JP6816041B2 - Zesteホモログ2エンハンサー阻害剤 - Google Patents
Zesteホモログ2エンハンサー阻害剤 Download PDFInfo
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- JP6816041B2 JP6816041B2 JP2017568109A JP2017568109A JP6816041B2 JP 6816041 B2 JP6816041 B2 JP 6816041B2 JP 2017568109 A JP2017568109 A JP 2017568109A JP 2017568109 A JP2017568109 A JP 2017568109A JP 6816041 B2 JP6816041 B2 JP 6816041B2
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- Prior art keywords
- alkyl
- methyl
- mmol
- piperidine
- cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- PHCBRBWANGJMHS-UHFFFAOYSA-J tetrasodium;disulfate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O PHCBRBWANGJMHS-UHFFFAOYSA-J 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- DAUYIKBTMNZABP-UHFFFAOYSA-N thiophene-3-carboxamide Chemical compound NC(=O)C=1C=CSC=1 DAUYIKBTMNZABP-UHFFFAOYSA-N 0.000 description 1
- PFLSMRPNBPVYCD-UHFFFAOYSA-N thiophene-3-carboxamide;hydrochloride Chemical compound Cl.NC(=O)C=1C=CSC=1 PFLSMRPNBPVYCD-UHFFFAOYSA-N 0.000 description 1
- 150000003577 thiophenes Chemical class 0.000 description 1
- 201000009657 thyroid sarcoma Diseases 0.000 description 1
- ZFEAMMNVDPDEGE-LGRGJMMZSA-N tifuvirtide Chemical compound C([C@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(C)=O)[C@@H](C)CC)[C@@H](C)O)[C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](C)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)C1=CC=C(O)C=C1 ZFEAMMNVDPDEGE-LGRGJMMZSA-N 0.000 description 1
- QQHMKNYGKVVGCZ-UHFFFAOYSA-N tipiracil Chemical compound N1C(=O)NC(=O)C(Cl)=C1CN1C(=N)CCC1 QQHMKNYGKVVGCZ-UHFFFAOYSA-N 0.000 description 1
- 229960002952 tipiracil Drugs 0.000 description 1
- 229960000838 tipranavir Drugs 0.000 description 1
- SUJUHGSWHZTSEU-FYBSXPHGSA-N tipranavir Chemical compound C([C@@]1(CCC)OC(=O)C([C@H](CC)C=2C=C(NS(=O)(=O)C=3N=CC(=CC=3)C(F)(F)F)C=CC=2)=C(O)C1)CC1=CC=CC=C1 SUJUHGSWHZTSEU-FYBSXPHGSA-N 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 230000017423 tissue regeneration Effects 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 150000004684 trihydrates Chemical class 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 description 1
- 239000000814 tuberculostatic agent Substances 0.000 description 1
- 208000022271 tubular adenoma Diseases 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229940094060 tykerb Drugs 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 238000004704 ultra performance liquid chromatography Methods 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 208000022810 undifferentiated (embryonal) sarcoma Diseases 0.000 description 1
- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
- 208000000143 urethritis Diseases 0.000 description 1
- 229940045145 uridine Drugs 0.000 description 1
- 210000001635 urinary tract Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 229950000578 vatalanib Drugs 0.000 description 1
- YCOYDOIWSSHVCK-UHFFFAOYSA-N vatalanib Chemical compound C1=CC(Cl)=CC=C1NC(C1=CC=CC=C11)=NN=C1CC1=CC=NC=C1 YCOYDOIWSSHVCK-UHFFFAOYSA-N 0.000 description 1
- 229950009860 vicriviroc Drugs 0.000 description 1
- CILBMBUYJCWATM-PYGJLNRPSA-N vinorelbine ditartrate Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.OC(=O)[C@H](O)[C@@H](O)C(O)=O.C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC CILBMBUYJCWATM-PYGJLNRPSA-N 0.000 description 1
- 229960002166 vinorelbine tartrate Drugs 0.000 description 1
- GBABOYUKABKIAF-IWWDSPBFSA-N vinorelbinetartrate Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC(C23[C@H]([C@@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-IWWDSPBFSA-N 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- WAEXFXRVDQXREF-UHFFFAOYSA-N vorinostat Chemical compound ONC(=O)CCCCCCC(=O)NC1=CC=CC=C1 WAEXFXRVDQXREF-UHFFFAOYSA-N 0.000 description 1
- 229960000237 vorinostat Drugs 0.000 description 1
- 229940069559 votrient Drugs 0.000 description 1
- 208000002003 vulvitis Diseases 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
- 229940071104 xylenesulfonate Drugs 0.000 description 1
- 229960000523 zalcitabine Drugs 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
R1は、−NH2、(C1−C4)アルキル、またはヒドロキシ(C1−C4)アルキルであり;
R2は、(C1−C4)アルキルであり;
R3およびR4は、それぞれ水素であるか、あるいは、R3およびR4は一緒になって−CH2CH2−または−CH2CH2CH2−を表し;
R5は、水素、ハロゲン、または(C1−C3)アルキルであり;
R6は、水素または(C1−C3)アルキルであり;
R7は、酸素、窒素および硫黄から独立して選択される1、2または3個のヘテロ原子を含んでいてもよい飽和または不飽和6員環であり、該環は、ハロゲン、(C1−C4)アルキル、ハロ(C1−C4)アルキル、ヒドロキシ(C1−C4)アルキル、(C1−C4)アルコキシ(C1−C4)アルキル、(C3−C6)シクロアルキル、シアノ、−CO2H、-CO2(C1−C4)アルキル、−CONH2、−CONH(C1−C4)アルキル、−CON(C1−C4)アルキル(C1−C4)アルキル、−NH2、−NH(C1−C4)アルキル、−N(C1−C4)アルキル(C1−C4)アルキル、オキソ、ヒドロキシル、(C1−C4)アルコキシ、ヒドロキシ(C2−C4)アルコキシ−、および(C1−C4)アルコキシ(C2−C4)アルコキシ−から独立して選択される1、2または3個の基によって置換されていてもよい。]
の化合物またはその薬学的に許容可能な塩に関する。
X1、X2、X3、X4、およびX5は、それぞれ独立して、N、CH、またはCR8であり、但し、X1、X2、X3、X4、およびX5の少なくとも2個は、CHであり;
R1は、−NH2、(C1−C4)アルキル、またはヒドロキシ(C1−C4)アルキルであり;
R2は、(C1−C4)アルキルであり;
R3およびR4は、それぞれ水素であるか、あるいは、R3およびR4は一緒になって−CH2CH2−またはCH2CH2CH2−を表し;
R5は、水素、ハロゲン、または(C1−C3)アルキルであり;
R6は、水素または(C1-C3)アルキルであり;
それぞれのR8は、ハロゲン、(C1−C4)アルキル、ハロ(C1−C4)アルキル、ヒドロキシ(C1−C4)アルキル、(C1−C4)アルコキシ(C1−C4)アルキル、(C3−C6)シクロアルキル、シアノ、−CO2H、−CO2(C1−C4)アルキル、−CONH2、−CONH(C1−C4)アルキル、−CON(C1−C4)アルキル(C1−C4)アルキル、−NH2、−NH(C1−C4)アルキル、−N(C1−C4)アルキル(C1−C4)アルキル、ヒドロキシル、(C1−C4)アルコキシ、ヒドロキシ(C2−C4)アルコキシ−、および(C1−C4)アルコキシ(C2−C4)アルコキシ−から独立して選択される。]。
X1、X2、X3、X4、おおよびX5は、それぞれ独立して、N、CH、またはCR8であり、但し、X1、X2、X3、X4、およびX5の少なくとも2個は、CHであり;
nは、1または2であり;
R1は、−NH2、(C1−C4)アルキル、またはヒドロキシ(C1−C4)アルキルであり;
R2は、(C1−C4)アルキルであり;
R5は、水素、ハロゲン、または(C1−C3)アルキルであり;
R6は、水素または(C1−C3)アルキルであり;
それぞれのR8は、ハロゲン、(C1−C4)アルキル、ハロ(C1−C4)アルキル、ヒドロキシ(C1−C4)アルキル、(C1−C4)アルコキシ(C1−C4)アルキル、(C3−C6)シクロアルキル、シアノ、−CO2H、−CO2(C1−C4)アルキル、−CONH2、−CONH(C1−C4)アルキル、−CON(C1−C4)アルキル(C1−C4)アルキル、−NH2、−NH(C1−C4)アルキル、−N(C1−C4)アルキル(C1−C4)アルキル、ヒドロキシル、(C1−C4)アルコキシ、ヒドロキシ(C2−C4)アルコキシ−、および(C1−C4)アルコキシ(C2−C4)アルコキシ−から独立して選択される。]。
X1、X2、X3、X4、およびX5は、それぞれ独立して、N、CH、またはCR8であり、但し、X1、X2、X3、X4、およびX5の少なくとも2個は、CHであり;
nは、1または2であり;
R1は、−NH2、(C1−C4)アルキル、またはヒドロキシ(C1−C4)アルキルであり;
R2は、(C1−C4)アルキルであり;
R5は、水素、ハロゲン、または(C1−C3)アルキルであり;
R6は、水素または(C1−C3)アルキルであり;
それぞれのR8は、ハロゲン、(C1−C4)アルキル、ハロ(C1−C4)アルキル、ヒドロキシ(C1−C4)アルキル、(C1−C4)アルコキシ(C1−C4)アルキル、(C3−C6)シクロアルキル、シアノ、−CO2H、−CO2(C1−C4)アルキル、−CONH2、−CONH(C1−C4)アルキル、−CON(C1−C4)アルキル(C1−C4)アルキル、−NH2、−NH(C1−C4)アルキル、−N(C1−C4)アルキル(C1−C4)アルキル、ヒドロキシル、(C1−C4)アルコキシ、ヒドロキシ(C2−C4)アルコキシ−、および(C1−C4)アルコキシ(C2−C4)アルコキシ−から独立して選択される。]。
X1、X2、X3、X4、およびX5は、それぞれ独立して、N、CH、またはCR8であり、但し、X1、X2、X3、X4、およびX5の少なくとも2個は、CHであり;
nは、1または2であり;
R1は、−NH2、(C1−C4)アルキル、またはヒドロキシ(C1−C4)アルキルであり;
R2は、(C1−C4)アルキルであり;
R5は、水素、ハロゲン、または(C1−C3)アルキルであり;
R6は、水素または(C1−C3)アルキルであり;
それぞれのR8は、ハロゲン、(C1−C4)アルキル、ハロ(C1−C4)アルキル、ヒドロキシ(C1−C4)アルキル、(C1−C4)アルコキシ(C1−C4)アルキル、(C3−C6)シクロアルキル、シアノ、−CO2H、−CO2(C1−C4)アルキル、−CONH2、−CONH(C1−C4)アルキル、−CON(C1−C4)アルキル(C1−C4)アルキル、−NH2、−NH(C1−C4)アルキル、−N(C1−C4)アルキル(C1−C4)アルキル、ヒドロキシル、(C1−C4)アルコキシ、ヒドロキシ(C2−C4)アルコキシ−、および(C1−C4)アルコキシ(C2−C4)アルコキシ−から独立して選択される。]。
X1、X2、X3、X4、およびX5は、それぞれ独立して、N、CH、またはCR8であり、但し、X1、X2、X3、X4、およびX5の少なくとも2個は、CHであり;
nは、1または2であり;
R1は、−NH2、(C1−C4)アルキル、またはヒドロキシ(C1−C4)アルキルであり;
R2は、(C1−C4)アルキルであり;
R5は、水素、ハロゲン、または(C1−C3)アルキルであり;
R6は、水素または(C1−C3)アルキルであり;
それぞれのR8は、ハロゲン、(C1−C4)アルキル、ハロ(C1−C4)アルキル、ヒドロキシ(C1−C4)アルキル、(C1−C4)アルコキシ(C1−C4)アルキル、(C3−C6)シクロアルキル、シアノ、−CO2H、−CO2(C1−C4)アルキル、−CONH2、−CONH(C1−C4)アルキル、−CON(C1−C4)アルキル(C1−C4)アルキル、−NH2、−NH(C1−C4)アルキル、−N(C1−C4)アルキル(C1−C4)アルキル、ヒドロキシル、(C1−C4)アルコキシ、ヒドロキシ(C2−C4)アルコキシ−、および(C1−C4)アルコキシ(C2−C4)アルコキシ−から独立して選択される。]。
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−(ピリジン−2−イルメチル)ピペリジン−4−イル)プロピル)−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン;
(R)−2−(1−(1−ベンジルピペリジン−4−イル)プロピル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン;
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−(ピリジン−4−イルメチル)ピペリジン−4−イル)プロピル)−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン;
(R)−2−(1−(1−((5−クロロピリジン−2−イル)メチル)ピペリジン−4−イル)プロピル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン;
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(1−(1−((2−メトキシピリジン−4−イル)メチル)ピペリジン−4−イリデン)プロピル)−4−メチルチオフェン−3−カルボキサミド;
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−(ピリジン−2−イルメチル)ピペリジン−4−イル)エチル)−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−2−(1−(1−((2−メトキシピリジン−4−イル)メチル)ピペリジン−4−イル)エチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;
(R)−2−(1−(1−((5−クロロピリジン−2−イル)メチル)ピペリジン−4−イル)エチル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−((6−メチルピリジン−2−イル)メチル)ピペリジン−4−イル)エチル)−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;
(R)−2−(1−(1−ベンジルピペリジン−4−イル)エチル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−2−(1−(1−((2−メトキシピリジン−4−イル)メチル)ピペリジン−4−イル)エチル)−3−メチル−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン;
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−2−(1−(1−((6−メトキシピリジン−2−イル)メチル)ピペリジン−4−イル)エチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;
(R)−2−(1−(1−(シクロヘキシルメチル)ピペリジン−4−イル)エチル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;または
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−((1−メチルシクロヘキシル)メチル)ピペリジン−4−イル)エチル)−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;
あるいは、その薬学的に許容可能な塩が含まれる。
ヌクレオチド逆転写酵素阻害剤、例えば、ジドブジン、ジダノシン、ラミブジン、ザルシタビン、アバカビル、スタブジン、アデホビル、アデホビル ジピボキシル、ホジブジン(fozivudine)、トドキシル、エムトリシタビン、アロブジン、アムドキソビル、エルブシタビン、及び類似の薬剤;
非ヌクレオチド逆転写酵素阻害剤(イムノカル、オルチプラズなどの抗酸化活性を有する薬剤を含む)、例えば、ネビラピン、デラビルジン、エファビレンツ(efavirenz)、ロビリデ、イムノカル、オルチプラズ、カプラビリン、レルシビリン、GSK2248761,TMC−278,TMC−125,エトラビリン、及び類似の薬剤;
プロテアーゼ阻害剤、例えば、サキナビル、リトナビル、インジナビル、ネルフィナビル、アンプレナビル、ホスアンプレナビル、ブレカナビル、ダルナビル、アタザナビル、チプラナビル、パリナビル、ラシナビル、及び類似の薬剤;
侵入、結合及び融合阻害剤、例えば、エンフュービルタイド(enfuvirtide)(T-20)、T−1249、PRO−542、PRO−140、TNX−355、BMS−806、BMS−663068、及びBMS−626529、5−Helix、並びに類似の薬剤;
インテグラーゼ阻害剤、例えば、ラルテグラビル、エルビテグラビル、ドルテグラビル、カボテグラビル、及び類似の薬剤;
成熟阻害剤、例えば、PA−344及びPA−457、並びに類似の薬剤;
CXCR4及び/又はCCR5阻害剤、例えば、ビクリビロク(Sch−C)、Sch−D、TAK779、マラビロク(UK427、857)、TAK449、並びに、WO02/74769、PCT/US03/39644、PCT/US03/39975、PCT/US03/39619、PCT/US03/39618、PCT/US03/39740、及びPCT/US03/39732に開示されたもの、並びに類似の薬剤
が挙げられる。
用語はそれらの許容される意味の範囲内で使用される。以下の定義は、定義された用語を限定するのではなく、明らかにすることを意味する。
略号
AcOH 酢酸
Ag2O 酸化銀
Ar Arガス
BnCl ベンジルクロリド
Boc tert−ブチルオキシカルボニル
Boc2O 二炭酸ジ−tert−ブチル
Bu4NCl テトラブチルアンモニウムクロリド
CHCl3 クロロホルム
CH3CN アセトニトリル
CH3NO2 ニトロメタン
DCE 1,2−ジクロロエタン
DCM ジクロロメタン
DIBAL−H ジイソブチルアルミニウム水素化物
DIPEA ジイソプロピルエチルアミン
DMF N,N−ジメチルホルムアミド
DMSO ジメチルスルホキシド
EDC 1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド
ES エレクトロスプレー
Et3N トリエチルアミン
Et2O ジエチルエーテル
EtOAc エチルアセテート
EtOH エタノール
h 時間(単数または複数)
H2 水素ガス
HATU 1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム3−オキシドヘキサフルオロホスフェート
HCl 塩酸
H2O 水
HOAt 1−ヒドロキシ−7−アザベンゾトリアゾール
H2SO4 硫酸
HPLC 高速液体クロマトグラフィー
In(OTf)3 インジウム(III)トリフルオロメタンスルホネート
i−PrOH イソプロパノール
[Ir(OMe)(1,5−cod)]2 (1,5−シクロオクタジエン)(メトキシ)イリジウム(I)ダイマー
KF フッ化カリウム
KOtBu tert−ブトキシドカリウム
LCMS 液体クロマトグラフィー質量分析
LiAlH4 水素化アルミニウムリチウム
LiBH4 ホウ化水素リチウム
LiClO4 過塩素酸リチウム
MeOH メタノール
MgSO4 硫酸マグネシウム
min 分(単数または複数)
M モル濃度(molar)
MS 質量分析
N 規定濃度(normal)
N2 窒素ガス
NaBH4 ホウ化水素ナトリウム
NaBH3CN シアノホウ化水素ナトリウム
NaBH(OAc)3 トリアセトキシホウ化水素ナトリウム
Na2CO3 炭酸ナトリウム
NaHCO3 重炭酸ナトリウム
NaHMDS ビス(トリメチルシリル)アミドナトリウム
NaOH 水酸化ナトリウム
Na2SO4 硫酸ナトリウム
NBS N−ブロモコハク酸イミド
NH4Cl 塩化アンモニウム
NH4OAc 酢酸アンモニウム
NH4OH 水酸化アンモニウム
NMM N−メチルモルホリン
Pd/C 炭素上のパラジウム
P2O5 五酸化二リン
Pd(OAc)2 酢酸パラジウム(II)
Pd(PPh3)4 テトラキス(トリフェニルホスフィン)パラジウム(0)
POCl3 塩化ホスホリル
(R,R)−[COD]Ir[cy2PThrePHOX] ((4R,5R)−(+)−O−[1−ベンジル−1−(5−メチル−2−フェニル−4,5−ジヒドロオキサゾール−4−イル)−2−フェニルエチル](ジシクロヘキシルホスフィナイト)(1,5−シクロオクタジエン)イリジウム(I)テトラキス(3,5−ビス(トリフルオロメチル)フェニルボレート
r.t. 室温
sat. 飽和
SOCl2 塩化チオニル
TBME tert−ブチルメチルエーテル
TFA トリフルオロ酢酸
THF テトラヒドロフラン
TiCl4 塩化チタン(IV)
TMSCl 塩化トリメチルシリル
本発明の化合物は、周知の標準的な合成法を含む様々な方法によって作製することができる。例示的な一般合成法を以下に示し、その後、本発明の具体的化合物を実施例において製造する。当業者ならば、本明細書に記載の置換基が本明細書に記載の合成法に適合しなければ、その置換基は反応条件に適した好適な保護基で保護されてもよい。保護基は、所望の中間体または目的化合物を提供するために、一連の反応の適切な時点で除去することができる。下記のスキームの総てにおいて、有機合成の一般原則に従い、要すれば、感受性または反応性の基に対する保護基が使用される。保護基は有機合成の標準的方法(T.W. Green and P.G.M. Wuts, (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons,保護基に関して引用することより本明細書の一部とされる)に従って操作される。これらの基は、化合物合成の都合のよい段階で、当業者に容易に明らかとなる方法を用いて除去される。方法の選択、ならびに反応条件およびそれらの実行順序は、本発明の化合物の製法と一致するものとする。出発材料は市販されているか、または市販の出発材料から、当業者に公知の方法を用いて製造される。
以下の指針は、本明細書に記載の総ての実験手順に当てはまる。反応は総て、特に断りのない限り、炉で乾燥させたガラス器具を用い、陽圧窒素下で行った。示されている温度は外部温度(すなわち、槽温)であり、およその数値である。空気および水分感受性の液体は、シリンジを介して移した。試薬は受け取ったものをそのまま使用した。使用溶媒は、販売者により「無水」として挙げられているものである。溶液中の試薬に関して挙げられているモル濃度はおよその数値であり、対応する標品に対して事前に滴定を行うことなく用いた。反応は総て、特に断りのない限り撹拌子により撹拌した。加熱は、特に断りのない限り、シリコーン油(silicon oil)を含有する加熱浴を用いて行った。マイクロ波照射(2.45GHzで0〜400W)により行う反応は、Biotageイニシエーター(商標)2.0装置をBiotage(商標)マイクロ波EXPバイアル(0.2〜20mL)およびセプタムおよびキャップとともに用いて行った。溶媒およびイオン電荷に基づいて使用した照射レベル(すなわち、高、通常、低)は、販売者の仕様書に基づいた。−70℃より低い温度への冷却は、ドライアイス/アセトンまたはドライアイス/2−プロパノールを用いて行った。乾燥剤として用いた硫酸マグネシウムおよび硫酸ナトリウムは無水級であり、互換的に使用された。「真空」または「減圧下」で除去されると記載されている溶媒は、回転蒸発によりこれを行った。
実施例1
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−(ピリジン−2−イルメチル)ピペリジン−4−イル)プロピル)−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン
(注意:エチル基の絶対立体化学は、EZH2阻害に関するR−異性体の既知の選択性(preference)に基づいて割り当てられた。)
(R)−2−(1−(1−ベンジルピペリジン−4−イル)プロピル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−(ピリジン−4−イルメチル)ピペリジン−4−イル)プロピル)−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン
(R)−2−(1−(1−((5−クロロピリジン−2−イル)メチル)ピペリジン−4−イル)プロピル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(1−(1−((2−メトキシピリジン−4−イル)メチル)ピペリジン−4−イリデン)プロピル)−4−メチルチオフェン−3−カルボキサミド
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−(ピリジン−2−イルメチル)ピペリジン−4−イル)エチル)−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−2−(1−(1−((2−メトキシピリジン−4−イル)メチル)ピペリジン−4−イル)エチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン
(R)−2−(1−(1−((5−クロロピリジン−2−イル)メチル)ピペリジン−4−イル)エチル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−((6−メチルピリジン−2−イル)メチル)ピペリジン−4−イル)エチル)−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン
(R)−2−(1−(1−ベンジルピペリジン−4−イル)エチル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−2−(1−(1−((2−メトキシピリジン−4−イル)メチル)ピペリジン−4−イル)エチル)−3−メチル−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−2−(1−(1−((6−メトキシピリジン−2−イル)メチル)ピペリジン−4−イル)エチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン
(R)−2−(1−(1−(シクロヘキシルメチル)ピペリジン−4−イル)エチル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−((1−メチルシクロヘキシル)メチル)ピペリジン−4−イル)エチル)−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン
本明細書に含まれる化合物を、PRC2複合体内のEZH2のメチルトランスフェラーゼ活性を阻害するそれらの能力に関して評価した。ヒトPRC2複合体は、Sf9細胞で5メンバーのタンパク質(FLAG−EZH2、EED、SUZ12、RbAp48、AEBP2)のそれぞれを共発現させた後、共精製することにより作製した。酵素活性を、トリチウム化メチル基が3H−SAMから、ヒストンH3に由来するビオチニル化非メチル化ペプチド基質上のリシン残基へ転移される、シンチレーション近接アッセイ(SPA)で測定した。ペプチドはストレプトアビジンコーティングSPAビーズに捕捉され、得られたシグナルはViewLuxプレートリーダーで読まれた。
1.100%DMSO中に、固体からの化合物の10mM原液を調製する。
2.384ウェルプレートに、DMSO対照用の第6列と第18列を残し、各試験化合物に関して100%DMSOで11点連続希釈系(1:4希釈、最高濃度10mM)を設定した。
3.希釈系プレートから反応プレート(Corning、384ウェル ポリスチレンNBSカタログ番号3673)に10nLの化合物を分注する。
以下の溶液を調製する。
1.1×基本バッファー、50mM Tris−HCl、pH8、2mM MgCl2:基本バッファー1L当たり、1M Tris−HCl、pH8(50mL)、1M MgCl2(2mL)および蒸留水(948mL)を合わせる。
2.1×アッセイバッファー:1×アッセイバッファー10mL当たり、1x基本バッファー(9.96mL)、1M DTT(40μL)、および10%Tween−20(1μL)を合わせ、50mM Tris−HCl、pH8、2mM MgCl2、4mM DTT、0.001%Tween−20の終濃度とする。
3.2×酵素溶液:2×酵素溶液10mL当たり、1×アッセイバッファー(9.99mL)および3.24μM EZH2 5メンバー複合体(6.17μL)を合わせ、1nMの最終酵素濃度とする。
4.SPAビーズ溶液:SPAビーズ溶液1mL当たり、ストレプトアビジンコーティングSPAビーズ(PerkinElmer、カタログ番号RPNQ0261、40mg)および1xアッセイバッファー(1mL)を合わせ、途中(working)濃度40mg/mLとする。
5.2×基質溶液:2×基質溶液10mL当たり、40mg/mLSPAビーズ溶液(375μL)、1mMビオチニル化ヒストンH3K27ペプチド(200μL)、12.5μM 3H−SAM(240μL;1mCi/mL)、1μM冷SAM(57μL)および1×アッセイバッファー(9.13mL)を合わせ、0.75mg/mLSPAビーズ溶液、10μMビオチニル化ヒストンH3K27ペプチド、0.15μM3H−SAM(〜12 uCi/mL 3H−SAM)および2.85μM冷SAMの終濃度とする。
6.2.67×クエンチ溶液:2.67×クエンチ溶液10mL当たり、1xアッセイバッファー(9.73mL)および10mM冷SAM(267μL)を合わせ、100μM冷SAMの終濃度とする。
化合物の添加
1.10nL/ウェルの1000×化合物を試験ウェル(上記の通り)に区分する。
2.第6列および第8列(それぞれ高対照および低対照用)には10nL/ウェルの100%DMSOを区分する。
1.第18列に5μL/ウェルの1×アッセイバッファーを分注する(低対照反応)。
2.第1〜24列に5μL/ウェルの2×基質溶液を分注する。(注記:基質溶液は、マトリックス貯蓄槽(reservoir)に分注する前に、均一なビーズ懸濁液を確保するために混合されるべきである。)
3.第1〜17、19〜24列に5μL/ウェルの2×酵素溶液を分注する。
4.反応物を室温で60分間インキュベートする。
1.第1〜24列に6μL/ウェルの2.67×クエンチ溶液を分注する。
2.アッセイプレートを封止し、約1分間500rpmで回転させる。
3.暗順応プレートを約15〜60分ViewLux装置に入れる。
1.Viewluxプレートリーダーにて、613nmの発光用フィルターまたは透明フィルター(300秒暴露)を用いてアッセイプレートを読み取る。
阻害パーセントは、各化合物濃度についてDMSO対照に対して計算し、得られた値は、ABASEデータフィッティングソフトウエアパッケージ内の標準的なIC50フィッティングパラメーターを用いて当てはめを行った。
Claims (14)
- 式(III):
X1、X2、X3、X4 、およびX5は、それぞれ独立して、N、CH、またはCR8であり、但し、X1、X2、X3、X4、およびX5の少なくとも2個は、CHであり;
nは、1または2であり;
R1は、−NH2、(C1−C4)アルキル、またはヒドロキシ(C1−C4)アルキルであり;
R2は、(C1−C4)アルキルであり;
R5は、水素、ハロゲン、または(C1−C3)アルキルであり;
R6は、水素または(C1−C3)アルキルであり;
それぞれのR8は、ハロゲン、(C1−C4)アルキル、ハロ(C1−C4)アルキル、ヒドロキシ(C1−C4)アルキル、(C1−C4)アルコキシ(C1−C4)アルキル、(C3−C6)シクロアルキル、シアノ、−CO2H、−CO2(C1−C4)アルキル、−CONH2、−CONH(C1−C4)アルキル、−CON(C1−C4)アルキル(C1−C4)アルキル、−NH2、−NH(C1−C4)アルキル、−N(C1−C4)アルキル(C1−C4)アルキル、ヒドロキシル、(C1−C4)アルコキシ、ヒドロキシ(C2−C4)アルコキシ−、および(C1−C4)アルコキシ(C2−C4)アルコキシ−から独立して選択される。]
で表される、化合物またはその薬学的に許容可能な塩。 - 式(IV):
X1、X2、X3、X4、およびX5は、それぞれ独立して、N、CH、またはCR8であり、但し、X1、X2、X3、X4、およびX5の少なくとも2個は、CHであり;
nは、1または2であり;
R1は、−NH2、(C1−C4)アルキル、またはヒドロキシ(C1−C4)アルキルであり;
R2は、(C1−C4)アルキルであり;
R5は、水素、ハロゲン、または(C1−C3)アルキルであり;
R6は、水素または(C1−C3)アルキルであり;
それぞれのR8は、ハロゲン、(C1−C4)アルキル、ハロ(C1−C4)アルキル、ヒドロキシ(C1−C4)アルキル、(C1−C4)アルコキシ(C1−C4)アルキル、(C3−C6)シクロアルキル、シアノ、−CO2H、−CO2(C1−C4)アルキル、−CONH2、−CONH(C1−C4)アルキル、−CON(C1−C4)アルキル(C1−C4)アルキル、−NH2、−NH(C1−C4)アルキル、−N(C1−C4)アルキル(C1−C4)アルキル、ヒドロキシル、(C1−C4)アルコキシ、ヒドロキシ(C2−C4)アルコキシ−、および(C1−C4)アルコキシ(C2−C4)アルコキシ−から独立して選択される。]
で表される、請求項1に記載の化合物またはその薬学的に許容可能な塩。 - 式(V):
X1、X2、X3、X4、およびX5は、それぞれ独立して、N、CH、またはCR8であり、但し、X1、X2、X3、X4、およびX5の少なくとも2個は、CHであり;
nは、1または2であり;
R1は、−NH2、(C1−C4)アルキル、またはヒドロキシ(C1−C4)アルキルであり;
R2は、(C1−C4)アルキルであり;
R5は、水素、ハロゲン、または(C1−C3)アルキルであり;
R6は、水素または(C1−C3)アルキルであり;
それぞれのR8は、ハロゲン、(C1−C4)アルキル、ハロ(C1−C4)アルキル、ヒドロキシ(C1−C4)アルキル、(C1−C4)アルコキシ(C1−C4)アルキル、(C3−C6)シクロアルキル、シアノ、−CO2H、−CO2(C1−C4)アルキル、−CONH2、−CONH(C1−C4)アルキル、−CON(C1−C4)アルキル(C1−C4)アルキル、−NH2、−NH(C1−C4)アルキル、−N(C1−C4)アルキル(C1−C4)アルキル、ヒドロキシル、(C1−C4)アルコキシ、ヒドロキシ(C2−C4)アルコキシ−、および(C1−C4)アルコキシ(C2−C4)アルコキシ−から独立して選択される。]
で表される、請求項1に記載の化合物またはその薬学的に許容可能な塩。 - nが1である、請求項1〜3のいずれか一項に記載の化合物またはその薬学的に許容可能な塩。
- X1、X2、X3、X4、およびX5が、それぞれ独立して、N、CH、またはCR8であり、但し、X1、X2、X3、X4、およびX5の1個以下がNであり、かつ、X1、X2、X3、X4、およびX5の少なくとも3個がCHである、請求項1〜4のいずれか一項に記載の化合物またはその薬学的に許容可能な塩。
- それぞれのR8が、ハロゲン、(C1−C4)アルキル、ハロ(C1−C4)アルキル、ヒドロキシル、および(C1−C4)アルコキシから独立して選択される、請求項1〜5のいずれか一項に記載の化合物またはその薬学的に許容可能な塩。
- R1およびR2が、それぞれ独立して、メチル、エチル、n−プロピル、またはn−ブチルである、請求項1〜6のいずれか一項に記載の化合物またはその薬学的に許容可能な塩。
- R5が、メチルまたはクロロである、請求項1〜7のいずれか一項に記載の化合物またはその薬学的に許容可能な塩。
- R6が、水素、メチル、またはエチルである、請求項1〜8のいずれか一項に記載の化合物またはその薬学的に許容可能な塩。
- 以下の化合物:
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−(ピリジン−2−イルメチル)ピペリジン−4−イル)プロピル)−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン;
(R)−2−(1−(1−ベンジルピペリジン−4−イル)プロピル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン;
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−(ピリジン−4−イルメチル)ピペリジン−4−イル)プロピル)−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン;
(R)−2−(1−(1−((5−クロロピリジン−2−イル)メチル)ピペリジン−4−イル)プロピル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン;
N−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−5−(1−(1−((2−メトキシピリジン−4−イル)メチル)ピペリジン−4−イリデン)プロピル)−4−メチルチオフェン−3−カルボキサミド;
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−(ピリジン−2−イルメチル)ピペリジン−4−イル)エチル)−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−2−(1−(1−((2−メトキシピリジン−4−イル)メチル)ピペリジン−4−イル)エチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;
(R)−2−(1−(1−((5−クロロピリジン−2−イル)メチル)ピペリジン−4−イル)エチル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−((6−メチルピリジン−2−イル)メチル)ピペリジン−4−イル)エチル)−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;
(R)−2−(1−(1−ベンジルピペリジン−4−イル)エチル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−2−(1−(1−((2−メトキシピリジン−4−イル)メチル)ピペリジン−4−イル)エチル)−3−メチル−6,7−ジヒドロチエノ[3,2−c]ピリジン−4(5H)−オン;
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−2−(1−(1−((6−メトキシピリジン−2−イル)メチル)ピペリジン−4−イル)エチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;
(R)−2−(1−(1−(シクロヘキシルメチル)ピペリジン−4−イル)エチル)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;もしくは
(R)−5−((4,6−ジメチル−2−オキソ−1,2−ジヒドロピリジン−3−イル)メチル)−3−メチル−2−(1−(1−((1−メチルシクロヘキシル)メチル)ピペリジン−4−イル)エチル)−5,6,7,8−テトラヒドロ−4H−チエノ[3,2−c]アゼピン−4−オン;
または、その薬学的に許容可能な塩。 - 請求項1〜10のいずれか一項に記載の化合物またはその薬学的に許容可能な塩と薬学的に許容可能な賦形剤とを含んでなる医薬組成物。
- 癌を治療するために使用される、請求項11に記載の医薬組成物。
- 前記癌が、脳腫瘍(神経膠腫)、膠芽腫、白血病、リンパ腫、バナヤン−ゾナナ症候群、カウデン病、レルミット−ダクロス病、乳癌、炎症性乳癌、ウィルムス腫瘍、ユーイング肉腫、横紋筋肉腫、脳室上衣細胞腫、髄芽細胞腫、結腸癌、胃癌、膀胱癌、頭頸部癌、腎臓癌、肺癌、肝臓癌、黒色腫、腎癌、卵巣癌、膵臓癌、前立腺癌、肉腫、骨肉腫、骨の巨細胞腫瘍、および甲状腺癌からなる群から選択される、請求項12に記載の医薬組成物。
- 請求項1〜10のいずれか一項に記載の化合物またはその薬学的に許容可能な塩を含んでなる、EZH2により媒介される障害の治療に使用するための医薬。
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