DK2809670T3 - 1h-pyrrolo[2,3-b]pyridin-derivater og deres anvendelse som kinaseinhibitorer - Google Patents
1h-pyrrolo[2,3-b]pyridin-derivater og deres anvendelse som kinaseinhibitorer Download PDFInfo
- Publication number
- DK2809670T3 DK2809670T3 DK13703121.7T DK13703121T DK2809670T3 DK 2809670 T3 DK2809670 T3 DK 2809670T3 DK 13703121 T DK13703121 T DK 13703121T DK 2809670 T3 DK2809670 T3 DK 2809670T3
- Authority
- DK
- Denmark
- Prior art keywords
- pyrrolo
- pyrazole
- pyridin
- amide
- carboxylic acid
- Prior art date
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- 150000005258 1H-pyrrolo(2,3-b)pyridines Chemical class 0.000 title description 4
- 229940043355 kinase inhibitor Drugs 0.000 title 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 337
- 239000002253 acid Substances 0.000 claims description 95
- -1 (R) -3-ethylamino-piperidin-1-yl Chemical group 0.000 claims description 93
- 239000000203 mixture Substances 0.000 claims description 64
- KGDOHXYALMXHLF-UHFFFAOYSA-N 1-benzylpyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=CC=C1 KGDOHXYALMXHLF-UHFFFAOYSA-N 0.000 claims description 53
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 28
- 125000000623 heterocyclic group Chemical group 0.000 claims description 21
- AKKPGUPOFLAXRN-UHFFFAOYSA-N 1-[(4-fluorophenyl)methyl]pyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=C(F)C=C1 AKKPGUPOFLAXRN-UHFFFAOYSA-N 0.000 claims description 20
- 206010028980 Neoplasm Diseases 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 125000003107 substituted aryl group Chemical group 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000001424 substituent group Chemical group 0.000 claims description 12
- 201000011510 cancer Diseases 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
- UORKPBOZTFYKBG-UHFFFAOYSA-N 1-benzyl-n-(5-bromo-1h-pyrrolo[2,3-b]pyridin-3-yl)pyrazole-4-carboxamide Chemical compound C12=CC(Br)=CN=C2NC=C1NC(=O)C(=C1)C=NN1CC1=CC=CC=C1 UORKPBOZTFYKBG-UHFFFAOYSA-N 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical class C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- MPVDXIMFBOLMNW-UHFFFAOYSA-N chembl1615565 Chemical compound OC1=CC=C2C=C(S(O)(=O)=O)C=C(S(O)(=O)=O)C2=C1N=NC1=CC=CC=C1 MPVDXIMFBOLMNW-UHFFFAOYSA-N 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 5
- 125000002757 morpholinyl group Chemical group 0.000 claims description 5
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 125000004450 alkenylene group Chemical group 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 230000005764 inhibitory process Effects 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000003386 piperidinyl group Chemical group 0.000 claims description 4
- JMWJJDKQQMMJRG-UHFFFAOYSA-N 1-[(4-methoxyphenyl)methyl]pyrazole-4-carboxylic acid Chemical compound C1=CC(OC)=CC=C1CN1N=CC(C(O)=O)=C1 JMWJJDKQQMMJRG-UHFFFAOYSA-N 0.000 claims description 3
- HYBRAUPLUXQZEG-UHFFFAOYSA-N 1-[(4-methylphenyl)methyl]pyrazole-4-carboxylic acid Chemical compound C1=CC(C)=CC=C1CN1N=CC(C(O)=O)=C1 HYBRAUPLUXQZEG-UHFFFAOYSA-N 0.000 claims description 3
- OETDPVHIOQFDBI-UHFFFAOYSA-N 1-benzyl-n-(4-bromo-1h-pyrrolo[2,3-b]pyridin-3-yl)pyrazole-4-carboxamide Chemical compound C1=2C(Br)=CC=NC=2NC=C1NC(=O)C(=C1)C=NN1CC1=CC=CC=C1 OETDPVHIOQFDBI-UHFFFAOYSA-N 0.000 claims description 3
- BJJLYPIQEQCYLS-UHFFFAOYSA-N 1-benzyl-n-[5-[4-(piperidin-1-ylmethyl)phenyl]-1h-pyrrolo[2,3-b]pyridin-3-yl]pyrazole-4-carboxamide Chemical compound C1=NN(CC=2C=CC=CC=2)C=C1C(=O)NC(C1=C2)=CNC1=NC=C2C(C=C1)=CC=C1CN1CCCCC1 BJJLYPIQEQCYLS-UHFFFAOYSA-N 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 125000005549 heteroarylene group Chemical group 0.000 claims description 3
- WPIMBSFJUGQKSO-GOSISDBHSA-N n-[4-[(3r)-3-aminopiperidin-1-yl]-5-methoxy-1h-pyrrolo[2,3-b]pyridin-3-yl]-1-benzylpyrazole-4-carboxamide Chemical compound C12=C(N3C[C@H](N)CCC3)C(OC)=CN=C2NC=C1NC(=O)C(=C1)C=NN1CC1=CC=CC=C1 WPIMBSFJUGQKSO-GOSISDBHSA-N 0.000 claims description 3
- NFVCVYOJNDBBOX-CTNGQTDRSA-N n-[4-[(3r,4r)-3-amino-4-cyclopropylpiperidin-1-yl]-5-bromo-1h-pyrrolo[2,3-b]pyridin-3-yl]-1-benzylpyrazole-4-carboxamide Chemical compound C1([C@H]2CCN(C[C@@H]2N)C=2C=3C(NC(=O)C4=CN(CC=5C=CC=CC=5)N=C4)=CNC=3N=CC=2Br)CC1 NFVCVYOJNDBBOX-CTNGQTDRSA-N 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 238000001959 radiotherapy Methods 0.000 claims description 3
- 125000005717 substituted cycloalkylene group Chemical group 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- IVDPFMFNQXHGNX-UHFFFAOYSA-N 1-[(3-fluorophenyl)methyl]pyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=CC(F)=C1 IVDPFMFNQXHGNX-UHFFFAOYSA-N 0.000 claims description 2
- PBGWCCZEAHKYKB-UHFFFAOYSA-N 1-[(3-methylphenyl)methyl]pyrazole-4-carboxylic acid Chemical compound CC1=CC=CC(CN2N=CC(=C2)C(O)=O)=C1 PBGWCCZEAHKYKB-UHFFFAOYSA-N 0.000 claims description 2
- ZBERGBQDTWNOJD-UHFFFAOYSA-N 1-benzylpyrazole-4-carboxylic acid 5-[4-[3-(dimethylamino)propoxy]phenyl]-1H-pyrrolo[2,3-b]pyridin-3-amine Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=CC=C1.C1=CC(OCCCN(C)C)=CC=C1C1=CN=C(NC=C2N)C2=C1 ZBERGBQDTWNOJD-UHFFFAOYSA-N 0.000 claims description 2
- 208000023275 Autoimmune disease Diseases 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- SHUUEBOBDREAPE-UHFFFAOYSA-N n-(5-bromo-4-fluoro-1h-pyrrolo[2,3-b]pyridin-3-yl)-1-[(4-methoxyphenyl)methyl]pyrazole-4-carboxamide Chemical compound C1=CC(OC)=CC=C1CN1N=CC(C(=O)NC=2C3=C(F)C(Br)=CN=C3NC=2)=C1 SHUUEBOBDREAPE-UHFFFAOYSA-N 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- YHWGALVHDQPEOA-HXUWFJFHSA-N tert-butyl n-[(3r)-1-[5-bromo-3-[[1-[(4-methoxyphenyl)methyl]pyrazole-4-carbonyl]amino]-1h-pyrrolo[2,3-b]pyridin-4-yl]piperidin-3-yl]carbamate Chemical compound C1=CC(OC)=CC=C1CN1N=CC(C(=O)NC=2C3=C(N4C[C@@H](CCC4)NC(=O)OC(C)(C)C)C(Br)=CN=C3NC=2)=C1 YHWGALVHDQPEOA-HXUWFJFHSA-N 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 229910052727 yttrium Inorganic materials 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 30
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 2
- 102000001253 Protein Kinase Human genes 0.000 claims 2
- 150000002431 hydrogen Chemical class 0.000 claims 2
- 108060006633 protein kinase Proteins 0.000 claims 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 1
- WMEWWDFWHBMCBM-UHFFFAOYSA-N 1-benzyl-n-(1h-pyrrolo[2,3-b]pyridin-3-yl)pyrazole-4-carboxamide Chemical compound C=1NC2=NC=CC=C2C=1NC(=O)C(=C1)C=NN1CC1=CC=CC=C1 WMEWWDFWHBMCBM-UHFFFAOYSA-N 0.000 claims 1
- FBLBZRLTZBPZFA-UHFFFAOYSA-N 1-benzyl-n-(5-phenyl-1h-pyrrolo[2,3-b]pyridin-3-yl)pyrazole-4-carboxamide Chemical compound C1=NN(CC=2C=CC=CC=2)C=C1C(=O)NC(C1=C2)=CNC1=NC=C2C1=CC=CC=C1 FBLBZRLTZBPZFA-UHFFFAOYSA-N 0.000 claims 1
- QPLMQVLSVQFQTH-UHFFFAOYSA-N 1-benzyl-n-(5-piperidin-1-yl-1h-pyrrolo[2,3-b]pyridin-3-yl)pyrazole-4-carboxamide Chemical compound C1=NN(CC=2C=CC=CC=2)C=C1C(=O)NC(C1=C2)=CNC1=NC=C2N1CCCCC1 QPLMQVLSVQFQTH-UHFFFAOYSA-N 0.000 claims 1
- VWYXZROHCKKTDY-UHFFFAOYSA-N 1-benzylpyrazole-4-carboxylic acid 5-[3-(2-morpholin-4-ylethoxy)phenyl]-1H-pyrrolo[2,3-b]pyridin-3-amine Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=CC=C1.C1=C2C(N)=CNC2=NC=C1C(C=1)=CC=CC=1OCCN1CCOCC1 VWYXZROHCKKTDY-UHFFFAOYSA-N 0.000 claims 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 1
- KVTUSMPNLUCCQO-UHFFFAOYSA-N 3,3-difluoropyrrolidine Chemical compound FC1(F)CCNC1 KVTUSMPNLUCCQO-UHFFFAOYSA-N 0.000 claims 1
- SPVXSBKORLMTPI-OGFXRTJISA-N 4-[(3R)-3-aminopiperidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine 1-benzylpyrazole-4-carboxylic acid Chemical compound N[C@H](CCC1)CN1C1=C(C(N)=CN2)C2=NC=C1C(F)(F)F.OC(C1=CN(CC2=CC=CC=C2)N=C1)=O SPVXSBKORLMTPI-OGFXRTJISA-N 0.000 claims 1
- SZDGCPAAQKHPFH-ZCFIWIBFSA-N 4-[(3R)-3-aminopyrrolidin-1-yl]-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-amine Chemical compound C1[C@H](N)CCN1C1=C(Cl)C=NC2=C1C(N)=CN2 SZDGCPAAQKHPFH-ZCFIWIBFSA-N 0.000 claims 1
- XBOFWHNVUMQWFJ-UHFFFAOYSA-N C(C1=CC=CC=C1)N1N=CC(=C1)C(=O)O.N1(CCCC1)CC1=CC=C(C=C1)C=1C=C2C(=NC1)NC=C2NC(=O)C=2C=NN(C2)CC2=CC=CC=C2 Chemical compound C(C1=CC=CC=C1)N1N=CC(=C1)C(=O)O.N1(CCCC1)CC1=CC=C(C=C1)C=1C=C2C(=NC1)NC=C2NC(=O)C=2C=NN(C2)CC2=CC=CC=C2 XBOFWHNVUMQWFJ-UHFFFAOYSA-N 0.000 claims 1
- QLEAMDSDDJDRHO-UHFFFAOYSA-N C(C1=CC=CC=C1)N1N=CC(=C1)C(=O)O.N1(CCCC1)CC1=CC=C(S1)C=1C=C2C(=NC1)NC=C2NC(=O)C=2C=NN(C2)CC2=CC=CC=C2 Chemical compound C(C1=CC=CC=C1)N1N=CC(=C1)C(=O)O.N1(CCCC1)CC1=CC=C(S1)C=1C=C2C(=NC1)NC=C2NC(=O)C=2C=NN(C2)CC2=CC=CC=C2 QLEAMDSDDJDRHO-UHFFFAOYSA-N 0.000 claims 1
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- RAWTWHZUOVGREI-RSAXXLAASA-N CN1[C@H](COC2=CC=CC(C(C=C34)=CN=C3NC=C4N)=C2)CCC1.OC(C1=CN(CC2=CC=CC=C2)N=C1)=O Chemical compound CN1[C@H](COC2=CC=CC(C(C=C34)=CN=C3NC=C4N)=C2)CCC1.OC(C1=CN(CC2=CC=CC=C2)N=C1)=O RAWTWHZUOVGREI-RSAXXLAASA-N 0.000 claims 1
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- JHZHSQCMNHPMQR-UHFFFAOYSA-N n-(5-bromo-1h-pyrrolo[2,3-b]pyridin-3-yl)-1-[(4-fluorophenyl)methyl]pyrazole-4-carboxamide Chemical compound C1=CC(F)=CC=C1CN1N=CC(C(=O)NC=2C3=CC(Br)=CN=C3NC=2)=C1 JHZHSQCMNHPMQR-UHFFFAOYSA-N 0.000 claims 1
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- 238000011269 treatment regimen Methods 0.000 description 1
- 150000003918 triazines Chemical class 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 208000022679 triple-negative breast carcinoma Diseases 0.000 description 1
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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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
- C07D471/04—Ortho-condensed systems
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- 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
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- 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
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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Claims (15)
1. Forbindelse af formel I:
(I) eller et farmaceutisk acceptabelt salt deraf, hvor: hvert Z er uafhængigt (Alk)n-Rn-(Alk)n-X, hvor hvert Alk er uafhængigt (Ci til C12) alkylen eller (C2 til C12) alkenylen, hver af hvilke kan eventuelt substitueres; hvert n er uafhængigt 0 eller 1; hvert R er uafhængigt eventuelt substitueret arylen eller heteroarylen, eller eventuelt substitueret cykloalkylen eller heterocykel, -O-, -S-, -(C=0)-, - (OS)-, -SO2-, -C( = 0)0-, -C(=0)NRA-, -C(=S)NRA-, -S02NRA-, -NRAC(=0)-, -NRaS02- eller -NRA- hvor RA er hydrogen, C1-C6 alkyl, -Ci-Ce alkyl(cykloalkyl), Ci-Ce alkyl(Ci-Ce alkoxy) eller CiCe alkoxy; hvert X er uafhængigt halogen, -H, -ORA, NRARA, eventuelt substitueret aryl eller heteroaryl, eller eventuelt substitueret cykloalkyl eller heterocykel, CN eller C(halogen)aHb, hvor a er 1, 2, eller 3, og b er (3-a); Y er eventuelt substitueret aryl eller heteroaryl, eller eventuelt substitueret cykloalkyl eller heterocykel; og R1 er H eller C1-C6 alkyl, med det forbehold at forbindelsen ikke er N-(5-brom-4-fluor-lH-pyrrolo[2,3-b]pyridin-3-yl)-l-(4-methoxybenzyl)-lH-pyrazol-4-carboxamid eller (R)-tert-butyl l-(5-brom-3-(l-(4-methoxybenzyl)-lHpyrazol-4-carboxamido)-lH-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamat.
2. Forbindelse ifølge krav 1, hvor de eventuelle substituenter for gruppen Y er valgt fra (Ci-Ce)alkyl, hydroxy, hydroxy(Ci-C6)alkyl, mercapto, mercapto(Ci-C6)alkyl, (Ci-C6)alkylthio, halo, trifluormethyl, trifluormethoxy, nitro, nitril (-CN), oxo, phenyl, -COOH, -COORA, -CORa, -S02Ra, -CONHz, -SO2NH2, -CONHRA, -so2nhra, -conrarb, -so2nrarb, -nh2, -nhra, -nrarb, -oconh2, -oconhra, - OCONRARB, -NHCORA, -NHbCOORa, -NRbCOORa, -NHS020Ra, -NRbS020Ra, -NHC0NH2, -NRaCONH2, -NHCONHR6, -NRaCONHR, -NHCONRaRb eller -NRACONRARB hvor RA og RB er uafhængigt en (CiC6)alkylgruppe, eller RA og RB når forbundet til det samme nitrogen kan danne en cyklisk amino-ring valgt fra en morpholinyl-, piperidinyl- eller piperazinyl-ring.
3. Forbindelse ifølge krav 1 eller krav 2, hvor RA er hydrogen eller C1-C6 alkyl.
4. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor mindst et Z er H, halogen, eventuelt substitueret aryl, eventuelt substitueret heteroaryl, eventuelt substitueret nitrogen-indeholdende heterocykel, Ci til C6 alkyl eller 0RA.
5. Forbindelse ifølge et hvilket som helst af kravene 1 til 3, hvor mindst et Z er (Alk)n-eventuelt substitueret arylen-(Alk)n-eventuelt substitueret heterocykel.
6. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor Ri er H og hvor Y er phenyl.
7. Forbindelse ifølge et hvilket som helst af de foregående krav, hvilken har formlen la:
eller et farmaceutisk acceptabelt salt deraf, hvor: Zi og Z2 er uafhængigt (Alk)n-Rn-(Alk)n-X; og Alk, n, R, X, Y, RA og R1 er som defineret i krav 1.
8. Forbindelse ifølge krav 7, hvor Zi er halogen, phenyl, ORA eller Ci til Ce alkyl, og Z2 er eventuelt substitueret aryl eller eventuelt substitueret heterocykel, eller hvor Z2 er halogen, CF3, cyklopropyl, phenyl, ORA eller Ci til C6 alkyl, og Zi er eventuelt substitueret aryl eller eventuelt substitueret heterocykel.
9. Forbindelse ifølge et hvilket som helst af de foregående krav, hvor heterocyklen eller den nitrogen-indeholdende heterocykel er en eventuelt substitueret piperidin, piperazin eller morpholin.
10. Forbindelse ifølge et hvilket som helst af de foregående krav, hvilken er en af forbindelserne anført nedenfor, eller et farmaceutisk acceptabelt salt deraf: l-Benzyl-lH-pyrazol-4-carboxylsyre (5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl)-amid; l-Benzyl-lH-pyrazol-4-carboxylsyre (lH-pyrrolo[2,3-b]pyridin-3-yl)-amid; l-Benzyl-lH-pyrazol-4-carboxylsyre (4-brom-lH-pyrrolo[2,3-b]pyridin-3-yl)-amid; l-Benzyl-lH-pyrazol-4-carboxylsyre (5-phenyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-amid; eller l-Benzyl-lH-pyrazol-4-carboxylsyre (5-piperidin-l-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-amid. N-{4-[(3R)-3-Aminopiperidin-l-yl]-5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl>- l-benzyl-lH-pyrazol-4-carboxamid l-Benzyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-pyrrolidin-l-yl)-5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-brom-4-((R)-3-methylamino-piperidin-l-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-brom-4-((R)-3-ethylamino-piperidin-l-yl)-lH-pyrrolo[2(3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-brom-4-((R)-3-hydroxy-pyrrolidin-l-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-brom-4-((R)-3-hydroxy-piperidin-l-yl)-l H-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-brom-4-(3-dimethylamino-piperidin-l-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-brom-4-[(R)-3-(cyclopentylmethyl-amino)-piperidin-l-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl>-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-brom-4-((R)-3-isobutylamino-piperidin-l-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-brom-4-[(R)-3-(2,2-dimethyl-propylamino)-piperidin-l-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-brom-4-[(R)-3-(cyclopropylmethyl-amino)-pipendin-l-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}-amid l-(4-Fluor-benzyl)-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-brom-l H-pyrrolo[2,3-b]pyridin-3-yl]-amid l-(4-Chlor-benzyl)-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-(4-Methyl-benzyl)-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-(4-Methoxy-benzyl)-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Pyridin-2-ylmethyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Pyridin-3-ylmethyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Pyridin-4-ylmethyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid N-{4-[(3R)-3-aminopiperidin-l-yl]-5-chlor-lH-pyrrolo[2,3-b]pyridin-3-yl}- l-benzyl-lH-pyrazol-4-carboxamid l-(4-Methyl-benzyl)-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-chlor-l H-pyrrolo[2,3-b]pyridin-3-yl]-amid l-(4-Fluor-benzyl)-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-chlor-l H-pyrrolo[2,3-b]pyridin-3-yl]-amid l-(4-Chlor-benzyl)-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-chlor-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-(4-Methoxy-benzyl)-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-chlor-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-pyrrolidin-l-yl)-5-chlor-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid N-{4-[(3R)-3-aminopiperidin-l-yl]-5-cyklopropyl-lH-pyrrolo[2,3-b]pyridin- 3-yl>-l-benzyl-lH-pyrazol-4-carboxamid l-Benzyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-hydroxy-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-(4-piperidin-l-ylmethyl-phenyl)-l H-pyrrolo[2,3-b]pyridin-3-yl]-amid
1-Benzyl-lH-pyrazol-4-carboxylsyre [5-(4-{[(2-methoxy-ethyl)-methyl-amino]-methyl>-phenyl)-l H-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-(4-pyrrolidin-l-ylmethyl-phenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-[4-(4-fluor-piperidin-l-ylmethyl)-phenyl]-lH-pyrrolo[2,3-b]pyridin-3-yl>-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-(4-dimethylaminomethyl-phenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-[4-(3-fluor-piperidin-l-ylmethyl)-phenyl]-lH-pyrrolo[2,3-b]pyridin-3-yl>-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-(4-methylaminomethyl-phenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-(4-morpholin-4-ylmethyl-phenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-[4-(3,3-difluor-pyrrolidin-l-ylmethyl)-phenyl]-lH-pyrrolo[2,3-b]pyridin-3-yl>-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-(3-dimethylaminomethyl-phenyl)-l H-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-[3-(3-fluor-piperidin-l-ylmethyl)-phenyl]-lH-pyrrolo[2,3-b]pyridin-3-yl>-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-[3-(3,3-difluor-piperidin-l-ylmethyl)-phenyl]-lH-pyrrolo[2,3-b]pyridin-3-yl>-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-(3-azetidin-l-ylmethyl-phenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-[3-(3,3-difluor-azetidin-l-ylmethyl)-phenyl]-lH-pyrrolo[2,3-b]pyridin-3-yl>-amid
1- Benzyl-lH-pyrazol-4-carboxylsyre [5-(5-pyrrolidin-l-ylmethyl-thiophen- 2- yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-(5-pyrrolidin-l-ylmethyl-thiophen- 3- yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-[5-(3,3-difluor-azetidin-l-ylmethyl)-thiophen-3-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-(3-pyrrolidin-l-ylmethyl-phenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-fluor-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-phenyl-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-cyano-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-[3-(2-morpholin-4-yl-ethoxy)-phenyl]-lH-pyrrolo[2,3-b]pyridin-3-yl}-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-[3-(3-dimethylamino-2,2-dimethyl-propoxy)-phenyl]-lH-pyrrolo[2,3-b]pyridin-3-yl}-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-[3-(3-morpholin-4-yl-propoxy)-phenyl]-lH-pyrrolo[2,3-b]pyridin-3-yl>-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-[3-(l-methyl-piperidin-3-ylmethoxy)-phenyl]-lH-pyrrolo[2,3-b]pyridin-3-yl>-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-[3-(oxetan-3-yloxy)-phenyl]-lH-pyrrolo[2,3-b]pyridin-3-yl>-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-[3-(2-pyrrolidin-l-yl-ethoxy)-phenyl]-lH-pyrrolo[2,3-b]pyridin-3-yl>-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [4-((3R,4R)-3-amino-4-cyklopropyl-piperidin-l-yl)-5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-(2-fluor-4-pyrrolidin-l-ylmethyl-phenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-(3-pyrrolidin-l-yl-phenyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre [5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Benzyl-lH-pyrazol-4-carboxylsyre (5-pyridin-4-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-amid l-Benzyl-lH-pyrazol-4-carboxylsyre (5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-amid l-(3-Methoxy-benzyl)-lH-pyrazol-4-carboxylsyre (5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl)-amid l-(2-Fluor-benzyl)-lH-pyrazol-4-carboxylsyre (5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl)-amid l-(2-Cyano-benzyl)-lH-pyrazol-4-carboxylsyre (5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl)-amid l-(lH-Pyrrol-2-ylmethyl)-lH-pyrazol-4-carboxylsyre (5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl)-amid l-(4-Fluor-benzyl)-lH-pyrazol-4-carboxylsyre (5-brom-lH-pyrrolo[2,3-b]pyridin-3-yl)-amid l-Benzyl-lH-pyrazol-4-carboxylsyre (5-methyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-amid l-Benzyl-lH-pyrazol-4-carboxylsyre (5-chlor-lH-pyrrolo[2,3-b]pyridin-3-yl)-amid l-(4-Fluor-benzyl)-lH-pyrazol-4-carboxylsyre (5-chlor-l H-pyrrolo[2,3-b]pyridin-3-yl)-amid l-(3-Methoxy-benzyl)-lH-pyrazol-4-carboxylsyre (5-chlor-l H-pyrrolo[2,3-b]pyridin-3-yl)-amid
1-Benzyl-l H-pyrazol-4-carboxylsyre {5-[3-((S)-l-methyl-pyrrolidin-2-ylmethoxy)-phenyl]-l H-pyrrolo[2,3-b]pyridin-3-yl}-amid
1-Benzyl-l H-pyrazol-4-carboxylsyre {5-[3-(l-methyl-piperidin-3-yloxy)-phenyl]-l H-pyrrolo[2,3-b]pyridin-3-yl}-amid
1-Benzyl-l H-pyrazol-4-carboxylsyre {5-[4-(3-dimethylamino-propoxy)-phenyl]-l H-pyrrolo[2,3-b]pyridin-3-yl}-amid l-Benzyl-lH-pyrazol-4-carboxylsyre {5-[l-(2-diethylamino-ethyl)-lH-pyrazol-4-yl]-l H-pyrrolo[2,3-b]pyridin-3-yl}-amid
1-Benzyl-l H-pyrazol-4-carboxylsyre {5-[l-(2-pyrrolidin-l-yl-ethyl)-lH-pyrazol-4-yl]-lH-pyrrolo[2,3-b]pyridin-3-yl}-amid l-Pyridin-4-ylmethyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Pyridin-3-ylmethyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Pyridin-2-ylmethyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Pyridin-3-ylmethyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-chlor-l H-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Pyridin-4-ylmethyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-chlor-l H-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Pyridin-2-ylmethyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-chlor-l H-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Pyridin-4-ylmethyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-methyl-l H-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Pyridin-3-ylmethyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-methyl-l H-pyrrolo[2,3-b]pyridin-3-yl]-amid l-(4-Fluor-benzyl)-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-(3-Methyl-benzyl)-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-(3-Fluor-benzyl)-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-(2-Chlor-benzyl)-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-(2-Methyl-benzyl)-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-(4-Fluor-benzyl)-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-trifluormethyl-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid
1-Benzyl-l H-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-trifluormethyl-1 H-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Pyridin-3-ylmethyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-trifluormethyl-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid l-Pyridin-2-ylmethyl-lH-pyrazol-4-carboxylsyre [4-((R)-3-amino-piperidin-l-yl)-5-trifluormethyl-lH-pyrrolo[2,3-b]pyridin-3-yl]-amid
11. Farmaceutisk sammensætning omfattende en forbindelse af formel I:
(l) eller et farmaceutisk acceptabelt salt deraf, hvor: hvert Z er uafhængigt (Alk)n-Rn-(Alk)n-X, hvor hvert Alk er uafhængigt (Ci til C12) alkylen eller (C2 til C12) alkenylen, hver af hvilke kan eventuelt substitueres; hvert n er uafhængigt 0 eller 1; hvert R er uafhængigt eventuelt substitueret arylen eller heteroarylen, eller eventuelt substitueret cykloalkylen eller heterocykel, -O-, -S-, -(C=0)-, - (C=S)-, -SO2-, -C( = 0)0-, -C(=0)NRA-, -C(=S)NRA-, -S02NRA-, -NRAC(=0)-, -NRAS02- eller -NRA- hvor RA er hydrogen, C1-C6 alkyl, -C1-C6 alkyl(cykloalkyl), C1-C6 alkyl(Ci-Ce alkoxy) eller Ci-Ce alkoxy; hvert X er uafhængigt halogen, -H, -ORA, NRARA, eventuelt substitueret aryl eller heteroaryl, eller eventuelt substitueret cykloalkyl eller heterocykel, CN eller C(halogen)aHb, hvor a er 1, 2, eller 3, og b er (3-a); Y er eventuelt substitueret aryl eller heteroaryl, eller eventuelt substitueret cykloalkyl eller heterocykel; og R1 er H eller C1-C6 alkyl, og en eller flere farmaceutisk acceptable bærere og/eller excipienser.
12. Farmaceutisk sammensætning ifølge krav 11, hvor forbindelsen haret hvilket som helst yderligere kendetegn ifølge et hvilket som helst af kravene 2 til 10.
13. Forbindelse eller sammensætning ifølge et hvilket som helst af de foregående krav, til anvendelse i terapi.
14. Forbindelse til anvendelse ifølge krav 13, til behandlingen afen tilstand, der reagerer på inhibering af proteinkinase-aktivitet, hvor proteinkinasen er CHK1, og hvor tilstanden er valgt fra cancer og autoimmune lidelser.
15. Forbindelse til anvendelse ifølge krav 13, til behandlingen af cancer ved administration i kombination med radioterapi eller kemoterapi.
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WO2003028724A1 (en) * | 2001-10-04 | 2003-04-10 | Smithkline Beecham Corporation | Chk1 kinase inhibitors |
US7531553B2 (en) * | 2003-03-21 | 2009-05-12 | Amgen Inc. | Heterocyclic compounds and methods of use |
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2012
- 2012-01-30 GB GBGB1201566.5A patent/GB201201566D0/en not_active Ceased
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2013
- 2013-01-30 CN CN202010405942.3A patent/CN111484493A/zh active Pending
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