JP7471297B2 - Trex1のモジュレータ - Google Patents
Trex1のモジュレータ Download PDFInfo
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- JP7471297B2 JP7471297B2 JP2021531909A JP2021531909A JP7471297B2 JP 7471297 B2 JP7471297 B2 JP 7471297B2 JP 2021531909 A JP2021531909 A JP 2021531909A JP 2021531909 A JP2021531909 A JP 2021531909A JP 7471297 B2 JP7471297 B2 JP 7471297B2
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- alkyl
- phenyl
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- 125000004852 dihydrofuranyl group Chemical group O1C(CC=C1)* 0.000 description 1
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000002540 macrophage Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
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- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- CRGZYKWWYNQGEC-UHFFFAOYSA-N magnesium;methanolate Chemical compound [Mg+2].[O-]C.[O-]C CRGZYKWWYNQGEC-UHFFFAOYSA-N 0.000 description 1
- IUYHWZFSGMZEOG-UHFFFAOYSA-M magnesium;propane;chloride Chemical compound [Mg+2].[Cl-].C[CH-]C IUYHWZFSGMZEOG-UHFFFAOYSA-M 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
- 238000005259 measurement Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- XGEGHDBEHXKFPX-NJFSPNSNSA-N methylurea Chemical compound [14CH3]NC(N)=O XGEGHDBEHXKFPX-NJFSPNSNSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
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- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
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- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000003566 oxetanyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
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- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
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- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
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- 239000002244 precipitate Substances 0.000 description 1
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- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
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- 125000003373 pyrazinyl group Chemical group 0.000 description 1
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- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000003007 single stranded DNA break Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 108010068698 spleen exonuclease Proteins 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- NPPZBNVNHLFCKW-UHFFFAOYSA-N tert-butyl 3-cyano-3-methylpiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(C)(C1)C#N NPPZBNVNHLFCKW-UHFFFAOYSA-N 0.000 description 1
- UEFZTXGFHKPSFS-UHFFFAOYSA-N tert-butyl 3-cyanopiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC(C#N)C1 UEFZTXGFHKPSFS-UHFFFAOYSA-N 0.000 description 1
- KEEIJBAOTMNSEN-UHFFFAOYSA-N tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCC=C1B1OC(C)(C)C(C)(C)O1 KEEIJBAOTMNSEN-UHFFFAOYSA-N 0.000 description 1
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 125000001113 thiadiazolyl 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
- 108010036169 three prime repair exonuclease 1 Proteins 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
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- 230000009385 viral infection Effects 0.000 description 1
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- 239000000080 wetting agent Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- 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
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Amplifiers (AREA)
- Plural Heterocyclic Compounds (AREA)
- Apparatus For Radiation Diagnosis (AREA)
- Magnetic Resonance Imaging Apparatus (AREA)
- Burglar Alarm Systems (AREA)
Description
本願は、2018年12月6日に出願された米国特許仮出願第62/776,301号の優先権を主張し、その全内容は参照により本明細書中に組み込まれる。
第一の実施形態において、式I:
R1は、水素、(C1-C4)アルキル、ハロ(C1-C4)アルキル、3~4員シクロアルキル、-ORf、-SRf、又は-NReRfである;
R2は、水素、(C1-C4)アルキル、ハロ(C1-C4)アルキル、又は3~4員シクロアルキルである;
Xは、結合、NR3、O、S、又は(C1-C4)アルキレンであり、前述の(C1-C4)アルキレンは、任意選択的に、R4から選択される1又は2個の基で置換されていてもよい;
R3は、水素、(C1-C4)アルキル、-C(O)Rd、又は-C(S)Rdである;
R4は、ハロ、(C1-C4)アルキル、フェニル、-NHC(O)ORa、-NHC(S)ORa、-C(O)Rb,-NHC(O)NHRg、-NHC(S)NHRg、-NHS(O)2NHRg、-C(S)Rb、S(O)2Rc、S(O)Rc、-C(O)ORd、-C(S)ORd、-C(O)NHRe、-C(S)NHRe、-NHC(O)Rd、-NHC(S)Rd、-ORe、-SRe、-O(C1-C4)アルキルORe、又は-NReRfであり、R4の前述のフェニルは、任意選択的に、ハロ、(C1-C4)アルキル、ハロ(C1-C4)アルキル、(C1-C4)アルコキシ、及びハロ(C1-C4)アルコキシから選択される1又は2個の基で置換されていてもよい;
環Aは、フェニル、5~6員ヘテロアリール、4~7員ヘテロシクリル、又は3~7員シクロアルキルであり、その各々は任意選択的かつ独立して、R5から選択される1又は2個の基で置換されていてもよい;
R5は、(C1-C4)アルキル、ハロ(C1-C4)アルキル、ハロ(C1-C4)アルコキシ、ハロ、フェニル、-NHC(O)ORa、-NHC(S)ORa、-C(O)Rb、-NHC(O)NHRg、-NHC(S)NHRg、-NHS(O)2NHRg、-C(S)Rb、S(O)2Rc、S(O)Rc、-C(O)ORd、-C(S)ORd、-C(O)NReRf、-C(S)NHRe、-NHC(O)Rd、-NHC(S)Rd、-ORe、-SRe、-O(C1-C4)アルキルORe、-NReRf、4~6員ヘテロアリール、又は4~7員ヘテロシクリルであり、R5の前述のフェニルは、任意選択的に、Rgから選択される1又は2個の基で置換されていてもよく、R5の前述の(C1-C4)アルキルは、任意選択的に、ORh、-NRjRk、フェニル、及び5~6員ヘテロアリールから選択される1又は2個の基で置換されていてもよく、前述の4~7員ヘテロシクリル及び4~6員ヘテロアリールは、各々任意選択的かつ独立して、Rmから選択される1又は2個の基で置換されていてもよく、そしてR5中の(C1-C4)アルキルについて列挙した任意の置換基の前述のフェニル及び5~6員ヘテロアリールは、各々、任意選択的かつ独立して、Rgから選択される1又は2個の基で置換されていてもよい;
Rg、Rh、Rj、Rk、及びRmは、各々独立して、水素、ハロ、(C1-C4)アルキル、ハロ(C1-C4)アルキル、(C1-C4)アルコキシ、ハロ(C1-C4)アルコキシ、フェニル、-(C1-C4)アルキルフェニル、3~4員シクロアルキル、4~6員ヘテロアリール、又は4~7員ヘテロシクリルであり、そしてRg、Rh、Rj及びRkの前述の4~7員ヘテロシクリルは、さらに任意選択的に、=Oで置換されていてもよい。
Ra、Rb、Rc、Rd、Re及びRfは、各々独立して、水素、ハロ、(C1-C4)アルキル、ハロ(C1-C4)アルキル、(C1-C4)アルコキシ、ハロ(C1-C4)アルコキシ、フェニル、3~4員シクロアルキル、4~6員ヘテロアリール、又は4~7員ヘテロシクリルであり、i)Ra、Rb、Rc、Rd、Re及びRfの前述の(C1-C4)アルキルは、任意選択的に、フェニル、-ORh、-NRjRkから選択される1又は2個の基で置換されていてもよく;ii)Ra、Rb、Rc、Rd、Re、及びRfの前述のフェニル、4~6員ヘテロアリール、及び4~7員ヘテロシクリルは、各々、任意選択的かつ独立して、Rgから選択される1又は2個の基で置換されていてもよく、そしてiii)Ra、Rb、Rc、Rd、Re、及びRfの前述の4~7員ヘテロシクリルは、さらに任意選択的に、=Oで置換されていてもよい。
複数の結合点を有し得る化学基を記載するために組み合わせて使用する場合、ハイフン(-)は、それが規定される変数の基の結合点を示す。例えば、-NHC(O)ORa及び-NHC(S)ORaは、この基の結合点が窒素原子上に存在することを意味する。
4.使用、処方及び投与
1H NMR(400MHz,DMSO-d6):δ 1.60-1.80(m,4H),1.85-1.95(m,1H),2.66-2.70(m,2H),2.70-3.02(m,6H),3.48(s,3H),7.18-7.28(m,5H),8.77(s,1H,),9.13(s,1H),10.25(bs,1H),11.50(bs,1H).
C6(200mg、0.769ミリモル)、ピペリジン(0.76mL、7.69ミリモル)及びDMSOの混合物を110℃で1時間加熱した。反応の進行をTLCによってモニタリングし、C6が消費されたら室温に冷却した。反応混合物を氷水の混合物(25mL)中に注ぎ、15分間よく撹拌した。固体物質をろ過で除去し、水で洗浄し(3×10mL)、真空下でよく乾燥させて、純粋な生成物を固体(172mg、72%)として得た。ESI-MS m/z=310.38[M+H]+ MW計算値:309.371H NMR(400MHz,DMSO-d6):δ 4.00(q,2H),4.26(q,2H),3.38(s,3H),3.04-3.06(m,4H),1.57-1.62(m,6H),1.20-1.30(m,6H).
1.腫瘍細胞におけるTREX1のサイレンシング
サイトゾルDNAのセンシングに際してのcGAS/STING経路の活性化と、それに続くI型IFN産生は、腫瘍細胞及び自然免疫細胞の両方、特に樹状細胞で起こり得る。STINGアゴニストによるI型IFNの活性化に際して免疫介在性拒絶反応を受ける、充分に説明された低温同系腫瘍モデルによって、TREX1がI型IFNの産生を抑制するか否かを評価するために、CRISPRを使用してB16F10腫瘍細胞においてTREX1をノックダウンした(図1A)。腫瘍細胞のDNAトランスフェクションを介したサイトゾルDNAの蓄積は、親腫瘍細胞と比較してTREX1ノックアウトB16F10細胞によるIFNβ産生の約5倍増加をもたらし、TREX1がB16F10腫瘍細胞におけるcGAS/STING経路の活性化を減弱したことを示す(図1B)。
2.インビボでのTREX1コンピテント及びTREX1欠損B16F10腫瘍細胞の成長
化合物の効力は、反対方向の鎖上にフルオロフォア-クエンチャ―対を有するカスタムdsDNA基質の分解を測定する蛍光アッセイによって評価した。dsDNAの分解により、遊離フルオロフォアが放出され、蛍光シグナルが生じる。具体的には、反応緩衝液(50mM Tris(pH7.4)、150mM NaCl、2mM DTT、0.1mg/mL BSA、0.01%(v/v)Tween-20及び100mM MgCl2)中7.5μLのN末端His-Tevタグ付完全長ヒトTREX1(E.coliで発現され、社内で精製されたもの)を、DMSO中10点用量-応答として様々な濃度の化合物(150nL)をすでに含んでいる384ウェルBlack ProxiPlate Plus(Perkin Elmer)に添加した。これに、反応緩衝液中7.5μLのdsDNA基質(鎖A:5’TEX615/GCT AGG CAG 3’;鎖B:5’CTG CCT AGC/IAbRQSp(Integrated DNA Technologies))を添加した。最終濃度は、1.0%DMSO(v/v)を含む反応緩衝液中、150pM TREX1、60nM dsDNA基質であった。室温で25分後、5μLの停止緩衝液(反応緩衝液+200mM EDTAと同じ)の添加により反応をクエンチした。クエンチされた反応物における最終濃度は、20μLの体積で、112.5pM TREX1、45nM DNA及び50mM EDTAであった。室温で5分のインキュベーション後、レーザー光源のEnvision(Perkin-Elmer)でプレートを読み取り、570nm光で励起した後、615nmの蛍光を測定した。IC50値は、非線形最小二乗4パラメータフィット及びGenedata又はGraphPad Prismのいずれか(GraphPad Software,Inc.)を使用して、停止緩衝液(100%阻害)及び阻害剤なし(0%阻害)対照であらかじめクエンチした対照ウェルと比べて、615nm比で測定された蛍光を比較することによって算出した。
化合物の効力は、反対方向の鎖上にフルオロフォア-クエンチャ―対を有するカスタムdsDNA基質の分解を測定する蛍光アッセイによって評価した。dsDNAの分解により、遊離フルオロフォアが放出され、蛍光シグナルが生じる。具体的には、反応緩衝液(50mM Tris(pH7.4)、150mM NaCl、2mM DTT、0.1mg/mL BSA、0.01%(v/v)Tween-20及び100mM MgCl2中7.5μLのN末端His-Tevタグ付ヒトTREX2(E.coliで発現され、社内で精製された残留M44-A279)を、DMSO中10点用量応答として様々な濃度の化合物(150nL)をすでに含んでいる384ウェルBlack ProxiPlate Plus(Perkin Elmer)に添加した。これに、反応緩衝液中7.5μLのdsDNA基質(鎖A:5’TEX615/GCT AGG CAG 3’;鎖B:5’CTG CCT AGC/IAbRQSp(IDT))を添加した。最終濃度は、1.0%DMSO(v/v)を含む反応緩衝液中、2.5nM TREX2、60nM dsDNA基質であった。室温で25分後、5μLの停止緩衝液(反応緩衝液+200mM EDTAと同じ)の添加により反応をクエンチした。クエンチされた反応混合物における最終濃度は、20μLの体積で、1.875pM TREX2、45nM DNA及び50mM EDTAであった。室温で5分のインキュベーション後、レーザー光源のEnvision(Perkin-Elmer)でプレートを読み取り、570nm光で励起した後、615nmの蛍光を測定した。IC50値は、非線形最小二乗4パラメータフィット及びGenedata又はGraphPad Prismのいずれか(GraphPad Software,Inc.)を使用して、停止緩衝液(100%阻害)及び阻害剤なし(0%阻害)対照であらかじめクエンチした対照ウェルと比べて、615nm比で測定された蛍光を比較することによって算出した。
HCT116二重細胞(dual cell)(Invivogen,San Diego,CA,USA)はヒトHCT116大腸がん細胞株由来である。細胞は、SEAP及びルシフェラーゼレポーター遺伝子の安定な組込みについて選択され、この発現は、それぞれ、NF-KB/AP1及びSTAT1/STAT2の5つのタンデム応答エレメントの制御下にある。細胞株を使用して、培地中に分泌されたLuciaルシフェラーゼの活性を測定することにより、I型インターフェロン誘導と、その後のシグナリングをモニタリングした。
Claims (21)
- 式I:
(式中:
R1は、水素、(C1-C4)アルキル、ハロ(C1-C4)アルキル、3~4員シクロアルキル、-ORf、-SRf、又は-NReRfである;
R2は、水素、(C1-C4)アルキル、ハロ(C1-C4)アルキル、又は3~4員シクロアルキルである;
Xは、結合、NR3、O、S、又は(C1-C4)アルキレンであり、前記(C1-C4)アルキレンは、任意選択的に、R4から選択される1又は2個の基で置換されていてもよい;
R3は、水素、(C1-C4)アルキル、-C(O)Rd、又は-C(S)Rdである;
R4は、ハロ、(C1-C4)アルキル、フェニル、-NHC(O)ORa、-NHC(S)ORa、-C(O)Rb,-NHC(O)NHRg、-NHC(S)NHRg、-NHS(O)2NHRg、-C(S)Rb、S(O)2Rc、S(O)Rc、-C(O)ORd、-C(S)ORd、-C(O)NHRe、-C(S)NHRe、-NHC(O)Rd、-NHC(S)Rd、-ORe、-SRe、-O(C1-C4)アルキルORe、又は-NReRfであり、R4の前記フェニルは、任意選択的に、ハロ、(C1-C4)アルキル、ハロ(C1-C4)アルキル、(C1-C4)アルコキシ、及びハロ(C1-C4)アルコキシから選択される1又は2個の基で置換されていてもよい;
環Aは、フェニル、5~6員ヘテロアリール、4~7員ヘテロシクリル、又は3~7員シクロアルキルであり、その各々は任意選択的かつ独立して、R5から選択される1又は2個の基で置換されていてもよい;
R5は、(C1-C4)アルキル、ハロ(C1-C4)アルキル、ハロ(C1-C4)アルコキシ、ハロ、フェニル、-NHC(O)ORa、-NHC(S)ORa、-C(O)Rb,-NHC(O)NHRg、-NHC(S)NHRg、-NHS(O)2NHRg、-C(S)Rb、S(O)2Rc、S(O)Rc、-C(O)ORd、-C(S)ORd、-C(O)NReRf、-C(S)NHRe、-NHC(O)Rd、-NHC(S)Rd、-ORe、-SRe、-O(C1-C4)アルキルORe、-NReRf、4~6員ヘテロアリール、又は4~7員ヘテロシクリルであり、R5の前記フェニルは、任意選択的に、Rgから選択される1又は2個の基で置換されていてもよく、R5の前記(C1-C4)アルキルは、任意選択的に、ORh、-NRjRk、フェニル、及び5~6員ヘテロアリールから選択される1又は2個の基で置換されていてもよく、前記4~7員ヘテロシクリル及び4~6員ヘテロアリールは、各々任意選択的かつ独立して、Rmから選択される1又は2個の基で置換されていてもよく、そしてR5中の(C1-C4)アルキルについて列挙した任意の置換基の前記フェニル及び5~6員ヘテロアリールは、各々、任意選択的かつ独立して、Rgから選択される1又は2個の基で置換されていてもよい;
Rg、Rh、Rj、Rk、及びRmは、各々独立して、水素、ハロ、(C1-C4)アルキル、ハロ(C1-C4)アルキル、(C1-C4)アルコキシ、ハロ(C1-C4)アルコキシ、フェニル、-(C1-C4)アルキルフェニル、3~4員シクロアルキル、4~6員ヘテロアリール、又は4~7員ヘテロシクリルであり、そしてRg、Rh、Rj及びRkの前記4~7員ヘテロシクリルは、さらに任意選択的に、=Oで置換されていてもよい;
Ra、Rb、Rc、Rd、Re及びRfは、各々独立して、水素、ハロ、(C1-C4)アルキル、ハロ(C1-C4)アルキル、(C1-C4)アルコキシ、ハロ(C1-C4)アルコキシ、フェニル、3~4員シクロアルキル、4~6員ヘテロアリール、又は4~7員ヘテロシクリルであり、i)Ra、Rb、Rc、Rd、Re及びRfの前記(C1-C4)アルキルは、任意選択的に、フェニル、-ORh、-NRjRkから選択される1又は2個の基で置換されていてもよく、ii)Ra、Rb、Rc、Rd、Re、及びRfの前記フェニル、4~6員ヘテロアリール、及び4~7員ヘテロシクリルは、各々、任意選択的かつ独立して、Rgから選択される1又は2個の基で置換されていてもよく、そしてiii)Ra、Rb、Rc、Rd、Re、及びRfの前記4~7員ヘテロシクリルは、さらに任意選択的に、=Oで置換されていてもよい)。 - 前記化合物が、式II:
- R2が(C1-C4)アルキルである、請求項1又は2に記載の化合物。
- 前記化合物が、式III:
- 環Aがフェニル、ピリジル、ピラゾリル、シクロプロピル、シクロブチル、アゼチジニル、又はピペリジニルであり、その各々は、任意選択的かつ独立して、1又は2個のR5で置換されていてもよい、請求項1~4のいずれか一項に記載の化合物。
- 環Aがトリアゾリル、ピロリジニル、ジアゼパニル、又はピペラジニルであり、その各々は、任意選択的かつ独立して、1又は2個のR5で置換されていてもよい、請求項1~4のいずれか一項に記載の化合物。
- R5が、(C1-C4)アルキル、ハロ(C1-C4)アルキル、ハロ(C1-C4)アルコキシ、ハロ、フェニル、-NHC(O)ORa、-C(O)Rb、S(O)2Rc、S(O)Rc、-C(O)ORd、-C(O)NReRf、-NHC(O)Rd、-ORe、-O(C1-C4)アルキルORe、-NReRf、4~6員ヘテロアリール、又は4~7員ヘテロシクリルであり、R5の前記フェニルが、任意選択的に、Rgから選択される1又は2個の基で置換されていてもよく、R5の前記(C1-C4)アルキルが、任意選択的に、-ORh、-NRjRk、フェニル、及び5~6員ヘテロアリールから選択される1又は2個の基で置換されていてもよく、前記4~6員ヘテロアリール及び4~7員ヘテロシクリルが、各々、任意選択的かつ独立して、Rmから選択される1又は2個の基で置換されていてもよく、そしてR5中の(C1-C4)アルキルについて列挙した任意の置換基の前記フェニル及び5~6員ヘテロアリールが、各々、任意選択的かつ独立して、Rgから選択される1又は2個の基で置換されていてもよい;
Raが、任意選択的にフェニルで置換されていてもよい(C1-C4)アルキルである;
Rbが、(C1-C4)アルキル、フェニル、5~6員ヘテロアリール又は4~7員ヘテロシクリルであり、前記(C1-C4)アルキルが、任意選択的に、フェニル、-ORh、及び-NRjRkから選択される1又は2個の基で置換されていてもよく、前記フェニル、5~6員ヘテロアリール、及び4~7員ヘテロシクリルが、各々、任意選択的かつ独立して、Rgから選択される1又は2個の基で置換されていてもよく、前記4~7員ヘテロシクリルがさらに、任意選択的に=Oで置換されていてもよい;
各Rcが、独立して、フェニル又は(C1-C4)アルキルである;
各Rdが、水素又は(C1-C4)アルキルである;
各Reが、独立して、水素、又は任意選択的にORhで置換されていてもよい(C1-C4)アルキルである;
各Rfが、独立して、水素、(C1-C4)アルキル、フェニル3~4員シクロアルキル、4~6員ヘテロアリール、又は5~6員ヘテロシクリルであり、前記フェニル、3~4員シクロアルキル、4~6員ヘテロアリール、及び5~6員ヘテロシクリルは、各々、任意選択的かつ独立して、Rgで置換されていてもよい;
各Rgは、独立して、(C1-C4)アルキル、ハロ(C1-C4)アルキル、(C1-C4)アルコキシ、ハロ(C1-C4)アルコキシ、又はハロである;
各Rhは、水素、(C1-C4)アルキル、又は-(C1-C4)アルキルフェニルである;
各Rjが、独立して、水素又は(C1-C4)アルキルである;
各Rkは、独立して、水素、(C1-C4)アルキル、又は3~4員シクロアルキルである;そして
各Rmが、(C1-C4)アルキルである、
請求項1~6のいずれか一項に記載の化合物。 - R5が、(C1-C4)アルキル、ハロ(C1-C4)アルキル、ハロ、フェニル、-NHC(O)ORa、-C(O)Rb、S(O)2Rc、-C(O)ORd、-C(O)NReRf、-NHC(O)Rd、-O(C1-C4)アルキルORe、-NReRf、4~6員ヘテロアリール、又は5~6員ヘテロシクリルであり、R5の前記(C1-C4)アルキルが、任意選択的に、-ORh、フェニル、又は5~6員ヘテロアリールで置換されていてもよく、前記4~6員ヘテロアリール及び5~6員ヘテロシクリルが、各々、任意選択的かつ独立して、Rmから選択される1又は2個の基で置換されていてもよく、R5中の(C1-C4)アルキルについて列挙した任意の置換基の前記フェニル及び5~6員ヘテロアリールが、各々、任意選択的かつ独立して、Rgから選択される1又は2個の基で置換されていてもよい、請求項1~7のいずれか一項に記載の化合物。
- R5が、(C1-C4)アルキル、ハロ(C1-C4)アルキル、ハロ、フェニル、-NHC(O)ORa、-C(O)Rb、S(O)2Rc、-C(O)ORd、-C(O)NReRf、-NHC(O)Rd、又は-O(C1-C4)アルキルORe、-NReRf、モルホリニル、ピペラジニル、又はピラゾリルであり、前記モルホリニル、ピペラジニル、及びピラゾリルは、各々任意選択的に、Rmから選択される1又は2個の基で置換されていてもよく、R5の前記(C1-C4)アルキルが、任意選択的に、-ORh、フェニル、ピラゾリル、ピリミジニル、又はピリジニルで置換されていてもよく、R5中の(C1-C4)アルキルについて列挙した任意の置換基の前記フェニル、ピラゾリル、ピリミジニル、及びピリジニルが、各々、任意選択的かつ独立して、Rgから選択される1又は2個の基で置換されていてもよい、請求項1~8のいずれか一項に記載の化合物。
- 各Rfが、独立して、水素、(C1-C4)アルキル、フェニルピラゾリル、ピリジニル、テトラヒドロピラニル、ピペリジニルであり、前記フェニルピラゾリル、ピリジニル、テトラヒドロピラニル、及びピペリジニルが、各々、任意選択的かつ独立して、(C1-C4)アルキルで置換されていてもよい、請求項1~9のいずれか一項に記載の化合物。
- 各Rgが、独立して、(C1-C4)アルキル、(C1-C4)アルコキシ、又はハロである、請求項1~10のいずれか一項に記載の化合物。
- Rbが、(C1-C4)アルキル、フェニル、5~6員ヘテロアリール又は4~7員ヘテロシクリルであり、Rbの前記フェニル及び5~6員ヘテロアリールが、各々、任意選択的かつ独立して、ハロ及び(C1-C4)アルコキシから選択される1又は2個の基で置換されていてもよく、Rbの前記4~7員ヘテロシクリルが、任意選択的に、=Oで置換されていてもよく、Rbの前記(C1-C4)アルキルが、任意選択的に、フェニル、-ORh、及び-NRjRkから選択される1又は2個の基で置換されていてもよい、請求項1~11のいずれか一項に記載の化合物。
- 各Rkが、独立して、水素又は(C1-C4)アルキルである、請求項1~12のいずれか一項に記載の化合物。
- Rbが(C1-C4)アルキル、フェニル、ピリジニル、ピラゾリル、ピリミジニル、又はピペリジニルであり、Rbの前記フェニル、ピリジニル、ピラゾリル、及びピリミジニルが、各々、任意選択的かつ独立して、ハロ及び(C1-C4)アルコキシから選択される1又は2個の基で置換されていてもよく、Rbの前記(C1-C4)アルキルが、任意選択的に、フェニル、OH、及びNMe2から選択される1又は2個の基で置換されていてもよく、Rbの前記ピペリジニルが、任意選択的に、=Oで置換されていてもよい、請求項1~13のいずれか一項に記載の化合物。
- R3が水素である、請求項1~14のいずれか一項に記載の化合物。
- Xが非置換(C1-C4)アルキレンである、請求項1~15のいずれか一項に記載の化合物。
- R4が、フェニル又は-NHC(O)ORaである、請求項1~16のいずれか一項に記載の化合物。
- Xが結合又はCH2である、請求項1~15のいずれか一項に記載の化合物。
- 請求項1~18のいずれか一項に記載の化合物、又はその薬剤的に許容される塩と、薬剤的に許容される担体とを含む、医薬組成物。
- 対象におけるTREX1の阻害に応答する疾患を治療する方法に用いるための、請求項1~18のいずれか一項に記載の化合物、若しくはその薬剤的に許容される塩、又は請求項19に記載の医薬組成物を含有する医薬組成物であって、前記方法は、前記対象に対して、請求項1~18のいずれか一項に記載の化合物、若しくはその薬剤的に許容される塩、又は請求項19に記載の医薬組成物の治療上有効な量を投与することを含む、医薬組成物。
- 前記疾患ががんである、請求項20に記載の医薬組成物。
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