CA3037064A1 - Spirocyclic compounds - Google Patents
Spirocyclic compounds Download PDFInfo
- Publication number
- CA3037064A1 CA3037064A1 CA3037064A CA3037064A CA3037064A1 CA 3037064 A1 CA3037064 A1 CA 3037064A1 CA 3037064 A CA3037064 A CA 3037064A CA 3037064 A CA3037064 A CA 3037064A CA 3037064 A1 CA3037064 A1 CA 3037064A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- cancer
- pharmaceutically acceptable
- acceptable salt
- group
- Prior art date
- 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.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 482
- 238000000034 method Methods 0.000 claims abstract description 182
- 201000011510 cancer Diseases 0.000 claims abstract description 117
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 107
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 53
- 150000003839 salts Chemical class 0.000 claims description 167
- -1 methylbenzoxazolyl Chemical group 0.000 claims description 150
- 125000001424 substituent group Chemical group 0.000 claims description 71
- 125000001072 heteroaryl group Chemical group 0.000 claims description 58
- 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 claims description 47
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
- 125000001153 fluoro group Chemical group F* 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 44
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 239000001257 hydrogen Chemical group 0.000 claims description 37
- 125000000623 heterocyclic group Chemical group 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 32
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 31
- 101000876610 Dictyostelium discoideum Extracellular signal-regulated kinase 2 Proteins 0.000 claims description 29
- 101001052493 Homo sapiens Mitogen-activated protein kinase 1 Proteins 0.000 claims description 29
- 230000000694 effects Effects 0.000 claims description 26
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 25
- 239000003814 drug Substances 0.000 claims description 23
- 230000002401 inhibitory effect Effects 0.000 claims description 23
- 125000004076 pyridyl group Chemical group 0.000 claims description 23
- 108040008097 MAP kinase activity proteins Proteins 0.000 claims description 22
- 102000019149 MAP kinase activity proteins Human genes 0.000 claims description 22
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 19
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 19
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 18
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 18
- 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 17
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical group [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 16
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 15
- 229910052805 deuterium Chemical group 0.000 claims description 14
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 14
- 201000001441 melanoma Diseases 0.000 claims description 13
- 206010009944 Colon cancer Diseases 0.000 claims description 12
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 12
- 208000029742 colonic neoplasm Diseases 0.000 claims description 12
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 claims description 12
- 201000005202 lung cancer Diseases 0.000 claims description 12
- 208000020816 lung neoplasm Diseases 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 206010061902 Pancreatic neoplasm Diseases 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 208000014829 head and neck neoplasm Diseases 0.000 claims description 11
- 208000008443 pancreatic carcinoma Diseases 0.000 claims description 11
- 208000001446 Anaplastic Thyroid Carcinoma Diseases 0.000 claims description 10
- 206010005003 Bladder cancer Diseases 0.000 claims description 10
- 208000034578 Multiple myelomas Diseases 0.000 claims description 10
- 206010029260 Neuroblastoma Diseases 0.000 claims description 10
- 206010033128 Ovarian cancer Diseases 0.000 claims description 10
- 206010061535 Ovarian neoplasm Diseases 0.000 claims description 10
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 10
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 10
- 201000010536 head and neck cancer Diseases 0.000 claims description 10
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 10
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 claims description 10
- 201000002528 pancreatic cancer Diseases 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 10
- 201000002510 thyroid cancer Diseases 0.000 claims description 10
- 201000008440 thyroid gland anaplastic carcinoma Diseases 0.000 claims description 10
- 208000019179 thyroid gland undifferentiated (anaplastic) carcinoma Diseases 0.000 claims description 10
- 208000003174 Brain Neoplasms Diseases 0.000 claims description 9
- 206010006187 Breast cancer Diseases 0.000 claims description 9
- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- 201000009030 Carcinoma Diseases 0.000 claims description 9
- 208000009905 Neurofibromatoses Diseases 0.000 claims description 9
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 9
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 9
- 206010038389 Renal cancer Diseases 0.000 claims description 9
- 206010039491 Sarcoma Diseases 0.000 claims description 9
- 201000001531 bladder carcinoma Diseases 0.000 claims description 9
- 239000003085 diluting agent Substances 0.000 claims description 9
- 208000025113 myeloid leukemia Diseases 0.000 claims description 9
- 201000004931 neurofibromatosis Diseases 0.000 claims description 9
- 201000010174 renal carcinoma Diseases 0.000 claims description 9
- 208000010570 urinary bladder carcinoma Diseases 0.000 claims description 9
- 230000012010 growth Effects 0.000 claims description 8
- 230000010076 replication Effects 0.000 claims description 8
- 125000005059 halophenyl group Chemical group 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 4
- 125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000001425 triazolyl group Chemical group 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 3
- WTTXBWVGGNDSDQ-UMSFTDKQSA-N (5S)-2-[3-(2-methyl-1,3-benzoxazol-5-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-7-[2-[4-[5-(1-methyl-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]-2,7-diazaspiro[4.4]nonan-1-one Chemical compound CN1N=C(N=C1)C1=CN=C(S1)C=1CCN(CC=1)C(CN1C[C@@]2(CCN(C2=O)C2=CC=C3C(=N2)C(=NN3)C=2C=CC3=C(N=C(O3)C)C=2)CC1)=O WTTXBWVGGNDSDQ-UMSFTDKQSA-N 0.000 claims 1
- GJGLAWCBXKJKDU-QNGWXLTQSA-N (5S)-2-[3-(2-methyl-[1,3]oxazolo[4,5-b]pyridin-5-yl)-1H-indazol-5-yl]-7-[2-[4-[4-(1-methyl-1,2,4-triazol-3-yl)phenyl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]-2,7-diazaspiro[4.4]nonan-1-one Chemical compound CN1C=NC(=N1)C1=CC=C(C=C1)C1=CCN(CC1)C(=O)CN1CC[C@]2(CCN(C2=O)C2=CC3=C(NN=C3C3=CC=C4OC(C)=NC4=N3)C=C2)C1 GJGLAWCBXKJKDU-QNGWXLTQSA-N 0.000 claims 1
- YLSRZNAHNMXOHU-YTTGMZPUSA-N (5S)-2-[3-(2-methylpyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-5-yl]-7-[2-[4-[5-(1-methyl-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]-2,7-diazaspiro[4.4]nonan-1-one Chemical compound CN1C=NC(=N1)C1=CN=C(S1)C1=CCN(CC1)C(=O)CN1CC[C@]2(CCN(C2=O)C2=NC3=C(NN=C3C3=CC(C)=NC=C3)C=C2)C1 YLSRZNAHNMXOHU-YTTGMZPUSA-N 0.000 claims 1
- WIRWAVLHCQROQG-ZCQIMEDXSA-N (5S)-7-[1,1-dideuterio-2-[4-[4-(1-methyl-1,2,4-triazol-3-yl)phenyl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]-2-[3-(5-fluoropyridin-2-yl)-1H-indazol-5-yl]-2,7-diazaspiro[4.4]nonan-1-one Chemical compound FC=1C=CC(=NC=1)C1=NNC2=CC=C(C=C12)N1C([C@@]2(CC1)CN(CC2)C(C(=O)N1CCC(=CC1)C1=CC=C(C=C1)C1=NN(C=N1)C)([2H])[2H])=O WIRWAVLHCQROQG-ZCQIMEDXSA-N 0.000 claims 1
- BPGVSQWUBDBBAJ-OZOQSGKISA-N (5S)-7-[1,1-dideuterio-2-[4-[4-(1-methyl-1,2,4-triazol-3-yl)phenyl]-3,6-dihydro-2H-pyridin-1-yl]-2-oxoethyl]-2-[3-(oxan-4-yl)-2H-indazol-5-yl]-2,7-diazaspiro[4.4]nonan-1-one Chemical compound CN1N=C(N=C1)C1=CC=C(C=C1)C=1CCN(CC=1)C(C([2H])([2H])N1C[C@@]2(CCN(C2=O)C=2C=C3C(=NNC3=CC=2)C2CCOCC2)CC1)=O BPGVSQWUBDBBAJ-OZOQSGKISA-N 0.000 claims 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 201
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 148
- 239000000203 mixture Substances 0.000 description 134
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 130
- 125000000217 alkyl group Chemical group 0.000 description 124
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 114
- 238000005160 1H NMR spectroscopy Methods 0.000 description 111
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 86
- 239000000243 solution Substances 0.000 description 82
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 78
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 74
- 239000002904 solvent Substances 0.000 description 70
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
- 125000003118 aryl group Chemical group 0.000 description 53
- 125000000753 cycloalkyl group Chemical group 0.000 description 48
- 239000012044 organic layer Substances 0.000 description 46
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- 239000007832 Na2SO4 Substances 0.000 description 44
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 44
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 44
- 229910052938 sodium sulfate Inorganic materials 0.000 description 44
- 235000011152 sodium sulphate Nutrition 0.000 description 44
- 239000007787 solid Substances 0.000 description 40
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 37
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 36
- 239000002585 base Substances 0.000 description 35
- 230000002829 reductive effect Effects 0.000 description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 30
- 125000004429 atom Chemical group 0.000 description 29
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 28
- 238000004440 column chromatography Methods 0.000 description 28
- 238000010438 heat treatment Methods 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 239000012267 brine Substances 0.000 description 27
- 229910052740 iodine Inorganic materials 0.000 description 27
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 26
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- 125000000392 cycloalkenyl group Chemical group 0.000 description 25
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical group OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 24
- 125000003342 alkenyl group Chemical group 0.000 description 24
- 125000000304 alkynyl group Chemical group 0.000 description 24
- 239000003054 catalyst Substances 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
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- 229910052763 palladium Inorganic materials 0.000 description 22
- 229910000027 potassium carbonate Inorganic materials 0.000 description 22
- 102100028651 Tenascin-N Human genes 0.000 description 20
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 19
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- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 18
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- 101710087911 Tenascin-N Proteins 0.000 description 17
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 17
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- 229910052794 bromium Inorganic materials 0.000 description 16
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- 150000002431 hydrogen Chemical class 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
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- 125000004432 carbon atom Chemical group C* 0.000 description 14
- 235000015320 potassium carbonate Nutrition 0.000 description 14
- 125000003545 alkoxy group Chemical group 0.000 description 13
- 102000016914 ras Proteins Human genes 0.000 description 13
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 12
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- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 11
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- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 9
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 9
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 8
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 125000002252 acyl group Chemical group 0.000 description 8
- 125000004122 cyclic group Chemical group 0.000 description 8
- 235000011181 potassium carbonates Nutrition 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 7
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 7
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- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 7
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
- 239000012824 ERK inhibitor Substances 0.000 description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
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- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 6
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical group [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
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- 238000005984 hydrogenation reaction Methods 0.000 description 6
- 230000005764 inhibitory process Effects 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
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- 230000000670 limiting effect Effects 0.000 description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 6
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Classifications
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- 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
- 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
- A61K31/435—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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
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| PCT/US2017/054865 WO2018067512A1 (en) | 2016-10-05 | 2017-10-03 | Spirocyclic compounds |
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| KR102269032B1 (ko) | 2013-04-19 | 2021-06-24 | 인사이트 홀딩스 코포레이션 | Fgfr 저해제로서 이환식 헤테로사이클 |
| ES2895769T3 (es) | 2015-02-20 | 2022-02-22 | Incyte Corp | Heterociclos bicíclicos como inhibidores de FGFR |
| MA41551A (fr) | 2015-02-20 | 2017-12-26 | Incyte Corp | Hétérocycles bicycliques utilisés en tant qu'inhibiteurs de fgfr4 |
| DK3277690T3 (da) | 2015-04-03 | 2020-05-04 | Recurium Ip Holdings Llc | Spirocykliske forbindelser |
| AR111960A1 (es) | 2017-05-26 | 2019-09-04 | Incyte Corp | Formas cristalinas de un inhibidor de fgfr y procesos para su preparación |
| SG11202010882XA (en) | 2018-05-04 | 2020-11-27 | Incyte Corp | Salts of an fgfr inhibitor |
| SI3788047T1 (sl) | 2018-05-04 | 2024-11-29 | Incyte Corporation | Trdne oblike inhibitorja fgfr in postopki priprave le-teh |
| CA3111878A1 (en) * | 2018-09-07 | 2020-03-12 | Merck Patent Gmbh | 5-morpholin-4-yl-pyrazolo[4,3-b]pyridine derivatives |
| WO2020185532A1 (en) | 2019-03-08 | 2020-09-17 | Incyte Corporation | Methods of treating cancer with an fgfr inhibitor |
| US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
| WO2021067374A1 (en) | 2019-10-01 | 2021-04-08 | Incyte Corporation | Bicyclic heterocycles as fgfr inhibitors |
| US11607416B2 (en) | 2019-10-14 | 2023-03-21 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
| US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
| WO2021113462A1 (en) | 2019-12-04 | 2021-06-10 | Incyte Corporation | Derivatives of an fgfr inhibitor |
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| CN110922421B (zh) * | 2019-12-17 | 2023-05-05 | 安徽英特美科技有限公司 | 一种n-甲基-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯的合成方法 |
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| CN103130775B (zh) | 2011-11-22 | 2015-09-30 | 山东亨利医药科技有限责任公司 | 作为酪氨酸激酶抑制剂的吲哚满酮衍生物 |
| US8987264B2 (en) | 2012-11-09 | 2015-03-24 | Bristol-Myers Squibb Company | 1,3,5-triazine derivatives of spiro bicyclic oxalamide-compounds for treatment of hepatitis C |
| JP6506248B2 (ja) | 2013-03-14 | 2019-04-24 | ゾーン・ロイヤリティズ・アンド・マイルストーンズ・エルエルシー | 二環式鎮痛化合物 |
| WO2016106009A1 (en) | 2014-12-22 | 2016-06-30 | Eli Lilly And Company | Erk inhibitors |
| CN105732636B (zh) * | 2014-12-30 | 2020-04-21 | 广东东阳光药业有限公司 | 杂芳化合物及其在药物中的应用 |
| DK3277690T3 (da) | 2015-04-03 | 2020-05-04 | Recurium Ip Holdings Llc | Spirocykliske forbindelser |
-
2017
- 2017-10-03 BR BR112019005305A patent/BR112019005305A2/pt not_active Application Discontinuation
- 2017-10-03 RU RU2019107667A patent/RU2019107667A/ru not_active Application Discontinuation
- 2017-10-03 MX MX2019003938A patent/MX2019003938A/es unknown
- 2017-10-03 CN CN201780067175.6A patent/CN109890827A/zh active Pending
- 2017-10-03 US US16/336,854 patent/US10934304B2/en not_active Expired - Fee Related
- 2017-10-03 JP JP2019518440A patent/JP6949952B2/ja not_active Expired - Fee Related
- 2017-10-03 WO PCT/US2017/054865 patent/WO2018067512A1/en not_active Ceased
- 2017-10-03 KR KR1020197012021A patent/KR20190075931A/ko not_active Ceased
- 2017-10-03 EP EP17858989.1A patent/EP3523306A4/en not_active Withdrawn
- 2017-10-03 AU AU2017339890A patent/AU2017339890A1/en not_active Abandoned
- 2017-10-03 CA CA3037064A patent/CA3037064A1/en not_active Abandoned
- 2017-10-05 TW TW106134299A patent/TW201817732A/zh unknown
-
2019
- 2019-04-01 IL IL265752A patent/IL265752A/en unknown
-
2020
- 2020-12-18 US US17/127,710 patent/US20210115058A1/en not_active Abandoned
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2021
- 2021-09-22 JP JP2021154677A patent/JP2021193138A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| CN109890827A (zh) | 2019-06-14 |
| JP2021193138A (ja) | 2021-12-23 |
| WO2018067512A8 (en) | 2018-11-01 |
| WO2018067512A1 (en) | 2018-04-12 |
| JP2019534261A (ja) | 2019-11-28 |
| RU2019107667A3 (enExample) | 2021-01-27 |
| MX2019003938A (es) | 2019-06-10 |
| US20210115058A1 (en) | 2021-04-22 |
| KR20190075931A (ko) | 2019-07-01 |
| US10934304B2 (en) | 2021-03-02 |
| IL265752A (en) | 2019-06-30 |
| AU2017339890A1 (en) | 2019-04-11 |
| RU2019107667A (ru) | 2020-11-06 |
| JP6949952B2 (ja) | 2021-10-13 |
| TW201817732A (zh) | 2018-05-16 |
| BR112019005305A2 (pt) | 2019-07-02 |
| EP3523306A1 (en) | 2019-08-14 |
| EP3523306A4 (en) | 2020-05-06 |
| US20200207776A1 (en) | 2020-07-02 |
| NZ751398A (en) | 2021-03-26 |
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| FZDE | Discontinued |
Effective date: 20240116 |