HRP20240861T1 - Derivati 6-(4-amino-3-metil-2-oksa-8-azaspiro[4.5]dekan-8-il)-3-(2,3-dihlorofenil)-2-metilpirimidin-4(3h)-ona i srodni spojevi kao inhibitori ptpn11 (shp2) za liječenje raka - Google Patents
Derivati 6-(4-amino-3-metil-2-oksa-8-azaspiro[4.5]dekan-8-il)-3-(2,3-dihlorofenil)-2-metilpirimidin-4(3h)-ona i srodni spojevi kao inhibitori ptpn11 (shp2) za liječenje raka Download PDFInfo
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- HRP20240861T1 HRP20240861T1 HRP20240861TT HRP20240861T HRP20240861T1 HR P20240861 T1 HRP20240861 T1 HR P20240861T1 HR P20240861T T HRP20240861T T HR P20240861TT HR P20240861 T HRP20240861 T HR P20240861T HR P20240861 T1 HRP20240861 T1 HR P20240861T1
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- 150000001875 compounds Chemical class 0.000 title claims 27
- 206010028980 Neoplasm Diseases 0.000 title claims 5
- 201000011510 cancer Diseases 0.000 title claims 5
- WYUIJDCKOPRFJO-UHFFFAOYSA-N 6-(4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidin-4-one Chemical class NC1C(OCC11CCN(CC1)C1=CC(N(C(=N1)C)C1=C(C(=CC=C1)Cl)Cl)=O)C WYUIJDCKOPRFJO-UHFFFAOYSA-N 0.000 title 1
- 239000003112 inhibitor Substances 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims 32
- 125000005843 halogen group Chemical group 0.000 claims 32
- 125000004093 cyano group Chemical group *C#N 0.000 claims 22
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 22
- 229910052739 hydrogen Inorganic materials 0.000 claims 21
- 239000001257 hydrogen Substances 0.000 claims 21
- 150000002431 hydrogen Chemical class 0.000 claims 18
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 17
- 125000005842 heteroatom Chemical group 0.000 claims 17
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 17
- 229910052799 carbon Inorganic materials 0.000 claims 16
- 229910052760 oxygen Inorganic materials 0.000 claims 16
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 15
- 229910052717 sulfur Inorganic materials 0.000 claims 15
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 14
- -1 hydroxy, amino Chemical group 0.000 claims 13
- 125000003118 aryl group Chemical group 0.000 claims 12
- 125000003545 alkoxy group Chemical group 0.000 claims 11
- 150000003839 salts Chemical class 0.000 claims 10
- 125000003282 alkyl amino group Chemical group 0.000 claims 9
- 125000000171 (C1-C6) haloalkyl 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
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 7
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims 7
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 7
- 125000004432 carbon atom Chemical group C* 0.000 claims 7
- 125000001072 heteroaryl group Chemical group 0.000 claims 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 6
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 6
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims 6
- 125000000623 heterocyclic group Chemical group 0.000 claims 6
- 229910052757 nitrogen Inorganic materials 0.000 claims 6
- 229920006395 saturated elastomer Polymers 0.000 claims 6
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 4
- 125000003368 amide group Chemical group 0.000 claims 4
- 125000004103 aminoalkyl group Chemical group 0.000 claims 4
- 229910052698 phosphorus Inorganic materials 0.000 claims 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims 3
- 201000010099 disease Diseases 0.000 claims 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 3
- 125000004043 oxo group Chemical group O=* 0.000 claims 3
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
- 206010006187 Breast cancer Diseases 0.000 claims 2
- 208000026310 Breast neoplasm Diseases 0.000 claims 2
- 101100240523 Caenorhabditis elegans nhr-19 gene Proteins 0.000 claims 2
- 206010009944 Colon cancer Diseases 0.000 claims 2
- 101001087416 Homo sapiens Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 claims 2
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 claims 2
- 208000029742 colonic neoplasm Diseases 0.000 claims 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 2
- 239000003814 drug Substances 0.000 claims 2
- 208000032839 leukemia Diseases 0.000 claims 2
- 201000001441 melanoma Diseases 0.000 claims 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 1
- 125000004530 1,2,4-triazinyl group Chemical group N1=NC(=NC=C1)* 0.000 claims 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 1
- 125000004990 dihydroxyalkyl group Chemical group 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 230000001404 mediated effect Effects 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 230000035772 mutation Effects 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 125000003373 pyrazinyl group Chemical group 0.000 claims 1
- 125000002098 pyridazinyl group Chemical group 0.000 claims 1
- 125000000714 pyrimidinyl group Chemical group 0.000 claims 1
- 229940124597 therapeutic agent Drugs 0.000 claims 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- 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
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- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—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
- 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
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
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- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Claims (26)
1. Spoj koji je predstavljen formulom I
[image]
ili koji je njegova sol, poželjno gdje je spomenuta sol terapeutski prihvatljiva sol, gdje:
donji indeks a je 0 ili 1;
donji indeks b je 0 ili 1;
Y1 je direktna veza ili CR17R18;
Y2je izabran iz grupe koja se sastoji od C1-4alkil, amino, C1-4alkilC(O)O-, C1-4alkilamino i C1-4aminoalkil;
R1 je izabran iz grupe koja se sastoji od C6-10aril, C3-8cikloalkil, C3-8cikloalkenil, i 5-10-očlane heteroaril grupe koja ima 1 do 4 heteroatoma ili grupa kao vrhove prstena neovisno izabrane od N, C(O), O, i S; spomenuti aril ili heteroaril od R1 je opcionalno supstituiran s 1 do 5 R12 grupa neovisno izabranih iz grupe koja se sastoji od halo, hidroksi, amino, C1-4alkilamino, di(C1-4alkil)amino, cijano, C1-4alkil, C1-4alkoksi, C1-4hidroksialkil, C1-4haloalkil, C1-4aminoalkil, C3-8cikloalkil, C3-8cikloalkenil, NR15C(O)R14, NR15C(O)OR14, NR14C(O)NR1sR16, NR15S(O)R14, NR15S(O)2R14, C(O)NR15R16, S(O)NR15R16, S(O)2NR15R16, C(O)R14, C(O)OR14, OR14, SR14, S(O)R14, i S(O)2R14;
R2, R3, R10, i R11 su svaki neovisno izabrani iz grupe koja se sastoji od vodika, C1-4alkil, i C3-8cikloalkil;
R4, R5, R8, i R9 su svaki neovisno izabrani iz grupe koja se sastoji od vodika, cijano, C1-4alkil, C1-4alkoksi, amino, hidroksi, C3-8cikloalkil, halo, i C1-4alkilamino;
R6 je izabran iz grupe koja se sastoji od amino, C1-4aminoalkil, i C1-4alkilamino;
R7 je izabran iz grupe koja se sastoji od vodika, amido, cijano, halo, i hidroksi, ili je izabran iz grupe koja se sastoji od C1-4alkil, C1-4hidroksialkil, C3-6cikloalkil, fenil, i 5- ili 6-očlanog heteroarila, od kojih bilo koji je opcionalno supstituiran s jednom do pet grupa neovisno izabranih iz grupe koja se sastoji od amino, halo, hidroksi, cijano, C1-4alkil, C1-4alkoksi, C1-4haloalkil, C1-4haloalkoksi, C1-4alkilamino, i C1-4aminoalkil;
ili R6 i R7 zajedno s atomom ugljika za koji su oba vezana formiraju 3- do 7-člani zasićeni ili nezasićeni prsten, koji ima 0 do 3 heteroatoma ili grupa kao vrhove prstena neovisno izabrane od N, C(O), O, i S(O)m;
donji indeks m je 0, 1, ili 2;
spomenuti zasićeni ili nezasićeni prsten nastao od R6 i R7 je nesupstituiran ili supstituiran s 1 do 3 grupe neovisno izabranih iz grupe koja se sastoji od amino, halo, hidroksi, cijano, C1-4alkil, C1-4alkoksi, C1-4haloalkil, C1-4haloalkoksi, C1-4alkilamino i C1-4aminoalkil;
bilo koje dvije grupe od R2, R3, R4, R5, R7, R8, R9, R10 i R11 mogu formirati 5 do 6-očlani prsten, koji ima 0 do 2 heteroatoma kao vrhove prstena izabrane između N, O i S;
bilo koje dvije grupe od R2, R4, R6, R8 i R10 mogu formirati direktnu vezu, ili most od 1 do 2 atoma ugljika; R13 je izabran iz grupe koja se sastoji od vodika, halo, cijano, C1-6alkil, C1-6haloalkil, C1-6hidroksialkil, C1-6 dihidroksialkil, -NH-NHR19, -NHR19, -OR19, -NHC(O)R19, -NHC(O)NHR19, -NHS(O)2NHR19, -NHS(O)2R19, -C(O)OR19, -C(O)NR19R20, -C(O)NH(CH2)qOH, -C(O)NH(CH2)qR21, -C(O)R21, -NH2, -OH, -S(O)2NR19R20, C3-8cikloalkil, aril, heterociklil koji ima 1-5 heteroatoma kao vrhove prstena izabrane od N, O, S i P, heteroaril koji ima 1-5 heteroatoma kao vrhove prstena izabrane od N, O, S i P; gdje donji indeks q je cijeli broj od 0 do 6; i gdje aril, heteroaril, heterociklil i cikloalkil su supstituirani s 0 do 3 grupe neovisno izabranih iz grupe koja se sastoji od C1-4alkil, -OH, -NH2, -OR21, halo, cijano, i okso;
R14, R15 i R16 su svaki neovisno izabran iz grupe koja se sastoji od vodika, C1-4alkil, C3-8cikloalkil, C6-10aril i 5-10-očlanog heteroaril, od kojih je svaki opcionalno supstituiran s jednom ili više grupa nezavisno izabranih iz grupe koja se sastoji od amido, amino, halo, hidroksi, cijano, C1-4alkil, C1-4alkoksi, C1-4haloalkil, C1-4haloalkoksi, C1-4alkilamino i C1-4aminoalkil;
R17 i R18 su svaki neovisno izabrani iz grupe koja se sastoji od vodika, C1-4alkil, i CF3;
R19 i R20 su svaki neovisno izabrani iz grupe koja se sastoji od vodika, C1-6alkil, C1-6haloalkil, C1-6hidroksialkil, C2-6alkenil, C2-6alkinil i C3-6cikloalkil; i
svaki R21 je neovisno izabran iz grupe koja se sastoji od vodika, -OH, C1-6 alkil, C1-6haloalkil, C1-6hidroksialkil, C2-6alkenil, C2-6alkinil i C3-6cikloalkil.
2. Spoj prema zahtjevu 1, gdje:
donji indeks a je 0 ili 1;
donji indeks b je 0 ili 1;
Y1 je direktna veza ili CR17R18;
Y2je izabran iz grupe koja se sastoji od C1-4alkil, amino, C1-4alkilC(O)O-, C1-4alkilamino i C1-4aminoalkil;
R1 je izabran iz grupe koja se sastoji od C6-10aril, C3-8cikloalkil, C3-8cikloalkenil, i 5-10-očlane heteroaril grupe koja ima 1 do 4 heteroatoma ili grupa kao vrhove prstena neovisno izabrane od N, C(O), O, i S; spomenuti aril ili heteroaril od R1 je opcionalno supstituiran sa 1 do 5 R12 grupa neovisno izabranih iz grupe koja se sastoji od halo, hidroksi, amino, C1-4alkilamino, di(C1-4alkil)amino, cijano, C1-4alkil, C1-4alkoksi, C1-4hidroksialkil, C1-4haloalkil, C1-4aminoalkil, C3-8cikloalkil, C3-8cikloalkenil, NR15C(O)R14, NR15C(O)OR14, NR14C(O)NR1sR16, NR15S(O)R14, NR15S(O)2R14, C(O)NR15R16, S(O)NR15R16, S(O)2NR15R16, C(O)R14, C(O)OR14, OR14, SR14, S(O)R14, i S(O)2R14;
R2, R3, R10, i R11 su svaki neovisno izabrani iz grupe koja se sastoji od vodika, C1-4alkil, i C3-8cikloalkil;
R4, R5, R8, i R9 su svaki neovisno izabrani iz grupe koja se sastoji od vodika, cijano, C1-4alkil, C1-4alkoksi, amino, hidroksi, C3-8cikloalkil, halo, i C1-4alkilamino;
R6 je izabran iz grupe koja se sastoji od amino, C1-4aminoalkil, i C1-4alkilamino;
R7 je izabran iz grupe koja se sastoji od vodika, halo, i hidroksi, ili je izabran iz grupe koja se sastoji od amido, C1-4alkil, C1-4hidroksialkil, C3-6cikloalkil, fenil, i 5- ili 6-očlanog heteroaril, od kojih bilo koji je opcionalno supstituiran s jednom do pet grupa neovisno izabranih iz grupe koja se sastoji od amino, halo, hidroksi, cijano, C1-4alkil, C1-4alkoksi, C1-4haloalkil, C1-4haloalkoksi, C1-4alkilamino, i C1-4aminoalkil;
ili R6 i R7 zajedno s atomom ugljika za koji su oba vezana formiraju 3- do 7-očlani zasićeni ili nezasićeni prsten, koji ima 0 do 3 heteroatoma ili grupa kao vrhove prstena neovisno izabrane od N, C(O), O, i S(O)m;
donji indeks m je 0, 1, ili 2;
spomenuti zasićen prsten nastao od R6 i R7 je nesupstituiran ili supstituiran sa 1 do 3 grupe nezavisno izabranih iz grupe koja se sastoji od amino, halo, hidroksi, cijano, C1-4alkil, C1-4alkoksi, C1-4haloalkil, C1-4haloalkoksi, C1-4alkilamino i C1-4aminoalkil;
bilo koje dvije grupe od R2, R3, R4, R5, R7, R8, R9, R10 i R11 mogu formirati 5 do 6-očlani prsten, koji ima 0 do 2 heteroatoma kao vrhove prstena izabrane od N, O i S;
bilo koje dvije grupe od R2, R4, R6, R8 i R10 mogu formirati direktnu vezu, ili most od 1 do 2 atoma ugljika; R13 je izabran iz grupe koja se sastoji od vodika, halo, cijano, C1-6 alkil, C1-6haloalkil, C1-6hidroksialkil, C1-6dihidroksialkil, -NH-NHR19, -NHR19, -OR19, -NHC(O)R19, -NHC(O)NHR19, -NHS(O)2NHR19, -NHS(O)2R19, -C(O)OR19, -C(O)NR19R20, -C(O)NH(CH2)qOH, -C(O)NH(CH2)qR21, -C(O)R21, -NH2, -OH, -S(O)2NR19R20, C3-8cikloalkil, aril, heterociklil koji ima 1-5 heteroatoma kao vrhove prstena izabrane od N, O, S i P, heteroaril koji ima 1-5 heteroatoma kao vrhove prstena izabrane od N, O, S i P; gdje donji indeks q je cijeli broj od 0 do 6; i gdje aril, heteroaril, heterociklil i cikloalkil su supstituirani s 0 do 3 grupe neovisno izabranih iz grupe koja se sastoji od C1-4alkil, -OH, -NH2, -OR21, halo, cijano, i okso;
R14, R15 i R16 su svaki neovisno izabrani iz grupe koja se sastoji od vodika, C1-4alkil, C3-8cikloalkil, C6-10aril i 5-10-očlanog heteroaril, od kojih je svaki opcionalno supstituiran s jednom ili više grupa neovisno izabranih iz grupe koja se sastoji od halo, hidroksi, cijano, i C1-4alkil;
R17 i R18 su svaki neovisno izabrani iz grupe koja se sastoji od vodika, C1-4alkil, i CF3;
R19 i R20 su svaki neovisno izabrani iz grupe koja se sastoji od vodika, C1-6alkil, C1-6haloalkil, C1-6hidroksialkil, C2-6alkenil, C2-6alkinil i C3-6cikloalkil; i
svaki R21 je neovisno izabran iz grupe koja se sastoji od vodika, -OH, C1-6 alkil, C1-6haloalkil, C1-6hidroksialkil, C2-6alkenil, C2-6alkinil i C3-6cikloalkil.
3. Spoj prema zahtjevu 1 ili 2, gdje su donji indeksi a i b svaki 1.
4. Spoj prema bilo kojem od zahtjeva 1 do 3, gdje je Y1direktna veza.
5. Spoj prema bilo kojem od zahtjeva 1 do 4, gdje je Y2 C1-4alkil, opcionalno gdje je Y2 je metil.
6. Spoj prema bilo kom od zahtjeva 1 do 5, gdje
R13 je izabran iz grupe koja se sastoji od vodika, halo, C1-6alkil, C1-6haloalkil, C1-6hidroksialkil, C1-6dihidroksialkil, C3-8cikloalkil, 3-ili 6-očlanog heterociklila koji ima 1-3 heteroatoma kao vrhove prstena izabrane od N, O i S; gdje heterociklil i cikloalkil su supstituirani s 0 do 3 grupe neovisno izabranih iz grupe koja se sastoji od C1-4alkil, -OH, -NH2, -OR21, halo, cijano i okso; opcionalno
gdje R13 je izabran iz grupe koja se sastoji od vodika, halo, C1-6alkil, i C1-6haloalkil; opcionalno gdje R13 je vodik, Cl, Br, metil, ili CF3.
7. Spoj prema bilo kojem od zahtjeva 1 do 6, gdje
R1 je izabran iz grupe koja se sastoji od C6-10aril i 5-do 9-očlane heteroaril grupe koja ima 1 do 4 heteroatomske grupe kao vrhove prstena neovisno izabrane od N, C(O), O, i S; i opcionalno je supstituiran s 1 do 5 R12 grupa neovisno izabranih iz grupe koja se sastoji od halo, hidroksi, amino, C1-4alkilamino, di(C1-4alkil)amino, cijano, C1-4alkil, C1-4alkoksi, C1-4hidroksialkil, C1-4haloalkil, C1-4aminoalkil, C3-8cikloalkil, C3-8cikloalkenil, NR15C(O)R14, NR15C(O)OR14, NR14C(O)NR1sR16, NR15S(O)R14, NR15S(O)2R14, C(O)NR15R16, S(O)NR15R16, S(O)2NR15R16, C(O)R14, C(O)OR14, OR14, SR14, S(O)R14, i S(O)2R14; opcionalno
gdje R1 je fenil ili 5-do 6-očlana heteroaril grupa koja ima 1 do 4 heteroatoma kao vrhove prstena neovisno izabrane od N, O, i S; i opcionalno je supstituiran sa 1, 2 ili 3 R12 grupe neovisno izabranih iz grupe koja se sastoji od halo, hidroksi, amino, C1-4alkilamino, di(C1-4alkil)amino, C1-4alkil, C1-4alkoksi, C1-4haloalkil, C1-4aminoalkil, i OR14.
8. Spoj prema bilo kojem od zahtjeva 1 do 7, gdje su R2, R3, R4, R5, R8, R9, R10 i R11 vodik.
9. Spoj prema bilo kom od zahtjeva 1 do 8, gdje:
(a) R6 je izabran iz grupe koja se sastoji od amino, C1-4aminoalkil, i C1-4alkilamino; i
R7 je izabran iz grupe koja se sastoji od vodika, amido, cijano, halo, i hidroksi, ili je izabran iz grupe koja se sastoji od C1-4alkil, C1-4hidroksialkil, C3-6cikloalkil, fenil, i 5- ili 6-očlanog heteroarila, od kojih je bilo koji opcionalno supstituiran s jednom ili dvije grupe odabrane iz grupe koja se sastoji od amino, halo, hidroksi, cijano, trifluorometil, trifluorometoksi, C1-4alkil, i C1-4alkoksi, opcionalno gdje R6 je amino ili aminometil; i
R7 je izabran iz grupe koja se sastoji od hidroksi, C1-4alkil, i C1-4hidroksialkil; ili
(b) R6 i R7 zajedno s atomom ugljika za koji su oba vezana formiraju 3- do 7-očlani zasićeni ili nezasićeni prsten koji ima 1 do 3 heteroatoma ili grupe kao vrhove prstena neovisno izabrane od N, C(O), O, i S(O)m, i on je opcionalno supstituiran s jednom ili dvije grupe neovisno izabranih iz grupe koja se sastoji od amino, halo, hidroksi, C1-4alkil, C1-4alkoksi, C1-4alkilamino i C1-4aminoalkil; opcionalno gdje R6 i R7 zajedno sa atomom ugljika za koji su oba vezana formiraju 4-do 6-očlani zasićeni prsten koji ima 1 do 3 heteroatoma kao vrhove prstena neovisno izabrane od N i O, i on je opcionalno supstituiran s jednom ili dvije grupe neovisno izabranih iz grupe koja se sastoji od amino, halo, hidroksi, C1-4alkil, C1-4alkoksi, C1-4alkilamino i C1-4aminoalkil; ili
(c) R6 i R7 zajedno s atomom ugljika za koji su oba vezana formiraju 3- do 7-očlani cikloalkil prsten koji je opcionalno supstituiran s jednom ili dvije grupe neovisno izabranih iz grupe koja se sastoji od amino, halo, hidroksi, C1-4alkil, C1-4alkoksi, C1-4alkilamino i C1-4aminoalkil.
10. Spoj prema bilo kojem od zahtjeva 1 do 9, gdje
(a) R1 je izabran iz grupe koja se sastoji od fenil, piridil, pirimidinil, pirazinil, piridazinil, i 1,2,4triazinil; i opcionalno je supstituiran sa 1, 2, ili 3 R12 neovisno izabranih iz grupe koja se sastoji od halo, hidroksi, amino, C1-4alkilamino, di(C1-4alkil)amino, C1-4alkil, C1-4alkoksi, C1-4haloalkil, C1-4aminoalkil, i OR14; opcionalno
gdje R1 je fenil ili piridil, od kojih je svaki supstituiran s jednim do tri R12; ili
(b) gdje R1 je izabran iz grupe koja se sastoji od:
[image]
[image]
svaki R12 je neovisno izabran iz grupe koja se sastoji od halo, hidroksi, amino, C1-4alkilamino, di(C1-4alkil)amino, C1-4alkil, C1-4alkoksi, C1-4haloalkil, C1-4aminoalkil, i OR14; opcionalno gdje R1 je izabran iz grupe koja se sastoji od:
[image]
11. Spoj prema bilo kojem od zahtjeva 1 do 10,
(a) gdje R14 je izabran iz grupe koja se sastoji od C6-10aril i 5-10-očlanog heteroaril, od kojih je svaki opcionalno supstituiran s jednom ili više grupa neovisno izabranih iz grupe koja se sastoji od halo, hidroksi, cijano, i C1-4alkil; opcionalno
gdje R14 je fenil ili 5-6-očlani heteroaril koji ima 1 do 4 heteroatoma kao vrhove prstena neovisno izabrane od N, O, i S, od kojih je svaki opcionalno supstituiran s jednom ili dvije grupe neovisno izabranih iz grupe koja se sastoji od halo, hidroksi, cijano, i C1-4alkil.
12. Spoj prema zahtjevu 1, gdje R14 je izabran iz grupe koja se sastoji od C6-10aril i 5-10-očlanog heteroaril, od kojih je svaki opcionalno supstituiran s jednom ili više grupa neovisno izabranih iz grupe koja se sastoji od C1-4alkilamido, amino, halo, hidroksi, cijano, C1-4alkil, C1-4alkoksi, C1-4haloalkil, C1-4haloalkoksi, C1-4alkilamino i C1-4aminoalkil.
13. Spoj prema zahtjevu 1, gdje R1 je
[image]
svaki R12 je neovisno izabran iz grupe koja se sastoji od halo, hidroksi, amino, C1-4alkilamino, di(C1-4alkil)amino, C1-4alkil, C1-4alkoksi, C1-4haloalkil, i C1-4aminoalkil; i
R14 je fenil ili 5-6-očlani heteroaril koji ima 1 do 4 heteroatoma kao vrhove prstena neovisno izabrane od N, O, i S, od kojih je svaki opcionalno supstiuiran s jednom ili dvije grupe neovisno izabranih iz grupe koja se sastoji od C1-4alkilamido, halo, hidroksi, cijano, i C1-4alkil.
14. Spoj prema zahtjevu 1, pri čemu svaki R12 je neovisno izabran iz grupe koja se sastoji od F, Cl, Br, CH3, OCH3, CF3,
[image]
15. Spoj prema zahtjevu 1, koje ima strukturu odabranu iz grupe koja se sastoji od:
[image]
[image]
[image]
[image]
i
[image]
Ili njegova sol, poželjno gdje je spomenuta sol terapeutski prihvatljiva sol.
16. Spoj prema zahtjevu 1, predstavljen formulom:
[image]
ili njegova terapeutski prihvatljiva sol.
17. Spoj prema zahtjevu 1, predstavljen formulom:
[image]
ili njegova terapeutski prihvatljiva sol.
18. Spoj prema zahtjevu 1, predstavljen formulom:
[image]
ili njegova terapeutski prihvatljiva sol.
19. Spoj prema zahtjevu 1, predstavljen formulom:
[image]
20. Spoj prema zahtjevu 1, predstavljen formulom:
[image]
21. Spoj prema zahtjevu 1, predstavljen formulom:
[image]
ili njegova terapeutski prihvatljiva sol.
22. Farmaceutski sastav koji sadrži spoj prema bilo kojem od zahtjeva 1 do 21, zajedno s farmaceutski prihvatljivim nosačem.
23. Spoj prema bilo kom od zahtjeva 1 do 21, za upotrebu kao lijek.
24. Spoj prema bilo kojem od zahtjeva 1 do 21, za upotrebu u liječenju bolesti izazvane jednom ili više PTPN11 mutacija.
25. Spoj prema bilo kojem od zahtjeva 1 do 21, za upotrebu u liječenju raka, opcionalno gdje je rak izabran iz grupe koja se sastoji od leukemije, melanoma, raka dojke, i raka debelog crijeva.
26. Spoj prema bilo kojem od zahtjeva 1 do 21 za upotrebu u postupku liječenja bolesti posredovane PTPN11 koja obuhvaća davanje:
c. terapeutski efikasne količine spomenutih spojeva; i
d. drugog terapeutskog sredstva,
opcionalno
gdje je bolest rak, opcionalno
gdje je rak izabran iz grupe koju čine rak dojke, rak debelog crijeva, leukemija, i melanom.
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| PCT/US2019/045903 WO2020033828A1 (en) | 2018-08-10 | 2019-08-09 | 6-(4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidin-4(3h)-one derivatives and related compounds as ptpn11 (shp2) inhibitors for treating cancer |
| EP19759185.2A EP3833670B1 (en) | 2018-08-10 | 2019-08-09 | 6-(4-amino-3-methyl-2-oxa-8-azaspiro[4.5]decan-8-yl)-3-(2,3-dichlorophenyl)-2-methylpyrimidin-4(3h)-one derivatives and related compounds as ptpn11 (shp2) inhibitors for treating cancer |
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