JP2021531290A - アザインドール誘導体とFGFR及びC−Met阻害剤としてのその使用 - Google Patents
アザインドール誘導体とFGFR及びC−Met阻害剤としてのその使用 Download PDFInfo
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- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000004628 isothiazolidinyl group Chemical group S1N(CCC1)* 0.000 description 1
- 230000000155 isotopic effect Effects 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000000921 morphogenic effect Effects 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- RLKHFSNWQCZBDC-UHFFFAOYSA-N n-(benzenesulfonyl)-n-fluorobenzenesulfonamide Chemical compound C=1C=CC=CC=1S(=O)(=O)N(F)S(=O)(=O)C1=CC=CC=C1 RLKHFSNWQCZBDC-UHFFFAOYSA-N 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 231100000822 oral exposure Toxicity 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- LMYJGUNNJIDROI-UHFFFAOYSA-N oxan-4-ol Chemical compound OC1CCOCC1 LMYJGUNNJIDROI-UHFFFAOYSA-N 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- ZLYYZGDBMXPXOA-UHFFFAOYSA-N oxetan-3-yl methanesulfonate Chemical compound CS(=O)(=O)OC1COC1 ZLYYZGDBMXPXOA-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- JLFNLZLINWHATN-UHFFFAOYSA-N pentaethylene glycol Chemical compound OCCOCCOCCOCCOCCO JLFNLZLINWHATN-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000005191 phase separation Methods 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 229940085991 phosphate ion Drugs 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 125000005936 piperidyl group Chemical group 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 239000011591 potassium Chemical class 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- CHWRSCGUEQEHOH-UHFFFAOYSA-N potassium oxide Chemical compound [O-2].[K+].[K+] CHWRSCGUEQEHOH-UHFFFAOYSA-N 0.000 description 1
- 229910001950 potassium oxide Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- VVWRJUBEIPHGQF-MDZDMXLPSA-N propan-2-yl (ne)-n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)\N=N\C(=O)OC(C)C VVWRJUBEIPHGQF-MDZDMXLPSA-N 0.000 description 1
- VVWRJUBEIPHGQF-UHFFFAOYSA-N propan-2-yl n-propan-2-yloxycarbonyliminocarbamate Chemical compound CC(C)OC(=O)N=NC(=O)OC(C)C VVWRJUBEIPHGQF-UHFFFAOYSA-N 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 1
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 230000008707 rearrangement Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000025053 regulation of cell proliferation Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- HXRDRJKAEYHOBB-UHFFFAOYSA-N tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(CO)C1 HXRDRJKAEYHOBB-UHFFFAOYSA-N 0.000 description 1
- XRRXRQJQQKMFBC-UHFFFAOYSA-N tert-butyl 3-hydroxyazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC(O)C1 XRRXRQJQQKMFBC-UHFFFAOYSA-N 0.000 description 1
- PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
- ROUYFJUVMYHXFJ-UHFFFAOYSA-N tert-butyl 4-oxopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=O)CC1 ROUYFJUVMYHXFJ-UHFFFAOYSA-N 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000002053 thietanyl group Chemical group 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 230000005747 tumor angiogenesis Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000002100 tumorsuppressive effect Effects 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
Description
CN201810798237.7、出願日は2018年07月19日であり、
CN201811039652.0、出願日は2018年09月06日であり、
CN201811445346.7、出願日は2018年11月29日である。
X1、X2及びX3はそれぞれ独立してCH、C(CH3)及びNから選択され、
TはCH及びNから選択され、
R1及びR4はそれぞれ独立してH、F、Cl、Br、I、OH、NH2から選択され、
R2及びR3はそれぞれ独立してH、F、Cl、Br、I、OH、NH2、CN、COOH、C1-6アルキル及びC1-6ヘテロアルキルから選択され、前記C1-6アルキル及びC1-6ヘテロアルキルは1、2又は3個のRaで任意に置換され、
R5はH、C1-6アルキル、C1-6ヘテロアルキル、C3-6シクロアルキル、4〜6員ヘテロシクロアルキル、5〜6員ヘテロシクロアルケニルから選択され、前記C1-6アルキル、C1-6ヘテロアルキル、C3-6シクロアルキル、4〜6員ヘテロシクロアルキル、5〜6員ヘテロシクロアルケニルは1、2又は3個のRbで任意に置換され、
環Bはフェニル及び5〜6員ヘテロアリールから選択され、前記フェニル及び5〜6員ヘテロアリールは1、2又は3個のR6で任意に置換され、
R6はそれぞれ独立してH、F、Cl、Br、I、OH、NH2、CN、COOH、C1-3アルキル及びC1-3ヘテロアルキルから選択され、前記C1-3アルキル及びC1-3ヘテロアルキルは1、2又は3個のRcで任意に置換され、
或は、それぞれ隣接した炭素原子に連結された二つのR6はそれらと連結されたC原子と一緒に1、2又は3個のRcで任意に置換された4〜6員ヘテロシクロアルキルを形成し、
Lは単結合及び−(CRdRe)m−から選択され、
mは1、2、3及び4から選択され、
Raはそれぞれ独立してH、F、Cl、Br、I、OH、NH2、CN、COOH、C1-3アルキル及びC1-3ヘテロアルキルから選択され、前記C1-3アルキル及びC1-3ヘテロアルキルは1、2又は3個のRで任意に置換され、
Rbはそれぞれ独立してH、F、Cl、Br、I、OH、NH2、CN、COOH、C1-3アルキル、C1-3ヘテロアルキル及び4〜6員ヘテロシクロアルキルから選択され、前記C1-3アルキル、C1-3ヘテロアルキル及び4〜6員ヘテロシクロアルキルは1、2又は3個のRで任意に置換され、
RcはH、F、Cl、Br、I、OH、NH2、CH3及びCH3CH2から選択され、
或は、同じ炭素原子に連結された二つのRcはそれらと連結されたC原子と一緒に1、2又は3個のRで置換された一つの4〜6員ヘテロシクロアルキルを形成し、
Rd及びReはそれぞれ独立してH、F、Cl、Br、I、OH、NH2、CH3及びCH3CH2から選択され、
RはF、Cl、Br、I、OH、CN、NH2、CN、COOH、CH3、CH3CH2、CH3CH2CH2、(CH3)2CH、CF3、CHF2、CH2F、CH3O及び
前記C1-6ヘテロアルキル、C1-3ヘテロアルキル、5〜6員ヘテロアリール、4〜6員ヘテロシクロアルキル及び5〜6員ヘテロシクロアルケニルはそれぞれ独立して1、2、3又は4個の独立的に−NH−、−O−、−S−、−C(=O)−、−S(=O)−、−S(=O)2−及びNから選択されるヘテロ原子又はヘテロ原子団を含有する。
T1、T2、T3及びT4はそれぞれ独立してC(R6)及びNから選択され、
T、X1、X2、X3、R1、R2、R3、R4、R5、R6及びLは本発明に定義される通りである。
LCMS(ESI)m/z:386.9388.9(M+1)+
LCMS(ESI)m/z:503.2(M+1)+
LCMS(ESI)m/z:419.1(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.60(s、1H)、8.04(s、1H)、8.01(s、1H)、7.78(s、1H)、7.73(m、1H)、7.03〜7.26(m、1H)、5.37〜5.43(m、1H)、4.30(t、J=5.6Hz、2H)、3.93(t、J=5.0Hz、2H)、1.96(d、J=7.2Hz、3H)。
LCMS(ESI)m/z:419.1(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.32(m,1H),7.84(s,1H),7.61(s,1H)7.50〜7.32(m、3H)、7.19(m、1H)、5.25〜5.30(m、1H)、5.25(t、J=5.2Hz、2H)、3.91(t、J=5.6Hz、2H)、1.88(d、J=7.2Hz、3H)。
LCMS(ESI)m/z:419.1(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.20(m、1H)、7.72(s、1H)、7.49(s、1H)、7.25〜7.28(m、3H)、7.05〜7.09(m、1H)、5.13〜5.19(m、1H)、4.13(t、J=5.6Hz、2H)、3.79(t、J=5.2Hz、2H)、1.76(d、J=7.2Hz、3H)。
LCMS(ESI)m/z:204.2(M+1)+
LCMS(ESI)m/z:392.1(M+1)+
LCMS(ESI)m/z:389.9(M+1)+
LCMS(ESI)m/z:384.1(M+1)+
実施例1H
LCMS(ESI)m/z:500.2(M+1)+
LCMS(ESI)m/z:416.2(M+1)+
1HNMR(400MHz、DMSO−d6)δ13.29(s、1H)、8.78(d、J=2.01Hz、1H)、8.28(d、J=1.76Hz、1H)、8.22(s、1H)、7.93(s、1H)、6.93(t、J=8.28Hz、1H)、4.30(s、2H)、4.19(t、J=5.65Hz、2H)、3.85(s、6H)、3.79(brt、J=5.52Hz、2H)。
LCMS(ESI)m/z:468.2(M+1)+
LCMS(ESI)m/z:456.1(M+1)+
LCMS(ESI)m/z:639.3(M+1)+
LCMS(ESI)m/z:455.2(M+1)+
1HNMR(400MHz、METHANOL−d4)δ9.02(s、1H)、8.85(d、J=1.50Hz、1H)、8.35(s、1H)、8.05(s、1H)、6.87(t、J=8.32Hz、1H)、4.64〜4.74(m、1H)、4.54(s、2H)、3.89(s、6H)、3.61〜3.64(m、2H)、3.23〜3.31(m、2H)、2.32〜2.47(m、4H)。
LCMS(ESI)m/z:483.2(M+1)+
1HNMR(400MHz、METHANOL−d4)δ9.05(s、1H)、8.89〜8.96(m、1H)、8.38(s、1H)、8.05(s、1H)、6.85(t、J=8.28Hz、1H)、4.62〜4.74(m、1H)、4.54(s、2H)、3.87(s、6H)、3.78(brd、J=12.55Hz、2H)、3.46〜3.61(m、1H)、3.19〜3.30(m、3H)、2.36〜2.50(m、4H)、1.38〜1.46(m、3H)。
LCMS(ESI)m/z:571.3(M+1)+
LCMS(ESI)m/z:476.9(M+1)+
1HNMR(400MHz、DMSO−d6)δ11.76(d、J=2.51Hz、1H)、8.74(brs、1H)、8.61(s、1H)、8.48(brd、J=8.03Hz、1H)、8.36(s、1H)、8.12(s、1H)、7.43(d、J=2.01Hz、1H)、6.89(t、J=8.28Hz、1H)、4.50〜4.68(m、1H)、4.10(s、2H)、3.85(s、6H)、3.47(brs、2H)、3.02〜3.23(m、2H)、2.03〜2.37(m、4H)。
LCMS(ESI)m/z:483.1(M+1)+
1HNMR(400MHz、DMSO−d6)δ11.77(d、J=2.01Hz、1H)、9.33(brs、1H)、8.57〜8.69(m、1H)、8.38(s、1H)、8.05〜8.20(m、1H)、7.30〜7.50(m、1H)、6.90(t、J=8.41Hz、1H)、4.45〜4.67(m、1H)、4.11(s、2H)、3.85(s、6H)、3.66〜3.68(m、1H)、3.08〜3.41(m、5H)、2.32〜2.42(m、2H)、2.15〜2.30(m、2H)、1.24〜1.32(m、3H)。
LCMS(ESI)m/z:368.2(M+1)+
LCMS(ESI)m/z:454.0(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.38(d、J=2.01Hz、1H)、8.14(d、J=2.01Hz、1H)、8.06(s、1H)、7.83(s、1H)、7.11(s、1H)、6.75(t、J=8.28Hz、1H)、4.29〜4.36(m、1H)、4.12(s、2H)、3.85(s、6H)、3.20(brd、J=12.55Hz、2H)、2.76(dt、J=2.51、12.55Hz、2H)、2.14(brd、J=12.55Hz、2H)、1.91〜2.06(m、2H)。
LCMS(ESI)m/z:482.2(M+1)+
1HNMR(400MHz、DMSO−d6)δ11.40(s、1H)、8.46(d、J=2.01Hz、1H)、8.24(s、1H)、8.07(d、J=1.76Hz、1H)、7.85(s、1H)、7.08(s、1H)、6.88(t、J=8.41Hz、1H)、4.12〜4.27(m、1H)、4.05(s、2H)、3.84(s、6H)、3.00(brd、J=11.04Hz、2H)、2.38‘2.65(m、4H)、1.97〜2.12(m、4H)、1.04(t、J=7.15Hz、3H)。
LCMS(ESI)m/z:496.2(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.47(brd、J=6.78Hz、1H)、8.32(s、1H)、8.14(s、1H)、7.95(s、1H)、7.20(s、1H)、6.79(t、J=8.28Hz、1H)、4.55‘4.71(m、1H)、4.16(s、2H)、3.88(s、6H)、3.57〜3.73(m、3H)、2.33〜2.58(m、4H)、1.37〜1.49(m、6H)。
LCMS(ESI)m/z:496.1(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.67(d、J=1.60Hz、1H)、8.57(s、1H)、8.26(s、1H)、7.98(s、1H)、7.33(s、1H)、6.81(t、J=8.28Hz、1H)、4.70(brd、J=13.40Hz、1H)、4.47〜4.62(m、1H)、4.23(s、2H)、4.06〜4.16(m、1H)、3.88(s、6H)、3.34〜3.42(m、1H)、2.81〜2.98(m、1H)、2.17〜2.31(m、5H)、1.94〜2.16(m、2H)。
LCMS(ESI)m/z:532.1(M+1)+
1HNMR(400MHz、CHLOROFORM−d)δ8.26(brs、1H)、8.05(s、1H)、7.75(s、1H)、7.70(s、1H)、7.13(s、1H)、6.46(t、J=8.03Hz、1H)、4.22〜4.32(m、1H)、4.06(s、2H)、3.89(brd、J=12.55Hz、2H)、3.79(s、6H)、2.92(brt、J=11.04Hz、2H)、2.82(s、3H)、2.22〜2.31(m、2H)、2.08〜2.19(m、2H)。
LCMS(ESI)m/z:260.1(M+1)+
1HNMR(400MHz、CHLOROFORM−d)δ7.81(d、J=1.51Hz、1H)、7.39(d、J=1.51Hz、1H)、4.66(brs、2H)、3.92(s、3H)、3.88(s、3H)。
LCMS(ESI)m/z:227.2(M+1)+
1HNMR(400MHz、CHLOROFORM−d)δ7.89(d、J=1.76Hz、1H)、7.50(d、J=1.76Hz、1H)、7.14(dd、J=10.92、17.44Hz、1H)、5.85(d、J=17.57Hz、1H)、5.48(d、J=11.04Hz、1H)、3.96(d、J=9.03Hz、6H)。
LCMS(ESI)m/z:426.9(M+1)+
LCMS(ESI)m/z:396.9(M+1)+
LCMS(ESI)m/z:409.9(M+1)+
LCMS(ESI)m/z:579.1(M+1)+
LCMS(ESI)m/z:479.1(M+1)+
1HNMR(400MHz、DMSO−d6)δ11.45(brs、1H)、8.69(brs、1H)、8.48〜8.52(m3H)、7.93〜8.27(m、2H)、7.34〜7.54(m、2H)、7.18(s、1H)、4.45〜4.50(m、1H)、4.15〜4.19(m、2H)、4.11(brs、1H)、3.89(s、3H)、3.10〜3.15(m、4H)、2.75(s、3H)、2.15〜2.33(m、4H)。
LCMS(ESI)m/z:308.0(M+1)+
1HNMR(400MHz、CHLOROFORM−d)δppm7.46(s、1H)、7.42(s、1H)、4.13〜4.23(m、2H)、3.56〜3.67(m、4H)、2.67〜2.76(m、2H)、2.45〜2.51(m、4H)。
LCMS(ESI)m/z:298.2(M+1)+
LCMS(ESI)m/z:500.4(M+1)+
LCMS(ESI)m/z:484.4(M+1)+
1HNMR(400MHz、DMSO−d6)δppm11.47(s、1H)、8.48(d、J=2.01Hz、1H)、8.27(s、1H)、8.10(s、1H)、7.13(s、1H)、6.89(t、J=8.41Hz、1H)、4.58〜4.62(m、2H)、4.06(s、2H)、3.84(s、6H)、3.70〜3.83(m、4H)、3.67〜3.69(m、4H)、2.55〜2.58(m、4H)。
LCMS(ESI)m/z:585.5(M+1)+
LCMS(ESI)m/z:485.4(M+1)+
LCMS(ESI)m/z:455.3(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.47(s、1H)、8.36(s、1H)、8.17(s、1H)、7.91(s、1H)
7.13〜7.23(m、3H)、6.79(t、J=8.53Hz、1H)、4.10〜4.22(m、6H)、3.88(s、6H)、3.58〜3.61(m、1H)、2.12〜2.15(m、4H)。
LCMS(ESI)m/z:656.3(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.45(brs、1H)、8.32(d、J=2.01Hz、1H)、8.11(d、J=13.55Hz、2H)、7.22(s、1H)、6.78(t、J=8.28Hz、1H)、5.44〜5.59(m、1H)、4.57〜4.67(m、4H)、4.16(s、2H)、3.87(s、6H)。
LCMS(ESI)m/z:249.9(M+1)+
1HNMR(400MHz、CHLOROFORM−d)δ7.76(s、1H)、7.72(s、1H)、5.58〜5.66(m、1H)、4.69〜4.75(m、4H)。
LCMS(ESI)m/z:293.9(M+1)+
1HNMR(400MHz、CHLOROFORM−d)δ7.54(s、1H)、7.50(s、1H)、4.92〜5.07(m、1H)、4.30〜4.44(m、4H)、4.16〜4.21(m、2H)、3.73〜3.78(m、2H)。
LCMS(ESI)m/z:431.3(M+1)+
1HNMR(400MHz、CHLOROFORM−d)δ8.60(d、J=1.00Hz、1H)、8.41(d、J=1.26Hz、1H)、7.19(s、1H)
6.99(s、1H)、6.40〜6.48(m、1H)、4.06(s、2H)、3.79(s、6H)、1.31(s、12H)。
LCMS(ESI)m/z:514.0(M+45)+
1HNMR(400MHz、DMSO−d6)δ11.44(s、1H)、8.48(d、J=2.01Hz、1H)、8.36(s、1H)、8.10(d、J=1.76Hz、1H)、8.00(s、1H)、7.09(s、1H)、6.89(t、J=8.53Hz、1H)、5.21〜5.43(m、1H)、4.82(t、J=5.65Hz、1H)、4.20〜4.47(m、4H)、4.02〜4.08(m、4H)、3.84(s、6H)、3.57(q、J=5.52Hz、2H)。
LCMS(ESI)m/z:561.2(M+1)+
1HNMR(400MHz、CHLOROFORM−d)δppm8.78(d、J=1.51Hz、1H)8.54(d、J=1.26Hz、1H)7.37(s、1H)7.13(s、1H)6.59〜6.69(m、1H)5.70(s、2H)4.23(brs、2H)3.98(s、6H)3.55〜3.61(m、2H)2.15(s、3H)1.48(s、12H)0.93〜0.99(m、2H)0.00(s、8H)。
LCMS(ESI)m/z:265.9(M+1)+
1HNMR(400MHz、CHLOROFORM−d)δ7.54(s、1H)、7.50(s、1H)、4.22(t、J=6.53Hz、2H)、2.73(t、J=6.53Hz、2H)、2.27(s、6H)。
LCMS(ESI)m/z:572.3(M+1)+
LCMS(ESI)m/z:472.2(M+1)+
LCMS(ESI)m/z:442.0(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.83(d、J=1.51Hz、1H)、8.65(s、1H)、8.33(s、1H)、8.10(s、1H)、7.41(s、1H)、6.80(t、J=8.41Hz、1H)、4.67〜4.76(m、2H)、4.24(s、2H)、3.86(s、6H)、3.76(t、J=5.65Hz、2H)、3.02(s、6H)。
LCMS(ESI)m/z:670.5(M+1)+
LCMS(ESI)m/z:470.3(M+1)+
LCMS(ESI)m/z:440.4(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.40(d、J=2.0Hz、1H)、8.18(d、J=2.0Hz、1H)、8.07(s、1H)、7.92(s、1H)、7.15(s、1H)、6.78(t、J=8.16Hz、1H)、4.62(s、2H)、4.48(d、J=6.52Hz、2H)、4.07〜4.20(m、6H)、3.87(s、6H)、3.52(brd、J=7.78Hz、1H)。
LCMS(ESI)m/z:273.2(M+1)+
1HNMR(400MHz、CHLOROFORM−d)δ8.33(s、1H)、7.91〜8.08(m、1H)、3.32(s、3H)、1.33(s、12H)。
LCMS(ESI)m/z:464.9(M+1)+
実施例30
LCMS(ESI)m/z:448.9(M+1)+
1HNMR(400MHz、DMSO−d6)δ11.54(brs、1H)、8.77(s、1H)、8.63(d、J=1.76Hz、1H)、8.49(s、1H)、8.33(d、J=1.51Hz、1H)、7.09(s、1H)、6.78〜6.97(m、1H)、4.08(s、2H)、3.85(s、6H)、3.61(s、3H)。
LCMS(ESI)m/z:641.1(M+1)+
実施例31C
LCMS(ESI)m/z:597.1(M+1)+
LCMS(ESI)m/z:599.2(M+1)+
LCMS(ESI)m/z:469.2(M+1)+
1HNMR(400MHz、DMSO−d6)δ11.46(brs、1H)、8.46(d、J=1.76Hz、1H)、8.20(s、1H)、8.10(s、1H)、7.83(s、1H)、7.09(s、1H)、6.89(t、J=8.41Hz、1H)、4.11〜4.24(m、1H)、4.06(s、2H)、3.84(s、6H)、2.06(brd、J=10.79Hz、2H)、1.95(brd、J=9.54Hz、2H)、1.77〜1.89(m、2H)、1.32〜1.44(m、2H)。
LCMS(ESI)m/z:289.8(M−56)+
1HNMR(400MHz、CHLOROFORM−d)δ7.41(s、1H)、7.34(s、1H)、4.24(brs、4H)、4.04〜4.17(m、3H)、2.84(brs、4H)、2.27(s、3H)、2.21(s、3H)、2.04〜2.16(m、4H)、1.73〜1.90(m、4H)、1.45(d、J=0.75Hz、18H)。
LCMS(ESI)m/z:392.3(M+1)+
LCMS(ESI)m/z:568.2(M+1)+
1HNMR(400MHz、CHLOROFORM−d)δ8.24〜8.32(m、1H)、7.97〜8.03(m、1H)、7.50(s、1H)、7.22(s、1H)、6.49(t、J=8.16Hz、1H)、4.18〜4.41(m、3H)、4.10〜4.15(m、2H)、3.84(s、6H)、2.90(brs、2H)、2.37〜2.42(m、3H)、2.18(brd、J=10.79Hz、2H)、1.96(dq、J=4.52、12.30Hz、2H)、1.68(s、3H)、1.44〜1.53(m、9H)。
LCMS(ESI)m/z:468.2(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.15(s、1H)、7.94(d、J=1.51Hz、1H)、7.58(s、1H)、7.20(s、1H)、6.71(t、J=8.28Hz、1H)、4.28〜4.42(m、1H)、4.09(s、2H)、3.82(s、6H)、3.20(d、J=12.55Hz、2H)、2.77(t、J=12.05Hz、2H)、2.39(s、3H)、2.04〜2.14(m、2H)、1.87〜1.99(m、2H)。
1HNMR(400MHz、METHANOL−d4)δ8.19(brs、1H)、7.94(s、1H)、7.64(s、1H)、7.19(brs、1H)、6.57(brt、J=8.03Hz、1H)、3.92〜4.09(m、3H)、3.67〜3.79(m、6H)、3.05(brd、J=12.05Hz、2H)、2.56(t、J=11.80Hz、2H)、2.28(s、3H)、1.90〜1.94(m、2H)、1.70〜1.85(m、2H)。
LCMS(ESI)m/z:482.2(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.50(s、1H)、8.40(brs、1H)、7.77(s、1H)、7.48(s、1H)、6.79(t、J=8.28Hz、1H)、4.73(brt、J=11.42Hz、1H)、4.21(s、2H)、3.85(s、6H)、3.65〜3.76(m、2H)、3.34〜3.42(m、2H)、2.98(s、3H)、2.25〜2.54(m、7H)。
1HNMR(400MHz、CHLOROFORM−d)δ2.27(s、6H)。
LCMS(ESI)m/z:266.9(M+1)+
1HNMR(400MHz、CHLOROFORM−d)δ4.48(t、J=3.51Hz、1H)、4.23(t、J=5.52Hz、2H)、3.99(td、J=5.08、10.42Hz、1H)、3.37〜3.72(m、3H)、2.31(s、3H)、2.20(s、3H)、1.41〜1.78(m、8H)。
LCMS(ESI)m/z:527.1(M+1)+
LCMS(ESI)m/z:443.1(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.58(s、1H)、8.46(s、1H)、7.59(s、1H)、6.79(t、J=8.28Hz、1H)、4.43(brt、J=4.52Hz、2H)、4.25(s、2H)、3.96(brt、J=4.27Hz、2H)、3.85(s、6H)、2.43(s、3H)、2.38(s、3H)。
LCMS(ESI)m/z:245.0(M−56)+
LCMS(ESI)m/z:265.8(M+1)+
1HNMR(400MHz、CHLOROFORM−d)δ7.51(s、1H)、4.51(brs、1H)、3.74〜4.17(m、4H)、3.37〜3.68(m、1H)、2.81〜3.23(m、2H)、2.27(brs、3H)、2.17(s、2H)、2.00〜2.03(m、1H)、1.14〜1.29(m、2H)。
LCMS(ESI)m/z:488.1(M+1)+
LCMS(ESI)m/z:516.2(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.82(brs、1H)、8.60(brs、1H)、8.04(s、1H)、7.54(s、1H)、6.79(t、J=8.28Hz、1H)、4.23(s、2H)、3.85(s、6H)、3.76〜3.79(m、2H)、3.22〜3.29(m、3H)、2.39〜2.58(m、2H)、2.31〜2.35(m、2H)、1.42(t、J=7.15Hz、3H)。
1HNMR(400MHz、CHLOROFORM−d)δ7.67(s、1H)、7.53(s、1H)、4.86〜4.90(m、2H)、4.17〜4.36(m、2H)、3.62〜3.75(m、4H)、3.27〜3.34(m、4H)、2.81〜2.96(m、2H)、2.06〜2.15(m、2H)、1.74〜2.01(m、10H)、1.45(s、9H)。
LCMS(ESI)m/z:479.1(M+1)+
LCMS(ESI)m/z:507.1(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.91(s、1H)、8.71(s、1H)、8.53(s、1H)、7.51(s、1H)、6.79(t、J=8.28Hz、1H)、4.25(s、2H)、3.85(s、6H)、3.80(brd、J=14.31Hz、2H)、3.55〜3.58(m、1H)、3.19〜3.29(m、2H)、2.44〜2.55(m、4H)、1.40〜1.46(m、3H)。
LCMS(ESI)m/z:410.0(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.49(s、1H)、8.38(d、J=2.0Hz、1H)、8.15(s、1H)、7.27(s、1H)、6.77(t、J=8.4Hz、1H)、4.17(s、2H)、4.07(s、3H)、3.87(s、6H)。
LCMS(ESI)m/z:313.4(M+1)+
1HNMR(400MHz、CHLOROFORM−d)δ9.11(brs、1H)、8.45(s、1H)、8.02(d、J=1.51Hz、1H)、7.81(d、J=7.28Hz、2H)、7.33(brs、1H)、6.51(d、J=2.01Hz、1H)、4.58(brt、J=3.51Hz、2H)、4.40(brt、J=5.14Hz、3H)、4.06〜4.18(m、2H)、3.83(td、J=5.24、10.85Hz、1H)、3.62〜3.73(m、2H)、3.40〜3.52(m、2H)、1.39〜1.64(m、10H)。
LCMS(ESI)m/z:514.5(M+1)+
1HNMR(400MHz、DMSO−d6)δ8.46(s、1H)、8.15(s、1H)、8.00(s、1H)、7.85(s、1H)、7.21(s、1H)、6.98(s、1H)、5.94〜6.06(m、2H)、5.53(s、1H)、4.56(s、1H)、4.33(brs、2H)、3.85(s、7H)、3.67〜3.83(m、5H)。
LCMS(ESI)m/z:414.5(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.52(s、2H)、8.14(s、1H)、7.95(s、1H)、7.29(s、1H)、6.80(t、J=8.53Hz、1H)、4.33(t、J=5.27Hz、2H)、4.21(s、2H)、3.97(t、J=5.40Hz、2H)、3.88(s、7H)。
LCMS(ESI)m/z:415.9(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.54(s、2H)8.15(s、1H)7.96(s、1H)7.34(s、1H)4.33(t、J=5.27Hz、2H)4.25(s、2H)3.98(s、6H)3.95〜3.97(m、2H)。
LCMS(ESI)m/z:489.1(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.99(d、J=1.5Hz、1H)、8.75(d、J=1.5Hz、1H)、7.94(s、1H)、7.91(s、1H)、7.96〜7.90(m、1H)、7.84(s、1H)、7.82(s、1H)、7.53(s、1H)、6.86〜6.74(m、1H)、4.31(s、2H)、3.90〜3.84(m、6H)、3.76〜3.65(m、2H)、3.52〜3.39(m、2H)、2.59〜2.40(m、4H)。
LCMS(ESI)m/z:517.1(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.54(brs、2H)、7.86〜7.80(m、2H)、7.74(brd、J=8.0Hz、2H)、7.37〜7.20(m、1H)、6.78(t、J=8.3Hz、1H)、4.21(brs、2H)、3.91(brs、2H)、3.87〜3.86(m、1H)、3.87(s、6H)、3.48〜3.35(m、4H)、2.66〜2.31(m、4H)、1.46(t、J=7.2Hz、3H)。
LCMS(ESI)m/z:694.3(M+1)+
LCMS(ESI)m/z:494.2(M+1)+
LCMS(ESI)m/z:464.2(M+1)+
1HNMR(400MHz、METHANOL−d4)δ9.20〜9.25(m、1H)、8.91(s、1H)、7.87(s、1H)、7.49(s、1H)、7.05(brs、1H)、6.78(brs、1H)、5.35(brs、1H)、4.26(s、2H)、4.05(brs、1H)、3.87(s、6H)、3.61(brt、J=6.02Hz、2H)、3.15(brs、1H)、2.21(brs、1H)、2.03〜2.05(m、1H)。
LCMS(ESI)m/z[M+H]+:696.3
LCMS(ESI)m/z[M+H]+:496.2
LCMS(ESI)m/z[M+H]+:466.2
LCMS(ESI)m/z[M+H]+:494.2
1HNMR(400MHz、METHANOL−d4)δ9.51(s、1H)、9.26(d、J=2.01Hz、1H)、9.25〜9.28(m、1H)、8.72(s、1H)、7.55(s、1H)、6.83(t、J=8.28Hz、1H)、4.33(s、2H)、3.88(s、6H)、3.81(brd、J=11.80Hz、2H)、3.35〜3.44(m、2H)、3.19〜3.28(m、2H)、2.37〜2.43(m、4H)、1.47(t、J=7.15Hz、3H)。
LCMS(ESI)m/z[M+H]+:443.5
1HNMR(400MHz、METHANOL−d4)δ8.39(d、J=1.76Hz、1H)、8.15(d、J=2.01Hz、1H)、8.01(s、1H)、7.84(s、1H)、7.12(s、1H)、6.75(t、J=8.28Hz、1H)、4.16(s、2H)、4.12(s、2H)、3.85(s、6H)、1.23(s、7H)。
LCMS(ESI)m/z:352.8(M+1)+
LCMS(ESI)m/z:212.9(M+1)+
LCMS(ESI)m/z:415.1(M+1)+
LCMS(ESI)m/z:398.9(M+1)+
LCMS(ESI)m/z:496.3(M+1)+
1HNMR(400MHz、METHANOL−d4)δ8.64〜8.66(m、1H)、8.54(s、1H)、8.37〜8.41(m、1H)、8.00〜8.01(m、1H)、6.77〜6.83(m、1H)、4.73(s、1H)、4.16(s、2H)、3.73(s、2H)、3.85(s、6H)、3.79〜3.82(m、2H)、3.28〜3.30(m、2H)、2.17(s、3H)、2.45(s、4H)、1.45(t、J=7.2Hz、3H)。
33P同位体標識キナーゼ活性試験(Reaction Biology Corp)を採用してIC50値を測定することにより、ヒトFGFR1、FGFR4、c−Metに対する試験化合物の阻害能力を評価した。
実験過程:特定の溶媒中の0.4mg/mlの試験化合物の澄清な溶液を、2mg/kgの用量で尾静脈を介してオスCD−1マウス(一晩禁食させ、7〜9週齢)に注射した。静脈内投与後、0.0833、0.25、0.5、1.0、2.0、4.0、8.0及び24時間後に頸静脈又は尾静脈から約30μLの血液を採取した。対応する溶媒に2.0mg/mlで懸濁した試験化合物を、10mg/kgの用量でオスCD−1マウス(一晩禁食させ、7〜9週齢)に胃内投与した。実験の詳細な条件は表3に示される通りであった。経口投与後、0.0833、0.25、0.5、1.0、2.0、4.0、6.0、8.0及び24時間後に、オスMaleCD−1マウスは頸静脈又は尾静脈から約30μLの血液を採取した。EDTA−K2を添加した抗凝固チューブに入れ、遠心分離して血漿を分離した。LC−MS/MS法を採用して血中薬物の濃度を測定し、WinNonlinTMVersion6.3(Pharsight、MountainView、CA)薬物動態ソフトウェアを利用して、非コンパートメントモデル線形対数台形法により、関連する薬物動態パラメータを計算した。実験結果は表4に示される通りであった。
SNU−16胃癌モデルの構築方法:対数増殖期のSNU−16細胞を収集し、細胞の数を数えた後、50%のPBS(pH7.4、0.01M)及び50%のMatrigelに再懸濁し、細胞の濃度を4×107セール/mLまでに調整し;細胞をアイスボックスに入れ、細胞懸濁液を1mLの注射器で吸引し、ヌードマウスの前に右脇の下に皮下注射し、各動物に200L(8×106セール/匹)を接種して、SNU−16移植腫瘍モデルを構築した。動物を定期的に観察し、電子ノギスを使用して腫瘍の直径を測定し、データをExcelスプレッドシートに入力し、腫瘍の体積を計算し、腫瘍の成長を監視した。腫瘍の体積が100〜300mm3に達した場合、健康状態が良好で、腫瘍体積が類似な担がんマウスを選択し、無作為でグループを分け、各グループの動物数n=7であり、各グループの平均腫瘍体積は約145mm3であった。実験開始後、週2回腫瘍径を測定し、腫瘍体積計算し、同時に動物の体重を測定して記録した。
%TGI=((中間腫瘍体積(対照)−中間腫瘍体積(投与群))/中間腫瘍体積(対照群))×100%
試験データは、SPSS 19.0を利用して計算し、統計的に処理された。データは特に明記しない限り、平均±標準誤差(平均±SE)で表され、2つのグループ間の比較はt検定によって分析された。p<0.05は、有意差があることを示した。単独溶媒30%PEG400(70%の脱イオン水を含有、v/v)は陰性対照群であった。実験結果は表5に示される通りであった。
Claims (24)
- 式(I)で表される化合物、その異性体又はその薬学的に許容される塩。
X1、X2及びX3はそれぞれ独立してCH、C(CH3)及びNから選択され、
TはCH及びNから選択され、
R1及びR4はそれぞれ独立してH、F、Cl、Br、I、OH及びNH2から選択され、
R2及びR3はそれぞれ独立してH、F、Cl、Br、I、OH、NH2、CN、COOH、C1-6アルキル及びC1-6ヘテロアルキルから選択され、前記C1-6アルキル及びC1-6ヘテロアルキルは1、2又は3個のRaで任意に置換され、
R5はH、C1-6アルキル、C1-6ヘテロアルキル、C3-6シクロアルキル、4〜6員ヘテロシクロアルキル及び5〜6員ヘテロシクロアルケニルから選択され、前記C1-6アルキル、C1-6ヘテロアルキル、C3-6シクロアルキル、4〜6員ヘテロシクロアルキル及び5〜6員ヘテロシクロアルケニルは1、2又は3個のRbで任意に置換され、
環Bはフェニル及び5〜6員ヘテロアリールから選択され、前記フェニル及び5〜6員ヘテロアリールは1、2又は3個のR6で任意に置換され、
R6はそれぞれ独立してH、F、Cl、Br、I、OH、NH2、CN、COOH、C1-3アルキル及びC1-3ヘテロアルキルから選択され、前記C1-3アルキル及びC1-3ヘテロアルキルは1、2又は3個のRcで任意に置換され、
或は、それぞれ隣接する炭素原子に連結された2つのR6はそれらと連結されたC原子と一緒に、1、2又は3個のRcで任意に置換された一つの4〜6員ヘテロシクロアルキルを形成し、
Lは単結合及び−(CRdRe)m−から選択され、
Mは1、2、3及び4から選択され、
Raはそれぞれ独立してH、F、Cl、Br、I、OH、NH2、CN、COOH、C1-3アルキル及びC1-3ヘテロアルキルから選択され、前記C1-3アルキル及びC1-3ヘテロアルキルは1、2又は3個のRで任意に置換され、
Rbはそれぞれ独立してH、F、Cl、Br、I、OH、NH2、CN、COOH、C1-3アルキル、C1-3ヘテロアルキル及び4〜6員ヘテロシクロアルキルから選択され、前記C1-3アルキル、C1-3ヘテロアルキル及び4〜6員ヘテロシクロアルキルは1、2又は3個のRで任意に置換され、
RcはH、F、Cl、Br、I、OH、NH2、CH3及びCH3CH2から選択され、
或は、同じ炭素原子に連結された二つのRcはそれらと連結されたC原子と一緒に1、2又は3個のRで任意に置換された4〜6員ヘテロシクロアルキルを形成し、
Rd及びReはそれぞれ独立してH、F、Cl、Br、I、OH、NH2、CH3及びCH3CH2から選択され、
RはF、Cl、Br、I、OH、CN、NH2、CN、COOH、CH3、CH3CH2、CH3CH2CH2、(CH3)2CH、CF3、CHF2、CH2F、CH3O及び
前記C1-6ヘテロアルキル、C1-3ヘテロアルキル、5〜10員ヘテロアリール、4〜6員ヘテロシクロアルキル及び5〜6員ヘテロシクロアルケニルはそれぞれ独立して1、2、3又は4個の独立的に−NH−、−O−、−S−、−C(=O)−、−S(=O)−、−S(=O)2−及びNから選択されるヘテロ原子又はヘテロ原子団を含む。) - R2及びR3はそれぞれ独立してH、F、Cl、Br、I、OH、NH2、CN、COOH、C1-3アルキル、C1-3アルキル−NC(=O)−及びC1-3アルコキシから選択され、ここで、前記C1-3アルキル、C1-3アルキル−NC(=O)−及びC1-3アルコキシは1、2又は3個のRaで任意に置換される、請求項1〜3のいずれか1項に記載の化合物、その異性体又はその薬学的に許容される塩。
- R5はH、C1-3アルキル、C1-3アルコキシ、C1-3アルキル−C(=O)−、C1-3アルキル−S(=O)2−、C1-3アルキル−S(=O)2−C1-3アルキル−、C1-3アルキルアミノ、シクロヘキサン、ピペリジニル、モルホリニル、テトラヒドロピラニル、テトラヒドロフラニル、1,2,3,6−テトラヒドロピリジン、アゼチジニル、オキセタニル、ピロリジニル及びピペラジニルから選択され、前記C1-3アルキル、C1-3アルコキシ、C1-3アルキル−C(=O)−、C1-3アルキル−S(=O)2−、C1-3アルキル−S(=O)2−C1-3アルキル−、C1-3アルキルアミノ、シクロヘキサン、ピペリジニル、モルホリニル、テトラヒドロピラニル、テトラヒドロフラニル、1,2,3,6−テトラヒドロピリジン、アゼチジニル、オキセタニル、ピロリジニル及びピペラジニルは1、2又は3個のRbで任意に置換される、請求項1〜3のいずれか1項に記載の化合物、その異性体又はその薬学的に許容される塩。
- 同じ炭素原子に連結された二つのRcは一緒に連結されて、1、2又は3個のRで置換されたピペリジニルを形成する、請求項1〜3のいずれか1項に記載の化合物、その異性体又はその薬学的に許容される塩。
- Lは単結合、−CH2−及び−CH2CH2−から選択される、請求項1〜3のいずれか1項に記載の化合物、その異性体又はその薬学的に許容される塩。
- 環Bはフェニル、ピラゾリル、イミダゾリル、ピリジル、ピラジニルから選択され、前記フェニル、ピラゾリル、イミダゾリル、ピリジル、ピラジニルは1、2又は3個のR6で任意に置換される、請求項1〜3のいずれか1項に記載の化合物、その異性体又はその薬学的に許容される塩。
- c−Met及びFGFR阻害剤に関連する疾患を治療するための医薬の調製における請求項1〜22のいずれか1項に記載の化合物、その異性体又はその薬学的に許容される塩の使用。
- c−Met及びFGFR阻害剤に関連する疾患は固形腫瘍であり、ここで、前記固形腫瘍には、非小細胞肺癌、多発性骨髄腫、腎細胞癌、乳癌、肝臓癌、胆管癌、甲状腺癌、脳癌、膀胱癌、血管腫、胆道癌、胃癌が含まれるが、これらに限定されない。
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