HRP20240055T1 - Derivati piperidinona kao inhibitori mdm2 za liječenje raka - Google Patents
Derivati piperidinona kao inhibitori mdm2 za liječenje raka Download PDFInfo
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- HRP20240055T1 HRP20240055T1 HRP20240055TT HRP20240055T HRP20240055T1 HR P20240055 T1 HRP20240055 T1 HR P20240055T1 HR P20240055T T HRP20240055T T HR P20240055TT HR P20240055 T HRP20240055 T HR P20240055T HR P20240055 T1 HRP20240055 T1 HR P20240055T1
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- Prior art keywords
- alkylene
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- alkyl
- heterocyclo
- cycloalkyl
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- 206010028980 Neoplasm Diseases 0.000 title claims 11
- 201000011510 cancer Diseases 0.000 title claims 7
- 239000012819 MDM2-Inhibitor Substances 0.000 title 1
- XUWHAWMETYGRKB-UHFFFAOYSA-N piperidin-2-one Chemical class O=C1CCCCN1 XUWHAWMETYGRKB-UHFFFAOYSA-N 0.000 title 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 20
- 125000001072 heteroaryl group Chemical group 0.000 claims 14
- 125000003118 aryl group Chemical group 0.000 claims 10
- 125000001475 halogen functional group Chemical group 0.000 claims 10
- -1 (C3-C8)heterocyclo Chemical group 0.000 claims 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 7
- 150000001875 compounds Chemical class 0.000 claims 7
- 125000001188 haloalkyl group Chemical group 0.000 claims 7
- 150000003839 salts Chemical class 0.000 claims 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims 6
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 6
- 125000003710 aryl alkyl group Chemical group 0.000 claims 5
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims 5
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 4
- 125000003342 alkenyl group Chemical group 0.000 claims 4
- 125000000217 alkyl group Chemical group 0.000 claims 4
- 125000000304 alkynyl group Chemical group 0.000 claims 4
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims 4
- 125000000623 heterocyclic group Chemical group 0.000 claims 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
- 108091008648 NR7C Proteins 0.000 claims 3
- 125000003545 alkoxy group Chemical group 0.000 claims 3
- 125000004122 cyclic group Chemical group 0.000 claims 3
- 125000004438 haloalkoxy group Chemical group 0.000 claims 3
- 201000005787 hematologic cancer Diseases 0.000 claims 3
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 claims 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims 2
- 208000032791 BCR-ABL1 positive chronic myelogenous leukemia Diseases 0.000 claims 2
- 208000010833 Chronic myeloid leukaemia Diseases 0.000 claims 2
- 206010025323 Lymphomas Diseases 0.000 claims 2
- 208000033761 Myelogenous Chronic BCR-ABL Positive Leukemia Diseases 0.000 claims 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims 2
- 206010039491 Sarcoma Diseases 0.000 claims 2
- 125000002947 alkylene group Chemical group 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- 125000000392 cycloalkenyl group Chemical group 0.000 claims 2
- 125000004043 oxo group Chemical group O=* 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 1
- DRLCSJFKKILATL-YWCVFVGNSA-N 2-[(3r,5r,6s)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-[(2s)-3-methyl-1-propan-2-ylsulfonylbutan-2-yl]-2-oxopiperidin-3-yl]acetic acid Chemical compound C1([C@@H]2[C@H](N(C([C@@](C)(CC(O)=O)C2)=O)[C@H](CS(=O)(=O)C(C)C)C(C)C)C=2C=CC(Cl)=CC=2)=CC=CC(Cl)=C1 DRLCSJFKKILATL-YWCVFVGNSA-N 0.000 claims 1
- 208000031261 Acute myeloid leukaemia Diseases 0.000 claims 1
- 208000036762 Acute promyelocytic leukaemia Diseases 0.000 claims 1
- 206010003571 Astrocytoma Diseases 0.000 claims 1
- 208000003950 B-cell lymphoma Diseases 0.000 claims 1
- 102000009508 Cyclin-Dependent Kinase Inhibitor p16 Human genes 0.000 claims 1
- 108010009392 Cyclin-Dependent Kinase Inhibitor p16 Proteins 0.000 claims 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims 1
- 206010014733 Endometrial cancer Diseases 0.000 claims 1
- 206010014759 Endometrial neoplasm Diseases 0.000 claims 1
- 201000008808 Fibrosarcoma Diseases 0.000 claims 1
- 208000004463 Follicular Adenocarcinoma Diseases 0.000 claims 1
- 206010018338 Glioma Diseases 0.000 claims 1
- 208000017604 Hodgkin disease Diseases 0.000 claims 1
- 208000021519 Hodgkin lymphoma Diseases 0.000 claims 1
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims 1
- 208000007766 Kaposi sarcoma Diseases 0.000 claims 1
- 206010025538 Malignant ascites Diseases 0.000 claims 1
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims 1
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 claims 1
- 206010029260 Neuroblastoma Diseases 0.000 claims 1
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims 1
- 201000010208 Seminoma Diseases 0.000 claims 1
- 206010042971 T-cell lymphoma Diseases 0.000 claims 1
- 208000027585 T-cell non-Hodgkin lymphoma Diseases 0.000 claims 1
- 230000001154 acute effect Effects 0.000 claims 1
- 206010006007 bone sarcoma Diseases 0.000 claims 1
- 210000000481 breast Anatomy 0.000 claims 1
- 210000004027 cell Anatomy 0.000 claims 1
- 210000003169 central nervous system Anatomy 0.000 claims 1
- 210000003679 cervix uteri Anatomy 0.000 claims 1
- 210000001072 colon Anatomy 0.000 claims 1
- 229910052805 deuterium Inorganic materials 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 210000003238 esophagus Anatomy 0.000 claims 1
- 210000000232 gallbladder Anatomy 0.000 claims 1
- 208000005017 glioblastoma Diseases 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000002367 halogens Chemical class 0.000 claims 1
- 201000010536 head and neck cancer Diseases 0.000 claims 1
- 208000014829 head and neck neoplasm Diseases 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 1
- 210000003734 kidney Anatomy 0.000 claims 1
- 208000032839 leukemia Diseases 0.000 claims 1
- 210000004185 liver Anatomy 0.000 claims 1
- 210000004072 lung Anatomy 0.000 claims 1
- 201000001441 melanoma Diseases 0.000 claims 1
- 230000035772 mutation Effects 0.000 claims 1
- 208000007538 neurilemmoma Diseases 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 229910052757 nitrogen Inorganic materials 0.000 claims 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 1
- 201000008968 osteosarcoma Diseases 0.000 claims 1
- 210000001672 ovary Anatomy 0.000 claims 1
- 210000000496 pancreas Anatomy 0.000 claims 1
- 210000001428 peripheral nervous system Anatomy 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 210000002307 prostate Anatomy 0.000 claims 1
- 210000000664 rectum Anatomy 0.000 claims 1
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims 1
- 210000003491 skin Anatomy 0.000 claims 1
- 210000002784 stomach Anatomy 0.000 claims 1
- 208000001608 teratocarcinoma Diseases 0.000 claims 1
- 210000001685 thyroid gland Anatomy 0.000 claims 1
- 208000030901 thyroid gland follicular carcinoma Diseases 0.000 claims 1
- 210000003932 urinary bladder Anatomy 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
- C07D211/74—Oxygen atoms
- C07D211/76—Oxygen atoms attached in position 2 or 6
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
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- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/20—Spiro-condensed ring systems
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- 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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- C07D401/00—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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- C07D401/02—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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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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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
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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
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two 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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- 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
- C07D409/12—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 linked by a chain containing hetero atoms as chain links
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
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- C07D413/06—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 only aliphatic carbon atoms
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- C07D417/00—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
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- C07D417/06—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 linked by a carbon chain containing only aliphatic carbon atoms
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- C07D417/00—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
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- C07D417/00—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
- C07D417/14—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 three or more hetero rings
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- 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
- C07D471/10—Spiro-condensed systems
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- 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
- C07D491/08—Bridged systems
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- C07D491/12—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 three hetero rings
- C07D491/14—Ortho-condensed systems
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Claims (9)
1. Spoj formule IE:
[image]
ili njegova farmaceutski prihvatljiva sol, naznačen time što:
Ra je pri svakom pojavljivanju neovisno odabran između H, (C1-C3)alkila, (halo)(C1-C3)alkila, (hidroksi)(C1-C3)alkila, (alkoksi)(C1-C3)alkila, ili cijano;
Rb je H, halo, (C1-C3)alkil, (halo)(C1-C3)alkil, (hidroksi)(C1-C3)alkil, (alkoksi)(C1-C3)alkil, ili cijano;
Rc i Rd su neovisno odabrani između H, halo, (C1-C3)alkila, (C1-C3)alkoksi, (halo)(C1-C3)alkila, (halo)(C1-C3)alkoksi, (alkoksi)(C1-C3)alkila, ili (hidroksi)(C1-C3)alkila,
ili Rc i Rd se mogu izborno kombinirati da tvore spiro-cikloalkilni ili heterociklo prstenasti sustav;
Re je
(a) H ili halo; ili
(b) (C1-C8)alkil, (C3-C8)cikloalkil, (C3-C8)heterociklo, cijano, halogen, hidroksil, -OR5, NR7R8, ili heterocikloalkil, od kojih bilo koji može biti izborno supstituiran s jednom ili više skupina Rx kako je dopušteno valencijom;
R1 je
(a) -COOH, -C(O)OR10, -C(O)NHOH, -C(O)NH-NH2, - C(O)NHS(O)2R10, -S(O)2NHC(O)R10, -S(O)2NR7R8, -NR7C(O)R10, -NR7C(O)OR5, -C(O)NR7R8, -NR7S(O)2R10,- NR7C(O)NR7R8, - S(O)vR10, hidroksilalkil, -ciklopropil-COOH, ili CN; ili
(b) heteroaril ili heterociklo, od kojih bilo koji može biti po izboru neovisno supstituiran s jednom ili više skupina Rx kako je dopušteno valencijom;
R2 je
(a) -NR7R8, NR7C(O)OR10, NR7C(O)NR7R10, ili -C(Ra)R5R6; ili
(b) aril, heteroaril, cikloalkil, ili heterociklo, od kojih bilo koji može biti izborno neovisno supstituiran s jednom ili više skupina Rx kako je dopušteno valencijom;
R5 i R6 se pri svakom pojavljivanju neovisno biraju od
(a) H ili CN;
(b) -(alkilen)t -OH, -(alkilen)t-OR9, -(alkilen)t-SR9, -(alkilen)t-NR10R11, -(alkilen)t-C(O)R9, -(alkilen)t-C(O)OR9, -(alkilen)t-OC(O)R9, -(alkilen)t-S(O)vR9, -(alkilen)t-NHS(O)2R10, -(alkilen)t-N(R11)S(O)2R10, -(alkilen)t-S(O)2NR10R11, -(alkilen)t-N(R11)S(O)2NR10R11, -NR10C(O)R9, -C(O)NR10R11, -NR10S(O)2R9, S(O)2NR10, ili NR10C(O)NR10R11; ili
(c) haloalkil, haloalkoksi, C1-6-alkil, C2-6alkenil, C2-6-alkinil, C3-8-cikloalkil, (C3-8-cikloalkil)(C1-3alkil), C4-8-cikloalkenil, aril, aril(C1-3-alkil), heteroaril, heteroaril(C1-3-alkil), heterociklo ili heterociklo(C1-3-alkil), od kojih bilo koji može biti izborno neovisno supstituiran s jednom ili više skupina Rx kako je dopušteno valencijom;
R7 i R8 pri svakom pojavljivanju, redom, su neovisno odabrani između H, cijano, -O C1-6-alkila, C1-6-alkil, halo(C1-6)-alkila, cikloalkila, C2-6-alkenila, C2-6-alkinial, arila, heteroarila, heterociklo, arilalkila, heteroarilalkila, heterociklo(C1-10alkil), ili (C3-8-cikloalkil)(C1-3alkil), od kojih bilo koji može biti po izboru supstituiran u skladu s valencijom s jednom ili više skupina Rx, ili R7 i R8 se mogu kombinirati tako da tvore C4-C8-heterociklo prsten izborno supstituiran s jednom ili više skupina Rx;
R9 je haloalkil, haloalkoksi, C1-6-alkil, C2-6alkenil, C2-6-alkinil, C3-8-cikloalkil, (C3-8-cikloalkil)(C1-3alkil), C4-8-cikloalkenil, aril, heteroaril, heterociklo, ili heterocikloalkil, od kojih bilo koji može biti izborno neovisno supstituiran s jednom ili više skupina Rx kako je dopušteno valencijom;
R10 i R11 pri svakom pojavljivanju su neovisno odabrani između H, alkila, haloalkila, cikloalkila, alkenila, alkinila, arila, heteroarila, heterociklo, arilalkila, heteroarilalkila, heterocikloalkila ili cikloalkilalkila, od kojih bilo koji može biti po izboru supstituiran u skladu s valencijom s jednom ili više skupina Rx, ili R10 i R11 se mogu kombinirati tako da tvore heterociklički prsten izborno supstituiran s jednom ili više skupina Rx;
Rx pri svakom pojavljivanju je neovisno, deuterij, halo, cijano, nitro, okso, alkil, haloalkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterociklo, aril, heteroaril, arilalkil, heteroarilalkil, cikloalkilalkil, heterocikloalkil, -(alkilen)t-OR∗, -(alkilen)t-S(O)vR∗, -(alkilen)t-NR+R++, -(alkilen)t-C(=O)R∗, -(alkilen)t-C(=S)R∗, -(alkilen)t-C(=O)OR∗, -(alkilen)t-OC(=O)R∗, -(alkilen)t-C(=S)OR*, (alkilen)t-C(=O)NR+R++, -(alkilen)t-C(=S)NR+R++, -(alkilen)t-N(R+)C(=O)NR+R++, -(alkilen)t-N(R+)C(=S)NR+R++, -(alkilen)t-N(R+)C(=O)R∗, -(alkilen)t-N(R+)C(=S)R∗, -(alkilen)t-OC(=O) NR+R++, -(alkilen)t-OC(=S)NR+R++, -(alkilen)t-SO2NR+R++, -(alkilen)t-N(R+)SO2R∗, -(alkilen)t-N(R+)SO2N R+R++, -(alkilen)t-N(R+)C(=O)OR∗, -(alkilen)t-N(R+)C(=S)OR∗, ili -(alkilen)t-N(R+)SO2R∗, pri čemu navedene skupine alkil, haloalkil, alkenil, alkinil, cikloalkil, cikloalkenil, heterociklo, aril, heteroaril, arilalkil, heteroarilalkil, cikloalkilalkil, i heterocikloalkil mogu dalje biti neovisno supstituirane s jednim ili više halo, cijano, okso, -(alkilen)t-OR∗, -(alkilen)t-S(O)vR∗, -(alkilen)t-NR+R++, -(alkilen)t-C(=O)R∗, -(alkilen)t-C(=S)R∗, -(alkilen)t-C(=O)OR∗, -(alkilen)t-OC(=O)R∗, -(alkilen)t-C(=S)OR*, -(alkilen)t-C(=O)NR+R++, -(alkilen)t-C(=S)NR+R++, -(alkilen)t-N(R+)C(=O)NR+R++, -(alkilen)t-N(R+)C(=S)NR+R++, -(alkilen)t-N(R+)C(=O)R∗, -(alkilen)t-N(R+)C(=S)R∗, -(alkilen)t-OC(=O) NR+R++, -(alkilen)t-OC(=S)NR+R++, -(alkilen)t-SO2NR+R++, -(alkilen)t-N(R+)SO2R∗, -(alkilen)t-N(R+)SO2N R+R++, -(alkilen)t-N(R+)C(=O)OR∗, -(alkilen)t-N(R+)C(=S)OR∗, ili -(alkilen)t-N(R+)SO2R∗;
R* je H, haloalkil, haloalkoksi, C1-6-alkil, C2-6alkenil, C2-6-alkinil, C3-8-cikloalkil, C4-8-cikloalkenil, aril, heteroaril, ili heterociklo;
R+ i R++ su neovisno H, alkil, haloalkil, cikloalkil, alkenil, alkinil, aril, heteroaril, heterociklo, arilalkil, heteroarilalkil, heterocikloalkil, ili cikloalkilalkil, ili R+ i R++ vezani na isti atom dušika se mogu po izboru kombinirati tako da tvore heterociklo prstenasti sustav;
p je 0, 1, 2 ili 3;
q je 0, 1, 2, ili 3;
t pri svakom pojavljivanju je neovisno 0 ili cijeli broj od 1 do 6; i
v pri svakom pojavljivanju je neovisno 0, 1 ili 2;
pri čemu izborno Rc i Rd se kombiniraju tako da tvore spiro-cikloalkilni ili heterociklo prstenasti sustav.
2. Spoj prema zahtjevu 1, ili njegova farmaceutski prihvatljiva sol, naznačen time što je R2 odabran između
[image]
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ili, od kojih bilo koja može biti izborno supstituirana s jednom ili više skupina Rx kako dopušta valencija.
3. Spoj prema zahtjevu 1, ili njegova farmaceutski prihvatljiva sol, naznačen time što je R2 odabran između
[image]
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od kojih bilo koja može biti po izboru supstituirana s jednom ili više skupina Rx kako dopušta valencija; i R1 je
[image]
ili heteroaril ili heterocikl odabran između
[image]
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[image]
[image]
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4. Spoj prema zahtjevu 1, ili njegova farmaceutski prihvatljiva sol, naznačen time što je R2 odabran između
[image]
[image]
[image]
[image]
[image]
[image]
[image]
od kojih bilo koja može biti po izboru supstituirana s jednom ili više skupina Rx kako dopušta valencija; i
R1 je
[image]
ili heteroaril ili heterocikl odabran između
[image]
[image]
[image]
5. Spoj prema zahtjevu 1, ili njegova farmaceutski prihvatljiva sol, naznačen time što je R2 odabran između
[image]
[image]
[image]
[image]
[image]
[image]
[image]
od kojih bilo koja može biti po izboru supstituirana s jednom ili više skupina Rx kako dopušta valencija; i
R1 je
[image]
ili heteroaril ili heterocikl odabran između
[image]
6. Farmaceutski pripravak naznačen time što sadrži spoj prema bilo kojem od zahtjeva 1 do 5, ili njegovu farmaceutski prihvatljivu sol, zajedno s farmaceutski prihvatljivom pomoćnom tvari, razrjeđivačem ili nosačem.
7. Farmaceutski pripravak prema zahtjevu 6 za upotrebu u liječenju raka, pri čemu je rak odabran između
(a) karcinoma, koji uključuju rak mokraćnog mjehura, dojke, debelog crijeva, rektuma, bubrega, jetre, pluća, jednjaka, žučnog mjehura, jajnika, gušterače, želuca, grlića maternice, štitnjače, prostate i kože;
(b) hematopoetskih tumora limfoidne loze, koji obuhvaćaju leukemiju, akutnu limfocitnu leukemiju, kroničnu mijelogenu leukemiju, akutnu limfoblastičnu leukemiju, B-stanični limfom, T-stanični limfom, Hodgkinov limfom, ne-Hodgkinov limfom, limfom vlasastih stanica i Burkettov limfom;
(c) hematopoetskih tumora mijeloidne loze, koji obuhvaćaju akutne i kronične mijelogene leukemije, mijelodisplastični sindrom i promijelocitnu leukemiju;
(d) tumore mezenhimalnog podrijetla, koji obuhvaćaju fibrosarkom i rabdomiosarkom, i druge sarkome, koji obuhvaćaju sarkome mekih tkiva i sarkome kostiju;
(e) tumore središnjeg i perifernog živčanog sustava, koji uključuju astrocitome, neuroblastome, gliome i švanome;
(f) melanoma, seminoma, teratokarcinoma, osteosarkoma, xenoderoma pigmentosum, keratoktantoma, folikularnog karcinoma štitnjače, Kaposijevog sarkoma, raka endometrija, raka glave i vrata, glioblastoma, maligni ascites ili hematopoetskih karcinoma.
8. Farmaceutski pripravak za upotrebu u liječenju raka prema zahtjevu 7, naznačen time što je rak identificiran kao p53 divlji tip (p53WT).
9. Spoj 2-((3R,5R,6S)-5-(3-klorofenil)-6-(4-klorofenil)-1-((S)-1-(izopropilsulfonil)-3-metilbutan-2-il)-3-metil-2-oksopiperidin-3-il) octena kiselina, ili njezina farmaceutski prihvatljiva sol za upotrebu u liječenju raka, pri čemu je rak identificiran kao p53 divlji tip (p53WT) i mutacija CDKN2A.
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