CA2772265A1

CA2772265A1 - Pyrazinylpyridines useful for the treatment of proliferative diseases

Pyrazinylpyridines useful for the treatment of proliferative diseases Download PDF

Info

Publication number: CA2772265A1
Authority: CA; Canada
Prior art keywords: alkyl; haloalkyl; branched; pyran; mmol
Prior art date: 2009-09-04
Legal status : Abandoned

Application number

CA2772265A

Other languages

English (en)

French (fr)

Inventor

Paul A. Barsanti

Cheng Hu

Keith B. Pfister

Martin Sendzik

James Sutton

Current Assignee

Novartis AG

Original Assignee

Novartis AG

Priority date

2009-09-04

Filing date

2010-09-02

Publication date

2011-03-10

2010-09-02 Application filed by Novartis AG filed Critical Novartis AG

2011-03-10 Publication of CA2772265A1 publication Critical patent/CA2772265A1/en

Status Abandoned legal-status Critical Current

Links

208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 39
201000010099 disease Diseases 0.000 title claims abstract description 26
230000002062 proliferating effect Effects 0.000 title description 4
IUEQMQXAVZARKU-UHFFFAOYSA-N 2-pyridin-2-ylpyrazine Chemical class N1=CC=CC=C1C1=CN=CC=N1 IUEQMQXAVZARKU-UHFFFAOYSA-N 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 164
150000003839 salts Chemical class 0.000 claims abstract description 38
238000000034 method Methods 0.000 claims abstract description 34
230000001404 mediated effect Effects 0.000 claims abstract description 11
125000000217 alkyl group Chemical group 0.000 claims description 253
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 208
229910052739 hydrogen Inorganic materials 0.000 claims description 123
239000001257 hydrogen Substances 0.000 claims description 122
-1 -O-C1-4 haloalkyl Chemical group 0.000 claims description 111
125000001188 haloalkyl group Chemical group 0.000 claims description 98
229910052736 halogen Chemical group 0.000 claims description 84
150000002367 halogens Chemical group 0.000 claims description 68
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 63
125000001424 substituent group Chemical group 0.000 claims description 44
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 40
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 38
125000001072 heteroaryl group Chemical group 0.000 claims description 36
125000000592 heterocycloalkyl group Chemical group 0.000 claims description 35
102100024457 Cyclin-dependent kinase 9 Human genes 0.000 claims description 28
101000980930 Homo sapiens Cyclin-dependent kinase 9 Proteins 0.000 claims description 28
229910052801 chlorine Inorganic materials 0.000 claims description 27
125000000753 cycloalkyl group Chemical group 0.000 claims description 23
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 19
125000003386 piperidinyl group Chemical group 0.000 claims description 18
125000002947 alkylene group Chemical group 0.000 claims description 17
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 17
239000003814 drug Substances 0.000 claims description 16
229910052757 nitrogen Inorganic materials 0.000 claims description 16
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 15
229910052731 fluorine Inorganic materials 0.000 claims description 15
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
125000003545 alkoxy group Chemical group 0.000 claims description 13
239000008194 pharmaceutical composition Substances 0.000 claims description 13
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 13
125000002757 morpholinyl group Chemical group 0.000 claims description 12
125000004445 cyclohaloalkyl Chemical group 0.000 claims description 11
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
229910052760 oxygen Inorganic materials 0.000 claims description 10
125000004429 atom Chemical group 0.000 claims description 9
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical group C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 8
229910052799 carbon Inorganic materials 0.000 claims description 8
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
238000004519 manufacturing process Methods 0.000 claims description 7
125000004433 nitrogen atom Chemical group N* 0.000 claims description 7
239000000546 pharmaceutical excipient Substances 0.000 claims description 7
125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 6
239000003085 diluting agent Substances 0.000 claims description 6
HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims description 6
ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical group C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 5
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
125000004766 (C3-C6) cyclohaloalkyl group Chemical group 0.000 claims description 4
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 4
ZNGWEEUXTBNKFR-UHFFFAOYSA-N 1,4-oxazepane Chemical group C1CNCCOC1 ZNGWEEUXTBNKFR-UHFFFAOYSA-N 0.000 claims description 4
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
239000003937 drug carrier Substances 0.000 claims description 4
125000003784 fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 4
125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 4
125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
VRYCHOOIFDFVLZ-HZPDHXFCSA-N (1r,3r)-n-[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]-3-(methanesulfonamido)cyclopentane-1-carboxamide Chemical compound C1[C@H](NS(=O)(=O)C)CC[C@H]1C(=O)NC1=CC(C=2N=C(NCC3CCOCC3)C=NC=2)=C(Cl)C=N1 VRYCHOOIFDFVLZ-HZPDHXFCSA-N 0.000 claims description 2
VRYCHOOIFDFVLZ-CVEARBPZSA-N (1r,3s)-n-[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]-3-(methanesulfonamido)cyclopentane-1-carboxamide Chemical compound C1[C@@H](NS(=O)(=O)C)CC[C@H]1C(=O)NC1=CC(C=2N=C(NCC3CCOCC3)C=NC=2)=C(Cl)C=N1 VRYCHOOIFDFVLZ-CVEARBPZSA-N 0.000 claims description 2
VRYCHOOIFDFVLZ-JKSUJKDBSA-N (1s,3r)-n-[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]-3-(methanesulfonamido)cyclopentane-1-carboxamide Chemical compound C1[C@H](NS(=O)(=O)C)CC[C@@H]1C(=O)NC1=CC(C=2N=C(NCC3CCOCC3)C=NC=2)=C(Cl)C=N1 VRYCHOOIFDFVLZ-JKSUJKDBSA-N 0.000 claims description 2
WDEUNOUUUPPGKR-MRXNPFEDSA-N (3r)-n-[5-chloro-4-[3-methyl-6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]piperidine-3-carboxamide Chemical compound N1=C(C=2C(=CN=C(NC(=O)[C@H]3CNCCC3)C=2)Cl)C(C)=NC=C1NCC1CCOCC1 WDEUNOUUUPPGKR-MRXNPFEDSA-N 0.000 claims description 2
GILLIMSAZFNGIM-YSSOQSIOSA-N (3r)-n-[5-chloro-4-[6-(oxan-3-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]piperidine-3-carboxamide Chemical compound C1=C(C=2N=C(NCC3COCCC3)C=NC=2)C(Cl)=CN=C1NC(=O)[C@@H]1CCCNC1 GILLIMSAZFNGIM-YSSOQSIOSA-N 0.000 claims description 2
YLGGCQPECSGIES-OAHLLOKOSA-N (3r)-n-[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]piperidine-3-carboxamide Chemical compound C1=C(C=2N=C(NCC3CCOCC3)C=NC=2)C(Cl)=CN=C1NC(=O)[C@@H]1CCCNC1 YLGGCQPECSGIES-OAHLLOKOSA-N 0.000 claims description 2
XVBHOBXWISVNSU-CQSZACIVSA-N (3r)-n-[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]pyrrolidine-3-carboxamide Chemical compound C1=C(C=2N=C(NCC3CCOCC3)C=NC=2)C(Cl)=CN=C1NC(=O)[C@@H]1CCNC1 XVBHOBXWISVNSU-CQSZACIVSA-N 0.000 claims description 2
HCJZOCWMRHCVJN-OAHLLOKOSA-N (3r)-n-[5-chloro-4-[6-[(2-fluorophenyl)methylamino]pyrazin-2-yl]pyridin-2-yl]piperidine-3-carboxamide Chemical compound FC1=CC=CC=C1CNC1=CN=CC(C=2C(=CN=C(NC(=O)[C@H]3CNCCC3)C=2)Cl)=N1 HCJZOCWMRHCVJN-OAHLLOKOSA-N 0.000 claims description 2
JZIJLCUAAJZXNK-OAHLLOKOSA-N (3r)-n-[5-chloro-4-[6-[(4-fluorophenyl)methylamino]pyrazin-2-yl]pyridin-2-yl]piperidine-3-carboxamide Chemical compound C1=CC(F)=CC=C1CNC1=CN=CC(C=2C(=CN=C(NC(=O)[C@H]3CNCCC3)C=2)Cl)=N1 JZIJLCUAAJZXNK-OAHLLOKOSA-N 0.000 claims description 2
DJKKOGHPJCAZPG-NVXWUHKLSA-N (3r)-n-[5-chloro-4-[6-[[(1r)-1-cyclohexylethyl]amino]pyrazin-2-yl]pyridin-2-yl]piperidine-3-carboxamide Chemical compound N([C@H](C)C1CCCCC1)C(N=1)=CN=CC=1C(C(=CN=1)Cl)=CC=1NC(=O)[C@@H]1CCCNC1 DJKKOGHPJCAZPG-NVXWUHKLSA-N 0.000 claims description 2
SVNANZCJJGNSQW-GOEBONIOSA-N (3r,4s)-n-[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]-4-fluoropyrrolidine-3-carboxamide Chemical compound F[C@@H]1CNC[C@@H]1C(=O)NC1=CC(C=2N=C(NCC3CCOCC3)C=NC=2)=C(Cl)C=N1 SVNANZCJJGNSQW-GOEBONIOSA-N 0.000 claims description 2
VACIRRBXVDLXFP-KRWDZBQOSA-N (3s)-1-acetyl-n-[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]piperidine-3-carboxamide Chemical compound C1N(C(=O)C)CCC[C@@H]1C(=O)NC1=CC(C=2N=C(NCC3CCOCC3)C=NC=2)=C(Cl)C=N1 VACIRRBXVDLXFP-KRWDZBQOSA-N 0.000 claims description 2
CITHMVXMPHGNKM-KRWDZBQOSA-N (3s)-n-[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]-1-(2-methoxyacetyl)piperidine-3-carboxamide Chemical compound C1N(C(=O)COC)CCC[C@@H]1C(=O)NC1=CC(C=2N=C(NCC3CCOCC3)C=NC=2)=C(Cl)C=N1 CITHMVXMPHGNKM-KRWDZBQOSA-N 0.000 claims description 2
WVEIJPAANLZESR-KRWDZBQOSA-N (3s)-n-[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]-1-ethylsulfonylpiperidine-3-carboxamide Chemical compound C1N(S(=O)(=O)CC)CCC[C@@H]1C(=O)NC1=CC(C=2N=C(NCC3CCOCC3)C=NC=2)=C(Cl)C=N1 WVEIJPAANLZESR-KRWDZBQOSA-N 0.000 claims description 2
HJAGKOWKSGKHBL-INIZCTEOSA-N (3s)-n-[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]-1-methylsulfonylpiperidine-3-carboxamide Chemical compound C1N(S(=O)(=O)C)CCC[C@@H]1C(=O)NC1=CC(C=2N=C(NCC3CCOCC3)C=NC=2)=C(Cl)C=N1 HJAGKOWKSGKHBL-INIZCTEOSA-N 0.000 claims description 2
DTEOIPWRZPEJMD-SFHVURJKSA-N (3s)-n-[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]-1-propan-2-ylsulfonylpiperidine-3-carboxamide Chemical compound C1N(S(=O)(=O)C(C)C)CCC[C@@H]1C(=O)NC1=CC(C=2N=C(NCC3CCOCC3)C=NC=2)=C(Cl)C=N1 DTEOIPWRZPEJMD-SFHVURJKSA-N 0.000 claims description 2
HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical group C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 2
125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
125000005347 halocycloalkyl group Chemical group 0.000 claims description 2
JGNVXJGDPBJIGG-JKSUJKDBSA-N methyl n-[(1r,3s)-3-[[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]carbamoyl]cyclopentyl]carbamate Chemical compound C1[C@H](NC(=O)OC)CC[C@@H]1C(=O)NC1=CC(C=2N=C(NCC3CCOCC3)C=NC=2)=C(Cl)C=N1 JGNVXJGDPBJIGG-JKSUJKDBSA-N 0.000 claims description 2
JGNVXJGDPBJIGG-CVEARBPZSA-N methyl n-[(1s,3r)-3-[[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]carbamoyl]cyclopentyl]carbamate Chemical compound C1[C@@H](NC(=O)OC)CC[C@H]1C(=O)NC1=CC(C=2N=C(NCC3CCOCC3)C=NC=2)=C(Cl)C=N1 JGNVXJGDPBJIGG-CVEARBPZSA-N 0.000 claims description 2
NMQZKVHNJUGGBS-UHFFFAOYSA-N n-[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]-2-methylpropanamide Chemical compound C1=NC(NC(=O)C(C)C)=CC(C=2N=C(NCC3CCOCC3)C=NC=2)=C1Cl NMQZKVHNJUGGBS-UHFFFAOYSA-N 0.000 claims description 2
NALIMZNVXZWEAY-UHFFFAOYSA-N n-[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]morpholine-2-carboxamide Chemical compound C1=C(C=2N=C(NCC3CCOCC3)C=NC=2)C(Cl)=CN=C1NC(=O)C1CNCCO1 NALIMZNVXZWEAY-UHFFFAOYSA-N 0.000 claims description 2
AIPMDGCEJGMDAX-UHFFFAOYSA-N n-[5-chloro-4-[6-(oxan-4-ylmethylamino)pyrazin-2-yl]pyridin-2-yl]oxane-4-carboxamide Chemical compound C1=C(C=2N=C(NCC3CCOCC3)C=NC=2)C(Cl)=CN=C1NC(=O)C1CCOCC1 AIPMDGCEJGMDAX-UHFFFAOYSA-N 0.000 claims description 2
125000004076 pyridyl group Chemical group 0.000 claims description 2
BUGOPWGPQGYYGR-UHFFFAOYSA-N thiane 1,1-dioxide Chemical compound O=S1(=O)CCCCC1 BUGOPWGPQGYYGR-UHFFFAOYSA-N 0.000 claims description 2
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 74
150000002431 hydrogen Chemical group 0.000 claims 40
125000006526 (C1-C2) alkyl group Chemical group 0.000 claims 9
125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 8
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 3
125000004209 (C1-C8) alkyl group Chemical group 0.000 claims 3
125000006645 (C3-C4) cycloalkyl group Chemical group 0.000 claims 3
DLRDNLCLJXEJEF-CQSZACIVSA-N (3r)-n-[5-chloro-4-[6-[(5-fluoropyridin-3-yl)methylamino]pyrazin-2-yl]pyridin-2-yl]piperidine-3-carboxamide Chemical compound FC1=CN=CC(CNC=2N=C(C=NC=2)C=2C(=CN=C(NC(=O)[C@H]3CNCCC3)C=2)Cl)=C1 DLRDNLCLJXEJEF-CQSZACIVSA-N 0.000 claims 1
125000006125 ethylsulfonyl group Chemical group 0.000 claims 1
229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 abstract description 7
239000002875 cyclin dependent kinase inhibitor Substances 0.000 abstract description 4
239000000203 mixture Substances 0.000 description 277
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 268
239000000243 solution Substances 0.000 description 216
230000002829 reductive effect Effects 0.000 description 185
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 158
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 146
238000002360 preparation method Methods 0.000 description 135
235000019439 ethyl acetate Nutrition 0.000 description 133
238000004895 liquid chromatography mass spectrometry Methods 0.000 description 118
239000011541 reaction mixture Substances 0.000 description 111
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 107
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 92
IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 92
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 91
229910052938 sodium sulfate Inorganic materials 0.000 description 90
235000011152 sodium sulphate Nutrition 0.000 description 90
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 86
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 82
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 81
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 76
239000012044 organic layer Substances 0.000 description 75
125000004435 hydrogen atom Chemical group [H]* 0.000 description 74
239000000741 silica gel Substances 0.000 description 72
229910002027 silica gel Inorganic materials 0.000 description 72
239000012267 brine Substances 0.000 description 69
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 69
238000004440 column chromatography Methods 0.000 description 68
239000002904 solvent Substances 0.000 description 63
238000000746 purification Methods 0.000 description 60
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 56
238000003786 synthesis reaction Methods 0.000 description 53
230000015572 biosynthetic process Effects 0.000 description 51
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 48
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 48
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 43
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 42
238000006243 chemical reaction Methods 0.000 description 42
229920006395 saturated elastomer Polymers 0.000 description 37
239000012230 colorless oil Substances 0.000 description 34
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 28
229960004132 diethyl ether Drugs 0.000 description 28
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 26
SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 26
ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 25
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
102000001253 Protein Kinase Human genes 0.000 description 24
KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 24
239000000460 chlorine Substances 0.000 description 24
239000000706 filtrate Substances 0.000 description 24
108060006633 protein kinase Proteins 0.000 description 24
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 24
229910000030 sodium bicarbonate Inorganic materials 0.000 description 24
235000017557 sodium bicarbonate Nutrition 0.000 description 24
238000010438 heat treatment Methods 0.000 description 23
239000000543 intermediate Substances 0.000 description 23
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 22
239000000651 prodrug Substances 0.000 description 22
229940002612 prodrug Drugs 0.000 description 22
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
238000005481 NMR spectroscopy Methods 0.000 description 20
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 19
239000010410 layer Substances 0.000 description 19
239000007787 solid Substances 0.000 description 19
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