 15.00 min: variable (see individual methods) 15.00 - 17.00 min: 100 % B analytical
LCMSBASl:
HPLC: Agilent 1100 Series
MS: Agilent LC/MSD SL column: Phenomenex Mercury Gemini C 18, 3 μm, 2 x 20 mm, Part.No. 00M-
4439-BO-CE eluant: A: 5 mM NH4HCO3/20 mM NH3 in H2O; B: acetonitrile (HPLC grade) detection: MS: Positive and negative mode mass range: 120 - 700 m/z flow: 1.00 mL/min column temp.: 400C gradient: 0.00 min: 5 % B
0.00 - 2.50 min: 5 % -> 95 % B
2.50 - 2.80 min: 95 % B
2.81 - 3.10 min: 95 % -> 5 % B
FECBS:
HPLC: Agilent 1100 Series MS: Agilent LC/MSD SL column: WatersXBridgeC182.1x50mm, 3.5μ eluant: A: 5 mM NH4HCO3/20 mM NH3 in H2O; B: acetonitrile (HPLC grade) detection: MS: Positive and negative mode mass range: 105 - 1200 m/z flow: 1.20 mL/min column temp.: 350C gradient: 0.01 min: 5 % B
0.01 - 1.25 min: 5 % -> 95 % B
1.25 - 2.00 min: 95 % B
2.00 - 2.01 min: 95 % -> 5 % B
FECB4/FECBM2:
HPLC: Agilent 1100 Series
MS: Agilent LC/MSD SL column: Agilent Zorbax Extend C 18, 3.5 μm, 2.1 x 50 mm, Part.No. 735700-902 eluant: A: 5 mM NH4HCO3/20 mM NH3 in H2O; B: acetonitrile (HPLC grade) detection: MS: Positive and negative mode mass range: 105 - 1200 m/z flow: 1.20 mL/min column temp.: 350C gradient: 0.01 min: 5 % B
0.01 - 1.25 min: 5 % -> 95 % B
1.25 - 2.00 min: 95 % B
2.00 - 2.01 min: 95 % -> 5 % B
FECS:
HPLC: Agilent 1100 Series
MS: Agilent LC/MSD SL column: Agilent Zorbax Zorbax SB-C8, 3.5 μm, 2.1 x 50 mm, Part.No. 871700-
906 eluant: A: H2O + 0.2 % HCOOH; B: acetonitrile (HPLC grade) + 0.2 %
HCOOH detection: MS: Positive and negative mode mass range: 105 - 1200 m/z flow: 1.20 mL/min column temp.: 350C gradient: 0.01 min: 5 % B
0.01 - 1.25 min: 5 % -> 95 % B
1.25 - 2.00 min: 95 % B
2.00 - 2.01 min: 95 % -> 5 % B
FSUN, FECSUNFIRE, FECSl:
HPLC: Agilent 1100 Series
MS: Agilent LC/MSD SL column: Waters Sunfϊre, 2.1 x 50 mm, 3.5 μm eluant: A: H2O + 0.2 % HCOOH; B: acetonitrile (HPLC grade) + 0.2 %
HCOOH detection: MS: Positive and negative mode mass range: 105 - 1200 m/z flow: 1.20 mL/min column temp.: 350C gradient: 0.01 min: 5 % B
0.01 - 1.50 min: 5 % -> 100 % B
1.50 - 2.00 min: 100 % B
2.00 - 2.01 min: 100 % -> 5 % B
FECB5:
HPLC: Agilent 1100 Series
MS: Agilent LC/MSD SL column: WatersXBridge Cl 8 2.1 x 50mm, 5.0 μm eluant: A: 5 mM NH4HCO3/20 mM NH3 in H2O; B: acetonitrile (HPLC grade) detection: MS: Positive and negative mode mass range: 105 - 1200 m/z flow: 1.20 mL/min column temp.: 350C gradient: 0.01 min: 5 % B
0.01 - 1.25 min: 5 % -> 95 % B
1.25 - 2.00 min: 95 % B
2.00 - 2.01 min: 95 % -> 5 % B
AFEC:
HPLC: Agilent 1100 Series
MS: Agilent LC/MSD column: Waters Sunfire, 21 x 50 mm, 3.5 μm eluant: A: H2O + 1 % HCOOH; B: acetonitrile (HPLC grade) detection: MS: Positive and negative mode; UV: 254 as well as 210 nm mass range: 100 - 750 m/z flow: 1.00 mL/min (0.9 mL H2O/MeCN, 0.I mL formic acid buffer) column temp.: 350C gradient: 0.1 min: 5 % B
0.1 - 1.50 min:5 % -> 100 % B 1.50 - 2.10 min: 100 % B 2.10 - 2.20 min: 100 % -> 5 % B 2.20 - 2.70 min: 5 % B
FEC3:
HPLC : Agilent 1 100 Series
MS: Agilent LC/MSD SL column: Agilent Zorbax SBC8, 2.1 x 50 mm, 3.5μm eluant: A: H2O + 0.2 % HCOOH; B: acetonitrile (HPLC grade) + 0.2 % HCOOH detection: MS: Positive and negative mode mass range: 105 - 1200 m/z flow: 1.20 mL/min column temp.: 35°C gradient: 0.01 min: 5 % B
0.01 - 1.50 min: 5 % -> 100 % B
1.50 - 2.00 min: 100 % B
2.00 - 2.01 min: 100 % -> 5 % B
The compounds according to the invention are prepared by the methods of synthesis described hereinafter, in which the substituents of the general formulae have the meanings given hereinbefore. These methods are intended as an illustration of the invention, without restricting its subject matter and the scope of the compounds claimed to these examples. Where the preparation of starting compounds is not described, they are commercially obtainable or may be prepared analogously to known compounds or methods described herein. Substances described in the literature are prepared according to the published methods of synthesis.
Reaction scheme A-I
Figure imgf000058_0001
A key intermediate in the synthesis of compounds (1) according to the invention are the pyridinonecarboxylic acids A.l. Starting from compounds A.1, compounds (1) are obtained directly by amide coupling with amines A.2, while A.1 is activated by coupling reagents such as for example DCC, DIC, TBTU, HATU, EDC or the like. Carrying out this reaction requires aminic synthesis components A.2 which contain both the linker unit L and the grouping QH.
Alternatively under the same coupling conditions, synthesis components A.2 may also be coupled, by means of which first of all a precursor QH* of the final grouping QH is introduced. The intermediate Cl obtained is then reacted in later steps to obtain compounds (1) (cf. Reaction scheme C).
In Reaction scheme A-I and the following schemes the term QH(A) is used as an abbreviation for these two alternatives, QH and QH*.
Reaction scheme A-2
Figure imgf000059_0001
A.5
EWG = electron-attracting group, e.g. halogen, triflate, mesylate, but also -OH or a leaving group -X in an (activated) carboxyl group -C(O)OH/-C(O)X [e.g. where L3 = -C(O)-]
EDG = electron-repelling group, e.g.. -B(OH)2/-B(OR')2, -MgHaI, -ZnHaI, SnFT3 or hydrogen PG = protecting group
The synthesis of the components A.2/A.2* proceeds via the incorporation of the ring system QH(A) into the amines A.3 or A.5 provided with protective groups, while QH(A) is introduced in the form of the activated species A.4/A.4* or A.6/A.6* (Reaction scheme A-2). These are simple reactions of substitution between nucleophils or electrophils activated by electron-attracting and -pushing groups, or transition metal-catalysed cross- coupling reactions, e.g. the BUCHWALD-HARTWIG, SUZUKI, KUMADA, STILLE, NEGISHI, HECK or SONOGASHIRA reaction. The activating groups EWG and EDG suitable for these reactions are generally known in the art. Electron-pulling groups EWG are particularly halogen, triflate, mesylate, but also -OH or a leaving group -X in an (activated) carboxyl group -C(O)OHAC(O)X [e.g. at L3 = -C(O)-]. Electron-pushing groups EDG are, in particular, boric acid and boric acid ester derivatives -B(OH)2Z-B(ORZ)2, -MgHaI, -ZnHaI and -SnR'3, but this term may also include hydrogen. Suitable groups R' are known to the skilled man. The activating groups act as leaving groups in all the types of reaction mentioned above. After the reaction of A.3 with A.4/A.4* or A.5 with A.6/A.6* the product obtained still contains the protective group PG (intermediate product A.2-PG or A.2*-PG), which is cleaved in order to obtain A.2/A.2*. Any of the amino protecting groups common in organic synthesis may be used as the protective group PG.
Optionally a component A.2* may also be converted into a component A.2, the final grouping QH being formed from the grouping QH*.
Reaction scheme A-3
Figure imgf000060_0001
(1) C.1
EWG = electron-attracting group, e.g. halogen, thflate, mesylate, but also -OH or a leaving group -X in an (activated) carboxyl group -C(O)OH/-C(O)X [e.g. where L3 = -C(O)-]
EDG = electron-repelling group, e.g.. -B(OH)2/-B(OR')2, -MgHaI, -ZnHaI, SnR' 3 or hydrogen
Alternatively, compounds (1) according to the invention may also be synthesised stepwise (Reaction scheme A-3). To do this, first of all an amine A.7 or A.8, which in each case contains only the linker unit L, is coupled to the carboxylic acid A.1 (-> A.9 or A.10) and only then is the grouping QH introduced via the components A.4 or A.6. The linking of the linker unit L and the grouping QH are carried out from a chemical-method point of view analogously to that described under Reaction scheme A-2. The amide coupling in the first reaction step is assisted by coupling reagents such as for example DCC, DIC, TBTU, HATU, EDC or the like.
Here too, alternatively, as in Reaction scheme A-I and A-2, instead of A.4 and A.6 and consequently A.2, a comparable component A.4 and A.6 may be used, which introduces only one precursor QH* of the final grouping QH (intermediate stages Cl, cf . Reaction scheme C).
The synthesis components to be used in the foregoing reaction schemes are optionally provided with the customary protective groups when used. Therefore, additional intermediate steps may be needed to remove these protective groups.
The compounds (1) which may be obtained directly or stepwise according to the foregoing reaction schemes may optionally be modified by associated synthesis steps (e.g. Substitutions, acylations etc.) to obtain further compounds according to the invention (1).
With regard to the feasibility of the reaction methods described and illustrated in the foregoing reaction schemes reference is made to WO 2008/005457. In the cited specification, pyridinonecarboxylic acids 2s are amidated in various ways. The methods and variants used therein for synthesising the example compounds 1-196 correspond substantially to those shown in reaction schemes A-I, A-2 and A-3, while the synthesis of intermediates that are comparable with the components A.2 to A.10 is disclosed in particular.
Reaction scheme A-4
PG- N.LL LL R-
A.11
A.1 PG = protecting group
, QHOj
Figure imgf000062_0001
Figure imgf000062_0002
(1) or C.1
In a departure from the cases shown in reaction schemes A-I to A-3 the incorporation of the grouping QH or a corresponding precursor QH* may also be carried out by amide coupling, esterification, carbamate or urea formation (Reaction scheme A-4). This is possible if the linker fragment L3 in the target compounds (1) is selected from among -C(O)O-, -C(O)NR8-, -OS(O)2-, -OS(O)2NR8-, -OC(O)-, -OC(O)O-, -OC(O)NR8-, -S(O)2O-, -S(O)2NR8-, -NR8C(O)-, -NR8C(O)O-, -NR8C(O)NR8-, -NR8S(O)2-, -NR8S(O)2O- and -NR8S(O)2NR8-. In these cases, one of the groups R* or R** of the components A.11, A.12/ A.12 or A.13 is an optionally activated carbon, sulphone, sulphur or carbonic acid function, while an alcohol or amine, is present as the other group in each case. A urea or carbamate unit for L3 may also be synthesised by reacting an isocyanate A.11/A.14 or A.12/A.12 (R or R = -N=C=O) with an alcohol/ amine A.12/A.12 or A.11/A.14.
Reaction scheme B
Figure imgf000063_0001
A.1
The method of synthesising pyridinonecarboxylic acids A.1 depends on the bridge unit W that joins together the ring systems Qa and Qb:
Starting from the esters B.I the grouping Qa-CR1R2- may be incorporated by nucleophilic substitution at component B.2, which is activated by an electron-attracting leaving group LG, e.g. a halogen, triflate or mesylate. B.I is optionally deprotonated for this purpose by the addition of a base.
The synthesis of a pyridinone ring system is carried out starting from malonic acid diester derivatives B.3. The derivatives used are di- or trielectrophils, which cyclise during the reaction with amines, hydroxylamines or hydrazines B.4. It is not absolutely essential for a leaving group LG to be present in compounds B.3. Instead of an electrophilic carbon activated by a leaving group, an electrophilic carbonylcarbon is also possible.
Using the synthesis methods described above, and starting from the cyclic carboxylic acid esters B.I or their precursor B.3, after reaction with B.2 or B.4 carboxylic acid esters A.1 are obtained first of all. These are saponified in each case to form the free acid A.1. In the grouping -COOR" it is possible to have groups R" which enable this saponification to take place easily and gently. These include in particular methyl, ethyl, tert-butyl and benzyl esters, while others are known to the skilled man from his general knowledge of the art.
The educts B.I and B.3 needed are commercially obtainable, have already been described in the literature or may be prepared according to published methods.
Reaction scheme C
Figure imgf000064_0001
(1)
EWG = electron-attracting group, e.g. halogen, thflate, mesylate, but also -OH or a leaving group -X in an (activated) carboxyl group -C(O)OH/-C(O)X [e.g. where L3 = -C(O)-]
EDG = electron-repelling group, e.g.. -B(OH)2/-B(OR')2, -MgHaI, -ZnHaI, SnR' 3 or hydrogen
The syntheses via the intermediates Cl described hereinbefore, wherein compounds (1) according to the invention are finally obtained in one or more steps by converting QH* into QH (e.g. by reaction with compounds C.2; reaction scheme C), are used mainly for the following embodiments of QH
Figure imgf000065_0001
QH-1a QH-1b QH-1c QH-1d QH-1e
Figure imgf000065_0002
QH-If QH-1g QH-1h Qn-1 i QH-Ij QH-Ik
wherein B denotes =CR9R10 or =NRπ and the dotted line indicates the cyclic atom(s) through which the ring system QH may be attached to the linker group L. The ring systems QH-la to QH-lk shown may each optionally be substituted independently of one another at one or more hydrogen-carrying carbon atom(s) by Ra and/or Rb.
Typical embodiments of B in the compounds (1) according to the invention are shown below on the basis of QH-la.
Figure imgf000065_0003
QH-1a.1 QH-1a.2 QH-1a.3
Figure imgf000065_0004
QH-1a.4 QH-1a.5 QH-1a.6 In addition, within the scope of the definitions for =CR9R10 or =NRπ many more embodiments are possible, and in particular, unlike QH-la.l to QH-la.6, in grouping B other ring systems may occur or these ring systems may also be mono- or polysubstituted within the scope of the definitions. Corresponding embodiments are also possible starting from QH-lb to QH-lk (QH-lb.l to QH-lb.6, QH-lc.l to QH-lc6 etc.). Embodiments QH-la to QH-lk or more especially QH-la.l to QH-la.6 for example can be synthesised via the following key intermediates QH*-la.l to QH*-la.3 (prepared on the basis of QH-la, also analogously for QH-lb to QH-lk)
Figure imgf000066_0001
QH*-1a.1 QH*-1a.2 QH*-1a.3
The use of these intermediates for synthesising the embodiments QH-la.l to QH-la.6 or for synthesising a plurality of embodiments analogous to QH-la.l to QH-la.6, the synthesis of reactants C.2 and the preparation of the intermediates themselves are described in detail in the literature.
■ QH-la.l or analogous embodiment: WO 96/40116, WO 98/07695, WO 98/50356, WO 00/35908, US 2005/0090541,
WO 2008/005457
■ QH-la.2, QH-la.3 or analogous embodiment: WO 99/15500, WO 00/56710
■ QH-la.4 or analogous embodiment: WO 02/094809, WO 03/053330, WO 03/082853, WO 2005/061519
■ QH-la.5 or analogous embodiment: WO 2005/087726, WO 2008/152013
■ QH-la.6 or analogous embodiment: In order to be able to incorporate ring systems QH or QH*, which are derived from the above-mentioned QH-la to QH-lk, in the target structures according to reaction schemes A-I to A-4 and reaction scheme C, the corresponding reactants
A.2 (R4-NH-L-QH) or A.2* (R4-NH-L-QH*), A.4 (EWG-QH) or A.4* (EWG-QH*), A.6 (EDG-QH) or A.6* (EDG-QH*) and
A.12 (R**-QH) or A.12* (R**-QH*) may be used, while the activating substituents EWG and EDG or the linker fragment R** are located at QH/QH* in such a way that their position corresponds to the later linkage point to the linker unit L. Numerous examples of the synthesis of such components can also be found in the literature referred to hereinbefore and additionally in EP 0 436 333. Other components of this kind are also directly commercially obtainable.
In addition to the embodiments QH-la to QH-lk there is also the possibility of incorporating further ring systems QH via the reactants A.2/ A.2*, A.4/ A.4*, A.6/ A.6* or A.12/ A.12* in compounds (1) according to the invention. These include in particular the following systems QH:
Figure imgf000067_0001
QH-2a QH-2a.1 QH-2b QH-2b.1 QH-2c QH-2c1
Figure imgf000067_0002
QH-2d QH-2d.1 QH-2e QH-2f QH-2g QH-2h
Figure imgf000067_0003
Figure imgf000068_0001
QH-3a QH-3b QH-3c QH-3d QH-3e
Figure imgf000068_0002
QH-4a QH-4b QH-4c QH-4d QH-4e
Figure imgf000068_0003
QH-5a QH-5b QH-6a QH-6b QH-6c QH-6d
Figure imgf000068_0004
-7a QH-7b QH-7c QH-7d -8a -8b
Figure imgf000068_0005
QH-9a QH-9b QH-9c QH-9d
Figure imgf000068_0006
QH-10a QH-10b QH-10c QH-10d QH-10e
Figure imgf000068_0007
QH-11a QH-11b QH-12a QH-12b
Figure imgf000068_0008
The above-mentioned ring systems QH may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by Ra and/or Rb, while R8, B, Ra and Rb are as hereinbefore defined.
The synthesis of corresponding reactants that are suitable for such incorporation is described in the literature or may be carried out analogously to published methods:
■ QH-2a, QH-2b, QH-2c, QH-2d: WO 2007/117607, WO 2008/079988
■ QH-2e, QH-2f: J. Med. Chem. 2000, 4606; J. Med. Chem. 2005, 2371
■ QH-3a, QH-3b, QH-3c, QH-3d, QH-3e: WO 01/53268, WO 03/035065, WO 03/024969, WO 2008/005457
■ QH-4a, QH-4b, QH-4c, QH-4d, QH-4e: WO 2008/005457
QH-5a, QH-5b: WO 2008/005457
QH-6a, QH-6b, QH-6c, QH-6d: WO 2008/005457
QH-7a, QH-7b, QH-7c, QH-7d: WO 2008/107444
QH-9a, QH-9b, QH-9c, QH-9d: WO 03/057695
■ QH-10a, QH-10b: WO 2006/134318, WO 2007/077435
QH-10c, QH-10d, QH-10e: WO 2007/099171, WO 2006/108488, WO 2007/068619, WO 2004/013144; J. Med. Chem. 2006, 7247
QH-lla, QH-llb: WO 2008/005457
QH-12a, QH-12b: WO 2008/003766
■ QH-13: WO 2004/087707 ■ QH-15: WO 2004/046120, WO 2006/050249
Typical embodiments of the linker unit L which may be incorporated or synthesised according to methods described in reaction schemes A-I to A-4 and reaction scheme C are as follows (the notation in each case being such that the bond to the amide nitrogen -NR4- is shown on the left and the bond to the ring system QH is shown on the right):
Figure imgf000070_0001
L-1 L-2 L-2a L-2b L-2c
Figure imgf000070_0002
L-2d L-2e L-2f L-2g L-2h
Figure imgf000070_0003
L-2i L-2j L-2k
Figure imgf000070_0004
L-3 L-3a L-3b L-3c L-3d
Figure imgf000070_0005
L-3e L-3f L-3g L-3h L-3i
Figure imgf000071_0001
L-3j L-3k L-31 L-3m L-3n
Figure imgf000071_0002
L-3t L-4 L-5 L-5a L-5b
Figure imgf000071_0003
L-5c L-6 L-7 L-8
Figure imgf000071_0004
(-NR4-)
L-9 L-10 L-11 L-12 L-13
Figure imgf000071_0005
L-14 L-15 L-16 L-16a L-16b
Figure imgf000072_0001
L-16c L-16d L-16e L-16f L-16g
Figure imgf000072_0002
L-16h L-16i L-17 L-18 L-19
Figure imgf000072_0003
L-22a L-22b
Figure imgf000072_0004
L-22c L-22d L-22e L-22f L-22g
Figure imgf000072_0005
L-22h L-22i L-22j L-23 L-24
Figure imgf000072_0006
L-25 L-26 L-27 L-28 L-28a
Figure imgf000073_0001
L-28b L-28C L-28d L-29 L-29a
Figure imgf000073_0002
°Me
L-29b L-29C L-29d L-29e L-29f
Figure imgf000073_0003
L-29g L-29h L-29i L-29J L-29k
Figure imgf000073_0004
L-291 L-29m L-29n L-29o L-29p
Figure imgf000073_0005
L-29q L-29r L-29S L-29t L-29u
Figure imgf000073_0006
L-30 L-31 L-31 a L-32 L-33
Figure imgf000074_0001
L-34 L-35 L-35a L-36 L-36a
Figure imgf000074_0002
L-37 L-37a L-37b L-37c L-37d
Figure imgf000074_0003
L-37e L-37f L-37g L-38 L-39
Figure imgf000074_0004
L-40 L-41 L-42 L -42a L-43
Figure imgf000074_0005
L-44 L-45 L-46 L-47 L-47a
Figure imgf000074_0006
L-48 L-49 L-50 L-51 L-52
Figure imgf000074_0007
L-53 L-54 L-55 L-56
Other typical linkers L in compounds according to the invention (1) are selected from among L-I, L-2, L-2a, L-2b, L-2c, L-2d, L-2e, L-2f, L-2g, L-2h, L-2i, L-2j, L-2k, L-3, L-3a, L-3b, L-3c, L-3d, L-3e, L-3f, L-3g, L-3h, L-3i, L-3j, L-3k, L-31, L-3m, L-3n, L- 3o, L-3p, L-3q, L-3r, L-3s, L-3t, L-4, L-5, L-5a, L-5b, L-5c, L-6, L-7, L-8, L-9, L-IO, L-Il, L-12, L-13, L-14, L-15, L-16, L-16a, L-16b, L-16c, L-16d, L-16e; L-16f, L-16g, L-16h, L-16i, L-17, L-18, L-19, L-20, L-21, L-22, L-22a, L-22b, L-22c, L-22d, L-22e, L-22f, L-22g, L-22h, L-22i, L-22J, L-23, L-24, L-25, L-26, L-27, L-28, L-28a, L-28b, L- 28c, L-28d, L-29, L-29a, L-29b, L-29c, L-29d, L-29e, L-29f, L-29g, L-29h, L-29i, L- 29j, L-29k, L-291, L-29m, L-29n, L-29o, L-29p, L-29q, L-29r, L-29s, L-29t, L-29u, L- 30, L-31, L-31a, L-32, L-33, L-34, L-35, L-35a, L-36, L-36a, L-37, L-37a, L-37b, L- 37c, L-37d, L-37e, L-37f, L-37g, L-38, L-39, L-40, L-41, L-42, L-42a, L-43, L-44, L-45, L-46, L-47, L-47a, 1-53, L-54, L-55 and L-56.
a) Synthesis of free cyclic carboxylic acids A.1
Method for svnthesising A. Ia
Figure imgf000075_0001
Amine B.4a (200 mg, 1.0 mmol) is taken up in 1.6 mL 2-butanol and combined with the malonic acid diester derivative B.3a (142 mg, 1.0 mmol), which is taken up in 0.4 mL 2- butanol, at 5°C. The mixture is stirred for 1 h at 200C, diluted with another 5 mL 2-butanol and refluxed for 48 h with stirring. Then the reaction solution is combined with 0.5 mL 2 N aqueous sodium hydroxide solution and 0.5 mL 2 N methanolic sodium hydroxide solution and stirred for 2 h at 200C. The reaction mixture is acidified with 1 N aqueous hydrochloric acid and extracted with DCM. The organic phase is dried, the solvent is eliminated in vacuo and A.la (MS(M+H)+ = 265/267; method FECS)is obtained.
The following carboxylic acids A.1 may also be synthesised from B.3a and the corresponding amines B.4 analogously to the synthesis of A. Ia:
Figure imgf000076_0001
A.1c A.1d A.1e A.1f
Method for svnthesising A. Ib
Figure imgf000076_0002
Sodium hydride (60 %; 28.6 mg, 0.714 mmol) is suspended in 1.5 mL DMF, combined with carboxylic acid ester B.la (99.4 mg, 0.649 mmol) and stirred for 45 min at 200C. Benzyl bromide B.2a (112 mg, 0.649 mmol) is metered into the suspension and it is stirred for a further 3 h at 200C. The reaction mixture is combined with 1 N hydrochloric acid and DCM, the organic phase is separated off and extracted 2 x with 1 N hydrochloric acid. Then the organic phase is dried, the solvent is eliminated in vacuo and carboxylic acid ester A.l*b (MS(M+H)+ = 245) is obtained.
Intermediate product A.l*b is taken up in methanol and combined with 1 N sodium hydroxide solution. After 16 h at 200C the mixture is diluted with water and extracted with DCM. The organic phase is discarded, the aqueous phase is acidified and extracted with DCM. The organic phase is dried, the solvent is eliminated in vacuo and the free carboxylic acid A.lb (MS(M+H)+ = 231; method FECS) is obtained. b) Synthesis of activated components EWG-QH A.4 or EWG-QH* A.4*
Method for synthesising A.4b
Figure imgf000077_0001
A.4*a A.4b
2,6-Dibromoquinazoline A.4*a (200 mg, 0.697 mmol) and aniline (97 mg, 1.045 mmol) are taken up in 1 rnL dioxane and combined with dioxanic HCl (174 μL, 4 mmol/mL). The reaction mixture is stirred for 16 h at 1000C, the solvent is eliminated in vacuo, the residue is purified by RP chromatography (method prep. HPLCl; 10 % acetonitrile to 60 % in 10 min) and A.4b (MS(M+H)+ = 300/302; method FECB3) is obtained.
Analogously to A.4b, A.4c may also be prepared from A.4*a and 4-dimethylaminomethyl- phenylamine. Generally speaking, structurally diverse anilines may be reacted with A.4*a in this way.
Figure imgf000077_0002
A.4c Method for svnthesising A.4d-PG and A.4f-PG
Figure imgf000078_0001
A.4d A.4d-PG A.4*e-PG A.4f-PG
4-chloro-7H-pyrrolo[2,3-ύT]pyrimidine A.4d (5.00 g, 32.56 mmol) is taken up in 150 rnL
TΗF and within 5 min combined with potassium-te/t-butoxide (4.60 g, 41.07 mmol). This mixture is cooled to 100C and within 10 min benzenesulphonyl chloride (5.40 mL,
42.31 mmol) is added thereto. The cooling is removed and the mixture is stirred at 200C.
After 3 h 10 mL water are added and the mixture is stirred for a further 10 min. Then the solvent is eliminated in vacuo, the residue is taken up in ethyl acetate and aqueous sodium chloride solution and extracted. The organic phase is dried, the solvent is eliminated in vacuo and A.4d-PG (MS(M+Η)+ = 294/296; method FECB3) is obtained.
A.4d-PG (2.50 g, 8.51 mmol) is taken up in 80 mL THF and cooled to -78°C under an argon atmosphere. LDA dissolved in cyclohexane (8.5 mL, 12.75 mmol) is added to this mixture within 15 min. After being stirred for 1 h at -78°C the mixture is combined with iodine (2.38 g, 9.36 mmol), which is dissolved in 20 mL THF, and stirred for a further hour at -78°C. The reaction mixture is combined with 10 mL of a 1 N hydrochloric acid solution and stirred for 1 h at 200C. Then the solvent is removed, the residue is purified by RP-chromatography (method prep. HPLC2; 20 % acetonitrile to 95 % in 12 min) and A.4*e-PG (HPLC-MS: tRet. = 2.07 min, MS(M+H)+ = 420/422; method FECSUNFIRE) is obtained. A.4*e-PG (300 mg, 0.715 mmol), phenylboric acid (90 mg, 0.738 mmol), caesium carbonate (348 μL, 1.72 mmol; 70 % aqueous solution) and Pd-DPPF (60 mg, 0.074 mmol) are taken up in 1.2 mL THF and stirred for 16 h at 200C. The solvent is removed, the residue is purified by RP-chromatography (method prep. HPLC2; 30 % acetonitrile to 95 % in 12 min) and A.4f-PG (HPLC-MS: tRet. = 2.04 min, MS(M+H)+ = 370/372; method FEC3) is obtained. Method for svnthesising A.4g-PG and A.4h
Figure imgf000079_0001
A.4h
A.4g-PG
A.4g-PG or A.4h is prepared according to WO 2007/117607:
2-amino-3-methoxybenzoic acid (20.0 g, 119.64 mmol) is suspended in chloroform, cooled to 00C and combined with bromine (6.48 mL, 126.56 mmol), which is dissolved in 100 mL chloroform. After the addition the reaction mixture is heated to 200C and stirred for 16 h at this temperature. The precipitate is filtered off, dried and 2-amino-5-bromo-3- methoxybenzoic acid (HPLC-MS: tRet. = 1.76 min, MS(M+H)+ = 246/248; method FECS) is obtained.
2-amino-5-bromo-3-methoxybenzoic acid (20.0 g, 81.30 mmol) is suspended in 250 mL THF, cooled to 00C and combined with borane-THF complex (315 mL, 0.315 mol). The reaction mixture is stirred for 5 d at 200C and then combined with 10 mL EtOH, stirred for 15 min and then stirred into 250 mL water. The mixture is extracted 3x with DCM, the combined organic phases are dried and the solvent is eliminated in vacuo. The crude product is suspended in DCM and extracted 2x with 400 mL 1 N hydrochloric acid. The combined aqueous phases are adjusted to pH 5-6 with potassium carbonate, the precipitate formed is filtered off and (2-amino-5-bromo-3-methoxy-phenyl)-methanol (HPLC-MS: tRet. = 1.41 min, MS(M+H)+ = 232/234; method FEC3) is obtained.
(2-amino-5-bromo-3-methoxy-phenyl)-methanol (10.1 g, 43.53 mmol) is taken up in 70 mL chloroform, combined with manganese dioxide (5.99 g, 68.94 mmol) and stirred for 16 h at 200C. The solids are filtered off, the solvent is eliminated in vacuo and 2-amino-5- bromo-3-methoxybenzaldehyde ((HPLC-MS: tRet. = 1.91 min MS(M+H)+ = 230/232; method FSUN) is obtained.
2-amino-5-bromo-3-methoxybenzaldehyde (2.5 g, 10.87 mmol) is homogeneously mixed with urea and the mixture is heated to 1800C. The melt formed is kept at this temperature for 1 h. Then the reaction mixture is mixed with water, the precipitate formed is filtered off, dried and 6-bromo-8-methoxy-lH-quinazolin-2-one (ΗPLC-MS: tRet. = 1.53 min MS(M+Η)+ = 255/257; method FSUN) is obtained.
6-bromo-8-methoxy-lH-quinazolin-2-one (2.62 g, 10.27 mmol) is suspended in 30 mL POCI3 and refluxed for 30 min. The reaction mixture is stirred into water, while the temperature never exceeds 15°C. The aqueous phase is extracted with DCM, the organic phase is dried and 6-bromo-2-chloro-8-methoxy-quinazoline (ΗPLC-MS: tRet. = 1-88 min, MS(M+Η)+ = 273/275/277; method FSUN) is obtained.
6-bromo-2-chloro-8-methoxy-quinazoline (1.24 g, 4.52 mmol) is taken up in 7 mL DCM, combined with boron tribromide (12.95 mL, 12.95 mmol) and stirred for 2 d at 200C. Then the mixture is diluted with ice water, the precipitate formed is filtered off, dried and 6-bromo-2-chloro-quinazolin-8-ol (HPLC-MS: tRet. = 1.77 min; method FSUN) is obtained.
Triphenylphosphine (577 mg, 2.20 mmol), di-tert-butylazodicarboxylate (506 mg, 2.20 mmol) and tert-butyl 4-hydroxy-piperidine-l-carboxylate (1.32 g, 6.62 mmol) are taken up in 6 mL THF, stirred for 15 min at 200C and then combined with 6-bromo-2- chloro-quinazolin-8-ol (1.16 g, 4.45 mmol). After stirring for 24 h at 200C the mixture is diluted with MeOH, the solvent is eliminated in vacuo, the crude product is purified by RP-chromatography (method prep. HPLCl; 20 % acetonitrile to 90 % in 6 min) and tert- butyl 4-(6-bromo-2-chloro-quinazolin-8-yloxy)-piperidine-l-carboxylate (HPLC-MS: tRet. = 1.99 min; method FECB5) is obtained.
Aniline (2.00 niL, 21.48 mmol), Hϋnig base (142 μL, 0.88 mmol) and tert-butyl 4-(6- bromo-2-chloro-quinazolin-8-yloxy)-piperidine-l-carboxylate (195 mg, 0.44 mmol) are stirred for 4 d at 800C. Then the mixture is combined with 1 N hydrochloric acid and extracted with DCM. The organic phase is dried and A.4g-PG (HPLC-MS: tRet. = 2.13 min MS(M+H)+ = 499/501; method FECB5) is obtained.
Method for svnthesising A.4i
Figure imgf000081_0001
A.4i
6-bromo-2-chloro-5-fluoro-quinazoline is prepared analogously to WO 2007/117607 or to the above-mentioned synthesis of 6-bromo-2-chloro-8-methoxy-quinazoline starting from 2-amino-5-bromo-6-fluoro-benzonitrile.
4-dimethylaminomethyl-phenylamine dihydrochloride (435 mg, 1.95 mmol), and 6-bromo- 2-chloro-5-fluoro-quinazoline (400 mg, 1.53 mmol) are taken up in 2.5 mL NMP, combined with 4 N dioxanic hydrochloric acid (1 mL, 4 mmol) and stirred for 24 h at 1000C. The solvent is eliminated in vacuo, the crude product is purified by RP- chromatography (method prep. HPLC2; 10 % acetonitrile to 80 % in 6 min) and A.4i (HPLC-MS: tRet. = 1.44 min; MS(M+H)+ = 375/377; method FECSl) is obtained. Method for svnthesising A.4j
Figure imgf000082_0001
A.4j
A.4j (HPLC-MS: tRet. = 1.92 min; MS(M+H)+ = 331/333; method FECSl) is prepared analogously to J. Med. Chem. 2000, 43, 4606 or J. Med. Chem. 2005, 2371.
Method for svnthesising A.4k
Figure imgf000082_0002
NBS AIBN mCPBA
Figure imgf000082_0003
A.4k
l-(2,4-dichloro-pyrimidin-5-yl)-ethanone (10 g, 0.052 mol), sodium hydrogen carbonate (19.35 g, 0.058 mol) and isopropylamine (5 mL, 0.058 mol) are taken up in 35 mL THF and 200 mL cyclohexane and stirred for 2 h at 200C. The reaction solution is filtered through silica gel, the solvent is eliminated in vacuo and l-(2-chloro-4-isopropylamino- pyrimidin-5-yl)-ethanone (HPLC-MS: tRet. = 1.73 min, MS(M+H)+ = 214/216; method FECB3) is obtained. l-(2-chloro-4-isopropylamino-pyrimidin-5-yl)-ethanone (11.1 g, 0.052 mol) and sodium thiomethoxide (5.75 g, 0.078 mol) are taken up in 100 mL dioxane and stirred for 16 h at 200C. The solvent is eliminated in vacuo, the residue is taken up in ethyl acetate and extracted 2x with water. The organic phase is dried, the solvent is eliminated in vacuo and l-(4-isopropylamino-2-methylsulphanyl-pyrimidin-5-yl)-ethanone (HPLC-MS: tRet. = 1.82 min, MS(M+H)+ = 226; method FECB3) is obtained.
Sodium hydride (16.75 g, 0.042 mol) is placed in 200 mL dioxane and combined with triethylphosphonoacetate (83.8 mL, 0.419 mmol), so that the temperature does not exceed 5°C. After the addition is complete, the mixture is heated to 200C and l-(4- isopropylamino-2-methylsulphanyl-pyrimidin-5-yl)-ethanone (11.1 g, 0.049 mol) dissolved in 100 mL dioxane is added thereto. The mixture is stirred for 16 h at 900C, then combined with 10 % sodium chloride solution and extracted with ethyl acetate. The organic phase is dried, the solvent is eliminated in vacuo and the crude product is purified by normal phase chromatography (cyclohexane/ethyl acetate 90:10 -> 50:50 in 45 min; flow 200 mL/min) and 8-isopropyl-5-methyl-2-methylsulphanyl-8H-pyrido[2,3- J]pyrimidin-7-one (HPLC-MS: tRet. = 1.74 min; MS(M+H)+ = 250; method FECSl) is obtained.
8-Isopropyl-5-methyl-2-methylsulphanyl-8/f-pyrido[2,3-ύT]pyrimidin-7-one (4.88 g,
0.02 mol), NBS (6.97 g, 0.039 mol) and AIBN (250 mg, 1.524 mmol) are taken up in 30 mL DMF and stirred for 3 h at 200C. Then the solvent is eliminated in vacuo, the residue is taken up in ethyl acetate and extracted with sodium thio sulphate solution and water. The organic phase is dried, the solvent is eliminated in vacuo and the residue is taken up in 300 mL DCM and combined with meto-chloroperbenzoic acid (7.68 g, 0.045 mol). After the mixture has been stirred for 2 h at 200C it is extracted with sodium thiosulphate solution and sodium hydrogen carbonate solution, dried, the solvent is eliminated in vacuo and 6-bromo-8-isopropyl-2-methanesulphonyl-5-methyl-8H- pyrido[2,3-<i]pyrimidin-7-one (HPLC-MS: tRet. = 1.62 min, MS(M+H)+ = 362; method FECB3) is obtained.
6-bromo-8-isopropyl-2-methanesulphonyl-5-methyl-8H-pyrido[2,3-(i]pyrimidin-7-one is reacted with 4-morpholin-4-yl-phenylamine under the same reaction conditions as described previously in the synthesis of A.4i and A.4k (HPLC-MS: tRet. = 2.15 min; MS(M+H)+ = 459; method LCMSBASl) is obtained.
Method for svnthesising A.41
Figure imgf000084_0001
A.4I
A.41 is prepared as described in WO 2008/008821.
Method for svnthesising A.4m
Figure imgf000084_0002
RT, 2 d
Figure imgf000084_0003
A.4m
2,6-dichloro-3-nitro-pyridine (2.5 g, 12.9 mmol) is taken up in a solvent mixture of THF and NMP (5:1, 13 mL), combined with two spatula tips of silicon carbide and CuCN (2.3 g, 26.0 mmol) and heated to 1800C in the microwave reactor for 45 min. Then the solid obtained is suspended in H2O, extracted with ethyl acetate, washed with NaCl-sln., the organic phase is dried on MgSO4, the solvent is eliminated in vacuo and 6-chloro-3- nitro-pyridine-2-carbonitrile (HPLC-MS: tRet. = 1.01 min, MS(M+H)+ = 182, method LCMSBASl) is obtained. β-chloro-S-nitro-pyridine-l-carbonitrile (100 mg, 0.54 mmol) is taken up in EtOH (1 niL), combined with SnCl2 (413 mg, 2.18 mmol) and heated to 900C for 3 h. Then the solvent is removed, the residue is taken up in ethyl acetate and first of all washed with NaHCO3 to pH 7, then washed with NaOH (2 M) to pH 8-9. Then the residue is filtered through
Celite®, the filtrate is extracted again with ethyl acetate and the combined organic phases are dried on Na2SO4. The solvent is eliminated in vacuo and 3-amino-6-chloro-pyridine-2- carboxylic acid amide is obtained (HPLC-MS: tRet. = 0.78 min, MS(M+H)+ = 172, method LCMSBASl).
3-amino-6-chloro-pyridine-2-carboxylic acid amide (94 mg, 0.55 mmol) is taken up in cone. HCl (0.5 mL) and heated to 1100C for 5 h. Then the solvent is removed and 3- amino-6-chloro-pyridine-2-carboxylic acid is obtained.
3-amino-6-chloro-pyridine-2-carboxylic acid (95 mg, 0.55 mmol) is taken up in THF (1 mL) and combined with BH3-THF complex (2.2 mL, 2.2mmol, 1 M in THF). The reaction mixture is stirred for 2 d at 200C. The reaction is ended with dilute HCl and H2O, then neutralised with NaHCO3, extracted with EtOAc, the organic phase is dried on MgSO4, the solvent is eliminated in vacuo and (3-amino-6-chloro-pyridin-2-yl)-methanol is obtained (HPLC-MS: tRet. = 0.79 min, MS(M+H)+ = 159; method AFEC). (3-amino-6-chloro-pyridin-2-yl)-methanol (998 mg, 4.0 mmol) is taken up in DCM and combined with MnO2 (697 mg, 8.0 mmol). After 24 h another 2 eq. MnO2 are added and the mixture is stirred for further 24 h at RT. Then the reaction mixture is filtered through Celite®, the solvent is removed and 3-amino-6-chloro-pyridine-2-carbaldehyde (HPLC- MS: tRet. = 1.88 min, MS(M+H)+ = 157; method AFEC) is obtained. 3-amino-6-chloro-pyridine-2-carbaldehyde (3.2 g, 13.0 mmol) is mixed thoroughly with urea (7.8 g, 130 mmol) and heated to 1800C in the preheated oil bath for 3 h. Then the reaction mixture is suspended in H2O, the precipitate is filtered off and 6-chloro-3H- pyrido[3,2-d]pyrimidin-2-one is obtained.
6-chloro-3H-pyrido[3,2-d]pyrimidin-2-one (3.4 g, 5.2 mmol) are taken up in POCl3 (55 niL) and the mixture is heated for 3 h to 1050C. Then the reaction mixture is added dropwise to ice water, extracted with DCM, the organic phase is dried on MgSO4, the solvent is eliminated in vacuo and 2,6-dichloro-pyrido[3,2-d]pyrimidine (HPLC-MS: MS(M+H)+ = 200; method AFEC) is obtained. 2,6-dichloro-pyrido[3,2-d]pyrimidine is reacted with aniline under the same reaction conditions as described hereinbefore for the synthesis of A.4i and A.4m (MS(M+H)+ = 257/259; method LCMSBASl) is obtained.
Compounds A.4n, A.4o and A.4p may be prepared analogously to A.4m starting from the corresponding carboxylic acids. 2-Amino-5-chloro-nicotinic acid is used for A.4n, while 3-amino-6-chloro-pyrazine-2-carboxylic acid is used for A.4o.
Figure imgf000086_0001
c) Synthesis of components HR4N-L-Q11* A.2* or HR4N-L-Q11 A.2
Method for svnthesising A.2 a
Figure imgf000086_0002
A.3a A.2*a
Bromoindolinone A.4*p (3.433 g, 16.19 mmol), A.3a (5.0 g, 19.43 mmol), palladium(II)- acetate (363 mg, 1.619 mmol), tri-o-tolylphosphine (986 mg, 3.24 mmol) and Hϋnig base (5.771 mL, 34.0 mmol) are suspended in 15 mL acetonitrile and stirred for 2 h at 900C. The reaction mixture is stirred into 0.1 N hydrochloric acid, extracted with DCM, the organic phase is dried and the solvent is eliminated in vacuo. The residue is taken up in 100 niL DCM, combined with 100 niL trifluoroacetic acid, stirred for 45 min at 200C and the solvent is eliminated in vacuo. The residue is purified by RP chromatography (method prep. HPLCl; 5 % acetonitrile to 50 % in 12 min) and the amine A.2*a (HPLC-MS: tRet. = 1.25 min; MS(M+H)+ = 189; method FECB3) is obtained.
A.3a may also be coupled with A.4c to form A.2b under analogous reaction conditions.
Figure imgf000087_0001
A.3a
A.2b
Method for svnthesising A.2c and A.2 d
Figure imgf000087_0002
A.2c A.2*d
Bromoindazole A.4q (1.50 g, 7.61 mmol), K2CO3 (2.60 g, 19.0 mmol), CuI (304 mg, 1.60 mmol) and Pd(PPh3)4 (1.76 g, 1.60 mmol) are taken up in DME/H2O (30 mL, 1 :1), combined with alkyne A.3b (1.18 g, 7.61 mmol) and stirred for 1 h at 600C. The solvent is removed, the reaction mixture is purified by column chromatography (cyclohexane/EtOAc, 10% to 70%) and A.2c-PG (HPLC-MS: tRet. = 1.78 min; MS(M+H)+ = 272; method LCMSBASl) is obtained.
A.2c-PG (800 mg, 2.85 mmol) is taken up in DMF, combined with KOH (578 mg, 10.3 mmol) and heated for 2 h to 400C. Then iodine is added (1.50 g, 5.89 mmol) and the reaction mixture is stirred for a further 30 min at 200C. The reaction is ended with Na2S2O3 solution, extracted with Et2O, washed with NaCl, dried on MgSO4, filtered off, the solvent is removed and A.2*d-PG (HPLC-MS: tRet. = 1.96 min; MS(M-H)" = 396; method LCMSBASl) is obtained.
The Boc-protective group on A.2c-PG and A.2*d-PG may be eliminated in TFA/DCM (I h, RT) and A.2c or A.2*d is then obtained.
Under analogous SONOGASHIRA conditions A.3b may also be reacted with A.4 p to form A.2 e-PG and after the Boc protective group has been cleaved A.2 e is obtained.
Figure imgf000088_0001
A.2*e
Method for svnthesising A.2f
Figure imgf000088_0002
A.2*d-PG (100 mg, 0.21 mmol) is taken up in MeOH/dioxane (1 mL, 1 :1), combined with Boc-pyrrole-2-boric acid (50 mg, 0.24 mmol), K2CO3 (0.32 mL, 0.63 mmol, 2 M in H2O) and Pd(PPh3)4 (12 mg, 10 mol%) and heated to 800C for 20 min in the microwave reactor. The reaction mixture is filtered off, purified by column chromatography (CH3CN/H2O, 15 % auf 98 %) and the A.2e provided with two Boc protective groups is obtained. This is taken up in DCM (2 rnL) and slowly combined with TFA (0.1 rnL). The reaction mixture is stirred for 1 h at RT, then the solvent is removed and A.2f (HPLC-MS: tRet. = 1.41 min; MS(M+H)+ = 237; method LCMSBASl) is obtained.
Method for synthesising A.2g
Figure imgf000089_0001
A.4f-PG A.2g
A.4f-PG (30 mg, 0.081 mmol) and 4-aminomethyl-phenylamine A.3c (20 mg, 0.164 mmol) are taken up in 0.3 mL NMP and combined with dioxanic HCl (81 μL, 4 mmol/mL). The reaction mixture is stirred for 16 h at 1000C, the solvent is eliminated in vacuo, the residue is purified by RP-chromatography (method prep. HPLC2; 3 % acetonitrile to 60 % in 12 min) and A.2g (HPLC-MS: tRet. = 1.32 min, MS(M+H)+ = 316; method FEC3) is obtained.
Method for svnthesising A.2h
Figure imgf000089_0002
A.3d A.2h
2-methyl-allylamine (1.04 g, 0.015 mol) and phthalic anhydride (2.00 g, 0.014 mol) are taken up in 50 niL acetic acid and stirred for 16 h under reflux conditions. Then the solvent is eliminated in vacuo, the residue is taken up in DCM and extracted with sodium hydrogen carbonate solution. The organic phase is dried, the solvent is eliminated in vacuo and A.3d (HPLC-MS: tRet. = 1.85 min, MS(M+H)+ = 202; method FECSUNFIRE) is obtained.
A.4c (200 mg, 0.56 mmol), A.3d (115 mg, 0.572 mmol), palladium(II)-acetate (14 mg, 0.063 mmol), tri-o-tolylphosphine (37 mg, 0.122 mmol) and Hϋnig base (0.2 mL, 1.214 mmol) are suspended in 1.5 mL THF/NMP (5:1) and the mixture is stirred for 7 h at 700C. The reaction mixture is stirred into 0.1 N hydrochloric acid, extracted with DCM, the organic phase is dried and the solvent is eliminated in vacuo. The residue is purified by RP-chromatography (method prep. HPLC2; 5 % acetonitrile to 65 % in 12 min). The phthalimide-protected intermediate product thus obtained is taken up in 3 mL EtOH, combined with hydrazine hydrate (70 μL, 1.41 mmol) and stirred for 3 h at 500C. The solvent is eliminated in vacuo and the residue is purified by normal phase chromatography (DCM/10 % ammonia in methanol: 95:5 -» 85:15 in 30 min) and A.2h (HPLC-MS: tRet. = 1.80 min; MS(M+H)+ = 348; method FECBM2) is obtained.
Method for svnthesising A.2i
Figure imgf000090_0001
A.3e A.2i
3-chloro-2-fluoro-propene (0.52 g, 5.50 mmol) and phthalimide (1.00 g, 5.40 mol) are taken up in 6 mL DMF and stirred for 16 h at 200C. The reaction mixture is stirred into water and A.3e (HPLC-MS: tRet. = 1.77 min, MS(M+H)+ = 206; method FECSUNFIRE) is obtained as precipitate.
A.3e is then coupled with A.4c to form A.2i, the reaction conditions being those used in the synthesis of A.2h from A.3d and A.4c (see above). (HPLC-MS: tRet. = 1.63 min; MS(M+H)+ = 352; method FECB5).
Method for svnthesising A.2j
Figure imgf000091_0001
A.3f A.2j
A.4c (50 mg, 0.14 mmol), A.3f (78 mg, 0.419 mmol), Pd2dba3 (13 mg, 0.014 mmol), X-Phos (20 mg, 0.042 mmol) and caesium carbonate (182 mg, 0.559 mmol) are suspended in 700 μL toluene and 36 μL NMP and stirred for 2 h at 115°C. The reaction mixture is stirred into 0.1 N hydrochloric acid, extracted with DCM, the organic phase is dried and the solvent is eliminated in vacuo. The residue is purified by RP-chromatography (method prep. HPLC2; 10 % acetonitrile to 60 % in 12 min) and the Boc-protected precursor of A.2j is obtained. This is taken up in 8 mL of a 4 N dioxanic hydrochloric acid solution and stirred for 16 h at 200C. The solvent is eliminated in vacuo and free A.2j (HPLC-MS: tRet. = 1.62 min; MS(M+H)+ = 363; method FECB5) is obtained. Method for svnthesising A.2k-PG
Figure imgf000092_0001
A.4r-PG (1.0 g, 2.8 mmol), 5-cyano-2-boric acid thiophene (479 mg, 3.1 mmol) and
Pd(dppf)Cl2 (232 mg, 10 mol%) are taken up in THF/NMP (7 niL, 1 :1). Then Cs2CO3 solution (1.9 g, 5.7 mmol in 2.5 mL H2O) is added and the reaction mixture is heated to
100 C for 1 h in the microwave reactor. The residue is taken up in H2O, extracted with
DCM, washed with NaCl-sln., the organic phase is dried on MgSO4 and the solvent is eliminated in vacuo. The residue is purified by column chromatography (MeOH/DCM,
5 % to 20 %) and 5-[l-(toluene-4-sulphonyl)-lH-pyrrolo[2,3-b]pyridin-5-yl)-thiophene-2- carbonitrile (ΗPLC-MS: tRet. = 2.48 min; MS(M+Η)+ = 380; method AFEC) is obtained.
5-[ 1 -(toluene-4-sulphonyl)- lH-pyrrolo[2,3-b]pyridin-5-yl)-thiophene-2-carbonitrile (155 mg, 0.41 mmol) is taken up in MeOΗ/NΗ3 (15 mL), combined with two spatula tips of Raney nickel and hydrogenated for 2 h at 5 bar. Then the reaction mixture is filtered, the solvent is removed and A.2k-PG (HPLC-MS: tRet. = 1.84 min; MS(M+H)+ = 384, method LCMSBAS 1) is obtained.
Method for svnthesising A.21-PG
Figure imgf000092_0002
A.2I A.2I-PG
2,4-dichloro-7H-pyrrolo[2,3-J]pyrimidine (500 mg, 2.66 mmol), palladium(II)acetate
(70 mg, 0.31 mmol) and BINAP (240 mg, 0.39 mmol) are dissolved in 6 mL TΗF and stirred for 20 min at 200C. Then TMEDA (300 μL; 2.0 mmol) is added, the mixture is stirred for 20 min and then sodium borohydride (189 mg; 5.11 mmol) dissolved in 10 rnL diglyme is added. After 1 h at 200C the mixture is combined with 1 N HCl and the solvent is eliminated in vacuo. The residue is purified by column chromatography (method prep. HPLC2; 3 % acetonitrile to 55 % in 12 min) and 2-chloro-7H-pyrrolo[2,3-</Jpyrimidine (ΗPLC-MS: tRet. = 1.25 min; MS(M+Η)+ = 154; method FEC3) is obtained.
2-chloro-7H-pyrrolo[2,3-ύT]pyrimidine (330 mg; 2.15 mmol) and JV-iodosuccinimide (580 mg; 2.58 mmol) are taken up in 3.3 mL DMF and stirred for 1 h at 200C. The reaction mixture is extracted with sodium thiosulphate solution and ethyl acetate. The combined organic phases are dried, the solvent is eliminated in vacuo and A.21 (ΗPLC- MS: tRet. = 1.60 min; MS(M+Η)+ = 280; method FEC3) is obtained.
A.21 (400 mg, 1.43 mmol), benzenesulphonyl chloride (272 μL, 2.13 mmol), DMAP (18 mg, 0.15 mmol) and Hϋnig base (350 μL, 2.17 mmol) are taken up in 10 mL DCM and stirred for 16 h at 200C. The solvent is eliminated in vacuo, the residue is purified by column chromatography (method prep. HPLC2; 10 % acetonitrile to 95 % in 12 min) and A.21-PG (HPLC-MS: tRet. = 1.98 min; MS(M+H)+ = 420; method FEC3) is obtained.
Method for svnthesising A.2m
Figure imgf000093_0001
A.5a A.2m
Carboxylic acid A.5a (71 mg, 0.376 mmol), HATU (214 mg, 0.564 mmol) and triethylamine (364 μL, 2.256 mmol) are suspended in 0.5 mL DMF and stirred for 5 min at 200C. Then A.6a (101 mg, 0.451 mmol) is added and the mixture is stirred for 60 min at 200C. It is combined with semi-saturated sodium hydrogen carbonate solution and DCM, the organic phase is separated off and the solvent is eliminated in vacuo. The residue is taken up in 5 mL DCM, combined with 5 mL trifluoroacetic acid and stirred for 4 h at 200C. Then the solvent is eliminated in vacuo. The residue is purified by RP chromatography (method prep. HPLCl; 20 % acetonitrile to 70 % in 10 min) and A.2m (MS(M+H)+ = 296; method FECB3) is obtained.
d) Synthesis of amides A.9
Method for svnthesising A.9a
Figure imgf000094_0001
A.1b A.9a
The carboxylic acid A.lb (86.5 mg, 0.376 mmol), HATU (214 mg, 0.564 mmol) and triethylamine (364 μL, 2.256 mmol) are suspended in 0.5 mL DMF and stirred for 5 min at 200C. Then the benzylamine A.7a is added as hydrochloride (84 mg, 0.451 mmol) and the mixture is stirred for 60 min at 200C. The solvent is eliminated in vacuo, the residue is purified by RP chromatography (method prep. HPLCl; 15 % acetonitrile to 65 % in 10 min) and A.9a (MS(M+H)+ = 364; method FECB3) is obtained.
Method for svnthesising A.9b
Figure imgf000094_0002
The carboxylic acid A.lb (86.5 mg, 0.376 mmol), HATU (214 mg, 0.564 mmol) and triethylamine (364 μL, 2.256 mmol) are suspended in 0.5 mL DMF and stirred for 5 min at 200C. Then the amine A.7b (25 mg, 0.451 mmol) is added and the mixture is stirred for 60 min at 200C. The solvent is eliminated in vacuo, the residue is purified by RP- chromatography (method prep. HPLCl; 5 % acetonitrile to 50 % in 10 min) and A.9b (MS(M+H)+ = 268; method FECB3) is obtained.
A.9c may also be prepared analogously to A.9b from A.la and allylamine.
Figure imgf000095_0001
e) Synthesis of amides Cl
Method for synthesising CIa
Figure imgf000095_0002
A.1a C.1a
The carboxylic acid A.la (233 mg, 0.528 mmol), HATU (201 mg, 0.528 mmol) and triethylamine (146 μL, 1.16 mmol) are suspended in 1 mL DMF and stirred for 5 min at
200C. Then the amine A.2 a (99 mg, 0.528 mmol) is added and the mixture is stirred for
60 min at 20 C. The reaction mixture is diluted with ethyl acetate and extracted with dilute sodium hydrogen carbonate solution. The organic phase is dried, the solvent is eliminated in vacuo and CIa (HPLC-MS: tRet. = 1.57 min; MS(M+H)+ = 435/437; method FECB3) is obtained. f) Synthesis of Example compounds of type I
Method for synthesising 1-1
Figure imgf000096_0001
C.1a 1-1
Amide CIa (85 mg, 0.172 mmol) and imidazolecarbaldehyde C.2a (38 mg, 0.396 mmol) are taken up in 0.5 rnL of a solvent mixture consisting of 2-propanol and DCM (3:1) and combined with piperidine (15 μL, 0.137 mmol). The reaction mixture is stirred for 1.5 h at 200C, then the solvent is eliminated in vacuo, the residue is purified by RP chromatography (method prep. HPLCl; 10 % acetonitrile to 60 % in 10 min) and 1-1 (HPLC-MS: tRet. = 1.68 min; MS(M+H)+ = 513/515; method LCMSBASl) is obtained.
The following Example compounds 1-2 to 1-27 (Table 1) are prepared analogously to 1-1, by reacting the corresponding carboxylic acid A.I first of all with component A.2*a and then with pyrrole- or imidazole-carbaldehydes C.2.
Table 1
Figure imgf000096_0002
1 1
Figure imgf000097_0001
Figure imgf000098_0001
1
1
1
1
1
1
Figure imgf000099_0001
Figure imgf000100_0001
g) Synthesis of Example compounds of type II
Method for svnthesising II- 1
Figure imgf000101_0001
11-1
A.9a
Amide A.9a (64.6 mg, 0.178 mmol), azaindole A.4s-PG (50 mg, 0.148 mmol), palladium DPPF (16 mg, 0.020 mmol) and caesium carbonate solution (72 μL, 5 mmol/mL) are suspended in 720 μL of a mixture consisting of THF/NMP (2:1) and stirred for 1 h at 1000C. The reaction mixture is diluted with water, extracted with DCM, the organic phase is dried and the solvent is eliminated in vacuo. The residue is suspended in 4 mL methanol and 1 mL water and combined with potassium carbonate (93 mg, 0.676 mmol). The reaction mixture is stirred for 1 h under reflux conditions and then freed from the solvent in vacuo. The residue is purified by RP chromatography (method prep. HPLCl; 30 % acetonitrile to 80 % in 8 min) and Example compound H-I (MS(M+H)+ = 436; method FECB3) is obtained.
Method for svnthesising II-2
Figure imgf000101_0002
Amide A.9b (88.4 mg, 0.33 mmol), bromoquinazoline A.4b (66 mg, 0.22 mmol), dichlorobis(triphenylphosphine)palladium (15 mg, 0.022 mmol), copper(I)-iodide (4.2 mg, 0.022 mmol), triphenylphosphine (12 mg, 0.046 mmol) and diethylamine (225 mg, 3.082 mmol) are suspended in 250 μL DMF under an argon atmosphere and stirred for 1 h at 800C. The solvents are eliminated in vacuo, the residue is purified by RP chromatography (method prep. HPLCl; 25 % acetonitrile to 90 % in 10 min) and the Example compound II-2 (MS(M+H)+ = 522; method FECB3) is obtained.
The following Example compounds III-3 to III- 18 (Table 2) are synthesised stepwise analogously to IH-I or III-2 by SUZUKI, SONOGASHIRA or HECK cross-coupling. For this the components A.9a, A.9b, A.9c or analogues thereof are reacted with components A.4. Optionally all the Example compounds may be synthesised by synthesising corresponding amino components A.2 and coupling with carboxylic acids A.l.
Table 2
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
h) Synthesis of Example compounds of type III
Method for synthesising M-I
H9N
Figure imgf000105_0001
Example compound HI-I is obtained analogously to CIa by amide coupling of A.2b and A.lb by means of HATU/TEA in DMF (MS(M+H)+ = 546; method LCMSBAS 1).
The following Example compounds III-2 to III-42 (Table 3) are synthesised analogously to the synthesis of IH-I described hereinbefore, by synthesising corresponding amino components A.2 and coupling them with carboxylic acids A.l.
Table 3
Figure imgf000105_0002
Figure imgf000106_0001
Figure imgf000107_0001
1
1
1
1
1
1
Figure imgf000108_0001
1
1
1
1
1
1
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
i) Synthesis of Example compounds of type IV
Method for synthesising IV-I
Figure imgf000112_0002
A.1 b IV-1
The carboxylic acid A.lb (43.2 mg, 0.188 mmol), HATU (107 mg, 0.282 mmol) and triethylamine (182 μL, 1.128 mmol) are suspended in 0.5 mL DMF and stirred for 5 min at 200C. Then the amine A.2m (67 mg, 0.226 mmol) is added and the mixture is stirred for 60 min at 200C. The solvent is eliminated in vacuo, the residue is purified by RP- chromatography (method prep. HPLCl; 5 % acetonitrile to 50 % in 10 min) and Example compound IV-I (MS(M+H)+ = 508; method FECB3) is obtained .
Analogously to compound IV-I the following Example compounds IV-2 and IV-3 may be prepared (Table 4).
Table 4
Figure imgf000113_0001
The following Examples describe the biological activity of the compounds according to the invention, without restricting the invention to these Examples.
Compounds of general formula (1) are characterised by their many possible applications in the therapeutic field. Particular mention should be made of those applications in which the inhibition of specific signal enzymes, particularly the inhibiting effect on the proliferation of cultivated human tumour cells but also on the proliferation of other cells such as endothelial cells, for example, are involved.
The activity of the compounds according to the invention on the kinase PDKl which inhibits the signal transduction pathway is determined in an in vitro kinase assay with recombinant Iy prepared protein:
PDKl Kinase Assay I
Recombinant human PDKl enzyme (aa 52-556) linked at its N-terminal end to HiS6 is isolated from baculo virus-infected insect cells. Purified enzyme may be obtained for example from the University of Dundee, Scotland. The following components are combined in a well of a 96-well round-based dish (Messrs. Greiner bio-one, No. 650101):
- 7.5 μL of compound to be tested in varying concentrations (e.g. Starting at 10 μM, and diluted in steps of 1 :5) in 3.33% DMSO (final concentration 1% DMSO)/assay buffer (50 mM Tris pH 7.5, 0.05% β-mercaptoethanol, 10 mM Mg-acetate)
- 7.5 μL PDKl (10 ng/well) and PDKtide (KTFCGTPEYLAPEVRREPRILSEEEQEM- FRDFDYIADWC) synthesised by Pepceuticals Limited, Nottingham, United Kingdom;
25 μM final concentration); PDKl and PDKtide are together diluted accordingly in assay buffer; PDKtide is present in this mixture as an 83.3 μM solution.
- 10 μL ATP solution (25 μM ATP with 0.5 μCi/well gamma-P33-ATP)
The reaction is started by adding the ATP solution and the mixture is incubated for 30 min at ambient temperature; at the start of the reaction the dishes are shaken gently. The reaction is stopped by the addition of 50 μL/well 125 mM phosphoric acid (H3PO4) and incubated for about 20 min at ambient temperature. The precipitate is transferred by harvesting onto filter plates (96-well microtitre filter plate: UniFilter GF/C; Messrs Perkin Elmer; No. 6005174), then washed 6 times with 50 mM H3PO4 and dried at 600C. Then the plate is stuck down with sealing tape, 25 μL/well of scintillation solution (Microscint 0; Messrs. Perkin Elmer; No. 6013611) are added and the amount of P33 precipitated is measured using the Wallac Betacounter. The measured data are evaluated using Graphpad Prism software.
PDKl Kinase Assay II
Another assay was developed in which a shortened PDKl enzyme (aa 51-359; Q66A mutation) is used that carries in the N-terminal position a HiS6 tag that is cleaved during purification. (ΔPH-PDK1).
The following components are combined in a well of a 96-well round-based dish (Messrs. Greiner bio-one, No. 650101):
- 15 μL of compound to be tested in varying concentrations (e.g. Starting at 10 μM, and diluted in steps of 1 :5) in 3.33% DMSO (final concentration 1% DMSO)/assay buffer (50 mM Tris pH 7.5, 0.05% β-mercaptoethanol, 10 mM Mg-acetate)
- 15 μL (ΔPH-PDK1; 12 ng/well) and PDKtide (KTFCGTPEYLAPEVRREPRILSEEE- QEMFRDFDYIADWC) synthesised by Pepceuticals Limited, Nottingham, United Kingdom; 25 μM final concentration); (ΔPH-PDK1 and PDKtide are together diluted accordingly in assay buffer; PDKtide is present in this mixture as an 83.3 μM solution. These 30 μL are incubated for 24 h at RT before ATP solution is added.
- 20 μL ATP solution (25 μM ATP with 1.0 μCi/well gamma-P33-ATP)
The reaction is started by adding the ATP solution and the mixture is incubated for 120 min at ambient temperature; at the start of the reaction the dishes are shaken gently. The reaction is stopped by the addition of 50 μL/well of 500 mM phosphoric acid (H3PO4) and incubated for about 20 min at ambient temperature. The precipitate is transferred by harvesting onto filter plates (96-well microtitre filter plate: UniFilter GF/C; Messrs Perkin Elmer; No. 6005174), then washed 6 times with 50 mM H3PO4 and dried at 600C. Then the plate is stuck down with sealing tape, 25 μL/well of scintillation solution (Microscint 0; Messrs. Perkin Elmer; No. 6013611) are added and the amount of P33 precipitated is measured using the Wallac Betacounter. The measured data are evaluated using Graphpad Prism software.
PDKl Kinase Assay III Another PDKl assay was developed which by comparison with PDKl assay 1 additionally contains Tween 20:
The following components are combined in a well of a 96-well round-based dish (Messrs. Greiner bio-one, No. 650101):
- 15 μL of compound to be tested in varying concentrations (e.g. Starting at 10 μM, and diluted in steps of 1 :5) in APT buffer (5OmM tris/Cl pH7.5; 0.05% β-mercaptoethanol;
1OmM Mg-acetate; 0.0166 % Tween 20; 3.33 % DMSO)
- 15 μL HiS6-PDKl (aa 52-556) 3.33 ng/well) and PDKtide (KTFCGTPEYLAPEVRRE PRILSEEEQEMFRDFDYIADWC), synthesised by Pepceuticals Limited, Nottingham, United Kingdom; 25 μM final concentration); HiS6-PDKl and PDKtide are together diluted accordingly in assay buffer (50 mM tris pH 7.5, 0.05 % β-mercaptoethanol, 10 mM Mg-acetate); PDKtide is present in this mixture as an 83.3 μM solution. These 30 μL are routinely incubated for 30 min at RT.
- 20 μL ATP solution (25 μM ATP with 1.0 μCi/well gamma-P33-ATP). The final concentration of Tween 20 is 0.005%.
The reaction is started by adding the ATP solution and the mixture is incubated for 90 min at ambient temperature; at the start of the reaction the dishes are shaken gently. The reaction is stopped by the addition of 50 μL/well of 500 mM phosphoric acid (H3PO4) and incubated for about 20 min at ambient temperature. The precipitate is transferred by harvesting onto filter plates (96-well microtitre filter plate: UniFilter GF/C; Messrs Perkin Elmer; No. 6005174), then washed 6 times with 50 mM H3PO4 and dried at 6O0C. Then the plate is stuck down with sealing tape, 25 μL/well of scintillation solution (Microscint 0; Messrs. Perkin Elmer; No. 6013611) are added and the amount of P33 precipitated is measured using the Wallac Betacounter. The measured data are evaluated using Graphpad Prism software. Compounds (1) according to the invention generally exhibit good to very good inhibition in at least one of the PDKl assays described hereinbefore, i.e. for example an IC50 value of less than 1 μmol/L, less than 0.25 μmol/L.
To demonstrate that compounds according to the invention with different structural elements have an inhibitory activity, Table 5 shows the %CTL values of the compound examples at a concentration of 10 μM. A value of 100 % indicates that there is no total inhibition with a value of 0%. The %CTL values indicate the residual activity of the enzyme after the addition of the inhibitory compound in the solvent DMSO in relation to the enzyme activity in the solvent DMSO without the addition of a compound (control). The majority of the values were determined using the PDKl kinase assay III described hereinbefore. The values marked with an asterisk ( ) were determined using the PDKl kinase assay II described hereinbefore.
Table 5
Figure imgf000117_0002
Figure imgf000117_0001
The antiproliferative activity of the compounds according to the invention is determined in the proliferation test on cultivated human tumour cells and/or in a cell cycle analysis, for example on HCTl 16 or PC-3 tumour cells:
Inhibition of proliferation on cultivated human tumour cells (HCTl 16) To measure proliferation on cultivated human tumour cells, cells of the colon carcinoma line HCTl 16 (obtained from American Type Culture Collection (ATCC)) are cultivated in McCoy medium (Gibco) and 10% foetal calf serum (Gibco) and harvested in the log growth phase. Then the HCTl 16 cells are placed in 96-well flat bottomed plates (Falcon) at a density of 1000 cells per well in McCoy medium and incubated overnight in an incubator (at 37°C and 5 % CO2). The active substances are added to the cells in various concentrations (dissolved in DMSO; DMSO final concentration: 0.1%). After 72 hours' incubation 20 μl AlamarBlue reagent (AccuMed International) are added to each well, and the cells are incubated for a further 5-7 hours. After incubation the colour change of the AlamarBlue reagent is determined in a Wallac Microbeta fluorescence spectrophotometer EC50 values are calculated by means of Standard Levenburg Marquard algorithms (GraphPadPrizm).
Inhibition of proliferation on cultivated human tumour cells (PC-3)
To measure proliferation on prostate carcinoma tumour cell line PC-3 (obtained from
American Type Culture Collection (ATCC)) the cells are cultivated in Ham's F12K (Gibco) and 10% foetal calf serum (Gibco) and harvested in the log growth phase. Then the PC-3 cells are placed in 96-well plates (Costar) at a density of 2000 cells per well and incubated overnight in an incubator (at 37°C and 5 % CO2), while on each plate 16 wells are used as controls (8 wells with cells to which only DMSO solution has been added (should yield 30 - 50% maximum value of reduced AlamarBlue), 4 wells containing only medium (medium control, after the addition of oxidised AlamarBlue reagent the background signal is obtained) and 4 wells where again only medium is added (after the addition of reduced AlamarBlue reagent it acts as a maximum value)). The active substances are added to the cells in various concentrations (dissolved in DMSO; DMSO final concentration: 0.2%) (in each case as a double or triple measurement). After 5 days' incubation 20 μl AlamarBlue reagent (Serotec) are added to each well, and the cells are incubated for a further 5-7 hours. As a control, 20 μl reduced AlamarBlue reagent is added to each of 4 wells (AlamarBlue reagent which is autoclaved for 30 min). After incubation the colour change of the AlamarBlue reagent in the individual wells is determined in a SpectraMax Photometer (Molecular Devices) (extinction 530 nm, emission 590 nm, 5 sec measuring time). The amount of AlamarBlue reagent reacted represents the metabolic activity of the cells. The relative cell activity is calculated in relation to the control (PC-3 cells without inhibitor) and the active substance concentration which inhibits the cell activity by 50% (EC50) is derived. The values are calculated from the average of two or three individual measurements.
Many of the compounds according to the invention cause inhibition of proliferation by interfering with intracellular signal transduction pathways which are important for cell survival, predominantly, but not exclusively, in cells which have become dependent on these signal pathways during their development. Inhibition of these pathways induces arrest in corresponding cells in the Gl phase of the cell cyle and/or apoptosis, i.e. cell responses that can be analysed using Cellomics Array Scan or FACS analysis (see below).
The compounds according to the invention are also tested accordingly on other tumour cells. For example these compounds are effective on carcinomas of all kinds of tissue (e.g. Gliomas (U87MG; U373MG), sarcoma (e.g. MES-SA; SK-UT-IB), breast (MDA- MB468), colon (HCTl 16), lung (NCIH460, NCI-H520), melanoma (MALME-3M; C32), prostate (DU- 145), ovary (SKO V-3)] and could be used in indications of this kind, particularly in indications which have activating changes in the PI3K-AKT-PDK1 signal pathway. This demonstrates the wide range of applications for the compounds according to the invention for the treatment of all kinds of tumour types.
Therefore cell lines such as U87MG, MALME-3M, NCI-H520, DU- 145, NCI-H460, SKO V-3 etc. are analysed for inhibition of proliferation, with suitable adjustment of the number of cells seeded per well and optionally the measuring time after the addition of the substance. Compounds (1) according to the invention generally demonstrate good activity in cell assays of this kind, i.e. for example an EC50 value in the PC-3 or HCTl 16 proliferation test of less than 10 μmol/L, very often less than 2 μmol/L.
FACS Analysis Propidium iodide (PI) binds stoichiometrically to double-stranded DNA, and is thus suitable for determining the proportion of cells in the Gl, S, and G2/M phase of the cell cycle on the basis of the cellular DNA content. Cells in the GO and Gl phase have a diploid DNA content (2N), whereas cells in the G2 or mitosis phase have a 4N DNA content.
For PI staining, for example, 1.0 x 106 PC-3 or HCTl 16 cells are seeded onto a 75 cm2 cell culture flask, and after 24 h either 0.1 % DMSO is added as control or the substance is added in various concentrations (in 0.1% DMSO). The cells are incubated for 42 h with the substance or with DMSO. Then the cells are detached with trypsin and centrifuged. The cell pellet is washed with buffered saline solution (PBS) and the cells are then fixed with 80% ethanol at -200C for at least 2 h. After another washing step with PBS the cells are permeabilised with Triton X-IOO (Sigma; 0.25% in PBS) on ice for 5 min, then washed with PBS and incubated with a mixture of PBS and anti-cyclin Bl (FITC conjugated) antibody for 30 min at RT. This step is optional, but helps improve the identification of cells in the G2/M phase as these specifically express cyclin Bl. Then the suspension is washed with PBS and the pellet is incubated in a solution of PI (Sigma; 10μg/ml)and RNAse (Serva; lmg/mLl) in the ratio 9:1 for at least 20 min in the dark. The DNA measurement is carried out in a Becton Dickinson FACScalibur, with an argon laser (500 mW, emission 488 nm); data are obtained and evaluated using the DNA Cell Quest Programme (BD).
Cellomics Array Scan
PC-3 cells are cultivated in Ham's F12K (Gibco) and 10% foetal calf serum (Gibco) and harvested in the log growth phase. Then the PC-3 cells are placed in 96-well plates [FALCON black/clear bottom (#353948)] in a density of 3000 cells per well and incubated overnight in an incubator (at 37°C and 5 % CO2). The active substances are added to the cells in various concentrations (dissolved in DMSO; DMSO final concentration: 0.1%). After 42 h incubation the medium is suction filtered, the cells are fixed for 10 min with 4% formaldehyde solution and Triton X-IOO (1 :200 in PBS) at ambient temperature and simultaneously permeabilised, and then washed twice with a 0.3% BSA solution (Calbiochem). Then the DNA is stained by the addition of 50 μL/well of 4',6-diamidino- 2-phenylindole (DAPI; Molecular Probes) in a final concentration of 300 nM for 1 h at RT, in the dark. Alternatively 50 μL/well of Hoechst 33342 (Invitrogen) in PBS may be used for the DNA staining (1 h at RT, final concentration: 5 μg/mL). The preparations are then carefully washed twice with PBS, the plates are stuck down with black adhesive film and analysed in the Cellomics ArrayScan using the CellCycle BioApplication programme and visualised and evaluated using Spotfire.
Compounds (1) according to the invention generally induce Gl arrest in PC-3 cells, for example, at concentrations of less than 30 μmol/L, often less than 5 μmol/L. In HCTl 16 or MALME-3M cells they generally induce apoptosis at similar or lower concentrations.
Biomarker inhibition:
The substances of the present invention bring about cellular inhibition of PDKl -substrates. Examples of the latter are Phospho-Thr308/AKT, Phospho-Ser221,227/RSK, or phosphorylation sites on p70S6 kinase (Thr229). In order to determine the inhibitory effect, the cells are treated with substance for e.g. 2 h, lysed and analysed by Western Blot and/or BioPlex analysis for phosphoproteins of this kind. Commercially obtainable phospho-specific antibodies against the above-mentioned phosphorylation sites are used.
In PC-3 or other signal pathway-mutated cell lines (see above) as a rule EC50 values of less than 5 μmol/L, often less than 0.5 μmol/L, are achieved with the present compounds on these phosphorylation sites compared with the carrier control and after standardisation to the corresponding whole protein.
On the basis of their biological properties the compounds of general formula (1) according to the invention, their tautomers, racemates, enantiomers, diastereomers, mixtures thereof and the salts of all the above-mentioned forms are suitable for treating diseases characterised by excessive or abnormal cell proliferation or by aberrant activation of the phosphatidylinositol-3-kinase (PBK)-PDKl-AKT signal pathway.
Such diseases include for example: viral infections (e.g. HIV and Kaposi's sarcoma); inflammatory 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 (e.g. carcinomas and sarcomas), skin diseases (e.g. psoriasis); diseases based on hyperplasia which are characterised by an increase in the number of cells (e.g. fibroblasts, hepatocytes, bones and bone marrow cells, cartilage or smooth muscle cells or epithelial cells (e.g. endometrial hyperplasia)); bone diseases and cardiovascular diseases (e.g. restenosis and hypertrophy). They are also suitable for protecting proliferating cells (e.g. hair, intestinal, blood and progenitor cells) from DNA damage caused by radiation, UV treatment and/or cytostatic treatment.
For example, the following 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 pilocytic astrocytomas, fibrillary astrocytoma, protoplasmic astrocytoma, gemistocytary astrocytoma, anaplastic astrocytoma and glioblastoma, brain lymphomas, brain metastases, hypophyseal tumour such as prolactinoma, HGH (human growth hormone) producing tumour and ACTH producing tumour (adrenocorticotropic hormone), craniopharyngiomas, medulloblastomas, meningeomas and oligodendrogliomas; nerve tumours (neoplasms) such as for example tumours of the vegetative nervous system such as neuroblastoma sympathicum, ganglioneuroma, paraganglioma (pheochromocytoma, chromaffϊnoma) and glomus- caroticum tumour, tumours on the peripheral nervous system such as amputation neuroma, neurofibroma, neurinoma (neurilemmoma, Schwannoma) and malignant Schwannoma, as well as tumours of the central nervous system such as brain and bone marrow tumours; intestinal cancer such as for example carcinoma of the rectum, colon, anus, small intestine and duodenum; eyelid tumours such as basalioma or basal cell carcinoma; pancreatic cancer or carcinoma of the pancreas; bladder cancer or carcinoma of the bladder; lung cancer (bronchial carcinoma) such as for example small-cell bronchial carcinomas (oat cell carcinomas) and non-small cell bronchial carcinomas such as plate epithelial carcinomas, adenocarcinomas and large-cell bronchial carcinomas; breast cancer such as for example mammary carcinoma such as infiltrating ductal carcinoma, colloid carcinoma, lobular invasive carcinoma, tubular carcinoma, adenocystic carcinoma and papillary carcinoma; non-Hodgkin's lymphomas (NHL) such as for example Burkitt's lymphoma, low- malignancy non-Hodgkin's lymphomas (NHL) and mucosis fungoides; uterine cancer or endometrial carcinoma or corpus carcinoma; CUP syndrome (Cancer of Unknown Primary); ovarian cancer or ovarian carcinoma such as mucinous, endometrial or serous cancer; gall bladder cancer; bile duct cancer such as for example Klatskin tumour; testicular cancer such as for example seminomas and non-seminomas; lymphoma (lymphosarcoma) such as for example malignant lymphoma, Hodgkin's disease, non- Hodgkin's lymphomas (NHL) such as chronic lymphatic leukaemia, leukaemic reticuloendotheliosis, immunocytoma, plasmocytoma (multiple myeloma), immunoblastoma, Burkitt's lymphoma, T-zone mycosis fungoides, large-cell anaplastic lymphoblastoma and lymphoblastoma; laryngeal cancer such as for example tumours of the vocal cords, supraglottal, glottal and subglottal laryngeal tumours; bone cancer such as for example osteochondroma, chondroma, chondroblastoma, chondromyxoid fibroma, osteoma, osteoid osteoma, osteoblastoma, eosinophilic granuloma, giant cell tumour, chondrosarcoma, osteosarcoma, Ewing's sarcoma, reticulo-sarcoma, plasmocytoma, fibrous dysplasia, juvenile bone cysts and aneurysmatic bone cysts; head and neck tumours such as for example tumours of the lips, tongue, floor of the mouth, oral cavity, gums, palate, salivary glands, throat, nasal cavity, paranasal sinuses, larynx and middle ear; liver cancer such as for example liver cell carcinoma or hepatocellular carcinoma (HCC); leukaemias, such as for example acute leukaemias such as acute lymphatic/lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML); chronic leukaemias such as chronic lymphatic leukaemia (CLL), chronic myeloid leukaemia (CML); stomach cancer or gastric carcinoma such as for example papillary, tubular and mucinous adenocarcinoma, signet ring cell carcinoma, adenosquamous carcinoma, small-cell carcinoma and undifferentiated carcinoma; melanomas such as for example superficially spreading, nodular, lentigo- maligna and acral-lentiginous melanoma; renal cancer such as for example kidney cell carcinoma or hypernephroma or Grawitz's tumour; oesophageal cancer or carcinoma of the oesophagus; penile cancer; prostate cancer; throat cancer or carcinomas of the pharynx such as for example nasopharynx carcinomas, oropharynx carcinomas and hypopharynx carcinomas; retinoblastoma such as for example vaginal cancer or vaginal carcinoma; plate epithelial carcinomas, adenocarcinomas, in situ carcinomas, malignant melanomas and sarcomas; thyroid carcinomas such as for example papillary, follicular and medullary thyroid carcinoma, as well as anaplastic carcinomas; spinalioma, epidormoid carcinoma and plate epithelial carcinoma of the skin; thymomas, cancer of the urethra and cancer of the vulva.
The new compounds may be used for the prevention, short-term or long-term treatment of the above-mentioned diseases, optionally also in combination with radiotherapy or other "state-of-the-art" compounds, such as e.g. cytostatic or cytotoxic substances, cell proliferation inhibitors, anti-angiogenic substances, steroids or antibodies.
The compounds of general formula (1) may be used on their own or in combination with other active substances according to the invention, optionally also in combination with other pharmacologically active substances.
Chemo therapeutic agents which may be administered in combination with the compounds according to the invention, include, without being restricted thereto, hormones, hormone analogues and antihormones (e.g. tamoxifen, toremifene, raloxifene, fulvestrant, megestrol acetate, flutamide, nilutamide, bicalutamide, aminoglutethimide, cyproterone acetate, finasteride, buserelin acetate, fludrocortisone, fluoxymesterone, medroxyprogesterone, octreotide), aromatase inhibitors (e.g. anastrozole, letrozole, liarozole, vorozole, exemestane, atamestane), LHRH agonists and antagonists (e.g. goserelin acetate, luprolide), inhibitors of growth factors (growth factors such as for example "platelet derived growth factor" and "hepatocyte growth factor", inhibitors are for example "growth factor" antibodies, "growth factor receptor" antibodies and tyrosinekinase inhibitors, such as for example cetuximab, gefitinib, imatinib, lapatinib and trastuzumab); antimetabolites (e.g. antifolates such as methotrexate, raltitrexed, pyrimidine analogues such as 5- fluorouracil, capecitabin and gemcitabin, purine and adenosine analogues such as mercaptopurine, thioguanine, cladribine and pentostatin, cytarabine, fludarabine); antitumour antibiotics (e.g. anthracyclins such as doxorubicin, daunorubicin, epirubicin and idarubicin, mitomycin-C, bleomycin, dactinomycin, plicamycin, streptozocin); platinum derivatives (e.g. Cisplatin, oxaliplatin, carboplatin); alkylation agents (e.g. Estramustin, meclorethamine, melphalan, chlorambucil, busulphan, dacarbazin, cyclophosphamide, ifosfamide, temozolomide, nitrosoureas such as for example carmustin and lomustin, thiotepa); antimitotic agents (e.g. Vinca alkaloids such as for example vinblastine, vindesin, vinorelbin and vincristine; and taxanes such as paclitaxel, docetaxel); topoisomerase inhibitors (e.g. epipodophyllotoxins such as for example etoposide and etopophos, teniposide, amsacrin, topotecan, irinotecan, mitoxantron) and various chemotherapeutic agents such as amifostin, anagrelid, clodronat, fϊlgrastin, interferon alpha, leucovorin, rituximab, procarbazine, levamisole, mesna, mitotane, pamidronate and porfϊmer.
Suitable preparations include for example tablets, capsules, suppositories, solutions - particularly solutions for injection (s.c, i.v., i.m.) and infusion - elixirs, emulsions or dispersible powders. The content of the pharmaceutically active compound(s) should be in the range from 0.1 to 90 wt.-%, preferably 0.5 to 50 wt.-% of the composition as a whole, i.e. in amounts which are sufficient to achieve the dosage range specified below. The doses specified may, if necessary, be given several times a day.
Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
Syrups or elixirs containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Solutions for injection and infusion are prepared in the usual way, e.g. with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilisers such as alkali metal salts of ethylenediamine tetraacetic acid, optionally using emulsifϊers and/or dispersants, whilst if water is used as the diluent, for example, organic solvents may optionally be used as solvating agents or dissolving aids, and transferred into injection vials or ampoules or infusion bottles.
Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose) emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
The preparations are administered by the usual methods, preferably by oral or transdermal route, most preferably by oral route. For oral administration the tablets may, of course contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above.
For parenteral use, solutions of the active substances with suitable liquid carriers may be used.
The dosage for intravenous use is from 1 - 1000 mg per hour, preferably between 5 and
500 mg per hour.
However, it may sometimes be necessary to depart from the amounts specified, depending on the body weight, the route of administration, the individual response to the drug, the nature of its formulation and the time or interval over which the drug is administered.
Thus, in some cases it may be sufficient to use less than the minimum dose given above, whereas in other cases the upper limit may have to be exceeded. When administering large amounts it may be advisable to divide them up into a number of smaller doses spread over the day.
The formulation examples which follow illustrate the present invention without restricting its scope: Examples of pharmaceutical formulations
A) Tablets per tablet
active substance according to formula (1) 100 mg lactose 140 mg corn starch 240 mg polyvinylpyrrolidone 15 mg magnesium stearate 5 mg ^^=^^=
500 mg
The finely ground active substance, lactose and some of the corn starch are mixed together. The mixture is screened, then moistened with a solution of polyvinylpyrrolidone in water, kneaded, wet-granulated and dried. The granules, the remaining corn starch and the magnesium stearate are screened and mixed together. The mixture is compressed to produce tablets of suitable shape and size.
B) Tablets per tablet
active substance according to formula (1) 80 mg lactose 55 mg corn starch 190 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15 mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg
400 mg
The finely ground active substance, some of the corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixed together, the mixture is screened and worked with the remaining corn starch and water to form a granulate which is dried and screened. The sodiumcarboxymethyl starch and the magnesium stearate are added and mixed in and the mixture is compressed to form tablets of a suitable size.
C) Ampoule solution
active substance according to formula (1) 50 mg sodium chloride 50 mg water for inj. 5 mL
The active substance is dissolved in water at its own pH or optionally at pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. The solution obtained is filtered free from pyrogens and the filtrate is transferred under aseptic conditions into ampoules which are then sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mg and 50 mg of active substance.

Claims

Patent Claims
1. Compounds of general formula (1)
Figure imgf000130_0001
(1) , wherein:
Qa is a ring system optionally substituted by one or more, identical or different Ra and/or Rb, selected from among C3-iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
W is selected from among -CR1R2-, -NR3- and -O-;
R1 and R2 independently of one another are selected from among Ra and Rb,
R3 denotes Ra;
the group Qa-W- is not an unsubstituted or substituted benzyl;
R4 denotes hydrogen or Ci_6-alkyl;
R5, R6 and R7 independently of one another are selected from among Ra and Rb;
L denotes the group -L1-L2-L3-, wherein L1 binds to the unit -NR4- and L3 binds to the ring system QH; L1, L2 and L3 are selected independently of one another from among Ci_6alkylene, 2-6 membered heteroalkylene, Ci-βhaloalkylene, C3_iocycloalkylene, Cβ-ioarylene, 5-12 membered heteroarylene, 3-14 membered heterocycloalkylene, while all the above-mentioned bivalent units may each optionally be substituted independently of one another by one or more, identical or different Ra and/or Rb, -O-, -S-, -NRg-, -N(ORg)-, -C(O)-, -C(O)O-, -C(O)NR8-, -OS(O)2-, -OS(O)2NR8-, -OC(O)-, -OC(O)O-, -OC(O)NR8-, -S(O)2-, -S(O)2O-, -S(O)2NR8-, -NR8C(O)-, -NR8C(O)O-, -NR8C(O)NR8-, -NR8S(O)2-, -NR8S(O)2O- and -NR8S(O)2NR8-, and/or
L 1 , T L 2 a „-nd L each independently of one another denotes a bond, while at least one of the units L1, L2 or L3 must be other than a bond;
the ring system QH is selected from among
Figure imgf000131_0001
QH-1a QH-1b QH-1c QH-Id QH-Ie
Figure imgf000131_0002
QH-If QH-1g QH-1h QH-Ii QH-1J QH-Ik
Figure imgf000131_0003
QH-2a QH-2a.1 QH-2b QH-2b.1 QH-2c QH-2C.1
Figure imgf000131_0004
QH-2d QH-2d.1 QH-2e QH-2f QH-2g QH-2h
Figure imgf000131_0005
Figure imgf000132_0001
QH-3a QH-3b QH-3c QH-3d QH-3e
Figure imgf000132_0002
QH-4a QH-4b QH-4c QH-4d QH-4e
Figure imgf000132_0003
QH-5a QH-5b QH-6a QH-6b QH-6c QH-6d
QH.7a QH-7b QH-7c QH-7d QH-8a QH-8b
Figure imgf000132_0005
QH-9a QH-9b QH-9c QH-9d
Figure imgf000132_0006
QH-10a QH-IOb QH-10c QH-10d QH-10e
Figure imgf000132_0007
QH-11a QH-11b QH-12a QH-12b
Figure imgf000132_0008
QH-13 QH-14 QH-15 , while the above mentioned ring systems QH may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by Ra and/or Rb,
R8 denotes Ra,
B denotes =CR9R10 or =NRπ,
R9 denotes a group Ral and R10 denotes a group R a2
or
=CR9R10 denotes a 5-12 membered heteroaryl or 5-14 membered heterocycloalkyl, optionally substituted by one or more, identical or different Ra and/or Rb,
R11 denotes a group Ra3;
Ral denotes a group optionally substituted by one or more, identical or different Rb and/or Rc selected from among Ci_6alkyl, Ci-βhaloalkyl, 2-6 membered heteroalkyl, C3_iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, or a suitable substituent, selected from among -ORC, -SRC, -NRCRC, -ONRCRC, -N(ORC)RC, -NRgNRcRc, -NRgC(O)Rc, -NRgC(O)ORc, -NRgC(O)NRcRc, -NRgC(O)NRgNRcRc, -NRgC(NRg)Rc, -NRgC(NRg)ORc, -NRgC(NRg)NRcRc, -NRgC(NORg)Rc, -NRgS(O)2Rc, -NRgNRgC(O)Rc, -NRgNRgC(O)NRcRc and -NRgNRgC(NRg)Rc;
Ra2 is hydrogen or a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among Chalky!, Ci-βhaloalkyl, 2-6 membered heteroalkyl, C3_iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, or a suitable substituent, selected from among -CN, -C(O)RC, -C(O)ORC, -C(O)NRCRC, -C(O)SRC, -C(O)NRgNRcRc and -C(O)NRgORc;
Ra3 is a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among Ci_6alkyl, Ci-βhaloalkyl, 2-6 membered heteroalkyl, C3_iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, or a suitable substituent, selected from among -ORC and -NRCRC;
each Ra independently of one another is hydrogen or a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among Ci_6alkyl, 2-6 membered heteroalkyl, Ci-βhaloalkyl, C3_iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
each Rb denotes a suitable substituent and each is selected independently of one another from among -ORC, -NRCRC, halogen, -CN, -NO2, -C(O)RC, -C(O)ORC, -C(O)NRCRC, -OC(O)RC, -OC(O)ORC, -OC(O)NRCRC, -S(O)2RC, -S(O)2OR0, -S(O)2NRCRC, -NRgC(O)Rc, -NRgC(O)ORc, -NRgC(0)NRcRc, -NRgS(O)2Rc, -NRgS(O)2ORc and -NRgS(O)2NRcRc, and the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring systems;
each Rc independently of one another is hydrogen or a group optionally substituted by one or more identical or different Rd and/or Re, selected from among Ci_6alkyl, 2-6 membered heteroalkyl, Ci-βhaloalkyl, C3-iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
each Rd is a suitable substituent and each is selected independently of one another from among -ORe, -NReRe, halogen, -CN, -NO2, -C(O)Re, -C(O)ORe, -C(0)NReRe, -OC(O)Re, -OC(O)ORe, -0C(0)NReRe, -S(O)2R6, -S(O)2OR6, -S(O)2NReRe, -NRgC(O)Re, -NRgC(0)0Re, -NRgC(O)NReRe, -NRgS(O)2Re, -NRgS(O)2ORe and -NRgS(0)2NReRe, and the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring systems;
each Re independently of one another is hydrogen or a group optionally substituted by one or more identical or different Rf and/or Rg, selected from among Ci_6alkyl, 2-6 membered heteroalkyl, Ci-βhaloalkyl, C3-iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl;
each Rf is a suitable substituent and each is selected independently of one another from among -ORg, -NRgRg, halogen, -CN, -NO2, -C(O)Rg, -C(O)OR8, -C(O)NR8R8, -OC(O)R8, -OC(O)OR8, -OC(O)NR8R8, -S(O)2R8, -S(O)2OR8, -S(O)2NR8R8, -NRhC(O)R8, -NRhC(O)OR8, -NR11C(O)NR8R8, -NRhS(O)2R8, -NRhS(O)2OR8 and -NR11S(O)2NR8R8, and the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring systems;
each Rg independently of one another is hydrogen or a group optionally substituted by one or more identical or different Rh, selected from among Ci_6alkyl, 2-6 membered heteroalkyl, Ci-βhaloalkyl, C3_iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, and
each Rh independently of one another is selected from among hydrogen, Ci_6alkyl, 2-6 membered heteroalkyl, Ci-βhaloalkyl, C3-iocycloalkyl,C6-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl.
2. Compounds according to claim 1 , wherein
Qa is a ring system optionally substituted by one or more, identical or different Ra and/or Rb, selected from among Cβ-ioaryl and 5-12 membered heteroaryl, and
Ra and Rb are defined as in claim 1.
3. Compounds according to claim 2, wherein
Qa is a ring system optionally substituted by one or more, identical or different Ra and/or Rb, selected from among phenyl, furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, iso thiazolyl, pyrimidyl and pyridyl, and
Ra and Rb are defined as in claim 1.
4. Compounds according to one of claims 1 to 3, wherein the ring system Qa may be substituted by one or more, identical or different substituents, selected from among Ci_6alkyl, Ci_6haloalkyl, -0Rhl, -NRhlRhl, halogen, -CN, -C(O)Rhl, -C(O)ORhl, -C(0)NRhlRhl, -S(O)2NR111R111, -NRhlC(0)Rhl, -NRhlC(0)0Rhl,
-NRhlC(0)NRhlRhl, -NRhlS(0)2Rhl and =0, wherein the latter may only be a substituent in non-aromatic ring systems, and
Rhl is in each case selected independently of one another from among hydrogen, Ci_6alkyl, 2-6 membered heteroalkyl and Ci-βhaloalkyl.
5. Compounds according to one of claims 1 to 4, wherein W is selected from among -NH-, -N(Ci_6alkyl)-, -CH2-, -CH(Ci_6alkyl)-, -C(Ci_6alkyl)2- and -O- .
6. Compounds according to one of claims 1 to 5, wherein R4 denotes hydrogen.
7. Compounds according to one of claims 1 to 6, wherein
R5, R6 and R7 are selected independently of one another from among hydrogen, Ci_6alkyl, Ci_6haloalkyl, -ORh2, -NRh2Rh2, halogen, -CN, -C(O)Rh2, -C(O)ORh2, -C(O)NRh2Rh2, -S(O)2NRh2Rh2, -NRh2C(O)Rh2, -NRh2C(O)ORh2, -NRh2C(O)NRh2Rh2 and -NRh2S(O)2Rh2 and
Rh2 is selected independently of one another in each case from among hydrogen, Ci_6alkyl, 2-6 membered heteroalkyl and Ci-βhaloalkyl.
8. Compounds according to claim 7, wherein
R5, R6 and R7 each denote hydrogen.
9. Compounds according to one of claims 1 to 8, wherein
L is selected from among
Figure imgf000137_0001
L-1 L-2 L-3 L-4 L-5 L-6
Figure imgf000137_0002
L-7 L-8 L-9 L-10 L-11 L-12
Figure imgf000137_0003
L-13 L-14 L-15 L-16 L-17
Figure imgf000137_0004
L-18 L-19 L-20 L-21 L-22 L-23
Figure imgf000137_0005
L-24 L-25 L-26 L-27 L-28 L-29
Figure imgf000137_0006
L-30 L-31 L-32 L-33 L-34 L-35
Figure imgf000137_0007
L-36 L-37 L-38 L-39 L-40
Figure imgf000137_0008
L-41 L-42 L-43 L-44 L-45 L-46
Figure imgf000138_0001
L-47 L-48 L-49 L-50 L-51
Figure imgf000138_0002
L-52 L-53 L-54 L-55 L-56
the bivalent units L shown bind on the right to the ring system QH and on the left to the amide nitrogen -NR .4 - according to formula (1) and may optionally each be substituted independently of one another by one or more identical or different R and/or R >b and Ra and Rb are defined as in claim 1.
10. Compounds according to one of claims 1 to 9, wherein
L is selected from among
Figure imgf000138_0003
L-I L-Il L-III L-IV
Figure imgf000138_0004
L-V L-Vl L-VII , wherein
the bivalent units L shown bind on the right to the ring system QH and on the left to the amide nitrogen -NR4- according to formula (1);
p denotes 0 or 1 ; R K.12 , RK.13 , RK.14 , RK.15 , RK.16 , RK.17 , RK.18 5 RK19 , RK.20 , RK.21 , RK.22 , R K23 , RK.24 , R K25 , RK.26 , R K27 , RK.28 , R K29 ,
R30, R31, R32, R33, R34, R35, R36, R37, R38 and R39 is in each case selected independently of one another from among Ra and Rb, and
R40 denotes Ra; or
R15 and R17 is in each case selected independently of one another from among Ra and
Rb,
R14 and R16 together with the carbon atoms to which they are bound form a C3_7Cycloalkylene or a 3-7 membered heterocycloalkylene, while the above-mentioned ring systems may optionally each be substituted independently of one another by one or more identical or different Ra and/or Rb; or
R19 and R21 is in each case selected independently of one another from among Ra and Rb,
R18 and R20 together with the carbon atoms to which they are bound form a C3_7Cycloalkylene or a 3-7 membered heterocycloalkylene, while the above-mentioned ring systems may optionally each be substituted independently of one another by one or more identical or different Ra and/or Rb; or
R23 and R24 is in each case selected independently of one another from among Ra and Rb,
R22 and R25 together with the carbon atoms to which they are bound form an unsaturated C^cycloalkylene or an unsaturated 4-7 membered heterocycloalkylene, while the above-mentioned ring systems may optionally each be substituted independently of one another by one or more identical or different Ra and/or Rb; or
R30, R31, R33 and R35 is in each case selected independently of one another from among Ra and Rb, R32 and R35 together with the carbon atoms to which they are bound form a
C3_7Cycloalkylene or a 3-7 membered heterocycloalkylene, while the above-mentioned ring systems may optionally each be substituted independently of one another by one or more identical or different Ra and/or Rb; or
R37, R38 and R39 are each selected independently of one another from among Ra and Rb,
R36 and R40 together with the atoms to which they are bound form a 3-7 membered heterocycloalkylene, while this heterocycloalkylene may optionally be substituted independently of one another in each case by one or more identical or different Ra and/or Rb; or
R36, R37 and R39 are each selected independently of one another from among Ra and Rb,
R38 and R40 together with the atoms to which they are bound form a 3-7 membered heterocycloalkylene, while this heterocycloalkylene may optionally be substituted independently of one another in each case by one or more identical or different Ra and/or Rb; and
Ra and Rb are defined as in claim 1.
11. Compounds according to claim 10, wherein
L is selected from among
Figure imgf000140_0001
(-NR4-) L-12 L-36 L-36 L-49 L-50 L-51
and the bivalent units L shown bind on the right to the ring system QH and on the left to the amide nitrogen -NR4- according to formula (1).
12. Compounds according to one of claims 1 to 11, while
QH is selected from among
QH-1a QH-1c QH-1e
Figure imgf000141_0002
QH-1f QH-1h QH-1i QH-1k
the ring systems QH shown may each optionally be substituted independently of one another at one or more hydrogen-carrying carbon atom(s) by Ra and/or Rb and
B, Ra and Rb are defined as in claim 1.
13. Compounds according to claim 12, wherein
B for =CRalRa2 steht; B denotes =CRalRa2;
Ral denotes a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among Cβ-ioaryl and 5-12 membered heteroaryl; Ra2 is selected from among hydrogen, Ci_6alkyl, Ci-βhaloalkyl, C3_iocycloalkyl,
Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl and
Rb and Rc are defined as in claim 1.
14. Compounds according to claim 13, wherein
Ral is a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among pyrrolyl, pyrazolyl and imidazolyl, and
Rb and Rc are defined as in claim 1.
15. Compounds according to one of claims 13 or 14, wherein
Ra2 is hydrogen, methyl or ethyl.
16. Compounds according to one of claims 13 to 15, wherein
Ral is substituted by one or more, identical or different Rbl and/or Rcl;
each Rbl is a suitable substituent and is selected in each case independently of one another from among -ORC, -SRC, -NRCRC, halogen, -CN, -NO2, -C(O)RC, -C(O)ORC, -C(O)NRCRC, -OC(O)RC, -OC(O)ORC, -OC(O)NRCRC, -S(O)2RC, -S(O)2OR0, -S(O)2NRCRC, -NRgC(0)Rc, -NRgC(0)0Rc, -NRgC(O)NRcRc, -NRgS(O)2Rc, -NRgS(O)2ORc and -NRgS(O)2NRcRc and the bivalent substituent =0, while the latter may only be a substituent in non-aromatic ring systems;
each Rcl in each case independently of one another is a group optionally substituted by one or more identical or different Rd and/or Re, selected from among Ci_6alkyl, 2-6 membered heteroalkyl, Ci-βhaloalkyl, C3_iocycloalkyl, Cβ-ioaryl, 5-12 membered heteroaryl and 3-14 membered heterocycloalkyl, and
Rc, Rd, Re and Rg are defined as in claim 1.
17. Compounds according to one of claims 1 to 11, wherein
QH is selected from among
Figure imgf000142_0001
QH.2a QH-2a.1 QH-2e QH-2g
Figure imgf000142_0002
QH-2h QH-2i QH-2j QH-2k the ring systems QH shown may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by Ra and/or Rb and
R , Ra and R are defined as in claim 1.
18. Compounds according to claim 17, wherein
QH is selected from among
Figure imgf000143_0001
QH-2a.1
the ring systems QH shown may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by Ra and/or Rb,
R8 denotes Rc and
Ra, R and Rc are defined as in claim 1.
19. Compounds according to one of claims 1 to 11, wherein
QH is selected from among
QH-3a QH-3c QH-3e
the ring systems QH shown may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by Ra and/or Rb and
Ra and Rb are defined as in claim 1.
20. Compounds according to claim 19, wherein
QH is selected from among
Figure imgf000144_0001
R45 independently of one another denote hydrogen or a group optionally substituted by one or more identical or different Rb and/or Rc, selected from among C3_7Cycloalkyl, phenyl, 5-10 membered heteroaryl, particularly lH-benzimidazolyl, lH-indolyl, pyrrolyl, imidazolyl or pyrazolyl, and 3-10 membered heterocycloalkyl, and
Rb and Rc are defined as in claim 1.
21. Compounds according to one of claims 1 to 11, wherein
QΗ is selected from among
Figure imgf000144_0002
QH-4a QH-4b QH-4c QH-4d QH-4e
the ring systems QH shown may each optionally be substituted independently of one another at one or more hydrogen-carrying ring atom(s) by Ra and/or Rb and
Ra and Rb are defined as in claim 1.
22. Compounds according to claim 21, wherein
QH is selected from among
Figure imgf000145_0001
R46 and R47 in each case independently of one another denote hydrogen or a group optionally substituted by one or more, identical or different Rb and/or Rc, selected from among C3_7Cycloalkyl, phenyl, 5-10 membered heteroaryl, particularly pyridyl, and 3-10 membered heterocycloalkyl,
R48 denotes Rc and
Rb and Rc are defined as in claim 1.
23. Compounds according to claim 22, wherein
QH denotes
Figure imgf000145_0002
R49 is selected from among Rd and Re, r denotes 0, 1, 2 or 3 and
Rd and Re are defined as in claim 1.
24. Compounds according to claim 1 selected from among
1-1 l-[(6-chloropyridin-3-yl)methyl]-N-{(2E)-3-[(3Z)-3-(lH-imidazol-5- ylmethylidene)-2-oxo-2,3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 ,2- dihy dropyridine-3 -carboxamide
1-2 l-[(6-chloropyridin-3-yl)methyl]-2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2- ylmethylidene)-2,3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} - 1 ,2-dihydropyridine-3- carboxamide;
1-3 l-[(6-chloropyridin-3-yl)methyl]-N-{(2E)-3-[(3Z)-3-{[4-(3-{[2-(dimethylamino)- ethyl] carbamoyl} phenyl)- lH-pyrrol-2-yl]methylidene} -2-oxo-2,3-dihydro- lH-indol-6- yl]prop-2-en- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3-carboxamide;
1-4 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-5 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(pyridin-4-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide; 1-6 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(pyridin-2-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-7 N-{(2E)-3-[(3Z)-3-(lH-imidazol-5-ylmethylidene)-2-oxo-2,3-dihydro-lH-indol-6- yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-8 N-{(2E)-3-[(3Z)-3-(lH-imidazol-5-ylmethylidene)-2-oxo-2,3-dihydro-lH-indol-6- yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-4-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-9 N-{(2E)-3-[(3Z)-3-(lH-imidazol-5-ylmethylidene)-2-oxo-2,3-dihydro-lH-indol-6- yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-2-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-10 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(pyrimidin-5-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide; 1-11 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(pyrimidin-4-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-12 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(pyrimidin-2-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-13 l-(cyclohexylmethyl)-2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2- ylmethylidene)-2,3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} - 1 ,2-dihydropyridine-3- carboxamide;
1-14 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(tetrahydro-2H-pyran-4-ylmethyl)- 1 ,2-dihydropyridine-3- carboxamide;
1-15 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(pyridazin-4-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide; 1-16 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2-ylmethylidene)-2,3-dihydro-lH- indol-6-yl]prop-2-en- 1 -yl} - 1 -(phenylamino)- 1 ,2-dihydropyridine-3-carboxamide;
1-17 l-[methyl(phenyl)amino]-2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2- ylmethylidene)-2,3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} - 1 ,2-dihy dropyridine-3 - carboxamide; 1-18 l-[(3,4-difluorophenyl)amino]-2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol-2- ylmethylidene)-2,3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} - 1 ,2-dihy dropyridine-3 - carboxamide;
1-19 l-[(3,4-difluorophenyl)(methyl)amino]-2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(lH-pyrrol- 2-ylmethylidene)-2,3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} - 1 ,2-dihy dropyridine-3 - carboxamide;
1-20 N- {(2E)-3-[(3Z)-3- {6-[(dimethylamino)methyl]-3,4-dihydroquinazolin-2(lH)-yli- den} -2-0X0-2, 3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2- dihy dropyridine-3 -carboxamide;
1-21 N-[(2E)-3-{(3Z)-3-[({4- [(dimethylamino)methyl]phenyl} amino)(phenyl)methylidene]-2-oxo-2,3-dihydro- IH- indol-6-yl}prop-2-en- 1 -yl]-2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihy dropyridine-3 - carboxamide;
1-22 N- {(2E)-3-[(3Z)-3-(2- {4-[(dimethylamino)methyl]phenyl}hydrazinyliden)-2-oxo- 2, 3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} -2-oxo-l -(pyridin-3-ylmethyl)- 1 ,2-dihydropy- ridine-3-carboxamide;
1-23 2-oxo-N-{(2E)-3-[(3Z)-2-oxo-3-(quinoline-2(lH)-yliden)-2,3-dihydro-lH-indol-6- yl]prop-2-en- 1 -yl} - 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
1-24 N-{(2E)-3-[(3Z)-3-(lH-imidazol-5-ylmethylidene)-2-oxo-2,3-dihydro-lH-indol-6- yl]prop-2-en- 1 -yl} - 1 -[(6-methylpyridin-3-yl)methyl]-2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
1-25 l-(cyclohexylmethyl)-N-{(2E)-3-[(3Z)-3-(lH-imidazol-5-ylmethylidene)-2-oxo- 2,3-dihydro- lH-indol-6-yl]prop-2-en- 1 -yl} -2-oxo-l ,2-dihydropyridine-3-carboxamide; 1-26 N-{(2E)-3-[(3Z)-3-(lH-imidazol-5-ylmethylidene)-2-oxo-2,3-dihydro-lH-indol-6- yl]prop-2-en- 1 -yl} - 1 -[(1 -methyl- lH-imidazol-5-yl)methyl]-2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
1-27 N-{(2E)-3-[(3Z)-3-(lH-imidazol-5-ylmethylidene)-2-oxo-2,3-dihydro-lH-indol-6- yl]prop-2-en- 1 -yl} - 1 -[(1 -methyl- lH-imidazol-4-yl)methyl]-2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
II-l 2-oxo-l-(pyridin-3-ylmethyl)-N-[3-(lH-pyrrolo[2,3-b]pyridin-3-yl)benzyl]-l,2- dihy dropyridine-3 -carboxamide;
II-2 2-oxo-N- {3-[2-(phenylamino)quinazolin-6-yl]prop-2-yn- 1 -yl} - 1 -(pyridin-3- ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide; II-3 l-[(6-chloropyridin-3-yl)methyl]-2-oxo-N-[3-(lH-pyrrolo[2,3-b]pyridin-3- yl)benzyl]- 1 ,2-dihydropyridine-3-carboxamide;
II-4 1 -[(6-chloropyridin-3-yl)methyl]-2-oxo-Λ/- {3-[2-(phenylamino)quinazolin-6- yl]prop-2-yn- 1 -yl} - 1 ,2-dihydropyridine-3-carboxamide;
II-5 N- {3-[2-( {4-[(dimethylamino)methyl]phenyl} amino)quinazolin-6-yl]prop-2-yn- 1 - yl}-2-oxo-l-(pyridin-3-ylmethyl)-l,2-dihydropyridine-3-carboxamide;
II-6 N- {3-[2-( {4-[(dimethylamino)methyl]phenyl} amino)quinazolin-6-yl]prop-2-yn- 1 - yl}-2-oxo-l-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-l,2-dihydropyridine-3- carboxamide;
II-7 7V-{3-[2-({3-fluoro-4-[(l-methylpiperidin-4-yl)amino]phenyl}amino)quinazolin-6- yl]prop-2-yn- 1 -yl} -2-oxo- 1 - { [6-(trifluoromethyl)pyridin-3-yl]methyl} - 1 ,2-dihydropyri- dine-3 -carboxamide;
II-8 Λ/-{3-[2-({4-[methyl(l-methylpiperidin-4-yl)amino]phenyl}amino)quinazolin-6- yl]prop-2-yn- 1 -yl} -2-oxo- 1 - { [6-(trifluoromethyl)pyridin-3-yl]methyl} - 1 ,2-dihydropyri- dine-3 -carboxamide;
II-9 Λ/-{3-[8-(3-aminopropoxy)-2-{[4-(morpholin-4-yl)phenyl]amino}quinazolin-6- yl]prop-2-yn- 1 -yl} -2-oxo- l-(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
II- 10 N- {3 - [8-(3-aminopropoxy)-2- { [4-(morpholin-4-yl)phenyl] amino } quinazo lin-6- yl]prop-2-yn- 1 -yl} - 1 -[(6-chlorpyridin-3-yl)methyl]-2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
H-Il N- {3-[2-( {4-[(dimethylamino)methyl]phenyl} amino)-5-fluoroquinazolin-6-yl]prop- 2-yn- 1 -yl} -2-oxo- l-(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
11-12 1 -[(6-chloropyridin-3-yl)methyl]-Λ/- {3-[2-( {4-[(dimethylamino)methyl]phenyl} - amino)-5-fluoroquinazolin-6-yl]prop-2-yn- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
11-13 Λ/-{3-[5-methyl-2-{[4-(morpholin-4-yl)phenyl]amino}-7-oxo-8-(propane-2-yl)-7.8- dihydropyrido [2,3-d]pyrimidin-6-yl]prop-2-yn- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-di- hydropyridine-3-carboxamide; 11-14 l-[(6-chloropyridin-3-yl)methyl]-N-{3-[5-methyl-2-{[4-(morpholin-4-yl)phenyl]- amino} -7-oxo-8-(propane-2-yl)-7.8-dihydropyrido[2,3-(i]pyrimidin-6-yl]prop-2-yn-l-yl}- 2-oxo- 1 ,2-dihydropyridine-3-carboxamide;
II- 15 N- {3 - [2-( {4- [(dimethylamino)methyl]phenyl} amino )pyrido [3 ,4-<i]pyrimidin-6- yl]prop-2-yn- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide; 11-16 1 -[(6-chloropyridin-3-yl)methyl]-JV- {3-[2-( {4-[(dimethylamino)methyl]phenyl} - amino)pyrido [3 ,4- J]pyrimidin-6-yl]prop-2-yn- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
11-17 Λ/-{3-[2-({4-[(dimethylamino)methyl]phenyl}amino)pyrido[2,3-(i]pyrimidin-6- yl]prop-2-yn- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide; 11-18 1 -[(6-chloropyridin-3-yl)methyl]-JV- {3-[2-( {4-[(dimethylamino)methyl]phenyl} - amino)pyrido[2,3- J]pyrimidin-6-yl]prop-2-yn- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
IH-I 2-oxo-N- {(2E)-3-[2-(phenylamino)quinazolin-6-yl]prop-2-en- 1 -yl} - 1 -(pyridin-3- ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
III-2 1 -[(6-chloropyridin-3-yl)methyl]-2-oxo-Λ/- {(2£)-3-[2-(phenylamino)quinazolin-6- yl]prop-2-en- 1 -yl} - 1 ,2-dihydropyridine-3-carboxamide;
III-3 N-[(2E)-3- {4-[5-amino-3-(phenylamino)- IH- 1 ,2,4-triazol- 1 -yl]-5-methoxypyrimi- din-2-yl}prop-2-en- 1 -yl]-2-oxo- 1 -(pyridin-3 -ylmethyl)- 1 ,2-dihy dropyridine-3 - carboxamide;
III-4 N- {(2E)-3-[4-(5-amino-3- {[4-(4-methylpiperazin- 1 -yl)phenyl] amino} - IH- 1 ,2,4- triazol- 1 -yl)-5-methoxypyrimidin-2-yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3 -ylmethyl)- 1 ,2- dihy dropyridine-3 -carboxamide; III-5 N-[(2E)-3- {4-[5-amino-3-(phenylamino)- IH- 1 ,2,4-triazol- 1 -yl]-5-methoxy-6-(pi- peridin-3-ylamino)pyrimidin-2-yl}prop-2-en- 1 -yl]-2-oxo- 1 -(pyridin-3 -ylmethyl)- 1 ,2-di- hydropyridine-3-carboxamide;
III-6 N-( {5-[5-amino-3-( {4-[(dimethylamino)methyl]phenyl} amino)- IH- 1 ,2,4-triazol- 1 - yl]-lH-pyrrolo[3.2-δ]pyridin-2-yl}methyl)-2-oxo-l-(pyridin-3-ylmethyl)-l,2-dihydropyri- dine-3 -carboxamide;
III-7 N-( {5-[5-amino-3-( {4-[(dimethylamino)methyl]phenyl} amino)- IH- 1 ,2,4-triazol- 1 - yl]- 1 -methyl- lH-pyrrolo[3.2-δ]pyridin-2-yl}methyl)-2-oxo- 1 -(pyridin-3 -ylmethyl)- 1 ,2-di- hydropyridine-3-carboxamide;
III-8 N-(I- {6-[5-amino-3-( {4-[(dimethylamino)methyl]phenyl} amino)- IH- 1 ,2,4-triazol- 1 -yl]pyridin-2-yl} ethyl)-2-oxo- 1 -(pyridin-3 -ylmethyl)- 1 ,2-dihy dropyridine-3 - carboxamide;
III-9 N- {2-[6-(5-amino-3- {[4-(4-methylpiperazin- 1 -yl)phenyl] amino} - IH- 1 ,2,4-triazol- 1 -yl)pyridin-2-yl] ethyl} -2-oxo- 1 -(pyridin-3 -ylmethyl)- 1 ,2-dihy dropyridine-3 - carboxamide; III-10 N-(I- {4-[5-amino-3-( {4-[(dimethylamino)methyl]phenyl} amino)- IH- 1 ,2,4-triazol- 1 -yl]pyrimidin-2-yl} ethyl)-2-oxo- 1 -(pyridin-3 -ylmethyl)- 1 ,2-dihy dropyridine-3 - carboxamide;
III-l 1 N- {2-[4-(5-amino-3- {[4-(4-methylpiperazin- 1 -yl)phenyl] amino} - IH- 1 ,2,4-triazol- 1 -yl)pyrimidin-2-yl]ethyl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3- carboxamide;
111-12 N- {(2E)-3-[2-( {4-[(dimethylamino)methyl]phenyl} amino)quinazolin-6-yl]prop-2- en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide; 111-13 1 -[(6-chloropyridin-3-yl)methyl]-N- {(2E)-3-[2-( {4-[(dimethylamino)methyl]- phenyl}amino)quinazolin-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3-carboxamide;
111-14 Λ/-{(2E)-3-[2-({3-fluoro-4-[(l-methylpiperidin-4-yl)amino]phenyl}amino)quinazo- lin-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 - { [6-(trifluoromethyl)pyridin-3-yl]methyl} - 1 ,2-dihydro- pyridine-3-carboxamide; 111-15 Λ/-{(2E)-3-[2-({4-[methyl(l-methylpiperidin-4-yl)amino]phenyl}amino)quinazolin- 6-yl]prop-2-en- 1 -yl} -2-oxo- 1 - { [6-(trifluoromethyl)pyridin-3-yl]methyl} - 1 ,2-dihydropyri- dine-3-carboxamide;
111-16 N- {(2E)-3-[2-( {4-[(dimethylamino)methyl]phenyl} amino)quinazolin-6-yl]prop-2- en- 1 -yl} -2-oxo- 1 - {[6-(trifluoromethyl)pyridin-3-yl]methyl} - 1 ,2-dihydropyridine-3- carboxamide;
III- 17 N- {(2E)-3 - [8-(3 -aminopropoxy)-2- { [4-(morpho lin-4-yl)phenyl]amino } quinazo lin- 6-yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
III- 18 N- {(2E)-3 - [8-(3 -aminopropoxy)-2- { [4-(morpho lin-4-yl)phenyl]amino } quinazo lin- 6-yl]prop-2-en- 1 -yl} - 1 -[(6-chlorpyridin-3-yl)methyl] -2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
111-19 N- {(2E)-3-[2-( {4-[(dimethylamino)methyl]phenyl} amino)-5-fluoroquinazolin-6- yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
111-20 1 -[(6-chloropyridin-3-yl)methyl]-JV- {(2E)-3-[2-( {4-[(dimethylamino)methyl]- phenyl}amino)-5-fluoroquinazolin-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
111-21 N-{(2E)-3-[5-methyl-2-{[4-(morpholin-4-yl)phenyl]amino}-7-oxo-8-(propane-2- yl)-7.8-dihydropyrido[2,3- J]pyrimidin-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- l,2-dihydropyridine-3-carboxamide; 111-22 l-[(6-chloropyridin-3-yl)methyl]-N-{(2E)-3-[5-methyl-2-{[4-(morpholin-4-yl)- phenyl]amino}-7-oxo-8-(propane-2-yl)-7.8-dihydropyrido[2,3-J]pyrimidin-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3-carboxamide;
111-23 Λ/-{(2E)-3-[2-({4-[(dimethylamino)methyl]phenyl}amino)pyrido[3,4-(i]pyrimidin- 6-yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
111-24 1 -[(6-chloropyridin-3-yl)methyl]-N- {(2E)-3-[2-( {4-[(dimethylamino)methyl]- phenyl} amino)pyrido [3 ,4-<i]pyrimidin-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
111-25 Λ/-{(2E)-3-[2-({4-[(dimethylamino)methyl]phenyl}amino)pyrido[2,3-(i]pyrimidin- 6-yl]prop-2-en- 1 -yl} -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
111-26 1 -[(6-chloropyridin-3-yl)methyl]-N- {(2E)-3-[2-( {4-[(dimethylamino)methyl]- phenyl} amino)pyrido[2,3- J]pyrimidin-6-yl]prop-2-en- 1 -yl} -2-oxo- 1 ,2-dihydropyridine-3- carboxamide;
111-27 2-oxo-l-(pyridin-3-ylmethyl)-N-{(2E)-3-[3-(lH-pyrrol-2-yl)-lH-indazol-6-yl]prop- 2-en- 1 -yl} - 1 ,2-dihydropyridine-3-carboxamide;
111-28 l-[(6-chloropyridin-3-yl)methyl]-2-oxo-N-{(2E)-3-[3-(lH-pyrrol-2-yl)-lH-indazol- 6-yl]prop-2-en- 1 -yl} - 1 ,2-dihydropyridine-3-carboxamide;
111-29 2-oxo-l-(pyridin-3-ylmethyl)-N-{3-[3-(lH-pyrrol-2-yl)-lH-indazol-6-yl]prop-2-yn- 1 -yl} - 1 ,2-dihydropyridine-3-carboxamide; 111-30 l-[(6-chloropyridin-3-yl)methyl]-2-oxo-N-{3-[3-(lH-pyrrol-2-yl)-lH-indazol-6- yl]prop-2-yn- 1 -yl} - 1 ,2-dihydropyridine-3-carboxamide;
111-31 N-[(2E)-3-(3- {4-[(dimethylamino)methyl]phenyl} - lH-indazol-6-yl)prop-2-en- 1 - yl] -2-oxo- 1 -(pyridin-3-ylmethyl)- 1 ,2-dihydropyridine-3-carboxamide;
111-32 1 -[(6-chloropyridin-3-yl)methyl]-N-[(2E)-3-(3- {4-[(dimethylamino)methyl]- phenyl} - lH-indazol-6-yl)prop-2-en- 1 -yl]-2-oxo- 1 ,2-dihydropyridine-3-carboxamide;
111-33 N-[3-(3- {4-[(dimethylamino)methyl]phenyl} - lH-indazol-6-yl)prop-2-yn- 1 -yl]-2- oxo-l-(pyridin-3-ylmethyl)-l,2-dihydropyridine-3-carboxamide; 111-34 1 -[(6-chloropyridin-3-yl)methyl]-JV-[3-(3- {4-[(dimethylamino)methyl]phenyl} - IH- indazol-6-yl)prop-2-yn- 1 -yl]-2-oxo- 1 ,2-dihydropyridine-3-carboxamide;
111-35 N- { 1 -[2-( {4-[(dimethylamino)methyl]phenyl} amino)quinazolin-6-yl]pyrrolidin-3- yl} -2-oxo- 1 -(pyridin-3 -ylmethyl)- 1 ,2-dihydropyridine-3 -carboxamide; 111-36 1 -[(6-chloropyridin-3-yl)methyl]-N- { 1 -[2-( {4-[(dimethylamino)methyl]phenyl} - amino)quinazolin-6-yl]pyrrolidin-3-yl} -2-oxo- 1 ,2-dihydropyridine-3 -carboxamide;
IV-I N-{3-[3-(lH-indole-2-yl)-4.6-dihydropyrrolo[3,4-c]pyrazol-5(lH)-yl]-3-oxopro- pyl}-2-oxo-l-(pyridin-3-ylmethyl)-l,2-dihydropyridine-3-carboxamide;
IV-2 l-[(6-chloropyridin-3-yl)methyl]-N-{3-[3-(lH-indol-2-yl)-4.6-dihydropyrrolo[3,4- c]pyrazol-5(lH)-yl]-3-oxopropyl}-2-oxo-l,2-dihydropyridine-3-carboxamide and
IV-3 N- {3-[3-( {[4-(4-methylpiperazin- 1 -yl)phenyl]carbonyl} amino)-4.6-dihydro- pyrrolo[3,4-c]pyrazol-5(lH)-yl]-3-oxopropyl} -2-oxo- l-(pyridin-3-ylmethyl)-l,2-dihydro- pyridine-3-carboxamide;
PCT/EP2009/059114 2008-07-16 2009-07-15 New chemical compounds WO2010007116A2 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US13/054,245 US8637549B2 (en) 2008-07-16 2009-07-15 Pyridons as PDK1 inhibitors
EP09780675.6A EP2321299B1 (en) 2008-07-16 2009-07-15 Pyridons as pdk1 inhibitors
CA2729990A CA2729990A1 (en) 2008-07-16 2009-07-15 New chemical compounds
JP2011517923A JP5612573B2 (en) 2008-07-16 2009-07-15 New chemical compounds

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP08160567.7 2008-07-16
EP08160567 2008-07-16
EP09160842 2009-05-20
EP09160842.2 2009-05-20

Publications (2)

Publication Number Publication Date
WO2010007116A2 true WO2010007116A2 (en) 2010-01-21
WO2010007116A3 WO2010007116A3 (en) 2010-06-17

Family

ID=41061260

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2009/059114 WO2010007116A2 (en) 2008-07-16 2009-07-15 New chemical compounds

Country Status (8)

Country Link
US (1) US8637549B2 (en)
EP (1) EP2321299B1 (en)
JP (1) JP5612573B2 (en)
AR (1) AR073255A1 (en)
CA (1) CA2729990A1 (en)
TW (1) TW201006837A (en)
UY (1) UY31982A (en)
WO (1) WO2010007116A2 (en)

Cited By (66)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011131741A1 (en) 2010-04-21 2011-10-27 Boehringer Ingelheim International Gmbh Heterocyclic carboxylic acid amides as pdk1 inihibitors
WO2011143430A1 (en) * 2010-05-12 2011-11-17 Abbott Laboratories Indazole inhibitors of kinase
WO2011144622A1 (en) 2010-05-17 2011-11-24 Boehringer Ingelheim International Gmbh 1h - imidazo [4, 5 - c] quinolines
JP2014516931A (en) * 2011-04-13 2014-07-17 エピザイム，インコーポレイティド Aryl-substituted or heteroaryl-substituted benzene compounds
US8853420B2 (en) 2008-07-29 2014-10-07 Boehringer Ingelheim International Gmbh Compounds
WO2014187932A1 (en) * 2013-05-24 2014-11-27 Janssen R&D Ireland Pyridone derivatives for the treatment of viral infections and further diseases
WO2014191911A1 (en) * 2013-05-28 2014-12-04 Novartis Ag Pyrazolo-pyrrolidin-4-one derivatives and their use in the treatment of disease
US8969341B2 (en) 2011-11-29 2015-03-03 Novartis Ag Pyrazolopyrrolidine compounds
US8975417B2 (en) 2013-05-27 2015-03-10 Novartis Ag Pyrazolopyrrolidine derivatives and their use in the treatment of disease
US9051279B2 (en) 2009-12-22 2015-06-09 Novartis Ag Substituted isoquinolinones and quinazolinones
US9133190B2 (en) 2012-11-08 2015-09-15 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands
US9365576B2 (en) 2012-05-24 2016-06-14 Novartis Ag Pyrrolopyrrolidinone compounds
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9403827B2 (en) 2013-01-22 2016-08-02 Novartis Ag Substituted purinone compounds
CN105859726A (en) * 2016-05-18 2016-08-17 南京富润凯德生物医药有限公司 Method for selective dehalogenation in pyrimidine fused ring
CN105949196A (en) * 2016-05-18 2016-09-21 南京富润凯德生物医药有限公司 Preparation method of MER/FLT3 dual-inhibitor intermediate
US9533984B2 (en) 2013-04-19 2017-01-03 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US9550796B2 (en) 2013-11-21 2017-01-24 Novartis Ag Pyrrolopyrrolone derivatives and their use as BET inhibitors
WO2017015152A1 (en) 2015-07-17 2017-01-26 Memorial Sloan-Kettering Cancer Center Combination therapy using pdk1 and pi3k inhibitors
US9556180B2 (en) 2013-01-22 2017-01-31 Novartis Ag Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the P53/MDM2 interaction
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9611267B2 (en) 2012-06-13 2017-04-04 Incyte Holdings Corporation Substituted tricyclic compounds as FGFR inhibitors
US9624247B2 (en) 2013-05-28 2017-04-18 Novartis Ag Pyrazolo-pyrrolidin-4-one derivatives as bet inhibitors and their use in the treatment of disease
US9708318B2 (en) 2015-02-20 2017-07-18 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9782408B2 (en) 2014-10-06 2017-10-10 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US9890166B2 (en) 2013-05-27 2018-02-13 Novartis Ag Imidazopyrrolidine derivatives and their use in the treatment of disease
US9890156B2 (en) 2015-02-20 2018-02-13 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10213427B2 (en) 2010-12-22 2019-02-26 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US10253003B2 (en) 2012-11-16 2019-04-09 Janssen Sciences Ireland Uc Heterocyclic substituted 2-amino quinazoline derivatives for the treatment of viral infections
US10259814B2 (en) 2012-10-10 2019-04-16 Janssen Sciences Ireland Uc Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
US10259793B2 (en) 2013-02-21 2019-04-16 Janssen Sciences Ireland Uc 2-aminopyrimidine derivatives for the treatment of viral infections
US10266543B2 (en) 2013-03-29 2019-04-23 Janssen Sciences Ireland Uc Macrocyclic deaza-purinones for the treatment of viral infections
US10272085B2 (en) 2011-04-08 2019-04-30 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US10280180B2 (en) 2012-07-13 2019-05-07 Janssen Sciences Ireland Uc Macrocyclic purines for the treatment of viral infections
US10280167B2 (en) 2011-11-09 2019-05-07 Janssen Sciences Ireland Uc Purine derivatives for the treatment of viral infections
US10316043B2 (en) 2013-07-30 2019-06-11 Janssen Sciences Ireland Unlimited Company Thieno[3,2-d]pyrimidines derivatives for the treatment of viral infections
US10385054B2 (en) 2013-06-27 2019-08-20 Janssen Sciences Ireland Unlimited Company Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
US10570115B2 (en) 2016-09-30 2020-02-25 Vertex Pharmaceuticals Incorporated Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US10611762B2 (en) 2017-05-26 2020-04-07 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US10654829B2 (en) 2017-10-19 2020-05-19 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US10738030B2 (en) 2016-03-31 2020-08-11 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10793547B2 (en) 2016-12-09 2020-10-06 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10968184B2 (en) 2016-09-29 2021-04-06 Janssen Sciences Ireland Unlimited Company Pyrimidine prodrugs for the treatment of viral infections and further diseases
US11053256B2 (en) 2016-07-01 2021-07-06 Janssen Sciences Ireland Unlimited Company Dihydropyranopyrimidines for the treatment of viral infections
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
US11179367B2 (en) 2018-02-05 2021-11-23 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for treating cystic fibrosis
US11253509B2 (en) 2017-06-08 2022-02-22 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US11414439B2 (en) 2018-04-13 2022-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11434201B2 (en) 2017-08-02 2022-09-06 Vertex Pharmaceuticals Incorporated Processes for preparing pyrrolidine compounds
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
US11465985B2 (en) 2017-12-08 2022-10-11 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US11517564B2 (en) 2017-07-17 2022-12-06 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11597704B2 (en) 2018-03-01 2023-03-07 Janssen Sciences Ireland Unlimited Company 2,4-diaminoquinazoline derivatives and medical uses thereof
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11642348B2 (en) 2012-10-15 2023-05-09 Epizyme, Inc. Substituted benzene compounds
US11672800B2 (en) 2017-04-21 2023-06-13 Epizyme, Inc. Combination therapies with EHMT2 inhibitors
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9266892B2 (en) 2012-12-19 2016-02-23 Incyte Holdings Corporation Fused pyrazoles as FGFR inhibitors
WO2014175370A1 (en) * 2013-04-25 2014-10-30 塩野義製薬株式会社 Pyrrolidine derivative and pharmaceutical composition containing same
WO2015068767A1 (en) * 2013-11-08 2015-05-14 小野薬品工業株式会社 Pyrrolo pyrimidine derivative
EP4116303A1 (en) * 2015-09-16 2023-01-11 Loxo Oncology, Inc. Pyrazolopyrimidine derivatives as btk inhibitors for the treatment of cancer
US11912668B2 (en) 2020-11-18 2024-02-27 Deciphera Pharmaceuticals, Llc GCN2 and perk kinase inhibitors and methods of use thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008005457A2 (en) * 2006-06-30 2008-01-10 Sunesis Pharmaceuticals Pyridinonyl pdk1 inhibitors
WO2008079371A1 (en) * 2006-12-22 2008-07-03 Encysive Pharmaceuticals, Inc. Modulators of c3a receptor and methods of use thereof

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7173031B2 (en) * 2004-06-28 2007-02-06 Bristol-Myers Squibb Company Pyrrolotriazine kinase inhibitors
WO2008152014A2 (en) * 2007-06-12 2008-12-18 Boehringer Ingelheim International Gmbh 3-hetrocyclylidene-indolinone derivatives as inhibitors of specific cell cycle kinases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008005457A2 (en) * 2006-06-30 2008-01-10 Sunesis Pharmaceuticals Pyridinonyl pdk1 inhibitors
WO2008079371A1 (en) * 2006-12-22 2008-07-03 Encysive Pharmaceuticals, Inc. Modulators of c3a receptor and methods of use thereof

Cited By (129)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8853420B2 (en) 2008-07-29 2014-10-07 Boehringer Ingelheim International Gmbh Compounds
US9051279B2 (en) 2009-12-22 2015-06-09 Novartis Ag Substituted isoquinolinones and quinazolinones
US20120094976A1 (en) * 2010-04-21 2012-04-19 Boehringer Ingelheim International Gmbh New chemical compounds
JP2013525333A (en) * 2010-04-21 2013-06-20 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Heterocyclic carboxylic amides as PDK1 inhibitors
WO2011131741A1 (en) 2010-04-21 2011-10-27 Boehringer Ingelheim International Gmbh Heterocyclic carboxylic acid amides as pdk1 inihibitors
WO2011143430A1 (en) * 2010-05-12 2011-11-17 Abbott Laboratories Indazole inhibitors of kinase
US8293738B2 (en) 2010-05-12 2012-10-23 Abbott Laboratories Indazole inhibitors of kinase
CN102958927A (en) * 2010-05-12 2013-03-06 Abbvie公司 Indazole inhibitors of kinase
JP2013526542A (en) * 2010-05-12 2013-06-24 アッヴィ・インコーポレイテッド Indazole inhibitor of kinase
WO2011144622A1 (en) 2010-05-17 2011-11-24 Boehringer Ingelheim International Gmbh 1h - imidazo [4, 5 - c] quinolines
JP2013526559A (en) * 2010-05-17 2013-06-24 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 1H-imidazo [4,5-c] quinoline
US8895581B2 (en) 2010-05-17 2014-11-25 Boehringer Ingelheim International Gmbh 1H-imidazo[4,5-c]quinolines
US10213427B2 (en) 2010-12-22 2019-02-26 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US10813930B2 (en) 2010-12-22 2020-10-27 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US11541050B2 (en) 2011-04-08 2023-01-03 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US10272085B2 (en) 2011-04-08 2019-04-30 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US10780089B2 (en) 2011-04-08 2020-09-22 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
US10420767B2 (en) 2011-04-08 2019-09-24 Janssen Sciences Ireland Uc Pyrimidine derivatives for the treatment of viral infections
JP2014516931A (en) * 2011-04-13 2014-07-17 エピザイム，インコーポレイティド Aryl-substituted or heteroaryl-substituted benzene compounds
US10155002B2 (en) 2011-04-13 2018-12-18 Epizyme, Inc. Aryl- or heteroaryl-substituted benzene compounds
US10420775B2 (en) 2011-04-13 2019-09-24 Epizyme, Inc. Aryl-or heteroaryl-substituted benzene compounds
JP2021042243A (en) * 2011-04-13 2021-03-18 エピザイム，インコーポレイティド Aryl- or heteroaryl-substituted benzene compounds
US11052093B2 (en) 2011-04-13 2021-07-06 Epizyme, Inc. Aryl-or heteroaryl-substituted benzene compounds
US10280167B2 (en) 2011-11-09 2019-05-07 Janssen Sciences Ireland Uc Purine derivatives for the treatment of viral infections
US11104678B2 (en) 2011-11-09 2021-08-31 Janssen Sciences Ireland Unlimited Company Purine derivatives for the treatment of viral infections
US8969341B2 (en) 2011-11-29 2015-03-03 Novartis Ag Pyrazolopyrrolidine compounds
US9365576B2 (en) 2012-05-24 2016-06-14 Novartis Ag Pyrrolopyrrolidinone compounds
US11053246B2 (en) 2012-06-13 2021-07-06 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US11840534B2 (en) 2012-06-13 2023-12-12 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US10131667B2 (en) 2012-06-13 2018-11-20 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US9611267B2 (en) 2012-06-13 2017-04-04 Incyte Holdings Corporation Substituted tricyclic compounds as FGFR inhibitors
US10280180B2 (en) 2012-07-13 2019-05-07 Janssen Sciences Ireland Uc Macrocyclic purines for the treatment of viral infections
US10822349B2 (en) 2012-07-13 2020-11-03 Janssen Sciences Ireland Unlimited Company Macrocyclic purines for the treatment of viral infections
US9745311B2 (en) 2012-08-10 2017-08-29 Incyte Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US9388185B2 (en) 2012-08-10 2016-07-12 Incyte Holdings Corporation Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors
US10259814B2 (en) 2012-10-10 2019-04-16 Janssen Sciences Ireland Uc Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
US11220504B2 (en) 2012-10-10 2022-01-11 Janssen Sciences Ireland Unlimited Company Pyrrolo[3,2-d] pyrimidine derivatives for the treatment of viral infections and other diseases
US11642348B2 (en) 2012-10-15 2023-05-09 Epizyme, Inc. Substituted benzene compounds
US9527843B2 (en) 2012-11-08 2016-12-27 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands
US9133190B2 (en) 2012-11-08 2015-09-15 Pfizer Inc. Heteroaromatic compounds and their use as dopamine D1 ligands
US10253003B2 (en) 2012-11-16 2019-04-09 Janssen Sciences Ireland Uc Heterocyclic substituted 2-amino quinazoline derivatives for the treatment of viral infections
US10723707B2 (en) 2012-11-16 2020-07-28 Janssen Sciences Ireland Unlimited Company Heterocyclic substituted 2-amino quinazoline derivatives for the treatment of viral infections
US9556180B2 (en) 2013-01-22 2017-01-31 Novartis Ag Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the P53/MDM2 interaction
US9403827B2 (en) 2013-01-22 2016-08-02 Novartis Ag Substituted purinone compounds
US10647684B2 (en) 2013-02-21 2020-05-12 Janssen Sciences Ireland Unlimited Company 2-aminopyrimidine derivatives for the treatment of viral infections
US10259793B2 (en) 2013-02-21 2019-04-16 Janssen Sciences Ireland Uc 2-aminopyrimidine derivatives for the treatment of viral infections
US11702426B2 (en) 2013-03-29 2023-07-18 Janssen Sciences Ireland Unlimited Company Macrocyclic deaza-purinones for the treatment of viral infections
US10266543B2 (en) 2013-03-29 2019-04-23 Janssen Sciences Ireland Uc Macrocyclic deaza-purinones for the treatment of viral infections
US10829494B2 (en) 2013-03-29 2020-11-10 Janssen Sciences Ireland Unlimited Company Macrocyclic deaza-purinones for the treatment of viral infections
US10040790B2 (en) 2013-04-19 2018-08-07 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US9533984B2 (en) 2013-04-19 2017-01-03 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US11530214B2 (en) 2013-04-19 2022-12-20 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10947230B2 (en) 2013-04-19 2021-03-16 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US10450313B2 (en) 2013-04-19 2019-10-22 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10377738B2 (en) 2013-05-24 2019-08-13 Janssen Sciences Ireland Unlimited Company Pyridone derivatives for the treatment of viral infections and further diseases
US10865193B2 (en) 2013-05-24 2020-12-15 Janssen Sciences Ireland Unlimited Company Pyridone derivatives for the treatment of viral infections and further diseases
WO2014187932A1 (en) * 2013-05-24 2014-11-27 Janssen R&D Ireland Pyridone derivatives for the treatment of viral infections and further diseases
EA034674B1 (en) * 2013-05-24 2020-03-05 Янссен Сайенсиз Айрлэнд Юси Pyridone derivatives for the treatment of disorders in which the modulation of tlr7 and/or tlr8 is involved
CN105377833B (en) * 2013-05-24 2018-11-06 爱尔兰詹森科学公司 Pyridione derivatives for treating virus infection and other disease
CN105377833A (en) * 2013-05-24 2016-03-02 爱尔兰詹森科学公司 Pyridone derivatives for treatment of viral infections and further diseases
KR20160013060A (en) * 2013-05-24 2016-02-03 얀센 사이언시즈 아일랜드 유씨 Pyridone derivatives for the treatment of viral infections and further diseases
US9890166B2 (en) 2013-05-27 2018-02-13 Novartis Ag Imidazopyrrolidine derivatives and their use in the treatment of disease
US8975417B2 (en) 2013-05-27 2015-03-10 Novartis Ag Pyrazolopyrrolidine derivatives and their use in the treatment of disease
WO2014191911A1 (en) * 2013-05-28 2014-12-04 Novartis Ag Pyrazolo-pyrrolidin-4-one derivatives and their use in the treatment of disease
EA028035B1 (en) * 2013-05-28 2017-09-29 Новартис Аг Pyrazolo-pyrrolidin-4-one derivatives and their use in the treatment of disease
US9714249B2 (en) 2013-05-28 2017-07-25 Novartis Ag Pyrazolo-pyrrolidin-4-one derivatives and their use in the treatment of disease
US9624247B2 (en) 2013-05-28 2017-04-18 Novartis Ag Pyrazolo-pyrrolidin-4-one derivatives as bet inhibitors and their use in the treatment of disease
CN105246896B (en) * 2013-05-28 2017-09-08 诺华股份有限公司 The ketone derivatives of pyrazoles pyrrolizine 4 and its purposes in treatment disease
AU2014272700B2 (en) * 2013-05-28 2016-12-01 Novartis Ag Pyrazolo-pyrrolidin-4-one derivatives and their use in the treatment of disease
CN105246896A (en) * 2013-05-28 2016-01-13 诺华股份有限公司 Pyrazolo-pyrrolidin-4-one derivatives and their use in the treatment of disease
US10385054B2 (en) 2013-06-27 2019-08-20 Janssen Sciences Ireland Unlimited Company Pyrrolo[3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
US10781216B2 (en) 2013-06-27 2020-09-22 Janssen Sciences Ireland Unlimited Company Pyrrolo [3,2-d]pyrimidine derivatives for the treatment of viral infections and other diseases
US10822347B2 (en) 2013-07-30 2020-11-03 Janssen Sciences Ireland Unlimited Company Thieno[3,2-d]pyrimidines derivatives for the treatment of viral infections
US10316043B2 (en) 2013-07-30 2019-06-11 Janssen Sciences Ireland Unlimited Company Thieno[3,2-d]pyrimidines derivatives for the treatment of viral infections
US9550796B2 (en) 2013-11-21 2017-01-24 Novartis Ag Pyrrolopyrrolone derivatives and their use as BET inhibitors
US10258624B2 (en) 2014-10-06 2019-04-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US9782408B2 (en) 2014-10-06 2017-10-10 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10758534B2 (en) 2014-10-06 2020-09-01 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11426407B2 (en) 2014-10-06 2022-08-30 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11014923B2 (en) 2015-02-20 2021-05-25 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11667635B2 (en) 2015-02-20 2023-06-06 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10251892B2 (en) 2015-02-20 2019-04-09 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10738048B2 (en) 2015-02-20 2020-08-11 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9580423B2 (en) 2015-02-20 2017-02-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9801889B2 (en) 2015-02-20 2017-10-31 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10214528B2 (en) 2015-02-20 2019-02-26 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9708318B2 (en) 2015-02-20 2017-07-18 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10632126B2 (en) 2015-02-20 2020-04-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US9890156B2 (en) 2015-02-20 2018-02-13 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11173162B2 (en) 2015-02-20 2021-11-16 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10016438B2 (en) 2015-02-20 2018-07-10 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11696924B2 (en) 2015-07-17 2023-07-11 Memorial Sloan-Kettering Cancer Center Combination therapy using PDK1 and PI3K inhibitors
WO2017015152A1 (en) 2015-07-17 2017-01-26 Memorial Sloan-Kettering Cancer Center Combination therapy using pdk1 and pi3k inhibitors
US10738030B2 (en) 2016-03-31 2020-08-11 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
CN105949196A (en) * 2016-05-18 2016-09-21 南京富润凯德生物医药有限公司 Preparation method of MER/FLT3 dual-inhibitor intermediate
CN105859726A (en) * 2016-05-18 2016-08-17 南京富润凯德生物医药有限公司 Method for selective dehalogenation in pyrimidine fused ring
CN105859726B (en) * 2016-05-18 2018-07-13 南京富润凯德生物医药有限公司 A kind of method of selective dehalogenate in pyrimido ring
CN105949196B (en) * 2016-05-18 2018-06-29 南京富润凯德生物医药有限公司 A kind of preparation method of MER/FLT3 double inhibitors intermediate
US11053256B2 (en) 2016-07-01 2021-07-06 Janssen Sciences Ireland Unlimited Company Dihydropyranopyrimidines for the treatment of viral infections
US10968184B2 (en) 2016-09-29 2021-04-06 Janssen Sciences Ireland Unlimited Company Pyrimidine prodrugs for the treatment of viral infections and further diseases
US11186566B2 (en) 2016-09-30 2021-11-30 Vertex Pharmaceuticals Incorporated Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US10570115B2 (en) 2016-09-30 2020-02-25 Vertex Pharmaceuticals Incorporated Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11453655B2 (en) 2016-12-09 2022-09-27 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US10793547B2 (en) 2016-12-09 2020-10-06 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11672800B2 (en) 2017-04-21 2023-06-13 Epizyme, Inc. Combination therapies with EHMT2 inhibitors
US10611762B2 (en) 2017-05-26 2020-04-07 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US11472801B2 (en) 2017-05-26 2022-10-18 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US11253509B2 (en) 2017-06-08 2022-02-22 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11517564B2 (en) 2017-07-17 2022-12-06 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11434201B2 (en) 2017-08-02 2022-09-06 Vertex Pharmaceuticals Incorporated Processes for preparing pyrrolidine compounds
US11155533B2 (en) 2017-10-19 2021-10-26 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US10654829B2 (en) 2017-10-19 2020-05-19 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US11465985B2 (en) 2017-12-08 2022-10-11 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US11179367B2 (en) 2018-02-05 2021-11-23 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for treating cystic fibrosis
US11597704B2 (en) 2018-03-01 2023-03-07 Janssen Sciences Ireland Unlimited Company 2,4-diaminoquinazoline derivatives and medical uses thereof
US11414439B2 (en) 2018-04-13 2022-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
US11168093B2 (en) 2018-12-21 2021-11-09 Celgene Corporation Thienopyridine inhibitors of RIPK2
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors

Also Published As

Publication number Publication date
EP2321299B1 (en) 2016-02-24
AR073255A1 (en) 2010-10-28
JP2011528026A (en) 2011-11-10
JP5612573B2 (en) 2014-10-22
CA2729990A1 (en) 2010-01-21
WO2010007116A3 (en) 2010-06-17
UY31982A (en) 2010-02-26
US20110269958A1 (en) 2011-11-03
TW201006837A (en) 2010-02-16
EP2321299A2 (en) 2011-05-18
US8637549B2 (en) 2014-01-28

Similar Documents

Publication Publication Date Title
WO2010007116A2 (en) New chemical compounds
WO2010007114A2 (en) New chemical compounds
EP2398797B1 (en) Pyrimido[5,4-d]pyrimidine derivatives for the inhibition of tyrosine kinases
JP2011528026A6 (en) New chemical compounds
AU2009289196A1 (en) Pyrido [5, 4-d] pyrimidines as cell proliferation inhibitors
US20100210644A1 (en) Chemical compounds
JP2011528025A6 (en) New chemical compounds
WO2009003998A2 (en) Antiproliferative compounds based on 5-membered heterocycles
CA2654670A1 (en) New compounds
EP2181108A2 (en) 3-hetrocyclylidene-indolinone derivatives as inhibitors of specific cell cycle kinases
AU2009275964A1 (en) New compounds
WO2008152013A1 (en) Indolinone derivatives and their use in treating disease-states such as cancer
US20090186901A1 (en) Chemical compounds
EP2032583B1 (en) New chemical compounds

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 09780675

Country of ref document: EP

Kind code of ref document: A2

ENP Entry into the national phase

Ref document number: 2729990

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2011517923

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2009780675

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 13054245

Country of ref document: US