CA3037064A1 - Spirocyclic compounds - Google Patents

Info

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

2016-10-05

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

• Espacenet
• Global Dossier
• CIPO
• Discuss

• 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
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical class CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
• 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
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
• 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
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 18
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 18
• 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 18
• 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
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
• 229910052794 bromium Inorganic materials 0.000 description 16
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
• 150000002431 hydrogen Chemical class 0.000 description 15
• 238000000746 purification Methods 0.000 description 15
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 14
• 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
• 125000002947 alkylene group Chemical group 0.000 description 12
• 150000001408 amides Chemical class 0.000 description 12
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
• 125000006239 protecting group Chemical group 0.000 description 12
• 239000011541 reaction mixture Substances 0.000 description 12
• 238000011282 treatment Methods 0.000 description 12
• 229910021595 Copper(I) iodide Inorganic materials 0.000 description 11
• 239000003153 chemical reaction reagent Substances 0.000 description 11
• 239000000460 chlorine Substances 0.000 description 11
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
• 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
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
• 238000006069 Suzuki reaction reaction Methods 0.000 description 10
• 201000010099 disease Diseases 0.000 description 10
• 229910052736 halogen Inorganic materials 0.000 description 10
• 150000002367 halogens Chemical class 0.000 description 10
• 230000004048 modification Effects 0.000 description 10
• 238000012986 modification Methods 0.000 description 10
• 230000037361 pathway Effects 0.000 description 10
• YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
• 102000043136 MAP kinase family Human genes 0.000 description 9
• 108091054455 MAP kinase family Proteins 0.000 description 9
• 229910052801 chlorine Inorganic materials 0.000 description 9
• 239000007788 liquid Substances 0.000 description 9
• 230000035772 mutation Effects 0.000 description 9
• 238000003786 synthesis reaction Methods 0.000 description 9
• 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
• 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 7
• 239000002253 acid Substances 0.000 description 7
• 238000006880 cross-coupling reaction Methods 0.000 description 7
• 239000012043 crude product Substances 0.000 description 7
• 229940079593 drug Drugs 0.000 description 7
• 150000002148 esters Chemical class 0.000 description 7
• SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 7
• 235000017557 sodium bicarbonate Nutrition 0.000 description 7
• 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
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
• 239000012298 atmosphere Substances 0.000 description 6
• 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
• 235000019253 formic acid Nutrition 0.000 description 6
• 238000005984 hydrogenation reaction Methods 0.000 description 6
• 230000005764 inhibitory process Effects 0.000 description 6
• 238000002347 injection Methods 0.000 description 6
• 239000007924 injection Substances 0.000 description 6
• 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
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