ZA200602581B - Heterocyclic inhibitors of mek and methods of use thereof - Google Patents

Info

Publication number

ZA200602581B

ZA200602581B ZA200602581A ZA200602581A ZA200602581B ZA 200602581 B ZA200602581 B ZA 200602581B ZA 200602581 A ZA200602581 A ZA 200602581A ZA 200602581 A ZA200602581 A ZA 200602581A ZA 200602581 B ZA200602581 B ZA 200602581B

Authority

ZA

South Africa

Prior art keywords

heteroaryl

aryl

heterocyclyl

arylalkyl

alkyl

Prior art date

2003-09-03

Links

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• Global Dossier
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• 125000000623 heterocyclic group Chemical group 0.000 title claims description 188
• 238000000034 method Methods 0.000 title description 89
• 239000003112 inhibitor Substances 0.000 title description 18
• 150000001875 compounds Chemical class 0.000 claims description 224
• 125000001072 heteroaryl group Chemical group 0.000 claims description 166
• 125000000217 alkyl group Chemical group 0.000 claims description 149
• 125000003118 aryl group Chemical group 0.000 claims description 148
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 123
• 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 101
• 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 97
• -1 triflucromethoxy Chemical group 0.000 claims description 88
• 125000003342 alkenyl group Chemical group 0.000 claims description 80
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 78
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 76
• 125000005843 halogen group Chemical group 0.000 claims description 64
• 238000002360 preparation method Methods 0.000 claims description 64
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 61
• 229920006395 saturated elastomer Polymers 0.000 claims description 60
• 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 59
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 59
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 59
• 229940002612 prodrug Drugs 0.000 claims description 58
• 239000000651 prodrug Substances 0.000 claims description 58
• 125000000304 alkynyl group Chemical group 0.000 claims description 56
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 55
• 150000003839 salts Chemical class 0.000 claims description 51
• 229910052739 hydrogen Inorganic materials 0.000 claims description 43
• 238000011282 treatment Methods 0.000 claims description 38
• 239000001257 hydrogen Substances 0.000 claims description 34
• 241000124008 Mammalia Species 0.000 claims description 31
• 125000004043 oxo group Chemical group O=* 0.000 claims description 27
• 125000002837 carbocyclic group Chemical group 0.000 claims description 24
• 125000004429 atom Chemical group 0.000 claims description 23
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 21
• 239000008194 pharmaceutical composition Substances 0.000 claims description 18
• 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 claims description 17
• 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 claims description 17
• 239000012453 solvate Substances 0.000 claims description 17
• 230000003463 hyperproliferative effect Effects 0.000 claims description 15
• 125000000539 amino acid group Chemical group 0.000 claims description 13
• 229910019142 PO4 Inorganic materials 0.000 claims description 12
• 230000002401 inhibitory effect Effects 0.000 claims description 11
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
• 239000010452 phosphate Substances 0.000 claims description 11
• 229910052792 caesium Inorganic materials 0.000 claims description 10
• 230000000694 effects Effects 0.000 claims description 10
• NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 9
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
• 239000003814 drug Substances 0.000 claims description 8
• 125000005647 linker group Chemical group 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 4
• 239000003937 drug carrier Substances 0.000 claims description 4
• GRFOHUBBUMAJMM-UHFFFAOYSA-N 3-(2-aminoquinolin-3-yl)-n-cyclohexyl-n-methylpropanamide Chemical compound C=1C2=CC=CC=C2N=C(N)C=1CCC(=O)N(C)C1CCCCC1 GRFOHUBBUMAJMM-UHFFFAOYSA-N 0.000 claims description 3
• KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 claims description 3
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
• 125000002757 morpholinyl group Chemical group 0.000 claims description 3
• 125000003386 piperidinyl group Chemical group 0.000 claims description 3
• 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 18
• 235000015429 Mirabilis expansa Nutrition 0.000 claims 1
• 244000294411 Mirabilis expansa Species 0.000 claims 1
• UREZNYTWGJKWBI-UHFFFAOYSA-M benzethonium chloride Chemical compound [Cl-].C1=CC(C(C)(C)CC(C)(C)C)=CC=C1OCCOCC[N+](C)(C)CC1=CC=CC=C1 UREZNYTWGJKWBI-UHFFFAOYSA-M 0.000 claims 1
• 235000013536 miso Nutrition 0.000 claims 1
• 239000004474 valine Substances 0.000 claims 1
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 183
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 157
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 135
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 110
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 102
• 239000000243 solution Substances 0.000 description 97
• 238000006243 chemical reaction Methods 0.000 description 93
• 230000015572 biosynthetic process Effects 0.000 description 91
• 238000003786 synthesis reaction Methods 0.000 description 90
• 239000000047 product Substances 0.000 description 85
• 235000019439 ethyl acetate Nutrition 0.000 description 75
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 71
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 68
• 238000005481 NMR spectroscopy Methods 0.000 description 66
• 239000007787 solid Substances 0.000 description 63
• 239000011541 reaction mixture Substances 0.000 description 61
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 55
• 239000000203 mixture Substances 0.000 description 52
• 239000012267 brine Substances 0.000 description 45
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 45
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
• 239000011734 sodium Substances 0.000 description 38
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 34
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 32
• 239000012044 organic layer Substances 0.000 description 32
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 30
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
• 238000003818 flash chromatography Methods 0.000 description 28
• 238000003756 stirring Methods 0.000 description 28
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 27
• 238000000746 purification Methods 0.000 description 26
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
• 239000000725 suspension Substances 0.000 description 25
• 239000002253 acid Substances 0.000 description 24
• 206010028980 Neoplasm Diseases 0.000 description 22
• 150000001732 carboxylic acid derivatives Chemical group 0.000 description 22
• 150000002148 esters Chemical class 0.000 description 21
• YHNRUSMOYCDMJS-UHFFFAOYSA-N o-(cyclopropylmethyl)hydroxylamine Chemical compound NOCC1CC1 YHNRUSMOYCDMJS-UHFFFAOYSA-N 0.000 description 21
• 201000010099 disease Diseases 0.000 description 19
• WWWTWPXKLJTKPM-UHFFFAOYSA-N 2-aminooxyethanol Chemical compound NOCCO WWWTWPXKLJTKPM-UHFFFAOYSA-N 0.000 description 18
• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 18
• 239000007788 liquid Substances 0.000 description 18
• 238000010992 reflux Methods 0.000 description 17
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 16
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 16
• 230000008878 coupling Effects 0.000 description 15
• 238000010168 coupling process Methods 0.000 description 15
• 238000005859 coupling reaction Methods 0.000 description 15
• 239000000284 extract Substances 0.000 description 15
• 150000001412 amines Chemical class 0.000 description 14
• 239000003960 organic solvent Substances 0.000 description 14
• 210000004027 cell Anatomy 0.000 description 13
• 208000035475 disorder Diseases 0.000 description 13
• 238000007363 ring formation reaction Methods 0.000 description 13
• 238000010561 standard procedure Methods 0.000 description 13
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
• WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 12
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 12
• 230000002159 abnormal effect Effects 0.000 description 12
• 239000004480 active ingredient Substances 0.000 description 12
• 239000002585 base Substances 0.000 description 12
• 230000010261 cell growth Effects 0.000 description 12
• UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 12
• YLPFLKCGZGXPFI-UHFFFAOYSA-N methyl 6-amino-4-(4-bromo-2-chloroanilino)-5-chloropyridine-3-carboxylate Chemical compound COC(=O)C1=CN=C(N)C(Cl)=C1NC1=CC=C(Br)C=C1Cl YLPFLKCGZGXPFI-UHFFFAOYSA-N 0.000 description 12
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 11
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
• 201000011510 cancer Diseases 0.000 description 11
• 238000001914 filtration Methods 0.000 description 11
• 239000007858 starting material Substances 0.000 description 11
• 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 10
• ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 10
• PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 10
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
• 239000000706 filtrate Substances 0.000 description 10
• YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 10
• 230000037361 pathway Effects 0.000 description 10
• 150000003254 radicals Chemical class 0.000 description 10
• 239000002904 solvent Substances 0.000 description 10
• 125000001424 substituent group Chemical group 0.000 description 10
• 229910052727 yttrium Inorganic materials 0.000 description 10
• HSFNEBWXUWQGNW-UHFFFAOYSA-N 7-(4-bromo-2-chloroanilino)-8-chloro-n-(2-hydroxyethoxy)imidazo[1,2-a]pyridine-6-carboxamide Chemical compound OCCONC(=O)C1=CN2C=CN=C2C(Cl)=C1NC1=CC=C(Br)C=C1Cl HSFNEBWXUWQGNW-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
• 229910052763 palladium Inorganic materials 0.000 description 9
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 8
• 102100024193 Mitogen-activated protein kinase 1 Human genes 0.000 description 8
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 8
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• 230000004913 activation Effects 0.000 description 8
• 125000003282 alkyl amino group Chemical group 0.000 description 8
• 125000004435 hydrogen atom Chemical class [H]* 0.000 description 8
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 8
• ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 8
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• CXNKXAGWACKPKC-UHFFFAOYSA-N 6-(4-bromo-2-chloroanilino)-7-fluoro-3-methyl-1,2-benzoxazole-5-carboxylic acid Chemical compound OC(=O)C=1C=C2C(C)=NOC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CXNKXAGWACKPKC-UHFFFAOYSA-N 0.000 description 7
• JENGFSJGUVYCHQ-UHFFFAOYSA-N 7-(4-bromo-2-chloroanilino)-n-(cyclopropylmethoxy)-8-fluoroimidazo[1,2-a]pyridine-6-carboxamide Chemical compound C1CC1CONC(=O)C1=CN2C=CN=C2C(F)=C1NC1=CC=C(Br)C=C1Cl JENGFSJGUVYCHQ-UHFFFAOYSA-N 0.000 description 7
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