HRP20210291T1 - Imunoregulatorna sredstva - Google Patents
Imunoregulatorna sredstva Download PDFInfo
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- HRP20210291T1 HRP20210291T1 HRP20210291TT HRP20210291T HRP20210291T1 HR P20210291 T1 HRP20210291 T1 HR P20210291T1 HR P20210291T T HRP20210291T T HR P20210291TT HR P20210291 T HRP20210291 T HR P20210291T HR P20210291 T1 HRP20210291 T1 HR P20210291T1
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- pharmaceutically acceptable
- cancer
- acceptable salt
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- 230000004957 immunoregulator effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 20
- 150000003839 salts Chemical class 0.000 claims 17
- 239000012453 solvate Substances 0.000 claims 10
- KRTIYQIPSAGSBP-KLAILNCOSA-N linrodostat Chemical compound C1(CCC(CC1)C1=C2C=C(F)C=CC2=NC=C1)[C@@H](C)C(=O)NC1=CC=C(Cl)C=C1 KRTIYQIPSAGSBP-KLAILNCOSA-N 0.000 claims 7
- 239000003814 drug Substances 0.000 claims 6
- 229940124597 therapeutic agent Drugs 0.000 claims 6
- 206010028980 Neoplasm Diseases 0.000 claims 4
- -1 SO2CH3 Chemical group 0.000 claims 4
- 239000000556 agonist Substances 0.000 claims 4
- 201000011510 cancer Diseases 0.000 claims 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 4
- 229910052739 hydrogen Inorganic materials 0.000 claims 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
- 239000005557 antagonist Substances 0.000 claims 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 3
- 229910052736 halogen Inorganic materials 0.000 claims 3
- 150000002367 halogens Chemical class 0.000 claims 3
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 239000001257 hydrogen Substances 0.000 claims 3
- 201000001441 melanoma Diseases 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 2
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- 229910006074 SO2NH2 Inorganic materials 0.000 claims 2
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- 201000010099 disease Diseases 0.000 claims 2
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- 125000001153 fluoro group Chemical group F* 0.000 claims 2
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- 230000001404 mediated effect Effects 0.000 claims 2
- 229910052757 nitrogen Inorganic materials 0.000 claims 2
- 229910052760 oxygen Inorganic materials 0.000 claims 2
- 125000000565 sulfonamide group Chemical group 0.000 claims 2
- 229910052717 sulfur Inorganic materials 0.000 claims 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims 2
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims 2
- ONKCBKDTKZIWHZ-MRWFHJSOSA-N (4r)-4-[[(2r)-6-amino-2-[[(2r)-2-[[4-(aminocarbamothioylamino)benzoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]hexanoyl]amino]-5-[[(2r)-1-amino-6-[bis[2-[[4-[2-(1h-imidazol-5-yl)ethylamino]-4-oxobutanoyl]amino]acetyl]amino]-1-oxohexan-2-yl]amino]-5-oxope Chemical compound C([C@H](C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN(C(=O)CNC(=O)CCC(=O)NCCC=1NC=NC=1)C(=O)CNC(=O)CCC(=O)NCCC=1NC=NC=1)C(N)=O)NC(=O)C=1C=CC(NC(=S)NN)=CC=1)C1=CC=C(O)C=C1 ONKCBKDTKZIWHZ-MRWFHJSOSA-N 0.000 claims 1
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 1
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- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 claims 1
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- 101000801234 Homo sapiens Tumor necrosis factor receptor superfamily member 18 Proteins 0.000 claims 1
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- 206010061535 Ovarian neoplasm Diseases 0.000 claims 1
- 229940124060 PD-1 antagonist Drugs 0.000 claims 1
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- 208000033133 Testicular seminomatous germ cell tumor Diseases 0.000 claims 1
- 102100033728 Tumor necrosis factor receptor superfamily member 18 Human genes 0.000 claims 1
- 101710165473 Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 claims 1
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- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 claims 1
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- 125000003107 substituted aryl group Chemical group 0.000 claims 1
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- 201000005112 urinary bladder cancer Diseases 0.000 claims 1
- 229950001067 varlilumab Drugs 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
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- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
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- A61K31/47—Quinolines; Isoquinolines
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- 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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- A61K31/505—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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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
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- C07D215/14—Radicals substituted by oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/24—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- 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
- C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
-
- 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
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- 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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Claims (23)
1. Spoj formule (I):
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ili njegov stereoizomer, farmaceutski prihvatljiva sol, hidrat ili solvat, pri čemu,
Z je O;
R1 i R2 su nezavisno vodik, halogen, opcionalno supstituiran C1-C4 haloalkil, opcionalno supstituiran C3-C6 cikloalkil, opcionalno supstituiran 3- do 6-člani cikloheteroalkil, opcionalno supstituiran fenil, opcionalno supstituiran heteroaril, opcionalno supstituiran C1-C4 alkil, opcionalno supstituiran C1-C4 alkoksi, CN, SO2NH2, NHSO2CH3, NHSO2CF3, OCF3, SO2CH3, SO2CF3, ili CONH2, i kada R1 i R2 su na susjednim tjemenima fenilnog prstena, oni mogu biti spojeni zajedno da bi formirali 5- ili 6-člani cikloheteroalkilni prsten koji ima jedan ili dva tjemena prstena nezavisno izabrana od O, N i S, pri čemu je spomenuti cikloheteroalkilni prsten opcionalno supstituiran sa jednim do tri člana izabrana od fluoro i C1-C3 alkila;
pri čemu J1 je CH, N ili opcionalno C(R2) kada R2 je vezan za teme prstena identificirano kao J1;
R3 i R3a su nezavisno vodik, opcionalno supstituiran C1-C6 alkil, opcionalno supstituiran C2-C6 alkenil, opcionalno supstituiran C2-C6 alkinil, opcionalno supstituiran C1-C6 haloalkil, opcionalno supstituiran C3-C6 cikloalkil-C1-C4 alkil, opcionalno supstituiran aril-Ci-C6 alkil, fluor, OH, CN, CO2H, C(O)NH2, N(R5)2, opcionalno supstituiran -O- C1-C6 alkil,-(CR5R5)m-OH, -(CR5R5)m-CO2H, -(CR5R5)m-C(O)NH2, -(CR5R5)m- C(O)NHR5,-(CR5R5)mN(R5)2, -NH(CR5R5)mCO2H ili -NH(CR5R5)m-C(O)NH2;
svaki R5 je nezavisno H, F, OH, ili opcionalno supstituiran C1-C6 alkil;
svaki R5a je nezavisno H, ili opcionalno supstituiran C1-C6 alkil;
R6 je H, OH, F, opcionalno supstituiran C1-C6 alkil, opcionalno supstituiran -O-C1-C6 alkil, ili -N(R5a)2;
svaki m je nezavisno 1, 2, ili 3
i R11 i R12 su nezavisno vodik, halogen, opcionalno supstituiran C1-C4 haloalkil, opcionalno supstituiran C3-C6 cikloalkil, opcionalno supstituiran 3- do 6-člani cikloheteroalkil, opcionalno supstituiran fenil, opcionalno supstituiran heteroaril, opcionalno supstituiran C1-C4 alkil, opcionalno supstituiran C1-C4 alkoksi, CN, SO2NH2, NHSO2CH3, NHSO2CF3, OCF3, SO2CH3, SO2CF3, ili CONH2, i kada R1 i R2 su na susjednim tjemenima fenilnog prstena, oni mogu biti spojeni zajedno da bi formirali 5- ili 6-člani cikloheteroalkilni prsten koji ima jedan ili dva tjemena prstena nezavisno izabrana od O, N i S, pri čemu je spomenuti cikloheteroalkilni prsten opcionalno supstituiran sa jednim do tri člana izabrana od fluoro i C1-C3 alkila.
2. Spoj prema patentnom zahtjevu 1, koji ima formulu
[image]
pri čemu R6 je H, i R11 i R12 su svaki nezavisno izabrani iz grupe koja se sastoji od halogena, CN i opcionalno supstituiranog C1-C4 alkila;
ili njegov stereoizomer, farmaceutski prihvatljiva sol, hidrat ili solvat.
3. Spoj prema patentnom zahtjevu 1, koji je izabran od:
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pri čemu
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ili
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ili stereoizomer ili farmaceutski prihvatljiva sol, hidrat ili solvat istog.
4. Spoj, koji je izabran od:
[image]
[image]
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[image]
[image]
ili
[image]
ili stereoizomer ili farmaceutski prihvatljiva sol, hidrat ili solvat istog.
5. Spoj prema bilo kojem od patentnih zahtjeva 1 do 3 koje je (R)-N-(4-klorofenil)-2-(cis-4-(6- fluorohinolin-4-il)cikloheksil)propanamid
[image]
ili njegova farmaceutski prihvatljiva sol.
6. Spoj prema bilo kojem od patentnih zahtjeva 1 do 3 koji je (R)-N-(4-klorofenil)-2-(cis-4-(6- fluorohinolin-4-il)cikloheksil)propanamid
[image]
ili njegov stereoizomer ili njegova farmaceutski prihvatljiva sol.
7. Spoj prema patentnom zahtjevu 5 koji je farmaceutski prihvatljiva sol (R)-N-(4-klorofenil)-2- (cis-4-(6-fluorohinolin-4-il)cikloheksil)propanamida.
8. Farmaceutska kompozicija koja sadrži spoj prema bilo kojem od patentnih zahtjeva 1 do 7, ili njegov stereoizomer, farmaceutski prihvatljivu sol, hidrat ili solvat i farmaceutski prihvatljiv ekscipijens.
9. Farmaceutska kompozicija prema patentnom zahtjevu 8, pri čemu je spoj (R)-N-(4- klorofenil)-2-(cis-4-(6-fluorohinolin-4-il)cikloheksil)propanamid
[image]
ili njegova farmaceutski prihvatljiva sol.
10. Farmaceutska kompozicija prema patentnom zahtjevu 8, pri čemu je spoj farmaceutski prihvatljiva sol (R)-N-(4-klorofenil)-2-(cis-4-(6-fluorohinolin-4-il)cikloheksil)propanamida.
11. Spoj prema bilo kojem od patentnih zahtjeva 1 do 7, ili njegov stereoizomer, farmaceutski prihvatljiva sol, hidrat ili solvat, za primjenu u postupku liječenja bolesti, poremećaja ili stanja, posredovanog barem dijelom pomoću IDO.
12. Spoj za primjenu prema patentnom zahtjevu 11, pri čemu je spoj (R)-N-(4-klorofenil)-2-(cis-4- (6-fluorohinolin-4-il)cikloheksil)propanamid
[image]
ili njegova farmaceutski prihvatljiva sol.
13. Spoj za primjenu prema patentnom zahtjevu 11, pri čemu je spoj farmaceutski prihvatljiva sol (R)-N-(4-klorofenil)-2-(cis-4-(6-fluorohinolin-4-il)cikloheksil)propanamida.
14. Spoj ili njegov stereoizomer, farmaceutski prihvatljiva sol, hidrat ili solvat za primjenu prema bilo kojem od patentnih zahtjeva 11 do 13, pri čemu se spomenuti spoj administrira u količini efikasnoj da preokrene ili zaustavi progresiju IDO-posredovane imunosupresije.
15. Spoj ili njegov stereoizomer, farmaceutski prihvatljiva sol, hidrat ili solvat za primjenu prema bilo kojem od patentnih zahtjeva 11 do 14, pri čemu je navedena bolest, poremećaj ili stanje rak,
opcionalno pri čemu spomenuti rak je rak prostate, debelog crijeva, rektuma, pankreasa, grlića materice, želuca, endometrija, mozga, jetre, mjehura, jajnika, testisa, glave, vrata, kože (uključujući melanom i bazalni karcinom), mezotelne obloge, bijelih krvnih zrnaca (uključujući limfom i leukemiju), jednjaka, dojke, mišića, vezivnog tkiva, pluća (uključujući sitnostanični karcinom pluća i nesitnostanični karcinom), nadbubrežne žlijezde, štitne žlijezde, bubrega ili kosti; ili je glioblastom, mezoteliom, karcinom bubrežnih stanica, gastrični karcinom, sarkom (uključujući Kaposijev sarkom), horiokarcinom, kožni bazocelularni karcinom ili seminom testisa; ili
opcionalno pri čemu spomenuti rak je izabran iz grupe koja se sastoji od melanoma, raka debelog crijeva, raka gušterače, raka dojke, raka prostate, raka pluća, raka grlića materice, leukemije, sarkoma, raka bubrega, tumora mozga, limfoma, raka jajnika i Kaposijevog sarkoma.
16. Spoj ili njegov stereoizomer, farmaceutski prihvatljiva sol, hidrat ili solvat za primjenu prema patentnom zahtjevu 15, pri čemu spomenuti rak je melanom, rak pluća, rak glave, rak vrata, rak bubrežnih stanica, ili rak mjehura.
17. Kombinacija koja sadrži spoj prema bilo kojem od patentnih zahtjeva 1 do 7, ili njegov stereoizomer, farmaceutski prihvatljiva sol, hidrat ili solvat, i najmanje jedno dodatno terapijsko sredstvo.
18. Kombinacija prema patentnom zahtjevu 17, pri čemu spomenuto dodatno terapijsko sredstvo je imuno-onkološko sredstvo.
19. Kombinacija prema patentnom zahtjevu 18, pri čemu spomenuto imuno-onkološko sredstvo je izabrano od CTLA-4 antagonista, PD-1 antagonista, PD-L1 antagonista, LAG-3 antagonista, CD137 agonista, GITR agonista, OX40 agonista, OX40L antagonista, CD40 agonista ili antagonista, CD27 agonista, ili B7H3 antitijela.
20. Kombinacija prema patentnom zahtjevu 18, pri čemu dodatno terapijsko sredstvo je ipilimumab.
21. Kombinacija prema patentnom zahtjevu 18, pri čemu dodatno terapijsko sredstvo je nivolumab.
22. Kombinacija prema patentnom zahtjevu 18, pri čemu dodatno terapijsko sredstvo je BMS- 986016, BMS-936559, urelumab, BMS-986153, ili BMS-986156.
23. Kombinacija prema patentnom zahtjevu 18, pri čemu dodatno terapijsko sredstvo je tremelimumab, pembrolizumab, MEDI-0680, pidilizumab, MPDL3280A, durvalumab, MSB0010718C, IMP-731, IMP-321, PF-05082566, TRX-518, MK-4166, MEDI-6383, MEDI- 6469, RG-7888, lukatumumab, dacetuzumab, varlilumab ili MGA271.
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