JP2017531686A - Ripk2阻害剤およびそれを用いた癌の治療方法 - Google Patents
Ripk2阻害剤およびそれを用いた癌の治療方法 Download PDFInfo
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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- 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
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Abstract
Description
本出願は、2014年10月27日出願の米国仮出願第62/068,985号の利益を主張するものである。上記出願の全教示は、参照により本明細書に組み込まれる。
Cyは、シクロ脂肪族、ヘテロシクリル、アリール、またはヘテロアリールであり;
Yは、存在しないか、−CRbRb−、−O−、−NRb−、−S(O)n−であり;
R1は、シクロ脂肪族、ヘテロシクリル、アリール、またはヘテロアリールであり、その各々は、必要に応じて、個々にRaによって表される1〜3個の基で置換されており;
R3は、H、必要に応じて、−F、−Cl、−Br、−I、−CN、−NO2、−ORb、−C1−C4アルキル、−(C1−C3)アルキレン−ORb、−(C1−C3)アルキレン−NRbRb、−C1−C4ハロアルキル、−C1−C4ハロアルコキシ、(C3−C8)シクロアルキル、−NRbRb、−C(=O)NRbRb、−NRb(C=O)NRbRb、−S(O)nNRbRb、C(=O)ORb、−OC(=O)ORb、−S(O)nRb、−NRbS(O)nRb、−C(=S)ORb、−O(C=S)Rb、−NRbC(=O)Rb、−C(=S)NRbRb、−NRbC(=S)Rb、−NRb(C=O)ORb、−O(C=O)NRbRb、−NRb(C=S)ORb、−O(C=S)NRbRb、−NR(C=S)NRbRb、−C(=S)Rbまたは−C(=O)Rbから選択される1〜3個の基で置換されたヘテロシクリルまたはヘテロアリールであり;
各R4は、独立して、−F、−Cl、−Br、I、−CN、−NRbRb、−ORb、−C1−C4アルキル、−(C1−C3)アルキレン−ORb、−(C1−C3)アルキレン−NRbRb、−C1−C4ハロアルキル、または−C1−C4ハロアルコキシから選択され;
各Raは、独立して、−F、−Cl、−Br、I、−CN、ORb、−C1−C4アルキル、(C2−C6)アルケニル、(C2−C6)アルキニル、−C1−C4ハロアルキル、−C1−C4ハロアルコキシ、−(C1−C3)アルキレン−ORb、または−(C1−C3)アルキレン−NRbRbから選択され;
各Rbは、独立して、−Hまたは−C1−C4アルキルであり;
xは、0、1、2、3、または4であり;
各mは、独立して、0、1、2、または3であり;ならびに
各nは、独立して、0、1、または2である)
によって表される化合物またはその薬学的に許容される塩に関する。
実施例A:合成
一般的方法
市販の出発物質、試薬、および溶媒を受け取ったままで使用した。一般的に、無水反応は、窒素またはアルゴンなどの不活性雰囲気下で行った。PoraPak(登録商標)Rxn CXは、Waters社から入手可能な市販の陽イオン交換樹脂を指す。
Ac アセチル
aq 水溶液
anh 無水
Ar アルゴン(実験パート中);スキーム中の芳香族/ヘテロ芳香族基
BINAP 2,2’−ビス(ジフェニルホスフィノ)−1,1’−ビナフチル
Boc tert−ブトキシカルボニル
br. ブロード
calcd 計算された
d 二重線(1H NMRスペクトル内で使用される場合にのみ)
d 日
DCM ジクロロメタン
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
dppf 1,1’−ビス(ジフェニルホスフィノ)フェロセン
h 時間
hal ハロゲン
HPLC 高速液体クロマトグラフィー
I.P. 腹腔内注射
LC−MS 質量分光器に連結された液体クロマトグラフィー
LDA リチウムジイソプロピルアミド
min 分
m 多重線
mw マイクロ波照射
MS ESI 質量スペクトル、エレクトロスプレーイオン化
ND 決定されなかった
NMP 1−メチル−2−ピロリドン
NMR 核磁気共鳴
O/N 一晩
pin ピナコール
prep 分取
p.o. 経口投与
Q.D. 一日一回投与した
Q.W.週一回投与した
rt 室温
RP 逆相
s 一重線
satd 飽和
SM 出発材料
SNAr 芳香族求核置換
SPE 固相抽出
t 三重線
TBTU O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウムテトラフルオロボレート
temp. 温度
TFA トリフルオロ酢酸
TLC 薄層クロマトグラフィー
THF テトラヒドロフラン
xs 過剰
キサントホス 4,5−ビス(ジフェニルホスフィノ)−9,9−ジメチルキサンテン
一般的方法A(薗頭カップリング、2−クロロ−4−(Ar/アルキルエチニル)ピリミジン−5−アミンの調製)
ハロピリミジン(1.0当量)、Et3N(0.9M)またはEt3N/DMF(1:1v/v、0.8M)中のアセチレン(1当量)をArで脱気し、CuI(0.1〜0.2当量)およびPd(PPh3)2Cl2(0.03当量)またはPd(PPh3)4(0.07当量)を入れ、完了まで100℃で加熱密封した。反応物を、室温まで冷却し、濾過するか、または減圧下で濃縮し、研和またはフラッシュクロマトグラフィーによる精製前に水性後処理に供した。
無水NMP(0.25M)中の2−クロロ−4−(アリール(アルキル)エチニル)ピリミジン−5−アミンの溶液に、t−BuOK(2当量)を室温で一度に加えて処理した(発熱)。反応物を室温で短時間撹拌し、次いで0.5〜1時間、50℃で攪拌した。後に、反応物を室温まで冷却し、H2Oで希釈した。生成物を濾過により回収し、H2Oですすいだ。
乾燥バイアルに無水ジオキサン(0.07M)中2−クロロ−5H−ピロロ[3,2−d]ピリミジンまたはtert−ブチル2−クロロ−5H−ピロロ[3,2−d]ピリミジン−5−カルボキシレート(1当量)、K2CO3(10当量)、ArNH2(1.8当量)およびPd(OAc)2(0.1当量)を入れた。反応混合物をArで脱気し、キサントホス(0.2ミリモル)を入れた。反応バイアルを密閉し、脱気を繰り返し、反応物を室温で短時間撹拌し、次いで、一晩、100℃の油浴中で攪拌した。典型的には、反応混合物を室温まで冷却し、DCMおよびMeOHを用いて濾過し、移して、すすいだ。濾液を減圧下で濃縮し、フラッシュクロマトグラフィー(DCM中のEtOAcまたはDCM中のMeOH)によって精製した。Bocで保護された材料の場合には(ある程度のBocの損失が最初のステップで観察され)、材料をDCM/TFA(5:1 v/v)に取りいれ、1時間室温で撹拌した。次いで、反応物を減圧下で濃縮し、フラッシュクロマトグラフィーおよび/またはRP HPLCによって精製した。
i−PrOH中の2−クロロ−6−(o−トリル)−5H−ピロロ[3,2−d]ピリミジンの溶液に、アミンまたはアニリン(4〜6当量)およびジオキサン中のHCl(4M、2当量)を加えた。あるいは、アミン(4〜6当量)およびDIPEA(2〜4当量)のHCl塩を使用した。密封したバイアルを、マイクロ波反応器(高圧:>10バール)中、2〜8時間、170℃でマイクロ波照射に供した。反応混合物を逆相クロマトグラフィーによって精製した。
ジオキサン(49mL)およびH2O(12mL)、2−クロロ−6−ヨード−5−(フェニルスルホニル)−5H−ピロロ[3,2−d]ピリミジン(0.744g、1.8ミリモル)、o−トリルボロン酸(0.264g、1.9ミリモル)、K2CO3(1.01g、7.3ミリモル)の脱気した混合物に、Pd(dppf)Cl2・DCM(0.145g、0.18ミリモル)を加えた。脱気を繰り返し、反応物を一晩、105℃でAr下、油浴中で加熱した。次いで、反応物を冷却し、減圧下で濃縮し、フラッシュクロマトグラフィー(EtOAc−DCM−10%)により精製した。
5H−ピロロ[3,2−d]ピリミジン、Boc2O(2〜4当量)、DMAP(0.2〜0.4当量)およびDIPEA(1.5当量)を室温で一晩、EtOAc中で攪拌した。次いで、反応物を減圧下で濃縮し、フラッシュクロマトグラフィーにより精製した。
2−(4−(3−アミノフェニル)ピペラジン−1−イル)エタノールの合成
1−(3−ニトロフェニル)ピペラジン(0.67g、3.2ミリモル)、2−ヒドロキシ酢酸(0.261g、3.4ミリモル)、DIPEA(1.2mL、6.9ミリモル)の無水DMF(10mL)溶液に、TBTU(1.10g、3.4ミリモル)を室温で一度に加えて処理した。反応物を室温で2時間撹拌し、xs H2Oおよび氷で希釈し、濾過して、黄色の固体(0.546g、64%)として2−ヒドロキシ−1−(4−(3−ニトロフェニル)ピペラジン−1−イル)エタノンを得た。1H NMR(400MHz、DMSO−d6)δppm 7.66(t,J=2.10Hz,1H),7.60(d,J=7.78Hz,1H),7.48(t,J=8.20Hz,1H),7.40(dd,J=8.30,2.10Hz,1H),4.69(t,J=5.50Hz,1H),4.13(d,J=5.50Hz,2H),3.56−3.66(m,4H),3.23−3.32(m,4H);MS ESI[M+H]+ 266.2、[C12H15N3O4+H]+についての計算値266.11。
2−ヒドロキシ−1−(4−(3−ニトロフェニル)ピペラジン−1−イル)エタノン(0.546g、2.06ミリモル)およびPd/C(224mg、0.2ミリモル)を室温で、1日、H2(1気圧)下、MeOH(200mL)中で撹拌した。反応物を、セライトを通して濾過し、MeOHで反応フラスコおよび濾過パッドをすすいだ。減圧下で濃縮すると、白色固体として1−(4−(3−アミノフェニル)ピペラジン−1−イル)−2−ヒドロキシエタノンが得られた(0.404g、83%)。1H NMR(400MHz,CD3OD)δppm 7.00(t,J=8.00Hz,1H),6.39(s,1H),6.37(d,J=8.00Hz,1H),6.30(d,J=8.00Hz,1H),4.27(s,2H),3.68−3.79(m,2H),3.49−3.58(m,2H),3.12(d,J=4.77Hz,4H);MS ESI[M+H]+236.2、[C12H17N3O2+H]+についての計算値235.28。
1−(4−(3−アミノフェニル)ピペラジン−1−イル)−2−ヒドロキシエタノン(0.404g、1.72ミリモル)の無水THF(24mL)溶液に、Ar下、0℃でLiAlH4(THF中1.0M、6.9mL、6.9ミリモル)を滴加して、処理した。さらに5分後、冷却浴を除去し、反応物を室温まで温め、次いで、一晩、加熱還流した。次いで、反応混合物を室温まで冷却し、0℃でDCM中xs Na2SO4・10H2Oの攪拌懸濁液に注意深く注いだ(滴下した)。後に、反応物を室温で30分間攪拌し、濾過し、淡褐色のガム状物として2−(4−(3−アミノフェニル)ピペラジン−1−イル)エタノールを得、さらなる精製をせずに使用した(0.52g)。1H NMR(400MHz,CD3OD)δppm 6.99(t,J=8.03Hz,1H),6.40(s,1H),6.37(d,J=8.03Hz,1H),6.29(d,J=8.03Hz,1H),3.73(t,J=6.00Hz,2H),3.12−3.19(m,4H),3.04−3.11(m,2H),2.93−2.98(m,2H),2.59(t,J=6.00Hz,2H);MS ESI[M+H]+ 222.2、[C12H19N3O+H]+についての計算値222.15。
無水のPhMe(32mL)中5−ブロモ−2−クロロ−4−(フェニルエチニル)ピリミジン(WO2013/078254 p.166)(0.82g、2.9ミリモル)、ジフェニルメタンイミン(0.58g、3.2ミリモル)、Pd(OAc)2(26mg、0.11ミリモル)およびCs2CO3(1.40g、4.3ミリモル)をArで脱気し、その後BINAP(108mg、0.17ミリモル)を加えた。反応物を17時間、105℃の油浴中で加熱密封し、室温まで冷却し、DCMで希釈し、2umフリットを通して濾過した。減圧濃縮およびフラッシュクロマトグラフィー(DCM−EtOAc)による精製により、オレンジ色のガム状物として2−クロロ−N−(ジフェニルメチレン)−4−(フェニルエチニル)ピリミジン−5−アミン(0.71g)を得た。MS ESI[M+H]+394.2、[C25H16ClN3+H]+についての計算値394.1。
2−クロロ−N−(ジフェニルメチレン)−4−(フェニルエチニル)ピリミジン−5−アミン(0.28g、0.71ミリモル)を室温で23時間、THF(6mL)および塩酸水溶液(2.7M、1.5mL)中で撹拌した。反応物をEtOAC中に取り入れ、飽和NaHCO3水溶液で洗浄し、乾燥させ(Na2SO4)、減圧下で濃縮し、フラッシュクロマトグラフィー(DCM−MeOH)で精製し、明黄色の固体として2−クロロ−4−(フェニルエチニル)ピリミジン−5−アミン(116mg、72%)を得た。MS ESI [M+H]+230.1、[C12H8ClN3+H]+についての計算値230.04。
t−BuOK(0.780g、6.9ミリモル)を、H2O浴中で冷却しながら無水THF(40mL)中の2−クロロ−5H−ピロロ[3,2−d]ピリミジン(0.861g、5.6ミリモル)に4回に分けて加えた。反応物を10分間撹拌し、PhSO2Clを15分かけて加え(0.9mL、7.0ミリモル)、反応物を室温で一晩撹拌した。THFを減圧下で除去し、残留物をEtOAcに取り入れ、ブラインで(2回)洗浄し、乾燥させ(Na2SO4)、白色固体として2−クロロ−5−(フェニルスルホニル)−5H−ピロロ[3,2−d]ピリミジンを得(1.59g、97%)、さらなる精製をせずに使用した。1H NMR(400MHz、CDCl3)δ ppm 9.22(s、1H)、7.91−7.99(m,3H)、7.65−7.71(m,1H)、7.52−7.60(m、2H)、6.82(d,J=3.76Hz,1H)。MS ESI [M+H]+ 294.1、[C12H8ClN3O2S+H]+についての計算値294.0。
LDA(6.2mL、THF中1.0M、6.2ミリモル)を、アルゴン下、−78℃で攪拌しながら2−クロロ−5−(フェニルスルホニル)−5H−ピロロ[3,2−d]ピリミジン(1.59g、5.4ミリモル)の無水THF(95mL)溶液に8分間かけて滴加した。次いで、反応物を80分間、温度で攪拌し、その後、I2(無水THF4mL中1.58g、6.2ミリモル)を、カニューレを介して数分かけて加えた。冷却しながら撹拌を3時間継続し、次いで、冷却浴を除去し、45分後にH2O(20mL)を加えた。反応物を、DCM(500mL)で希釈し、洗浄し(ブライン、2回)、乾燥させ(Na2SO4)、減圧下で濃縮した。フラッシュクロマトグラフィー(EtOAc−DCM 0〜10%)により精製して、白色固体として2−クロロ−6−ヨード−5−(フェニルスルホニル)−5H−ピロロ[3,2−d]ピリミジンを得た(1.05g、46%)。MS ESI[M+H]+419.9、[C12H7ClIN3O2S+H]+についての計算値419.9。
ジオキサン(49mL)およびH2O(12mL)、2−クロロ−6−ヨード−5−(フェニルスルホニル)−5H−ピロロ[3,2−d]ピリミジン(0.744g、1.8ミリモル)、o−トリルボロン酸(0.264g、1.9ミリモル)、K2CO3(1.01g、7.3ミリモル)の脱気した混合物に、Pd(dppf)Cl2・DCM(0.145g、0.18ミリモル)を加えた。脱気を繰り返し、反応物を一晩105℃で、Ar下、油浴中で加熱した。次いで、反応物を冷却し、減圧下で濃縮し、フラッシュクロマトグラフィー(EtOAc−DCM 0〜10%)により精製し、白色固体として2−クロロ−6−(o−トリル)−5H−ピロロ[3,2−d]ピリミジンを得た(0.32g、74%)。1H NMR(400MHz、CD3OD) δppm 8.72(s、1H)、7.55(d,J=7.28Hz,1H)、7.32−7.43(m,3H)、6.69(s、1H)、2.49(s,3H);MS ESI[M+H]+244.1、[C13H10ClN3+H]+についての計算値244.06。
N,6−ジフェニル−5H−ピロロ[3.2−d]ピリミジン−2−アミン)の合成(実施例A1)
2−クロロ−6−フェニル−5H−ピロロ[3,2−d]ピリミジン(83.8mg、0.365ミリモル)、Boc2O(350mg、1.60ミリモル)、DMAP(29mg、0.23ミリモル)およびDIPEA(0.1mL、0.57ミリモル)を22時間室温で、EtOAc(24mL)中で撹拌した。次いで、反応物を減圧下で濃縮し、フラッシュクロマトグラフィー(DCM中0〜30%のEtOAc)によって精製し、白色固体としてtert−ブチル2−クロロ−6−フェニル−5H−ピロロ[3,2−d]ピリミジン−5−カルボキシレート(0.106g、88%)を得た。1H NMR(400MHz、CDCl3)δppm 9.31(s、1H)、7.41−7.53(m、5H)、6.68(d、J=0.75Hz、1H)、1.37(s、9H);MS ESI [M+H]+330.2、[C17H16ClN3O2+H]+についての計算値330.09。
乾燥バイアルに、無水ジオキサン(3mL)中のtert−ブチル2−クロロ−6−フェニル−5H−ピロロ[3,2−d]ピリミジン−5−カルボキシレート(62mg、0.19モル)、K2CO3(245mg、1.8ミリモル)、PhNH2(32mg、0.34ミリモル)およびPd(OAc)2(5.6mg、0.025ミリモル)を入れた。反応混合物をArで脱気し、キサントホス(28.5mg、0.049ミリモル)を入れた。反応バイアルを密閉し、脱気を繰り返し、反応物を室温で短時間撹拌し、次いで、22時間100℃の油浴中で攪拌した。反応混合物を室温まで冷却し、DCMおよびMeOHを用いて濾過し、移して、すすいだ。濾液を、減圧下で濃縮し、フラッシュクロマトグラフィー(DCM中のEtOAc)によって精製して、粗製tert−ブチル2−クロロ−6−フェニル−5H−ピロロ[3,2−d]ピリミジン−5−カルボキシレート(MS ESI [M+H]+387.3、[C23H22N4O2+H]+についての計算値387.17)を得、DCM/TFA(25mL、5:1 v/v)に入れ、1時間室温で撹拌した。次いで、この反応物を減圧下で濃縮し、フラッシュクロマトグラフィー(DCM中のEtOAc 0〜>60%)により精製した。ヘキサンで研和し、次いで、Et2O−ヘキサン(1:1 v/v)で研和し、淡黄色固体としてN,6−ジフェニル−5H−ピロロ[3,2−d]ピリミジン−2−アミン(50mg、92%)を得た。1H NMR(400MHz、CD3OD)δppm 8.70(s、1H)、7.95(d、J=8.30Hz、2H)、7.55−7.65(m,5H)、7.42−7.49(m,2H)、7.26(t、J=7.50Hz、1H)、6.91(s、1H);MS ESI [M+H]+287.2、[C18H14N4+H]+についての計算値287.12。
活性RIPK2を、昆虫細胞で発現させたHisタグ付きヒトRIPK2キナーゼの触媒ドメイン(アミン酸1〜299)としてLife Technologies社から購入した。アミノ末端6ヒスチジン、sumoタグ付きヒトTTK(残基1〜275)を大腸菌で発現させ、Ni2+アガロース、ゲル濾過、およびイオン交換クロマトグラフィーにより>95%の均一性まで精製した。
化合物を重層する24時間前に、乳癌細胞(MDA−MB−231およびMDA−MB−468)、結腸癌細胞(HCT116およびHT−29)および卵巣癌細胞(SKOV−3およびOVCAR−3)を96ウェルプレートに播種した(細胞増殖速度に応じて、1ウェルあたり80μL中1000〜4000個)。化合物を、10%FBS(ウシ胎児血清)を含有するDMEM(ダルベッコ改変イーグル培地)細胞増殖培地(Invitrogen,Burlington,ON,Canada)で50nM〜250μΜの範囲の濃度まで希釈した100%DMSO中10mMのストック溶液として調製した。10nM〜50μΜの最終濃度にするために、各濃度のアリコート(20μL)を96ウェルプレートに予め播種した細胞の80μLに重層した。細胞を5日間培養し、その後、スルホローダミンBアッセイ(SRB)を、化合物の細胞増殖阻害活性を決定するために行った。
HCT116結腸癌細胞をATCC(アメリカン・タイプ・カルチャー・コレクション)から購入し、10%ウシ胎児血清を補充したDMEM(GIBCOから購入したダルベッコ改変イーグル培地)で培養した。500万個の細胞を6〜8週齢の雄のCB−17 SCIDマウスの右脇腹に皮下注射した。平均腫瘍体積が80〜120mm3に達したときに、マウスを5群(n=5)に無作為に分け、ビヒクル(10%NMP、40%PEG、50%H2O)または示した用量の化合物のいずれかを与えた。
IL−12−黄色蛍光タンパク質(YFP)レポーターマウス骨髄樹状細胞を、例A3の存在下で、0.3ng/mlのLPS±1μg/mlのMDP(すなわち、NOD2アゴニスト)で24時間刺激した(図2A)。IL−12−黄色蛍光タンパク質(YFP)レポーターマウス骨髄樹状細胞を、例A3の存在下で、0.3μg/mlのPam3Cys±1μg/mlのMDP(すなわち、NOD2アゴニスト)で24時間刺激した(図2B)。フローサイトメトリー分析は、例A3が平均蛍光強度YFPの用量依存的減少を引き起こしたことを示した(すなわち、IL−12の量;左パネル)。この例A3の効果は、MDP依存的であり、それがNOD2−RIPK2応答の遮断に関与することを示唆している。例A3は、YFP陽性細胞のパーセンテージに対して最小の効果を有し(すなわち、IL−12陽性細胞のパーセンテージ;中央のパネル)、7AAD除外によって評価されるように細胞生存率に対して測定可能な効果を有していなかった(右パネル)。データは、3回の測定の平均±SEMとして表される。Aからの細胞培養上清中のIL−12 p70(図2C、左パネル)およびTNFα(図2C、右パネル)のレベルを、市販のキットを用いてELISA法により測定した。例A3は、両方のサイトカインレベルの用量依存的減少を引き起こした。データは、3回の測定の平均±SEMとして表される。
Claims (18)
- 式(I):
Cyは、シクロ脂肪族、ヘテロシクリル、アリール、またはヘテロアリールであり;
Yは、存在しないか、−CRbRb−、−O−、−NRb−、−S(O)n−であり;
R1は、シクロ脂肪族、ヘテロシクリル、アリール、またはヘテロアリールであり、その各々は、必要に応じて、個々にRaによって表される1〜3個の基で置換されており;
R3は、H、必要に応じて、−F、−Cl、−Br、−I、−CN、−NO2、−ORb、−C1−C4アルキル、−(C1−C3)アルキレン−ORb、−(C1−C3)アルキレン−NRbRb、−C1−C4ハロアルキル、−C1−C4ハロアルコキシ、(C3−C8)シクロアルキル、−NRbRb、−C(=O)NRbRb、−NRb(C=O)NRbRb、−S(O)nNRbRb、C(=O)ORb、−OC(=O)ORb、−S(O)nRb、−NRbS(O)nRb、−C(=S)ORb、−O(C=S)Rb、−NRbC(=O)Rb、−C(=S)NRbRb、−NRbC(=S)Rb、−NRb(C=O)ORb、−O(C=O)NRbRb、−NRb(C=S)ORb、−O(C=S)NRbRb、−NR(C=S)NRbRb、−C(=S)Rbまたは−C(=O)Rbから選択される1〜3個の基で置換されたヘテロシクリルまたはヘテロアリールであり;
各R4は、独立して、−F、−Cl、−Br、I、−CN、−NRbRb、−ORb、−C1−C4アルキル、−(C1−C3)アルキレン−ORb、−(C1−C3)アルキレン−NRbRb、−C1−C4ハロアルキル、または−C1−C4ハロアルコキシから選択され;
各Raは、独立して、−F、−Cl、−Br、I、−CN、ORb、−C1−C4アルキル、(C2−C6)アルケニル、(C2−C6)アルキニル、−C1−C4ハロアルキル、−C1−C4ハロアルコキシ、−(C1−C3)アルキレン−ORb、または−(C1−C3)アルキレン−NRbRbから選択され;
各Rbは、独立して、−Hまたは−C1−C4アルキルであり;
xは、0、1、2、3、または4であり;
各mは、独立して、0、1、2、または3であり;ならびに
各nは、独立して、0、1、または2である)
によって表される化合物またはその薬学的に許容される塩。 - R1が、必要に応じて置換されたフェニル、必要に応じて置換されたシクロペンチル、必要に応じて置換されたシクロヘキシル、必要に応じて置換されたチエニル、必要に応じて置換されたピリジニル、必要に応じて置換されたチアゾリル、必要に応じて置換されたピロリル、必要に応じて置換されたイミダゾリル、必要に応じて置換されたフラニル、必要に応じて置換されたオキサゾリル、必要に応じて置換されたイソオキサゾリル、必要に応じて置換されたピラゾリル、必要に応じて置換されたイソチアゾリル、必要に応じて置換されたピルミジニル(pyrmidinyl)、必要に応じて置換されたピラジニル、必要に応じて置換されたピリダジニル、必要に応じて置換されたオキサジアゾリル、必要に応じて置換されたテトラヒドロピラニル、必要に応じて置換されたトリアゾリル、または必要に応じて置換されたチアジアゾリルである、請求項1〜3のいずれかに記載の化合物。
- R1が、必要に応じて置換されたフェニル、必要に応じて置換されたシクロペンチル、必要に応じて置換されたチエニル、または必要に応じて置換されたテトラヒドロピラニルである、請求項1〜4のいずれか一項に記載の化合物。
- R3が、必要に応じて置換された単環式ヘテロシクリルまたは必要に応じて置換された単環式ヘテロアリールである、請求項1〜5のいずれか一項に記載の化合物。
- mが0である、請求項1〜6のいずれか一項に記載の化合物。
- R3が、必要に応じて置換されたアゼチジニル、必要に応じて置換されたモルホリニル、必要に応じて置換されたピペラジニル、必要に応じて置換されたピペリジニル、必要に応じて置換されたテトラヒドロピラニル、必要に応じて置換されたピロリジニル、必要に応じて置換されたチオモルホリニル、必要に応じて置換されたテトラヒドロピラニル、または必要に応じて置換されたテトラヒドロフラニル、必要に応じて置換されたホモモルホリニル、必要に応じて置換されたホモピペラジニル、必要に応じて置換されたチオモルホリンジオキシド、または必要に応じて置換されたチエノモルホリンオキシドである、請求項1〜7のいずれか一項に記載の化合物。
- R3が、必要に応じて置換されたモルホリニル、必要に応じて置換されたピペラジニル、必要に応じて置換されたピペリジニル、または必要に応じて置換されたチオモルホリニルである、請求項1〜8のいずれか一項に記載の化合物。
- 各Raが、独立して、−F、−Cl、または−CH3から選択される、請求項13に記載の化合物。
- 請求項1〜14のいずれか一項に記載の化合物および薬学的に許容される担体または希釈剤を含む医薬組成物。
- 癌を有する対象を治療する方法であって、請求項1〜14のいずれか一項に記載の有効量の化合物を前記対象に投与することを含む方法。
- 自己炎症性疾患を有する対象を治療する方法であって、請求項1〜14のいずれか一項に記載の有効量の化合物を前記対象に投与することを含む方法。
- 自己免疫疾患を有する対象を治療する方法であって、請求項1〜14のいずれか一項に記載の有効量の化合物を前記対象に投与することを含む方法。
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KR102472736B1 (ko) | 2016-09-15 | 2022-12-02 | 베링거 인겔하임 인터내셔날 게엠베하 | Ripk2의 저해제로서의 헤테로아릴 카복스아미드 화합물 |
JP6965083B2 (ja) * | 2017-10-04 | 2021-11-10 | 公益財団法人微生物化学研究会 | 化合物、及び発光化合物 |
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