CA3020778A1 - Heterocyclic compounds as ret kinase inhibitors - Google Patents

Info

Publication number

CA3020778A1

CA3020778A1 CA3020778A CA3020778A CA3020778A1 CA 3020778 A1 CA3020778 A1 CA 3020778A1 CA 3020778 A CA3020778 A CA 3020778A CA 3020778 A CA3020778 A CA 3020778A CA 3020778 A1 CA3020778 A1 CA 3020778A1

Authority

CA

Canada

Prior art keywords

amino

alkyl

pyrazolo

pyrimidin

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.)

Pending

Links

• Espacenet
• Global Dossier
• CIPO
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• 229940043355 kinase inhibitor Drugs 0.000 title description 7
• 239000003757 phosphotransferase inhibitor Substances 0.000 title description 7
• 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
• 150000001875 compounds Chemical class 0.000 claims abstract description 280
• 238000000034 method Methods 0.000 claims abstract description 69
• 238000011282 treatment Methods 0.000 claims abstract description 42
• 206010028980 Neoplasm Diseases 0.000 claims abstract description 34
• 201000011510 cancer Diseases 0.000 claims abstract description 28
• 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 24
• 125000000217 alkyl group Chemical group 0.000 claims description 384
• -1 cyano, hydroxy, carboxy, carbamoyl Chemical group 0.000 claims description 234
• 229910052739 hydrogen Inorganic materials 0.000 claims description 225
• 239000001257 hydrogen Substances 0.000 claims description 224
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 132
• 125000001424 substituent group Chemical group 0.000 claims description 129
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 117
• 125000001072 heteroaryl group Chemical group 0.000 claims description 92
• 125000003118 aryl group Chemical group 0.000 claims description 90
• 150000003839 salts Chemical class 0.000 claims description 90
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 88
• 125000001188 haloalkyl group Chemical group 0.000 claims description 84
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 83
• 125000000623 heterocyclic group Chemical group 0.000 claims description 81
• 239000012453 solvate Substances 0.000 claims description 81
• 125000003545 alkoxy group Chemical group 0.000 claims description 80
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 72
• 229910052757 nitrogen Inorganic materials 0.000 claims description 61
• 125000003282 alkyl amino group Chemical group 0.000 claims description 54
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 49
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 39
• 125000002947 alkylene group Chemical group 0.000 claims description 35
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 31
• 125000000304 alkynyl group Chemical group 0.000 claims description 26
• 229910052799 carbon Inorganic materials 0.000 claims description 23
• 150000002431 hydrogen Chemical group 0.000 claims description 19
• 229910052760 oxygen Inorganic materials 0.000 claims description 19
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 16
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 14
• 208000023356 medullary thyroid gland carcinoma Diseases 0.000 claims description 12
• 229910052717 sulfur Inorganic materials 0.000 claims description 12
• 125000003342 alkenyl group Chemical group 0.000 claims description 10
• 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 9
• 238000002560 therapeutic procedure Methods 0.000 claims description 8
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 7
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 7
• 125000001425 triazolyl group Chemical group 0.000 claims description 7
• 125000002883 imidazolyl group Chemical group 0.000 claims description 6
• 125000002971 oxazolyl group Chemical group 0.000 claims description 6
• 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
• 125000004076 pyridyl group Chemical group 0.000 claims description 5
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 5
• 125000000335 thiazolyl group Chemical group 0.000 claims description 5
• 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 5
• 208000009018 Medullary thyroid cancer Diseases 0.000 claims description 4
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
• 125000001113 thiadiazolyl group Chemical group 0.000 claims description 4
• RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 2
• 229910052736 halogen Inorganic materials 0.000 claims description 2
• 150000002367 halogens Chemical class 0.000 claims description 2
• 229910052705 radium Inorganic materials 0.000 claims description 2
• 229910052701 rubidium Inorganic materials 0.000 claims description 2
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
• 125000001475 halogen functional group Chemical group 0.000 claims 29
• DSKWNVPCROYIQW-UHFFFAOYSA-N 2-(4-amino-1-cyclobutylpyrazolo[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)C1CCC1 DSKWNVPCROYIQW-UHFFFAOYSA-N 0.000 claims 1
• JATHVEVHCNBUNG-UHFFFAOYSA-N 2-(4-amino-1-cyclohexylpyrazolo[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)C1CCCCC1 JATHVEVHCNBUNG-UHFFFAOYSA-N 0.000 claims 1
• QBXTYIQNVFGQQN-UHFFFAOYSA-N 2-(4-amino-1-propan-2-ylpyrazolo[4,3-c]pyridin-3-yl)-3-chloro-N-methyl-1H-indole-6-carboxamide Chemical compound NC1=NC=CC2=C1C(=NN2C(C)C)C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC QBXTYIQNVFGQQN-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
• JENIHZJYWBWMAT-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-1H-indole-6-carboxylic acid Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)O)C(C)(C)C JENIHZJYWBWMAT-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
• JONUNFKBZRKJSB-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-(oxan-4-yl)-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC1CCOCC1)C(C)(C)C JONUNFKBZRKJSB-UHFFFAOYSA-N 0.000 claims 1
• ACNNJWMMLBYERQ-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-(2-hydroxyethyl)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)CCO)C(C)(C)C ACNNJWMMLBYERQ-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
• XEDLQHAQDJOFQI-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-(2-morpholin-4-ylethyl)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)CCN1CCOCC1)C(C)(C)C XEDLQHAQDJOFQI-UHFFFAOYSA-N 0.000 claims 1
• ZLLYPULBPHUOLR-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-[1-[2-(dimethylamino)ethyl]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)CCN(C)C)C(C)(C)C ZLLYPULBPHUOLR-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
• FFPFOCJSSHPGFQ-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-cyclopropyl-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC1CC1)C(C)(C)C FFPFOCJSSHPGFQ-UHFFFAOYSA-N 0.000 claims 1
• PYVFQLBTKLTYTG-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-ethyl-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NCC)C(C)(C)C PYVFQLBTKLTYTG-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
• JPKMVXLPXRWJMH-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[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)C(C)(C)C JPKMVXLPXRWJMH-UHFFFAOYSA-N 0.000 claims 1
• MERLQASBRDWKDQ-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C1=C(C=2C(=NC(=CC=2)C(=O)NC)N1)Cl)C(C)(C)C MERLQASBRDWKDQ-UHFFFAOYSA-N 0.000 claims 1
• QYNGSKKAMMMUSU-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-phenyl-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC1=CC=CC=C1)C(C)(C)C QYNGSKKAMMMUSU-UHFFFAOYSA-N 0.000 claims 1
• AHVGUCBWHJIREZ-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-3-chloro-N-propan-2-yl-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC(C)C)C(C)(C)C AHVGUCBWHJIREZ-UHFFFAOYSA-N 0.000 claims 1
• ZKCVPKGPHDGZDJ-UHFFFAOYSA-N 2-(4-amino-1-tert-butylpyrazolo[3,4-d]pyrimidin-3-yl)-N,1-dimethylindole-6-carboxamide Chemical compound CNC(=O)c1ccc2cc(-c3nn(c4ncnc(N)c34)C(C)(C)C)n(C)c2c1 ZKCVPKGPHDGZDJ-UHFFFAOYSA-N 0.000 claims 1
• VYARLCVNNHTNAM-UHFFFAOYSA-N 2-(4-amino-7-propan-2-ylimidazo[5,1-f][1,2,4]triazin-5-yl)-3-chloro-N-methyl-1H-indole-6-carboxamide Chemical compound NC1=NC=NN2C1=C(N=C2C(C)C)C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC VYARLCVNNHTNAM-UHFFFAOYSA-N 0.000 claims 1
• DILHJTZQDCOPRO-UHFFFAOYSA-N 2-(4-amino-7-propan-2-ylpyrrolo[2,1-f][1,2,4]triazin-5-yl)-3-chloro-N-methyl-1H-indole-6-carboxamide Chemical compound NC1=NC=NN2C1=C(C=C2C(C)C)C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC DILHJTZQDCOPRO-UHFFFAOYSA-N 0.000 claims 1
• ZWNXAOSIOZQDJI-UHFFFAOYSA-N 2-(4-amino-7-propan-2-ylpyrrolo[2,3-d]pyrimidin-5-yl)-3-chloro-N-methyl-1H-indole-6-carboxamide Chemical compound NC=1C2=C(N=CN=1)N(C=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC)C(C)C ZWNXAOSIOZQDJI-UHFFFAOYSA-N 0.000 claims 1
• BYSACNLCTNNHPN-UHFFFAOYSA-N 2-(4-amino-7-propan-2-ylpyrrolo[2,3-d]pyrimidin-5-yl)-N-methyl-1H-indole-6-carboxamide Chemical compound CNC(=O)c1ccc2cc([nH]c2c1)-c1cn(C(C)C)c2ncnc(N)c12 BYSACNLCTNNHPN-UHFFFAOYSA-N 0.000 claims 1
• PROVTCUQULPWSW-UHFFFAOYSA-N 2-(4-aminothieno[2,3-d]pyrimidin-5-yl)-3-chloro-N-methyl-1H-indole-6-carboxamide Chemical compound NC=1C2=C(N=CN=1)SC=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC PROVTCUQULPWSW-UHFFFAOYSA-N 0.000 claims 1
• IHZHNFHAODVCHG-UHFFFAOYSA-N 2-(4-aminothieno[2,3-d]pyrimidin-5-yl)-N-methyl-1H-indole-6-carboxamide Chemical compound CNC(=O)c1ccc2cc([nH]c2c1)-c1csc2ncnc(N)c12 IHZHNFHAODVCHG-UHFFFAOYSA-N 0.000 claims 1
• VDNPELONOYHGLO-UHFFFAOYSA-N 2-(8-amino-3-propan-2-ylimidazo[1,5-a]pyrazin-1-yl)-N-methyl-1H-indole-6-carboxamide Chemical compound CNC(=O)c1ccc2cc([nH]c2c1)-c1nc(C(C)C)n2ccnc(N)c12 VDNPELONOYHGLO-UHFFFAOYSA-N 0.000 claims 1
• CZHZUJVGXKKWOK-UHFFFAOYSA-N 2-[4-amino-1-(1-methylpiperidin-4-yl)pyrazolo[3,4-d]pyrimidin-3-yl]-3-chloro-N-cyclopropyl-1H-indole-6-carboxamide Chemical compound NC1=C2C(=NC=N1)N(N=C2C=1NC2=CC(=CC=C2C=1Cl)C(=O)NC1CC1)C1CCN(CC1)C CZHZUJVGXKKWOK-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
• ZMQADKSJKPBTEQ-UHFFFAOYSA-N 2-[4-amino-1-(2-aminoethyl)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)CCN ZMQADKSJKPBTEQ-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
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• 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 1
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