HRP20110498T1 - Azetidini kao inhibitori mek za liječenje proliferativnih bolesti - Google Patents
Azetidini kao inhibitori mek za liječenje proliferativnih bolesti Download PDFInfo
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- HRP20110498T1 HRP20110498T1 HR20110498T HRP20110498T HRP20110498T1 HR P20110498 T1 HRP20110498 T1 HR P20110498T1 HR 20110498 T HR20110498 T HR 20110498T HR P20110498 T HRP20110498 T HR P20110498T HR P20110498 T1 HRP20110498 T1 HR P20110498T1
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- optionally substituted
- alkyl
- heteroaryl
- hydrogen
- heterocycloalkyl
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- 201000010099 disease Diseases 0.000 title claims 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims 2
- 230000002062 proliferating effect Effects 0.000 title claims 2
- 150000001539 azetidines Chemical class 0.000 title 1
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims abstract 197
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract 100
- 239000001257 hydrogen Substances 0.000 claims abstract 100
- 229910052736 halogen Inorganic materials 0.000 claims abstract 82
- 150000002367 halogens Chemical class 0.000 claims abstract 82
- 150000001875 compounds Chemical class 0.000 claims abstract 79
- 125000003342 alkenyl group Chemical group 0.000 claims abstract 72
- 150000002431 hydrogen Chemical class 0.000 claims abstract 49
- 239000000203 mixture Substances 0.000 claims abstract 43
- 150000003839 salts Chemical class 0.000 claims abstract 42
- 239000012453 solvate Substances 0.000 claims abstract 42
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 40
- 125000000304 alkynyl group Chemical group 0.000 claims abstract 37
- 125000001188 haloalkyl group Chemical group 0.000 claims abstract 25
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract 23
- 125000003545 alkoxy group Chemical group 0.000 claims abstract 18
- 125000004438 haloalkoxy group Chemical group 0.000 claims abstract 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract 9
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims abstract 5
- 125000000732 arylene group Chemical group 0.000 claims abstract 2
- 125000001072 heteroaryl group Chemical group 0.000 claims 96
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims 87
- 125000000753 cycloalkyl group Chemical group 0.000 claims 53
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 46
- -1 R14 Chemical compound 0.000 claims 30
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims 26
- 125000003107 substituted aryl group Chemical group 0.000 claims 25
- 125000003118 aryl group Chemical group 0.000 claims 21
- 125000004093 cyano group Chemical group *C#N 0.000 claims 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 17
- 229910052799 carbon Inorganic materials 0.000 claims 17
- 125000003710 aryl alkyl group Chemical group 0.000 claims 14
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 10
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 claims 10
- 125000005415 substituted alkoxy group Chemical group 0.000 claims 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 5
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims 4
- 125000004104 aryloxy group Chemical group 0.000 claims 4
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims 4
- 125000000547 substituted alkyl group Chemical group 0.000 claims 4
- 101100451196 Caenorhabditis elegans hizr-1 gene Proteins 0.000 claims 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims 3
- 229910052731 fluorine Inorganic materials 0.000 claims 3
- 239000011737 fluorine Substances 0.000 claims 3
- 206010028980 Neoplasm Diseases 0.000 claims 2
- 125000005092 alkenyloxycarbonyl group Chemical group 0.000 claims 2
- 201000011510 cancer Diseases 0.000 claims 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 2
- 239000000945 filler Substances 0.000 claims 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- 208000001446 Anaplastic Thyroid Carcinoma Diseases 0.000 claims 1
- 206010002240 Anaplastic thyroid cancer Diseases 0.000 claims 1
- 206010006187 Breast cancer Diseases 0.000 claims 1
- 208000026310 Breast neoplasm Diseases 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 206010009944 Colon cancer Diseases 0.000 claims 1
- 206010014733 Endometrial cancer Diseases 0.000 claims 1
- 206010014759 Endometrial neoplasm Diseases 0.000 claims 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 1
- 206010033128 Ovarian cancer Diseases 0.000 claims 1
- 206010061535 Ovarian neoplasm Diseases 0.000 claims 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims 1
- 208000015634 Rectal Neoplasms Diseases 0.000 claims 1
- 206010041067 Small cell lung cancer Diseases 0.000 claims 1
- 125000005090 alkenylcarbonyl group Chemical group 0.000 claims 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims 1
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims 1
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims 1
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims 1
- 125000005605 benzo group Chemical group 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 229910052801 chlorine Chemical group 0.000 claims 1
- 239000000460 chlorine Chemical group 0.000 claims 1
- 208000029742 colonic neoplasm Diseases 0.000 claims 1
- 125000005170 cycloalkyloxycarbonyl group Chemical group 0.000 claims 1
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 125000001153 fluoro group Chemical group F* 0.000 claims 1
- 125000005549 heteroarylene group Chemical group 0.000 claims 1
- 238000000338 in vitro Methods 0.000 claims 1
- 230000005764 inhibitory process Effects 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 208000014294 lung papilloma Diseases 0.000 claims 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims 1
- 201000001441 melanoma Diseases 0.000 claims 1
- 238000000034 method Methods 0.000 claims 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims 1
- 201000002528 pancreatic cancer Diseases 0.000 claims 1
- 208000008443 pancreatic carcinoma Diseases 0.000 claims 1
- 206010038038 rectal cancer Diseases 0.000 claims 1
- 201000001275 rectum cancer Diseases 0.000 claims 1
- 208000000587 small cell lung carcinoma Diseases 0.000 claims 1
- 208000019179 thyroid gland undifferentiated (anaplastic) carcinoma Diseases 0.000 claims 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims 1
Classifications
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- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
-
- 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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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
- C07D401/02—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
- C07D401/06—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 carbon chain containing only aliphatic carbon atoms
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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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- C07D405/12—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 linked by a chain containing hetero atoms as chain links
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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
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- C07D409/06—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 carbon chain containing only aliphatic carbon atoms
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- 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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- C07D417/12—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 chain containing hetero atoms as chain links
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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
Abstract
Spoj formule I: ili pojedinačni stereoizomer ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat, naznačen time što su A, X, R1, R2, R3, R4, R5, R6 i R7 kako je definirano za grupu A, grupu B, grupu C ili grupu D: Grupa A: A je arilen po izboru supstituiran s jednom, dvije, tri ili četiri skupine izabrane između R10, R12, R14 iR16 gdje su R1O, R12, R14 i R16 nezavisno jedan od drugog vodik, alkil, alkenil, alkinil, halogen, halogenalkoksi, hidroksi, alkoksi, amino, alkilamino, dialkilamino, halogenalkil, -NHS(O)2R8, -CN, -C(O)R8, -C(O)OR8, -C(O)NR8R8' i -NR8C(O)R8'; X je alkil, halogen, halogenalkil ili halogenalkoksi; R1, R2, R3, R4, R5 i R6 su nezavisno vodik, halogen, nitro, NR8R8', -OR8, -NHS(O)2R8, -CN, -S(O)mR8,
Claims (43)
1. Spoj formule I:
[image]
ili pojedinačni stereoizomer ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat, naznačen time što su A, X, R1, R2, R3, R4, R5, R6 i R7 kako je definirano za grupu A, grupu B, grupu C ili grupu D:
Grupa A:
A je arilen po izboru supstituiran s jednom, dvije, tri ili četiri skupine izabrane između R10, R12, R14 iR16 gdje su R1O, R12, R14i R16 nezavisno jedan od drugog vodik, alkil, alkenil, alkinil, halogen, halogenalkoksi, hidroksi, alkoksi, amino, alkilamino, dialkilamino, halogenalkil, -NHS(O)2R8, -CN, -C(O)R8, -C(O)OR8, -C(O)NR8R8' i -NR8C(O)R8';
X je alkil, halogen, halogenalkil ili halogenalkoksi;
R1, R2, R3, R4, R5 i R6 su nezavisno vodik, halogen, nitro, NR8R8', -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8', -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)OR8', -NR8C(O)NR8'R8", -NR8C(O)OR8', -NR8C(O)R8', -CH2N(R25)(NR25aR25b), -CH2NR25C(=NH)(NR25aR25b),-CH2NR25C(=NH)(N(R25)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)),-CH2NR25C(=NH)(R25), -CH2NR25C(NR25aR25b)=CH(NO2), alkil, alkenil, alkinil, cikloalkil, heteroaril ili heterocikloalkil; gdje su alkil, alkenil, alkinil, cikloalkil, heteroaril i heterocikloalkil nezavisno po izboru supstituirani s jednom. dvije, tri, četiri, pet, šest ili sedam skupina nezavisno izabranih između halogena, alkil, halogenalkil, nitro, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil, po izboru supstituirani aril, po izboru supstituirani arilaikil, po izboru supstituirani heteroaril, -OR8, -NR8R8', -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)NR8'R8",-NR8C(O)OR8' i -NR8C(O)R8'; ili jedan od R1 i R2 zajedno s ugljikom na koji su spojeni, R3 i R4 zajedno s ugljikom na koji su spojeni, i R5 i R6 zajedno s ugljikom na koji su spojeni čine C(O) ili C(=NOH);
m je 0, 1 ili 2;
R7 je vodik, halogen ili alkil;
R8, R8' i R8'' su nezavisno izabrani između vodika, hidroksi, po izboru supstituirani alkoksi, alkil, alkenil, alkinil, aril, cikloalkil, heteroaril, i heterocikloalkil; gdje alkil, alkenil, alkinil, aril, cikloalkil, heteroaril, i heterocikloalkil su nezavisno po izboru supstituiran s jednom, dvije, tri, četiri ili pet skupina nezavisno izabranih između alkil, halogen, hidroksi, hidroksialkil, po izboru supstituirani alkoksi, alkoksialkil, halogenalkil, karboksi, alkoksikarbonil, alkeniloksikarbonil, po izboru supstituirani cikloalkil, po izboru supstituirani cikloalkiloksikarbonil, po izboru supstituirani aril, po izboru supstituirani ariloksi, po izboru supstituirani ariloksikarbonil, po izboru supstituirani arilaikii, po izboru supstituirani arilalkiloksi, po izboru supstituirani arilalkiloksikarbonil, nitro, cijano, po izboru supstituirani heterocikloalkil, po izboru supstituirani heteroaril, -S(O)nR31 (gdje n je 0, 1 ili 2 i R31 je po izboru supstituirani alkil, po izboru supstituirani aril, po izboru supstituirani heterocikloalkil ili po izboru supstituirani heteroaril), -NR34SO2R34a (gdje R34 je vodik ili alkil i R34a je alkil, alkenil, cikloalkil, aril, heteroaril ili heterocikloalkil), -SO2NR35R35a (gdje R35 je vodik ili alkil i R35a je alkil, alkenil, cikloalkil, aril, heteroaril ili heterocikloalkil), -NR32C(O)R32a (gdje R32 je vodik ili alkil i R32a je alkil, alkenil, alkoksi ili cikloalkil), -NR30R30' (gdje R30 i R30' su nezavisno vodik, alkil ili hidroksialkil), i -C(O)NR33R33a(gdje R33 je vodik ili alkil i R33a je alkil, alkenil, alkinil ili cikloalkil); i
R9 je alkil, alkenil, alkinil, aril, cikloalkil, heteroaril, i heterocikloalkil; gdje alkil, alkenil, alkinil, aril, cikloalkil, heteroaril, i heterocikloalkil su nezavisno po izboru supstituirani jednom, dvije, tri, četiri ili pet skupina izabranih između halogena, hidroksi, alkil, halogenalkil, halogenalkoksi, amino, alkilamino, i dialkilamino;
R25i R25b su nezavisno vodik, alkil, alkenil, po izboru supstituirani cikloalkil ili po izboru supstituirani aril; i
R25a je vodik, alkil ili alkenil;
Grupa B:
A je heteroarilen po izboru supstituiran s jednom, dvije, tri ili četiri skupine izabrane između R10, R12, R14, R16 i R19 gdje R10, R12, R14i R16 su nezavisno vodik, alkil, alkenil, alkinil, halogen, halogenalkoksi, hidroksi, alkoksi, cijano, amino, alkilamino, dialkilamino, halogenalkil, alkilsulfonilamino, alkilkarbonil, alkenilkarbonil, alkoksikarbonil, alkeniloksikarbonil, aminokarbonil, alkilaminokarbonil, dialkilaminokarbonil ili alkilkarbonilamino; gdje R19 je vodik, alkil ili alkenil; i gdje je svaki alkil i alkenil, sam ili kao dio druge skupine unutar R10, R12, R14, R16, i R19 nezavisno po izboru supstituiran s halogenom, hidroksi ili alkoksi;
X je alkil, halogen, halogenalkil ili halogenalkoksi;
R1, R2, R3, R4, R5 i R6 su nezavisno vodik, halogen, nitro, -NR8R8', -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8', -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)OR8', -NR8C(O)NR8'R8", -NR8C(O)OR8', -NR8C(O)R8', alkil, alkenil, alkinil, cikloalkil, heteroaril ili heterocikloalkil, gdje su alkil, alkenil, alkinil, cikloalkil, heteroaril, i heterocikloalkil nezavisno po izboru supstituirani s jednom, dvije, tri, četiri, pet, šest ili sedam skupina nezavisno izabranih između halogen, alkil, halogenalkil, nitro, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil, po izboru supstituirani aril, po izboru supstituirani arilaikil, po izboru supstituirani heteroaril, -OR8, -NR8R8', -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)NR8'R8", -NR8C(O)OR8' i -NR8C(O)R8'; ili jedan od R1 i R2 zajedno s ugljikom na koji su spojeni, R3 i R4 zajedno s ugljikom na koji su spojeni, i R5 i R6 zajedno s ugljikom na koji su spojeni čine C(O) ili C(=NOH);
m je 1 ili 2;
R7 je vodik, halogen ili alkil; i
R8, R8' i R8" su nezavisno izabrani između vodika, hidroksi, po izboru supstituirani alkoksi, alkil, halogenalkil, alkenil, alkinil, aril, cikloalkil, heteroaril, i heterocikloalkil, gdje su alkil, alkenil, alkinil, aril, cikloalkil, heteroaril, i heterocikloalkil nezavisno po izboru supstituiran s jednom, dvije, tri, četiri ili pet skupina nezavisno izabranih između alkil, halogen, hidroksi, hidroksialkil, po izboru supstituirani alkoksi, alkoksialkil, halogenalkil, karboksi, karboksi ester, nitro, cijano, -S(O)nR31 (gdje n je 0, 1 ili 2 i R31 je po izboru supstituirani alkil, po izboru supstituirani aril, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil ili po izboru supstituirani heteroaril), -NR36S(O)2R36a (gdje R36 je vodik, alkil ili alkenil i R36a je alkil, alkenil, po izboru supstituirani aril, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil ili po izboru supstituirani heteroaril), -S(O)2NR37R37a (gdje R37 je vodik, alkil ili alkenil i R37a je alkil, alkenil, po izboru supstituirani aril, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil ili po izboru supstituirani heteroaril), po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil, po izboru supstituirani aril, po izboru supstituirani arilalkil, po izboru supstituirani ariloksi. do izboru supstituirani arilalkiloksi, po izboru supstituirani heteroaril, -NHC(O)R32 (gdje R32 je alkil, alkenil, alkoksi ili cikloalkil) i -NR30R30' (gdje R30 i R30' su nezavisno vodik, alkil ili hidroksialkil), i -C(O)NHR33 (gdje R33 je alkil, alkenil, alkinil ili cikloalkil);
Grupa C:
[image]
gdje je R10 vodik, alkil, alkenil, alkinil, halogen, halogenalkoksi, hidroksi, alkoksi, amino, alkilamino, dialkilamino, halogenalkil, -NHS(O)2R8, -CN, -C(O)R8, -C(O)OR8, -C(O)NR8R8' i -NR8C(O)R8';
R10a je vodik, alkil ili alkenil;
Y1 je =CH- ili =N-;
X je alkil, halogen, halogenalkil ili halogenalkoksi;
R1, R2, R3, R4, R5 i R6 su nezavisno vodik, halogen, nitro, -NR8R8', -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8', -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)OR8', -NR8C(O)NR8'R8", -NR8C(O)OR8', -NR8C(O)R8', alkil, alkenil, alkinil, cikloalkil, heteroaril ili heterocikloalkil, gdje su alkil, alkenil, alkinil, cikloalkil, heteroaril, i heterocikloalkil nezavisno po izboru supstituirani s jednom, dvije, tri, četiri, pet, šest ili sedam skupina nezavisno izabranih između halogen, alkil, halogenalkil, nitro, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil, po izboru supstituirani aril, po izboru supstituirani arilalkil, po izboru supstituirani heteroaril, -OR8, -NR8R8', -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)NR8'R8", -NR8C(O)OR8' i -NR8C(O)R8'; ili jedan od R1 i R2 zajedno s ugljikom na koji su spojeni, R3 i R4 zajedno s ugljikom na koji su spojeni, i R5 i R6 zajedno s ugljikom na koji su spojeni čine C(O) ili C(=NOH);
m je 1 ili 2;
R7 je vodik, halogen ili alkil; i
R8, R8' i R8'' su nezavisno izabrani između vodika, hidroksi, po izboru supstituirani alkoksi, alkil, halogenalkil, alkenil, alkinil, aril, cikloalkil, heteroaril, i heterocikloalkil, gdje su alkil, alkenil, alkinil, aril, cikloalkil, heteroaril, i heterocikloalkil nezavisno po izboru supstituirani s jednom, dvije, tri, četiri ili pet skupina nezavisno izabranih između alkil, halogen, hidroksi, hidroksialkil, po izboru supstituirani alkoksi, alkoksialkil, halogenalkil, karboksi, karboksi ester, nitro, cijano, -S(O)nR31 (gdje n je 0, 1 ili 2 i R31 je po izboru supstituirani alkil, po izboru supstituirani aril, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil ili po izboru supstituirani heteroaril), -NR36S(O)2R36a (gdje R36 je vodik, alkil ili alkenil i R36a je alkil, alkenil, po izboru supstituirani aril, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil ili po izboru supstituirani heteroaril), -S(O)2NR37R37a (gdje R37 je vodik, alkil ili alkenil i R37a je alkil, alkenil, po izboru supstituirani aril, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil ili po izboru supstituirani heteroaril), po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil, po izboru supstituirani aril, po izboru supstituirani arilalkil, po izboru supstituirani ariloksi, po izboru supstituirani arilalkiloksi, po izboru supstituirani heteroaril, -NHC(O)R32 (gdje R32 je alkil, alkenil, alkoksi ili cikloalkil) i -NR30R30' (gdje R30 i R30' su nezavisno vodik, alkil ili hidroksialkil), i -C(O)NHR33 (gdje R33 je alkil, alkenil, alkinil ili cikloalkil); ili
Grupa D:
A e
[image]
R40 i R40a su nezavisno vodik ili alkil;
X je alkil, halogen, halogenalkil ili halogenalkoksi;
R1, R2, R3, R4, R5 i R6 su nezavisno vodik, halogen, nitro, -NR8R8', -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8', -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)OR8', -NR8C(O)NR8'R8", -NR8C(O)OR8', -NR8C(O)R8', alkil, alkenil, alkinil, cikloalkil, heteroaril ili heterocikloalkil, gdje su alkil, alkenil, alkinil, cikloalkil, heteroaril, i heterocikloalkil nezavisno po izboru supstituirani s jednom, dvije, tri, četiri, pet, šest ili sedam skupina nezavisno izabranih između halogen, alkil, halogenalkil, nitro, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil, po izboru supstituirani aril, po izboru supstituirani arilaikil, po izboru supstituirani heteroaril, -OR8, -NR8R8', -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)NR8'R8", -NR8C(O)OR8' i -NR8C(O)R8'; ili jedan od R1 i R2 zajedno s ugljikom na koji su spojeni, R3 i R4 zajedno s ugljikom na koji su spojeni, i R5 i R6 zajedno s ugljikom na koji su spojeni čine C(O) ili C(=NOH);
m je 1 ili 2;
R7 je vodik, halogen ili alkil; i
R8, R8' i R8'' su nezavisno izabrani između vodik, hidroksi, po izboru supstituirani alkoksi, alkil, halogenalkil, alkenil, alkinil, aril, cikloalkil, heteroaril, i heterocikloalkil, gdje su alkil, alkenil, alkinil, aril, cikloalkil, heteroaril, i heterocikloalkil nezavisno po izboru supstituiran s jednom, dvije, tri, četiri ili pet skupina nezavisno izabranih između alkil, halogen, hidroksi, hidroksialkil, po izboru supstituirani alkoksi, alkoksialkil, halogenalkil, karboksi, karboksi ester, nitro, cijano, -S(O)nR31 (gdje n je 0, 1 ili 2 i R31 je po izboru supstituirani alkil, po izboru supstituirani aril, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil ili po izboru supstituirani heteroaril), -NR36S(O)2R36a (gdje R36 je vodik, alkil ili alkenil i R36a je alkil, alkenil, po izboru supstituirani aril, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil ili po izboru supstituirani heteroaril), -S(O)2NR37R37a (gdje R37 je vodik, alkil ili alkenil i R37a je alkil, alkenil, po izboru supstituirani aril, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil ili po izboru supstituirani heteroaril), po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil, po izboru supstituirani aril, po izboru supstituirani arilaikil, po izboru supstituirani ariloksi, po izboru supstituirani arilalkiloksi, po izboru supstituirani heteroaril, -NHC(O)R32 (gdje R32 je alkil, alkenil, alkoksi ili cikloalkil) i -NR30R30' (gdje R30 i R30' su nezavisno vodik, alkil ili hidroksialkil), i -C(O)NHR33 (gdje R33 je alkil, alkenil, alkinil ili cikloalkil).
2. Spoj prema zahtjevu 1, naznačen time što je izabran između Grupe A, Grupe B i Grupe C gdje
Grupa A
A je fenilen po izboru supstituiran s jednom ili dvije skupine izabrane između R10, R12, R14 i R16 gdje R10, R12, R14 i R16 su nezavisno vodik ili halogen;
X je halogen;
R1, R2, R5i R6 su vodik;
R3 je vodik, halogen, hidroksi, alkoksi ili amino;
R4 je vodik, -NR8R8', -C(O)NR8R8', -NR8C(O)OR8', -NR8C(O)R8', -CH2N(R25)(NR25aR25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR25C(=NH)(N(R25a)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR25C(=NH)(R25), -CH2NR25C(NR25aR25b)=CH(NO2), alkil, alkenil, cikloalkil, heterocikloalkil ili heteroaril; gdje je alkil po izboru supstituiran jednom, dvije ili tri skupine nezavisno izabrane između -OR8, halogen, nitro, -S(O)mR9, po izboru supstituirani heterocikloalkil, -NR8R8', -NR8C(O)R8', -NR8S(O)2R9, -NR8C(O)OR8', i aril; gdje je cikloalkil po izboru supstituiran jednom ili dvije skupine izabrane između -OR8 i -NR8R8'; gdje je heterocikloalkil po izboru supstituiran s jednom ili dvije skupine nezavisno izabrane između alkil i -C(O)OR8; i gdje je heteroaril po izboru supstituiran s _NR8R8'; ili
R3 i R4 zajedno s ugljikom na koji su spojeni čine C(O) ili C(=NOH);
m je 0;
R7je halogen;
R8 i R8' su nezavisno izabrani između vodik, hidroksi, alkil, alkenil, alkinil, aril, heterocikloalkil, heteroaril, i cikloalkil;
gdje su R8 i R8' alkil nezavisno po izboru supstituiran s jednom, dvije ili tri skupine nezavisno izabrane između hidroksi, -NR30R30' (gdje R30 i R30 su nezavisno vodik, alkil ili hidroksialkil), po izboru supstituirani heteroaril, po izboru supstituirani cikloalkil), po izboru supstituirani alkoksi, po izboru supstituirani cikloalkil, po izboru supstituirani aril, po izboru supstituirani heterocikloalkil, po izboru supstituirani heteroaril, -C(O)NR33R33a (gdje R33 je vodik ili alkil i R33a je alkil, alkenil, alkinil ili cikloalkil), po izboru supstituirani ariloksi, -S(O)nR31 (gdje n je O i R31 je alkii), karboksi, alkoksikarbonil, i _NR32C(O)R32a (gdje R32 je vodik ili alkil i R32a je alkil, alkenil, alkoksi ili cikloalkil); ili gdje alkil je po izboru supstituiran s jednim, dva, tri, četiri ili pet halogena;
gdje su R8 i R8' heteroaril nezavisno po izboru supstituiran s jednom ili dvije skupine nezavisno izabrane između amino i alkil;
gdje su R8 i R8' heterocikloalkil nezavisno po izboru supstituiran s jednom, dvije ili tri skupine nezavisno izabrane između alkil, alkoksikarbonil, po izboru supstituirani arilaikii, hidroksi, alkoksi, i hidroksialkil;
gdje su R8 i R8'aril nezavisno po izboru supstituiran s jednom ili dvije skupine nezavisno izabrane između hidroksi, alkoksi, halogen, -NR32C(O)R32a (gdje R32 je vodik ili alkil i R32a je alkil, alkenil, alkoksi ili cikloalkil), i -NR34SO2R34a (gdje R34 je vodik ili alkil i R34a je alkil, alkenil, cikloalkil, aril, heteroaril ili heterocikloalkil); i
gdje su R8 i R8' cikloalkil nezavisno po izboru supstituiran s jednom, dvije ili tri skupine nezavisno izabrane između hidroksi, hidroksialkil, alkoksi, karboksi, -C(O)NR33R33a (gdje R33 je vodik ili alkil i R33a je alkil, alkenil, alkinil ili cikloalkil), i po izboru supstituirani cikloalkil; i
R9 je alkil ili aril;
Grupa B
A je tien-3,4-diil, benzo[d]izoksazol-5,6-diil, 1H-indazol-5,6-diil (po izboru supstituirani na N1 položaju s R19 gdje R19 je alkil ili alkenil), benzo[d]oksazol-5,6-diil, 1H-benzo[d]imidazol-5,6-diil (po izboru supstituirani na N1 položaju s R19 gdje R19 je alkil ili alkenil), 1H-benzo[d][1,2,3]triazol-5,6-diil (po izboru supstituirani na N1 položaju s R19 gdje R19 je alkil ili alkenil), imidazo[1,2-a]piridin-6,7-diil, cinnolin-6,7-diil, kinolin-6,7-diil, piridin-3,4-diil, 1-oksido-piridin-3,4-diil, [1,2,4]triazolo[4,3-a]piridin-6,7-diil ili 2,3-dihidroimidazo[1,2-a]piridin-6,7-diil; gdje A je po izboru supstituiran s jednom, dvije ili tri skupine nezavisno izabrane između R10, R12, R14, R16 i R19 gdje R10, R12, R14i R16 su nezavisno vodik, alkil, halogen ili amino; i R19 je vodik ili alkil;
X je halogen;
R1, R2, R5 i R6 su vodik;
R3je vodik ili hidroksi;
R4 je -NR8R8', heterocikloalkil, heteroaril ili alkil; gdje je alkil po izboru supstituiran s -NR8R8' i gdje je heteroaril po izboru supstituiran s alkilom;
R7je halogen;
R8 je vodik ili alkil; i
R8'je vodik, alkil ili cikloalkil; gdje cikloalkil je po izboru supstituiran s jednom ili dvije skupine nezavisno izabrane između hidroksi i alkil;
Grupa C
A je
[image]
R10 je vodik ili halogen;
R10a je vodik ili alkil;
Y1 je =CH- ili =N-;
X je halogen;
R1, R2, R5i R6 su vodik;
R3 je vodik ili hidroksi;
R4 je -NR8R8', heterocikloalkil, heteroaril ili alkil; gdje alkil je po izboru supstituiran s -NR8R8' i gdje heteroaril je po izboru supstituiran s alkilom;
R7je halogen;
R8 je vodik ili alkil; i
R8' je vodik, alkil ili cikloalkil; gdje cikloalkil je po izboru supstituiran s jednom ili dvije skupine nezavisno izabrane između hidroksi i alkil; ili
pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
3. Spoj prema zahtjevu 1, naznačen time što je R3 halogen, nitro, -NR8R8', -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8', -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)OR8', -NR8C(O)NR8'R8", -NR8C(O)OR8', -NR8C(O)R8', -CH2N(R25)(NR25aR25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR25C(=NH)(N(R25a)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR25C(=NH)(R25), -CH2NR25C(NR25aR25b)=CH(NO2), alkil, alkenil, alkinil, cikloalkil, heteroaril ili heterocikloalkil; gdje alkil, alkenil, alkinil, cikloalkil, heteroaril, i heterocikloalkil su nezavisno po izboru supstituirani s jednom, dvije, tri, četiri, pet, šest ili sedam skupina nezavisno izabranih između halogen, alkil, halogenalkil, nitro, po. izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil, po izboru supstituirani aril, po izboru supstituirani arilaikii, po izboru supstituirani heteroaril, po izboru supstituirani heteroarilalkil, -OR8, -NR8R8', -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)NR8'R8", -NR8C(O)OR8' i -NR8C(O)R8'; i R4 je kako je defniran u zahtjevu 1; ili R3 i R4 zajedno s ugljikom na koji su spojeni čine C(O) ili C(=NOH); ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
4. Spoj prema zahtjevu 1, naznačen time što R3 i R4 su nezavisno halogen, nitro, -NR8R8', -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8', -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)OR8', -NR8C(O)NR8'R8", -NR8C(O)OR8', -NR8C(O)R8', -CH2N(R25)(NR25aR25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR25C(=NH)(N(R25a)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR25C(=NH)(R25), -CH2NR25C(NR25aR25b)=CH(NO2), alkil, alkenil, alkinil, cikloalkil, heteroaril ili heterocikloalkil; gdje alkil, alkenil, alkinil, cikloalkil, heteroaril, i heterocikloalkil su nezavisno po izboru supstituirani s jednom, dvije, tri, četiri, pet, šest ili sedam skupina nezavisno izabranih između halogen, alkil, halogenalkil, nitro, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil, po izboru supstituirani aril, po izboru supstituirani arilaikil, po izboru supstituirani heteroaril, po izboru supstituirani heteroarilalkil, -OR8, -NR8R8', -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)NR8'R8", -NR8C(O)OR8' i -NR8C(O)R8'; ili R3 i R4 zajedno s ugljikom na koji su spojeni čine C(O) ili C(=NOH); ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
5. Spoj prema zahtjevu 1, naznačen time što R7 je halogen; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
6. Spoj prema zahtjevu 1, naznačen time što X je halogen; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
7. Spoj prema zahtjevu 1, naznačen time što R1, R2, R5 i R6 su vodik; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
8. Spoj prema zahtjevu 1, naznačen time što je izabran između Grupe A gdje A je fenilen; i R4 je -NR8R8' (gdje R8 je vodik, hidroksi, alkil, alkoksi, aril, cikloalkil, heteroaril ili heterocikloalkil i R8' je hidroksi, alkoksi, aril, cikloalkil, heteroaril ili heterocikloalkil), -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8', -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)OR8', -NR8C(O)NR8'R8", -NR8C(O)OR8', -NR8C(O)R8', -CH2N(R25)(NR25aR25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR25C(=NH)(N(R25a)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR25C(=NH)(R25), -CH2NR25C(NR25aR25b)=CH(NO2), alkenil ili alkinil; gdje su alkenil i alkinil po izboru supstituirani s jednom, dvije, tri, četiri, pet, šest ili sedam skupina nezavisno izabranih između halogen, alkil, halogenalkil, nitro, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil, po izboru supstituirani aril, po izboru supstituirani arilaikii, po izboru supstituirani heteroaril, po izboru supstituirani heteroarilalkil, -OR8, -NR8R8', -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C(O)NR8R8',-NR8C(O)NR8'R8", -NR8C(O)OR8' i -NR8C(O)R8'; ili R3 i R4 zajedno s ugljikom na koji su spojeni čine C(O) ili C(=NOH); ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
9. Spoj prema zahtjevu 1, naznačen time što R3 je vodik, halogen, hidroksi, amino ili alkoksi; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
10. Spoj prema zahtjevu 1, naznačen time što R4 je vodik, -NR8R8', -C(O)NR8R8', -NR8C(O)OR8', -NR8C(O)R8', -CH2N(R25)(NR25aR25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR25C(=NH)(N(R25a)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR25C(=NH)(R25), -CH2NR25C(NR25aR25b)=CH(NO2), alkil, alkenil, cikloalkil, heterocikloalkil ili heteroaril; gdje je alkil po izboru supstituiran s jednom, dvije ili tri -OR8, halogen, nitro, -S(O)mR9, po izboru supstituirani heterocikloalkil, -NR8R8', -NR8C(O)R8', -NR8S(O)2R9, -NR8C(O)OR8', aril; gdje je cikloalkil po izboru supstituiran s jednom ili dvije -NR8R8'; gdje heterocikloalkil je po izboru supstituiran s jednom ili dvije skupine nezavisno izabrane između alkil i -C(O)OR8; i gdje je heteroaril po izboru supstituiran s -NR8R8'; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
11. Spoj prema zahtjevu 1, naznačen time što je izabran između Grupe A gdje A je fenilen po izboru supstituiran s jednom ili dvije skupine nezavisno izabrane između R10, R12, R14 i R16 gdje R10, R12, R14 i R16 su nezavisno vodik ili halogen; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
12. Spoj prema zahtjevu 1, naznačen time što je izabran između Grupe A gdje A je fenilen; R3 je vodik; i R4 je vodik, -NR8R8', -C(O)NR8R8', -NR8C(O)OR8', -NR8C(O)R8', alkil ili heterocikloalkil; gdje je alkil po izboru supstituiran s jednom ili dvije skupine nezavisno izabrane između -OR8 i -NR8R8'; i gdje heterocikloalkil je po izboru supstituiran s -NR8R8'; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
13. Spoj prema zahtjevu 1, naznačen time što je izabran između Grupe A gdje A je fenilen; R3 je alkoksi; i R4 je alkil ili heterocikloalkil gdje je alkil supstituiran s -NR8R8'; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
14. Spoj prema zahtjevu 1, naznačen time što je izabran između Grupe A gdje A je fenilen; R3 je halogen; i R4 je alkil ili heterocikloalkil gdje je alkil supstituiran s -NR8R8'; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
15. Spoj prema zahtjevu 1, naznačen time što je izabran između Grupe A gdje A je fenilen i R3 i R4 zajedno s ugljikom na koji su spojeni čine C(O) ili C(=NOH); ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
16. Spoj prema zahtjevu 1, naznačen time što je izabran između Grupe A gdje A je fenilen; R3 je hidroksi; i R4 je vodik, -C(O)NR8R8', -CH2N(R25)(NR25aR25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR25C(=NH)(N(R25a)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR25C(=NH)(R25), -CH2NR25C(NR25aR25b)=CH(NO2), alkil, alkenil, heterocikloalkil, cikloalkil, heterocikloalkil ili heteroaril; gdje je alkil po izboru supstituiran s jednom, dvije ili tri skupine izabrane između -OR8, halogen, nitro, -S(O)mR9, po izboru supstituirani heterocikloalkil, -NR8R8', -NR8C(O)R8', po izboru supstituirani heteroaril, -NR8S(O)2R9, -NR8C(O)OR8', i aril; gdje cikloalkil je po izboru supstituiran s jednom ili dvije skupine nezavisno izabrane između -NR8R8' i -C(O)NR33R33a; gdje heterocikloalkil je po izboru supstituiran s jednom, dvije ili tri skupine nezavisno izabrane između alkil i -C(O)OR8; i gdje heteroaril je po izboru supstituiran s -NR8R8'; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
17. Spoj prema zahtjevu 1, naznačen time što je izabran između Grupe A gdje A je fenilen; R7 je jod ili brom; X je fluor ili klor; i R1, R2, R5 i R6 su vodik; i R10, R12, R14 i R16 su nezavisno vodik ili fluor; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
18. Spoj prema zahtjevu 17, naznačen time što R10 je 3-fluor i R12, R14 i R16 su vodik ili halogen; R10 je 3-fluor, R12 je 4-fluor, i R14 i R16 su vodik; R10 je 4-fluor, R12 je 5-fluor, i R14 i R16 su vodik; R10 je 4-fluor, R12 je 6-fluor, i R14 i R16 su vodik; ili R12 je 4-fluor i R10, R14, i R16 su vodik; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
19. Spoj prema zahtjevu 1, naznačen time što je izabran između Grupe A gdje A je fenilen i R3je hidroksi; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
20. Spoj prema zahtjevu 19, naznačen time što R4 je -C(O)NR8R8', -CH2N(R2S)(NR25aR25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR25C(=NH)(N(R25a)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR25C(=NH)(R25), -CH2NR25C(NR25aR25b)=CH(NO2), alkil, cikloalkil, heterocikloalkil ili heteroaril; gdje su alkil, cikloalkil, heteroaril, i heterocikloalkil nezavisno po izboru supstituirani s jednom, dvije, tri ili četiri skupine nezavisno izabrane između halogena, alkil, halogenalkil, nitro, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil, po izboru supstituirani aril, po izboru supstituirani arilalkil, po izboru supstituirani heteroaril, po izboru supstituirani heteroarilalkil, -OR8, -NR8R8', -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)NR8'R8", -NR8C(O)OR8' i -NR8C(O)R8'; ili gdje je alkil po izboru supstituiran s jednim, dva, tri, četiri, pet, šest ili sedam halogena; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
21. Spoj prema zahtjevu 20, naznačen time što R4 je alkil, heterocikloalkil ili heteroaril; gdje je alkil po izboru supstituiran s -NR8R8'; gdje heterocikloalkil je po izboru supstituiran s alkil ili -C(O)OR8; i gdje heteroaril je po izboru supstituiran s alkilom; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
22. Spoj prema zahtjevu 1, naznačen time što R1 je halogen, nitro, -NR8R8', -OR8, -NHS(O)2R8, -CN, -S(O)mR8, -S(O)2NR8R8', -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)OR8', -NR8C(O)NR8'R8", -NR8C(O)OR8', -NR8C(O)R8', -CH2N(R25)(NR25aR25b), -CH2NR25C(=NH)(NR25aR25b), -CH2NR25C(=NH)(N(R25a)(NO2)), -CH2NR25C(=NH)(N(R25a)(CN)), -CH2NR25C(=NH)(R25) ili -CH2NR25C(NR25aR25b)=CH(NO2), alkil, alkenil, alkinil, cikloalkil, heteroaril ili heterocikloalkil; gdje the alkil, alkenil, alkinil, cikloalkil, heteroaril ili heterocikloalkil su nezavisno po izboru supstituirani s jednom, dvije, tri, četiri, pet, šest ili sedam skupina nezavisno izabranih između halogen, alkil, halogenalkil, nitro, po izboru supstituirani cikloalkil, po izboru supstituirani heterocikloalkil, po izboru supstituirani aril, po izboru supstituirani arilaikil, po izboru supstituirani heteroaril, -OR8, -NR8R8', -NR8S(O)2R9, -CN, -S(O)mR9, -C(O)R8, -C(O)OR8, -C(O)NR8R8', -NR8C(O)NR8'R8", -NR8C(O)OR8' i -NR8C(O)R8'; R3 je hidroksi; i R4 je heterocikloalkil, alkil ili heteroaril, gdje je alkil po izboru supstituiran s -NR8R8' i gdje heteroaril je po izboru supstituiran s alkilom; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
23. Spoj prema zahtjevu 1, naznačen time što je izabran između Grupe B gdje A je tien-3,4-diil, benzo[d]izoksazol-5,6-diil, 1H-indazol-5,6-diil (po izboru supstituirani na N1 položaju s R19 gdje R19 je alkil ili alkenil), benzo[d]oksazol-5,6-diil, 1 H-benzo[d]imidazol-5,6-diil (po izboru supstituirani na N1 položaiu s R19 gdje R19 je alkil ili alkenil), 1H-benzo[d][1,2,3]triazol-5,6-diil (po izboru supstituirani na N1 položaju s R19 gdje R19 je alkil ili alkenil), imidazo[1,2-a]piridin-6,7-diil, cinnolin-6,7-diil, kinolin-6,7-diil, piridin-3,4-diil, 1-oksido-piridin-3,4-diil, [1,2,4]triazolo[4,3-a]piridin-6,7-diil ili 2,3-dihidroimidazo[1,2-a]piridin-6,7-diil; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
24. Spoj prema zahtjevu 1, naznačen time što A je tien-3,4-diil; R10 i R12 su vodik; X i R7 su halogen; i R1, R2, R5, i R6 su vodik; ili stereoizomer tog spoja ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
25. Spoj prema zahtjevu 24, naznačen time što R3 je vodik ili hidroksi; i R4 je -NR8R8', heterocikloalkil, heteroaril ili alkil, gdje je alkil po izboru supstituiran s -NR8R8'; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
26. Spoj prema zahtjevu 1, naznačen time što je izabran između Grupe B gdje A je benzo[d]izoksazol-5,6-diil; R10, R12, i R14 su nezavisno vodik, halogen ili alkil; R1, R2, R5, i R6 su vodik; X i R7 su halogen; R3 je hidroksi; i R4 je heterocikloalkil, alkil ili heteroaril, gdje je alkil po izboru supstituiran s -NR8R8' i gdje heteroaril je po izboru supstituiran s alkilom; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
27. Spoj prema zahtjevu 23 prema formuli I(g) ili I(h):
[image]
naznačen time što R10, R12 i R14 su nezavisno vodik, halogen ili alkil; R19 je alkil ili alkenil; R1, R2, R5, i R6 su vodik; X i R7 su halogen; R3 je hidroksi; i R4 je heterocikloalkil, alkil ili heteroaril, gdje je alkil po izboru supstituiran s -NR8R8' i gdje je heteroaril po izboru supstituiran s alkilom; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
28. Spoj prema zahtjevu 23 prema formuli I(i) ili 10):
[image]
naznačen time što R10, R12 i R14 su nezavisno vodik, halogen ili alkil; R1, R2, R5, i R6 su vodik; X i R7 su halogen; R3 je hidroksi; i R4 je heterocikloalkil, alkil ili heteroaril, gdje je alkil po izboru supstituiran s -NR8R8' i gdje je heteroaril po izboru supstituiran s alkilom; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
29. Spoj prema zahtjevu 23 prema formuli I(n) ili 1(0):
[image]
naznačen time što R7 je halogen ili alkil; X je halogen; R19 je alkil; R1, R2, R5, i R6 su vodik; R10, R12, i R14 su nezavisno vodik ili halogen; R3 je hidroksi; i R4 je heterocikloalkil, alkil ili heteroaril, gdje je alkil po izboru supstituiran s -NR8R8' i gdje je heteroaril po izboru supstituiran s alkilom; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
30. Spoj prema zahtjevu 23 prema formuli I(p):
[image]
naznačen time što R1, R2, R5, i R6 su vodik; X i R7 su halogen; R10 i R12 su nezavisno vodik, halogen ili alkil; R19 je vodik ili alkil; R3 je hidroksi; i R4 je heterocikloalkil, alkil ili heteroaril, gdje je alkil po izboru supstituiran s -NR8R8' i gdje je heteroaril po izboru supstituiran s alkilom; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
31. Spoj prema zahtjevu 23 prema formuli I(q):
[image]
naznačen time što R1, R2, R5, i R6 su vodik; X i R7 su halogen; R10, R12, R14, i R16 su nezavisno vodik ili halogen; R3 je hidroksi; i R4 je heterocikloalkil, alkil ili heteroaril, gdje je alkil po izboru supstituiran s -NR8R8' i gdje je heteroaril po izboru supstituiran s alkilom; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
32. Spoj prema zahtjevu 23 prema formuli I(r):
[image]
naznačen time što R1, R2, R5, i R6 su vodik; X i R7 su halogen; R10 i R12 su nezavisno vodik, halogen ili alkil; R14 je vodik, halogen, alkil ili amino; R3 je hidroksi; i R4 je heterocikloalkil, alkil ili heteroaril, gdje je alkil po izboru supstituiran s -NR8R8' i gdje je heteroaril po izboru supstituiran s alkilom; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
33. Spoj prema zahtjevu 23 prema formuli I(s):
[image]
naznačen time što R1, R2, R5, i R6 su vodik; X i R7 su halogen; R10 i R12 su nezavisno vodik, halogen ili alkil; R14 je vodik, halogen, alkil ili amino; R3 je hidroksi; i R4 je heterocikloalkil, alkil ili heteroaril, gdje je alkil po izboru supstituiran s -NR8R8' i gdje je heteroaril po izboru supstituiran s alkilom; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
34. Spoj prema zahtjevu 23 prema formuli I(u), I(v), I(w) ili I(x):
[image]
naznačen time što R1, R2, R5, i R6 su vodik; X i R7 su halogen; R10, R12, i R14 su nezavisno vodik, halogen ili alkil; R3 je hidroksi; i R4 je heterocikloalkil, alkil ili heteroaril, gdje je alkil po izboru supstituiran s -NR8R8' i gdje je heteroaril po izboru supstituiran s alkilorn: ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
35. Spoj prema zahtjevu 1 izabran između Grupe C i prema formuli I(y) ili I(z):
[image]
naznačen time što R1, R2, R5, i R6 su vodik; X i R7 su halogen; R10 je vodik, halogen ili alkil; R10a je alkil; R3 je hidroksi; i R4 je heterocikloalkil, alkil ili heteroaril, gdje je alkil po izboru supstituiran s -NR8R8' i gdje je heteroaril po izboru supstituiran s alkilom; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
36. Spoj prema zahtjevu 1 izabran između Grupe D i prema formuli I(aa) ili I(bb):
[image]
naznačen time što R1, R2, R5, i R6 su vodik; X i R7 su halogen; R3 je hidroksi; i R4 je heterocikloalkil, alkil ili heteroaril, gdje je alkil po izboru supstituiran s -NR8R8' i gdje je heteroaril po izboru supstituiran s alkilom; ili pojedinačni stereoizomer tog spoja ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvat.
37. Spoj prema zahtjevu 1, naznačen time što je izabran iz grupe koja obuhvaća:
[image]
[image]
[image]
[image]
[image]
[image]
[image]
[image]
38. Farmaceutska smjesa, naznačena time što sadrži spoj prema zahtjevu 1, ili njegov pojedinačni stereoizomer ili smjesu stereoizomera, ili po izboru njegovu farmaceutski prihvatljivu sol ili solvat, i farmaceutski prihvatljiv nosač, pomoćnu tvar ili punilo.
39. In vitro postupak inhibicije MEK-a u stanici, naznačen time što obuhvaća dovođenje te stanice u doticaj sa spojem prema zahtjevu 1, ili njegovim pojedinačnim stereoizomerom ili smjesom stereoizomera, ili po izboru s njegovom farmaceutski prihvatljivom soli ili solvatom, i po izboru s farmaceutski prihvatljivim nosačem, pomoćnom tvari ili punilom.
40. Spoj, njegov pojedinačni stereoizomer ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvate, prema bilo kojem od zahtjeva 1 do 37, naznačen time što je za uporabu u medicini.
41. Spoj, njegov pojedinačni stereoizomer ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvate, prema zahtjevu 40, naznačen time što je uporaba liječenje proliferativne bolesti.
42. Spoj, njegov pojedinačni stereoizomer ili smjesa stereoizomera, ili po izboru njegova farmaceutski prihvatljiva sol ili solvate, prema bilo kojem od zahtjeva 1 do 37, naznačen time što je za uporabu u liječenju raka.
43. Spoj, njegov pojedinačni stereoizomer ili smjesa stereoizomera prema zahtjevu 42, naznačen time što je rak melanom, rak kolona, rak rektuma, rak gušterače, rak dojke, rak ne-malih stanica pluća, rak malih stanica pluća, papilami i anaplastični rak štitnjače, rak endometrija ili rak jajnika.
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