HRP20210365T1 - Dna-pk inhibitori - Google Patents
Dna-pk inhibitori Download PDFInfo
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- HRP20210365T1 HRP20210365T1 HRP20210365TT HRP20210365T HRP20210365T1 HR P20210365 T1 HRP20210365 T1 HR P20210365T1 HR P20210365T T HRP20210365T T HR P20210365TT HR P20210365 T HRP20210365 T HR P20210365T HR P20210365 T1 HRP20210365 T1 HR P20210365T1
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- Prior art keywords
- 4alkyl
- group
- 2alkyl
- alkyl
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- 239000003112 inhibitor Substances 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims 39
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 38
- 229910052739 hydrogen Inorganic materials 0.000 claims 36
- 239000001257 hydrogen Substances 0.000 claims 34
- -1 pyrrolidinonyl Chemical group 0.000 claims 30
- 150000002431 hydrogen Chemical group 0.000 claims 28
- 125000000623 heterocyclic group Chemical group 0.000 claims 24
- 125000001153 fluoro group Chemical group F* 0.000 claims 22
- 150000001875 compounds Chemical class 0.000 claims 20
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 14
- 125000002757 morpholinyl group Chemical group 0.000 claims 14
- 125000002883 imidazolyl group Chemical group 0.000 claims 12
- 125000003566 oxetanyl group Chemical group 0.000 claims 12
- 125000003386 piperidinyl group Chemical group 0.000 claims 12
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims 12
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims 12
- 229910052799 carbon Inorganic materials 0.000 claims 10
- 229910052736 halogen Inorganic materials 0.000 claims 10
- 150000002367 halogens Chemical class 0.000 claims 10
- 125000001072 heteroaryl group Chemical group 0.000 claims 10
- 125000003226 pyrazolyl group Chemical group 0.000 claims 10
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 10
- 150000003839 salts Chemical class 0.000 claims 10
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 8
- 125000002393 azetidinyl group Chemical group 0.000 claims 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 8
- 125000004193 piperazinyl group Chemical group 0.000 claims 8
- 125000004076 pyridyl group Chemical group 0.000 claims 8
- 125000001544 thienyl group Chemical group 0.000 claims 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 6
- 125000004429 atom Chemical group 0.000 claims 6
- 125000004069 aziridinyl group Chemical group 0.000 claims 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 6
- 125000000532 dioxanyl group Chemical group 0.000 claims 6
- 125000005879 dioxolanyl group Chemical group 0.000 claims 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims 6
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 6
- 125000003831 tetrazolyl group Chemical group 0.000 claims 6
- 125000000335 thiazolyl group Chemical group 0.000 claims 6
- 125000001425 triazolyl group Chemical group 0.000 claims 6
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 4
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims 4
- 125000003545 alkoxy group Chemical group 0.000 claims 4
- 150000001721 carbon Chemical group 0.000 claims 4
- 125000004122 cyclic group Chemical group 0.000 claims 4
- 229910052805 deuterium Inorganic materials 0.000 claims 4
- 229910052731 fluorine Inorganic materials 0.000 claims 4
- 125000002541 furyl group Chemical group 0.000 claims 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 4
- 125000001715 oxadiazolyl group Chemical group 0.000 claims 4
- 229920006395 saturated elastomer Polymers 0.000 claims 4
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 claims 4
- 125000004001 thioalkyl group Chemical group 0.000 claims 4
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 3
- 206010009944 Colon cancer Diseases 0.000 claims 3
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 2
- 206010006187 Breast cancer Diseases 0.000 claims 2
- 208000026310 Breast neoplasm Diseases 0.000 claims 2
- 201000008808 Fibrosarcoma Diseases 0.000 claims 2
- 206010062878 Gastrooesophageal cancer Diseases 0.000 claims 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims 2
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 2
- 206010060862 Prostate cancer Diseases 0.000 claims 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims 2
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 claims 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- 208000029742 colonic neoplasm Diseases 0.000 claims 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 201000006974 gastroesophageal cancer Diseases 0.000 claims 2
- 208000005017 glioblastoma Diseases 0.000 claims 2
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 claims 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- 201000005202 lung cancer Diseases 0.000 claims 2
- 208000020816 lung neoplasm Diseases 0.000 claims 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 2
- 201000001441 melanoma Diseases 0.000 claims 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 2
- 125000002971 oxazolyl group Chemical group 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 239000001301 oxygen Substances 0.000 claims 2
- 201000002528 pancreatic cancer Diseases 0.000 claims 2
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 2
- 229910052717 sulfur Inorganic materials 0.000 claims 2
- 239000011593 sulfur Substances 0.000 claims 2
- 238000011285 therapeutic regimen Methods 0.000 claims 2
- 125000001113 thiadiazolyl group Chemical group 0.000 claims 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 230000001093 anti-cancer Effects 0.000 claims 1
- 239000012829 chemotherapy agent Substances 0.000 claims 1
- 230000003389 potentiating effect Effects 0.000 claims 1
- 230000005855 radiation Effects 0.000 claims 1
Classifications
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- 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
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/545—Heterocyclic compounds
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
- A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
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- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A—HUMAN NECESSITIES
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
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- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
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- 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
- C07D403/10—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 aromatic rings
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- 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
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- 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
- C07D405/14—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 three or more hetero rings
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- 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
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- C07D413/04—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 directly linked by a ring-member-to-ring-member bond
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- 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
- C07D413/10—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 carbon chain containing aromatic rings
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
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- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- 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
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- 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
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- 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
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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Claims (11)
1. Farmaceutski prihvatljiva količina spoja, naznačena time, da je spoj predstavljen strukturnom formulom (I), ili njegova farmaceutski prihvatljiva sol:
[image]
za uporabu u liječenju karcinoma odabranog iz skupine koju čine: rak dojke, rak debelog crijeva, debelog crijeva, gastroezofagealni rak, fibrosarkom, glioblastom, hepatocelularni karcinom, skvamozni karcinom glave i vrata, melanom, rak pluća, rak gušterače ili rak prostate, pri čemu:
Q je N ili CH;
R1 je vodik, CH3, ili CH2CH3, ili R1, ugljik na koji je vezan tvori C=CH2 skupinu;
Prsten A je sistem prstena odabran između
[image]
[image]
[image]
RA1 je vodik, halogen, C1-4alkil, C0-4alkil-C3-6cikloalkil, C0-4alkil-ORA1a, C0-4alkil-SRA1a, C0- 4alkil- C(O)N(RA1a)2, C0-4alkil-CN, C0-4alkil-S(O)-C1-4alkil, C0-4alkil-S(O)2-C1-4alkil, C0-4alkil-C(O)ORA1b, C0-4alkil-C(O)C1-4alkil, C0-4alkil-N(RA1b)C(O)RA1a, C0-4alkil-N(RA1b)S(O)2RA1a, C0-4alkil-N(RA1a)2, C0-4alkil-N(RA1b) (3 do 6-člani -cikloalkil), C0-4alkil-N(RA1b)(4 do 6-člani - heterociklil), N(RA1b)C2-4alkil-N(RA1a)2, N(RA1b)C2-4alkil-ORA1a, N(RA1b)C1-4alkil-(5 do 10 člani heteroaril), N(RA1b)C1-4alkil-(4 do 6-člani heterociklil), N(RA1b)C2-4alkil- N(RA1b)C(O)RA1a, C0-4alkil- N(RA1b)C(O)C1-4alkil, C0-4alkil-N(RA1b)C(O)OC1-4alkil, C0-4alkil- (fenil), C0-4alkil-(3-10 membered-heterociklil), C0-4alkil-C(O)-(4 do 6-člani -heterociklil), C0-4alkil-O-C0-4alkil-(4 do 6-člani -heterociklil), C0-4alkil-(5 do 6-člani -heteroaril), C0- 4alkil-C(O)-(5 do 6-člani -heteroaril), C0-4alkil-O-C0-4alkil-(5 do 6-člani -heteroaril), C0- 4alkil-N(RA1a)(4 do 6-člani -heterociklil), ili C0-4alkil-N(RA1b)(5 do 6-člani heteroaril), pri čemu je svaki od navedenih RA1 heterociklila sustav prstena odabran iz skupine koju čine aziridinil, oksetanil, tetrahidrofuranil, tetrahidropiranil, dioksanil, dioksolanil, azetidinil, pirolidinil, pirolidinonil, pirolidinedionil, morfolinil, piperidinil, piperazinil, piperazinonil, tetrahidrotiofenedioksidil, 1,1-dioksotietanil, 2-oksa-6-azaspiro[3.4]oktanil, i izoindolinonil pri čemu je svaki od navedenih RA1 heteroarila sustav prstena odabran iz skupine koju čine furanil, tiofenil, imidazolil, benzoimidazolil, oksazolil, oksadiazolil, tiazolil, pirazolil, tiadiazolil, piridinil, pirimidinil, pirazinil, triazolil, i tetrazolil, i pri čemu svaki od navedenih: RA1 alkil, cikloalkil, fenil, heterociklil, i heteroaril skupine su po izboru supstituirani s najviše do tri atoma fluora, do dvije C1-2alkil skupine, C3-6cikloalkil skupina, fenil skupina, benzil skupina, alkenil-C0-2alkil skupina, alkinil-C0-2alkil skupina, do dvije C0-2alkil-ORA1b skupine, C0-2alkil-N(RA1b)2 skupina, SC1-4alkil skupina, S(O)2C1- 4alkil skupina, C(O)RA1b skupina, C(O)ORA1b skupina, C(O)N(RA1b)2 skupina, -CN skupina, ili je C4-6heterociklički sustav prstena odabran iz skupine koju čine oksetanil, tetrahidrofuranil, tetrahidropiranil, piperidinil, i morfolinil;
svaki RA1a je, neovisno, vodik, C1-4alkil, C3-6cikloalkil, C4-6heterociklil odabran iz skupine koju čine oksetanil, tetrahidrofuranil, tetrahidropiranil, pirolidinil, i piperidinil, C5- 6heteroaril je odabran iz skupine koju čine imidazolil, triazolil, tetrazolil, pirazolil, tiofenil, tiazolil, piridinil, pirimidinil, i pirazinil, ili dva RA1a i intervenirajući atom dušika tvore 3 do 6-člani heterociklički prsten odabran iz skupine koju čine aziridinil, azetidinil, pirolidinil, pirolidinonil, piperidinil, piperidinonil, tetrahidropiridinil, piperazinil, i morfolinil, pri čemu svaka od navedene skupine RA1a alkil, cikloalkil, heterociklil i heteroaril je po izboru supstituirana s najviše do tri atoma fluora, do dvije C1-2alkil skupine, C3-6cikloalkil skupine, do dvije C0-2alkil-ORA1b skupine, C0-2alkil-N(RA1b)2 skupine, SC1-4alkil skupine, C(O)RA1b skupine, C(O)ORA1b skupine, C(O)N(RA1b)2 skupine, ili -CN skupinom; svaki RA1b je, neovisno, vodik, C1-2alkil, ili C3-4cikloalkil;
RA2 je vodik, C1-4alkil, C0-4alkil-C3-6cikloalkil, C0-2alkil-(4 do 6-člani)heterociklil, C2-4alkil- ORA2a, C0-2alkil-C(O)N(RA2a)2, C0-2alkil-S(O)2-C1-4alkil, C0-2alkil-C(O)OC1-4alkil, ili C0-2alkil- C(O)-(4 do 6-člani) heterociklil, pri čemu je svaki od navedenih heterociklila odabran od sljedećeg: oksetanil, tetrahidropiranil, tetrahidrofuranil, dioksanil, dioksolanil, azetidinil, pirolidinil, pirolidinonil, pirolidinedionil, morfolinil, piperidinil, piperazinil, piperazinonil, i 1,1-dioksotietanil, i svaka od navedenih RA2 skupina osim vodika je po izboru supstituirana s najviše do tri atoma fluora, do dvije C1-2alkil skupine, C3-6cikloalkil skupinom, alkenil-C0-2alkil skupinom, alkinil-C0-2alkil skupinom, do dvije ORA2b skupine, C0-2alkil-N(RA2b)2 skupinom, SC1-4alkil skupinom, S(O)2C1-4alkil skupinom, C(O)RA2b skupinom, C(O)ORA2b skupinom, C(O)N(RA2b)2 skupinom, ili -CN skupinoma; svaki RA2a je, neovisno, vodik, C1-4alkil, C5-6heteroaril selected from imidazolil, triazolil, tetrazolil, pirazolil, tiofenil, tiazolil, piridinil, pirimidinil, i pirazinil, ili dva RA2a i intervenirajući atom dušika tvori 3 do 6-člani heterociklički prsten odabran od sljedećeg: aziridinil, azetidinil, pirolidinil, pirolidinonil, piperidinil, piperidinonil, tetrahidropiridinil, piperazinil, i morfolinil;
svaki RA2b je, neovisno, vodik, C1-4alkil, ili C3-4cikloalkil;
RA3 je vodik ili C1-2alkil;
svaki RA4 je, neovisno, deuterij, halogen, CN, C1-4alkil, ili OC1-4alkil, pri čemu je svaki RA4 alkil po izboru supstituiran s najviše do tri atoma fluora, do dvije ne-geminalne OH skupine, ili jednim OC1-2alkilom, ili dva RA4 zajedno s intervenirajućim zasićenim atomom ugljika tvore spiralni ciklopropil ili ciklobutil prsten;
n je 0-3;
Prsten B je sustav prstena odabran od sljedećeg:
[image]
[image]
[image]
[image]
RB1 je vodik, C1-4alkil, (CH2)0-1C3-6cikloalkil, C(O)C1-2alkil, (CH2)0-1-(4 do 6- člani)heterociklil prsten pri čemu je navedeni heterociklički prsten odabran od: oksetanil, tetrahidrofuranil, tetrahidropiranil, dioksanil, dioksolanil, i pirolidinonil, fenil, benzil, ili (CH2)1-2(5 do 6-člani)heteroaril prsten pri čemu je navedeni heteroaril prsten odabran od sljedećeg: piridinil, imidazolil, i pirazolil, i pri čemu je svaki navedeni od sljedećeg: RB1 alkil, cikloalkil, fenil, benzil, heterociklil i heteroaril skupina po izboru supstituiran s najviše do tri atoma fluora, do dvije C1-2alkil skupine, dvije ne-geminalne OH skupine, ili jednim OC1-2alkilom;
RB2 je vodik, C1-4alkil, ili OC1-4alkil;
svaki RB3 je, neovisno, vodik, halogen, C1-4alkil, C2-4alkenil, C2-4alkinil, CN, C(O)H, C(O)C1-4alkil, C(O)OC1-4alkil, C(O)C1-4alkil, C(O)NH2, C(O)NHC1-4alkil, C(O)NH(CH2)0-1C3-6cikloalkil, C(O)NHCH2oksetanil, C(O)NHCH2tetrahidrofuranil, C(O)NHCH2tetrahidropiranil, C(O)NHfenil, C(O)NHbenzil, C(O)NHOH, C(O)NHOC1-4alkil, C(O)NHO(CH2)0-1C3-6cikloalkil, C(O)NHO(CH2)0-1oksetanil, C(O)NHO(CH2)0-1tetrahidrofuranil, C(O)NHO(CH2)0- 1tetrahidropiranil, C(O)NHOfenil, C(O)NHObenzil, NH2, NHC(O)C1-4alkil, OC1-4alkil, SC1- 4alkil, S(O)C1-4alkil, ili 5-člani -heteroarilni sustav prstena odabran od sljedećeg: furanil, tiofenil, imidazolil, pirol, pirazolil, i oksadiazolil, pri čemu je svaka RB3 skupina osima vodika ili halogena po izboru supstituirana s Cl, do najviše tri atoma fluora, do dvije ne- geminalne OH skupine, do dva OC1-2alkila, jednim NH2, jednim NHC1-2alkil, jednim NHC(O)C1-2alkil, ili jednim N(C1-2alkil)2;
svaki RB4 je, neovisno, vodik, halogen, C1-4alkil, OC1-4alkil, SC1-4alkil, NH2, NH(C1-4alkil), N(C1-4alkil)2, NHC(O)C1-4alkil, C(O)OH, C(O)OC1-4alkil, C(O)NH2, C(O)NHC1-4alkil, C(O)N(C1-4alkil)2, CN, morfolinil prsten, ili imidazolil prsten, pri čemu je svaki RB4 alkil dodatno supstituiran s najviše do 3 atoma fluora, dvije ne-geminalne OH skupine, ili jednim OC1-2alkilom;
RB5 je vodik, C1-4alkil, C(O)C1-4alkil, C(O)OC1-4alkil, C(O)NH2, C(O)NHC1-4alkil, ili C(O)N(C1-4alkil)2, pri čemu je navedeni RB5 alkil po izboru supstituiran s najviše do 3 atoma fluora, dvije ne-geminalne OH skupine, ili jednim OC1-2alkilom i RB6 je F ili C1-2alkil, ili dva RB6 i intervenirajući atom ugljika tvore a spirociklopropil ili spirociklobutil prsten;
nadalje pri čemu:
"alkil" ili "alkilna skupina" znači ravnolančani ili razgranani, supstituirani ili nesupstituirani ugljikovodični lanac koji je potpuno zasićen; a "alkoksi" ili "tioalkil" odnosi se na alkilnu skupinu, vezanu na glavni ugljikov lanac preko atoma kisika ("alkoksi") ili sumpora ("tioalkil").
2. Spoj za uporabu u skladu s patentnim zahtjevom 1, naznačen time, da je spoj predstavljen strukturnom formulom (II), ili njegova farmaceutski prihvatljiva sol:
[image]
pri čemu:
X je N ili CRA5;
RA1 je F, C1-4alkil, C3-5cikloalkil, OC1-4alkil, OC1-4alkil-C3-5cikloalkil, NH2, NHC1-4alkil, NHC1-4alkil-C3-5cikloalkil ili C0-4alkil-heterociklil, pri čemu navedeni heterociklički prstenasti sustav je odabran između oksetanila, tetrahidrofuranila, tetrahidropiranila ili morfolinila, a svaki od spomenutih alkila, cikloalkila ili heterociklila je po želji supstituiran s do tri atoma F, do tri 2H atoma, do dvije ne- geminalne OH skupine ili do dva OC1-2alkil;
svaki RA4 je, neovisno, H ili 2H;
RA5 je vodik, F, C1-4alkil ili OC1-4alkil, pri čemu je svaki od navedenih alkila po izboru supstituiran s do tri F atoma ili do tri 2H atoma;
RB3 je C(0)NHCl-4 alkil, pri čemu je navedeni alkil po izboru supstituiran s do tri F atoma, do tri 2H atoma, do dvije ne-geminalne OH skupine ili do dvije OC1-2alkil; i
svaki RB4 je neovisno vodik, deuterij, F ili C1-4alkil.
3. Spoj za uporabu u skladu s patentnim zahtjevom 1 ili 2, naznačen time, da se spoj bira između:
[image]
[image]
ili njegova farmaceutski prihvatljiva sol.
4. Spoj za uporabu u skladu s bilo kojim od patentnih zahtjeva 1 do 3, naznačen time, da je spoj
[image]
ili njegova farmaceutski prihvatljiva sol.
5. Spoj za uporabu u skladu s bilo kojim od patentnih zahtjeva 1 do 3, naznačen time, da je spoj
[image]
ili njegova farmaceutski prihvatljiva sol.
6. Farmaceutski prihvatljiva količina spoja predstavljenog strukturnom formulom (I), ili njegova farmaceutski prihvatljiva sol:
[image]
za uporabu u potenciranju terapijskog režima za liječenje karcinoma odabranog iz skupine koju čine:
rak dojke, kolorektalni karcinom, rak želučano-jednjaka, fibrosarkom, glioblastom, hepatocelularni karcinom, skvamozni karcinom glave i vrata, melanom, rak pluća, gušterača rak ili rak prostate, pri čemu:
Q je N ili CH;
R1 je vodik, CH3, ili CH2CH3, ili R1, a ugljik na koji je vezan tvore C=CH2 skupinu;
Prsten A je sustav prstena odabran između
[image]
[image]
RA1 je vodik, halogen, C1-4alkil, C0-4alkil-C3-6cikloalkil, C0-4alkil-ORA1a, C0-4alkil-SRA1a, C0- 4alkil-C(O)N(RA1a)2, C0-4alkil-CN, C0-4alkil-S(O)-C1-4alkil, C0-4alkil-S(O)2-C1-4alkil, C0-4alkil- C(O)ORA1b, C0-4alkil-C(O)C1-4alkil, C0-4alkil-N(RA1b)C(O)RA1a, C0-4alkil-N(RA1b)S(O)2RA1a, C0- 4alkil-N(RA1a)2, C0-4alkil-N(RA1b)(3 do 6-člani -cikloalkil), C0-4alkil-N(RA1b)(4 do 6-člani - heterociklil), N(RA1b)C2-4alkil- N(RA1a)2, N(RA1b)C2-4alkil-ORA1a, N(RA1b)C1-4alkil-(5 do 10 člani heteroaril), N(RA1b)C1-4alkil-(4 do 6-člani heterociklil), N(RA1b)C2-4alkil- N(RA1b)C(O)RA1a, C0-4alkil-N(RA1b)C(O)C1-4alkil, C0-4alkil- N(RA1b)C(O)OC1-4alkil, C0-4alkil- (fenil), C0-4alkil-(3-10 membered-heterociklil), C0-4alkil-C(O)-(4 do 6-člani - heterociklil), C0-4alkil-O-C0-4alkil-(4 do 6-člani -heterociklil), C0-4alkil-(5 do 6-člani -heteroaril), C0- 4alkil-C(O)-(5 do 6-člani -heteroaril), C0-4alkil-O-C0-4alkil-(5 do 6-člani -heteroaril), C0- 4alkil- N(RA1a)(4 do 6-člani -heterociklil), ili C0-4alkil-N(RA1b)(5 do 6-člani -heteroaril), pri čemu je svaki od navedenih RA1 heterociklila sustav prstena odabran iz skupine koju čine aziridinil, oksetanil, tetrahidrofuranil, tetrahidropiranil, dioksanil, dioksolanil, azetidinil, pirolidinil, pirolidinonil, pirolidinedionil, morfolinil, piperidinil, piperazinil, piperazinonil, tetrahidrotiofenedioksidil, 1,1-dioksotietanil, 2-oksa-6-azaspiro[3.4]oktanil, i izoindolinonil pri čemu je svaki od navedenih RA1 heteroarila sustav prstena odabran iz skupine koju čine furanil, tiofenil, imidazolil, benzoimidazolil, oksazolil, oksadiazolil, tiazolil, pirazolil, tiadiazolil, piridinil, pirimidinil, pirazinil, triazolil, i tetrazolil, i pri čemu svaki of navedenih: RA1 alkil, cikloalkil, fenil, heterociklil i heteroaril skupine su po izboru supstituirani s najviše do tri atoma fluora, do dvije C1-2alkil skupine, C3-6cikloalkil skupina, fenil skupina, benzil skupina, alkenil-C0-2alkil skupina, alkinil-C0-2alkil skupina, do dvije C0- 2alkil-ORA1b skupine, C0-2alkil- N(RA1b)2 skupina, SC1-4alkil skupina, S(O)2C1-4alkil skupina, C(O)RA1b skupina, C(O)ORA1b skupina, C(O)N(RA1b)2 skupina, -CN skupina, ili je C4- 6heterociklički sustav prstena odabran između : oksetanil, tetrahidrofuranil, tetrahidropiranil, piperidinil, i morfolinil;
svaki RA1a je, neovisno, vodik, C1-4alkil, C3-6cikloalkil, C4-6heterociklil selected from oksetanil, tetrahidrofuranil, tetrahidropiranil, pirolidinil, i piperidinil, C5-6heteroaril odabran od sljedećih: imidazolil, triazolil, tetrazolil, pirazolil, tiofenil, tiazolil, piridinil, pirimidinil, i pirazinil, ili dva RA1a i intervenirajući atom dušika tvore 3 do 6-člani heterociklički prsten odabran od sljedećeg: aziridinil, azetidinil, pirolidinil, pirolidinonil, piperidinil, piperidinonil, tetrahidropiridinil, piperazinil, i morfolinil, pri čemu svaki od navedenih RA1a alkila, cikloalkila, heterociklila, i heteroaril skupine je po izboru supstituiran s najviše do tri atoma fluora, do dvije C1-2alkil skupine, C3-6cikloalkil skupina, do dvije C0-2alkil-ORA1b skupine, C0-2alkil-N(RA1b)2 skupinom, SC1-4alkil skupinom, C(O)RA1b skupinom, C(O)ORA1b skupinom, C(O)N(RA1b)2 skupinom, ili -CN skupinom ; svaki RA1b je, neovisno, vodik, C1-2alkil, ili C3-4cikloalkil;
RA2 je vodik, C1-4alkil, C0-4alkil-C3-6cikloalkil, C0-2alkil-(4 do 6-člani)heterociklil, C2-4alkil- ORA2a, C0-2alkil-C(O)N(RA2a)2, C0-2alkil-S(O)2-C1-4alkil, C0-2alkil-C(O)OC1-4alkil, ili C0-2alkil- C(O)-(4 do 6-člani) heterociklil, pri čemu je svaki od navedenih heterociklila odabran od sljedećeg: oksetanil, tetrahidropiranil, tetrahidrofuranil, dioksanil, dioksolanil, azetidinil, pirolidinil, pirolidinonil, pirolidinedionil, morfolinil, piperidinil, piperazinil, piperazinonil, i 1,1-dioksotietanil, i svaka od navedene RA2 skupine osim vodika je po izboru supstituirana s najviše do tri atoma fluora, do dvije C1-2alkil skupine, C3-6cikloalkil skupinom, alkenil-C0-2alkil skupinom, alkinil-C0-2alkil skupinom, up to two ORA2b skupine, C0-2alkil-N(RA2b)2 skupinom, SC1-4alkil skupinom, S(O)2C1-4alkil skupinom, C(O)RA2b skupinom, C(O)ORA2b skupinom, C(O)N(RA2b)2 skupinom, ili -CN skupinom ;
svaki RA2a je, neovisno, vodik, C1-4alkil, C5-6heteroaril odabran od sljedećeg: imidazolil, triazolil, tetrazolil, pirazolil, tiofenil, tiazolil, piridinil, pirimidinil, i pirazinil, ili two RA2a i intervenirajući atom dušika čine 3 do 6-člani heterociklički prsten odabran od sljedećeg : aziridinil, azetidinil, pirolidinil, pirolidinonil, piperidinil, piperidinonil, tetrahidropiridinil, piperazinil i morfolinil;
svaki RA2b je, neovisno, vodik, C1-4alkil, ili C3-4cikloalkil;
RA3 je vodik ili C1-2alkil;
svaki RA4 je, neovisno, deuterij, halogen, CN, C1-4alkil, ili OC1-4alkil, pri čemu je svaki RA4 alkil po izboru supstituiran s najviše do 3 atoma fluora, dvije ne-geminalne OH skupine, ili jednim OC1-2alkilom, ili dva RA4 zajedno s intervenirajućim zasićenim atomom ugljika tvori spiralni ciklopropil ili ciklobutil prsten;
n je 0-3;
Prsten B je sustav prstena odabran od sljedećeg:
RB1 je vodik, C1-4alkil, (CH2)0-1C3-6cikloalkil, C(O)C1-2alkil, (CH2)0-1-(4 do 6- člani)heterociklil prsten pri čemu je navedeni heterociklički prsten odabran od sljedećeg: oksetanil, tetrahidrofuranil, tetrahidropiranil, dioksanil, dioksolanil, i pirolidinonil, fenil, benzil, ili (CH2)1-2(5 do 6-člani)heteroarilni prsten, pri čemu je navedeni heteroarilni prsten odabran od sljedećeg: piridinil, imidazolil, i pirazolil, i pri čemu je svaki od navedenog: RB1 alkil, cikloalkil, fenil, benzil, heterociklil i heteroaril skupina, po izboru supstituiran s najviše do tri atoma fluora, do dvije C1-2alkil skupine, dvije ne-geminalne OH skupine, ili jednim OC1-2alkilom;
RB2 je vodik, C1-4alkil, ili OC1-4alkil;
svaki RB3 je, neovisno, vodik, halogen, C1-4alkil, C2-4alkenil, C2-4alkinil, CN, C(O)H, C(O)C1-4alkil, C(O)OC1-4alkil, C(O)C1-4alkil, C(O)NH2, C(O)NHC1-4alkil, C(O)NH(CH2)0-1C3- 6cikloalkil, C(O)NHCH2oksetanil, C(O)NHCH2tetrahidrofuranil, C(O)NHCH2tetrahidropiranil, C(O)NHfenil, C(O)NHbenzil, C(O)NHOH, C(O)NHOC1-4alkil, C(O)NHO(CH2)0-1C3-6cikloalkil, C(O)NHO(CH2)0-1oksetanil, C(O)NHO(CH2)0-1tetrahidrofuranil, C(O)NHO(CH2)0- 1tetrahidropiranil, C(O)NHOfenil, C(O)NHObenzil, NH2, NHC(O)C1-4alkil, OC1-4alkil, SC1- 4alkil, S(O)C1-4alkil, ili 5-člani heteroarilni sustav prsten odabran od sljedećeg: furanil, tiofenil, imidazolil, pirol, pirazolil, i oksadiazolil, pri čemu je svaka RB3 skupina osim vodika ili halogena, po izboru supstituirana s Cl, s najviše do tri atoma fluora, do dvije ne-geminalne OH skupine, do dva OC1-2alkila, jednim NH2, jednim NHC1-2alkil, jednim NHC(O)C1-2alkilom, ili jednim N(C1-2alkilom)2;
svaki RB4 je, neovisno, vodik, halogen, C1-4alkil, OC1-4alkil, SC1-4alkil, NH2, NH(C1-4alkil), N(C1-4alkil)2, NHC(O)C1-4alkil, C(O)OH, C(O)OC1-4alkil, C(O)NH2, C(O)NHC1-4alkil, C(O)N(C1-4alkil)2, CN, morfolinil prsten, ili imidazolil prsten, pri čemu je svaki RB4 alkil po izboru supstituiran s najviše do tri atoma fluora, dvije ne-geminalne OH skupine, ili jednim OC1-2alkilom;
RB5 je vodik, C1-4alkil, C(O)C1-4alkil, C(O)OC1-4alkil, C(O)NH2, C(O)NHC1-4alkil ili C(O)N(C1-4alkil) 2, pri čemu je spomenuti RB5 alkil po želji supstituiran s do 3 F atoma, dvije ne-geminalne OH skupine ili jednom OC1-2alkil i RB6 je F ili C1-2alkil, ili dva RB6 i intervenirajući atom ugljika čine spirociklopropilni ili spirociklobutilni prsten ;
nadalje pri čemu:
"alkil" ili "alkilna skupina" znači ravnolančani ili razgranati, supstituirani ili nesupstituirani ugljikovodični lanac koji je potpuno zasićen; a "alkoksi" ili "tioalkil" odnosi se na alkilnu skupinu, vezanu na glavni ugljikov lanac preko atoma kisika ("alkoksi") ili sumpora ("tioalkil").
7. Spoj za uporabu u skladu s patentnim zahtjevom 6, naznačen time, da je spoj predstavljen strukturnom formulom (II), ili njegova farmaceutski prihvatljiva sol:
[image]
pri čemu:
X je N ili CRA5;
RA1 je F, C1-4alkil, C3-5cikloalkil, OC1-4alkil, OC1-4alkil-C3-5cikloalkil, NH2, NHC1-4alkil, NHC1-4alkil-C3-5cikloalkil ili C0-4alkil-heterociklil, pri čemu navedeni heterociklički prstenasti sustav je odabran između oksetanila, tetrahidrofuranila, tetrahidropiranila ili morfolinila, a svaki od spomenutih alkila, cikloalkila ili heterociklila je po želji supstituiran s do tri atoma F, do tri 2H atoma, do dvije ne- geminalne OH skupine ili do dva OC1-2alkila;
svaki RA4 je, neovisno, H ili 2H;
RA5 je vodik, F, C1-4alkil ili OC1-4alkil, pri čemu je svaki od navedenih alkila po izboru supstituiran s do tri F atoma ili do tri 2H atoma;
RB3 je C (0) NHCl-4 alkil, pri čemu je navedeni alkil po izboru supstituiran s do tri F atoma, do tri 2H atoma, do dvije ne-geminalne OH skupine ili do dvije OC1-2alkil; i
svaki RB4 je neovisno vodik, deuterij, F ili C1-4alkil.
8. Spoj za uporabu u skladu s patentnim zahtjevom 6 ili 7, naznačen time, da je spoj odabran između:
[image]
[image]
ili njegova farmaceutski prihvatljiva sol.
9. Spoj za uporabu u skladu s bilo kojim od patentnih zahtjeva 6 do 8, naznačen time, da je spoj
[image]
ili njegova farmaceutski prihvatljiva sol.
10. Spoj za uporabu u skladu s bilo kojim od patentnih zahtjeva 6 do 8, naznačen time, da je spoj
[image]
ili njegova farmaceutski prihvatljiva sol.
11. Spoj za uporabu u skladu s bilo kojim od patentnih zahtjeva 6 do 10, naznačen time, da je terapijski režim zračenje ili antikancerogeno kemoterapijsko sredstvo.
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