HRP20220251T1 - Novi heterociklički derivati korisni kao shp2 inhibitori - Google Patents
Novi heterociklički derivati korisni kao shp2 inhibitori Download PDFInfo
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- HRP20220251T1 HRP20220251T1 HRP20220251TT HRP20220251T HRP20220251T1 HR P20220251 T1 HRP20220251 T1 HR P20220251T1 HR P20220251T T HRP20220251T T HR P20220251TT HR P20220251 T HRP20220251 T HR P20220251T HR P20220251 T1 HRP20220251 T1 HR P20220251T1
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- Prior art keywords
- alkyl
- membered
- heterocyclic ring
- ring
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- 125000000623 heterocyclic group Chemical group 0.000 title claims 45
- 239000003112 inhibitor Substances 0.000 title 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 44
- 229910052736 halogen Inorganic materials 0.000 claims 33
- 150000002367 halogens Chemical group 0.000 claims 33
- 125000001072 heteroaryl group Chemical group 0.000 claims 32
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 29
- 125000005842 heteroatom Chemical group 0.000 claims 29
- 150000001875 compounds Chemical class 0.000 claims 28
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 24
- 125000004043 oxo group Chemical group O=* 0.000 claims 24
- 125000002837 carbocyclic group Chemical group 0.000 claims 23
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 23
- 229910052760 oxygen Inorganic materials 0.000 claims 22
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims 20
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 19
- -1 -OH Chemical group 0.000 claims 19
- 125000004122 cyclic group Chemical group 0.000 claims 19
- 229910052717 sulfur Inorganic materials 0.000 claims 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 17
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 15
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 14
- 125000000217 alkyl group Chemical group 0.000 claims 13
- 125000003341 7 membered heterocyclic group Chemical group 0.000 claims 10
- 125000003545 alkoxy group Chemical group 0.000 claims 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 10
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims 8
- 229910052799 carbon Inorganic materials 0.000 claims 8
- 125000004432 carbon atom Chemical group C* 0.000 claims 8
- 125000006163 5-membered heteroaryl group Chemical group 0.000 claims 6
- 125000005330 8 membered heterocyclic group Chemical group 0.000 claims 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims 6
- 125000003118 aryl group Chemical group 0.000 claims 5
- 229910052757 nitrogen Inorganic materials 0.000 claims 5
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims 4
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims 4
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 4
- 125000001960 7 membered carbocyclic group Chemical group 0.000 claims 3
- 125000003627 8 membered carbocyclic group Chemical group 0.000 claims 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 3
- 125000000131 cyclopropyloxy group Chemical group C1(CC1)O* 0.000 claims 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 3
- 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims 2
- 125000003466 9 membered carbocyclic group Chemical group 0.000 claims 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims 2
- 108010081348 HRT1 protein Hairy Proteins 0.000 claims 2
- 102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims 2
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims 2
- 125000003386 piperidinyl group Chemical group 0.000 claims 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims 2
- 125000006593 (C2-C3) alkynyl group Chemical group 0.000 claims 1
- 125000001831 (C6-C10) heteroaryl group Chemical group 0.000 claims 1
- HGYTYZKWKUXRKA-MRXNPFEDSA-N 1-[4-[3-amino-5-[(4S)-4-amino-2-oxa-8-azaspiro[4.5]decan-8-yl]pyrazin-2-yl]sulfanyl-3,3-difluoro-2H-indol-1-yl]ethanone Chemical compound NC=1C(=NC=C(N=1)N1CCC2([C@@H](COC2)N)CC1)SC1=C2C(CN(C2=CC=C1)C(C)=O)(F)F HGYTYZKWKUXRKA-MRXNPFEDSA-N 0.000 claims 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 1
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 1
- 125000006519 CCH3 Chemical group 0.000 claims 1
- 239000004215 Carbon black (E152) Substances 0.000 claims 1
- 125000002947 alkylene group Chemical group 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 125000006165 cyclic alkyl group Chemical group 0.000 claims 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 229930195733 hydrocarbon Natural products 0.000 claims 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000002950 monocyclic group Chemical group 0.000 claims 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000006574 non-aromatic ring group Chemical group 0.000 claims 1
- 125000003367 polycyclic group Chemical group 0.000 claims 1
- 125000006238 prop-1-en-1-yl group Chemical group [H]\C(*)=C(/[H])C([H])([H])[H] 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 229920006395 saturated elastomer Polymers 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
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
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- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
-
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- 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
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- 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
- A61K31/537—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 spiro-condensed or forming part of bridged ring systems
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- 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
- A61K31/538—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with carbocyclic ring systems
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- 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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- 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
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- C—CHEMISTRY; METALLURGY
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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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
- C07D471/04—Ortho-condensed systems
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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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- C07D471/12—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 three hetero rings
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Claims (25)
1. Spoj, naznačen time, da je predstavljen Formulom I, ili njegova farmaceutski prihvatljiva sol:
[image]
X je S;
Y1 je N ili CR1;
Y2 je N ili CR2;
R1 se ujedinjuje s R3, ili se R2 ujedinjuje s R3, u svrhu tvorbe 5-10-članog heteroarila, 5-10-članog karbocikličkog prstena ili 5-10-članog heterocikličkog prstena, pri čemu je svaki od prstenskih sustava neovisno opcionalno supstituiran s halogenom, -CN, -OH, -NR8R9, -N3, -NO2, karbonilom, =O, okso, supstituiranim ili nesupstituiranim C1-6 alkilom, supstituiranim ili nesupstituiranim C1-6 alkoksi ili C(O)R8;
kada se R1 ujedinjuje s R3 u svrhu tvorbe 5-10-članog heteroarila, 5-10-članog karbocikličkog prstena ili 5-10-članog heterocikličkog prstena, R2 je -H, halogen, -CN, -OH, -NH2, -N3, -NO2, supstituirani ili nesupstituirani C1-6 alkoksi, ili supstituirani ili nesupstituirani C1-6 alkil;
kada se R2 ujedinjuje s R3 u svrhu tvorbe 5-10-članog heteroarila, 5-10-članog karbocikličkog prstena ili 5-10-članog heterocikličkog prstena, R1 je -H, halogen, -CN, -OH, -NH2, -N3, -NO2, supstituirani ili nesupstituirani
C1-6 alkoksi, ili supstituirani ili nesupstituirani C1-6 alkil;
R4 je halogen, -CN, -OH, -NR8R9, -N3, -NO2, supstituirani ili nesupstituirani C1-6 alkoksi, supstituirani ili nesupstituirani C1-6 alkil, C5-18 heterociklički prsten ili C5-18 karbociklički prsten; pri čemu je svaki od prstenskih sustava neovisno opcionalno supstituiran s s halogenom, -CN, -OH, karbonilom, =O, okso, supstituiranim ili nesupstituiranim C1-6 alkilom, supstituiranim ili nesupstituiranim C1-6 alkoksi, -NR8R9 ili -CH2NR8R9;
R5 je -H, halogen, -CN, -OH, -NR8R9, -N3, -NO2, C1-6 alkil, C1-6 alkoksi, C6-10 aril, C6-10 arilalkil, C6-10 heteroaril, C5-18 heterociklički prsten ili C5-18 karbociklički prsten; i od kojih je svaki neovisno opcionalno supstituiran s halogenom, -CN, -OH, -N3, -NO2, -NH2, karbonilom, =O, okso, supstituiranim ili nesupstituiranim C1-6 alkilom, supstituiranim ili nesupstituiranim C1-6 alkoksi, (CH2)kNR8R9, (CH2)kNHC(O)OR6 ili C(O)R8; i k je 0, 1 ili 2;
svaki od R8 i R9 je neovisno -H, halogen, -CN, -OH, -N3, -NO2, C1-6 alkil, C1-6 alkoksi, C2-6 alkenil, NH(C1-6 alkil), N(C1-6 alkil)2, C5-10 heterociklički prsten ili C5-10 karbociklički prsten; i od kojih svaki može biti neovisno opcionalno supstituiran s halogenom, -CN, -OH, -NH2, -N3, -NO2, -C1-6 alkilen-NH2, -C1-6 alkilen-NH-C1-6 alkilom, -C1-6 alkilen-N(C1-6 alkilom)2, -NHBoc, CH2NHBoc, -NH-C1-6 alkilom, -N(C1-6 alkilom)2, -NH-C1-6 alkoksi, -N(C1-6 alkoksi)2, supstituiranim ili nesupstituiranim C1-6 alkilom, ili supstituiranim ili nesupstituiranim C1-6 alkoksi; i svaki heterociklički prsten sadrži 1, 2, 3 ili 4 heteroatoma odabrana od N, O ili S;
pri čemu je alkil zasićeni monovalentni ugljikovodični radikal koji ima ravne, razgranate ili cikličke ostatke, alkoksi je ravna, razgranata lančana ili ciklička alkilna skupina, i heterocikl je nesupstituirani ili supstituirani mono- ili policiklički nearomatski prstenski sustav koji sadrži jedan ili više heteroatoma.
2. Spoj prema patentnom zahtjevu 1, naznačen time, da
kada se R2 ujedinjuje s R3 u svrhu tvorbe 5-10-članog heteroarila, 5-10-članog karbocikličkog prstena ili 5-10-članog heterocikličkog prstena, R1 je -H, -F, -Cl, -Br, -I, -CN, -OH, -NH2, supstituirani ili nesupstituirani C1-3 alkoksi, ili supstituirani ili nesupstituirani C1-3 alkil;
kada se R1 ujedinjuje s R3 u svrhu tvorbe 5-10-članog heteroarila, 5-10-članog karbocikličkog prstena ili 5-10-članog heterocikličkog prstena, R2 je -H, -F, -Cl, -Br, -I, -CN, -OH, -NH2, supstituirani ili nesupstituirani C1-3 alkoksi, ili supstituirani ili nesupstituirani C1-3 alkil;
R4 je -F, -Cl, -Br, -CN, -OH, -NR8R9, supstituirani ili nesupstituirani C1-6 alkil, supstituirani ili nesupstituirani C1-6 alkoksi, C5-18 heterociklički prsten ili C5-10 karbociklički prsten, pri čemu je svaki od prstenskih sustava opcionalno supstituiran s -F, -Cl, -Br, -CN, -OH, -NO2, karbonilom, =O, okso, supstituiranim ili nesupstituiranim C1-6 alkilom, supstituiranim ili nesupstituiranim C1-6 alkoksi, -NH2, -NH-C1-6 alkilom, -NH-C1-6 alkoksi, -C1-6 alkilen-NH2 ili -C1-6 alkilen-NH-C1-6 alkilom-;
R5 je -H, -F, -Cl, -Br, -I, -NR8R9, C1-3 alkil, C1-3 alkoksi, C6-9 aril, C6-9 arilalkil, C6-9 heteroaril, C6-17 heterociklički prsten ili C6-17 karbociklički prsten, pri čemu je svaki od njih neovisno opcionalno supstituiran s halogenom, -CN, -OH, -N3, -NO2, -NH2, karbonilom, =O, okso, supstituiranim ili nesupstituiranim C1-6 alkilom, supstituiranim ili nesupstituiranim C1-6 alkoksi, (CH2)kNR8R9, (CH2)kNHC(O)OR6 ili C(O)R8; i k je 0, 1 ili 2; gdje svaki C6-9 heteroaril sadrži 1, 2, 3 ili 4 heteroatoma odabrana od N, O ili S, i C6-9 heteroaril je 6-člani heteroaril, 7-člani heteroaril, 8-člani heteroaril ili 9-člani heteroaril; C6-17 heterociklički prsten sadrži 1, 2, 3, 4, 5 ili 6 heteroatoma odabrana od N, O ili S, i C6-17 heterociklički prsten je 6-člani heterociklički prsten, 7-člani heterociklički prsten, 8-člani heterociklički prsten, 9-člani heterociklički prsten, 10-člani heterociklički prsten, 11-člani heterociklički prsten, 12-člani heterociklički prsten, 13-člani heterociklički prsten, 14-člani heterociklički prsten, 15-člani heterociklički prsten, 16-člani heterociklički prsten ili 17-člani heterociklički prsten;
svaki od R8 i R9 je neovisno -H, halogen, -CN, -OH, -NO2, -C1-6 alkilen-NH2, -C1-6 alkilen-NH-C1-6 alkil, -C1-6 alkilen-N(C1-6 alkil)2, -CH2NHBoc, -NH-C1-6 alkil, -N(C1-6 alkil)2, -NH-C1-6 alkoksi, -N(C1-6 alkoksi)2, C1-6 alkil, C1-6 alkoksi, C2-6 alkenil, C5-10 heterociklički prsten ili C5-10 karbociklički prsten; od kojih svaki može biti opcionalno supstituiran s halogenom, -CN, -OH, -NH2, -N3, -NO2, -C1-6 alkilen-NH2, -C1-6 alkilen-NH-C1-6 alkilom, -C1-6 alkilen-N(C1-6 alkilom)2, -NHBoc, -CH2NHBoc, -NH-C1-6 alkilom, -N(C1-6 alkilom)2, -NH-C1-6 alkoksi, -N(C1-6 alkoksi)2, supstituiranim ili nesupstituiranim C1-6 alkilom, ili supstituiranim ili nesupstituiranim C1-6 alkoksi; i svaki heterociklički prsten sadrži 1, 2, 3 ili 4 heteroatoma odabrana od N, O ili S.
3. Spoj prema patentnom zahtjevu 1 ili 2, naznačen time, da
kada se R2 ujedinjuje s R3 u svrhu tvorbe 5-10-članog heteroarila, 5-10-članog karbocikličkog prstena ili 5-10-članog heterocikličkog prstena, R1 je -H, -F, -Cl, -NH2, metil, etil, propil, izopropil, metoksi, etoksi, propoksi ili izopropoksi; i svaki je metil, etil, propil, izopropil, metoksi, etoksi, propoksi ili izopropoksi, neovisno opcionalno supstituiran s halogenom, OH ili NH2;
kada se R1 ujedinjuje s R3 u svrhu tvorbe 5-10-članog heteroarila, 5-10-članog karbocikličkog prstena ili 5-10-članog heterocikličkog prstena, R2 je -H, -F, -Cl, -NH2, metil, etil, propil, izopropil, metoksi, etoksi, propoksi ili izopropoksi; i svaki je metil, etil, propil, izopropil, metoksi, etoksi, propoksi ili izopropoksi, neovisno opcionalno supstituiran s halogenom, OH ili NH2;
R4 je -F, -Cl, -CN, -OH, -NH2, supstituirani ili nesupstituirani C1-3 alkil, supstituirani ili nesupstituirani C1-3 alkoksi, 5-člani heterociklički prsten koji sadrži 1, 2 ili 3 heteroatoma odabrana od N ili O, 6-člani heterociklički prsten koji sadrži 1, 2 ili 3 heteroatoma odabrana od N ili O, 5-člani karbociklički prsten ili 6-člani karbociklički prsten; pri čemu je svaki od prstenskih sustava opcionalno supstituiran s -F, -Cl, -Br, -CN, -OH, karbonilom, =O, okso, supstituiranim ili nesupstituiranim C1-3 alkilom, supstituiranim ili nesupstituiranim C1-3 alkoksi, -NH2, -NH-C1-3 alkilom, -NH-C1-3 alkoksi, -C1-3 alkilen-NH2 ili -C1-3 alkilen-NH-C1-3 alkilom;
R5 je -F, -Cl, -Br, -NR8R9, metil, etil, propil, izopropil, metoksi, etoksi, propoksi, izopropoksi, 6-člani aril, 7-člani aril, 8-člani aril, 9-člani aril, 6-člani arilalkil, 7-člani arilalkil, 8-člani arilalkil, 9-člani arilalkil, 6-člani heteroaril, 7-člani heteroaril, 8-člani heteroaril, 9-člani heteroaril, 6-člani heterociklički prsten, 7-člani heterociklički prsten, 8-člani heterociklički prsten, 9-člani heterociklički prsten, 10-člani heterociklički prsten, 11-člani heterociklički prsten, 12-člani heterociklički prsten, 13-člani heterociklički prsten, 14-člani heterociklički prsten, 15-člani heterociklički prsten, 16-člani heterociklički prsten, 6-člani karbociklički prsten, 7-člani karbociklički prsten, 8-člani karbociklički prsten, 9-člani karbociklički prsten, 10-člani karbociklički prsten, 11-člani karbociklički prsten, 12-člani karbociklički prsten, 13-člani karbociklički prsten, 14-člani karbociklički prsten, 15-člani karbociklički prsten ili 16-člani karbociklički prsten; i svaki heteroaril sadrži 1, 2 ili 3 heteroatoma odabrana od N, O ili S, i svaki heterociklički prsten sadrži 1, 2, 3 ili 4 heteroatoma odabrana od N, O ili S; pri čemu je svaki od njih neovisno opcionalno supstituiran s -F, -Cl, -Br, -I, -CN, -OH, -NO2, -NH2, karbonilom, =O, okso, supstituiranim ili nesupstituiranim C1-3 alkilom, supstituiranim ili nesupstituiranim C1-3 alkoksi, (CH2)kNR8R9, (CH2)kNHC(O)OR8 ili supstituiranim ili nesupstituiranim C(O)R8; i k je 0, 1 ili 2; i/ili
svaki od R8 i R9 je neovisno -H, -F, -Cl, -CN, -OH, -NO2, -C1-3 alkilen-NH2, -C1-3 alkilen-NH-C1-3 alkil, -C1-3 alkilen-N(C1-3 alkil)2, CH2NHBoc, -NH-C1-3 alkil, -N(C1-3 alkil)2, -NH-C1-3 alkoksi, -N(C1-3 alkoksi)2, C1-4 alkil, C1-3 alkoksi, C2-3 alkenil, 5-člani heterociklički prsten, 6-člani heterociklički prsten, 7-člani heterociklički prsten, 8-člani heterociklički prsten, 9-člani heterociklički prsten, 10-člani heterociklički prsten, 5-člani karbociklički prsten, 6-člani karbociklički prsten, 7-člani karbociklički prsten, 8-člani karbociklički prsten, 9-člani karbociklički prsten, 10-člani karbociklički prsten; i od kojih svaki može biti neovisno opcionalno supstituiran s halogenom, -CN, -OH, -NH2, -N3, -NO2, -C1-6 alkilen-NH2, -C1-6 alkilen-NH-C1-6 alkilom, -C1-6 alkilen-N(C1-6 alkilom)2, -NHBoc, -CH2NHBoc, -NH-C1-6 alkilom, N(C1-6 alkilom)2, -NH-C1-6 alkoksi, -N(C1-6 alkoksi)2, supstituiranim ili nesupstituiranim C1-6 alkilom, ili supstituiranim ili nesupstituiranim C1-6 alkoksi; i svaki heterociklički prsten sadrži 1, 2, 3 ili 4 heteroatoma odabrana od N, O ili S.
4. Spoj prema bilo kojem od patentnih zahtjeva 1 do 3, naznačen time, da se R1 ujedinjuje s R3, ili se R2 ujedinjuje s R3, u svrhu tvorbe 5-članog heteroarila, 6-članog heteroarila, 7-članog heteroarila, 8-članog heteroarila, 5-članog heterocikličkog prstena, 6-članog heterocikličkog prstena, 7-članog heterocikličkog prstena ili 8-članog heterocikličkog prstena, pri čemu svaki od prstenskih sustava sadrži 1, 2, 3 ili 4 heteroatoma odabrana od N, O ili S, i opcionalno je supstituiran s -F, -Cl, -Br, -I, -CN, -OH, -NH2, karbonilom, =O, okso, supstituiranim ili nesupstituiranim C1-3 alkilom, supstituiranim ili nesupstituiranim C1-3 alkoksi ili C(O)R8.
5. Spoj prema bilo kojem od patentnih zahtjeva 1 do 4, naznačen time, da se R1 ujedinjuje s R3 u svrhu tvorbe 5-članog heteroarila, 6-članog heteroarila, 5-članog heterocikličkog prstena ili 6-članog heterocikličkog prstena, pri čemu svaki od prstenskih sustava sadrži 1 ili 2 heteroatoma odabrana od N ili O, i opcionalno je supstituiran s -F, -Cl, -Br, -OH, -NH2, karbonilom, =O, okso, metilom, etilom, propilom, izopropilom, metoksi, CHF2, CH2F, CF3 ili C(O)R8; i svaki je metil, etil, propil, izopropil, metoksi, CHF2, CH2F, CF3 ili C(O)R8, neovisno opcionalno supstituiran s -F, -Cl, -Br ili -I.
6. Spoj prema bilo kojem od patentnih zahtjeva 1 do 5, naznačen time, da se R2 ujedinjuje s R3 u svrhu tvorbe 5-članog heteroarila, 6-članog heteroarila, 7-članog heteroarila, 8-članog heteroarila, 5-članog heterocikličkog prstena, 6-članog heterocikličkog prstena, 7-članog heterocikličkog prstena ili 8-članog heterocikličkog prstena, pri čemu svaki od prstenskih sustava sadrži 1, 2, 3 ili 4 heteroatoma odabrana od N, O ili S, i opcionalno je supstituiran s -F, -Cl, -Br, -I, -CN, -OH, -NH2, karbonilom, =O, okso, supstituiranim ili nesupstituiranim C1-3 alkilom, supstituiranim ili nesupstituiranim C1-3 alkoksi ili C(O)R8; i C1-3 alkil je neovisno metil, etil, propil, izopropil ili ciklopropil; C1-3 alkoksi je neovisno metoksi, etoksi, propoksi, izopropoksi ili ciklopropiloksi.
7. Spoj prema bilo kojem od patentnih zahtjeva 1 do 6, naznačen time, da R4 je -Cl, -NH2, metil ili piperidinil, pri čemu je piperidinil opcionalno supstituiran s metilom, -NH2 ili -CH2NH2.
8. Spoj prema bilo kojem od patentnih zahtjeva 1 do 7, naznačen time, da:
R5 je
[image]
svaki od R21 i R22 je neovisno halogen, C1-3 alkil, -NH2, -C1-3 alkilen-NH2, -C1-2 alkilen-NH-C1-3 alkil, -C1-2 alkilen-N(C1-3 alkil)2, -NHBoc ili -CH2NHBoc, ili R21 i R22 zajedno s ugljikovim atomom s kojim su oba vezani, tvore 5-10-člani heteroaril, 5-10-člani karbociklički prsten ili 5-10-člani heterociklički prsten, gdje je svaki od prstenskih sustava opcionalno supstituiran s halogenom, -CN, -OH, karbonilom, =O, okso, -C1-3 alkilen-NH2, -C1-2 alkilen-NH-C1-3 alkilom, -C1-2 alkilen-N(C1-3 alkilom)2, -NHBoc, -CH2NHBoc, -NH2, C1-3 alkoksi ili C1-3 alkilom.
9. Spoj prema patentnom zahtjevu 8, naznačen time, da R21 i R22 zajedno s ugljikovim atomom s kojim su oba vezani, tvore 5-člani heteroaril, 6-člani heteroaril, 7-člani heteroaril, 8-člani heteroaril, 9-člani heteroaril, 10-člani heteroaril, 5-člani heterociklički prsten, 6-člani heterociklički prsten, 7-člani heterociklički prsten, 8-člani heterociklički prsten, 9-člani heterociklički prsten ili 10-člani heterociklički prsten; gdje svaki od prstenskih sustava sadrži 1, 2 ili 3 heteroatoma odabrana od N, O ili S, i neovisno je opcionalno supstituiran s halogenom, -CN, -OH, karbonilom, =O, okso, -NH2, C1-3 alkoksi ili C1-3 alkilom; i C1-3 alkoksi je neovisno metoksi, etoksi, propoksi, izopropoksi ili ciklopropiloksi; C1-3 alkil je neovisno metil, etil, propil, izopropil ili ciklopropil.
10. Spoj prema bilo kojem od patentnih zahtjeva 1 do 9, naznačen time, da R5 je -NH2,
[image]
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11. Spoj prema bilo kojem od patentnih zahtjeva 1 do 10, naznačen time, da su R8 i R9 neovisno -H, metil, terc-butil, -CH=CH2, N(CH3)2,
[image]
12. Spoj prema bilo kojem od patentnih zahtjeva 1 do 11, naznačen time, da
X je S;
Y1 je N i Y2 je CR2;
Y2 je N i Y1 je CR1; i/ili
R4 je -NH2.
13. Spoj prema bilo kojem od patentnih zahtjeva 1 do 12, naznačen time, da je spoj predstavljen Formulom II:
[image]
u kojoj
X je S;
Y1 je N ili CR25;
Y2 je C;
R25 je H, halogen, C1-3 alkil ili C1-3 alkoksi-,
prsten
[image]
je 5-8-člani heteroaril koji sadrži 1, 2, 3 ili 4 heteroatoma odabrana od N, O ili S, 5-8-člani karbociklički prsten ili 5-8-člani heterociklički prsten koji sadrži 1, 2, 3 ili 4 heteroatoma odabrana od N, O ili S;
R31 je -H, halogen, -OH, -NH2, -(C=O)C1-3 alkil, -CN, -NO2, karbonil, =O, okso, karboksil, -C1-3 alkilen-NH2, -NH-C1-3 alkil, -N(C1-3 alkil)2, -NH-C1-3 alkoksi, -N(C1-3 alkoksi)2, supstituirani ili nesupstituirani C1-3 alkil, ili supstituirani ili nesupstituirani C1-3 alkoksi;
m je 0, 1, 2, 3 ili 4;
R4 je -H, halogen, -NH2, supstituirani ili nesupstituirani C1-3 alkoksi, ili supstituirani ili nesupstituirani C1-3 alkil;
svaki od R32 i R33 je neovisno -H, halogen, -OH, -NH2, -CN, -NO2, -C1-3 alkilen-NH2, -C1-2 alkilen-NH-C1-3 alkil, -C1-2 alkilen-N(C1-3 alkil)2, -NHBoc, -CH2NHBoc, -NH-C1-3 alkil, -N(C1-3 alkil)2, -NH-C1-3 alkoksi, -N(C1-3 alkoksi)2, supstituirani ili nesupstituirani C1-3 alkil, ili supstituirani ili nesupstituirani C1-3 alkoksi-,
ili R32 i R33 zajedno s ugljikovim atomom s kojim su oba vezani, tvore 5-8-člani heteroaril koji sadrži 1, 2 ili 3 heteroatoma odabrana od N, O ili S, ili 5-8-člani heterociklički prsten koji sadrži 1, 2 ili 3 heteroatoma odabrana od N, O ili S, pri čemu je svaki od prstenskih sustava opcionalno supstituiran s halogenom, -CN, -OH, -NH2, karbonilom, =O, okso, -CH2NH2, -C1-3 alkilen-NH2, -C1-2 alkilen-NH-C1-3 alkilom, -C1-2 alkilen-N(C1-3 alkilom)2, -NHBoc, -CH2NHBoc, -NH-C1-3 alkilom, -N(C1-3 alkilom)2, -NH-C1-3 alkoksi, -N(C1-3 alkoksi)2, supstituiranim ili nesupstituiranim C1-3 alkilom, ili supstituiranim ili nesupstituiranim C1-3 alkoksi.
14. Spoj prema patentnom zahtjevu 13, naznačen time, da je
prsten
[image]
5-člani heteroaril, 6-člani heteroaril, 7-člani heteroaril, 5-člani heterociklički prsten, 6-člani heterociklički prsten, 7-člani heterociklički prsten, 5-člani karbociklički prsten, 6-člani karbociklički prsten, 7-člani karbociklički prsten ili 8-člani karbociklički prsten; i svaki od prstenskih sustava sadrži 1, 2 ili 3 heteroatoma odabrana od N, O ili S;
R31 je -H, -F, -Cl, -Br, -I, -OH, -NH2, karbonil, =O, okso, -(CO)C1-3 alkil, -C1-3 alkilen-NH2, -NH-C1-3 alkil, -N(C1-3 alkil)2, supstituirani ili nesupstituirani C1-3 alkil, ili supstituirani ili nesupstituirani C1-3 alkoksi-;
R32 i R33 zajedno s ugljikovim atomom s kojim su oba vezani, tvore 5-člani heterociklički prsten, 6-člani heterociklički prsten ili 7-člani heterociklički prsten; pri čemu svaki od prstenskih sustava sadrži 1 ili 2 heteroatoma neovisno odabrana od O ili N, i opcionalno je supstituiran s halogenom, -CN, -OH, -NH2, karbonilom, =O, okso, -NO2, C1-3 alkilom ili C1-3 alkoksi; i/ili
svaki R32 i R33 je neovisno -CH2NH2, -CH2NHBoc ili metil.
15. Spoj prema patentnom zahtjevu 13 ili 14, naznačen time, da je
prsten
[image]
5-člani heterociklički prsten koji sadrži 1, 2 ili 3 heteroatoma odabrana od N ili O, 6-člani heterociklički prsten koji sadrži 1 ili 2 heteroatoma odabrana od N ili O, ili 5-člani karbociklički prsten;
R31 je -F, -COCH3, karbonil, =O, okso, -CH3 ili -CF3; i/ili
R32 i R33 zajedno s ugljikovim atomom s kojim su oba vezani, tvore 5-člani heterociklički prsten; i heterociklički prsten sadrži 1 heteroatom odabran od O ili N, i opcionalno je supstituiran s -F, -Cl, -OH, -NH2, karbonilom, =O, okso, metilom ili metoksi.
16. Spoj prema bilo kojem od patentnih zahtjeva 13 do 15, naznačen time, da
Y1 je N;
Y2 je C;
R25 je -H ili -Cl; i/ili
R4 je -NH2.
17. Spoj prema bilo kojem od patentnih zahtjeva 1 do 12, naznačen time, da je spoj predstavljen Formulom III:
[image]
u kojoj
X je S;
R26 je -H, halogen, supstituirani ili nesupstituirani C1-3 alkil, ili supstituirani ili nesupstituirani C1-3 alkoksi-;
prsten
[image]
je 5-8-člani heteroaril ili 5-8-člani heterociklički prsten; i svaki od prstenskih sustava neovisno sadrži 1, 2, 3 ili 4 heteroatoma odabrana od N, O ili S;
R34 je -H, halogen, -OH, -NR35R36, -CN, -NO2, karbonil, =O, okso, supstituirani ili nesupstituirani C1-3 alkil, ili supstituirani ili nesupstituirani C1-3 alkoksi-;
n je 0, 1, 2, ili 3;
R4 je halogen, -NH2, supstituirani ili nesupstituirani C1-3 alkoksi, ili supstituirani ili nesupstituirani C1-3 alkil;
svaki od R35 i R36 je neovisno -H, halogen, -OH, -NH2, -CN, -NO2, -CH2NH2, supstituirani ili nesupstituirani C1-3 alkil, ili supstituirani ili nesupstituirani C1-3 alkoksi-,
ili R35 i R36 zajedno s ugljikovim atomom s kojim su oba vezani, tvore 5-8-člani heteroaril ili 5-8-člani heterociklički prsten, pri čemu svaki od prstenskih sustava neovisno sadrži 1, 2 ili 3 heteroatoma odabrana od N, O ili S, i opcionalno je supstituiran s halogenom, -CN, -OH, -NH2, karbonilom, =O, okso, -CH2NH2, -C1-3 alkilen-NH2, -C1-2 alkilen-NH-C1-3 alkilom, -C1-2 alkilen-N(C1-3 alkilom)2, -NHBoc, -CH2NHBoc, -NH-C1-3 alkilom, -N(C1-3 alkilom)2, -NHC1-3 alkoksi, -N(C1-3 alkoksi)2, supstituiranim ili nesupstituiranim C1-3 alkilom, ili supstituiranim ili nesupstituiranim C1-3 alkoksi.
18. Spoj prema patentnom zahtjevu 17, naznačen time, da je
prsten
[image]
5-člani heteroaril, 6-člani heteroaril, 7-člani heteroaril, 5-člani heterociklički prsten, 5-člani heterociklički prsten, 6-člani heterociklički prsten ili 7-člani heterociklički prsten; i svaki od prstenskih sustava neovisno sadrži 1, 2 ili 3 heteroatoma odabrana od N, O ili S; i/ili
R35 i R36 zajedno s ugljikovim atomom s kojim su oba vezani, tvore 5-člani heterociklički prsten, 6-člani heterociklički prsten ili 7-člani heterociklički prsten; pri čemu svaki od prstenskih sustava neovisno sadrži 1 ili 2 heteroatoma neovisno odabrana od O ili N, i opcionalno je supstituiran s halogenom, -CN, -OH, -NH2, karbonilom, =O, okso, -NO2, C1-3 alkilom ili C1-3 alkoksi.
19. Spoj prema patentnom zahtjevu 17 ili 18, naznačen time, da je
prsten
[image]
5-člani heterociklički prsten ili 6-člani heterociklički prsten; i svaki od prstenskih sustava neovisno sadrži 1 ili 2 heteroatoma odabrana od N ili O; i/ili
R35 i R36 zajedno s ugljikovim atomom s kojim su oba vezani, tvore 5-člani heterociklički prsten; pri čemu prstenski sustav sadrži 1 heteroatom neovisno odabran od O ili N, i opcionalno je supstituiran s -F, -Cl, -OH, -NH2, karbonilom, =O, okso, metilom ili metoksi.
20. Spoj prema bilo kojem od patentnih zahtjeva 17 do 19, naznačen time, da
R26 je -H ili -Cl;
R4 je -NH2; i/ili
R34 je -F, -COCH3, =O, -CH3 ili -CF3.
21. Spoj prema bilo kojem od patentnih zahtjeva 1 do 20, naznačen time, da svaki supstituirani ili nesupstituirani C1-6 alkil je neovisno C1-6 alkil, ili C1-6 alkil supstituiran s halogenom, -OH, -CN, -NH2, -NO2, karbonilom, =O, okso, -C1-6alkilen-NH2, -C1-6alkilen-NH-C1-6alkilom ili -C1-6alkilen-N(C1-6alkilom)2; svaki supstituirani ili nesupstituirani C1-6 alkoksi je neovisno C1-6 alkoksi, ili C1-6 alkoksi supstituiran s halogenom, -OH, -CN, -NH2, -NO2, karbonilom, =O, okso, -C1-6 alkilen-NH2, -C1-6 alkilen-NH-C1-3alkilom ili -C1-6 alkilen-N(C1-6 alkilom)2.
22. Spoj prema bilo kojem od patentnih zahtjeva 1 do 21, naznačen time, da
svaki C1-6 alkil je neovisno metil, etil, propil, izopropil, ciklopropil, n-butil, izobutil, terc-butil, n-pentil, neopentil, izopentil, ciklopentil, n-heksil ili cikloheksil;
svaki C1-3 alkoksi je neovisno metoksi, etoksi, propoksi, izopropoksi ili ciklopropoksi;
svaki C2-3 alkenil je neovisno -CH=CH2, -CH2-CH=CH2 ili -CH=CH-CH3;
svaki C2-3 alkinil je neovisno -C=CH, -CH2-C≡CH ili -C≡C-CH3; i/ili
svaki halogen je neovisno -F, -Cl, -Br ili -I.
23. Spoj prema bilo kojem od patentnih zahtjeva 1 do 22, naznačen time, da svaka skupina heterocikličkog prstena i svaka skupina karbocikličkog prstena obuhvaća jednostruki prsten, spiralni prsten, premošteni prsten, spojeni prsten, i sve različite kombinacije spiralnog prstena, premoštenog prstena i/ili spojenog prstena.
24. Spoj prema patentnom zahtjevu 23, naznačen time, da navedeni spiralni prsten uključuje
[image]
i navedene različite kombinacije spiralnog prstena, premoštenog prstena i/ili spojenog prstena, uključuju
[image]
25. Spoj prema patentnom zahtjevu 1, naznačen time, da spoj jest
(S)-1-(4-((3-amino-5-(4-amino-2-oksa-8-azaspiro[4.5]dekan-8-il)pirazin-2-il)tio)-3,3-difluoroindolin-1-il)etanon.
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