DK2748166T3 - Pyrimido-pyridazinonforbindelser og anvendelse deraf - Google Patents

Pyrimido-pyridazinonforbindelser og anvendelse deraf Download PDF

Info

Publication number
DK2748166T3
DK2748166T3 DK12756865.7T DK12756865T DK2748166T3 DK 2748166 T3 DK2748166 T3 DK 2748166T3 DK 12756865 T DK12756865 T DK 12756865T DK 2748166 T3 DK2748166 T3 DK 2748166T3
Authority
DK
Denmark
Prior art keywords
amino
phenyl
pyridazin
oxo
alkyl
Prior art date
Application number
DK12756865.7T
Other languages
English (en)
Inventor
Aranapakam Venkatesan
Roger Astbury Smith
Subramanya Hosahalli
Vijay Potluri
Sunil Kumar Panigrahi
Karunasree Kuntu
Vishnu Basetti
Original Assignee
Asana Biosciences Llc
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 Asana Biosciences Llc filed Critical Asana Biosciences Llc
Application granted granted Critical
Publication of DK2748166T3 publication Critical patent/DK2748166T3/da

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • 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
    • 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
    • A61P25/00—Drugs for disorders of the nervous 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • 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
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Pulmonology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Diabetes (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Psychiatry (AREA)
  • Dermatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Transplantation (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Claims (19)

1. Forbindelse med formlen (I):
hvor: R1 erNR4R5, en Ci- til C6-alkoxy, der er usubstitueret eller substitueret med én eller flere af halogen, OH, alkoxy, NH2, (alkyl)amino-, di(alkyl)amino-, (alkyl)C(O)N(Ci-C3-alkyl)-, (alkyl)carboxyamido-, HC(O)NH-, H2NC(O)-, (alkyl)NHC(O)-, di(alkyl)NC(O)-, CN, C(O)OH, (alkoxy)carbonyl-, (alkyl)C(O)-, aryl, heteroaryl, cycloalkyl, haloalkyl, amino(Ci-C6-alkyl)-, (alkyl)carboxyl-, carboxyamidoalkyl- eller NO2, en C6- til Cw-aryl, der er usubstitueret eller substitueret med én eller flere af alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, OH, hydroxyalkyl, -O-(hydroxyalkyl), -O-(alkyl)-C(O)OH, -(alkyl)-(alkoxy)-halogen, NH2, aminoalkyl-, dialkylamino-, C(O)OH, -C(O)O-(alkyl),-OC(O)(alkyl), -O-(alkyl)-N(alkyl)(alkyl), N-alkylamido-, -C(O)NH2, (alkyl)amido-, NO2, (aryl)alkyl, aryloxy, heteroaryloxy, (aryl)amino, (alkoxy)carbonyl-, (alkyl)amido-, (alkyl)amino, alkylcarboxyl-, (alkyl)carboxyamido-, (aryl)alkyl-, (aryl)amino-, cycloalkenyl, heteroaryl, (heteroaryl)alkyl-, heterocyclyl, -O-(heterocyclyl), heterocyclyl(alkyl)-, (hydroxyalkyl)NH-, (hydroxyalkyl)2N, -SO2(alkyl) eller en spiro-substituent, en heteroaryl, der er usubstitueret eller substitueret med én eller flere af Ci-C6-alkyl, halogen, haloalkyl, OH, CN, hydroxyalkyl, NH2, aminoalkyl-, dialkylamino-, C(O)OH, -C(O)O-(alkyl), -OC(O)(alkyl), N-alkylamido-,-C(O)NH2, (alkyl)amido-, -NO2, (aryl)alkyl, alkoxy, aryloxy, heteroaryloxy, (aryl)amino, (alkoxy)carbonyl-, (alkyl)amido-, (alkyl)amino, aminoalkyl-, alkylcarboxyl-, (alkyl)carboxyamido-, (aryl)alkyl-, (aryl)amino-, cycloalkenyl, heteroaryl, (heteroaryl)alkyl-, heterocyclyl, hetyerocyclyl(alkyl)-, (hydroxyalkyl)NH-, (hydroxyalkyl)2N eller en spiro-substituent, en 3-1 O-leddet monocyklisk eller bicyklisk cycloalkyl, der er usubstitueret eller substitueret med én eller flere af halogen, NH2, (alkyl)NH, (alkyl)(alkyl)N-, -N(alkyl)C(O)(alkyl), -NHC(O)(alkyl), -NHC(O)H, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)(alkyl), CN, OH, alkoxy, alkyl, C(O)OH, -C(O)O(alkyl), -C(O)alkyl), aryl, heteroaryl, cycloalkyl, haloalkyl, aminoalkyl-, -OC(O)(alkyl), carboxyamidoalkyl- og NO2,
eller en 3-1 O-leddet monocyklisk eller bicyklisk heterocyclyl, der er usubstitueret eller substitueret med én eller flere af alkyl, halogen, alkoxy, haloalkyl, OH, hydroxyalkyl, -C(O)-(hydroxyalkyl), NH2, aminoalkyl-, dialkylamino-, C(O)OH, -C(O)O-(alkyl), -OC(O)(alkyl), N-alkylamido-, -C(O)NH2, (alkyl)amido-, -C(O)-(alkyl)-CN, (alkyl)-CN eller NO2, hvor: (i) 3-4-leddede cycloalkyl og heterocyclyl er mættede; (ii) hydrogenatomer på det samme carbonatom af cycloalkyl eller heterocyclyl eventuelt er udskiftet med en 3-6-leddet cycloalkyl, der er usubstitueret eller substitueret med én eller flere af halogen, NH2, (alkyl)NH, (alkyl)(alkyl)N-, -N(alkyl)C(O)(alkyl), -NHC(O)(alkyl), -NHC(O)H, -C(O)NH2, -C(O)NH(alkyl), -C(O)N(alkyl)(alkyl), CN, OH, alkoxy, alkyl, C(O)OH, -C(O)O(alkyl),-C(O)alkyl), aryl, heteroaryl, cycloalkyl, haloalkyl, aminoalkyl-, -OC(O)(alkyl), carboxyamidoalkyl- og NO2 eller en heterocyclyl, der er usubstitueret eller substitueret med én eller flere af alkyl, halogen, alkoxy, haloalkyl, OH, hydroxyalkyl, -C(O)-(hydroxyalkyl), NH2, aminoalkyl-, dialkylamino-, C(O)OH, -C(O)O-(alkyl), -OC(O)(alkyl), N-alkylamido-, -C(O)NH2, (alkyl)amido-, -C(O)-(alkyl)-CN, (alkyl)-CN eller NO2 for at danne en spirocycloalkyl eller spiroheterocyclyl; og (iii) hydrogenatomer på det samme carbonatom af cycloalkyl eller heterocyclyl eventuelt er udskiftet med O for at danne en oxo-substituent; R2 er phenyl, phenyl substitueret med C(O)NR4R5, phenyl substitueret med NR4R5 eller phenyl substitueret med (Ci- til C6-alkyl) NR4R5, phenyl substitueret med én eller flere Ci- til C6-alkoxy, (Ci- til C6-alkyl)halogen, Ci- til C6-trifluoralkoxy, (Ci- til C6-alkyl)C(O)OH, halogen, den usubstituerede eller substituerede C3- til Cg-cycloalkyl, den usubstituerede eller substituerede heterocyclyl, den usubstituerede eller substituerede heteroaryl, -O-(Ci- til C6-alkyl)C(O)OH, -O-(Ci-til C6-alkyl)-NR4R5, -O-(den usubstituerede eller substituerede heterocyklus), -O(Ci- til C6-alkyl)-N(Ci- til C6-alkyl)(Ci- til C6-alkyl), -O-(Ci- til C6-alkyl)NH2, Ci- til C6-hydroxyalkyl, -O-(Ci- til C6-hydroxyalkyl), O-(Ci- til C6-alkyl)-C(O)OH, -Ci- til C6-alkoxy-Ci- til C6-alkoxy, O-(heterocyklus)-(Ci- til C6-hydroxyalkyl), SO2-(Ci- til C6-alkyl) eller -(Ci- til C6-alkyl)-(Ci- til C6-alkoxy)-halogen; phenyl substitueret med -O-(Ci- til C6-alkyl)-heterocyklus; eller en 5-6-leddet heteroaryl, der er usubstitueret eller substitueret med (Ci- til C6-alkyl)NR4R5 eller substitueret med NR4R5, forudsat, når R2 er 4-pyridyl, at 4-pyridyl ikke har en carbonylsubstituent ved den anden position; R4 og R5 er: (a) uafhængigt valgt fra gruppen bestående af H, Ci- til C6-alkyl, Ci- til C6-hydroxyalkyl, C3- til Cg-cycloalkyl og -(Ci- til C6-alkyl)N(Ci- til C6-alkyl)(Ci- til C6-alkyl); (b) samles for at danne en 3-8-leddet heterocyclyl, der er usubstitueret eller substitueret med én eller flere af alkyl, halogen, alkoxy, haloalkyl, OH, hydroxyalkyl, -C(O)-(hydroxyalkyl), NH2, aminoalkyl-, dialkylamino-, C(O)OH, -C(O)O-(alkyl), -OC(O)(alkyl), N-alkylamido-, -C(O)NH2, (alkyl)amido-, -C(O)-(alkyl)-CN, (alkyl)-CN eller NO2, hvor; (bi) hydrogenatomer på det samme carbonatom af heterocyclyl eventuelt er udskiftet med en 3-6-leddet cycloalkyl, der er usubstitueret eller substitueret med én eller flere af halogen, NH2, (alkyl)NH, (alkyl)(alkyl)N-, -N(alkyl)C(O)(alkyl), -NHC(O)(alkyl), -NHC(O)H, -C(O)NH2, -C(O)NH(alkyl),-C(O)N(alkyl)(alkyl), CN, OH, alkoxy, alkyl, C(O)OH, -C(O)O(alkyl), -C(O) alkyl), aryl, heteroaryl, cycloalkyl, haloalkyl, aminoalkyl-, -OC(O)(alkyl), carboxyamidoalkyl- og NO2 eller en heterocyclyl, der er usubstitueret eller substitueret med én eller flere af alkyl, halogen, alkoxy, haloalkyl, OH, hydroxyalkyl, -C(O)-(hydroxyalkyl), NH2, aminoalkyl-, dialkylamino-, C(O)OH, -C(O)O-(alkyl), -OC(O)(alkyl), N-alkylamido-, -C(O)NH2, (alkyl) amido-, -C(O)-(alkyl)-CN, (alkyl)-CN eller NO2, for at danne en spirocycloalkyl eller spiroheterocyclyl; og (bii) hydrogenatomer på det samme carbonatom af heterocyclyl (b), cycloalkyl (bi) eller heterocyclyl (bi), eventuelt er udskiftet med O for at danne en oxo-substituent; eller et farmaceutisk acceptabelt salt eller en ester deraf.
2. Forbindelse med formlen (I):
hvor: R1 er NR4R5, en Ci- til C6-alkoxy, en C6- til Cn-aryl, en heteroaryl, en 3-10-leddet monocyklisk eller bicyklisk cycloalkyl eller en 3-10-leddet monocyklisk eller bicyklisk heterocyclyl, hvor: (i) 3-4-leddet cycloalkyl og heterocyclyl er mættede;
(ii) hydrogenatomer på det samme carbonatom af cycloalkyl eller heterocyclyl eventuelt er udskiftet med en 3-6-leddet cycloalkyl eller heterocyclyl for at danne en spirocycloalkyl eller spiroheterocyclyl; og (iii) hydrogenatomer på det samme carbonatom af cycloalkyl eller heterocyclyl eventuelt i er udskiftet med O for at danne en oxo-substituent; R2 er en phenyl eller en 5-6-leddet heteroaryl, forudsat, når R2 er 4-pyridyl, at 4-pyridyl ikke har en carbonylsubstituent ved den anden position; R4 og R5 er: (a) uafhængigt valgt fra gruppen bestående af H, Ci- til C6-alkyl, Ci- til C6-hydroxyalkyl, ) C3- til Cg-cycloalkyl og -(Ci- til C6-alkyl)N(Ci- til C6-alkyl)(Ci- til C6-alkyl); (b) samles for at dannes en 3-8-leddet heterocyclyl, hvor; (bi) hydrogenatomer på det samme carbonatom af heterocyclyl eventuelt er udskiftet med en 3-6-leddet cycloalkyl eller heterocyclyl for at danne en spirocycloalkyl eller spiroheterocyclyl; og i (bii) hydrogenatomer på det samme carbonatom af heterocyclyl (b), cycloalkyl (bi) eller heterocyclyl (bi), eventuelt er udskiftet med O for at danne en oxo-substituent; eller et farmaceutisk acceptabelt salt eller ester deraf.
3. Forbindelse ifølge krav 2, hvor R2 er a) phenyl substitueret med C(O)NR4R5; b) phenyl ) substitueret med NR4R5 eller c) phenyl substitueret med (Ci- til C6-alkyl)NR4R5.
4. Forbindelse ifølge krav 1 eller 3, hvor R2 er phenyl substitueret med C(O)NR4R5, hvor C(O)NR4R5 er:
5. Forbindelse ifølge krav 1 eller 3, hvor R2 er phenyl substitueret med NR4R5 eller (Ci- til C6-alkyl)NR4R5, hvor a) NR4R5 er: )
eller
b) R4 og R5 tages sammen med det nitrogenatom, hvortil de er bundet, for at danne en gruppe valgt fra følgende: bl) hvor R4 og R5 tages sammen for at danne en 6-leddet ring eller en 7-leddet ring; b2) hvor R4 og R5 samles for at danne en heterocyclyl med strukturen:
hvor: a, b, c, d og e uafhængigt er fraværende, (CH2), CH(R3), Z eller C=O; R3 er H, C(O)OH, Ci- til C6-hydroxyalkyl eller C(O)O(Ci- til C6-alkyl); R10, R11, R12 og R13 uafhængigt er H eller Ci- til C6-alkyl; og Z er O, S eller NH; b3) hvor R4 og R5 tages sammen for at danne en heterocyclyl med strukturen:
hvor: R10, R11, R12 og R13 uafhængigt er H eller Ci- til C6-alkyl; Y er O eller NR9; og R9 er H, Ci- til C6-alkyl, OH, C(O)OH, Ci- til C6-hydroxyalkyl, (Ci- til C6-alkyl)NH2, (Ci- til C6-alkyl)N(Ci- til C6-alkyl)(Ci- til C6-alkyl), (Ci- til C6-alkyl)(Ci- til C6-alkoxy), C(O)(Ci- til C6-alkyl)NH2, (Ci- til C6-alkyl)C(O)OH, C(O)(Ci- til C6-hydroxyalkyl), C(O)(Ci- til C6-alkyl)CN, (Ci- til C6-alkyl)CN, (Ci- til C6-alkyl)halogen eller (Ci- til C6-alkyl)O(Ci- til C6-alkyl)C(O)(Ci- til C6-alkyl)NH2; hvor 2 hydrogenatomer bundet til det samme carbonatom eventuelt er udskiftet med =0; eller b4) hvor R4 og R5 tages sammen for at danne et morpholin eller piperazin med strukturen:
eller
eller hvor c) R4 og R5 hver uafhængigt er (Ci- til C6-hydroxyalkyl). )
6. Forbindelse ifølge krav 5, hvor R4 og R5 samles for at danne en heterocyclyl med strukturen:
or
hvor: i R10, R11, R12 og R13 uafhængigt er H eller Ci- til C6-alkyl; R14 er halogen, OH, C(O)OH, Ci- til C6-alkoxy, (Ci- til C6-alkyl)halogen, (Ci- til C6-alkyl)C(O)OH, Ci- til C6-hydroxyalkyl, C3- til Cg-cycloalkyl, (Ci- til C6-alkyl)C(O)NH2, (Ci- til C6-alkyl)C(O)NH(Ci- til C6-hydroxyalkyl), (Ci- til C6-alkyl)C(O)N(Ci- til C6-hydroxyalkyl)2, (Ci- til C6-alkyl)CN, (Ci- til C6-alkyl)heteroaryl eller heteroaryl; og ) R18 er Ci- til C6-hydroxyalkyl eller Ci- til C6-alkyl-C(O)OH.
7. Forbindelse ifølge krav 6, hvor R4 og R5 samles for at danne piperidin eller et diazepan eller et substitueret piperidin eller diazepan valgt fra gruppen bestående af:
)
8. Forbindelse ifølge krav 5, hvor R4 og R5 samles for at danne:
9. Forbindelse ifølge krav 5, hvor den 6-leddede ring er a)
hvor: ) R14 er H, OH, C(O)OH, Ci- til C6-alkyl eller (Ci- til C6-alkyl)CN; b)
hvor: Y er O eller NR9; og i R9 er H, Ci- til C6-alkyl, OH, Ci- til C6-hydroxyalkyl, C(O) (Ci- til C6-hydroxyalkyl), C(O)(Ci- til C6-alkyl)CN, (Cr til C6-alkyl)CN, (Cr til C6-alkyl)NH2, (Cr til C6-alkyl)halogen, C(O) (Ci- til C6-alkyl)CN eller (Ci- til C6-alkyl)O(Ci- til C6-alkyl)C(O)(Ci- til C6-alkyl)NH2; eller c) )
hvor: a, b, c, d og e uafhængigt er fraværende, (CH2), CH(R3) eller O; og R3 er H eller C(O)OH.
10. Forbindelse ifølge krav 2, hvor R2 er a) en heteroaryl substitueret med (Ci- til C6-alkyl)NR4R5; eller b) hvor R2 er en heteroaryl substitueret med NR4R5; eller c) hvor R2 er phenyl substitueret med én eller flere Ci- til C6-alkoxy, (Ci- til C6- i alkyl)halogen, Ci- til C6-trifluoralkoxy, (Ci- til C6-alkyl)C(O(OH, halogen, den usubstituerede eller substituerede C3- til Cg-cycloalkyl, den usubstituerede eller substituerede heterocyclyl, den usubstituerede eller substituerede heteroaryl, -O-(Ci- til C6-alkyl)C(O)OH, -O-(Ci- til C6-alkyl)-NR4R5, -O-(den usubstituerede eller substituerede heterocyklus), -O(Ci- til C6-alkyl)-N(Ci- til C6-alkyl)(Ci- til C6-alkyl), -Ο Ι (Ci- til C6-alkyl)NH2, Ci- til C6-hydroxyalkyl, -O-(Ci- til C6-hydroxyalkyl), O-(Ci- til C6-alkyl)-C(O)OH, -Ci- til C6-alkoxy-Ci- til C6-alkoxy, O-(heterocyklus)-(Ci- til C6-hydroxyalkyl), SO2-(Ci- til C6-alkyl) eller -(Ci- til C6-alkyl)-(Ci- til C6-alkoxy)-halogen; eller d) hvor R2 er phenyl substitueret med -O-(Ci- til C6-alkyl)-heterocyklus.
11. Forbindelse ifølge krav 1 eller 10, hvor R2 er: a) )
b)
c)
hvor, R80 er OH, -(Ci- til C6-alkyl) CN, Ci- til C6-hydroxyalkyl, (Ci- til C6-alkyl)C(O)NH2, (Ci- til C6-alkyl)heterocyklus eller -(Ci- til C6-alkyl)C(O)OH;
d)
hvor: p er 1 til 6; og R81 er H eller C(O)OH; e)
hvor, R90 er H, Ci- til C6-alkyl, C(O)(Ci- til C6-alkyl) CN, (Ci- til C6-alkyl)C(O)OH eller C(O)Ci- til C6-hydroxyalkyl; f)
) hvor, R6 er H, (Ci- til C6-alkyl)C(O)OH eller (Ci- til C6-alkyl)CN; g)
hvor, z er 1, 2, 3, 4, 5 eller 6; h)
hvor, R6 er H eller (Cr til C6-alkyl)C(O)OH; i)
hvor: y er 2 til 6; og R50 er H, OH, Ci- til C6-alkyl, Ci- til C6-hydroxyalkyl eller -(Ci- til ) C6-alkyl)C(O)OH;
j)
hvor: m er 2 til 6; i y er 0 eller 1; Z er O eller NR60; og R60 er H, Ci- til C6-alkyl, Ci- til C6-hydroxyalkyl, -(Ci- til C6-alkyl)CN, -(Ci- til C6-alkyl)C(O) OH, -(Ci- til C6-alkyl)CONH2 eller -C(O)(Ci- til C6-alkyl) OH; hvor 2 hydrogenatomer bundet til ét carbonatom af nitrogenringen er udskiftet med en oxo eller ) eventuelt substitueret med en 3-8-leddet spirocyklisk ring; k)
hvor: r er 2 til 6; og i R70 er H, C(O)OH eller Ci- til C6-hydroxyalkyl; l)
eller m) )
12. Forbindelse ifølge krav 1 eller 10, heteroarylen i R2 er pyridin.
13. Forbindelse ifølge krav 1 eller 2, hvor R1 er: a) N(Ci- til C6-alkyl)(Ci- til C6-alkyl); b) Ci- til C6-alkoxy;
c) phenyl eller en substitueret phenyl med strukturen:
hvor Rzz, RZJ, RZ4, R25 og R26 uafhængigt er H, C(O)(Cr til C6-alkoxy), C(O)OH, O(Cr til C3-perfluoralkyl), O(Ci- til C6-perfluoralkoxy), Ci- til C6-alkoxy, halogen, (Ci- til C6-i alkyl)heterocyclyl eller (Ci- til C6-alkyl)CN; d) en 5-9-leddet mættet heterocyclyl eller en substitueret 5-9-leddet mættet heterocyclyl med strukturen
hvor: ) R34, R35, R36 og R37 uafhængigt er H, Ci- til C6-alkyl eller CN; ¥ er (C(R8)2)x, NR7(C(R8)2)x, O, (S=O), SO2 eller NR7; R7 og R8 uafhængigt er H, Ci- til C6-alkyl, C(O)OH, (Ci- til C6-alkyl)CN, (Ci- til C6-alkyl)C(O)OH, C(O)(Cr til C6-alkyl)CN eller CN; og x er 0 til 2; i e) en heterocyclyl med strukturen:
hvor: f, g, h, j og m uafhængigt er fraværende, (CH2), CH(R3), Z eller C=O; R3 er H, C(O)OH eller C(O)O(Ci- til C6-alkyl); ) R45, R46, R47 og R48 uafhængigt er H eller Ci- til C6-alkyl; og ZerO, S, SO, SO2 eller NH; f) en heteroaryl; g) monocyklisk C3- til Ck-cycloalkyl eller h) piperidin substitueret med C(O)(Ci- til C6-alkyl)CN.
14. Forbindelse ifølge krav 13, hvor R1 er: a) N(CH(CH3)2)2, N(CH3)2, OCH2CH3 eller OCH3;
b)
c) )
d)
e) thiophen, benzooxol eller pyridin; ) f) cycloheptyl eller cyclohexyl, begge eventuelt substitueret med -N(Ci- til C6-alkyl)(Ci- til C6-alkyl); eller
g)
15. Forbindelse ifølge krav et hvilket som helst af kravene 1 til 14, der er et salt af en syre valgt i fra gruppen bestående af eddike-, propion-, mælke-, citron-, vinsyre-, succin-, fumar-, malein-, malon-, mandel-, æble-, phthal-, salt-, brombrinte-, phosphor-, salpeter-, svovl-, methansulfon-, napthalensulfon-, benzensulfon-, toluensulfon-, trifluoreddike- og camphorsulfonsyrer.
16. Forbindelse ifølge krav 1 eller 2, der er: ) 4-(4-morpholinophenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-on; methyl 4-(5-oxo-4-(4-(piperazin-l-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)benzoat-hydrochlorid; 2-morpholino-4-(4-(piperazin-l-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-on-hydrochlorid; i 4-(4-(morpholinomethyl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-on; 4-(4-(4-ethylpiperazin-l-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-on; 4-(4-((4-ethylpiperazin-l-yl)methyl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-on; 2-phenyl-4-(4-(piperazin-l-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-on- ) hydrochlorid; 2-phenyl-4-(4-(piperazin-l-yl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-on; 4-(4-(morpholin-4-carbonyl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-on; 4-(4-(bis(2-hydroxyethyl)amino)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-on; i 4-(4-(4-(2-aminoacetyl)piperazin-l-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin- 5(6H)-on-hydrochlorid; 2-(4-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)piperazin-1 -yl)eddikesyre; l-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)piperidin- ) 4-carboxylsyre; 4-(4-(4-(2-aminoacetyl)piperazin-l-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-on;
N-(2-(dimethylamino)ethyl)-N-methyl-4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5- d]pyridazin-4-ylamino)benzamid; 4-(4-(2-oxo-1,7-diazaspiro[3.5]nonan-7-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5 (6H)-on; i 4-(4-(2-oxa-7-azaspiro[3.5]nonan-7-yl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin- 5(6H)-on; 4-(4-morpholinophenylamino)-2-(6-azaspiro[2.5]octan-6-yl)pyrimido[4,5-d]pyridazin-5(6H)-on; 6-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)-6- ) azaspiro [2.5 ]octan-1 -carboxylsyre; ethyl 6-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)-6-azaspiro [2.5 ]octan-1 -carboxylat; 6-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)benzyl)-6-azaspiro [2.5 ]octan-1 -carboxylsyre; i natrium 6-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)- 6-azaspiro[2.5]octan-1 -carboxylat; 4-(4-(2-oxa-7-azaspiro[3.5]nonan-7-ylmethyl)phenylamino)-2-phenylpyrimido[4,5-d]pyridazin-5 (6H)-on; 4-(4-(piperazin-l-ylmethyl)phenylamino)-2-(thiophen-3-yl)pyrimido[4,5-d]pyridazin- ) 5(6H)-on-hydrochlorid; 6-(5-oxo-4-(4-(piperazin-l-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)-6-azaspiro[2.5]octan-l-carboxylsyre-hydrochlorid; 4-(4-(4-ethylpiperazin-l-yl)phenylamino)-2-morpholinopyrimido[4,5-d]pyridazin-5(6H)- on; i 4-(5-oxo-4-(4-(piperazin-l-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)benzoesyre-hydrochlorid; 4-(4-(4-ethylpiperazin-1 -yl)phenylamino)-2-(4-(trifluormethoxy)phenyl)pyrimido [4,5-d]pyridazin-5 (6H)-on; methyl 4-(4-(4-morpholinophenylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2- ) yl)benzoat; 4-(4-(piperazin-1 -ylmethyl)phenylamino)-2-(piperidin-1 -yl)pyrimido [4,5 -d]pyridazin-5(6H)-on-hydrochlorid; 2-(3-methoxyphenyl)-4-(4-(piperazin-l-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-on-hydrochlorid; 2-(piperazin-l-yl)-4-(4-(piperazin-l-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-on-dihydrochlorid; 2-(benzo [d] [ 1,3 ]dioxol-5-yl)-4-(4-(piperazin-1-ylmethyl)phenylamino)pyrimido [4,5 -d]pyridazin-5(6H)-on-hydrochlorid; i 2-(l-(4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4- ylamino)phenyl)piperidin-4-yl)eddikesyre; 1- (4-(5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)benzyl)piperidin-4-carboxylsyre; 2- (2-methoxyphenyl)-4-(4-(piperazin-l-ylmethyl)phenylamino)pyrimido[4,5- ) d]pyridazin-5(6H)-on-hydrochlorid; 4-(4-(4-ethylpiperazin-l-yl)phenylamino)-2-(thiophen-3-yl)pyrimido[4,5-d]pyridazin-5(6H)-on-hydrochlorid; 9-(5-oxo-4-(4-(piperazin-l-ylmethyl)phenylamino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)-3,9-diazaspiro[5.5]undecan-2,4-dion-hydrochlorid; i 6-(4-(5-oxo-2-(thiophen-3-yl)-5,6-dihydropyrimido[4,5-d]pyridazin-4-ylamino)phenyl)- 6-azaspiro[2.5]octan-1 -carboxylsyre; 2-(4-chlorphenyl)-4-(4-(piperazin-l-ylmethyl)phenylamino)pyrimido[4,5-d]pyridazin-5(6H)-on-hydrochlorid; 2-(4-methoxyphenyl)-4-(4-(piperazin-l-ylmethyl)phenylamino)pyrimido[4,5- ) d]pyridazin-5(6H)-on-hydrochlorid; 6-(4-((2-morpholino-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro [2.5 ]octan-1 -carboxylsyre; 2-(l-(5-oxo-4-((4-(piperazin-l-ylmethyl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)eddikesyre-hydrochlorid; i 2-(l-oxidothiomorpholino)-4-((4-(piperazin-l-ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5(6H)-on-hydrochlorid; 2-(4-methylpiperazin-1 -yl)-4-((4-(piperazin-1 -ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on-hydrochlorid; 6-(4-((2-(4-methoxyphenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 6-(4-((2-(3-methoxyphenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 4-((4-(piperazin-1 -ylmethy l)phenyl)amino)-2-(pyrro lidin-1 -yl)pyrimido [4,5 -djpyridazin-5(6H)-on-hydrochlorid; 2-(dimethylamino)-4-((4-(piperazin-l-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on-hydrochlorid; 2-ethoxy-4-((4-(piperazin-l-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on-hydrochlorid; i l-(5-oxo-4-((4-(piperazin-l-ylmethyl)phenyl)amino)-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4-carboxylsyre-hydrochlorid; 2-(azepan-l-yl)-4-((4-(piperazin-l-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on-hydrochlorid; 6-(4-((2-(2-methoxyphenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 2-(diisopropylamino)-4-((4-(piperazin-l-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on-hydrochlorid; 2-(4-(morpholinomethyl)phenyl)-4-((4-(piperazin-1 -ylmethyl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on-hydrochlorid; i l-(5-oxo-4-((4-(piperazin-l-ylmethyl)phenyl)amino)-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4-carbonitril-hydrochlorid; 2-(4-ethylpiperazin-l-yl)-4-((4-(piperazin-l-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on-hydrochlorid; 4-((1 -(2 -morpholinoethyl)- lH-pyrazol-4-yl)amino)-2-phenylpyrimido[4,5-d]pyridazin- ) 5(6H)-on; 2-(1,4-diazepan-1 -yl)-4-((4-(piperazin-1 -yhnethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on-dihydrochlorid; 2-(azepan-l-yl)-4-((4-morpholinophenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-methoxy-4-((4-(piperazin-l-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)- i on-hydrochlorid; 6-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 2-phenyl-4-(( 1 -(2-(piperazin-1 -yl)ethyl)-1 H-pyrazol-4-yl)amino)pyrimido [4,5 -d]pyridazin-5(6H)-on-hydrochlorid; ) 4-((l-(2-(4-methylpiperazin-l-yl)ethyl)-lH-pyrazol-4-yl)amino)-2-phenylpyrimido[4,5- d]pyridazin-5 (6H)-on; 4-((l-(2-(4-ethylpiperazin-l-yl)ethyl)-lH-pyrazol-4-yl)amino)-2-phenylpyrimido[4,5-d]pyridazin-5 (6H)-on; 6-(4-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- i yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 2-(azepan-l-yl)-4-((3,4,5-trimethoxyphenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(azepan-l-yl)-4-((4-(morpholin-4-carbonyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(l-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- i yl)amino)phenyl)piperidin-4-yl)eddikesyre; 2-(l-(4-((2-(4-(cyanomethyl)piperazin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; 2-(l-(4-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; ) 6-(4-((2-(1,4-diazepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro [2.5 ]octan-1 -carboxylsyre-hydrochlorid; 6-(4-((2-(4-(cyanomethyl)piperazin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 6-(4-((2-(4-cyanopiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- i yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 2-(l-(4-((2-(4-cyanopiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; l-(4-((2-(4-cyanopiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-carboxylsyre; ) 2-(l-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidin-4-yl)eddikesyre; 1- (4-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-carboxylsyre; 6-(4-((2-cyclohexyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6- i azaspiro [2.5 ]octan-1 -carboxylsyre; 2- (l-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitril; 6-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro [2.5 ]octan-1 -carboxylsyre; ) 2-(l-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetonitril; 4-((4-((4-(2-hydroxy-2-methylpropanoyl)piperazin-l-yl)methyl)phenyl)amino)-2-pheny lpyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(azepan-1 -yl)-4-((4-((4-(2-hydroxy-2-methylpropanoyl)piperazin-1 - i yl)methyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(azepan-l-yl)-4-((4-((4-methylpiperazin-l-yl)methyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; 2-(4-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-1 -yl)eddikesyre; i 2-(4-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)cyclohexyl)eddikesyre; 2-(l-(4-((2-(azocan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; 2-(azepan-l-yl)-4-((4-(2-(piperazin-l-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-) 5(6H)-on-hydrochlorid; 2-(l-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; 2-(4-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)cyclohexyl)eddikesyre; i 4-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenoxy)butansyre; 2-(azepan-l-yl)-4-((4-(2-morpholinoethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 4-((4-(2-morpholinoethoxy )phenyl)amino)-2-phenylpyrimido[4,5-d]pyridazin-5(6H)-on; ) 2-(azepan-l-yl)-4-((4-(2-(4-methylpiperazin-l-yl)ethoxy)phenyl)amino)pyrimido[4,5- d]pyridazin-5 (6H)-on; 2-(l-(2-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)ethyl)piperidin-4-yl)eddikesyre; 2-(l-(5-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- i yl)amino)pyridin-2-yl)piperidin-4-yl)acetonitril; 1- (2-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)ethyl)piperidin-4-carboxylsyre; 2- (l-(5-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetamid; ) 2-(l-(4-((2-(4-(2-cyanopropan-2-yl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; 2-(l-(5-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetonitril; 2-(l-(5-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2- i yl)piperidin-4-yl)acetamid; 2-(l-(5-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(piperazin-l-carbonyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on-hydrochlorid; i 2-(l-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)acetamid; 2-(4-(2-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)ethyl)piperazin-1 -yl)eddikesyre; 2-(azepan-l-yl)-4-((4-(2-(piperazin-l-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-) 5(6H)-on; 2-(l-(5-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)eddikesyre; 2-(l-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)-N-(2-hydroxyethyl)acetamid; i 2-(azepan-l-yl)-4-((4-(((2S,5S)-5-(hydroxymethyl)-l,4-dioxan-2- yl)methoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(4-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperazin-1 -yl)-2-methylpropannitril; 2-(4-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)phenyl)piperazin-1 -yl)-2-methylpropanamid; 2-(l-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitril; 2-(l-(5-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)acetonitril; i 2-(azepan-1 -yl)-4-((4-(2-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1 - yl)ethoxy)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(l-(5-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)pyridin-2-yl)piperidin-4-yl)eddikesyre; 2-(1-(4-((2-(3,5-dimethylpiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)phenyl)piperidin-4-yl)eddikesyre; 2-(l-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)-N,N-bis(2-hydroxyethyl)acetamid; 2-methyl-2-(l-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)propannitril; 2-(4-(2-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)ethyl)piperazin-1 -yl)-2-methylpropannitril; 2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; ’ 4-((4-(((2S,5S)-5-(hydroxymethyl)-l,4-dioxan-2-yl)methoxy)phenyl)amino)-2- pheny lpyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-((1 S, 4S)-4-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)cyclohexyl)eddikesyre; (2R,5S)-5-((4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)phenoxy)methyl)-1,4-dioxan-2-carboxylsyre; 2-(4-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperazin-1 -yl)eddikesyre; 2-(l-(3-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)propyl)piperidin-4-yl)eddikesyre; i 6-(4-((2-(cyclohexylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)spiro[2.5]octan-1 -carboxylsyre; 6-(4-((5-oxo-2-(piperidin-l-yl)-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)spiro[2.5]octan-1 -carboxylsyre; 2- ((lR,4R)-4-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)phenyl)cyclohexyl)eddikesyre; 3- (l-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)propionsyre; 2-(l-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)cyclopropancarboxylsyre; i 3-(l-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)propionsyre; 6-(4-((2-(4-fluorphenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 6-(5-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-) yl)-6-azaspiro [2.5 ]octan-l-carboxylsyre; 6-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)-2- fluorphenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 2-(azepan-l-yl)-4-((4-(3-(piperazin-l-yl)propoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; 6-(5-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)-6-azaspiro [2.5 ]octan-1 -carboxylsyre; 6-(4-((5-oxo-2-(pyridin-4-yl)-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; i 2-(azepan-1 -yl)-4-((4-(4-(2-hydroxypropan-2-yl)piperidin-1 - yl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(4-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1 -yl)-2-methylpropionsyre; 6-(4-((2-(azocan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)- ) 6-azaspiro[2.5]octan-1 -carboxylsyre; 2-(l-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)-2-methylpropionsyre; 2-methyl-2-(l-(4-((5-oxo-2-phenyl-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)propionsyre; i 2-(2,6-dimethylpiperidin-l-yl)-4-((4-(piperazin-l-ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5 (6H)-on; 2-(l-(4-((2-(2,6-dimethylpiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; 6-(4-((2-(2,6-dimethylpiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 2-(l-(4-((2-(2,6-dimethylpiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitril; 2-(2,6-dimethylpiperidin-1 -yl)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1 -yl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; i 2-(l-(5-((2-(2,6-dimethylpiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)pyridin-2-yl)piperidin-4-yl)eddikesyre; 2-(3,5 -dimethylpiperidin-1 -yl)-4-((4-(piperazin-1 -ylmethyl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(l-(4-((2-(3,5-dimethylpiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)phenyl)piperidin-4-yl)eddikesyre; 6-(4-((2-(3,5-dimethylpiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 2-(1-(4-((2-(3,5-dimethylpiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitril; 2-(3,5-dimethylpiperidin-1 -yl)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-1 -yl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(1-(5-((2-(3,5-dimethylpiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)eddikesyre; i 2-(2,6-dimethylmorpholino)-4-((4-(piperazin-1 -ylmethyl)phenyl)amino)pyrimido[4,5- d]pyridazin-5 (6H)-on; 2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; 6-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 2-(1-(4-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitril; 2-(2,6-dimethylmorpholino)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-l-yl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; i 2-(1-(5-((2-(2,6-dimethylmorpholino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)pyridin-2-yl)piperidin-4-yl)eddikesyre; 2-(diisopropylamino)-4-((4-(piperazin-l-ylmethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; 2-(l-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)phenyl)piperidin-4-yl)eddikesyre; 6-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 2-(l-(4-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitril; i 2-(diisopropylamino)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-1 - yl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(l-(5-((2-(diisopropylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)pyridin-2-yl)piperidin-4-yl)eddikesyre; 2-(2-methylpiperidin-1 -yl)-4-((4-(piperazin-1 -ylmethyl)phenyl)amino)pyrimido [4,5- ) d]pyridazin-5(6H)-on; 2-(1-(4-((2-(2-methylpiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; 6-(4-((2-(2-methylpiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 2-(1-(4-((2-(2-methylpiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitril; 4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperidin-l-yl)phenyl)amino)-2-(2-methylpiperidin-l-yl)pyrimido[4,5-d]pyridazin-5(6H)-on; i 2-(1-(5-((2-(2-methylpiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)pyridin-2-yl)piperidin-4-yl)eddikesyre; l-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-carboxylsyre; l-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)benzyl)piperidin-4-carboxylsyre; 4-((4-((4-(2H-tetrazol-5-yl)piperidin-1 -yl)methyl)phenyl)amino)-2-(azepan-1 -yl)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1 -yl)methyl)phenyl)amino)-2-(azepan-1 -yl)pyrimido [4,5 -d]pyridazin-5 (6H)-on; i 2-(l-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)piperidin-4-yl)eddikesyre; 1- (4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-carboxylsyre; 6-(4-((2-(3-cyanopiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 2- (l-(4-((2-(3-cyanopiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; l-(4-((2-(3-cyanopiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-carboxylsyre; i l-(4-((2-(3-cyanopiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)benzyl)piperidin-4-carboxylsyre; 1- (4-((4-((4-(2H-tetrazol-5-yl)piperidin-l-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-3-carbonitril; 2- (l-(4-((2-(3-cyanopiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)benzyl)piperidin-4-yl)eddikesyre; l-(4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-l-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-3-carbonitril; l-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-carboxylsyre; 4-((4-((4-(2H-tetrazol-5-yl)piperidin-l-yl)methyl)phenyl)amino)-2- cy clohepty lpyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(l-(4-((2-cycloheptyl-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)eddikesyre; ’ 4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1 -yl)methyl)phenyl)amino)-2- cy clohepty lpyrimido [4,5 -d]pyridazin-5 (6H)-on; l-(4-((2-(4-cyanopiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-carboxylsyre; l-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-l-yl)methyl)phenyl)amino)-5-oxo-5,6- ) dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-carbonitril; l-(4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-l-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-carbonitril; 1- (4-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-carboxylsyre; i 2-(l-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-l-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2- (l-(4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-l-yl)methyl)phenyl)amino)-5-oxo- 5.6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; l-(4-((2-(4-(cyanomethyl)piperazin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)phenyl)piperidin-4-carboxylsyre; 1- (4-((2-(4-(cyanomethyl)piperazin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-carboxylsyre; 2- (4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-l-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-l-yl)acetonitril; i 2-(l-(4-((2-(4-(cyanomethyl)piperazin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)benzyl)piperidin-4-yl)eddikesyre; 2-(4-(4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-l-yl)methyl)phenyl)amino)-5-oxo- 5.6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-l-yl)acetonitril; 6-(4-((2-(1,4-diazepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 2-(1-(4-((2-(1,4-diazepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; 1-(4-((2-(1,4-diazepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-carboxylsyre; 1-(4-((2-(1,4-diazepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-carboxylsyre; 6-(4-((2-(4-(2-cyanoacetyl)piperazin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)-6-azaspiro[2.5]octan-l-carboxylsyre; i 2-(l-(4-((2-(4-(2-cyanoacetyl)piperazin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; l-(4-((2-(4-(2-cyanoacetyl)piperazin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenyl)piperidin-4-carboxylsyre; 1- (4-((2-(4-(2-cyanoacetyl)piperazin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- ) 4-yl)amino)benzyl)piperidin-4-carboxylsyre; 3- (4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-l-yl)methyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-l-yl)-3-oxopropannitril; 2- (l-(4-((2-(4-(2-cyanoacetyl)piperazin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)eddikesyre; ’ 4-((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-1 -yl)methyl)phenyl)amino)-2-(4-(2- isocyanoacetyl)piperazin-l-yl)pyrimido[4,5-d]pyridazin-5(6H)-on; 6-(4-((2-(l-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 2-(l-(4-((2-(l-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5- ) d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; l-(4-((2-(l-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-carboxylsyre; 1- (4-((2-(l-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)benzyl)piperidin-4-carboxylsyre; i 3-(4-(4-((4-((4-(2H-tetrazol-5-yl)piperidin-l-yl)methyl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-l-yl)-3-oxopropannitril; 2- (l-(4-((2-(l-(2-cyanoacetyl)piperidin-4-yl)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-4-yl)amino)benzyl)piperidin-4-yl)eddikesyre; 4- ((4-((4-((2H-tetrazol-5-yl)methyl)piperidin-l-yl)methyl)phenyl)amino)-2-( 1-(2- ) isocyanoacetyl)piperidin-4-yl)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(4-(5-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)pyridin-2-yl)piperazin-1 -yl)eddikesyre; 2-(4-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-1,4-diazepan-1 -yl)eddikesyre; 2- (1 -(4-((4-(4-(2-hydroxypropan-2-yl)piperidin-1 -yl)phenyl)amino)-5 -oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 3- (l-(4-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4- yl)amino)phenyl)piperidin-4-yl)propionsyre; i 6-(5-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)pyridin-2-yl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 1- (5-oxo-4-((4-(2-(piperazin-l-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-carbonitril; 2- (l-(5-oxo-4-((4-(2-(piperazin-l-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5- ) d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(2-(4-ethylpiperazin-l-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; 2-phenyl-4-((4-(2-(piperazin-l-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; i 4-((4-(2-(piperazin-l-yl)ethoxy)phenyl)amino)-2-(piperidin-l-yl)pyrimido[4,5- d]pyridazin-5 (6H)-on; 2-(4-(4-((5-oxo-2-(piperidin-l-yl)-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)-1,4-diazepan-1 -yl)eddikesyre; 6-(4-((2-(4-methylpiperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- ) yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 2-(4-methylpiperidin-1 -yl)-4-((4-(2-(piperazin-1 -y l)ethoxy)phenyl)amino)pyrimido [4,5 -d]pyridazin-5(6H)-on-hydrochlorid; 2-(azepan-l-yl)-4-((4-(2-(3-oxopiperazin-l-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; i 6-(2-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenoxy)ethyl)-6-azaspiro [2.5 ]octan-1 -carboxylsyre; 2-(azepan-l-yl)-4-((4-(2-(diethylamino)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(cyclohexyl(methyl)amino)-4-((4-(2-(piperazin-1 - ) yl)ethoxy)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(l-(4-((2-(cyclohexyl(methyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)eddikesyre; 2-(4-(4-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1 -yl)eddikesyre; 2-(l-(4-((2-(3-methoxyphenyl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-4-yl)acetonitril; 4-((4-(2-(1,4-diazepan-l-yl)ethoxy)phenyl)amino)-2-(azepan-l-yl)pyrimido[4,5-d]pyridazin-5 (6H)-on; i 2-(azepan-l-yl)-4-((4-(3-oxopiperazin-l-yl)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-on; 2-(3-methoxyphenyl)-4-((4-(2-(piperazin-l-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; 2-(azepan-l-yl)-4-((4-(2-(dimethylamino)ethoxy)phenyl)amino)pyrimido[4,5- ) d]pyridazin-5(6H)-on; 2-(azepan-l-yl)-4-((4-(2-(piperidin-4-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(l-(5-oxo-4-((4-(2-(piperidin-4-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; i 6-(4-((2-(cyclohexyl(methyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-6-azaspiro[2.5]octan-1 -carboxylsyre; 4-((4-(2-(l,4-diazepan-l-yl)ethoxy)phenyl)amino)-2-(piperidin-l-yl)pyrimido[4,5-d]pyridazin-5 (6H)-on; 2-(azepan-1 -yl)-4-((4-(2-(4-hydroxypiperidin-1 -yl)ethoxy)phenyl)amino)pyrimido [4,5- ) d]pyridazin-5(6H)-on; 2-(azepan-l-yl)-4-((4-(3-(piperazin-l-yl)propyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(l-(5-oxo-4-((4-(3-(piperazin-l-yl)propyl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; i 2-(azepan-l-yl)-4-((4-(4-ethyl-3-oxopiperazin-l-yl)phenyl)amino)pyrimido[4,5- d]pyridazin-5 (6H)-on; 2-morpholino-4-((4-(2-(piperazin-l-yl)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin- 5(6H)-on; 2-(2,6-dimethylmorpholino)-4-((4-(2-(piperazin-1 - ) yl)ethoxy)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(l-(4-((4-(4-ethyl-3-oxopiperazin-l-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(3-(4-hydroxypiperidin-l-yl)propyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; 2-(azepan-l-yl)-4-((4-(4-ethylpiperazin-l-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 4-((6-(2-(piperazin-l-yl)ethoxy)pyridin-3-yl)amino)-2-(piperidin-l-yl)pyrimido[4,5-d]pyridazin-5 (6H)-on; i 2-(azepan-l-yl)-4-((6-(2-(piperazin-l-yl)ethoxy)pyridin-3-yl)amino)pyrimido[4,5- d]pyridazin-5 (6H)-on; 4-((4-(2-(4-hydroxypiperidin-l-yl)ethoxy)phenyl)amino)-2-(piperidin-l-yl)pyrimido[4,5-d]pyridazin-5 (6H)-on; 2-(azepan-1 -yl)-4-((4-(2-(4-hydroxy-4-methylpiperidin-1 - ) yl)ethoxy)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(1 -(4-((4-(2-(4-hydroxy-4-methy lpiperidin-1 -yl)ethoxy)phenyl)amino)-5 -oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(4-hydroxypiperidin-l-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; i 2-(l-(4-((4-(4-ethylpiperazin-l-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(2-(diisopropylamino)ethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; 2-(l-(4-((4-(4-hydroxypiperidin-l-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5- ) d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(4-(2-hydroxyethyl)piperazin-l-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; 2-(1 -(4-((4-(4-(2-hydroxy ethyl)piperazin-1 -yl)phenyl)amino)-5 -oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; i 2-(azepan-l-yl)-4-((4-(piperazin-l-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(l-(5-oxo-4-((4-(piperazm-l-yl)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(4-(3-hydroxypropyl)piperidin-l-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; ) 2-(azepan-1 -yl)-4-((4-(4-(2-hydroxyethyl)piperidin-1 -yl)phenyl)amino)pyrimido [4,5 - d]pyridazin-5 (6H)-on; 2-(1 -(4-((4-(4-(2-hydroxy ethyl)piperidin-1 -yl)phenyl)amino)-5 -oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(1 -(4-((4-(2-(4-ethylpiperazin-1 -yl)ethyl)phenyl)amino)-5 -oxo-5,6- i dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(2-(piperazin-l-yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 4-((4-(2-aminoethoxy)phenyl)amino)-2-(azepan-l-yl)pyrimido[4,5-d]pyridazin-5(6H)- on; i 2-(l-(4-((4-(2-aminoethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(2-(4-hydroxypiperidin-l-yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; 2-(azepan-l-yl)-4-((4-(4-(hydroxymethyl)piperidin-l-yl)phenyl)amino)pyrimido[4,5- ) d]pyridazin-5(6H)-on; 2-(azepan-1 -yl)-4-((4-(2-(4-(hy droxymethy l)piperidin-1 -yl)ethoxy)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(l-(2-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)piperidin-1 -yl)ethyl)piperidin-4-yl)acetonitril; i 2-( 1-(4-((4-(4-(3-hydroxypropyl)piperidin-l-yl)phenyl)amino)-5 -oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(4-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1 -yl)acetonitril; 2- (1 -(4-((4-(4-(cyanomethyl)piperazin-1 -yl)phenyl)amino)-5 -oxo-5,6- ) dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 3- (4-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1 -yl)propionsyre; 2-(azepan-l-yl)-4-((4-(2-(4-ethylpiperazin-l-yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; i 2-(azepan-1 -yl)-4-((4-(2-(4-hydroxy-4-methylpiperidin-1 - yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(azepan-1 -yl)-4-((4-(2-(4-(2-hydroxyethyl)piperazin-1 - yl)ethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(1 -(4-((4-(2-(4-(2-hydroxy ethyl)piperazin-1 -yl)ethyl)phenyl)amino)-5 -oxo-5,6- ) dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(4-(4-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4- yl)amino)phenyl)piperazin-1 -yl)-2-methylpropionsyre; 2-(azepan-1 -yl)-4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1 -yl)phenyl) amino)pyrimido [4,5-d]pyridazin-5 (6H)-on; 3-(4-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperazin-1 -yl)-3-oxopropannitril; 2-(1 -(4-((4-(4-(hydroxymethyl)piperidin-1 -yl)phenyl)amino)-5 -oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; i 2-(azepan-l-yl)-4-((6-(4-hydroxypiperidin-l-yl)pyridin-3-yl)amino)pyrimido[4,5- d]pyridazin-5 (6H)-on; 2- (1 -(4-((4-(2-(4-(hydroxymethyl)piperidin-1 -yl)ethoxy)phenyl)amino)-5 -oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; (phosphonooxy)methyl 6-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5- ) d]pyridazin-4-yl)amino)phenyl)-6-azaspiro[2.5]octan-l-carboxylat; 3- (4-(4-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4- yl)amino)phenyl)piperazin-1 -yl)propionsyre; 2-(azepan-l-yl)-4-((6-(piperazin-l-yl)pyridin-3-yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; i 2-(azepan-l-yl)-4-((4-(2-(2-hydroxyethyl)-2H-tetrazol-5-yl)phenyl)amino)pyrimido[4,5- d]pyridazin-5 (6H)-on; 2-(1 -(4-((4-(4-(2-hydroxy-2-methylpropanoyl)piperazin-1 -yl)phenyl)amino)-5 -oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(l-(4-((4-(2-(diethylamino)ethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5- ) d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(2-ethyl-2H-tetrazol-5-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(l-(4-((4-(2-ethyl-2H-tetrazol-5-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; i 4-((4-(2H-tetrazol-5-yl)phenyl)amino)-2-(azepan-l-yl)pyrimido[4,5-d]pyridazin-5(6H)- on; 2-(l-(4-((6-(4-ethylpiperazin-l-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-1-yl)-4-((6-(4-ethylpiperazin-1-yl)pyridin-3-yl)amino)pyrimido [4,5- ) d]pyridazin-5(6H)-on; 2-(4-(5-oxo-4-((4-(2-(piperazin-l-yl)ethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperazin-1 -yl)acetonitril; 2-(l-(5-oxo-4-((6-(piperazin-l-yl)pyridin-3-yl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(l-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-3-yl)eddikesyre; 2-(l-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-3-yl)eddikesyre; i 3-(4-(5-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)pyridin-2-yl)piperazin-1 -y 1)-3 -oxopropannitril; 2-(5-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)-2H-tetrazol-2-yl)eddikesyre; 2- (azepan-l-yl)-4-((6-(4-(2-hydroxyethyl)piperidin-l-yl)pyridin-3- ) yl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 3- (4-(5-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4- yl)amino)pyridin-2-yl)piperazin-1 -yl)-3-oxopropannitril; 2- (azepan-l-yl)-4-((6-(4-(2-hydroxy-2-methylpropanoyl)piperazin-l-yl)pyridin-3-yl)amino)pyrimido [4,5-d]pyridazin-5 (6H)-on; i 2-(azepan-1 -yl)-4-((4-(2-(4-(2-hydroxyethyl)piperazin-1 - yl)ethoxy)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 3- (4-(4-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4- yl)amino)phenyl)piperazin-1 -y 1)-3 -oxopropannitril; 2-(5-(4-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-) 4-yl)amino)phenyl)-2H-tetrazol-2-yl)eddikesyre; 2-(azepan-1 -yl)-4-((6-(4-methylpiperazin-1 -yl)pyridin-3 -yl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(l-(4-((6-(4-methylpiperazin-l-yl)pyridin-3-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; i 4-((4-(4-((2H-tetrazol-5-yl)methyl)piperidin-l-yl)phenyl)amino)-2-(azepan-l- yl)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(l-(4-((4-(2H-tetrazol-5-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 2-yl)piperidin-4-yl)acetonitril; 2-(l-(4-((4-(4-((2H-tetrazol-5-yl)methyl)piperidin-l-yl)phenyl)amino)-5-oxo-5,6- ) dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-1 -yl)-4-((4-(4-methylpiperazin-1 -yl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5(6H)-on; 2-(l-(4-((4-(4-methylpiperazin-l-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(l-(5-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)pyridin-2-yl)piperidin-3-yl)eddikesyre; 2-(l-(4-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)piperidin-3-yl)eddikesyre; i 2-(l-(4-((6-(4-(2-hydroxy-2-methylpropanoyl)piperazin-l-yl)pyridin-3-yl)amino)-5-oxo- 5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 4-((6-(4-((2H-tetrazol-5-yl)methyl)piperidin-1 -yl)pyridin-3-yl)amino)-2-(azepan-1 -yl)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(l-(4-((6-(4-((2H-tetrazol-5-yl)methyl)piperidin-l-yl)pyridin-3-yl)amino)-5-oxo-5,6- ) dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(4-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)piperidin-1 -yl)eddikesyre; 2-(azepan-l-yl)-4-((4-(4-(2-methoxyethyl)piperazin-l-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; i 2-(1 -(4-((4-(4-(2-methoxy ethyl)piperazin-1 -yl)phenyl)amino)-5 -oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-( 1 -(4-((4-(4-(2-aminoethyl)piperazin-1 -yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(l-(hydroxymethyl)-6-azaspiro[2.5]octan-6- ) yl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(1-(4-((4-(1-(hydroxymethyl)-6-azaspiro[2.5]octan-6-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-1 -yl)-4-((4-(4-(3 -hydroxypropyl)piperazin-1 -yl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; i 2-(l-(4-((4-(4-(3-hydroxypropyl)piperazin-l-yl)phenyl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(4-(4-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 4-yl)amino)phenoxy)piperidin-1 -yl)eddikesyre; 2-(azepan-1 -yl)-4-((4-(4-(2-hydroxy ethyl)-1,4-diazepan-1 - ) yl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(1 -(4-((4-(4-(2-hydroxy ethyl)-1,4-diazepan-1 -yl)phenyl)amino)-5 -oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-1 -yl)-4-((4-(4-( 1 -hydroxy-2-methylpropan-2-yl)piperazin-1 -yl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(1-(4-((4-(4-(1 -hydroxy-2-methylpropan-2-yl)piperazin-1 -yl)phenyl)amino)-5 -oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-1 -yl)-4-((4-(4-(2-(dimethylamino)ethyl)piperazin-1 -yl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; i 2-(1 -(4-((4-(4-(2-(dimethylamino)ethyl)piperazin-1 -yl)phenyl)amino)-5 -oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-1 -yl)-4-((4-(2-(4-ethylpiperazin-1 -yl)-2-oxoethoxy)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(1 -(4-((4-(2-(4-ethylpiperazin-1 -yl)-2-oxoethoxy)phenyl)amino)-5 -oxo-5,6- ) dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(1 -(4-((4-(2-(4-methylpiperazin-1 -yl)-2-oxoethoxy)phenyl)amino)-5 -oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(3-(2-hydroxyethyl)piperidin-l-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; i 2-(azepan-l -yl)-4-((4-(4-(2,3-dihydroxypropyl)piperazin-1 - yl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(1-(4-((4-(4-(2,3-dihydroxypropyl)piperazin-l-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-1 -yl)-4-((4-(4-(2-fluorethyl)piperazin-1 -yl)phenyl)amino)pyrimido[4,5- ) d]pyridazin-5(6H)-on; 2-(1 -(4-((4-(4-(2-fluorethyl)piperazin-1 -yl)phenyl)amino)-5 -oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-1 -yl)-4-((6-(3 -hydroxypiperidin-1 -yl)pyridin-3 -yl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; i 2-(l-(4-((6-(3-hydroxypiperidin-l-yl)pyridin-3-yl)amino)-5-oxo-5,6- dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(4,4-difluorpiperidin-l-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(l-(4-((4-(4,4-difluorpiperidin-l-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5- ) d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(3-hydroxypiperidin-l-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(l-(4-((4-(3-hydroxypiperidin-l-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-1 -yl)-4-((4-(2-(4-methylpiperazin-1 -yl)-2-oxoethoxy)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-( 1-(4-((4-(3-(hydroxymethyl)piperidin-l-yl)phenyl)amino)-5 -oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; i 2-(azepan-l-yl)-4-((4-(3-(hydroxymethyl)piperidin-l-yl)phenyl)amino)pyrimido[4,5- d]pyridazin-5 (6H)-on; 2-(1-(4-((4-(3-(2-hydroxyethyl)piperidin-l-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(l-(4-((4-(4-methoxypiperidin-l-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5- ) d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-1 -yl)-4-((4-(4-methoxypiperidin-1 -yl)phenyl)amino)pyrimido [4,5 -d]pyridazin-5(6H)-on; 2-(azepan-l-yl)-4-((4-(4-fluorpiperidin-l-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; i 2-(l-(4-((4-(4-fluorpiperidin-l-yl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(1 -(4-((4-(( 1 -(2-hydroxyethyl)piperidin-4-yl)oxy)phenyl)amino)-5 -oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(piperidin-4-yloxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-) on-hydrochlorid; 2-(l-(4-((4-(2-hydroxyethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(2-hydroxyethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; i 2-(l-(4-((4-(3-hydroxypropoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5- d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(3-hydroxypropoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-( 1-(4-((4-(4-( l-hydroxy-2-methylpropan-2-yl)-1,4-diazepan-l-yl)phenyl)amino)-5-oxo-) 5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(4-(2-fluorethyl)piperidin-l-yl)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; 2-(1 -(4-((4-(4-(2-fluorethyl)piperidin-1 -yl)phenyl)amino)-5 -oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(1-(4-((3,5-dimethoxyphenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(l-(5-oxo-4-((4-(trifluormethoxy)phenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; i 2-(azepan-l-yl)-4-((3,5-dimethoxyphenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2- (azepan-1 -yl)-4-((4-(trifluormethoxy)phenyl)amino)pyrimido [4,5-d]pyridazin-5 (6H)-on; 3- (4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenyl)propionsyre; ) 3-(4-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4- yl)amino)phenyl)propionsyre; 2-(azepan-l-yl)-4-((4-(bis(2-hydroxyethyl)amino)phenyl)amino)pyrimido[4,5-d]pyridazin-5 (6H)-on; 2-(l-(4-((4-(bis(2-hydroxyethyl)amino)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5- i d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(3-hydroxypropyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(l-(4-((4-(3-hydroxypropyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; ) 2-(azepan-l-yl)-4-((3-(hydroxymethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)- on; 2-(l-(4-((3-(hydroxymethyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(l-(4-((4-fluorphenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2- i yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-fluorphenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(azepan-1 -yl)-4-((4-(( 1 -hydroxy-2-methylpropan-2-yl)oxy)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; 2-(1 -(4-((4-(( 1 -hydroxy-2-methylpropan-2-yl)oxy)phenyl)amino)-5 -oxo-5,6- ) dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(4-((2-(azepan-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)-2-methylpropionsyre; 2-(4-((2-(4-(cyanomethyl)piperidin-l-yl)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-4-yl)amino)phenoxy)-2-methylpropionsyre; i 2-(azepan-l-yl)-4-((3,4-dimethoxyphenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(1-(4-((3,4-dimethoxyphenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((3-methoxyphenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(l-(4-((3-methoxyphenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2- i yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(2-hydroxyethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(l-(4-((4-(2-hydroxyethyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; ) 2-(azepan-l-yl)-4-((4-(2-methoxyethoxy)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)- on; 2-(1-(4-((4-(2-methoxyethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(l-(5-oxo-4-((3,4,5-trimethoxyphenyl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2- i yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-(benzo[d][l,3]dioxol-5-ylamino)pyrimido[4,5-d]pyridazin-5(6H)-on; 2-(l-(4-(benzo[d][l,3]dioxol-5-ylamino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-((l-(2-hydroxyethyl)piperidin-4- ) yl)oxy)phenyl)amino)pyrimido [4,5 -d]pyridazin-5 (6H)-on; natrium (2-(4-(cyanomethyl)piperidin-1 -yl)-4-((4-(4-hydroxypiperidin-1 -yl)phenyl)amino)-5-oxopyrimido[4,5-d]pyridazin-6(5H)-yl)methylphosphat; 2-(azepan-l-yl)-4-((4-(hydroxymethyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)- on; i 2-(l-(4-((4-(hydroxymethyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin- 2-yl)piperidin-4-yl)acetonitril; 2-(l-(4-((4-(methylsulfonyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(azepan-l-yl)-4-((4-(methylsulfonyl)phenyl)amino)pyrimido[4,5-d]pyridazin-5(6H)- ) on; 2-(l-(4-((lH-benzo[d][l,2,3]triazol-5-yl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(l-(5-oxo-4-((2-oxo-2,3-dihydro-lH-benzo[d]imidazol-5-yl)amino)-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(l-(4-((4-(3-fluorpropyl)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril; 2-(l-(4-((4-(difluormethoxy)phenyl)amino)-5-oxo-5,6-dihydropyrimido[4,5-d]pyridazin-2-yl)piperidin-4-yl)acetonitril og i 4-((lH-benzo[d][l,2,3]triazol-5-yl)amino)-2-(azepan-l-yl)pyrimido[4,5-d]pyridazin- 5(6H)-on.
17. Farmaceutisk sammensætning, der omfatter en forbindelse ifølge et hvilket som helst af kravene 1 til 16 og en farmaceutisk acceptabel bærer. )
18. Kit, der omfatter en forbindelse ifølge et hvilket som helst af kravene 1 til 16.
19. Forbindelse ifølge et hvilket som helst af kravene 1 til 16 eller farmaceutisk acceptabelt salt deraf til anvendelse ved reduktion af inflammation.
DK12756865.7T 2011-08-23 2012-08-23 Pyrimido-pyridazinonforbindelser og anvendelse deraf DK2748166T3 (da)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161526525P 2011-08-23 2011-08-23
PCT/US2012/051980 WO2013028818A1 (en) 2011-08-23 2012-08-23 Pyrimido- pyridazinone compounds and use thereof

Publications (1)

Publication Number Publication Date
DK2748166T3 true DK2748166T3 (da) 2018-10-29

Family

ID=46829884

Family Applications (2)

Application Number Title Priority Date Filing Date
DK18175788.1T DK3392252T3 (da) 2011-08-23 2012-08-23 Pyrimido-pyridazinonforbindelser og deres anvendelse
DK12756865.7T DK2748166T3 (da) 2011-08-23 2012-08-23 Pyrimido-pyridazinonforbindelser og anvendelse deraf

Family Applications Before (1)

Application Number Title Priority Date Filing Date
DK18175788.1T DK3392252T3 (da) 2011-08-23 2012-08-23 Pyrimido-pyridazinonforbindelser og deres anvendelse

Country Status (14)

Country Link
US (5) US8729079B2 (da)
EP (4) EP3392252B1 (da)
JP (1) JP5993010B2 (da)
CN (2) CN103974955B (da)
BR (1) BR112014003981A2 (da)
CA (1) CA2846187A1 (da)
DK (2) DK3392252T3 (da)
ES (2) ES2690971T3 (da)
FI (1) FI3392252T3 (da)
HU (1) HUE065564T2 (da)
IL (1) IL231082A (da)
MX (1) MX361458B (da)
PL (1) PL2748166T3 (da)
WO (1) WO2013028818A1 (da)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUE065564T2 (hu) * 2011-08-23 2024-06-28 Libertas Bio Inc Pirimido-piridazinon vegyületek és alkalmazásuk
AR106830A1 (es) * 2015-12-04 2018-02-21 Asana Biosciences Llc Usos de piridazinonas para tratar el cáncer
WO2018187294A1 (en) * 2017-04-03 2018-10-11 Asana Biosciences, Llc Pyrimido-pyridazinone compound combinations, methods, kits and formulations thereof
KR20190140011A (ko) * 2017-04-28 2019-12-18 아사나 바이오사이언시스 엘엘씨 아토피성 피부염을 치료하고, 활성 약학적 성분의 안정성을 개선하기 위한 제형물, 방법, 키트, 및 투여형
CN111961035B (zh) * 2019-05-20 2022-11-01 南京科技职业学院 一类含有羟基异喹啉类结构的化合物、药物组合物以及其应用
CN114174298B (zh) * 2019-08-14 2023-08-01 正大天晴药业集团南京顺欣制药有限公司 哒嗪酮并嘧啶类衍生物及其医药用途
CN113583026B (zh) * 2020-04-30 2024-06-14 杭州英创医药科技有限公司 一类含有稠合三环结构的化合物
TW202202498A (zh) * 2020-07-01 2022-01-16 大陸商四川海思科製藥有限公司 一種並環雜環衍生物及其在醫藥上的應用
EP4452416A1 (en) * 2021-12-22 2024-10-30 The Regents Of The University Of California Covalently binding inhibitors of g12s, g12d and/or g12e mutants of k-ras gtpase
KR20240151808A (ko) 2022-02-23 2024-10-18 테바 파마슈티컬스 인터내셔널 게엠베하 구사시티닙의 고체 상태 형태
WO2023192989A2 (en) * 2022-04-01 2023-10-05 Azkarra Therapeutics, Inc. Phthalazinone compounds as parp7 inhibitors

Family Cites Families (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE756508A (fr) * 1969-09-24 1971-03-01 Takeda Chemical Industries Ltd Derives de pyrimidopyridazine
CA1004223A (en) * 1972-05-12 1977-01-25 Theodor Denzel Amino derivatives of pyrido(2,3-d)pyridazine carboxylic acids and esters
JPS4948695U (da) 1972-07-29 1974-04-27
JPS50101387A (da) * 1974-01-16 1975-08-11
CA1052046A (en) 1974-01-21 1979-04-03 American Cyanamid Company Unsymmetrically substituted 1,4-dioxane-2,5-diones
US5369086A (en) 1993-04-28 1994-11-29 Zeneca Limited N-benzotriazoles
IL112249A (en) 1994-01-25 2001-11-25 Warner Lambert Co Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds
JPH0948695A (ja) 1995-08-02 1997-02-18 Toshiba Ceramics Co Ltd シリコン単結晶の製造方法
WO1999043671A1 (en) 1998-02-25 1999-09-02 Pharmacia & Upjohn Company Substituted aminomethyl isoxazoline derivatives useful as antimicrobials
IL143023A0 (en) 1998-11-10 2002-04-21 Janssen Pharmaceutica Nv Hiv replication inhibiting pyrimidines
WO2002024703A1 (en) * 2000-09-22 2002-03-28 Akzo Nobel N.V. Bicyclic heteroaromatic compounds
ATE386727T1 (de) 2001-04-30 2008-03-15 Glaxo Group Ltd Kondensierte pyrimidine als antagonisten des corticotropin releasing factor (crf)
WO2003075828A2 (en) 2002-03-11 2003-09-18 Zetiq Technologies Ltd. Compounds useful in the treatment of cancer
SG176311A1 (en) 2002-07-29 2011-12-29 Rigel Pharmaceuticals Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds
JP4887139B2 (ja) 2003-03-25 2012-02-29 武田薬品工業株式会社 ジペプチジルペプチダーゼインヒビター
EP1656372B1 (en) 2003-07-30 2013-04-10 Rigel Pharmaceuticals, Inc. 2,4-pyrimidinediamine compounds for use in the treatment or prevention of autoimmune diseases
EP1724268A4 (en) 2004-02-20 2010-04-21 Kirin Pharma Kk COMPOUND HAVING TGF-BETA INHIBITING ACTIVITY AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
CA2577467C (en) 2004-09-30 2013-05-28 Tibotec Pharmaceuticals Ltd. Hiv inhibiting 5-heterocyclyl pyrimidines
JP4966202B2 (ja) 2004-12-24 2012-07-04 スピニフェクス ファーマシューティカルズ ピーティーワイ リミテッド 治療または予防のための方法
US20070066632A1 (en) 2005-03-25 2007-03-22 Scios, Inc. Fused bicyclic inhibitors of TGFbeta
MX2007011850A (es) 2005-03-25 2007-10-03 Tibotec Pharm Ltd Inhibidores heterobiciclicos de virus de hepatitis c.
KR20080000584A (ko) 2005-04-29 2008-01-02 얀센 파마슈티카 엔.브이. 카나비노이드 수용체 길항제로서의 벤조트리아졸 유도체
EP1970373A1 (en) * 2005-12-02 2008-09-17 Mitsubishi Tanabe Pharma Corporation Alicyclic heterocyclic compound
US20070161670A1 (en) 2006-01-09 2007-07-12 Bristol-Myers Squibb Company Process for the preparation of substituted heterocycles
WO2007125405A2 (en) 2006-05-01 2007-11-08 Pfizer Products Inc. Substituted 2-amino-fused heterocyclic compounds
GB0625196D0 (en) 2006-12-18 2007-01-24 7Tm Pharma As Modulators of cannabinoid receptor
KR101449436B1 (ko) * 2006-12-28 2014-10-14 애브비 인코포레이티드 폴리(ａｄｐ-리보스)폴리머라제 억제제
BRPI0808772A2 (pt) 2007-03-14 2014-08-12 Exelixis Inc Inibidores da via de hedgehog
TW200938542A (en) 2008-02-01 2009-09-16 Irm Llc Compounds and compositions as kinase inhibitors
MX2011003447A (es) * 2008-09-30 2011-07-29 Astrazeneca Ab Inhibidores heterociclicos de jak quinasa.
US20100137313A1 (en) 2008-10-03 2010-06-03 Astrazeneca Ab Heterocyclic derivatives and methods of use thereof
UA107917C2 (ru) 2008-10-21 2015-03-10 Сімабей Терапьютікс, Інк. Арильный агонист рецептора gpr120 и его применение
WO2011053861A1 (en) * 2009-10-29 2011-05-05 Genosco Kinase inhibitors
TW201130852A (en) * 2009-12-23 2011-09-16 Abbott Lab Novel thienopyrrole compounds
US8440662B2 (en) 2010-10-31 2013-05-14 Endo Pharmaceuticals, Inc. Substituted quinazoline and pyrido-pyrimidine derivatives
HUE065564T2 (hu) * 2011-08-23 2024-06-28 Libertas Bio Inc Pirimido-piridazinon vegyületek és alkalmazásuk
US9145411B2 (en) 2012-08-02 2015-09-29 Asana Biosciences, Llc Substituted amino-pyrimidine derivatives
AR106830A1 (es) * 2015-12-04 2018-02-21 Asana Biosciences Llc Usos de piridazinonas para tratar el cáncer
KR20190140011A (ko) * 2017-04-28 2019-12-18 아사나 바이오사이언시스 엘엘씨 아토피성 피부염을 치료하고, 활성 약학적 성분의 안정성을 개선하기 위한 제형물, 방법, 키트, 및 투여형

Also Published As

Publication number Publication date
US20200190095A1 (en) 2020-06-18
EP3392252A1 (en) 2018-10-24
US8729079B2 (en) 2014-05-20
MX2014002112A (es) 2014-09-25
CN108707151A (zh) 2018-10-26
WO2013028818A1 (en) 2013-02-28
CN103974955B (zh) 2018-06-19
US20140221315A1 (en) 2014-08-07
WO2013028818A8 (en) 2013-09-19
EP2748166A1 (en) 2014-07-02
US10647720B2 (en) 2020-05-12
DK3392252T3 (da) 2024-01-08
EP4327886A2 (en) 2024-02-28
EP2748166B1 (en) 2018-07-11
IL231082A0 (en) 2014-03-31
CN108707151B (zh) 2022-06-03
MX361458B (es) 2018-12-06
ES2969977T3 (es) 2024-05-23
HUE065564T2 (hu) 2024-06-28
EP3392252B1 (en) 2023-10-04
PL2748166T3 (pl) 2019-05-31
CN103974955A (zh) 2014-08-06
EP3404029A3 (en) 2018-12-12
US9382277B2 (en) 2016-07-05
US20130053346A1 (en) 2013-02-28
BR112014003981A2 (pt) 2017-03-07
EP4327886A3 (en) 2024-05-22
CA2846187A1 (en) 2013-02-28
EP3404029A2 (en) 2018-11-21
US10183944B2 (en) 2019-01-22
FI3392252T3 (fi) 2024-01-08
US20190092779A1 (en) 2019-03-28
JP5993010B2 (ja) 2016-09-14
JP2014524475A (ja) 2014-09-22
US20160257691A1 (en) 2016-09-08
IL231082A (en) 2016-09-29
ES2690971T3 (es) 2018-11-23

Similar Documents

Publication Publication Date Title
DK2748166T3 (da) Pyrimido-pyridazinonforbindelser og anvendelse deraf
ES2562419T3 (es) Compuestos de 2,4-pirimidinodiamina y sus profármacos y sus usos
ES2607083T3 (es) Derivados de 5,6-dihidro-2H-[1,4]oxazin-3-ilamina útiles como inhibidores de beta-secretasa (BACE)
JP2024513554A (ja) ユビキチン特異的プロテアーゼ１（ｕｓｐ１）阻害剤
CN101460175A (zh) 用于fgf受体激酶抑制剂的组合物和方法
US10221192B2 (en) Compounds as tyrosine kinase modulators
CN104910137A (zh) Cdk激酶抑制剂
CN105283454A (zh) 作为ras/raf/mek/erk和pi3k/akt/pten/mtor通路双重抑制剂的喹唑啉和氮杂喹唑啉
CN104177338B (zh) 一类布鲁顿激酶抑制剂
TW201629036A (zh) 喹啉及喹唑啉化合物類
CA3177164A1 (en) Bicyclic kinase inhibitors and uses thereof
TW202416989A (zh) 作為pi3k抑制劑的苯并嘧啶-4(3h)-酮
ES2852123T3 (es) Derivados de ((piridin-2-il)-amino)pirido[3,4-d]pirimidina y ((piridazin-3-il)-amino)pirido[3,4-d]pirimidina como inhibidores de CDK4/6 para tratar p. ej. artritis reumatoide, arteriosclerosis, fibrosis pulmonar, infarto cerebral o cáncer
CA3049820A1 (en) Compounds for inhibiting lrrk2 kinase activity
WO2018187294A1 (en) Pyrimido-pyridazinone compound combinations, methods, kits and formulations thereof
CA3023460A1 (en) Cdk4/6 inhibitors for the treatment of hyper-proliferative diseases
CA2929742C (en) Sulfoximine substituted quinazolines for pharmaceutical compositions
CN115916350B (zh) Akt抑制剂的单位剂量组合物
CN108658976B (zh) 一类新型吡唑并[4,3-c]吡啶-4(5)-酮布鲁顿激酶抑制剂
CN111961035B (zh) 一类含有羟基异喹啉类结构的化合物、药物组合物以及其应用
US11766443B2 (en) Cyclopentathiophene carboxamide derivatives as platelet activating factor receptor antagonists