TWI429434B - 作為受體酪胺酸激酶抑制劑之咪唑并〔１，２-ａ〕吡啶化合物 - Google Patents

Info

Publication number

TWI429434B

TWI429434B TW097111550A TW97111550A TWI429434B TW I429434 B TWI429434 B TW I429434B TW 097111550 A TW097111550 A TW 097111550A TW 97111550 A TW97111550 A TW 97111550A TW I429434 B TWI429434 B TW I429434B

Authority

TW

Taiwan

Prior art keywords

alkyl

imidazo

hetcyc

pyridin

compound

Prior art date

2007-04-03

Links

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• 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 title description 2
• 150000005234 imidazo[1,2-a]pyridines Chemical class 0.000 title 1
• 125000000217 alkyl group Chemical group 0.000 claims description 301
• 150000001875 compounds Chemical class 0.000 claims description 170
• 238000002360 preparation method Methods 0.000 claims description 108
• -1 hexahydropyridyl Chemical group 0.000 claims description 68
• SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 57
• 229910052739 hydrogen Inorganic materials 0.000 claims description 53
• 238000000034 method Methods 0.000 claims description 49
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 46
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 39
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 39
• 229910052731 fluorine Inorganic materials 0.000 claims description 36
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 35
• 229910052801 chlorine Inorganic materials 0.000 claims description 29
• 239000002585 base Substances 0.000 claims description 27
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
• 125000004429 atom Chemical group 0.000 claims description 21
• 150000003839 salts Chemical class 0.000 claims description 21
• 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 19
• 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 18
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 17
• 229910052736 halogen Inorganic materials 0.000 claims description 16
• 150000002367 halogens Chemical class 0.000 claims description 16
• 125000005842 heteroatom Chemical group 0.000 claims description 16
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 16
• 239000002904 solvent Substances 0.000 claims description 15
• RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 14
• 125000001424 substituent group Chemical group 0.000 claims description 14
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
• 239000001257 hydrogen Substances 0.000 claims description 12
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 12
• 229910052757 nitrogen Inorganic materials 0.000 claims description 11
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 11
• 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 10
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
• 229910052763 palladium Inorganic materials 0.000 claims description 10
• 125000003118 aryl group Chemical group 0.000 claims description 9
• 230000008569 process Effects 0.000 claims description 9
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 8
• UTCSSFWDNNEEBH-UHFFFAOYSA-N imidazo[1,2-a]pyridine Chemical compound C1=CC=CC2=NC=CN21 UTCSSFWDNNEEBH-UHFFFAOYSA-N 0.000 claims description 8
• 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 7
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 7
• 125000006242 amine protecting group Chemical group 0.000 claims description 7
• 239000003054 catalyst Substances 0.000 claims description 7
• 229910052760 oxygen Inorganic materials 0.000 claims description 7
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 6
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 6
• 125000003277 amino group Chemical group 0.000 claims description 6
• 125000003943 azolyl group Chemical group 0.000 claims description 6
• 239000003153 chemical reaction reagent Substances 0.000 claims description 6
• 125000001072 heteroaryl group Chemical group 0.000 claims description 6
• 125000000468 ketone group Chemical group 0.000 claims description 6
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 6
• 150000001335 aliphatic alkanes Chemical class 0.000 claims description 5
• 230000008878 coupling Effects 0.000 claims description 5
• 238000010168 coupling process Methods 0.000 claims description 5
• 238000005859 coupling reaction Methods 0.000 claims description 5
• 125000000623 heterocyclic group Chemical group 0.000 claims description 5
• 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 5
• 125000003709 fluoroalkyl group Chemical group 0.000 claims description 4
• 150000002460 imidazoles Chemical class 0.000 claims description 4
• 239000008194 pharmaceutical composition Substances 0.000 claims description 4
• 125000006239 protecting group Chemical group 0.000 claims description 4
• RAXXELZNTBOGNW-UHFFFAOYSA-O Imidazolium Chemical compound C1=C[NH+]=CN1 RAXXELZNTBOGNW-UHFFFAOYSA-O 0.000 claims description 3
• 239000003638 chemical reducing agent Substances 0.000 claims description 3
• 239000007822 coupling agent Substances 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 3
• 125000001153 fluoro group Chemical group F* 0.000 claims description 3
• 239000003444 phase transfer catalyst Substances 0.000 claims description 3
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
• 125000003554 tetrahydropyrrolyl group Chemical group 0.000 claims description 3
• RNDLZUAZVRFLRS-UHFFFAOYSA-N 2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-8-(piperidin-3-ylmethoxy)quinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2OCC1CCCNC1 RNDLZUAZVRFLRS-UHFFFAOYSA-N 0.000 claims description 2
• IQACVVFBPSXQID-UHFFFAOYSA-N 2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-8-(pyrrolidin-3-ylmethoxy)quinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2OCC1CCNC1 IQACVVFBPSXQID-UHFFFAOYSA-N 0.000 claims description 2
• CKGYOCHUFHHZBI-GOSISDBHSA-N 2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-8-[(3r)-pyrrolidin-3-yl]oxyquinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2O[C@@H]1CCNC1 CKGYOCHUFHHZBI-GOSISDBHSA-N 0.000 claims description 2
• TXAFYFWHBVJGHQ-IBGZPJMESA-N 2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-8-[(3s)-piperidin-3-yl]oxyquinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2O[C@H]1CCCNC1 TXAFYFWHBVJGHQ-IBGZPJMESA-N 0.000 claims description 2
• RROPCZKHYUPTGO-UHFFFAOYSA-N 2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-8-piperidin-4-yloxyquinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2OC1CCNCC1 RROPCZKHYUPTGO-UHFFFAOYSA-N 0.000 claims description 2
• KHQNCCQHMLMRSX-QGZVFWFLSA-N 2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-n-[(3r)-pyrrolidin-3-yl]quinolin-8-amine Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2N[C@@H]1CCNC1 KHQNCCQHMLMRSX-QGZVFWFLSA-N 0.000 claims description 2
• KHQNCCQHMLMRSX-KRWDZBQOSA-N 2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-n-[(3s)-pyrrolidin-3-yl]quinolin-8-amine Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2N[C@H]1CCNC1 KHQNCCQHMLMRSX-KRWDZBQOSA-N 0.000 claims description 2
• OEQLYHXNGSLNQN-UHFFFAOYSA-N 3-[2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]quinolin-8-yl]oxy-2,2-dimethylpropan-1-amine Chemical compound C1=CC=C(OCC(C)(C)CN)C2=NC(C=3N4C=CC(=CC4=NC=3)OCCOC)=CC=C21 OEQLYHXNGSLNQN-UHFFFAOYSA-N 0.000 claims description 2
• URCODTVVEBNHBV-WIYYLYMNSA-N 5-fluoro-8-[(3r,4r)-3-fluoropiperidin-4-yl]oxy-2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]quinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C(F)=CC=C2O[C@@H]1CCNC[C@H]1F URCODTVVEBNHBV-WIYYLYMNSA-N 0.000 claims description 2
• XSEPWAKOMGUUGZ-WIYYLYMNSA-N 6-fluoro-8-[(3r,4r)-3-fluoropiperidin-4-yl]oxy-2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]quinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=C(F)C=C2O[C@@H]1CCNC[C@H]1F XSEPWAKOMGUUGZ-WIYYLYMNSA-N 0.000 claims description 2
• AADYTTDFFQOMQO-NFBKMPQASA-N 8-[(3r,4r)-1-ethyl-3-fluoropiperidin-4-yl]oxy-2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]quinoline Chemical compound F[C@@H]1CN(CC)CC[C@H]1OC1=CC=CC2=CC=C(C=3N4C=CC(OCCOC)=CC4=NC=3)N=C12 AADYTTDFFQOMQO-NFBKMPQASA-N 0.000 claims description 2
• BHTLCFNWNNFOFE-NFBKMPQASA-N 8-[(3r,4r)-3-fluoropiperidin-4-yl]oxy-2-(7-pyridin-3-ylimidazo[1,2-a]pyridin-3-yl)quinoline Chemical compound F[C@@H]1CNCC[C@H]1OC1=CC=CC2=CC=C(C=3N4C=CC(=CC4=NC=3)C=3C=NC=CC=3)N=C12 BHTLCFNWNNFOFE-NFBKMPQASA-N 0.000 claims description 2
• FREBNXPQQZJEKM-NNMXDRDESA-N 8-[(3r,4r)-3-fluoropiperidin-4-yl]oxy-2-[7-[(3s)-oxolan-3-yl]oxyimidazo[1,2-a]pyridin-3-yl]quinoline Chemical compound F[C@@H]1CNCC[C@H]1OC1=CC=CC2=CC=C(C=3N4C=CC(O[C@@H]5COCC5)=CC4=NC=3)N=C12 FREBNXPQQZJEKM-NNMXDRDESA-N 0.000 claims description 2
• LWHKFZNLONZVNC-WMZHIEFXSA-N 8-[(3r,4s)-4-fluoropyrrolidin-3-yl]oxy-2-(7-pyridin-3-ylimidazo[1,2-a]pyridin-3-yl)quinoline Chemical compound F[C@H]1CNC[C@H]1OC1=CC=CC2=CC=C(C=3N4C=CC(=CC4=NC=3)C=3C=NC=CC=3)N=C12 LWHKFZNLONZVNC-WMZHIEFXSA-N 0.000 claims description 2
• CEECEQWHEAERFB-UHFFFAOYSA-N 8-piperidin-4-yloxy-2-(7-pyridin-3-ylimidazo[1,2-a]pyridin-3-yl)quinoline Chemical compound C1CNCCC1OC1=CC=CC2=CC=C(C=3N4C=CC(=CC4=NC=3)C=3C=NC=CC=3)N=C12 CEECEQWHEAERFB-UHFFFAOYSA-N 0.000 claims description 2
• 241000156724 Antirhea Species 0.000 claims description 2
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
• 125000002757 morpholinyl group Chemical group 0.000 claims description 2
• 150000004032 porphyrins Chemical class 0.000 claims description 2
• 238000006467 substitution reaction Methods 0.000 claims description 2
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims 2
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 2
• PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 claims 2
• LHOJRSNEPLRYJS-TZIWHRDSSA-N (3r,4r)-4-[2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]quinolin-8-yl]oxypyrrolidin-3-ol Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2O[C@@H]1CNC[C@H]1O LHOJRSNEPLRYJS-TZIWHRDSSA-N 0.000 claims 1
• RSFHJWJNNOAZMN-UHFFFAOYSA-N 2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-8-(2-piperidin-2-ylethoxy)quinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2OCCC1CCCCN1 RSFHJWJNNOAZMN-UHFFFAOYSA-N 0.000 claims 1
• KPBBCDRZGUBDOM-UHFFFAOYSA-N 2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-8-[(1-methylpyrrolidin-3-yl)methoxy]quinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2OCC1CCN(C)C1 KPBBCDRZGUBDOM-UHFFFAOYSA-N 0.000 claims 1
• TXAFYFWHBVJGHQ-LJQANCHMSA-N 2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-8-[(3r)-piperidin-3-yl]oxyquinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2O[C@@H]1CCCNC1 TXAFYFWHBVJGHQ-LJQANCHMSA-N 0.000 claims 1
• NQOAYTFDSNONAL-FGZHOGPDSA-N 2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-8-[(3r,4r)-4-methoxypyrrolidin-3-yl]oxyquinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2O[C@@H]1CNC[C@H]1OC NQOAYTFDSNONAL-FGZHOGPDSA-N 0.000 claims 1
• XSWXDGBUKRJVOH-GOSISDBHSA-N 2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]-8-[[(2r)-pyrrolidin-2-yl]methoxy]quinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2OC[C@H]1CCCN1 XSWXDGBUKRJVOH-GOSISDBHSA-N 0.000 claims 1
• DDRZDPGSGJJQRD-DENIHFKCSA-N 2-[7-(cyclopropylmethoxy)imidazo[1,2-a]pyridin-3-yl]-8-[(3r,4r)-3-fluoropiperidin-4-yl]oxyquinoline Chemical compound F[C@@H]1CNCC[C@H]1OC1=CC=CC2=CC=C(C=3N4C=CC(OCC5CC5)=CC4=NC=3)N=C12 DDRZDPGSGJJQRD-DENIHFKCSA-N 0.000 claims 1
• TZIXXHVIMUUDMH-UHFFFAOYSA-N 2-[[2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]quinolin-8-yl]oxymethyl]morpholine Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2OCC1CNCCO1 TZIXXHVIMUUDMH-UHFFFAOYSA-N 0.000 claims 1
• NRYVSERERSAPDZ-NFBKMPQASA-N 5-[8-[(3r,4r)-3-fluoropiperidin-4-yl]oxy-2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]quinolin-4-yl]-1,3-oxazole Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C1C(O[C@H]2[C@@H](CNCC2)F)=CC=CC1=1)=CC=1C1=CN=CO1 NRYVSERERSAPDZ-NFBKMPQASA-N 0.000 claims 1
• PPPOUAQYRUUFNJ-WIYYLYMNSA-N 8-[(3r,4r)-3-fluoropiperidin-4-yl]oxy-2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]quinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2O[C@@H]1CCNC[C@H]1F PPPOUAQYRUUFNJ-WIYYLYMNSA-N 0.000 claims 1
• PPPOUAQYRUUFNJ-NQIIRXRSSA-N 8-[(3r,4s)-3-fluoropiperidin-4-yl]oxy-2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]quinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2O[C@H]1CCNC[C@H]1F PPPOUAQYRUUFNJ-NQIIRXRSSA-N 0.000 claims 1
• SXFXTYDCDKSPCU-LAUBAEHRSA-N 8-[(3r,4s)-4-fluoropyrrolidin-3-yl]oxy-2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]quinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2O[C@@H]1CNC[C@@H]1F SXFXTYDCDKSPCU-LAUBAEHRSA-N 0.000 claims 1
• PPPOUAQYRUUFNJ-RXVVDRJESA-N 8-[(3s,4s)-3-fluoropiperidin-4-yl]oxy-2-[7-(2-methoxyethoxy)imidazo[1,2-a]pyridin-3-yl]quinoline Chemical compound C=1N=C2C=C(OCCOC)C=CN2C=1C(N=C12)=CC=C1C=CC=C2O[C@H]1CCNC[C@@H]1F PPPOUAQYRUUFNJ-RXVVDRJESA-N 0.000 claims 1
• DIOQZVSQGTUSAI-NJFSPNSNSA-N decane Chemical compound CCCCCCCCC[14CH3] DIOQZVSQGTUSAI-NJFSPNSNSA-N 0.000 claims 1
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• DIOQZVSQGTUSAI-UHFFFAOYSA-N n-butylhexane Natural products CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims 1
• 125000004430 oxygen atom Chemical group O* 0.000 claims 1
• 125000004159 quinolin-2-yl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C([H])C(*)=NC2=C1[H] 0.000 claims 1
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