TWI678370B - 新穎7員雙環化合物 - Google Patents
新穎7員雙環化合物 Download PDFInfo
- Publication number
- TWI678370B TWI678370B TW104109652A TW104109652A TWI678370B TW I678370 B TWI678370 B TW I678370B TW 104109652 A TW104109652 A TW 104109652A TW 104109652 A TW104109652 A TW 104109652A TW I678370 B TWI678370 B TW I678370B
- Authority
- TW
- Taiwan
- Prior art keywords
- substituted
- pyridine
- carbonyl
- alkyl
- phenyl
- Prior art date
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- 125000002619 bicyclic group Chemical group 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 144
- 238000000034 method Methods 0.000 claims abstract description 23
- -1 2,3-dihydro-1H-isoindol-2-yl Chemical group 0.000 claims description 241
- 125000000217 alkyl group Chemical group 0.000 claims description 133
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 60
- 125000003545 alkoxy group Chemical group 0.000 claims description 54
- 125000004076 pyridyl group Chemical group 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 30
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 27
- 201000010099 disease Diseases 0.000 claims description 26
- 230000001684 chronic effect Effects 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 23
- 230000003176 fibrotic effect Effects 0.000 claims description 21
- 125000001544 thienyl group Chemical group 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 150000002367 halogens Chemical class 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 210000003734 kidney Anatomy 0.000 claims description 18
- 210000004185 liver Anatomy 0.000 claims description 17
- 230000001154 acute effect Effects 0.000 claims description 16
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- 125000001424 substituent group Chemical group 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- 210000000056 organ Anatomy 0.000 claims description 13
- 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 12
- 125000004122 cyclic group Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 12
- 230000002265 prevention Effects 0.000 claims description 12
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 206010052779 Transplant rejections Diseases 0.000 claims description 10
- 150000001412 amines Chemical class 0.000 claims description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
- 230000000926 neurological effect Effects 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 125000003277 amino group Chemical group 0.000 claims description 8
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 8
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 7
- 125000002249 indol-2-yl group Chemical group [H]C1=C([H])C([H])=C2N([H])C([*])=C([H])C2=C1[H] 0.000 claims description 7
- 206010061218 Inflammation Diseases 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000005149 cycloalkylsulfinyl group Chemical group 0.000 claims description 6
- 125000005366 cycloalkylthio group Chemical group 0.000 claims description 6
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 6
- 230000004054 inflammatory process Effects 0.000 claims description 6
- 150000004702 methyl esters Chemical class 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 125000006413 ring segment Chemical group 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 5
- OTLNTAZCEJJZBD-UHFFFAOYSA-N 2,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbaldehyde Chemical compound C1N(C=O)CCC2=NNN=C21 OTLNTAZCEJJZBD-UHFFFAOYSA-N 0.000 claims description 4
- PMPYFSRSUQARIV-UHFFFAOYSA-N 2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridine-5-carbonyl)-4,5,7,8-tetrahydropyrazolo[1,5-d][1,4]diazepine-6-carboxylic acid Chemical compound N1N=NC=2CN(CCC=21)C(=O)C1=NN2CCN(CCC2=C1)C(=O)O PMPYFSRSUQARIV-UHFFFAOYSA-N 0.000 claims description 4
- WKMTUZREUZQAOM-UHFFFAOYSA-N FC(F)(F)OC1=CC=C(CCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 Chemical compound FC(F)(F)OC1=CC=C(CCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 WKMTUZREUZQAOM-UHFFFAOYSA-N 0.000 claims description 4
- 125000005144 cycloalkylsulfonyl group Chemical group 0.000 claims description 4
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- ZVBXGHZQUZNITD-DUXPYHPUSA-N FC(F)OC1=C(F)C=C(\C=C\C(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 Chemical compound FC(F)OC1=C(F)C=C(\C=C\C(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 ZVBXGHZQUZNITD-DUXPYHPUSA-N 0.000 claims description 3
- RLQNNQXQAXRJKB-UHFFFAOYSA-N O=C(OCC1=CC=C(C=C1)C#N)N1CCN2N=C(C=C2CC1)C(=O)N1CCC2=C(C1)N=NN2 Chemical compound O=C(OCC1=CC=C(C=C1)C#N)N1CCN2N=C(C=C2CC1)C(=O)N1CCC2=C(C1)N=NN2 RLQNNQXQAXRJKB-UHFFFAOYSA-N 0.000 claims description 3
- 239000013543 active substance Substances 0.000 claims description 3
- 230000004968 inflammatory condition Effects 0.000 claims description 3
- 210000000653 nervous system Anatomy 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- UFUASNAHBMBJIX-UHFFFAOYSA-N propan-1-one Chemical compound CC[C]=O UFUASNAHBMBJIX-UHFFFAOYSA-N 0.000 claims description 3
- HGINCPLSRVDWNT-UHFFFAOYSA-N Acrolein Chemical compound C=CC=O HGINCPLSRVDWNT-UHFFFAOYSA-N 0.000 claims description 2
- JGLOZZNBXVELFE-UHFFFAOYSA-N FC(F)(F)OC1=C(Cl)C=C(CCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 Chemical compound FC(F)(F)OC1=C(Cl)C=C(CCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 JGLOZZNBXVELFE-UHFFFAOYSA-N 0.000 claims description 2
- HKKWTYODSDDPLH-UHFFFAOYSA-N FC(F)(F)OC1=C(Cl)C=C(CCC(=O)N2CCN3N=C(N=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 Chemical compound FC(F)(F)OC1=C(Cl)C=C(CCC(=O)N2CCN3N=C(N=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 HKKWTYODSDDPLH-UHFFFAOYSA-N 0.000 claims description 2
- YDCAZIJEAPBGIW-UHFFFAOYSA-N FC1=C(OC(F)(F)F)C=CC(CCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)=C1 Chemical compound FC1=C(OC(F)(F)F)C=CC(CCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)=C1 YDCAZIJEAPBGIW-UHFFFAOYSA-N 0.000 claims description 2
- PPSXRPJETOLWAU-UHFFFAOYSA-N FC1=C(OC(F)(F)F)C=CC(CCC(=O)N2CCN3N=C(N=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)=C1 Chemical compound FC1=C(OC(F)(F)F)C=CC(CCC(=O)N2CCN3N=C(N=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)=C1 PPSXRPJETOLWAU-UHFFFAOYSA-N 0.000 claims description 2
- MXSFTQSOVZLBEH-UHFFFAOYSA-N FC1=CC=C(COC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 Chemical compound FC1=CC=C(COC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 MXSFTQSOVZLBEH-UHFFFAOYSA-N 0.000 claims description 2
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 28
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims 9
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 3
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims 2
- 125000004749 (C1-C6) haloalkylsulfinyl group Chemical group 0.000 claims 2
- 125000006636 (C3-C8) cycloalkylcarbonyl group Chemical group 0.000 claims 2
- FVLGQVYCQKGRNS-UHFFFAOYSA-N N1N=CC=CC(=C1)C(=O)OCC1=CC=CC=C1 Chemical compound N1N=CC=CC(=C1)C(=O)OCC1=CC=CC=C1 FVLGQVYCQKGRNS-UHFFFAOYSA-N 0.000 claims 2
- XIPFMBOWZXULIA-UHFFFAOYSA-N pivalamide Chemical group CC(C)(C)C(N)=O XIPFMBOWZXULIA-UHFFFAOYSA-N 0.000 claims 2
- 229940124530 sulfonamide Drugs 0.000 claims 2
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims 1
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 1
- 125000004741 (C1-C6) haloalkylsulfonyl group Chemical group 0.000 claims 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims 1
- QMIHGQNAZMSDDC-UHFFFAOYSA-N C(C)(C)(C)C=1C=C(C#N)C=CC1OCC(N1CCN2C(CC1)=CC(=N2)C(=O)N2CC1=C(CC2)NN=N1)=O Chemical compound C(C)(C)(C)C=1C=C(C#N)C=CC1OCC(N1CCN2C(CC1)=CC(=N2)C(=O)N2CC1=C(CC2)NN=N1)=O QMIHGQNAZMSDDC-UHFFFAOYSA-N 0.000 claims 1
- YUOJULDAKIAAMA-UHFFFAOYSA-N CCC1=C(OCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=CC(=C1)C#N Chemical compound CCC1=C(OCC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=CC(=C1)C#N YUOJULDAKIAAMA-UHFFFAOYSA-N 0.000 claims 1
- NSYSENPPXUMHGR-UHFFFAOYSA-N COC1=CC(C)=C(COC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 Chemical compound COC1=CC(C)=C(COC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 NSYSENPPXUMHGR-UHFFFAOYSA-N 0.000 claims 1
- PRWLPVCFKAAQDK-UHFFFAOYSA-N FC(F)OC1=C(F)C=C(COC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 Chemical compound FC(F)OC1=C(F)C=C(COC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)C=C1 PRWLPVCFKAAQDK-UHFFFAOYSA-N 0.000 claims 1
- NBUPLPLOLPUNAJ-UHFFFAOYSA-N FC1=CC=CC(COC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)=C1 Chemical compound FC1=CC=CC(COC(=O)N2CCN3N=C(C=C3CC2)C(=O)N2CCC3=C(C2)N=NN3)=C1 NBUPLPLOLPUNAJ-UHFFFAOYSA-N 0.000 claims 1
- 125000003396 thiol group Chemical group [H]S* 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 43
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 106
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 83
- 239000000243 solution Substances 0.000 description 58
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- 239000000543 intermediate Substances 0.000 description 40
- 239000011541 reaction mixture Substances 0.000 description 38
- 235000019439 ethyl acetate Nutrition 0.000 description 36
- 239000002904 solvent Substances 0.000 description 36
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 31
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 29
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- 239000007787 solid Substances 0.000 description 25
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 23
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- 150000002148 esters Chemical class 0.000 description 22
- 125000001188 haloalkyl group Chemical group 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- 239000011734 sodium Substances 0.000 description 22
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- WRGQSWVCFNIUNZ-GDCKJWNLSA-N 1-oleoyl-sn-glycerol 3-phosphate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)COP(O)(O)=O WRGQSWVCFNIUNZ-GDCKJWNLSA-N 0.000 description 20
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 20
- 102100021977 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Human genes 0.000 description 19
- 239000012267 brine Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- 108050004000 Ectonucleotide pyrophosphatase/phosphodiesterase family member 2 Proteins 0.000 description 18
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- 229910002027 silica gel Inorganic materials 0.000 description 17
- 238000003818 flash chromatography Methods 0.000 description 15
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 14
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 7
- 208000003251 Pruritus Diseases 0.000 description 7
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- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
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Classifications
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Landscapes
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| MA39792B1 (fr) | 2014-03-26 | 2019-12-31 | Hoffmann La Roche | Composés bicycliques en tant qu'inhibiteurs de production d'autotaxine (atx) et d'acide lysophosphatidique (lpa) |
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| TWI757266B (zh) | 2016-01-29 | 2022-03-11 | 美商維它藥物有限責任公司 | ROR-γ調節劑 |
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| KR20190129924A (ko) * | 2017-03-16 | 2019-11-20 | 에프. 호프만-라 로슈 아게 | 이중 오토탁신(atx)/탄산 무수화효소(ca) 억제제로서 유용한 헤테로환형 화합물 |
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| WO2019018975A1 (en) | 2017-07-24 | 2019-01-31 | Vitae Pharmaceuticals, Inc. | INHIBITORS OF ROR GAMMA |
| CR20200168A (es) | 2017-10-31 | 2020-07-12 | Hoffmann La Roche | Sulfonas y sulfóxidos bicíclicos y métodos de uso de los mismos |
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| WO2011006569A1 (de) * | 2009-07-16 | 2011-01-20 | Merck Patent Gmbh | Heterocyclische verbindungen als autotaxin-inhibitoren |
| WO2011151461A2 (en) * | 2010-06-04 | 2011-12-08 | B.S.R.C. "Alexander Fleming" | Autotaxin pathway modulation and uses thereof |
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| CN106029667B (zh) | 2019-08-23 |
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| PH12016501633B1 (en) | 2017-02-06 |
| KR20160128428A (ko) | 2016-11-07 |
| CN106029667A (zh) | 2016-10-12 |
| EA201691794A1 (ru) | 2017-01-30 |
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