[go: up one dir, main page]

WO2019038683A1 - Composés ciblant les domaines brct en tandem de brca1, compositions et procédés associés - Google Patents

Composés ciblant les domaines brct en tandem de brca1, compositions et procédés associés Download PDF

Info

Publication number
WO2019038683A1
WO2019038683A1 PCT/IB2018/056344 IB2018056344W WO2019038683A1 WO 2019038683 A1 WO2019038683 A1 WO 2019038683A1 IB 2018056344 W IB2018056344 W IB 2018056344W WO 2019038683 A1 WO2019038683 A1 WO 2019038683A1
Authority
WO
WIPO (PCT)
Prior art keywords
benzo
methanone
piperazin
imidazol
fluorobenzyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2018/056344
Other languages
English (en)
Inventor
Kavitha BHARATHAM
Vadiraj KURDEKAR
Vijay Potluri
Ashok R VENKITARAMAN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Institute For Stem Cell Biology And Regenerative Medicine
Original Assignee
Institute For Stem Cell Biology And Regenerative Medicine
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 Institute For Stem Cell Biology And Regenerative Medicine filed Critical Institute For Stem Cell Biology And Regenerative Medicine
Publication of WO2019038683A1 publication Critical patent/WO2019038683A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/08—Radicals containing only hydrogen and carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • 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
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds, compositions, methods, and applications in the treatment of cancer or other diseases.
  • the invention relates to compounds, compositions and methods for inhibiting the interaction of breast cancer gene 1 (BRCAl) tandem carboxyl (C)-terminal (BRCT) domains with phosphorylated substrates including BTB Domain and CNC Homolog 1 (BACH1) helicase.
  • BRCAl breast cancer gene 1
  • C carboxyl
  • BACH1 CNC Homolog 1
  • the compounds of the present invention are useful in treating diseases or conditions responsive to or requiring the inhibition of ATM, ATR, DNA-PK, BRCAl, BRC A2, PALB2, RAD51 or CHEK1 and/or other BRCT- domain containing proteins.
  • phosphopeptide recognizing domains Over 10 different structural mechanisms for such recognition have been identified through distinct protein domains that bind to pSer, pThr or pTyr residues in proteins. Inhibition of phosphopeptide substrate recognition by these domains using small molecule drugs is an attractive approach to selectively modulate intracellular signalling(Cell Chem. Biol. 24, 1-12, 2017).
  • the BRCT (BRCA1 C-terminal) domain represents one member of a family of
  • BRCT domains were originally identified in Breast cancer associated 1 (BRCA1) protein but exist in many proteins from prokaryotes to eukaryotes.
  • BRCA1 Breast cancer associated 1
  • the BRCT domain typically consists of repeats containing approximately -90-
  • Each BRCT repeat adopts a characterized fold with a central, parallel four- stranded ⁇ -sheet, along with a pair of a -helices packed against one face and a single a -helix packed against the opposite face of the sheet.
  • the arrangement of the a 1 , a 3 and the central ⁇ -sheet is conserved in all repeats as a number of key hydrophobic residues maintain the packing of the BRCT fold.
  • the two BRCT repeats in BRCA1 interact in a head-to-tail manner. In this arrangement, the N-terminal half of the one BRCT domain forms a pocket for pSer as the C-terminal half of the same domain generates a hydrophobic pocket for Phe.
  • the tandem BRCT (tBRCT) domain pair in BRCA1 recognizes the phosphorylated peptide motif pS-P-T-F in various protein partners such as BRC A 1 -associated C-terminal helicase protein (BACH1), CtlPand Abraxas/Coiled-coil domain-containing protein and the ability of BRCA1 to recognize different binding partners in DDR signalling regulates BRCA1 recruitment and function(Science 302, 636-639, 2003; J. biol. chem. 278, 52914- 52918,2003).
  • BACH1 BRC A 1 -associated C-terminal helicase protein
  • CtlPand Abraxas/Coiled-coil domain-containing protein the ability of BRCA1 to recognize different binding partners in DDR signalling regulates BRCA1 recruitment and function(Science 302, 636-639, 2003; J. biol. chem. 278, 52914- 52918,2003).
  • Crystal structures of the BRCAltBRCTdomainbound to their respective phosphopeptides reveal a conserved bipartite recognition involving two distinct pockets: a pS/pT binding pocket in the N-terminal BRCT and a secondary specificity pocket at the BRCT-BRCT interface that generally provides selectivity for a hydrophobic residue at the +3 position in the
  • the tBRCT domain of BRCA1 is critical forthe cellular DNA damage response
  • DDR through the recognition of phosphorylated proteins that have been modified by protein kinases activated by DNA damage, including but not limited to CDKs, ATM, ATR and DNA- PK.
  • the DDR is proposed to constitute an early barrier to tumorigenesis and current cancer therapy regimens, including but not limited to radiation therapy exploit weaknesses in this system to selectively kill cancer cells.
  • the establishment of a platform for the identification of chemical compounds that inhibit the interaction of the BRCA1 tBRCT domains with their phosphopeptide substrates will lead to the discovery of potential sensitizers to cancer therapyand should accelerate the development of new treatment strategies.
  • Small-molecule chemical tools that target aforesaid interactions could offer an advanced therapeutic approach for the selective modulation of intracellular signalling pathways.
  • BRCA1 activity through phosphopeptide recognition by its tBRCT domain selectively propagates intracellular signals downstream of protein kinases like ATM, ATR or DNA-PK.
  • protein kinases like ATM, ATR or DNA-PK.
  • synthesizing improved and advantageous small molecules for selective modulation of intracellular signalling pathways via phosphopeptide recognition or other protein-protein interactions has been difficult in the prior art.
  • the present invention provides compounds of formula I
  • Rl, R2 and R3 are independently selected from a group consisting of H, C1-C6 alkyl, C6-C10 aryl and wherein each of them is unsubstituted or substituted;
  • Q is N or C and wherein each of them is unsubstituted or substituted;
  • R4 and R5 are selected from a group consisting of phenyl, 5-10 membered heteroaryl, 5-10 membered bicyclic heteroaryland wherein each of them is unsubstituted or substituted.
  • Rl is H, methyl, S-Methyl, R-Methyl,isopropyl, S-Isopropyl, benzyl, R-Isopropyl, S-benzyl or R-benzyl.
  • R2 and R3 are independently H or Methyl.
  • L and M are linkers independently selected from ⁇
  • n 0 to 6 and R9 is-H, -CH 3 , -CH 2 -CN, -OCH 3 , -OCH 2 CN, -OCH 2 CH 2 OH,
  • RIO is F, CI, Br, I, CN, OH, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, alkylthio, arylthio, nitro, azido, hydrazino, carboxyl acid and carboxylic acid ester.
  • R5 is also provided as
  • the compounds of the invention are provided (from 1 to 129) in Table I.
  • the invention provides a method of inhibiting phosphopeptide recognition by the human BRCA1 (t)BRCT domain by using the compounds of the invention encompassed by Formula I along with its substitutions described above.
  • the invention also provides a method of inhibiting the function of BRCA1 by using the compounds of the invention encompassed by Formula I along with its substitutions described above.
  • the invention presents a method of inhibiting cell cycle arrest induced by DNA damage by using the compounds of the invention encompassed by Formula I along with its substitutions described above.
  • the invention provides a method of inhibiting the recruitment of cellular proteins essential for G2 arrest and DNA repair by homologous DNA recombination by using the compounds of the invention encompassed by Formula I along with its substitutions described above.
  • the invention also provides a method of sensitizing cancer cells to the cytostatic or cytotoxic effects of radiation or DNA damaging agents by using the compounds of the invention encompassed by Formula I along with its substitutions described above and the said DNA damaging agents are cisplatin, carboplatin, doxorubicin, toposide, topotecan, irinotecan or mitomycin C, inhibitors of poly-ADP ribose polymerase (PARP) enzymes, inhibitors of telomerase or inhibitors of polymerase theta or any combination thereof.
  • PARP poly-ADP ribose polymerase
  • the compounds of the invention formulated into pharmaceutical composition comprising at least one pharmaceutical excipient are useful in the treatment of diseases responsive to inhibition of ATM, ATR, DNA-PK, BRCA1, BRCA2, PALB2, RAD51 or CHEK1
  • the compounds of the invention formulated into pharmaceutical composition comprising at least one pharmaceutical excipient are useful in the treatment of cancer, proliferative disorders (for example: rheumatoid arthritis, idiopathic pulmonary fibrosis and psoriasis), inflammatory disorders associated with cell proliferation or Fanconi Anemia.
  • proliferative disorders for example: rheumatoid arthritis, idiopathic pulmonary fibrosis and psoriasis
  • inflammatory disorders associated with cell proliferation or Fanconi Anemia.
  • the invention also provides a combination of the compounds of invention along with at least one additional active therapeutic agent wherein the said active therapeutic agent is an anti-cancer, immune modulatory, cytostatic, cytotoxic, anti-hyperproliferative, anti-inflammatory and chemotherapeutic agents
  • FIG 1 shows the direct binding assay for Compound 6 by Micro Scale Thermophoresis (MST).
  • Figure 2 shows the competitive binding assay for selected compounds by Micro Scale
  • Thermophoresis (MST).
  • Figure 3 shows target engagement studies for Compound 6 using FRET sensitized emission and acceptor photobleaching measurement methodologies.
  • Figure 4 shows inhibition of endogenous recruitment of BRCA1 foci by selected compounds.
  • Figure 5 shows inhibition of endogenous recruitment of RAD 1 foci by Compound 6.
  • Figure6 shows cell cycle and G2 checkpoint regulation studies using selected compounds of the invention.
  • Figure 7 showssynergistic effect of Compound 6 with Olaparib under steady state conditions in HEK293 cells.
  • Figure 8 shows decreased cell survival in the presence of Compound 6 in different cancer cell lines as indicated in the Figure.
  • Figure 9 shows cellular proliferation and radiation sensitivity studies by Compound 6.
  • the present disclosure relates to compounds and compositions as modulators of intracellular signalling pathways. Corresponding methods of treating/managingdiseases or conditions responsive to said modulation are also disclosed. As used in the present disclosure, modulation comprises inhibition, activation or a combination thereof.
  • compounds and compositions of the present disclosure are inhibitors of proteins including BRCA1 involved in intracellular signallingpathwaysresponsible for DNA damage response (DDR) in cells.
  • DDR DNA damage response
  • Rl, R2, R3 are independently selected from a group consisting of H, C1-C6 alkyl and C6-C10 aryl, and wherein each of them is unsubstituted or substituted;
  • Q isNor C, and wherein each of them is unsubstituted or substituted;
  • R4 and R5 are independently selected from a group consisting of phenyl, 5-10 membered heteroaryl, 5-10 membered bicyclic heteroaryland wherein each of them is unsubstituted or substituted; and salt, derivative, tautomeric form, isomer, polymorph, solvate and intermediates thereof of the above compound.
  • Rl in the compound of formula I is selected from a group comprising Hydrogen, Methyl, S-methyl, R-methyl,isopropyl, S- isopropyl, R-isopropyl, Benzyl, S-benzyl and R-benzyl.
  • R2 and R3 in the compound of formula I are either Hydrogen or Methyl.
  • R2 in the compound of formula I is hydrogen and R3 is methyl.
  • L and M of formula I are linker moieties. In another non-limiting embodiment of the present disclosure, L and M of the compound of formula I are linkers independently selected from
  • n 0 to 6.
  • R4 of the compound of formula I is selected from a group comprising
  • R6 is H or Carboxylic acid (COOH) and R8 is -H, -CH 3 -CH 2 -CH 2 -OH or -CH 2 - CH 2 -CN and R7 is
  • R5 of the compound of formula I is
  • RIO is selected from a group consisting of F, CI, Br, I, CN, OH, alkyl, alkenyl, alkynyl, alkoxy, aryoxy, alkylthio, arylthio, nitro, azido, hydrazino, carboxyl acid
  • R5 of formula I is:
  • Rl, R2, R3, R7 and Q are as defined in general formula I.
  • the present disclosure also provides salts, derivatives, tautomers, isomers, polymorphs, solvates and intermediates thereof of the above compounds of Table 1.
  • the protecting group PG as provided here is selected from a group comprising BOC, Fmoc,
  • the present disclosure provides the following method for preparing compound of formula I
  • R3 R3 R3 R3 G protecting group * wherein Q, Rl, R2, R3, R4, R5, L and M are as defined in compound of general Formula I.
  • Coupling reaction for preparing compound of formula I is carried out in the presence of coupling reagentselected from a group consisting K 2 C0 3 /DMF, HATU DIPEA, EDC/HOBt and combinations thereof.
  • PG protecting group !l wherein Q, Rl, R2, R3, L and M are as defined in compound of general Formula I or compound of Formula II.
  • Coupling reaction for preparing compound of formula II is carried out in presence of coupling reagentselected from a group comprising K 2 C0 3 /DMF, HATU DIPEA, EDC/HOBt and combinations thereof.
  • Deprotection reaction for preparing compound of formula II is carried out in presence of deprotecting reagentselected from a group comprising Pd/C, HCl DCM, TFA/DCM, Aq. NaOH and combinations thereof.
  • the present disclosure also provides the following method for preparing compound of formula
  • the present disclosure provides a general method for preparing compound of formula III as follows:
  • R7 is as defined in compound of general formula I or compound of formula III.
  • the present disclosure provides the following method for preparing compound of formula ⁇
  • the present disclosure provides the following method for preparing
  • the invention also encompassespharmaceutically acceptable salts of the compound of formula I-IV which is selected from a group consisting of sodium, potassium, calcium, magnesium, ammonium and combinations thereof.
  • the present invention also provides isomers of compounds of formula I-IV or the compounds described above which is selected from a group consisting of positional isomers, geometric isomers, optical isomers, tautomers, enantiomers and their pharmaceutically acceptable salt thereof.
  • the present disclosure further provides a pharmaceutical composition
  • a pharmaceutical composition comprising compound of formula I-IV as defined above, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, optionally along with at least one pharmaceutically acceptable excipient.
  • the pharmaceutical composition further comprises one or more additional active agents/drugs.
  • the compounds of the present invention are delivered to the subjects by forms suitable for each administration route.
  • the compounds are administered as tablets, capsules, injection, drops, inhaler, ointment, foams suppository.
  • the route of administration is oral (buccal or sublingual), parenteral, rectal, vaginal, or topical.
  • the route of administration may further include transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, local administration, intralesional administration.
  • Parenteral administration include but not restricted to intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration, or any combination thereof.
  • Topical or transdermal administration include powders, sprays, ointments, pastes creams, lotions, gels, solutions, patches and inhalants.
  • the pharmaceutical composition defined above is formulated into forms selected from a group comprising, but not limited to, solution, aqueous suspension, capsule, tablet, injection, cream, gel, ointment, lotion, solutions, dispersions, emulsion, foam, troche, lozenge, oily suspension, powders, sprays, suppositories, patch, dentifrice, spray, drops, dispersible powder or granule, syrup, elixir, food stuff, and any combination of forms thereof.
  • the compounds of the invention selectively inhibit the interaction of BRCAl with multiple partner proteins that contain phosphopeptide motifs recognized by the BRCAl tBRCT domain.
  • DDR DNA damage response
  • protein kinases including ATM, ATR or DNA-PK.
  • DDR DNA damage response
  • Proper execution of the DDR enforces cell cycle checkpoints that arrest cell division at different phases of the cell cycle, enables the efficient repair of DNA damage by different mechanisms, and promotes cell survival.
  • Proper execution of the DDR also suppresses the occurrence of abnormal DNA intermediates that may cause genomic DNA mutations, impede accurate gene expression, or activate the innate or adaptive immune response.
  • DDR failure or inhibition of the DDR can lead to multiple effects, including (a) increased sensitivity of cells including cancer cells to DNA damage caused by agents such as radiation or chemotherapeutic drugs, (b) increased sensitivity of cells including cancer cells to targeted inhibitors (for example, inhibitors of poly-ADP ribose polymerase (PARP) enzymes), or (c) enhanced responsiveness of cancers to immune checkpoint inhibitors (for example, therapeutic antibodies or drugs that block signalling via PD-1, PD-L1 or CTLA4)
  • PARP poly-ADP ribose polymerase
  • Compounds of the invention are expected to suppress the DDR by inhibiting the interactions of BRCAl with multiple partner proteins via the BRCl tBRCT domain.
  • BRCAl has been implicated as a key modulator of cellular processes including: (a) RNA processing after DNA damage, (b) mitotic progression including centrosome function or cytokinesis, (c) maintenance of heterochromatin and the repression of satellite RNA expression, (d) X-chromosome inactivation, (e) DNA replication (f) telomere maintenance and (g) prevention of chromosomal lesions, micronuclei formation and immune activation.
  • Compounds of the invention will affect such processes by inhibiting the interactions of BRCAl with multiple partner proteins via the BRC1 tBRCT domain.
  • compounds of the invention or compositions thereof of present invention are usefulalone or in combination with other agents in the treatment of cancer or other diseases (a) to inhibit the growth or viability of diseased cells such as cancer cells, (b) to sensitize diseased cells to the effects of radiation or chemotherapy, (c) to sensitize diseased cells to targeted inhibitors of poly-
  • the small molecule inhibitors described as compounds of formula I-IV are useful for the treatment of cancers of specific molecular types which may exhibit characteristic patterns of genome instability detected by next-generation sequencing of tumor DNA followed by bio- informatic analysis to identify said patterns of genome instability.
  • the compounds of present invention are used for treatment of any disease responsive to the inhibition of genes ATM, ATR, CDKs, DNA-PK, BRCAl, BRCA2, PALB2, RAD51 or CHEK1 or diseases or conditions related to inhibition of ATM, ATR, DNA-PK, BRCAl, BRCA2, PALB2, RAD51 or CHEK1.
  • the compounds of Formula I-IV as defined above are useful for the treatment or management of conditions including but not limited to cancer, proliferative disorders
  • the kit comprises: a) the
  • Inhibition of the DDR can lead to multiple effects, including (a) increased sensitivity of cells including cancer cells to DNA damage caused by agents such as radiation or chemotherapeutic drugs, (b) increased sensitivity of cells including cancer cells to targeted inhibitors (for example, inhibitors of poly-ADP ribose polymerase (PARP) enzymes), or (c) enhanced responsiveness of cancers to immune checkpoint inhibitors (for example, therapeutic antibodies or drugs that block signalling via PD-1, PD-Ll or CTLA4).
  • Targets for example, inhibitors of poly-ADP ribose polymerase (PARP) enzymes
  • PARP poly-ADP ribose polymerase
  • immune checkpoint inhibitors for example, therapeutic antibodies or drugs that block signalling via PD-1, PD-Ll or CTLA4
  • the kit further comprises one additional active agents/drugs.
  • the additional active agents are selected from a group consisting of anti-hyperproliferative, anti-cancer, cytostatic, cytotoxic, anti-inflammatory and chemotherapeutic agents.
  • checkpoint inhibitors for example, therapeutic antibodies or drugs that block signalling via PD-1, PD-L1 or CTLA4.
  • the additional active agents are therapeutic antibodies that target immune checkpoints selected from the group essentially consisting of anti-CTLA4, anti-PDl, anti-PD-Ll, or any combination thereof.
  • the present disclosure further provides a method for combination therapy for treating or managing cancer, other proliferative disorder including rheumatoid arthritis, idiopathic pulmonary fibrosis or psoriasis, inflammatory disorder associated with cell proliferation such as rheumatoid arthritis, Fanconi Anemia , any disease responsive to the inhibition of BRCA1 activity or any combination thereof, comprising administering a therapeutically effective amount of compound(s) of formula I-IVor a composition as described above along with anti- hyperproliferative, anti-cancer, cytostatic, cytotoxic, anti-inflammatory or chemotherapeutic agents selected from the group essentially consisting of cisplatin, carboplatin, doxorubicin, paclitaxel (including albumin-bound formulations), docetaxel, etoposide, topotecan, irinotecan or mitomycin C, or any combination thereof.
  • the present disclosure provides use of compound of formula I-IV as described above, or salt,derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or composition as described above for selective disruption of homologous DNA recombination mediated by RAD51, thereby suppressing DNA repair or the response to replication stress.
  • the compounds or compositions described above inhibit homologous DNA recombination by inhibiting BRCAl tBRCT signalling and suppressing the recruitment and assembly of RAD51 at sites of DNA damage or replication stress.
  • the present disclosure further provides methods or use of compounds or compositions as
  • BRCAltBRCT and phosphorylated BACH1 helicase comprising administering the compounds or compositions described above.
  • the present disclosure also provides a method or use of compound of formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or composition described above to treat a disease responsive to or requiring the inhibition of RAD51 assembly at sites of DNA damage or replication stress.
  • BRCA1 co-localizes with RAD51 at sites of DNA damage or replication stress and activates RAD51 -mediated homologous recombination repair of DNA double-strand breaks.
  • inhibition of BRCA1 supresses translocation of RAD51 to site of DNA damage.
  • the present disclosure provides a method or use of compound of formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, as biomarkers for prognosis of cancer, stratification of cancer, or a combination thereof.
  • the compounds or compositions of the present disclosure are used for predicting the likelihood of a response to exposure to BRCA1 tBRCT modulator as a method of cancer treatment.
  • the method for predicting the likelihood of a response to exposure to BRCA1 tBRCT modulator comprises administering the BRCAltBRCT modulator and collecting biological samples and measuring the cellular localization and level of one or more biomarkers selected from a group comprising BRCA1, RAD51, CTIP, BARDl or
  • the biological sample for such purpose is a tissue sample comprising cancer cells which is fixed, paraffin-embedded, fresh, or frozen, or any combination thereof.
  • Biological samples may also include any other sample from a human subject in which
  • the subject/patient refers to a mammal including human. In a preferred embodiment of the present disclosure, the subject/patient is human.
  • a method for treating malignancy or cancer in a patient in need thereof comprises administering to said patient a first amount of compound of formula I-IV or, salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or their compositions in a first treatment procedure, and a second amount of other active agent/drug in a second treatment procedure wherein, the first and second amounts together comprise a therapeutically effective amount.
  • Compounds of present disclosure selectively bind to BRCAl protein in normal cellsor tumor tissues when coupled to a signal agent, and are thereby useful as bioimaging agent/molecular probe. These molecular probes are used for early disease detection, characterization, and real-time monitoring of therapeutic responses, as well as for investigating drug efficacy.
  • the present disclosure also provides a method or use of compound of formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or their compositions as described above for treating viral infections by inhibiting for protein-protein interaction critical for viral proliferation.
  • BRCAl plays an important role in viral transcription and cells that lack BRCAl activity show resistance to viral infection.
  • Tat protein a viral protein that play an important role in viral transcription forms complex with BRCAl to initiate viral protein transcription.
  • inhibition of interaction of Tat protein and BRCAl using the present compounds/small molecule inhibitors are potentially used as antiviral therapy.
  • the present disclosure additionally provides a method or use of compound of formula I-IV, or salt, derivative, tautomeric form, isomer, polymorph, solvate or intermediates thereof, or their compositions as described aboveas radiosensitizers in clinical settings during cancer therapy to avoid possible disease relapse. Additional embodiments and features of the present disclosure will be apparent to one of ordinary skill in art based upon description provided herein. The disclosure is further illustrated with the following Examples and Figures. These Examples are for better understanding of the invention and should not be construed to limit the scope of the invention in any way. Examples
  • Example 1 Direct binding assay by Micro Scale Thermophoresis (MST)
  • MST Micro Scale Thermophoresis
  • FIG. 3 indicates that Compound 6 disrupts FRET activity, indicating that the compound directly engages its target and selectively disrupts phosphopeptide substrate recognition by the BRCA1 tBRCT domain in the cellular milieu.
  • Example 4 Recruitment of DNA damage response (DDR) proteins to sites of DNA damage
  • the cellular DNA damage response (DDR) enforces cell cycle checkpoints that arrest cell division at different phases of the cell cycle, enables the efficient repair of DNA damage by different mechanisms, and promotes cell survival.
  • BRCA1 is essential for the DDR. It interacts via the BRCA1 tBRCT domain with multiple protein partners like Claspin, CtIP, CHK1/CHK2, BACHl, RAD51 and so on to mediate G2 checkpoint control, to enable DNA repair, and to promote cell survival after DNA damage.
  • Several of these protein partners are recruited to sites of DNA damage via their interaction with the BRCA1 tBRCT domain.
  • DNA damage-activated protein kinases including ATM, ATR or DNA-PK that normally lead to the recruitment of RAD51 to sites of DNA damage, mediated by BRCA1, BRCA2, PALB2 and other proteins.
  • the cellular DNA damage response enforces cell cycle checkpoints that arrest cell division at different phases of the cell cycle, enables the efficient repair of DNA damage by different mechanisms, and promotes cell survival.
  • BRCA1 is essential for the DDR. It interacts via the BRCA1 tBRCT domain with multiple protein partners like Claspin, CtIP,
  • the cellular DNA damage response enforces cell cycle checkpoints that arrest cell division at different phases of the cell cycle, enables the efficient repair of DNA damage by different mechanisms, and promotes cell survival.
  • BRCA1 is essential for the DDR. It interacts via the BRCA1 tBRCT domain with multiple protein partners like Claspin, CtIP, CHK1/CHK2, BACHl, RAD51 etc. tomediate G2 checkpoint control, to enable DNA repair, and to promote cell survival after DNA damage. Accordingly, the ability of compounds of the present disclosure to affect survival after DNA damage was measured.
  • the assay below measures the survival curve (Dose Response Curve; DRC)reporting the relationship between the dose of radiationadministered, and the fraction of cells retaining their ability to survive or divide.
  • DRC Dose Response Curve
  • the Examples illustrated herein also enable the compounds of invention and establish their role in treatment of a disease responsive to inhibition of protein kinases including ATM, ATR or DNA-PK, and DDR factors including BRCA1, BRCA2, PALB2, RAD51 or CHEK1.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne le domaine des sciences médicales/pharmaceutiques. La présente invention concerne des composés, des compositions, des procédés et des utilisations pour le diagnostic et le traitement d'une maladie ou d'états sensibles à la modulation de BRCA1, et/ou à la modulation d'autres protéines qui contiennent des domaines BRCT. En particulier, l'invention concerne un composé de formule I, des compositions et des procédés correspondants pour inhiber l'activité de BRCA1 et ainsi une réponse aux dommages de l'ADN (DDR) dans les cellules, médiée par ATM, ATR, les CDK, ADN-PK, BRCA1, BRCA2, PALB2, RAD51 ou CHEK1, ainsi que d'autres molécules. Ladite modulation d'étapes dans la DDR permet le traitement ou la prise en charge des troubles prolifératifs, y compris du cancer. 1
PCT/IB2018/056344 2017-08-24 2018-08-22 Composés ciblant les domaines brct en tandem de brca1, compositions et procédés associés Ceased WO2019038683A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201741030084 2017-08-24
IN201741030084 2017-08-24

Publications (1)

Publication Number Publication Date
WO2019038683A1 true WO2019038683A1 (fr) 2019-02-28

Family

ID=65439422

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2018/056344 Ceased WO2019038683A1 (fr) 2017-08-24 2018-08-22 Composés ciblant les domaines brct en tandem de brca1, compositions et procédés associés

Country Status (1)

Country Link
WO (1) WO2019038683A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109879839A (zh) * 2019-03-12 2019-06-14 沈阳大学 6-哌嗪甲基-7-羟基苯并呋喃类化合物及其医药用途
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12043632B2 (en) 2020-12-23 2024-07-23 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12162881B2 (en) 2021-11-09 2024-12-10 Ajax Therapeutics, Inc. Forms and compositions of inhibitors of JAK2
US12415816B2 (en) 2018-11-07 2025-09-16 Dana-Farber Cancer Institute, Inc. Benzothiazole derivatives and 7-aza-benzothiazole derivatives as janus kinase 2 inhibitors and uses thereof
US12509455B2 (en) 2018-11-07 2025-12-30 Dana-Farber Cancer Institute, Inc. Imidazopyridine derivatives and aza-imidazopyridine derivatives as Janus kinase 2 inhibitors and uses thereof
US12522583B2 (en) 2018-11-07 2026-01-13 Dana-Farber Cancer Institute, Inc. Benzimidazole derivatives and aza-benzimidazole derivatives as Janus kinase 2 inhibitors and uses thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM Compound [o] 26 March 2005 (2005-03-26), ANONYMOUS: "1,4-Diphenylpiperazine CID 69173", XP055578524, retrieved from NCBI Database accession no. CID 69173 *
PERIASAMY, J ET AL.: "Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling", CELL CHEMICAL BIOLOGY, vol. 25, no. 6, 21 June 2018 (2018-06-21), pages 677 - 690, XP085410738, ISSN: 2451-9456, DOI: :10.1016/j.chembiol.2018.02.012 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12415816B2 (en) 2018-11-07 2025-09-16 Dana-Farber Cancer Institute, Inc. Benzothiazole derivatives and 7-aza-benzothiazole derivatives as janus kinase 2 inhibitors and uses thereof
US12509455B2 (en) 2018-11-07 2025-12-30 Dana-Farber Cancer Institute, Inc. Imidazopyridine derivatives and aza-imidazopyridine derivatives as Janus kinase 2 inhibitors and uses thereof
US12522583B2 (en) 2018-11-07 2026-01-13 Dana-Farber Cancer Institute, Inc. Benzimidazole derivatives and aza-benzimidazole derivatives as Janus kinase 2 inhibitors and uses thereof
CN109879839A (zh) * 2019-03-12 2019-06-14 沈阳大学 6-哌嗪甲基-7-羟基苯并呋喃类化合物及其医药用途
CN109879839B (zh) * 2019-03-12 2023-04-25 沈阳大学 6-哌嗪甲基-7-羟基苯并呋喃类化合物及其医药用途
US11691963B2 (en) 2020-05-06 2023-07-04 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12275717B2 (en) 2020-05-06 2025-04-15 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12043632B2 (en) 2020-12-23 2024-07-23 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US11970494B2 (en) 2021-11-09 2024-04-30 Ajax Therapeutics, Inc. 6-heteroaryloxy benzimidazoles and azabenzimidazoles as JAK2 inhibitors
US12162881B2 (en) 2021-11-09 2024-12-10 Ajax Therapeutics, Inc. Forms and compositions of inhibitors of JAK2

Similar Documents

Publication Publication Date Title
WO2019038683A1 (fr) Composés ciblant les domaines brct en tandem de brca1, compositions et procédés associés
Heerding et al. Identification of 4-(2-(4-amino-1, 2, 5-oxadiazol-3-yl)-1-ethyl-7-{[(3 S)-3-piperidinylmethyl] oxy}-1 H-imidazo [4, 5-c] pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase
DK2935244T3 (en) UNTIL UNKNOWN BENZIMIDAZOLE DERIVATIVES AS KINASE INHIBITORS
AU2016341445B2 (en) 2-aryl- and 2-heteroaryl-substituted 2-pyridazin-3(2H)-one compounds as inhibitors of FGFR tyrosine kinases
EP2499117B1 (fr) Composé, son procédé de préparation, composition pharmaceutique, utilisation d'un composé, procédé de modulation ou de régulation de serine/thréonine kinases et agent de modulation de serine/thréonine kinases
BRPI0117360B1 (pt) inibidores de proteína de quinase de 2-indolinona de pirrol substituído, seus sais e composições farmacêuticas compreendendo os mesmos
HK1219432A1 (zh) 以嘧啶化合物爲有效成分的医药组合物
WO2014145642A9 (fr) Inhibiteurs de nrf2 à petite molécule pour traitement anticancéreux
ES2930106T3 (es) Compuesto derivado de pirrol-piridina, procedimiento para preparar el mismo y composición farmacéutica que contiene el mismo como ingrediente activo para la prevención o el tratamiento de enfermedades relacionadas con la proteína quinasa
WO2018170204A1 (fr) Composés 9,10,11,12-tétrahydro-8h-[1,4] diazépino[5',6':4,5]thiéno[3,2-f]quinolin-8-one et leurs utilisations
JP2019507779A (ja) 尿素系化合物、その製造方法及びその医薬用途
CN118271322A (zh) Wrn解旋酶抑制剂
KR20150074186A (ko) 헤테로아릴기 알킨 화합물 및 그 응용
CN116568671A (zh) 杂环Cullin-RING泛素连接酶化合物及其用途
BR112019015269A2 (pt) compostos
EP3661935B1 (fr) Pyrazolopyrimidines substituées pouvant être employées en tant qu'inhibiteurs de kinases
AU2022226671B2 (en) Aminopyrimidine compounds and methods of their use
WO2010096395A1 (fr) Amides utilisés en tant qu'inhibiteurs des kinases
CN111072640A (zh) 喹唑啉类衍生物及其制备方法和应用
JP7176798B2 (ja) インダゾールキナーゼ阻害剤及びその使用
Jung et al. A novel indole derivative, 2‐{3‐[1‐(benzylsulfonyl) piperidin‐4‐yl]‐2‐methyl‐1H‐indol‐1‐yl}‐1‐(pyrrolidin‐1‐yl) ethenone, suppresses hedgehog signaling and drug‐resistant tumor growth
TWI759829B (zh) 作為第iii型受體酪胺酸激酶抑制劑之雜環吡唑衍生物
EP4393908A1 (fr) Composés bis-pyrazolyl-méthane affectant kras
Panzeca New indole and 7-azaindole derivatives as protein kinase inhibitors
TW202535388A (zh) 用於治療胃腸道基質瘤（ｇｉｓｔ）之化合物

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: 18849361

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18849361

Country of ref document: EP

Kind code of ref document: A1