JP7323985B2 - トリプトファンジオキシゲナーゼ(ido1とtdo)の阻害剤及び治療におけるその使用 - Google Patents
トリプトファンジオキシゲナーゼ(ido1とtdo)の阻害剤及び治療におけるその使用 Download PDFInfo
- Publication number
- JP7323985B2 JP7323985B2 JP2017507807A JP2017507807A JP7323985B2 JP 7323985 B2 JP7323985 B2 JP 7323985B2 JP 2017507807 A JP2017507807 A JP 2017507807A JP 2017507807 A JP2017507807 A JP 2017507807A JP 7323985 B2 JP7323985 B2 JP 7323985B2
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- JP
- Japan
- Prior art keywords
- pyridin
- amine
- isoxazolo
- optionally substituted
- nhr
- Prior art date
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- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 title claims description 49
- 239000003112 inhibitor Substances 0.000 title description 22
- 101001037256 Homo sapiens Indoleamine 2,3-dioxygenase 1 Proteins 0.000 title description 6
- 238000002560 therapeutic procedure Methods 0.000 title description 5
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- 102000016680 Dioxygenases Human genes 0.000 title 1
- 108010028143 Dioxygenases Proteins 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 128
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- 206010028980 Neoplasm Diseases 0.000 claims description 65
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- 150000003839 salts Chemical class 0.000 claims description 43
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- 201000011510 cancer Diseases 0.000 claims description 29
- 241001465754 Metazoa Species 0.000 claims description 28
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- 229910052736 halogen Inorganic materials 0.000 claims description 27
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- 125000004122 cyclic group Chemical group 0.000 claims description 24
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- 238000011282 treatment Methods 0.000 claims description 22
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- 230000002401 inhibitory effect Effects 0.000 claims description 11
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- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 229960001612 trastuzumab emtansine Drugs 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 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
- 229940045145 uridine Drugs 0.000 description 1
- 208000037965 uterine sarcoma Diseases 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 208000013139 vaginal neoplasm Diseases 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
- 229960003862 vemurafenib Drugs 0.000 description 1
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- UGGWPQSBPIFKDZ-KOTLKJBCSA-N vindesine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(N)=O)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1N=C1[C]2C=CC=C1 UGGWPQSBPIFKDZ-KOTLKJBCSA-N 0.000 description 1
- 229960004355 vindesine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound 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 GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
Classifications
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- 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
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- 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
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/423—Oxazoles condensed with carbocyclic rings
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- 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
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
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- A—HUMAN NECESSITIES
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- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/14—Ortho-condensed systems
-
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Cardiology (AREA)
- Ophthalmology & Optometry (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Psychiatry (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
WはCR1、N、又はN-オキシドであり;
XはCR2、N、又はN-オキシドであり;
YはCR3、N、又はN-オキシドであり;
ZはCR4、N、又はN-オキシドであり;
W、X、Y、及びZの少なくとも1つは、N又はN-オキシドであり;
(c)R9とR10は一緒になって、O、N、及びSから選択される1~3個のヘテロ原子を任意に含む、炭素原子の部分飽和又は完全不飽和の5又は6員環を形成することができ、前記環は、R9とR10について上記(a)で定義されたものと同じ任意の置換基から選択される1~5個の置換基で任意に独立して置換され得る]、
別の態様において本発明は、医学に使用するための式Iの化合物又はその医薬的に許容し得る塩を提供する。
更なる態様において本発明は、ヒトを含む温血動物における癌の治療に使用するための、式Iの化合物又はその医薬的に許容し得る塩を提供する。
更なる態様において本発明は、ヒトを含む温血動物における癌を治療するための薬剤の製造における、式Iの化合物又はその医薬的に許容し得る塩の使用を提供する。
(a)式Iの化合物又はその医薬的に許容し得る塩と、
(b)化学療法剤、及び免疫調節剤、例えば抗癌ワクチン、免疫チェックポイントタンパク質のモジュレーター、及び養子T細胞免疫療法剤(例えば、キメラ抗原受容体T細胞(CART細胞))からなる群から選択される1又は2以上の追加の薬剤と、
を含む、上記組み合わせ又はキットを提供する。
(a)式Iの化合物又はその医薬的に許容し得る塩と、
(b)化学療法剤、及び免疫調節剤、例えば抗癌ワクチン、免疫チェックポイントタンパク質のモジュレーター、及び養子T細胞免疫療法剤(例えば、キメラ抗原受容体T細胞(CART細胞))からなる群から選択される1又は2以上の追加の薬剤と、
を含む上記組み合わせ又はキットを提供する。
R1、R2、R3、及びR4は、それぞれ以下の基:H、ハロ、R、-OH、-OR、-OC(O)H、-OC(O)R、-OC(O)NH2、-OC(O)NHR、-OC(O)NRR、-OP(O)(OH)2、-OP(O)(OR)2、-NO2、-NH2、-NHR、-NRR、-NHC(OH)、-NHC(O)R、-NRC(O)R、-NHC(O)NH2、-NHC(O)NRR、-NRC(O)NHR、-SH、-SR、-S(O)H、-S(O)R、-SO2R、-SO2NH2、-SO2NHR、-SO2NRR、-CF3、-OCF3、-OCHF2、-CN、-C≡CH、-C≡CR、-CH=CHR、-CH=CRR、-CR=CHR、-CR=CRR、-CO2H、-CO2R、-CHO、-C(O)R、-C(O)NH2、-C(O)NHR、-C(O)NRR、-CONHSO2H、-CONHSO2R、-CONRSO2R、環状C3~C7アルキルアミノ、イミダゾリル、C1~C6アルキルピペラジニル、モルホリニル、及びチオモルホリニル、から選択され;
5-ブロモ-4,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(1)
イソオキサゾロ[5,4-b]ピリジン-3-アミン(2)
5-クロロ-4,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(3)
4,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(4)
4,5,6-トリメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(5)
5-ブロモイソオキサゾロ[5,4-b]ピリジン-3-アミン(6)
6-メチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(7)
5-クロロイソオキサゾロ[5,4-b]ピリジン-3-アミン(8)
イソオキサゾロ[5,4-b]キノリン-3-アミン(9)
5,6,7,8-テトラヒドロイソオキサゾロ[5,4-b]キノリン-3-アミン(10)
イソオキサゾロ[5,4-d]ピリミジン-3-アミン(12)
4-フェニルイソオキサゾロ[5,4-b]ピリジン-3-アミン(13)
5-フルオロイソオキサゾロ[5,4-b]ピリジン-3-アミン(14)
6-フェニルイソオキサゾロ[5,4-b]ピリジン-3-アミン(15)
5-ヨードイソオキサゾロ[5,4-b]ピリジン-3-アミン(16)
イソオキサゾロ[4,5-c]ピリジン-3-アミン(17)
N6,N6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(18)
N4,N4-ジメチルイソオキサゾロ[5,4-b]ピリジン-3,4-ジアミン(19)
5-クロロ-N3,4,6-トリメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(20)
5-(3-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(22)
5-(2-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(23)
5-フェニルイソオキサゾロ[5,4-b]ピリジン-3-アミン(24)
5-(3-フルオロ-4-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(25)
5-(ピリジン-3-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(26)
5-(ピリジン-4-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(27)
2-(3-アミノイソオキサゾロ[5,4-b]ピリジン-5-イル)フェノール(28)
4-(3-アミノイソオキサゾロ[5,4-b]ピリジン-5-イル)フェノール(29)
5-(4-フルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(30)
5-(2,4-ジフルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(32)
5-(3,5-ジフルオロ-2-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(33)
5-(2,4-ジクロロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(34)
5-(2,3,4-トリクロロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(35)
5-(4-(トリフルオロメチルフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(36)
5-(3-アミノフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(37)
メチル3-(3-アミノイソオキサゾロ[5,4-b]ピリジン-5-イル)ベンゾエート(38)
5-(6-フルオロピリジン-3-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(39)
5-(2-クロロ-4-(トリフルオロメチル)フェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(40)
6-クロロ-4-メチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(42)
イソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(43)
5-メチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(44)
5,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(45)
6-メチル-4-(トリフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(46)
6-(トリフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(47)
6-イソプロピルイソオキサゾロ[5,4-b]ピリジン-3-アミン(48)
5-ニトロイソオキサゾロ[5,4-b]ピリジン-3-アミン(49)
エチル3-アミノ-6-(トリフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-5-カルボキシラート(50)
5-(ジフルオロメトキシ)-4,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(52)
エチル3-アミノ-6-メチルイソオキサゾロ[5,4-b]ピリジン-5-カルボキシラート(53)
エチル3-アミノ-6-(ジフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-5-カルボキシラート(54)
5-フルオロ-6-モルホリノイソオキサゾロ[5,4-b]ピリジン-3-アミン(55)
N6-シクロプロピル-5-フルオロイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(56)
5-フルオロ-N6,N6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(57)
6-(フラン-2-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(58)
6,7-ジヒドロ-5H-シクロペンタ[b]イソオキサゾロ[4,5-e]ピリジン-3-アミン(59)
6,7,8,9-テトラヒドロ-5H-シクロヘプタ[b]イソオキサゾロ[4,5-e]ピリジン-3-アミン(60)
7,8-ジヒドロ-5H-イソオキサゾロ[5,4-b]ピラノ[3,4-e]ピリジン-3-アミン(62)
6-(メチルチオ)イソオキサゾロ[5,4-d]ピリミジン-3-アミン(63)
6-メチルイソオキサゾロ[5,4-d]ピリミジン-3-アミン(64)
4-(メチルチオ)-6-フェニルイソオキサゾロ[5,4-d]ピリミジン-3-アミン(65)
6-クロロ-5-フルオロイソオキサゾロ[5,4-b]ピリジン-3-アミン(66)
5,6-ジクロロイソオキサゾロ[5,4-b]ピリジン-3-アミン(67)
6-クロロ-4-(トリフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(68)
5-(3-メトキシプロパ-1-イン-1-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(69)
6-(4-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(70)
6-(2,4-ジクロロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(72)
6-(2,4-ジフルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(73)
6-(2-チエニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(74)
6-(1-メチル-1H-ピラゾール-5-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(75)
6-(3-(ジメチルアミノ)プロポキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(76)
6-(2-(ジメチルアミノ)エトキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(77)
6-(2-モルホリノエトキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(78)
6-(メチルチオ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(79)
6-(メチルスルホニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(80)
メチル3-アミノイソオキサゾロ[5,4-b]ピリジン-6-カルボキシラート(82)
6-フェノキシイソオキサゾロ[5,4-b]ピリジン-3-アミン(83)
6-(2-クロロフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(84)
6-(3-クロロフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(85)
6-(4-クロロフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(86)
6-(2-(トリフルオロメトキシ)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(87)
6-(3-(トリフルオロメトキシ)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(88)
6-(4-(トリフルオロメトキシ)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(89)
6-(2-メトキシフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(90)
6-(4-メトキシフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(92)
6-(3-(トリフルオロメチル)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(93)
N6-フェニルイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(94)
N6-(3-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(95)及び
N6-(4-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(96)、
からなる群から選択される段落(1)で定義される化合物と、
その医薬的に許容し得る塩。
5-ブロモ-4,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(1)
4,5,6-トリメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(5)
5-クロロイソオキサゾロ[5,4-b]ピリジン-3-アミン(8)
4-フェニルイソオキサゾロ[5,4-b]ピリジン-3-アミン(13)
5-フルオロイソオキサゾロ[5,4-b]ピリジン-3-アミン(14)
6-フェニルイソオキサゾロ[5,4-b]ピリジン-3-アミン(15)
5-ヨードイソオキサゾロ[5,4-b]ピリジン-3-アミン(16)
N6,N6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(18)
N4,N4-ジメチルイソオキサゾロ[5,4-b]ピリジン-3,4-ジアミン(19)
5-クロロ-N3,4,6-トリメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(20)
5-(3-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(22)
5-(2-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(23)
5-(3-フルオロ-4-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(25)
5-(ピリジン-3-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(26)
5-(ピリジン-4-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(27)
2-(3-アミノイソオキサゾロ[5,4-b]ピリジン-5-イル)フェノール(28)
4-(3-アミノイソオキサゾロ[5,4-b]ピリジン-5-イル)フェノール(29)
5-(4-フルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(30)
5-(2,4-ジフルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(32)
5-(3,5-ジフルオロ-2-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(33)
5-(2,4-ジクロロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(34)
5-(2,3,4-トリクロロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(35)
5-(4-(トリフルオロメチルフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(36)
5-(3-アミノフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(37)
メチル3-(3-アミノイソオキサゾロ[5,4-b]ピリジン-5-イル)ベンゾエート(38)
5-(6-フルオロピリジン-3-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(39)
5-(2-クロロ-4-(トリフルオロメチル)フェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(40)
イソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(43)
5-メチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(44)
5,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(45)
6-メチル-4-(トリフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(46)
6-イソプロピルイソオキサゾロ[5,4-b]ピリジン-3-アミン(48)
5-ニトロイソオキサゾロ[5,4-b]ピリジン-3-アミン(49)
エチル3-アミノ-6-(トリフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-5-カルボキシラート(50)
5-(ジフルオロメトキシ)-4,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(52)
エチル3-アミノ-6-メチルイソオキサゾロ[5,4-b]ピリジン-5-カルボキシラート(53)
エチル3-アミノ-6-(ジフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-5-カルボキシラート(54)
5-フルオロ-6-モルホリノイソオキサゾロ[5,4-b]ピリジン-3-アミン(55)
N6-シクロプロピル-5-フルオロイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(56)
5-フルオロ-N6,N6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(57)
6-(フラン-2-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(58)
6,7,8,9-テトラヒドロ-5H-シクロヘプタ[b]イソオキサゾロ[4,5-e]ピリジン-3-アミン(60)
7,8-ジヒドロ-5H-イソオキサゾロ[5,4-b]ピラノ[3,4-e]ピリジン-3-アミン(62)
6-(メチルチオ)イソオキサゾロ[5,4-d]ピリミジン-3-アミン(63)
式 4-(メチルチオ)-6-フェニルイソオキサゾロ[5,4-d]ピリミジン-3-アミン(65)
6-クロロ-5-フルオロイソオキサゾロ[5,4-b]ピリジン-3-アミン(66)
5,6-ジクロロイソオキサゾロ[5,4-b]ピリジン-3-アミン(67)
6-クロロ-4-(トリフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(68)
5-(3-メトキシプロパ-1-イン-1-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(69)
6-(4-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(70)
6-(2,4-ジクロロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(72)
6-(2,4-ジフルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(73)
6-(2-チエニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(74)
6-(1-メチル-1H-ピラゾール-5-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(75)
6-(3-(ジメチルアミノ)プロポキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(76)
6-(2-(ジメチルアミノ)エトキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(77)
6-(2-モルホリノエトキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(78)
6-(メチルチオ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(79)
6-(メチルスルホニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(80)
メチル3-アミノイソオキサゾロ[5,4-b]ピリジン-6-カルボキシラート(82)
6-フェノキシイソオキサゾロ[5,4-b]ピリジン-3-アミン(83)
6-(2-クロロフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(84)
6-(3-クロロフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(85)
6-(4-クロロフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(86)
6-(2-(トリフルオロメトキシ)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(87)
6-(3-(トリフルオロメトキシ)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(88)
6-(4-(トリフルオロメトキシ)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(89)
6-(2-メトキシフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(90)
6-(4-メトキシフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(92)
6-(3-(トリフルオロメチル)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(93)
N6-フェニルイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(94)
N6-(3-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(95)及び
N6-(4-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(96)、
から選択される式Iの化合物と、
その医薬的に許容し得る塩とを、更に提供する。
本明細書で使用される用語「放射線療法」は、ガン細胞を殺し腫瘍を縮小するための、X線、ガンマ線、中性子、陽子、及び他の源からの高エネルギー放射線の使用を意味する。放射線は体外の機械(外部放射線療法)から来ることもあれば、がん細胞近くの体内に置かれた放射性物質(内部放射線療法)から来ることもある。全身放射線療法は、血液中を移動して体内の組織に到達する放射標識されたモノクローナル抗体などの放射性物質を使用する。照射及び放射線療法という用語は同じ意味を持つ。
上記で定義したように、本発明は広義には、一般式Iの化合物を含有する医薬組成物、及び治療、特に癌治療における、そのような化合物の使用に関する。式Iの化合物は、インドールアミン2,3-ジオキシゲナーゼ1(IDO1)及び/又はトリプトファン2,3-ジオキシゲナーゼ(TDO)の阻害剤であることが見出されている。このように、本発明の化合物は、単独で、又は抗癌ワクチン、免疫チェックポイントタンパク質のモジュレーター、養子T細胞免疫療法(例えばキメラ抗原受容体T細胞(CART細胞))、放射線療法及び他の化学療法剤のような他の薬剤と組み合わせて、癌治療に有用であることが期待される。式Iの化合物はまた、癌以外の種々の他の症状の治療において有用であることが期待される(下記の本発明の治療法の項でより詳細に記載される)。
式Iのいくつかの化合物は、カリウムtert-ブトキシド、炭酸カリウム、又は炭酸セシウムのような塩基の存在下で、適切に置換されたハロ-シアノピリジンとアセトヒドロキサム酸との反応によって調製することができる(方法1)。この反応には、DMF、p-ジオキサン、及びN-メチルモルホリンを含む様々な溶媒を使用することができる。
方法1
方法5
方法6
方法7
方法8
本発明の式Iの化合物は、IDO1又はTDOの阻害剤、又はIDO1及びTDOの両方の阻害剤であり得る。IDO1又はTDOのいずれかの阻害剤である化合物、ならびにIDO1及びTDOの二重阻害剤である化合物は、癌療法において有用であると予想される。したがって、ある実施態様では本発明は、ヒトを含む温血動物における癌の治療を必要とする対象に、治療有効量の式Iの化合物、又は式Iの化合物を含む医薬組成物を投与することによって、癌を治療する方法を提供する。
本発明は、本発明の式Iの1又は2以上の化合物及び医薬的に許容し得る担体を含む医薬組成物を含む。
明示されていない出発物質は、商業的に入手可能であるか、又はその合成が化学文献に記載されているか、又は当業者に公知の方法によって調製することができる。例示化合物は、1NMR分光法、APCIイオン化質量分析法、融点、及び燃焼又はHRMS分析により解析された。例示化合物の純度はHPLC分析によって測定し、すべての化合物について>95%であることが判明した。
NMR: 核磁気共鳴
ESI: 電子噴霧イオン化
APCI: 大気圧化学イオン化
HPLC: 高速液体クロマトグラフィー
LCMS: 液体クロマトグラフィー-質量分析
HRMS: 高分解能質量分析
mp: 融点
DMF: ジメチルホルムアミド
EtOAc: 酢酸エチル
DCM: ジクロロメタン
MeOH: メタノール
THF: テトラヒドロフラン
HOAc: 酢酸
dppf: 2-(ジフェニルホスフィノ)フェロセン
EDCI: 1-エチル-(3-ジメチルアミノプロピル)カルボジイミド塩酸塩
TEA: トリエチルアミン
6-メチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(248mg、1.66mmol)を、冷却した濃H2SO4(10ml)に0℃で溶解し、次にCrO3(350mg、3.5mmol)を加え、混合物20℃で3日間攪拌した。0℃に冷却後、MeOH(1ml)を加え、20℃で20時間撹拌を続けた。混合物を水で希釈し、EtOAc中に抽出した。合わせた抽出物を乾燥させ(Na2SO4)、溶媒を蒸発させた後、残渣をHPLCで分離して82(44mg)を得た。1H NMR [(CD3)2SO] δ 8.48 (d, J = 8.0 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 6.84 (brs, 2 H), 3.92 (s, 3H) 元素分析: C8H7N3O3: 計算値: C, 49.7; H, 3.6; N, 21.7; 実測値: C, 49.8; H, 3.5; N, 21.8%. HPLC 99.6%。
pREP4及びpQE9-IDOプラスミドで形質転換した大腸菌のEC538株の培養物から、組換えヒトIDO1(rhIDO1)を発現させ、精製した。総容量30μLのアッセイ培地中で9nMの最終濃度のrhIDO1(15μL)と混合した、50mMリン酸緩衝液、10mMアスコルビン酸、10μMメチレンブルー、100μg/mLカタラーゼ、80μM TRP、0.01%ツイーン20(v/v)を含む384ウェルマイクロプレートに、反応混合物を入れた。プレートを37℃で30分間インキュベートし、ピペリジン(200mM)を加え、65℃で20分間加熱して酵素反応を停止させた。蛍光強度をλex400nm及びλem500nmで読み取った。試験化合物を100%DMSOに溶解し、rhIDO1を添加する前にアッセイ培地で予め希釈した。IDO1阻害率(%)は、
([阻害されていない酵素アッセイシグナル]-[阻害された酵素アッセイシグナル]×100)/
([阻害されていない酵素アッセイシグナル]-[アッセイ培地シグナル])
として計算される。
すべての実験を3重測定で行い、Prism v5 (Graphpad Software, Inc., La Jolla, CA, USA) を用いて統計分析を行った。
細胞IDO1活性の阻害のアッセイのために、ヒトIDO1(LLTC-hIDO1)又はネズミ(LLTC-mIDO1)を発現するようにトランスフェクトされたルイス肺癌細胞を、試験化合物と共に37℃、5%CO2 で24時間培養した。次に、各ウェルからの培養上清を新鮮な平底96ウェルプレートに移し、トリクロロ酢酸(最終濃度10%)と混合し、60℃で20分間インキュベートした。次に、プレートを遠心分離し(2500gで10分間)、新しいプレート中に上清を移し、4-(ジメチルアミノ)ベンズアルデヒド(酢酸中20mg/mL)と1:1で混合した。各ウェルの吸光度を480nmで読み取り、細胞酵素活性を50%阻害した濃度を計算した。
細胞TDOの阻害のアッセイのために、完全長ヒトTDOを過剰発現するようにトランスフェクトされたGL261細胞を試験化合物とともに、37℃、5%CO2で24時間培養した。次に、各ウェルからの培養上清を新鮮な平底96ウェルプレートに移し、IDO1アッセイについて上記したようにキヌレニン含量を測定し、細胞酵素活性を50%阻害する濃度を計算した。
同系のC57Bl/6マウスの皮下に腫瘍を移植し、腫瘍が約3×3mmのサイズに達した時に、異なる治療群に割り当てた。化合物をDMSOに溶解し、50mlの用量を腹腔内注射又は皮下注射のいずれかによって毎日投与した。腫瘍を1日おきに測定し、人道的倫理的終点に達するまでマウスを追跡した。
16日間の皮下GL-261-hIDO1腫瘍(腫瘍サイズ15~20mm)を有するマウスの血漿及び腫瘍中のK:T比を、150mg/kgの化合物3で処置後、0.25時間、1時間、2時間、4時間、6時間、及び24時間目に、分析HPLCにより測定した。1時点についてn=3。3匹のマウスからプールしたDMSOビヒクル対照群(n=21)、DMSOで処置後0.25時間、1時間、2時間、4時間、6時間、及び24時間目。*及び**は、片側分散分析と、DMSO対照と比較したSidakの多重比較による有意性(それぞれp<0.05、p<0.01)を示す。
この試験の結果を図2に示す。
図3は、ビヒクル(A);腫瘍移植の8日後に開始した、毎日75mg/kgの化合物3(B)の腹腔内投与;抗PD1(上:腫瘍移植後8,11及び14日目に250μg/マウスを腹腔内投与)又は抗CTLA4(下:腫瘍移植の6日後に1mg/マウスを腹腔内投与)に対する抗免疫チェックポイント抗体(C);又は化合物3+免疫チェックポイント抗体の組み合わせ(D)、で処置したsc GL261-hIDO1腫瘍を有するマウスを用いた試験の、人道的倫理的終点に対するまでの生存率を示す。P値は、ビヒクル生存曲線と比較した対数順位分析による有意差を示す。色付きの矢頭は投与スケジュールを示す。
この試験の結果を図3に示す。
Claims (17)
- インドールアミン2,3-ジオキシゲナーゼ1(IDO1)及び/又はトリプトファン2,3-ジオキシゲナーゼ(TDO)の阻害を必要とする温血動物において、IDO1及び/又はTDOを阻害するための医薬組成物であって、前記医薬組成物は、式Iの化合物、又はその医薬的に許容し得る塩:
(a)ZがN又はN-オキシド、例えばNであり、WがCR1であり、XがCR2であり、YがCR3であるか、
(b)XがN又はN-オキシド、例えばNであり、WがCR1であり、YがCR3であり、ZがCR4であるか、あるいは
(c)X及びZが共にN又はN-オキシド、例えばNであり、WがCR1であり、YがCR3であり、
R1、R2、R3、及びR4は、それぞれ独立して以下の基:H、ハロゲン、R、-OH、-OR、-OC(O)H、-OC(O)R、-OC(O)NH2、-OC(O)NHR、-OC(O)NRR、-OP(O)(OH)2、-OP(O)(OR)2、-NO2、-NH2、-NHR、-NRR、-NHC(O)H、-NHC(O)R、-NRC(O)R、-NHC(O)NH2、-NHC(O)NRR、-NRC(O)NHR、-SH、-SR、-S(O)H、-S(O)R、-SO2R、-SO2NH2、-SO2NHR、-SO2NRR、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-C≡CH、-C≡CR、-CH=CHR、-CH=CRR、-CR=CHR、-CR=CRR、-CO2H、-CO2R、-CHO、-C(O)R、-C(O)NH2、-C(O)NHR、-C(O)NRR、-CONHSO2H、-CONHSO2R、-CONRSO2R、環状C3~C7アルキルアミノ、イミダゾリル、C1~C6アルキルピペラジニル、モルホリニル、及びチオモルホリニル、から選択され;
又はR1とR2が一緒になって、又はR2とR3が一緒になって、又はR3とR4が一緒になって、O、N、及びSから選択される1~3個のヘテロ原子を任意に含む、炭素原子の飽和又は部分飽和又は完全不飽和の5又は6員環を形成することができ、前記環は、Rから選択される1~4個の置換基で任意に独立して置換され;
各Rは、以下の段落(a)及び(b)で定義される基のいずれかから独立して選択される:
(a)任意に置換されたC1-6アルキル基、任意に置換されたC2-6アルケニル基、任意に置換されたC2-6アルキニル基、及び任意に置換されたC3-7環状アルキル基;ここで、前記アルキル、アルケニル、アルキニル、及び環状アルキル基の各々の1又は2以上の任意の置換基は、それぞれ独立して、以下の基:ハロゲン、-OH、-OR5、-OC(O)R5、-OC(O)NH2、-OC(O)NHR5、-OC(O)NR5R5、-OP(O)(OH)2、-OP(O)(OR5)2、-NO2、-NH2、-NHR5、-NR5R5、-N+(O-)R5R5、-NHC(O)H、-NHC(O)R5、-NR5C(O)R5、-NHC(O)NH2、-NHC(O)NR5R5、-NR5C(O)NHR5、-SH、-SR5、-S(O)H、-S(O)R5、-SO2R5、-SO2NH2、-SO2NHR5、-SO2NR5R5、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-CO2H、-CO2R5、-CHO、-C(O)R5、-C(O)NH2、-C(O)NHR5、-C(O)NR5R5、-CONHSO2H、-C(O)NHSO2R5、-C(O)NR5SO2R5、環状C3~C7アルキルアミノ、イミダゾリル、ピペラジニル、モルホリニル、チオモルホリニル、ピペリジニル、アゼパニル、ピロリジニル、及びアゼチジニル、からなる群から選択される;ここで、基イミダゾリル、ピペラジニル、モルホリニル、チオモルホリニル、ピペリジニル、アゼパニル、ピロリジニル、及びアゼチジニルのそれぞれは、1又は2以上の以下の基:C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7環状アルキル、ハロゲン、-OH、-OR7、-OC(O)R7、-OC(O)NH2、-OC(O)NHR7、-OC(O)NR7R7、-OP(O)(OH)2、-OP(O)(OR7)2、-NO2、-NH2、-NHR7、-NR7R7、-N+(O-)R7R7、-NHC(O)H、-NHC(O)R7、-NR7C(O)R7、-NHC(O)NH2、-NHC(O)NR7R7、-NR7C(O)NHR7、-SH、-SR7、-S(O)H、-S(O)R7、-SO2R7、-SO2NH2、SO2NHR7、SO2NR7R7、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-CO2H、-CO2R7、-CHO、-C(O)R7、-C(O)NH2、-C(O)NHR7、C(O)NR7R7、-CONHSO2H、-C(O)NHSO2R7、-C(O)NR7SO2R7、任意に置換されたアリール基、及び、最大12個の炭素原子を有し、かつ、O、N、及びSから独立して選択される1又は2以上のヘテロ原子をその環系に有する任意に置換されたヘテロアリール基、により任意に置換される;ここで、前記アリール及びヘテロアリール基の各々の前記1又は2以上の任意の置換基は、それぞれ独立して、以下の基:C1-6アルキル、C2-6アルケニル、C2-6アルキニル、又はC3-7環状アルキル、ハロゲン、-OH、-OR8、-OC(O)R8、-OC(O)NH2、-OC(O)NHR8、-OC(O)NR8R8、-OP(O)(OH)2、-OP(O)(OR8)2、-NO2、-NH2、-NHR8、-NR8R8、-N+(O)R8R8、-NHC(O)H、-NHC(O)R8、-NR8C(O)R8、-NHC(O)NH2、NHC(O)NR8R8、-NR8C(O)NHR8、-SH、-SR8、-S(O)H、-S(O)R8、-SO2R8、-SO2NH2、-SO2NHR8、-SO2NR8R8、-CF3、-CHF2、-CH2F、-OCF3、-OCHF2、-CN、-CO2H、-CO2R8、-CHO、-C(O)R8、-C(O)NH2、-C(O)NHR8、-C(O)NR8R8、-C(O)NHSO2H、-C(O)NHSO2R8、及び-C(O)NR8SO2R8、から選択される;ここで、各R5、R7、及びR8は、C1-6アルキル基、C2-6アルケニル基、C2-6アルキニル基、及びC3-7環状アルキル基から、独立して選択される;及び
(b)任意に置換されたアリール基、及び最大12個の炭素原子を有し、かつ、O、N、及びSから独立して選択される1又は2以上のヘテロ原子をその環系に有する任意に置換されたヘテロアリール基;ここで、前記1又は2以上の任意の置換基は、Rについて上記(a)で定義したものと同じ任意の置換基から、それぞれ独立して選択される;
R9とR10は、H及びメチルから、それぞれ独立して選択される]、
及び医薬的に許容し得る担体を含む、医薬組成物。 - R1、R2、R3、及びR4は、存在する場合、H、ハロゲン、任意に置換されたC1~C6アルキル、-O-R(式中、Rは任意に置換されたC1~C6アルキル及び任意に置換されたアリール(例えばフェニル)から任意に選択される)、-NHR(式中、Rは任意に置換されたアリール、任意に置換されたアリール、及び最大12個の炭素原子を有し、かつ、O、N、及びSから独立して選択される1又は2以上のヘテロ原子をその環系に有する任意に置換されたヘテロアリールである)からなる群から、それぞれ独立して選択される、請求項1に記載の医薬組成物。
- (a)R1、R2、R3、及びR4は、存在する場合、H、ハロゲン、-CF3、-CHF2、-OCF3、-OCHF2、メチルなどのC1-6アルキル、置換アリール、置換ヘテロアリール、-OR(式中、Rは任意に置換されたアリールである)、及び-NHR(式中、Rは任意に置換されたアリールである)からなる群から、それぞれ独立して選択されるか、
(b)R1、R2、R3、及びR4の1つ又は2つは、存在する場合、Hであり、HではないR1、R2、R3、及びR4のその他は、ハロゲン、-CF3、-CHF2、-OCF3、-OCHF2、メチルなどのC1-6アルキル、置換アリール、置換ヘテロアリール、-OR(式中、Rは任意に置換されたアリールである)、及び-NHR(式中、Rは任意に置換されたアリールである)からなる群から、独立して選択される、請求項2に記載の医薬組成物。 - R3が存在し、ハロゲン、-OR(式中、Rは任意に置換されたアリールである)、及び-NHR(式中、Rは任意に置換されたアリールである)からなる群から選択される、請求項3に記載の医薬組成物。
- ZがN又はN-オキシド、例えばNであり、WがCR1であり、XがCR2であり、YがCR3であり、R3が、ハロゲン、-OR(式中、Rは任意に置換されたアリールである)、及び-NHR(式中、Rは任意に置換されたアリールである)からなる群から選択される、請求項1に記載の医薬組成物。
- ZがN又はN-オキシド、例えばNであり、WがCR1であり、XがCR2であり、YがCR3であり、R1がHであり、R2とR3の一方又は両方がH以外である、請求項1に記載の医薬組成物。
- (a)H以外であるR2とR3の各々が、ハロゲン、任意に置換されたC1~C6アルキル、-OR(式中、Rは任意に置換されたC1~C6アルキル、及び任意に置換されたアリールから選択される)、-NHR(式中、Rは任意に置換されたアリール基、置換フェニルなどの任意に置換されたアリール基、及び任意に置換されたヘテロアリール基である)からなる群から独立して選択されるか、あるいは
(b)H以外であるR2とR3の各々が、ハロゲン、-CF3、-CHF2、-OCF3、-OCHF2、メチルなどのC1-6アルキル、置換アリール、置換ヘテロアリール、-OR(式中、Rは任意に置換されたアリールである)、及び-NHR(式中、Rは任意に置換されたアリールである)からなる群から、それぞれ独立して選択される、請求項6に記載の医薬組成物。 - R1とR2が一緒になって、又はR2とR3が一緒になって、又はR3とR4が一緒になって、O、N、及びSから選択される1~3個のヘテロ原子を任意に含む、炭素原子の飽和又は部分飽和又は完全不飽和の5又は6員環を形成し、前記環は、Rから独立して選択される1~4個の置換基で任意に置換され、前記環の一部ではないR1、R2、R3、及びR4の置換基は、H、ハロゲン、任意に置換されたC1~C6アルキル、O-R(式中、Rは任意に置換されたC1~C6アルキル、任意に置換されたアリール、及び最大12個の炭素原子を有し、かつ、O、N、及びSから独立して選択される1又は2以上のヘテロ原子をその環系に有する任意に置換されたヘテロアリール基である)から独立して選択される、請求項1に記載の医薬組成物。
- R9とR10が両方ともHである、請求項1~8のいずれか1項に記載の医薬組成物。
- ZがN又はN-オキシド、例えばNであり、WがCR1であり、XがCR2であり、YがCR3であり、R9とR10が両方ともHである、請求項1に記載の医薬組成物。
- (a)R1、R2、及びR3が、それぞれ独立して、H、ハロゲン、-CF3、-CHF2、-OCF3、-OCHF2、メチルなどのC1-6アルキル、置換アリール、置換ヘテロアリール、-OR(式中、Rは任意に置換されたアリールである)、及び-NHR(式中、Rは任意に置換されたアリールである)からなる群から選択されるか、
(b)R1、R2、及びR3の1つ又は2つがHであり、HではないR1、R2、及びR3のその他は、独立して、ハロゲン、-CF3、-CHF2、-OCF3、-OCHF2、メチルなどのC1-6アルキル、置換アリール、置換ヘテロアリール、-OR(式中、Rは任意に置換されたアリールである)、及び-NHR(式中、Rは任意に置換されたアリールである)からなる群から選択されるか、
(c)R1がHであり、R2とR3の一方又は両方がH以外であり、HではないR2とR3の各々が、独立して、ハロゲン、-CF3、-CHF2、-OCF3、-OCHF2、メチルなどのC1-6アルキル、置換アリール、置換ヘテロアリール、-OR(式中、Rは任意に置換されたアリールである)、及び-NHR(式中、Rは任意に置換されたアリールである)からなる群から選択されるか、
(d)R3が、ハロゲン、-OR(式中、Rは任意に置換されたアリールである)、及び-NHR(式中、Rは任意に置換されたアリールである)からなる群から選択されるか、あるいは
(e)R1がHであり、R2とR3が、O、N、及びSから選択される1~3個のヘテロ原子を任意に含む、炭素原子の飽和又は部分飽和又は完全不飽和の5又は6員環を形成し、前記環が、Rから独立して選択される1~4個の置換基で任意に置換される、請求項10に記載の医薬組成物。 - 以下:
5-ブロモ-4,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(1)
イソオキサゾロ[5,4-b]ピリジン-3-アミン(2)
5-クロロ-4,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(3)
4,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(4)
4,5,6-トリメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(5)
5-ブロモイソオキサゾロ[5,4-b]ピリジン-3-アミン(6)
6-メチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(7)
5-クロロイソオキサゾロ[5,4-b]ピリジン-3-アミン(8)
イソオキサゾロ[5,4-b]キノリン-3-アミン(9)
5,6,7,8-テトラヒドロイソオキサゾロ[5,4-b]キノリン-3-アミン(10)
6-クロロイソオキサゾロ[5,4-b]ピリジン-3-アミン(11)
イソオキサゾロ[5,4-d]ピリミジン-3-アミン(12)
4-フェニルイソオキサゾロ[5,4-b]ピリジン-3-アミン(13)
5-フルオロイソオキサゾロ[5,4-b]ピリジン-3-アミン(14)
6-フェニルイソオキサゾロ[5,4-b]ピリジン-3-アミン(15)
5-ヨードイソオキサゾロ[5,4-b]ピリジン-3-アミン(16)
イソオキサゾロ[4,5-c]ピリジン-3-アミン(17)
N6,N6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(18)
N4,N4-ジメチルイソオキサゾロ[5,4-b]ピリジン-3,4-ジアミン(19)
5-クロロ-N3,4,6-トリメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(20)
5-クロロ-N3,N3,4,6-テトラメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(21)
5-(3-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(22)
5-(2-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(23)
5-フェニルイソオキサゾロ[5,4-b]ピリジン-3-アミン(24)
5-(3-フルオロ-4-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(25)
5-(ピリジン-3-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(26)
5-(ピリジン-4-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(27)
2-(3-アミノイソオキサゾロ[5,4-b]ピリジン-5-イル)フェノール(28)
4-(3-アミノイソオキサゾロ[5,4-b]ピリジン-5-イル)フェノール(29)
5-(4-フルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(30)
5-(3-フルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(31)
5-(2,4-ジフルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(32)
5-(3,5-ジフルオロ-2-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(33)
5-(2,4-ジクロロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(34)
5-(2,3,4-トリクロロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(35)
5-(4-(トリフルオロメチルフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(36)
5-(3-アミノフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(37)
メチル3-(3-アミノイソオキサゾロ[5,4-b]ピリジン-5-イル)ベンゾエート(38)
5-(6-フルオロピリジン-3-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(39)
5-(2-クロロ-4-(トリフルオロメチル)フェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(40)
6-メトキシイソオキサゾロ[5,4-b]ピリジン-3-アミン(41)
6-クロロ-4-メチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(42)
イソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(43)
5-メチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(44)
5,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(45)
6-メチル-4-(トリフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(46)
6-(トリフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(47)
6-イソプロピルイソオキサゾロ[5,4-b]ピリジン-3-アミン(48)
5-ニトロイソオキサゾロ[5,4-b]ピリジン-3-アミン(49)
エチル3-アミノ-6-(トリフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-5-カルボキシラート(50)
4-メトキシイソオキサゾロ[5,4-b]ピリジン-3-アミン(51)
5-(ジフルオロメトキシ)-4,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(52)
エチル3-アミノ-6-メチルイソオキサゾロ[5,4-b]ピリジン-5-カルボキシラート(53)
エチル3-アミノ-6-(ジフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-5-カルボキシラート(54)
5-フルオロ-6-モルホリノイソオキサゾロ[5,4-b]ピリジン-3-アミン(55)
N6-シクロプロピル-5-フルオロイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(56)
5-フルオロ-N6,N6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(57)
6-(フラン-2-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(58)
6,7-ジヒドロ-5H-シクロペンタ[b]イソオキサゾロ[4,5-e]ピリジン-3-アミン(59)
6,6-ジメチル-5,6,7,8-テトラヒドロイソオキサゾロ[5,4-b]キノリン-3-アミン(61)
7,8-ジヒドロ-5H-イソオキサゾロ[5,4-b]ピラノ[3,4-e]ピリジン-3-アミン(62)
6-(メチルチオ)イソオキサゾロ[5,4-d]ピリミジン-3-アミン(63)
6-メチルイソオキサゾロ[5,4-d]ピリミジン-3-アミン(64)
4-(メチルチオ)-6-フェニルイソオキサゾロ[5,4-d]ピリミジン-3-アミン(65)
6-クロロ-5-フルオロイソオキサゾロ[5,4-b]ピリジン-3-アミン(66)
5,6-ジクロロイソオキサゾロ[5,4-b]ピリジン-3-アミン(67)
6-クロロ-4-(トリフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(68)
5-(3-メトキシプロパ-1-イン-1-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(69)
6-(4-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(70)
6-(4-フルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(71)
6-(2,4-ジクロロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(72)
6-(2,4-ジフルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(73)
6-(2-チエニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(74)
6-(1-メチル-1H-ピラゾール-5-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(75)
6-(3-(ジメチルアミノ)プロポキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(76)
6-(2-(ジメチルアミノ)エトキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(77)
6-(2-モルホリノエトキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(78)
6-(メチルチオ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(79)
6-(メチルスルホニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(80)
3-アミノイソオキサゾロ[5,4-b]ピリジン-6-カルボン酸(81)
メチル3-アミノイソオキサゾロ[5,4-b]ピリジン-6-カルボキシラート(82)
6-フェノキシイソオキサゾロ[5,4-b]ピリジン-3-アミン(83)
6-(2-クロロフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(84)
6-(3-クロロフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(85)
6-(4-クロロフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(86)
6-(2-(トリフルオロメトキシ)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(87)
6-(3-(トリフルオロメトキシ)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(88)
6-(4-(トリフルオロメトキシ)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(89)
6-(2-メトキシフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(90)
6-(3-メトキシフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(91)
6-(4-メトキシフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(92)
6-(3-(トリフルオロメチル)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(93)
N6-フェニルイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(94)
N6-(3-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(95)及び
N6-(4-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(96)、
から選択される式Iの化合物、又はその医薬的に許容し得る塩を含む、請求項1に記載の医薬組成物。 - 以下:
5-ブロモ-4,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(1)
4,5,6-トリメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(5)
5-クロロイソオキサゾロ[5,4-b]ピリジン-3-アミン(8)
4-フェニルイソオキサゾロ[5,4-b]ピリジン-3-アミン(13)
5-フルオロイソオキサゾロ[5,4-b]ピリジン-3-アミン(14)
6-フェニルイソオキサゾロ[5,4-b]ピリジン-3-アミン(15)
5-ヨードイソオキサゾロ[5,4-b]ピリジン-3-アミン(16)
N6,N6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(18)
N4,N4-ジメチルイソオキサゾロ[5,4-b]ピリジン-3,4-ジアミン(19)
5-クロロ-N3,4,6-トリメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(20)
5-クロロ-N3,N3,4,6-テトラメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(21)
5-(3-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(22)
5-(2-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(23)
5-(3-フルオロ-4-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(25)
5-(ピリジン-3-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(26)
5-(ピリジン-4-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(27)
2-(3-アミノイソオキサゾロ[5,4-b]ピリジン-5-イル)フェノール(28)
4-(3-アミノイソオキサゾロ[5,4-b]ピリジン-5-イル)フェノール(29)
5-(4-フルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(30)
5-(3-フルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(31)
5-(2,4-ジフルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(32)
5-(3,5-ジフルオロ-2-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(33)
5-(2,4-ジクロロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(34)
5-(2,3,4-トリクロロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(35)
5-(4-(トリフルオロメチルフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(36)
5-(3-アミノフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(37)
メチル3-(3-アミノイソオキサゾロ[5,4-b]ピリジン-5-イル)ベンゾエート(38)
5-(6-フルオロピリジン-3-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(39)
5-(2-クロロ-4-(トリフルオロメチル)フェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(40)
6-クロロ-4-メチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(42)
イソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(43)
5-メチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(44)
5,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(45)
6-メチル-4-(トリフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(46)
6-イソプロピルイソオキサゾロ[5,4-b]ピリジン-3-アミン(48)
5-ニトロイソオキサゾロ[5,4-b]ピリジン-3-アミン(49)
エチル3-アミノ-6-(トリフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-5-カルボキシラート(50)
4-メトキシイソオキサゾロ[5,4-b]ピリジン-3-アミン(51)
5-(ジフルオロメトキシ)-4,6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3-アミン(52)
エチル3-アミノ-6-メチルイソオキサゾロ[5,4-b]ピリジン-5-カルボキシラート(53)
エチル3-アミノ-6-(ジフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-5-カルボキシラート(54)
5-フルオロ-6-モルホリノイソオキサゾロ[5,4-b]ピリジン-3-アミン(55)
N6-シクロプロピル-5-フルオロイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(56)
5-フルオロ-N6,N6-ジメチルイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(57)
6-(フラン-2-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(58)
6,6-ジメチル-5,6,7,8-テトラヒドロイソオキサゾロ[5,4-b]キノリン-3-アミン(61)
7,8-ジヒドロ-5H-イソオキサゾロ[5,4-b]ピラノ[3,4-e]ピリジン-3-アミン(62)
6-(メチルチオ)イソオキサゾロ[5,4-d]ピリミジン-3-アミン(63)
4-(メチルチオ)-6-フェニルイソオキサゾロ[5,4-d]ピリミジン-3-アミン(65)
6-クロロ-5-フルオロイソオキサゾロ[5,4-b]ピリジン-3-アミン(66)
5,6-ジクロロイソオキサゾロ[5,4-b]ピリジン-3-アミン(67)
6-クロロ-4-(トリフルオロメチル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(68)
5-(3-メトキシプロパ-1-イン-1-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(69)
6-(4-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(70)
6-(4-フルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(71)
6-(2,4-ジクロロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(72)
6-(2,4-ジフルオロフェニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(73)
6-(2-チエニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(74)
6-(1-メチル-1H-ピラゾール-5-イル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(75)
6-(3-(ジメチルアミノ)プロポキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(76)
6-(2-(ジメチルアミノ)エトキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(77)
6-(2-モルホリノエトキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(78)
6-(メチルチオ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(79)
6-(メチルスルホニル)イソオキサゾロ[5,4-b]ピリジン-3-アミン(80)
3-アミノイソオキサゾロ[5,4-b]ピリジン-6-カルボン酸(81)
メチル3-アミノイソオキサゾロ[5,4-b]ピリジン-6-カルボキシラート(82)
6-フェノキシイソオキサゾロ[5,4-b]ピリジン-3-アミン(83)
6-(2-クロロフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(84)
6-(3-クロロフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(85)
6-(4-クロロフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(86)
6-(2-(トリフルオロメトキシ)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(87)
6-(3-(トリフルオロメトキシ)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(88)
6-(4-(トリフルオロメトキシ)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(89)
6-(2-メトキシフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(90)
6-(3-メトキシフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(91)
6-(4-メトキシフェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(92)
6-(3-(トリフルオロメチル)フェノキシ)イソオキサゾロ[5,4-b]ピリジン-3-アミン(93)
N6-フェニルイソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(94)
N6-(3-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(95)
N6-(4-メトキシフェニル)イソオキサゾロ[5,4-b]ピリジン-3,6-ジアミン(96)、
から選択される化合物、又は
その医薬的に許容し得る塩。 - ヒトを含む温血動物における癌の治療における使用のための、請求項1~12のいずれか1項に定義される式Iの化合物又はその医薬的に許容し得る塩、あるいは請求項13に記載の化合物又はその医薬的に許容し得る塩、及び医薬的に許容し得る担体を含む医薬組成物。
- ヒトを含む温血動物における癌の治療における使用のための医薬の製造における、請求項1~12のいずれか1項に定義される式Iの化合物又はその医薬的に許容し得る塩、あるいは請求項13に記載の化合物又はその医薬的に許容し得る塩、及び医薬的に許容し得る担体の使用。
- インドールアミン2,3-ジオキシゲナーゼ1(IDO1)及び/又はトリプトファン2,3-ジオキシゲナーゼ(TDO)の阻害を必要とする温血動物において、IDO1及び/又はTDOを阻害するための医薬組み合わせ又はキットであって、前記医薬組み合わせ又はキットが、
(a)請求項1~12のいずれか1項に定義される式Iの化合物又はその医薬的に許容し得る塩、あるいは請求項13に記載の化合物又はその医薬的に許容し得る塩と、
(b)化学療法剤、及び免疫調節剤、例えば抗癌ワクチン、免疫チェックポイントタンパク質のモジュレーター、及び養子T細胞免疫療法剤(例えば、キメラ抗原受容体T細胞(CART細胞))からなる群から選択される1又は2以上の追加の薬剤と、
を含む、組み合わせ又はキット。 - インドールアミン2,3-ジオキシゲナーゼ1(IDO1)及び/又はトリプトファン2,3-ジオキシゲナーゼ(TDO)の阻害を必要とする温血動物において、IDO1及び/又はTDOを阻害するための医薬の製造における、請求項1~12のいずれか1項に定義される式Iの化合物又はその医薬的に許容し得る塩、あるいは請求項13に記載の化合物又はその医薬的に許容し得る塩の使用。
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