JP2021519786A - チエノピリミジノン化合物 - Google Patents
チエノピリミジノン化合物 Download PDFInfo
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- JP2021519786A JP2021519786A JP2020552869A JP2020552869A JP2021519786A JP 2021519786 A JP2021519786 A JP 2021519786A JP 2020552869 A JP2020552869 A JP 2020552869A JP 2020552869 A JP2020552869 A JP 2020552869A JP 2021519786 A JP2021519786 A JP 2021519786A
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- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 229940076372 protein antagonist Drugs 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- CPNGPNLZQNNVQM-UHFFFAOYSA-N pteridine Chemical compound N1=CN=CC2=NC=CN=C21 CPNGPNLZQNNVQM-UHFFFAOYSA-N 0.000 description 1
- 230000002685 pulmonary effect Effects 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
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 230000022983 regulation of cell cycle Effects 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229960004641 rituximab Drugs 0.000 description 1
- 229960000953 salsalate Drugs 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 190014017285 satraplatin Chemical compound 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000036573 scar formation Effects 0.000 description 1
- FVLVBPDQNARYJU-UHFFFAOYSA-N semustine Chemical compound CC1CCC(NC(=O)N(CCCl)N=O)CC1 FVLVBPDQNARYJU-UHFFFAOYSA-N 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- 230000020347 spindle assembly Effects 0.000 description 1
- LBJQKYPPYSCCBH-UHFFFAOYSA-N spiro[3.3]heptane Chemical group C1CCC21CCC2 LBJQKYPPYSCCBH-UHFFFAOYSA-N 0.000 description 1
- CTDQAGUNKPRERK-UHFFFAOYSA-N spirodecane Chemical compound C1CCCC21CCCCC2 CTDQAGUNKPRERK-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000565 sulfonamide group Chemical group 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009897 systematic effect Effects 0.000 description 1
- 238000012385 systemic delivery Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 229960002197 temoporfin Drugs 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 229960000331 teriflunomide Drugs 0.000 description 1
- UTNUDOFZCWSZMS-YFHOEESVSA-N teriflunomide Chemical compound C\C(O)=C(/C#N)C(=O)NC1=CC=C(C(F)(F)F)C=C1 UTNUDOFZCWSZMS-YFHOEESVSA-N 0.000 description 1
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- MODVSQKJJIBWPZ-VLLPJHQWSA-N tesetaxel Chemical compound O([C@H]1[C@@H]2[C@]3(OC(C)=O)CO[C@@H]3CC[C@@]2(C)[C@H]2[C@@H](C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C(=CC=CN=4)F)C[C@]1(O)C3(C)C)O[C@H](O2)CN(C)C)C(=O)C1=CC=CC=C1 MODVSQKJJIBWPZ-VLLPJHQWSA-N 0.000 description 1
- 229950009016 tesetaxel Drugs 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- VOVUARRWDCVURC-UHFFFAOYSA-N thiirane Chemical compound C1CS1 VOVUARRWDCVURC-UHFFFAOYSA-N 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-M thiophene-2-carboxylate Chemical compound [O-]C(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-M 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229960001350 tofacitinib Drugs 0.000 description 1
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- IUCJMVBFZDHPDX-UHFFFAOYSA-N tretamine Chemical compound C1CN1C1=NC(N2CC2)=NC(N2CC2)=N1 IUCJMVBFZDHPDX-UHFFFAOYSA-N 0.000 description 1
- 229950001353 tretamine Drugs 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 125000005039 triarylmethyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 125000004952 trihaloalkoxy group Chemical group 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 102000003298 tumor necrosis factor receptor Human genes 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- MSRILKIQRXUYCT-UHFFFAOYSA-M valproate semisodium Chemical compound [Na+].CCCC(C(O)=O)CCC.CCCC(C([O-])=O)CCC MSRILKIQRXUYCT-UHFFFAOYSA-M 0.000 description 1
- 229960000604 valproic acid Drugs 0.000 description 1
- 229950000386 vapaliximab Drugs 0.000 description 1
- 229950005208 vepalimomab Drugs 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
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical group 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
- 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
- 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
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000006516 vital cellular process Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 239000012130 whole-cell lysate Substances 0.000 description 1
- 229950009002 zanolimumab Drugs 0.000 description 1
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Abstract
Description
本出願は、参照により全体として本明細書に組み込まれる、2018年3月30日出願の米国仮出願第62/650,922号の優先権の利益を主張する。
ユビキチンを媒介とするタンパク質分解は、特定のタンパク質基質への1つまたは複数のユビキチン分子のライゲーションによって始まる。ユビキチン化は、順を追ってユビキチンを基質タンパク質のリシン残基に結合させる働きをする、ユビキチン活性化酵素(E1)、ユビキチン結合酵素(E2)、およびユビキチン−タンパク質リガーゼ(E3)の活性によって起こる。E3リガーゼは、特定の基質に直接結合することにより、ユビキチン化反応に特異性を付与する。
Q1は、CR1または−S−であり、
Q2は、CR2または−S−であり、
Q3は、CR3または−S−であり、
Q1、Q2、およびQ3のうちの1つは、−S−であり、
各
R1、R2、およびR3はそれぞれ、独立に、水素、ジュウテリウム、ヒドロキシル、ハロゲン、シアノ、ニトロ、置換もしくは非置換アミノ、置換もしくは非置換C−アミド、置換もしくは非置換N−アミド、置換もしくは非置換エステル、置換もしくは非置換尿素、置換もしくは非置換C1〜C6アルコキシ、置換もしくは非置換C1〜C6アルキル、置換もしくは非置換C2〜C6アルケニル、置換もしくは非置換C2〜C6アルキニル、置換もしくは非置換C1〜C6ハロアルキル、置換もしくは非置換C3〜C8シクロアルキル、置換もしくは非置換C6〜C10アリール、置換もしくは非置換3〜10員ヘテロシクリル、または置換もしくは非置換5〜10員ヘテロアリールであり、
R4およびR5はそれぞれ、水素、ジュウテリウム、ハロゲン、および置換または非置換C1〜C6アルキルからなる群から独立に選択され、
R6は、水素、ジュウテリウム、ヒドロキシ、置換または非置換C1〜C6アルキル、および置換または非置換C1〜C6アルコキシからなる群から選択され、
Xは、O、NH、またはSであり、
nは、1、2、または3である。
Q1Aは、CR1Aまたは−S−であり、
Q2Aは、CR2Aまたは−S−であり、
Q3Aは、CR3Aまたは−S−であり、
各
Q1、Q2、およびQ3のうちの1つは、−S−であり、
R1A、R2A、およびR3Aはそれぞれ、独立に、水素、ジュウテリウム、ヒドロキシル、ハロゲン、シアノ、ニトロ、置換もしくは非置換アミノ、置換もしくは非置換C−アミド、置換もしくは非置換N−アミド、置換もしくは非置換エステル、置換もしくは非置換尿素、置換もしくは非置換C1〜C6アルコキシ、置換もしくは非置換C1〜C6アルキル、置換もしくは非置換C2〜C6アルケニル、置換もしくは非置換C2〜C6アルキニル、置換もしくは非置換C1〜C6ハロアルキル、置換もしくは非置換C3〜C8シクロアルキル、置換もしくは非置換C6〜C10アリール、置換もしくは非置換3〜10員ヘテロシクリル、置換もしくは非置換5〜10員ヘテロアリール、
R1A、R2A、およびR3Aの少なくとも1つは、
R4AおよびR5Aはそれぞれ、水素、ジュウテリウム、ハロゲン、および置換または非置換C1〜C6アルキルからなる群から独立に選択され、
R6Aは、水素、ジュウテリウム、ヒドロキシ、置換または非置換C1〜C6アルキル、および置換または非置換C1〜C6アルコキシからなる群から選択され、
XAは、O、NH、またはSであり、
sは、1、2、または3であり、
各X1Aは、独立に、O、NH、またはSであり、
各X2Aは、−NR9A−、−(CH2)h−(NR9A)−(CH2)i−、−(CH2)h−(NR9A)−(CH2)i−(NR9A)−、−(CH2)1〜5−、−(CF2)1〜5−、−(CD2)1〜5−、−O−、−C(=O)−、および−S−からなる群から独立に選択され、
各X3Aは、−(CH2)t−(NR9A)−(CH2)j−、−(CH2)t−(NR9A)−(CH2)j−(NR9A)−、−(CH2)1〜5−、−(CF2)1〜5−、および−(CD2)1〜5−からなる群から独立に選択され、
各mは、独立に、0、1、2、3、4、または5であり、
各h、i、およびjは、独立に、0、1、2、3、4、または5であり、
各tは、独立に、1、2、3、4、または5であり、
各R7AおよびR8Aは、置換または非置換C3〜C10シクロアルキル、置換または非置換C6〜C10アリール、置換または非置換5〜10員ヘテロアリール、置換または非置換3〜10員ヘテロシクリル、および置換または非置換C1〜C10アルキルからなる群から独立に選択され、
R9Aは、水素、または置換もしくは非置換C1〜C6アルキルである。
定義
℃ 摂氏度での温度
DCM ジクロロメタン(塩化メチレン)
DMSO ジメチルスルホキシド
EA 酢酸エチル
g グラム
hまたはhr H(s)
HCl 塩酸
HOBt ヒドロキシベンゾトリアゾール
IL インターロイキン
LPS リポ多糖
MeOH メタノール
MS 質量分析
mg ミリグラム
mL ミリリットル
NaCl 塩化ナトリウム
NaOH 水酸化ナトリウム
NBS N−ブロモスクシンイミド
PBMC 末梢血単核球
PG 保護基
ppt 沈殿
psi 重量ポンド毎平方インチ
RPMI ロズウェルパーク記念研究所培地
rt 室温
TNF 腫瘍壊死因子
μL マイクロリットル
μM マイクロモル濃度
wt. 重量
式(I)の化合物
一部のさらなる実施形態では、R1A、R2A、およびR3Aのうちの1つは、
処置方法
追加の治療剤
投薬レジメン
医薬組成物
(実施例1)
一般的な合成
スキーム1
スキーム2
スキーム3
スキーム4
(実施例2)
化合物1:3−(2−メチル−4−オキソチエノ[3,2−d]ピリミジン−3(4H)−イル)ピペリジン−2,6−ジオン
(実施例3)
化合物2:3−(2−メチル−4−オキソチエノ[3,4−d]ピリミジン−3(4H)−イル)ピペリジン−2,6−ジオン
(実施例4)
化合物3:3−(2−メチル−4−オキソチエノ[2,3−d]ピリミジン−3(4H)−イル)ピペリジン−2,6−ジオン
(実施例5)
化合物4:3−(6−ブロモ−2−メチル−4−オキソチエノ[3,2−d]ピリミジン−3(4H)−イル)ピペリジン−2,6−ジオン
(実施例6)
化合物5:3−(5−ブロモ−2−メチル−4−オキソチエノ[2,3−d]ピリミジン−3(4H)−イル)ピペリジン−2,6−ジオン
(実施例7)
化合物6:3−(2,6−ジメチル−4−オキソチエノ[2,3−d]ピリミジン−3(4H)−イル)ピペリジン−2,6−ジオン
(実施例8)
化合物7:3−(5−アミノ−2,6−ジメチル−4−オキソチエノ[2,3−d]ピリミジン−3(4H)−イル)ピペリジン−2,6−ジオン
(実施例9)
化合物8:3−(6−ブロモ−2−メチル−4−オキソチエノ[2,3−d]ピリミジン−3(4H)−イル)ピペリジン−2,6−ジオン
(実施例10)
化合物9:3−(7−アミノ−2−メチル−4−オキソチエノ[3,2−d]ピリミジン−3(4H)−イル)ピペリジン−2,6−ジオン
(実施例11)
化合物10:3−(5−アミノ−2−メチル−4−オキソチエノ[2,3−d]ピリミジン−3(4H)−イル)ピペリジン−2,6−ジオン
(実施例12)
化合物11:3−(7−(アミノメチル)−2−メチル−4−オキソチエノ[3,4−d]ピリミジン−3(4H)−イル)ピペリジン−2,6−ジオン2,2,2−トリフルオロアセテート
(実施例13)
化合物12:1−(3−クロロ−4−メチルフェニル)−3−((3−(2,6−ジオキソピペリジン−3−イル)−2−メチル−4−オキソ−3,4−ジヒドロチエノ[3,4−d]ピリミジン−7−イル)メチル)尿素
(実施例14)
化合物13:1−(3−クロロ−4−メチルフェニル)−3−((3−(2,6−ジオキソピペリジン−3−イル)−2−メチル−4−オキソ−3,4−ジヒドロチエノ[3,2−d]ピリミジン−6−イル)メチル)尿素
(実施例15)
化合物14:(S)−3−(5−メチル−7−オキソ−1−チア−4,6−ジアザ−6H−インデン−6−イル)−2,5−ピロリジンジオン
(実施例16)
化合物15:(S)−3−(5−メチル−7−オキソ−1−チア−4,6−ジアザ−6H−インデン−6−イル)−2,7−アゼパンジオン
(実施例17)
生物学的アッセイ
ウェスタンブロット解析
細胞に基づくアッセイ
Claims (63)
- 式(I):
Q1は、CR1または−S−であり、
Q2は、CR2または−S−であり、
Q3は、CR3または−S−であり、
Q1、Q2、およびQ3のうちの1つは、−S−であり、
各
R1、R2、およびR3はそれぞれ、独立に、水素、ジュウテリウム、ヒドロキシル、ハロゲン、シアノ、ニトロ、置換もしくは非置換アミノ、置換もしくは非置換C−アミド、置換もしくは非置換N−アミド、置換もしくは非置換エステル、置換もしくは非置換尿素、置換もしくは非置換C1〜C6アルコキシ、置換もしくは非置換C1〜C6アルキル、置換もしくは非置換C2〜C6アルケニル、置換もしくは非置換C2〜C6アルキニル、置換もしくは非置換C1〜C6ハロアルキル、置換もしくは非置換C3〜C8シクロアルキル、置換もしくは非置換C6〜C10アリール、置換もしくは非置換3〜10員ヘテロシクリル、または置換もしくは非置換5〜10員ヘテロアリールであり、
R4およびR5はそれぞれ、水素、ジュウテリウム、ハロゲン、および置換または非置換C1〜C6アルキルからなる群から独立に選択され、
R6は、水素、ジュウテリウム、ヒドロキシ、置換または非置換C1〜C6アルキル、および置換または非置換C1〜C6アルコキシからなる群から選択され、
Xは、O、NH、またはSであり、
nは、1、2、または3である]。 - nが2である、請求項1または2に記載の化合物。
- nが1である、請求項1または2に記載の化合物。
- nが3である、請求項1または2に記載の化合物。
- R4が、水素、ハロゲン、または非置換C1〜C6アルキルである、請求項1から5のいずれか一項に記載の化合物。
- R5が、水素、ハロゲン、または非置換C1〜C6アルキルである、請求項1から6のいずれか一項に記載の化合物。
- R5が非置換C1〜C6アルキルである、請求項7に記載の化合物。
- R6が、水素、または置換もしくは非置換C1〜C6アルキルである、請求項1から8のいずれか一項に記載の化合物。
- XがOである、請求項1から9のいずれか一項に記載の化合物。
- R1、R2、およびR3がそれぞれ、独立に、水素、ジュウテリウム、ヒドロキシル、ハロゲン、シアノ、ニトロ、置換もしくは非置換アミノ、置換もしくは非置換C−アミド、置換もしくは非置換N−アミド、置換もしくは非置換エステル、置換もしくは非置換尿素、置換もしくは非置換C1〜C6アルコキシ、置換もしくは非置換C1〜C6アルキル、置換もしくは非置換C1〜C6ハロアルキル、置換もしくは非置換C3〜C6シクロアルキル、置換もしくは非置換フェニル、置換もしくは非置換ナフチル、置換もしくは非置換4〜6員ヘテロシクリル、または置換もしくは非置換5もしくは6員ヘテロアリールである、請求項1から10のいずれか一項に記載の化合物。
- R1、R2、およびR3がそれぞれ、独立に、水素、ジュウテリウム、ヒドロキシル、ハロゲン、シアノ、非置換アミノ、非置換または置換C1〜C3アルコキシ、非置換または置換C1〜C6アルキル、置換または非置換C1〜C3ハロアルキル、非置換C3〜C6シクロアルキル、および非置換4〜6員ヘテロシクリルである、請求項11に記載の化合物。
- 前記式(I)の化合物が、式(Ia)によって表され、R1およびR2のうちの少なくとも一方またはそれぞれが水素である、請求項1から12のいずれか一項に記載の化合物。
- R1およびR2の一方が水素であり、R1およびR2の他方が、非置換C3〜C6シクロアルキル、非置換C1〜C3アルコキシ、非置換C1〜C3アルキル;C1〜C6アルコキシ、アミノ、−N(C1〜C3アルキル)2、または−NH(C1〜C3アルキル)で置換されているC1〜C6アルキル;非置換C1〜C2ハロアルキル、ハロゲン、および非置換アミノからなる群から選択される、請求項13に記載の化合物。
- 前記式(I)の化合物が、式(Ib)によって表され、R1およびR3のうちの少なくとも一方またはそれぞれが水素である、請求項1から12のいずれか一項に記載の化合物。
- R1およびR3の一方が水素であり、R1およびR3の他方が、非置換C3〜C6シクロアルキル、非置換C1〜C3アルコキシ、非置換C1〜C3アルキル;C1〜C6アルコキシ、アミノ、−N(C1〜C3アルキル)2、または−NH(C1〜C3アルキル)で置換されているC1〜C6アルキル;非置換C1〜C2ハロアルキル、ハロゲン、および非置換アミノからなる群から選択される、請求項15に記載の化合物。
- 前記式(I)の化合物が、式(Ic)によって表され、R2およびR3のうちの少なくとも一方またはそれぞれが水素である、請求項1から12のいずれか一項に記載の化合物。
- R2およびR3の一方が水素であり、R2およびR3の他方が、非置換C3〜C6シクロアルキル、非置換C1〜C3アルコキシ、非置換C1〜C3アルキル;C1〜C6アルコキシ、アミノ、−N(C1〜C3アルキル)2、または−NH(C1〜C3アルキル)で置換されているC1〜C6アルキル;非置換C1〜C2ハロアルキル、ハロゲン、および非置換アミノからなる群から選択される、請求項17に記載の化合物。
- 式(II):
Q1Aは、CR1Aまたは−S−であり、
Q2Aは、CR2Aまたは−S−であり、
Q3Aは、CR3Aまたは−S−であり、
各
Q1、Q2、およびQ3のうちの1つは、−S−であり、
R1A、R2A、およびR3Aはそれぞれ、独立に、水素、ジュウテリウム、ヒドロキシル、ハロゲン、シアノ、ニトロ、置換もしくは非置換アミノ、置換もしくは非置換C−アミド、置換もしくは非置換N−アミド、置換もしくは非置換エステル、置換もしくは非置換尿素、置換もしくは非置換C1〜C6アルコキシ、置換もしくは非置換C1〜C6アルキル、置換もしくは非置換C2〜C6アルケニル、置換もしくは非置換C2〜C6アルキニル、置換もしくは非置換C1〜C6ハロアルキル、置換もしくは非置換C3〜C8シクロアルキル、置換もしくは非置換C6〜C10アリール、置換もしくは非置換3〜10員ヘテロシクリル、置換もしくは非置換5〜10員ヘテロアリール、
R1A、R2A、およびR3Aのうちの1つは、
R4AおよびR5Aはそれぞれ、水素、ジュウテリウム、ハロゲン、および置換または非置換C1〜C6アルキルからなる群から独立に選択され、
R6Aは、水素、ジュウテリウム、ヒドロキシ、置換または非置換C1〜C6アルキル、および置換または非置換C1〜C6アルコキシからなる群から選択され、
XAは、O、NH、またはSであり、
sは、1、2、または3であり、
各X1Aは、独立に、O、NH、またはSであり、
各X2Aは、−NR9A−、−(CH2)h−(NR9A)−(CH2)i−、−(CH2)h−(NR9A)−(CH2)i−(NR9A)−、−(CH2)1〜5−、−(CF2)1〜5−、−(CD2)1〜5−、−O−、−C(=O)−、および−S−からなる群から独立に選択され、
各X3Aは、−(CH2)t−(NR9A)−(CH2)j−、−(CH2)t−(NR9A)−(CH2)j−(NR9A)−、−(CH2)1〜5−、−(CF2)1〜5−、および−(CD2)1〜5−からなる群から独立に選択され、
各mは、独立に、0、1、2、3、4、または5であり、
各h、i、およびjは、独立に、0、1、2、3、4、または5であり、
各tは、独立に、1、2、3、4、または5であり、
各R7AおよびR8Aは、置換または非置換C3〜C10シクロアルキル、置換または非置換C6〜C10アリール、置換または非置換5〜10員ヘテロアリール、置換または非置換3〜10員ヘテロシクリル、および置換または非置換C1〜C10アルキルからなる群から独立に選択され、
R9Aは、水素、または置換もしくは非置換C1〜C6アルキルである]。 - 各X2Aが、−NR9A−、−(CH2)h−(NR9A)−(CH2)i−、−(CH2)h−(NR9A)−(CH2)i−(NR9A)−、−(CH2)1〜5−、−(CF2)1〜5−、−(CD2)1〜5−、−O−、および−S−からなる群から独立に選択される、請求項20に記載の化合物。
- sが2である、請求項20から22のいずれか一項に記載の化合物。
- sが1である、請求項20から22のいずれか一項に記載の化合物。
- sが3である、請求項20から22のいずれか一項に記載の化合物。
- R4Aが、水素、ハロゲン、または非置換C1〜C6アルキルである、請求項20から25のいずれか一項に記載の化合物。
- R5Aが、水素、ハロゲン、または非置換C1〜C6アルキルである、請求項20から26のいずれか一項に記載の化合物。
- R5Aが非置換C1〜C6アルキルである、請求項27に記載の化合物。
- R6Aが、水素、または置換もしくは非置換C1〜C6アルキルである、請求項20から28のいずれか一項に記載の化合物。
- XAがOである、請求項20から29のいずれか一項に記載の化合物。
- mが1または2である、請求項20から39のいずれか一項に記載の化合物。
- X1AがOである、請求項20から40のいずれか一項に記載の化合物。
- X2Aが−NR9A−である、請求項20から41のいずれか一項に記載の化合物。
- X2Aが、−(CH2)h−(NR9A)−(CH2)i−または−(CH2)h−(NR9A)−(CH2)i−(NR9A)−である、請求項20から41のいずれか一項に記載の化合物。
- hおよびiがそれぞれ、独立に、0または1である、請求項43に記載の化合物。
- R9Aが、水素または非置換C1〜C6アルキルである、請求項43または44のいずれか一項に記載の化合物。
- X2Aが−C(=O)−または−(CH2)1〜5−である、請求項20から41のいずれか一項に記載の化合物。
- X3Aが、−(CH2)t−(NR9A)−(CH2)j−または−(CH2)t−(NR9A)−(CH2)j−(NR9A)−である、請求項20から41のいずれか一項に記載の化合物。
- R9Aが水素である、請求項47に記載の化合物。
- tが、独立に、1または2であり、jが、独立に、0、1、または2である、請求項47または48に記載の化合物。
- R7AおよびR8Aがそれぞれ、置換または非置換C3〜C6シクロアルキル、置換または非置換フェニル、置換または非置換ナフチル、置換または非置換5または6員ヘテロアリール、置換または非置換3〜7員ヘテロシクリル、および置換または非置換C1〜C6アルキルからなる群から独立に選択される、請求項20から49のいずれか一項に記載の化合物。
- R7AおよびR8Aがそれぞれ、独立に、置換もしくは非置換フェニル、置換もしくは非置換チエニル、置換もしくは非置換ピリジニル、置換もしくは非置換ピリミジニル、置換もしくは非置換ピラジニル、置換もしくは非置換ピリダジニル、置換もしくは非置換ピロリジニル、置換もしくは非置換モルホリノ、置換もしくは非置換ピペリジニル、置換もしくは非置換ピペラジニル、または置換もしくは非置換アゼパニルである、請求項50に記載の化合物。
- R7AおよびR8Aがそれぞれ、独立に、ハロゲン、非置換C1〜C6アルキル、置換または非置換C3〜C6シクロアルキル、置換または非置換ヘテロシクリル、(非置換C1〜C6アルキル)アミン、−N(C1〜C3アルキル)2、−NH(C1〜C3アルキル)、置換または非置換C3〜C7シクロアルキル(非置換C1〜C6アルキル)、および置換または非置換ヘテロシクリル(非置換C1〜C6アルキル)からなる群から選択される1つ、2つ、または3つの置換基で置換されているフェニルである、請求項51に記載の化合物。
- R7AおよびR8Aがそれぞれ、独立に、ハロゲン、−N(C1〜C3アルキル)2、−NH(C1〜C3アルキル)、および非置換C1〜C6アルキルからなる群から選択される1つまたは2つの置換基で置換されているフェニルである、請求項20から52のいずれか一項に記載の化合物。
- 請求項1から54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される塩と、薬学的に許容される1種または複数種の賦形剤とを含む医薬組成物。
- GSPT1と関連する疾患、障害、または状態を処置、改善、または予防する方法であって、治療有効量の請求項1から54のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または請求項55に記載の医薬組成物を投与することを含む方法。
- サイトカイン、アイオロス、PDE6、イカロス、ヘリオス、およびCK1αからなる群から選択される1種または複数種のタンパク質と関連する疾患、障害、または状態を処置、改善、または予防する方法であって、治療有効量の請求項1から54のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または請求項55に記載の医薬組成物を投与することを含む方法。
- 前記サイトカインが、IL−1β、IL−6、TNFα、およびIL−2、ならびにこれらの組合せからなる群から選択される、請求項57に記載の方法。
- 前記疾患、障害、または状態が、炎症、線維筋痛症、関節リウマチ、骨関節炎、強直性脊椎炎、乾癬、乾癬性関節炎、炎症性腸疾患、クローン病、潰瘍性大腸炎、ブドウ膜炎、炎症性肺疾患、慢性閉塞性肺疾患、アルツハイマー病、およびがんからなる群から選択される、請求項56または57に記載の方法。
- 前記疾患、障害、または状態が、乳がん、肺がん、白血病、リンパ腫、肝細胞癌、胃がん、前立腺がん、およびアストログリオーシス、ならびにこれらの組合せからなる群から選択されるがんである、請求項59に記載の方法。
- 前記疾患、障害、または状態が、白血病、リンパ腫、および肝細胞癌からなる群から選択されるがんである、請求項59に記載の方法。
- 皮膚がんのリスクを低減することを必要とする対象において皮膚がんのリスクを低減する方法であって、治療有効量の請求項1から54のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または請求項55のいずれか一項に記載の医薬組成物を投与することを含む方法。
- 対象において皮膚の障害、疾患、または状態を処置、改善、または予防する方法であって、治療有効量の請求項1から54のいずれか一項に記載の化合物もしくはその薬学的に許容される塩、または請求項55に記載の組成物を前記対象に投与することを含む方法。
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EP3774815A1 (en) | 2021-02-17 |
WO2019191451A1 (en) | 2019-10-03 |
CA3094988A1 (en) | 2019-10-03 |
CN112313236A (zh) | 2021-02-02 |
TW202003524A (zh) | 2020-01-16 |
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