AU2013213954B2 - 1H-pyrrolo[2,3-b] pyridine derivatives and their use as kinase inhibitors - Google Patents

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Publication number

AU2013213954B2

AU2013213954B2 AU2013213954A AU2013213954A AU2013213954B2 AU 2013213954 B2 AU2013213954 B2 AU 2013213954B2 AU 2013213954 A AU2013213954 A AU 2013213954A AU 2013213954 A AU2013213954 A AU 2013213954A AU 2013213954 B2 AU2013213954 B2 AU 2013213954B2

Authority

AU

Australia

Prior art keywords

pyrrolo

pyrazole

carboxylic acid

amide

benzyl

Prior art date

2012-01-30

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

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• 150000005258 1H-pyrrolo(2,3-b)pyridines Chemical class 0.000 title description 5
• 229940043355 kinase inhibitor Drugs 0.000 title description 3
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 3
• 150000001875 compounds Chemical class 0.000 claims abstract description 365
• 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 128
• 239000000203 mixture Substances 0.000 claims description 68
• 238000000034 method Methods 0.000 claims description 66
• -1 pyrrolo[2,3-b]pyridin-4-yl Chemical group 0.000 claims description 59
• NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 28
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 26
• 125000000623 heterocyclic group Chemical group 0.000 claims description 26
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
• 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 23
• 206010028980 Neoplasm Diseases 0.000 claims description 21
• 229910052736 halogen Inorganic materials 0.000 claims description 20
• 150000002367 halogens Chemical group 0.000 claims description 20
• 125000003107 substituted aryl group Chemical group 0.000 claims description 19
• 125000001072 heteroaryl group Chemical group 0.000 claims description 17
• 150000003839 salts Chemical class 0.000 claims description 17
• 229910052739 hydrogen Inorganic materials 0.000 claims description 15
• RJAFVJZCUMEOBR-UHFFFAOYSA-N 1-(pyridin-4-ylmethyl)pyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=NC=C1 RJAFVJZCUMEOBR-UHFFFAOYSA-N 0.000 claims description 13
• 238000011282 treatment Methods 0.000 claims description 13
• 229910052799 carbon Inorganic materials 0.000 claims description 12
• 201000011510 cancer Diseases 0.000 claims description 11
• 230000000694 effects Effects 0.000 claims description 11
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
• WCMWZVWZYCRAIW-UHFFFAOYSA-N 1-(pyridin-3-ylmethyl)pyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=CN=C1 WCMWZVWZYCRAIW-UHFFFAOYSA-N 0.000 claims description 10
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
• 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 10
• 239000000460 chlorine Chemical group 0.000 claims description 9
• 239000001257 hydrogen Substances 0.000 claims description 9
• 241000124008 Mammalia Species 0.000 claims description 7
• 102000001253 Protein Kinase Human genes 0.000 claims description 7
• 125000002947 alkylene group Chemical group 0.000 claims description 7
• 230000005764 inhibitory process Effects 0.000 claims description 7
• 108060006633 protein kinase Proteins 0.000 claims description 7
• SOUZKMFQFRDGKE-UHFFFAOYSA-N 1-(pyridin-2-ylmethyl)pyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=CC=N1 SOUZKMFQFRDGKE-UHFFFAOYSA-N 0.000 claims description 6
• 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 6
• 125000004450 alkenylene group Chemical group 0.000 claims description 6
• 150000001408 amides Chemical class 0.000 claims description 6
• ACKKVNVNGUYIAR-UHFFFAOYSA-N 1-[(3-methoxyphenyl)methyl]pyrazole-4-carboxylic acid Chemical compound COC1=CC=CC(CN2N=CC(=C2)C(O)=O)=C1 ACKKVNVNGUYIAR-UHFFFAOYSA-N 0.000 claims description 5
• IKIIMRKHGIWFEP-UHFFFAOYSA-N 1-[(4-chlorophenyl)methyl]pyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=C(Cl)C=C1 IKIIMRKHGIWFEP-UHFFFAOYSA-N 0.000 claims description 5
• 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 5
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical class C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 5
• 239000002253 acid Substances 0.000 claims description 5
• 125000000732 arylene 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
• 125000005549 heteroarylene group Chemical group 0.000 claims description 5
• 150000002431 hydrogen Chemical class 0.000 claims description 5
• 239000008194 pharmaceutical composition Substances 0.000 claims description 5
• 125000005717 substituted cycloalkylene group Chemical group 0.000 claims description 5
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
• 125000004076 pyridyl group Chemical group 0.000 claims description 4
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 4
• ALSCRMRUUIZZBO-UHFFFAOYSA-N 1-[(2-cyanophenyl)methyl]pyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=CC=C1C#N ALSCRMRUUIZZBO-UHFFFAOYSA-N 0.000 claims description 3
• SEVWRBACKOQREE-UHFFFAOYSA-N 1-[(2-fluorophenyl)methyl]pyrazole-4-carboxylic acid Chemical compound C1=C(C(=O)O)C=NN1CC1=CC=CC=C1F SEVWRBACKOQREE-UHFFFAOYSA-N 0.000 claims description 3
• 208000023275 Autoimmune disease Diseases 0.000 claims description 3
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
• 210000000056 organ Anatomy 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• 238000001959 radiotherapy Methods 0.000 claims description 3
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
• 238000002560 therapeutic procedure Methods 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 2
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
• 206010052779 Transplant rejections Diseases 0.000 claims description 2
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
• 229910052794 bromium Inorganic materials 0.000 claims description 2
• 229910052801 chlorine Chemical group 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 206010025135 lupus erythematosus Diseases 0.000 claims description 2
• DUAGZNPOPXJGOT-UHFFFAOYSA-N n-(5-bromo-1h-pyrrolo[2,3-b]pyridin-3-yl)-1-(1h-pyrrol-2-ylmethyl)pyrazole-4-carboxamide Chemical compound C12=CC(Br)=CN=C2NC=C1NC(=O)C(=C1)C=NN1CC1=CC=CN1 DUAGZNPOPXJGOT-UHFFFAOYSA-N 0.000 claims description 2
• 201000008482 osteoarthritis Diseases 0.000 claims description 2
• 150000003053 piperidines Chemical class 0.000 claims description 2
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
• 229910052727 yttrium Inorganic materials 0.000 claims description 2
• 101000777293 Homo sapiens Serine/threonine-protein kinase Chk1 Proteins 0.000 claims 2
• 102100031081 Serine/threonine-protein kinase Chk1 Human genes 0.000 claims 2
• 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
• VAZGKVZODODPDU-UHFFFAOYSA-N 1-benzyl-n-(5-methyl-1h-pyrrolo[2,3-b]pyridin-3-yl)pyrazole-4-carboxamide Chemical compound C12=CC(C)=CN=C2NC=C1NC(=O)C(=C1)C=NN1CC1=CC=CC=C1 VAZGKVZODODPDU-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
• LNYMJXVFIFMSOW-UHFFFAOYSA-N 1-benzylpyrazole-4-carboxamide Chemical compound C1=C(C(=O)N)C=NN1CC1=CC=CC=C1 LNYMJXVFIFMSOW-UHFFFAOYSA-N 0.000 claims 1
• ZVXKYWHJBYIYNI-UHFFFAOYSA-N 1h-pyrazole-4-carboxamide Chemical compound NC(=O)C=1C=NNC=1 ZVXKYWHJBYIYNI-UHFFFAOYSA-N 0.000 claims 1
• RTADYVMNEDWFEV-SSDOTTSWSA-N 4-[(3R)-3-aminopiperidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine Chemical compound C1[C@H](N)CCCN1C1=C(C(F)(F)F)C=NC2=C1C(N)=CN2 RTADYVMNEDWFEV-SSDOTTSWSA-N 0.000 claims 1
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