IL312378A - Aminothiazole compounds as C-KIT inhibitors - Google Patents

Info

Publication number

IL312378A

IL312378A IL312378A IL31237824A IL312378A IL 312378 A IL312378 A IL 312378A IL 312378 A IL312378 A IL 312378A IL 31237824 A IL31237824 A IL 31237824A IL 312378 A IL312378 A IL 312378A

Authority

IL

Israel

Prior art keywords

alkyl

methyl

another embodiment

optionally substituted

heterocycloalkyl

Prior art date

2016-12-15

Links

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• Global Dossier
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• 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 title description 50
• 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 title description 50
• 239000003112 inhibitor Substances 0.000 title description 9
• RAIPHJJURHTUIC-UHFFFAOYSA-N 1,3-thiazol-2-amine Chemical class NC1=NC=CS1 RAIPHJJURHTUIC-UHFFFAOYSA-N 0.000 title description 3
• 125000000217 alkyl group Chemical group 0.000 description 288
• 125000000592 heterocycloalkyl group Chemical group 0.000 description 178
• 150000001875 compounds Chemical class 0.000 description 168
• 125000005842 heteroatom Chemical group 0.000 description 159
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 113
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 106
• 125000001424 substituent group Chemical group 0.000 description 103
• 125000004663 dialkyl amino group Chemical group 0.000 description 81
• 238000000034 method Methods 0.000 description 75
• -1 tetrahydronaphthalenyl Chemical group 0.000 description 74
• 125000003282 alkyl amino group Chemical group 0.000 description 68
• 125000003545 alkoxy group Chemical group 0.000 description 65
• 125000001188 haloalkyl group Chemical group 0.000 description 64
• 229910052760 oxygen Inorganic materials 0.000 description 62
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 61
• OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 54
• 201000010099 disease Diseases 0.000 description 54
• 239000000203 mixture Substances 0.000 description 53
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 53
• 208000035475 disorder Diseases 0.000 description 52
• 125000004076 pyridyl group Chemical group 0.000 description 51
• 229910052739 hydrogen Inorganic materials 0.000 description 49
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 description 47
• 235000002639 sodium chloride Nutrition 0.000 description 43
• 150000003839 salts Chemical class 0.000 description 41
• 239000000651 prodrug Substances 0.000 description 37
• 229940002612 prodrug Drugs 0.000 description 37
• 239000012453 solvate Substances 0.000 description 36
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 30
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
• 229910052757 nitrogen Inorganic materials 0.000 description 29
• 125000004438 haloalkoxy group Chemical group 0.000 description 28
• 125000004433 nitrogen atom Chemical group N* 0.000 description 28
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
• 125000000753 cycloalkyl group Chemical group 0.000 description 27
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 26
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
• 238000005160 1H NMR spectroscopy Methods 0.000 description 24
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 24
• 150000001412 amines Chemical class 0.000 description 24
• 229910052717 sulfur Inorganic materials 0.000 description 24
• 206010028980 Neoplasm Diseases 0.000 description 23
• 125000001072 heteroaryl group Chemical group 0.000 description 23
• 239000000543 intermediate Substances 0.000 description 22
• 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 22
• 239000007787 solid Substances 0.000 description 20
• 201000011510 cancer Diseases 0.000 description 19
• 229910052736 halogen Inorganic materials 0.000 description 19
• 230000002401 inhibitory effect Effects 0.000 description 19
• ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical compound CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 18
• AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 18
• PFEOZHBOMNWTJB-UHFFFAOYSA-N 3-methylpentane Chemical compound CCC(C)CC PFEOZHBOMNWTJB-UHFFFAOYSA-N 0.000 description 18
• 150000002367 halogens Chemical class 0.000 description 18
• 125000002768 hydroxyalkyl group Chemical group 0.000 description 18
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 18
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 18
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
• 150000004677 hydrates Chemical class 0.000 description 17
• 239000012044 organic layer Substances 0.000 description 17
• HNRMPXKDFBEGFZ-UHFFFAOYSA-N 2,2-dimethylbutane Chemical compound CCC(C)(C)C HNRMPXKDFBEGFZ-UHFFFAOYSA-N 0.000 description 16
• IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 16
• 125000003118 aryl group Chemical group 0.000 description 16
• 239000003814 drug Substances 0.000 description 16
• 125000003386 piperidinyl group Chemical group 0.000 description 16
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
• 125000004193 piperazinyl group Chemical group 0.000 description 15
• 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 14
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 12
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
• 235000019439 ethyl acetate Nutrition 0.000 description 12
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 12
• 239000002904 solvent Substances 0.000 description 12
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
• 210000004027 cell Anatomy 0.000 description 11
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
• HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 10
• 101150041968 CDC13 gene Proteins 0.000 description 10
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 10
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 10
• 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 10
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 10
• 239000000741 silica gel Substances 0.000 description 10
• 229910002027 silica gel Inorganic materials 0.000 description 10
• 238000003786 synthesis reaction Methods 0.000 description 10
• 206010027476 Metastases Diseases 0.000 description 9
• 238000003818 flash chromatography Methods 0.000 description 9
• 230000009401 metastasis Effects 0.000 description 9
• 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 9
• 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 9
• 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
• 239000000243 solution Substances 0.000 description 9
• 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
• 125000003342 alkenyl group Chemical group 0.000 description 8
• 125000002393 azetidinyl group Chemical group 0.000 description 8
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 8
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 8
• 239000008194 pharmaceutical composition Substances 0.000 description 8
• 239000011734 sodium Substances 0.000 description 8
• 238000003756 stirring Methods 0.000 description 8
• 206010051066 Gastrointestinal stromal tumour Diseases 0.000 description 7
• QKPQEZKQSIMTEA-UHFFFAOYSA-N N-[3-[2-[2-[[2-(dimethylamino)ethyl-methylcarbamoyl]amino]-1,3-thiazol-5-yl]ethynyl]-4-methylphenyl]-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound CN(CCN(C(NC=1SC(=CN=1)C#CC=1C=C(C=CC=1C)NC(C1=NC=CC(=C1)C(F)(F)F)=O)=O)C)C QKPQEZKQSIMTEA-UHFFFAOYSA-N 0.000 description 7
• 230000001363 autoimmune Effects 0.000 description 7
• 239000003937 drug carrier Substances 0.000 description 7
• 125000001153 fluoro group Chemical group F* 0.000 description 7
• 201000011243 gastrointestinal stromal tumor Diseases 0.000 description 7
• 230000008506 pathogenesis Effects 0.000 description 7
• 125000000719 pyrrolidinyl group Chemical group 0.000 description 7
• 239000011541 reaction mixture Substances 0.000 description 7
• 125000004890 (C1-C6) alkylamino group Chemical group 0.000 description 6
• RHWMBOKAMGTPMZ-UHFFFAOYSA-N 3-[2-[2-(cyclopropanecarbonylamino)-1,3-thiazol-5-yl]ethynyl]-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide Chemical compound C1(CC1)C(=O)NC=1SC(=CN=1)C#CC=1C=C(C(=O)NC2=NC=CC(=C2)C(F)(F)F)C=CC=1C RHWMBOKAMGTPMZ-UHFFFAOYSA-N 0.000 description 6
• IQUIYULXNQVRQR-UHFFFAOYSA-N 3-[2-[2-(dimethylcarbamoylamino)-1,3-thiazol-5-yl]ethynyl]-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide Chemical compound CN(C(NC=1SC(=CN=1)C#CC=1C=C(C(=O)NC2=NC=CC(=C2)C(F)(F)F)C=CC=1C)=O)C IQUIYULXNQVRQR-UHFFFAOYSA-N 0.000 description 6
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
• 206010061218 Inflammation Diseases 0.000 description 6
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
• 230000015572 biosynthetic process Effects 0.000 description 6
• 239000003085 diluting agent Substances 0.000 description 6
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 6
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 6
• 229940079593 drug Drugs 0.000 description 6
• 230000004054 inflammatory process Effects 0.000 description 6
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• 125000002757 morpholinyl group Chemical group 0.000 description 6
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
• 238000002390 rotary evaporation Methods 0.000 description 6
• 125000000041 C6-C10 aryl group Chemical group 0.000 description 5
• 239000005517 L01XE01 - Imatinib Substances 0.000 description 5
• 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 5
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• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 5
• 150000002148 esters Chemical class 0.000 description 5
• KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 5
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 5
• DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
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• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
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• 125000005605 benzo group Chemical group 0.000 description 4
• WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
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• 238000004519 manufacturing process Methods 0.000 description 4
• BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
• MXJKAJTZKDDREU-UHFFFAOYSA-N n-(5-bromo-1,3-thiazol-2-yl)cyclopropanecarboxamide Chemical compound S1C(Br)=CN=C1NC(=O)C1CC1 MXJKAJTZKDDREU-UHFFFAOYSA-N 0.000 description 4
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• 239000007858 starting material Substances 0.000 description 4
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• 239000000725 suspension Substances 0.000 description 4
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
• 239000003643 water by type Substances 0.000 description 4
• 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
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• 125000001313 C5-C10 heteroaryl group Chemical group 0.000 description 3
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
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• KTHLRVWHJZWHAR-UHFFFAOYSA-N N-(3-iodo-4-methylphenyl)-4-(trifluoromethyl)pyridine-2-carboxamide Chemical compound IC=1C=C(C=CC=1C)NC(C1=NC=CC(=C1)C(F)(F)F)=O KTHLRVWHJZWHAR-UHFFFAOYSA-N 0.000 description 3
• IQIAJMAYRLMTGM-UHFFFAOYSA-N N-[5-(2-trimethylsilylethynyl)-1,3-thiazol-2-yl]cyclopropanecarboxamide Chemical compound C[Si](C)(C)C#CC1=CN=C(S1)NC(=O)C1CC1 IQIAJMAYRLMTGM-UHFFFAOYSA-N 0.000 description 3
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• NJWUZECXAWOASR-UHFFFAOYSA-N tert-butyl N-[(2-methylpropan-2-yl)oxycarbonyl]-N-[5-[2-[2-methyl-5-[[4-(trifluoromethyl)pyridine-2-carbonyl]amino]phenyl]ethynyl]-1,3-thiazol-2-yl]carbamate Chemical compound C(C)(C)(C)OC(=O)N(C(OC(C)(C)C)=O)C=1SC(=CN=1)C#CC1=C(C=CC(=C1)NC(=O)C1=NC=CC(=C1)C(F)(F)F)C NJWUZECXAWOASR-UHFFFAOYSA-N 0.000 description 3
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• 238000004704 ultra performance liquid chromatography Methods 0.000 description 3
• LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
• NUSVDASTCPBUIP-UHFFFAOYSA-N (5-bromo-1,3-thiazol-2-yl)azanium;bromide Chemical compound [Br-].BrC1=C[NH2+]C(=N)S1 NUSVDASTCPBUIP-UHFFFAOYSA-N 0.000 description 2
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