HRP20210949T1 - Spojevi i sastavi za moduliranje aktivnosti egfr mutant kinaze - Google Patents
Spojevi i sastavi za moduliranje aktivnosti egfr mutant kinaze Download PDFInfo
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- HRP20210949T1 HRP20210949T1 HRP20210949TT HRP20210949T HRP20210949T1 HR P20210949 T1 HRP20210949 T1 HR P20210949T1 HR P20210949T T HRP20210949T T HR P20210949TT HR P20210949 T HRP20210949 T HR P20210949T HR P20210949 T1 HRP20210949 T1 HR P20210949T1
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- alkyl
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- 150000001875 compounds Chemical class 0.000 title claims 9
- 108060006698 EGF receptor Proteins 0.000 title 1
- 108091000080 Phosphotransferase Proteins 0.000 title 1
- 239000000203 mixture Substances 0.000 title 1
- 102000020233 phosphotransferase Human genes 0.000 title 1
- 125000004433 nitrogen atom Chemical group N* 0.000 claims 33
- 125000005842 heteroatom Chemical group 0.000 claims 28
- 229910052739 hydrogen Inorganic materials 0.000 claims 23
- 239000001257 hydrogen Substances 0.000 claims 23
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 22
- 125000002950 monocyclic group Chemical group 0.000 claims 22
- -1 N-methyl pyrrolidinyl Chemical group 0.000 claims 20
- 229910052760 oxygen Inorganic materials 0.000 claims 20
- 229910052717 sulfur Inorganic materials 0.000 claims 20
- 229910052757 nitrogen Inorganic materials 0.000 claims 19
- 125000000217 alkyl group Chemical group 0.000 claims 17
- 150000002431 hydrogen Chemical group 0.000 claims 16
- 239000008194 pharmaceutical composition Substances 0.000 claims 16
- 229920006395 saturated elastomer Polymers 0.000 claims 16
- 125000004432 carbon atom Chemical group C* 0.000 claims 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 14
- 125000001072 heteroaryl group Chemical group 0.000 claims 14
- 229910052736 halogen Inorganic materials 0.000 claims 11
- 125000000623 heterocyclic group Chemical group 0.000 claims 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 8
- 101100516572 Caenorhabditis elegans nhr-8 gene Proteins 0.000 claims 8
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims 7
- 125000003118 aryl group Chemical group 0.000 claims 6
- 229910052731 fluorine Inorganic materials 0.000 claims 6
- 125000005843 halogen group Chemical group 0.000 claims 6
- 150000002367 halogens Chemical class 0.000 claims 6
- 150000003839 salts Chemical class 0.000 claims 6
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 4
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims 4
- 229910006074 SO2NH2 Inorganic materials 0.000 claims 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims 4
- 239000004480 active ingredient Substances 0.000 claims 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 4
- 229910052794 bromium Inorganic materials 0.000 claims 4
- 229910052801 chlorine Inorganic materials 0.000 claims 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 4
- 239000001301 oxygen Substances 0.000 claims 4
- 150000003457 sulfones Chemical class 0.000 claims 4
- 150000003462 sulfoxides Chemical class 0.000 claims 4
- 239000011593 sulfur Substances 0.000 claims 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 3
- 125000003342 alkenyl group Chemical group 0.000 claims 3
- 229910052799 carbon Inorganic materials 0.000 claims 3
- 125000002541 furyl group Chemical group 0.000 claims 3
- 125000001544 thienyl group Chemical group 0.000 claims 3
- 125000001313 C5-C10 heteroaryl group Chemical group 0.000 claims 2
- RRMJMHOQSALEJJ-UHFFFAOYSA-N N-[5-[[4-[4-[(dimethylamino)methyl]-3-phenylpyrazol-1-yl]pyrimidin-2-yl]amino]-4-methoxy-2-morpholin-4-ylphenyl]prop-2-enamide Chemical compound CN(C)CC=1C(=NN(C=1)C1=NC(=NC=C1)NC=1C(=CC(=C(C=1)NC(C=C)=O)N1CCOCC1)OC)C1=CC=CC=C1 RRMJMHOQSALEJJ-UHFFFAOYSA-N 0.000 claims 2
- 125000002393 azetidinyl group Chemical group 0.000 claims 2
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 2
- 125000003386 piperidinyl group Chemical group 0.000 claims 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- 125000004076 pyridyl group Chemical group 0.000 claims 2
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims 1
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- LRLRHXPCZZRKSZ-UHFFFAOYSA-N N-[2-(dimethylamino)-5-[[4-[4-[(dimethylamino)methyl]-3-methylpyrazol-1-yl]pyrimidin-2-yl]amino]-4-methoxyphenyl]prop-2-enamide Chemical compound CN(C1=C(C=C(C(=C1)OC)NC1=NC=CC(=N1)N1N=C(C(=C1)CN(C)C)C)NC(C=C)=O)C LRLRHXPCZZRKSZ-UHFFFAOYSA-N 0.000 claims 1
- OEJUXJLOTVQEPZ-UHFFFAOYSA-N N-[5-[[4-[3-cyclopropyl-4-[(dimethylamino)methyl]pyrazol-1-yl]-5-methylpyrimidin-2-yl]amino]-4-methoxy-2-morpholin-4-ylphenyl]prop-2-enamide Chemical compound C1(CC1)C1=NN(C=C1CN(C)C)C1=NC(=NC=C1C)NC=1C(=CC(=C(C=1)NC(C=C)=O)N1CCOCC1)OC OEJUXJLOTVQEPZ-UHFFFAOYSA-N 0.000 claims 1
- SEKXPOMGSBSXQJ-UHFFFAOYSA-N N-[5-[[4-[3-cyclopropyl-4-[(dimethylamino)methyl]pyrazol-1-yl]pyrimidin-2-yl]amino]-4-methoxy-2-morpholin-4-ylphenyl]prop-2-enamide Chemical compound C1(CC1)C1=NN(C=C1CN(C)C)C1=NC(=NC=C1)NC=1C(=CC(=C(C=1)NC(C=C)=O)N1CCOCC1)OC SEKXPOMGSBSXQJ-UHFFFAOYSA-N 0.000 claims 1
- MLWCILRSAFUNTG-UHFFFAOYSA-N N-[5-[[4-[4-(azetidin-1-ylmethyl)-3-cyclopropylpyrazol-1-yl]-5-methylpyrimidin-2-yl]amino]-4-methoxy-2-morpholin-4-ylphenyl]prop-2-enamide Chemical compound N1(CCC1)CC=1C(=NN(C=1)C1=NC(=NC=C1C)NC=1C(=CC(=C(C=1)NC(C=C)=O)N1CCOCC1)OC)C1CC1 MLWCILRSAFUNTG-UHFFFAOYSA-N 0.000 claims 1
- YAKQOIJYXLEFKD-UHFFFAOYSA-N N-[5-[[4-[4-(azetidin-1-ylmethyl)-3-phenylpyrazol-1-yl]pyrimidin-2-yl]amino]-4-methoxy-2-morpholin-4-ylphenyl]prop-2-enamide Chemical compound N1(CCC1)CC=1C(=NN(C=1)C1=NC(=NC=C1)NC=1C(=CC(=C(C=1)NC(C=C)=O)N1CCOCC1)OC)C1=CC=CC=C1 YAKQOIJYXLEFKD-UHFFFAOYSA-N 0.000 claims 1
- JZEBZKZRBNPQLB-UHFFFAOYSA-N N-[5-[[4-[4-[(dimethylamino)methyl]-3-propan-2-ylpyrazol-1-yl]-5-methylpyrimidin-2-yl]amino]-4-methoxy-2-morpholin-4-ylphenyl]prop-2-enamide Chemical compound CN(C)CC=1C(=NN(C=1)C1=NC(=NC=C1C)NC=1C(=CC(=C(C=1)NC(C=C)=O)N1CCOCC1)OC)C(C)C JZEBZKZRBNPQLB-UHFFFAOYSA-N 0.000 claims 1
- FREOCLQNGDCPBB-UHFFFAOYSA-N N-[5-[[4-[4-[[ethyl(methyl)amino]methyl]-3-phenylpyrazol-1-yl]pyrimidin-2-yl]amino]-4-methoxy-2-morpholin-4-ylphenyl]prop-2-enamide Chemical compound C(C)N(C)CC=1C(=NN(C=1)C1=NC(=NC=C1)NC=1C(=CC(=C(C=1)NC(C=C)=O)N1CCOCC1)OC)C1=CC=CC=C1 FREOCLQNGDCPBB-UHFFFAOYSA-N 0.000 claims 1
- 125000004850 cyclobutylmethyl group Chemical group C1(CCC1)C* 0.000 claims 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims 1
- 125000002757 morpholinyl group Chemical group 0.000 claims 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims 1
- 125000003566 oxetanyl group Chemical group 0.000 claims 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D405/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- General Health & Medical Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
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- Communicable Diseases (AREA)
- Heart & Thoracic Surgery (AREA)
- Oncology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pulmonology (AREA)
- Cardiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Claims (13)
1. Farmaceutski sastav za upotrebu u liječenju karcinoma nemalih stanica pluća, a spomenut farmaceutski sastav sadrži kao aktivni sastojak spoj formule (I):
[image]
gdje:
X je CH ili N;
R1 je H, R8 ili -OR8;
R2 je vodik, C1-6 alkil, 6-10 člani monociklični ili biciklični aril, ili 5-10 člani heteroaril koji sadrži 1-4 heteroatoma izabranih između N, O i S, gdje heteroaril ili aril jeopcionalno i nezavisno supstituiran na jednom ili više ugljikovih atoma sa R13; i gdje heteroaril koji ima jedan ili više dušikovih atoma je opcionalno i nezavisno supstituiran na jednom ili više dušikovih atoma sa R8;
R3 je vodik, 4-7 člani monociklični heterociklil koji sadrži 1-2 heteroatoma izabranih između N, O i S, i opcionalno supstituiranih sa okso, 5-6 članim heteroarilom koji sadrži 1-3 heteroatoma izabranih između N, O i S, NR9R10, NR11R12, ili fenil, gdje heteroaril ili fenil jeopcionalno i nezavisno supstituiran na jednom ili više ugljikovih atoma sa R13; i gdje heterociklil ili heteroaril koji ima jedan ili više dušikovih atoma je opcionalno i nezavisnosupstituiran na jednom ili više dušikovih atoma sa R8;
R4 je vodik, C1-4 alkil, C3-5 cikloalkil, F, Cl, Br, CN, ili CF3;
R5 je vodik, CF3, C1-6 alkil, C3-7 cikloalkil, 5-6 člani heteroaril koji sadrži 1-3 heteroatoma izabranih između N, O i S, ili 6-10 člani monociklični ili biciklični aril, gdje heteroaril ili aril je opcionalno i nezavisnosupstituiran na jednom ili više ugljikovih atoma sa R13;
R6 je vodik ili C1-6 alkil;
R7 je vodik, -CH2OH, -CH2OR8, C1-3 alkil, (CH2)nNR9R10, (CH2)nNR11R12, C(O)NR9R10, ili C(O)NR11R12, gdje svaki n je nezavisno 1 ili 2;
R8 je izabran između C1-6 alkil ili C3-7 cikloalkil;
R9 je izabran između C1-6 alkil, C3-7 cikloalkil ili 4-7 člani heterociklil koji sadrži 1-2 heteroatoma izabranih između N, O i S, gdje C1-6 alkil ili C3-7 cikloalkil je opcionalno supstituiran s halogenom ili -OR8, i gdje 4-7 člani heterociklil koji ima jedan dušikov atom koji je opcionalno i nezavisno supstituiran s -R8,-C(O)R8, -C(O)OR8, ili C(O)NHR8;
R10 je C1-6 alkil, C3-7 cikloalkil, ili (CH2)nNR9R9, gdje je svaki n nezavisno 1 ili 2;
R11 i R12, uzeti zajedno s atomom dušika za koji su vezaniformiraju, nezavisno od svakog javljanja,
i) 3-8 članu zasićenu ili djelomično zasićenu monocikličnu grupu koja nema drugih heteroatoma osim dušikovih atoma za koji su vezani R11 i R12 , gdje spomenuta 3-8 člana zasićena ili djelomično zasićena monociklična grupa je opcionalno i nezavisno supstituirana na jednom ili više ugljikovih atoma s halogenom, hidroksilom, -OR8, -NR9R10, ili -NR11R12; ili
ii) 5-8 članu zasićenu ili djelomično zasićenu monocikličnu grupu koja ima 1 ili 2 heteroatoma, pored dušikovog atoma za koji su vezani R11 i R12, gdje spomenuti heteroatomi su nezavisno izabrani između dušika, kisika, sumpora, sulfona ili sulfoksida, gdje spomenuta 5-8 člana zasićena ili djelomično zasićena monociklična grupa koja ima 1 ili 2 atomadušika je opcionalno supstituirana s jednim ili više ugljikovih ili dušikovih atoma sa -R8, -C(O)R8, -C(O)OR8, -C(O)NHR8, -SO2R8, -SO2NH2, ili -SO2NR82; i
R13 je izabran između halogena, CN, CF3, R8, -OR8 ili C2-4 alkenil,
ili njegovu farmaceutski prihvatljivu sol.
2. Farmaceutski sastav za upotrebu prema zahtjevu 1, gdje spomenutfarmaceutski sastav sadrži kao aktivni sastojak spoj prikazan formulom (II) ili njegovu farmaceutski prihvatljivu sol:
[image]
gdje:
R3 je vodik, 4-7 člani monociklični heterociklil koji sadrži 1-2 heteroatoma izabranih između N, O i S, i opcionalno supstituiranih sa okso, 5-6 člani heteroaril koji sadrži 1-3 heteroatoma izabranih između N, O i S, NR9R10, NR11R12, ili fenil, gdje heteroaril ili fenil je opcionalno i nezavisno supstituiran na jednom ili višeugljikovih atoma s R13; i gdje heterociklil ili heteroaril koji imaju jedan ili više dušikovih atoma je opcionalno i nezavisno supstituiran na jednom ili više dušikovih atoma s R8;
R4 je vodik, C1-4 alkil, C3-5 cikloalkil, F, Cl, Br, CN, ili CF3;
R5 je vodik, CF3, C1-6 alkil, C3-7 cikloalkil, 5-6 člani heteroaril koji sadrži 1-3 heteroatoma izabranih između N, O i S, ili 6-10 člani monociklični ili biciklični aril, gdje heteroaril ili aril je opcionalno i nezavisno supstituiran na jednom ili više ugljikovih atoma sa R13;
R6 je vodik ili C1-6 alkil;
R7 je vodik, -CH2OH, -CH2OR8, C1-3 alkil, (CH2)nNR9R10, (CH2)nNR11R12, C(O)NR9R10, ili C(O)NR11R12, gdje svaki n je nezavisno 1 ili 2;
R8 je izabran između C1-6 alkil ili C3-7 cikloalkil;
R9 je izabran između C1-6 alkil, C3-7 cikloalkil ili 4-7 člani heterociklil koji sadrži 1-2 heteroatoma izabranih između N, O i S, gdje C1-6 alkil ili C3-7 cikloalkil je opcionalno supstituiran sa halogen ili -OR8, gdje 4-7 člani heterociklil koji ima jedan atom dušika jeopcionalnoi nezavisno supstituiran s -R8, -C(O)R8,-C(O)OR8, ili C(O)NHR8;
R10 je C1-6 alkil, C3-7 cikloalkil, ili (CH2)nNR9R9, gdje svaki n je nezavisno 1 ili 2;
R11 i R12, uzeti zajedno s atomom dušika za koji su vezaniformiraju, nezavisno u svakom pojavljivanju,
i) 3-8 člana zasićenu ili djelomično zasićenu monocikličnu grupu koja nema drugih heteroatoma osim dušikova atoma za koji su vezani R11 i R12 , gdje spomenuta 3-8 člana zasićena ili ddjelomično zasićena monociklična grupa je opcionalno i nezavisno supstituiranana jednom ili više atoma s halogenom, hidroksilom, -OR8, -NR9R10, ili -NR11R12; ili
ii) 5-8 člana zasićenu ili djelomično zasićenu monocikličnu grupu koja ima 1 ili 2 heteroatoma, pored dušikovog atoma za koji su vezani R11 i R12 , gdje spomenuti heteroatomi su nezavisno izabrani između dušika, kisika, sumpora, sulfona ili sulfoksida, gdje spomenuta 5-8 člana zasićena ili djelomično zasićena monociklična grupa koja ima 1 ili 2 dušikova atoma je opcionalno supstituirana s jednim ili više ugljikovih atoma sa -R8, -C(O)R8, -C(O)OR8, -C(O)NHR8, -SO2R8, -SO2NH2, ili -SO2NR82; i
R13 je izabran između halogena, CN, CF3, R8, -OR8 ili C2-4 alkenila.
3. Farmaceutski sastav za upotrebu prema zahtjevu 1, gdje spomenut farmaceutski sastav sadrži kao aktivni sastojak spoj formule (III) ili njegovu farmaceutski prihvatljivu sol:
[image]
gdje:
R3 je vodik, 4-7 člani monociklični heterociklil koji sadrži 1-2 heteroatoma izabranih između N, O i S, i opcionalno supstituiranih sa okso, 5-6 člani heteroarilom koji sadrži 1-3 heteroatoma izabranih između N, O i S, NR9R10, NR11R12, ili fenil, gdje heteroaril ili fenil je opcionalno i nezavisno supstituiran na jednom ili više ugljikovih atoma sa R13; i gdje heterociklil ili heteroaril koji ima jedan ili više dušikovih atoma je opcionalno i nezavisno supstituiran na jednom ili više dušikovih atoma sa R8;
R4 je vodik, C1-4 alkil, C3-5 cikloalkil, F, Cl, Br, CN, ili CF3;
R5 je vodik, CF3, C1-6 alkil, C3-7 cikloalkil, 5-6 člani heteroaril koji sadrži 1-3 heteroatoma izabranih između N, O i S, ili 6-10 člani monociklični ili biciklični aril, gdje heteroaril ili aril je opcionalno i nezavisno supstituiran na jednom ili više ugljikovih atoma sa R13;
R6 je vodik ili C1-6 alkil;
R7 je vodik, -CH2OH, -CH2OR8, C1-3 alkil, (CH2)nNR9R10, (CH2)nNR11R12, C(O)NR9R10, ili C(O)NR11R12, gdje svaki n je nezavisno 1 ili 2;
R8 je izabran između C1-6 alkil ili C3-7 cikloalkil;
R9 je izabran između C1-6 alkil, C3-7 cikloalkil ili 4-7 člani heterociklil koji sadrži 1-2 heteroatoma izabranih između N, O i S, gdje C1-6 alkil ili C3-7 cikloalkil je opcionalno supstituiran s halogenom ili -OR8, gdje 4-7 člani heterociklil koji ima jedan dušikov atom je opcionalno i nezavisno supstituran s -R8, -C(O)R8,-C(O)OR8, ili C(O)NHR8;
R10 je C1-6 alkil, C3-7 cikloalkil, ili (CH2)nNR9R9, gdje svaki n je nezavisno 1 ili 2;
R11 i R12, uzeti zajedno s dušikovim atomom za koji su vezaniformiraju, nezavisno u svakom pojavljivanju,
i) 3-8 člana zasićenu ili djelomično zasićenu monocikličnu grupu koja nema drugih heteroatoma osim dušikovog atoma za koji su vezani R11 i R12 , gdje spomenuta 3-8 člana zasićena ili djelomično zasićena monociklična grupa je opcionalno i nezavisno supstituirana na jednom ili više ugljikovih atoma s halogenom, hidroksilom, -OR8, -NR9R10, ili -NR11R12; ili
ii) 5-8 članu zasićenu ili djelomično zasićenu monocikličnu grupu koja ima 1 ili 2 heteroatoma, pored dušikovog atoma za koji su vezani R11 i R12 , gdje spomenuti heteroatomi su nezavisno izabrani između dušika, kisika, sumpora, sulfona ili sulfoksida, gdje spomenuta 5-8 člana zasićena ili djelomično zasićena monociklična grupa koja ima 1 ili 2 atoma dušika je opcionalno supstituirana s jednim ili više atoma ugljika ili dušika s -R8, -C(O)R8, -C(O)OR8, -C(O)NHR8, -SO2R8, -SO2NH2, ili -SO2NR82; i
R13 je izabran između halogena, CN, CF3, R8, -OR8 ili C2-4 alkenil.
4. Farmaceutski sastav za upotrebu prema zahtjevu 1, gdje spomenut farmaceutski sastav sadrži kao aktivni sastojak spoj formule (IV) ili njegovu farmaceutski prihvatljivu sol:
[image]
gdje:
X je CH ili N;
R1 je H, R8 ili -OR8;
R2 je vodik, C1-6 alkil, 6-10 člani monociklični ili biciklični aril, ili 5-10 člani heteroaril koji sadrži 1-4 heteroatoma izabranih između N, O i S, gdje heteroaril ili aril je opcionalno i nezavisno supstituiran na jednom ili više ugljikovih atoma s R13; i gdje heteroaril koji ima jedan ili više dušikovih atoma je opcionalno i nezavisno supstituiran na jednom ili više dušikovih atoma sa R8;
R4 je vodik, C1-4 alkil, C3-5 cikloalkil, F, Cl, Br, CN, ii CF3;
R5 je vodik, CF3, C1-6 alkil, C3-7 cikloalkil, 5-6 člani heteroaril koji sadrži 1-3 heteroatoma izabranih između N, O i S, ili 6-10 člani monociklični ili biciklični aril, gdje heteroaril ili aril je opcionalno i nezavisno supstituiran na jednom ili više ugljikovih atoma s R13;
R7 je vodik, -CH2OH, -CH2OR8, C1-3 alkil, (CH2)nNR9R10, (CH2)nNR11R12, C(O)NR9R10, ili C(O)NR11R12, gdje svaki n je nezavisno 1 ili 2;
R8 je izabran između C1-6 alkil ili C3-7 cikloalkil;
R9 je izabran između C1-6 alkil, C3-7 cikloalkil ili 4-7 člani heterociklil koji sadrži 1-2 heteroatoma izabranih između N, O i S, gdje C1-6 alkil ili C3-7 cikloalkil jeopcionalno supstituiran s halogenom ili -OR8, gdje 4-7 člani heterociklil koji ima jedan dušikov atom je opcionalno i nezavisno supstituiran s -R8, -C(O)R8,-C(O)OR8, ili C(O)NHR8;
R10 je C1-6 alkil, C3-7 cikloalkil, ili (CH2)nNR9R9, gdje svaki n je nezavisno 1 ili 2;
R11 i R12, uzeti zajedno s dušikovim atomom za koji su vezaniformiraju, nezavisno u svakom pojavljivanju,
i) 3-8 članu zasićenu ili djelomično zasićenu monocikličnu grupu koja nema drugih heteroatoma osim dušikovog atoma za koji su vezani R11 i R12 , gdje spomenuta 3-8 člana zasićena ili djelomično zasićena monociklična grupa je opcionalno i nezavisno supstituirana na jednom ili više ugljikovih atoma s halogenom, hidroksilom, -OR8, -NR9R10, ili -NR11R12; ili
ii) 5-8 članu zasićenu ili djelomično zasićenu monocikličnu grupu koja ima 1 ili 2 heteroatoma, pored dušikovog atoma za koji su vezani R11 i R12 , gdje spomenuti heteroatomi su nezavisno izabrani između dušika, kisika, sumpora, sulfona ili sulfoksida, gdje spomenuta 5-8 člana zasićena ili djelomično zasićena monociklična grupa koja ima 1 ili 2 atoma dušika je opcionalno supstiturana na jednom ili više atoma ugljika ili dušika s -R8, -C(O)R8, -C(O)OR8, -C(O)NHR8, -SO2R8, -SO2NH2, ili -SO2NR82; i
R13 je izabrana između halogena, CN, CF3, R8, -OR8 ili C2-4 alkenil.
5. Farmaceutski sastav za upotrebu prema bilo kojem od zahtjeva 1-3, gdje R1 je -OCH3; R4 je H, -CH3, F, ili Cl; R5 je vodik, C1-6 alkil, C3-7 cikloalkil, piridinil, tiofenil, furanil, N-metil pirolidinil, N-metil pirazolil, ili fenil; R8 je metil; i n je 1.
6. Farmaceutski sastav za upotrebu prema zahtjevu 4, gdje R1 je H; R2 je furanil, tiofenil, N-metil pirazolil, ili fenil; R4 je H, -CH3, F,ili Cl; R5je vodik, C1-6 alkil, C3-7 cikloalkil, piridinil, tiofenil, furanil,N-metilpirolil, N-metilpirazolil, ili fenil; i n je 1.
7. Farmaceutski sastav za upotrebu prema zahtjevu 5, gdje R2 je H; R6 je H; R3 je morfolino, N-metil piperazinil, piperidinil, azetidinil, pirodinil, 4-acetilpiperidinil, N,N-dimetilamino, 1,4-oksazepan-4-il, ili 4-metil-1,4,-diazepan-1-il; i R7 je -(CH2)NR9R10 ili -(CH2)NR11R12.
8. Farmaceutski sastav za upotrebu prema zahtjevu 6, gdje R7 je -(CH2)NR9R10 ili -(CH2)NR11R12.
9. Farmaceutski sastav za upotrebu prema zahtjevu 7 ili zahtjevu 8, gdje R9 je metil, etil, propil, ciklopropilmetil, ili ciklobutilmetil; i R10 je metil, etil, propil, ciklopropilmetil, oksetanil, oksetanmetil, N-metiazetinil, N,N-dimetiletil, ili metoksietil; i NR11R12 je azetidinil, 3-hidroksi azetidinil, 3-metoksi azetidinil, pirolidinil, (S)-3-hidroksi pirolidinil, (R)-3-hidroksi pirolidinil, (3R,4S)-3,4-dihidroksipirolidinil, (3S,4R)-3-hidroksi-4-metoksipirolidinil, piperidinil, morfolinil, N-metilpiperazinil, azamorfolinil, N-metilazapiperazinil, N-acetil piperazinil, ili tiomorfolinil.
10. Farmaceutski sastav za upotrebu prema zahtjevu 5 ili 6, gdje R5 je vodik, metil, izopropil, t-butil, ciklopropil, 2-tiofenil, 2-furanil, 3-furanil, 3-piridil, 4-piridil ili fenil.
11. Spoj izabran između:
N-(2-(dimetilamino)-5-(4-(4-((dimetilamino)metil)-3-metil-1H-pirazol-1-il)pirimidin-2-ilamino)-4-metoksifenil)akrilamida,
N-(5-(4-(4-((dimetilamino)metil)-3-fenil-1H-pirazol-1-il)pirimidin-2-ilamino)-4-metoksi-2-morfolinofenil)akrilamida,
N-(5-(4-(3-ciklopropil-4-((dimetilamino)metil)-1H-pirazol-1-il)pirimidin-2-ilamino)-4-metoksi-2-morfolinofenil)akrilamida,
N-(5-(4-(4-(azetidin-1-ilmetil)-3-fenil-1H-pirazol-1-il)pirimidin-2-ilamino)-4-metoksi-2-morfolinofenil)akrilamida,
N-(5-(4-(4-((etil(metil)amino)metil)-3-fenil-1H-pirazol-1-il)pirimidin-2-ilamino)-4-metoksi-2-morfolinofenil)akrilamida,
N-(5-(4-(3-ciklopropil-4-((dimetilamino)metil)-1H-pirazol-1-il)-5-metilpirimidin-2-ilamino)-4-metoksi-2-morfolinofenil)akrilamida,
N-(5-(4-(4-(azetidin-1-ilmetil)-3-ciklopropil-1H-pirazol-1-il)-5-metilpirimidin-2-ilamino)-4-metoksi-2-morfolinofenil)akrilamida,
N-(5-(4-(4-((dimetilamino)metil)-3-izopropil-1H-pirazol-1-il)-5-metilpirimidin-2-ilamino)-4-metoksi-2-morfolinofenil)akrilamida,
ili njihova farmaceutski prihvatljiva sol.
12. Spoj prema zahtjevu 11, gdje je spomenuti spoj N-(5-(4-(4-((dimetilamino)metil)-3-fenil-1H-pirazol-1-il)pirimidin-2-ilamino)-4-metoksi-2-morfolinofenil)akrilamid ili njegova farmaceutski prihvatljiva sol.
13. Farmaceutski sastav za upotrebu prema zahtjevu 1, gdje spomenut farmaceutski sastav sadrži spoj prema zahtjevu 11 ili zahtjevu 12.
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