ES2886587T3 - Compuestos heterocíclicos como inhibidores de la quinasa RET - Google Patents

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Publication number

ES2886587T3

ES2886587T3 ES17719687T ES17719687T ES2886587T3 ES 2886587 T3 ES2886587 T3 ES 2886587T3 ES 17719687 T ES17719687 T ES 17719687T ES 17719687 T ES17719687 T ES 17719687T ES 2886587 T3 ES2886587 T3 ES 2886587T3

Authority

ES

Spain

Prior art keywords

alkyl

hydrogen

amino

carboxamide

indole

Prior art date

2016-04-15

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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• 229940043355 kinase inhibitor Drugs 0.000 title description 8
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 8
• 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 375
• 150000001875 compounds Chemical class 0.000 claims abstract description 271
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 248
• 239000001257 hydrogen Substances 0.000 claims abstract description 247
• -1 cyano, hydroxy , carboxy, carbamoyl Chemical group 0.000 claims abstract description 200
• 125000001424 substituent group Chemical group 0.000 claims abstract description 144
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 138
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 128
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 101
• 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 100
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 100
• 125000001188 haloalkyl group Chemical group 0.000 claims abstract description 93
• 125000004438 haloalkoxy group Chemical group 0.000 claims abstract description 92
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 88
• 125000003118 aryl group Chemical group 0.000 claims abstract description 88
• 150000003839 salts Chemical class 0.000 claims abstract description 87
• 239000012453 solvate Substances 0.000 claims abstract description 81
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 72
• 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 63
• 229910052760 oxygen Inorganic materials 0.000 claims abstract description 61
• 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 58
• 125000000392 cycloalkenyl group Chemical group 0.000 claims abstract description 54
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract description 53
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 44
• 125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 43
• 229910052799 carbon Inorganic materials 0.000 claims abstract description 40
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 39
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 34
• 125000000304 alkynyl group Chemical group 0.000 claims abstract description 30
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 28
• 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 20
• 125000004663 dialkyl amino group Chemical group 0.000 claims abstract description 18
• 125000004103 aminoalkyl group Chemical group 0.000 claims abstract description 15
• 229910052703 rhodium Inorganic materials 0.000 claims abstract description 15
• 125000003342 alkenyl group Chemical group 0.000 claims abstract description 11
• 125000002883 imidazolyl group Chemical group 0.000 claims abstract description 8
• 125000001715 oxadiazolyl group Chemical group 0.000 claims abstract description 8
• 125000002971 oxazolyl group Chemical group 0.000 claims abstract description 8
• 125000003226 pyrazolyl group Chemical group 0.000 claims abstract description 8
• 125000003831 tetrazolyl group Chemical group 0.000 claims abstract description 8
• 125000001425 triazolyl group Chemical group 0.000 claims abstract description 8
• 125000000335 thiazolyl group Chemical group 0.000 claims abstract description 7
• 125000004076 pyridyl group Chemical group 0.000 claims abstract description 6
• 125000000168 pyrrolyl group Chemical group 0.000 claims abstract description 6
• RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims abstract description 5
• 229910052705 radium Inorganic materials 0.000 claims abstract description 4
• 229910052701 rubidium Inorganic materials 0.000 claims abstract description 4
• 125000001113 thiadiazolyl group Chemical group 0.000 claims abstract description 4
• 101150110809 ORM1 gene Proteins 0.000 claims abstract description 3
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims abstract description 3
• 150000002431 hydrogen Chemical group 0.000 claims abstract 7
• 239000000203 mixture Substances 0.000 claims description 88
• 238000011282 treatment Methods 0.000 claims description 41
• 206010028980 Neoplasm Diseases 0.000 claims description 33
• 201000011510 cancer Diseases 0.000 claims description 25
• 239000008194 pharmaceutical composition Substances 0.000 claims description 21
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 16
• 208000023356 medullary thyroid gland carcinoma Diseases 0.000 claims description 10
• 208000009018 Medullary thyroid cancer Diseases 0.000 claims description 8
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 6
• 238000002560 therapeutic procedure Methods 0.000 claims description 6
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 229910052736 halogen Inorganic materials 0.000 claims description 3
• 150000002367 halogens Chemical class 0.000 claims description 3
• UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 claims description 3
• HZTDCOHZKXSXBA-UHFFFAOYSA-N NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1)C(=O)NC)C(C)(C)C Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1)C(=O)NC)C(C)(C)C HZTDCOHZKXSXBA-UHFFFAOYSA-N 0.000 claims description 2
• HKSZYXFMRVEQGF-UHFFFAOYSA-N NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1)C(=O)NC)C(C)C Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1)C(=O)NC)C(C)C HKSZYXFMRVEQGF-UHFFFAOYSA-N 0.000 claims description 2
• LRVFBQIOCULFNX-UHFFFAOYSA-N NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1)C(=O)NC1=NN(C=C1)C)C(C)(C)C Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1)C(=O)NC1=NN(C=C1)C)C(C)(C)C LRVFBQIOCULFNX-UHFFFAOYSA-N 0.000 claims description 2
• 208000032839 leukemia Diseases 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 29
• 206010058467 Lung neoplasm malignant Diseases 0.000 claims 2
• 201000005202 lung cancer Diseases 0.000 claims 2
• 208000020816 lung neoplasm Diseases 0.000 claims 2
• RWRGPXWEFDKJOP-UHFFFAOYSA-N 1-methylindole-6-carboxamide Chemical compound C1=C(C(N)=O)C=C2N(C)C=CC2=C1 RWRGPXWEFDKJOP-UHFFFAOYSA-N 0.000 claims 1
• OGUFXWBZNKEOCD-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-bromo-N-methyl-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Br)C(=O)NC)C(C)(C)C OGUFXWBZNKEOCD-UHFFFAOYSA-N 0.000 claims 1
• XKSROQSJCOMSFN-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(2-hydroxyethyl)-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NCCO)C(C)(C)C XKSROQSJCOMSFN-UHFFFAOYSA-N 0.000 claims 1
• GATYLOYCUAPWMB-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(2-morpholin-4-ylethyl)-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NCCN1CCOCC1)C(C)(C)C GATYLOYCUAPWMB-UHFFFAOYSA-N 0.000 claims 1
• MJSDVPHVJFPGEB-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(3-piperidin-1-ylpropyl)-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NCCCN1CCCCC1)C(C)(C)C MJSDVPHVJFPGEB-UHFFFAOYSA-N 0.000 claims 1
• RAKDOBWGYQVOPT-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-(2-methoxyethyl)pyrazol-3-yl]-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC1=NN(C=C1)CCOC)C(C)(C)C RAKDOBWGYQVOPT-UHFFFAOYSA-N 0.000 claims 1
• CDNJXEIHIBWNAM-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[2-(2-morpholin-4-ylethoxy)ethyl]-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NCCOCCN1CCOCC1)C(C)(C)C CDNJXEIHIBWNAM-UHFFFAOYSA-N 0.000 claims 1
• SVRNPAWUQSRQDR-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methoxy-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NOC)C(C)(C)C SVRNPAWUQSRQDR-UHFFFAOYSA-N 0.000 claims 1
• HDRICYBPUIHGFB-UHFFFAOYSA-N 2-[4-amino-1-(1-methylsulfonylpiperidin-4-yl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N-methyl-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC)C1CCN(CC1)S(=O)(=O)C HDRICYBPUIHGFB-UHFFFAOYSA-N 0.000 claims 1
• MTVIBLNIVAZDBD-UHFFFAOYSA-N 2-[4-amino-1-(2-hydroxyethyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N-methyl-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC)CCO MTVIBLNIVAZDBD-UHFFFAOYSA-N 0.000 claims 1
• VEEAEHXPQMQIAP-UHFFFAOYSA-N 2-[4-amino-1-(3-methoxypropyl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N-methyl-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC)CCCOC VEEAEHXPQMQIAP-UHFFFAOYSA-N 0.000 claims 1
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 1
• 208000003174 Brain Neoplasms Diseases 0.000 claims 1
• 206010006187 Breast cancer Diseases 0.000 claims 1
• 208000026310 Breast neoplasm Diseases 0.000 claims 1
• 206010009944 Colon cancer Diseases 0.000 claims 1
• CYVKVOPCYGSDOV-UHFFFAOYSA-N NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1)C(=O)N)C(C)(C)C Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1)C(=O)N)C(C)(C)C CYVKVOPCYGSDOV-UHFFFAOYSA-N 0.000 claims 1
• MZFCMOLBCALXEP-UHFFFAOYSA-N NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)N(C)C)C(C)(C)C Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)N(C)C)C(C)(C)C MZFCMOLBCALXEP-UHFFFAOYSA-N 0.000 claims 1
• ZELOUUNVLVPBJP-UHFFFAOYSA-N NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC)C Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC)C ZELOUUNVLVPBJP-UHFFFAOYSA-N 0.000 claims 1
• WQTOJCOBZONGBQ-UHFFFAOYSA-N NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC)C(C)C Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC)C(C)C WQTOJCOBZONGBQ-UHFFFAOYSA-N 0.000 claims 1
• GIPYCLYLHPZHLE-UHFFFAOYSA-N NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NCCCN(C)C)C(C)(C)C Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NCCCN(C)C)C(C)(C)C GIPYCLYLHPZHLE-UHFFFAOYSA-N 0.000 claims 1
• UTEHJJONBHRFOU-UHFFFAOYSA-N NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NCCCN1CCOCC1)C(C)(C)C Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NCCCN1CCOCC1)C(C)(C)C UTEHJJONBHRFOU-UHFFFAOYSA-N 0.000 claims 1
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• ZUWBNSACERMTQQ-UHFFFAOYSA-N NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NCCOCCN(C)C)C(C)(C)C Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NCCOCCN(C)C)C(C)(C)C ZUWBNSACERMTQQ-UHFFFAOYSA-N 0.000 claims 1
• KSCPVLNFZOVQNN-UHFFFAOYSA-N NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NCCOCCOC)C(C)(C)C Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NCCOCCOC)C(C)(C)C KSCPVLNFZOVQNN-UHFFFAOYSA-N 0.000 claims 1
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• 206010061902 Pancreatic neoplasm Diseases 0.000 claims 1
• 206010060862 Prostate cancer Diseases 0.000 claims 1
• 208000000236 Prostatic Neoplasms Diseases 0.000 claims 1
• 208000000453 Skin Neoplasms Diseases 0.000 claims 1
• UTHPECSQYAWGLE-UHFFFAOYSA-N [2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-1H-indol-6-yl]-pyrrolidin-1-ylmethanone Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)N1CCCC1)C(C)(C)C UTHPECSQYAWGLE-UHFFFAOYSA-N 0.000 claims 1
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• 125000005843 halogen group Chemical group 0.000 abstract description 102
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 132
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• 235000019439 ethyl acetate Nutrition 0.000 description 66
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 63
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