JP2016536333A - 免疫調節剤として有用な化合物 - Google Patents
免疫調節剤として有用な化合物 Download PDFInfo
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- JP2016536333A JP2016536333A JP2016540311A JP2016540311A JP2016536333A JP 2016536333 A JP2016536333 A JP 2016536333A JP 2016540311 A JP2016540311 A JP 2016540311A JP 2016540311 A JP2016540311 A JP 2016540311A JP 2016536333 A JP2016536333 A JP 2016536333A
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- methyl
- methoxy
- phenylphenyl
- phenyl
- amino
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
- C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/396—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having three-membered rings, e.g. aziridine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- 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
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
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- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
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- A61K31/47—Quinolines; Isoquinolines
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- 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
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
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- C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
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Abstract
Description
本願は、2013年9月4日付け出願の米国仮特許出願番号61/873398に関して優先権を主張するものであり、その内容をそのまま本明細書に組み込むものとする。
環Bはフェニルまたはチエニルであり;
環Aは
ここで、A’’はCHまたはNであって、R1およびR2の一方はQであり、R1およびR2の他方はRbであり;
R3はHまたは−CH2C(O)OHであり;
R4は−NHCH2CH2NHC(O)CH3であり;
Qは
(i)
(ii)−CH2NH−Rxであり、ここでRxはシクロブチル、−(CH2)シクロブチル(2個のフッ素原子で所望により置換されてもよい)、シクロプロピル、ヒドロキシシクロペンチル、シクロペンチル、シクロヘキシル、ヒドロキシシクロヘキシル、ヒドロキシテトラヒドロフラニル、N−メチルピペリジニル、N−エチルピペリジニル、ヒドロキシテトラヒドロチエニル、または
(iii)−CH2NRa−CRaRa−(CH2)n−Rxであり、ここでRxは水素、アゼチジノニル、シクロヘキシル、ヒドロキシフェニル、ピロリジノニル、ピペリジノニル、ピペラジノニル、モルホリニル、イミダゾリル、N−メチルイミダゾリル、−C(O)(モルホリニル)、ピペラジニル(メチル、フェニル、アルコキシフェニル、ヒドロキシフェニル、ピリジニル、ピリミジニル、または−C(O)OC(CH3)3基で所望により置換されてもよい)、ピロリジニル、ピリジニル、チオモルホリンジオキシド、またはメチルトリアゾリルであるか;あるいは
(iv)−CHRa−NRa−CRaRa−(CHRa)n−Rxであり、ここでRxは−OH、−OCH3、−C(O)OH、−OPh、−CH(CO2H)−NHC(O)CH3、−O(CH2)2O(CH2)2OH、−O(CH2)2O(CH2)2O(CH2)2OH、−O(CH2)2O(CH2)2O(CH2)2O(CH2)2CO2H、−O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2CO2H、−C(O)CH3、−C(O)NRaRa、−C(O)NRqRq、−N(CH3)2、−NHC(O)CH3、−NHC(O)Ph、−C(O)NH(CH2)2−イミダゾリル、NHC(O)OCH2Ph、−N(CH3)S(O)2CH3、−NHC(O)CH=CH2、−NHC(O)CH=CHC(O)CH2CH3、−NHS(O)2CH3、または
Raは、各々、独立して、H、−CH(OH)CH3、OH、−(CH2)2OH、−CH2OH、−(CH2)2NH2、−CH2CH3、または−CH3であるか;
または、同じ炭素原子上にある2個のRa基が4員、5員または6員の炭素環式環、N−メチルピペリジニル環、またはピラニル環を形成することができ;
Rbは、各々、独立して、H、F、Cl、Br、−CF3、−CN、CH3、または−OCH3であり;
Rcは、各々、独立して、−OCH3、−OH、−OCH2CH3、−O(CH2)OCH3、−OCH2CH=CH2、−O(CH2)2CH3、−O(CH2)2−モルホリニル、またはFであるか;
または、隣接する炭素原子に結合した2個のRcは−O−(CH2)v−O−を形成し、ここでvは1または2であり;
Rqは、各々、水素、−CH2C(O)NHCH2CO2H、−(CH2)C(O)NHCH(CO2H)CH2CH(CH3)2、−CH(Bn)−C(O)NHCH(CO2H)(CH2)3NHC(NH)NH2より選択され;
mは0または1であり;
nは0、1、2または3であり;
pは、各々、独立して、0または1であり;および
qは0、1または2である]
で示される少なくとも1つの化合物、またはその塩を提供する。
環Aは
R1およびR2の一方はQであり、R1およびR2の他方はRbであり;
R3はHまたは−CH2C(O)OHであり;
R4は−NHCH2CH2NHC(O)CH3であり;
Qは
(i)
(ii)−CH2NH−Rxであり、ここでRxはシクロブチル、ヒドロキシシクロヘキシル、N−メチルピペリジニル、またはN−エチルピペリジニルであるか;
(iii)−CH2NRa−CRaRa−(CH2)n−Rxであり、ここでRxはピロリジノニル、ピペリジノニル、ピペラジノニル、モルホリニル、−C(O)(モルホリニル)、N−メチルピペラジニル、またはメチルトリアゾリルであるか;あるいは
(iv)−CHRa−NRa−CRaRa−(CH2)n−Rxであり、ここでRxは−OH、−C(O)OH、−C(O)CH3、−C(O)NRaRa、−NHC(O)CH3、または−NHS(O)2CH3であり;
Raは、各々、独立して、Hまたは−CH3であり;
Rbは、各々、独立して、H、F、Cl、Br、−CH3、または−OCH3であり;
Rcは、各々、独立して、−OCH3またはFであるか;
あるいは隣接する炭素原子に結合する2個のRcが−O−CH2−O−を形成し;
mが0または1であり;
nが0、1または2であり;
pが、各々、独立して、0または2であり;および
qが0、1または2である]
で示される化合物またはその塩を提供する。
で示される構造を有する。R1がQであり、R2がRbである、式(IIIA):
で示される式(IIIA−1)はこの実施態様に含まれる。
で示される式(IIIA−2)の化合物はこの実施態様に含まれる。構造式:
で示される構造を有する、式(IIIA)の化合物を提供する。R2が−OCH3である、化合物はこの実施態様に含まれる。
で示される構造を有する、化合物はこの実施態様に含まれる。式(IIIA−5)の化合物の例として、(i)R2が−OCH3であるか;(ii)R2が−CH3または−OCH3であるか;(iii)Rbが−CH3であって、R2が−CH3であるか;(iv)Rbが−OCH3であって、R2が−OCH3あるか;あるいは(v)Rbが−CH3または−OCH3であって、R2が−CH3または−OCH3である、化合物が挙げられる。
で示される構造を有する。Rbの各々が、独立して、−CH3または−OCH3である、化合物はこの実施態様に含まれる。
で示される構造を有する。Rbの各々がBrであり、R2が−OCH3である、化合物はこの実施態様に含まれる。
で示される式(II−1)の化合物はこの実施態様に含まれる。
で示される、式(IIIA−8)の化合物はこの実施態様に含まれる。
2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]ブタン酸(84);(2R)−2−[メチル({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン酸(85);3−[({2,6−ジメチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパンアミド(86);N−{2−[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}アセトアミド(87);N−{2−[({4−メチル−3−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}アセトアミド(88);(2S)−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アゼチジン−2−カルボン酸(90);5−{[({4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]メチル}ピロリジン−2−オン(91);5−{[({4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]メチル}ピロリジン−2−オン(92);(2S)−2−[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン酸(93);2−[メチル({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]酢酸(94);3−[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパンアミド(95);(2R)−2−[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン酸(96);1−({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アゼチジン(97);1−({2−メトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アゼチジン(98);1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アゼチジン(99);1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アゼチジン(100);2−[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エタン−1−オール(102);2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エタン−1−オール(103);(2S)−2−[({3−ブロモ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン酸(104);(2R)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン酸(105);(2R)−2−{[(2,6−ジメトキシ−4−{[3−(3−メトキシフェニル)−2−メチルフェニル]メトキシ}フェニル)メチル]アミノ}プロパン酸(106);(2R)−2−{[(4−{[3−(3−フルオロ−5−メトキシフェニル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル]アミノ}プロパン酸(107);(2R)−2−{[(4−{[3−(2H−1,3−ベンゾジオキソール−5−イル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル]アミノ}プロパン酸(108);およびその塩より選択される式(IIIA)の化合物を提供する。
a)The Practice of Medicinal Chemistry, Camille G. Wermuthら、Ch 31 (Academic Press, 1996);
b)Design of Prodrugs, Bundgaard, H.編 (Elsevier, 1985)
c)A Textbook of Drug Design and Development, P. Krosgaard-LarsonおよびH. Bundgaard編, Ch 5, pp.113-191(Harwood Academic Publishers, 1991);および
d)Hydrolysis in Drug and Prodrug Metabolism, Bernard TestaおよびJoachim M. Mayer(Wiley-VCH, 2003)
に記載されている。
本発明を実施例を用いてさらに詳しく説明する。その実施例は単に例示として付与されることを理解すべきである。上記の説明および実施例から、当業者は、本発明の本質的な特徴を解明することができ、その精神および範囲から逸脱することなく、種々の変形および修飾を施し、本発明を種々の使用および条件に適応させることができる。その結果、本発明は、下記の例示としての実施例に限定されないで、むしろ添付した特許請求の範囲によって限定されることとなる。
(S)−1−(2,6−ジメトキシ−4−((2−メチルビフェニル−3−イル)メトキシ)ベンジル)ピペリジン−2−カルボン酸
2,6−ジメトキシ−4−((2−メチルビフェニル−3−イル)メトキシ)ベンズアルデヒド(20mg、0.055ミリモル)、(S)−ピペリジン−2−カルボン酸および水素化トリアセトキシホウ素ナトリウム(35.1mg、0.166ミリモル)のジクロロメタン(4mL)中溶液を85℃で45分間攪拌した。その粗物質をプレパラティブLC/MSを介して次の条件:カラム:Waters XBridge C18、19x200mm、5−μm粒子;移動相A:水+20mM酢酸アンモニウム;移動相B:95:5 アセトニトリル:水+20mM酢酸アンモニウム;勾配:20分間にわたり25−65%Bとし、次に100%Bで5分間保持する;流速:20mL/分で精製した。所望の生成物を含有するフラクションを集め、遠心式エバポレーションを介して乾燥させた。生成物の収量は20.3mgであり、LCMS分析により評価されるその純度は99%であった。LC/MS 方法A:2.8分、M+1:476.3、M−1:474.4、正確な質量:475.2;1H NMR(500MHz、DMSO−d6)δ 7.55−7.15(m,8H)、6.43(s,2H)、5.20(s,2H)、4.12(s,2H)、3.80(s,6H)、3.20−3.04(m,3H)、3.22−3.02(m,3H)、2.65(br.s.,1H)、2.22(s,3H)、1.82(br.s.,2H)、1.57(br.s.,2H)、1.40(d,J=6.7Hz,2H)
実施例2
2−(6−((2−メチル−[1,1’−ビフェニル]−3−イル)メトキシ)−3,4−ジヒドロイソキノリン−2(1H)−イル)酢酸
炭酸カリウム(0.055g、0.400ミリモル)および6−((2−メチル−[1,1’−ビフェニル]−3−イル)メトキシ)−1,2,3,4−テトラヒドロイソキノリン(0.066g、0.2ミリモル)をアセトニトリル(2.000ml)中で合わせることで混合物を調製した。メチル 2−ブロモアセタートをスモールプラグの炭酸カリウムを通して濾過し、臭化水素を除去した。そのメチル 2−ブロモアセタート(0.034g、0.220ミリモル)を該混合物に加えた。得られた混合物を3時間攪拌した。反応の程度は約20%であると測定された。混合物を35℃で1時間加熱した。残りの出発物質は消費された。さらに精製することなく得られた物質を用いた。
2−[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エタン−1−オール
3−クロロ−4−((2−メチル−[1,1’−ビフェニル]−3−イル)メトキシ)ベンズアルデヒド(20mg、0.059ミリモル)および2−アミノエタノール(3.99mg、0.065ミリモル)のジクロロメタン(5mL)中溶液を室温で1時間攪拌した。溶媒を除去し、トルエン(3mL)を加え、ロータリーエバポレーターで除去した。残渣にジクロロメタン(5mL)および水素化トリアセトキシホウ素ナトリウム(37.8mg、0.178ミリモル)を加えた。得られた明黄色混合物を室温で一夜攪拌した。溶媒を除去し、残渣を精製のためにメタノールに溶かした。その粗物質をプレパラティブLC/MSを介して次の条件:カラム:XBridge C18、19x200mm、5μm粒子;移動相A:5:95 アセトニトリル:水+10mM 酢酸アンモニウム+10mM 酢酸アンモニウム;移動相B:95:5 アセトニトリル:水+10mM 酢酸アンモニウム;勾配:15分にわたって20−60%Bにし、ついで100%Bで5分間保持する;流速:20mL/分で精製した。所望の生成物を含有するフラクションを集め、遠心式エバポレーションを介して乾燥させた。生成物の収量は10.7mgであり、LCMS分析により評価されるその純度は100%である。LC/MS 方法A:2.7分、M+1:382.4、正確な質量:381.2。1H NMR(500MHz、DMSO−d6)δ 7.51(d,J=7.6Hz,1H)、7.49−7.44(m,2H)、7.42(s,1H)、7.41−7.36(m,1H)、7.34−7.28(m,3H)、7.27(s,2H)、7.21(d,J=7.6Hz,1H)、5.23(s,2H)、3.65(s,2H)、3.46(t,J=5.8Hz,2H)、2.55(t,J=5.8Hz,2H)、2.23(s,3H)、1.90(s,1H,アセタート)
1−(4−((3’−メトキシ−2−メチルビフェニル−3−イル)メトキシ)ベンジル)アゼチジン
1−(4−((3−ブロモ−2−メチルベンジル)オキシ)ベンジル)アゼチジン(330mg、880マイクロモル)のジオキサン(22mL)中溶液を調製した。次に、炭酸セシウム(568mg、1.8ミリモル)の水(4.4mL)中溶液を調製した。2mLのマイクロウェーブバイアルに入れた3−メトキシフェニルボロン酸に、(S)−2−((4−((3−ブロモ−2−メチルベンジル)オキシ)ベンジル)アミノ)プロパン酸溶液(1mL)、炭酸セシウム溶液(200μL)および1,1’−ビス(ジフェニルホスフィノ)フェロセンパラジウム(II)ジクロリド・ジクロロメタン(3.56mg、4.33マイクロモル)を添加した。バイアルに栓をし、20秒間攪拌し、一定の保持時間を用いるバイオタージ・イニシエータ(400W)マイクロウェーブで10分間にわたり140℃で加熱した。中身を(メタノールで調節された)6mLのPL−チオールSPEカートリッジに移した。反応バイアルを500μLずつのメタノールで濯ぎ、その濯ぎ液をSPEカートリッジに移した。生成物を各々4mLのメタノールで溶出し、16x100mmの培養管に集めた。サンプルをザイマーク(Zymark)タブレットップ乾燥器にて35℃で3時間乾燥させた。次に、DMF(1mL)を各バイアルに加え、逆相HPLC:カラム:Waters Xbridge C18、19x200mm、5μm粒子;移動相A:水+20mM酢酸アンモニウム;移動相B:95:5 アセトニトリル:水+20mM酢酸アンモニウム;勾配:20分間にわたり15−100%Bとし、次に100%Bで5分間保持する;流速:20mL/分、に付して精製した。所望の生成物を含有するフラクションを集め、遠心式エバポレーションを介して乾燥させた。LC/MS 方法M:3.9分、M+1:374.4、正確な質量:373.2;1H NMR(500MHz、DMSO−d6)δ 7.44(d,J=7.0Hz,1H)、7.36(t,J=7.5Hz,1H)、7.26(t,J=7.5Hz,1H)、7.20(d,J=5.5Hz,3H)、6.99(d,J=8.2Hz,2H)、6.95(d,J=8.5Hz,1H)、6.87(d,J=7.9Hz,1H)、6.84(br.s.,1H)、5.11(s,2H)、3.79(s,3H)、3.49(br.s.,2H)、3.14(t,J=6.9Hz,4H)、2.19(s,3H)、2.02−1.95(m,2H)
N−{2−[({3−ブロモ−2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}アセトアミド
N−{2−[(1−{3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}エチル)アミノ]エチル}アセトアミド
1−(3−クロロ−4−((2−メチル−[1,1’−ビフェニル]−3−イル)メトキシ)フェニル)エタノン(20mg、0.057ミリモル)のTHF(2mL)中溶液に、N−アセチルエチレンジアミン(12.94mg、0.114ミリモル)およびテトラ−tert−ブチル オルトチタン酸エステル(0.050mL、0.143ミリモル)を添加した。得られた白色混合物をマイクロウェーブにて85℃で1時間加熱した。さらにテトラ−tert−ブチル オルトチタン酸エステル(0.050mL、0.143ミリモル)を加え、100℃で1時間加熱した。水素化ホウ素ナトリウム(6.47mg、0.171ミリモル)を、つづいてエタノール(2mL)を添加した。混合物を室温で2時間攪拌した。その粗物質をプレパラティブLC/MSを介して次の条件:カラム:Waters Xbridge C18、19x200mm、5μm粒子;移動相A:水+20mM酢酸アンモニウム;移動相B:95:5 アセトニトリル:水+20mM酢酸アンモニウム;勾配:20分間にわたり10−100%Bとし、次に100%Bで5分間保持する;流速:20mL/分で精製した。所望の生成物を含有するフラクションを集め、遠心式エバポレーションを介して乾燥させた。生成物の収量は12.6mgであり、LCMS分析により評価されるその純度は98%であった。1H NMR(500MHz、DMSO−d6)δ 7.77(br.s.,1H)、7.51(d,J=7.3Hz,1H)、7.49−7.43(m,2H)、7.43−7.35(m,2H)、7.35−7.24(m,5H)、7.21(d,J=7.6Hz,1H)、5.22(s,2H)、3.66(d,J=6.4Hz,1H)、3.14−2.99(m,2H)、2.42−2.28(m,2H)、2.23(s,3H)、1.77(s,3H)、1.26−1.18(m,3H)
(2S)−1−[(4−{[3−(2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル)−2−メチルフェニル]メトキシ}−3−(トリフルオロメチル)フェニル)メチル]ピペリジン−2−カルボン酸
4−((3−(2,3−ジヒドロベンゾ[b][1,4]ジオキシン−6−イル)−2−メチルベンジル)オキシ)−3−(トリフルオロメチル)ベンズアルデヒド(15mg、0.035ミリモル)のDMF(1.5mL)溶液を(S)−ピペリジン−2−カルボン酸(13.57mg、0.105ミリモル)と一緒に室温で1時間攪拌した。シアノ水素化ホウ素ナトリウム(6.60mg、0.105ミリモル)および3滴の酢酸(2.004μl、0.035ミリモル)を添加した。反応物を室温で一夜攪拌した。その粗物質をプレパラティブLC/MSを介して次の条件:カラム:XBridge C18、19x200mm、5μm粒子;移動相A:5:95 アセトニトリル:水+10mM 酢酸アンモニウム;移動相B:95:5 アセトニトリル:水+10mM 酢酸アンモニウム;勾配:15分間にわたって40−80%Bとし、次に100%Bで5分間保持する;流速:20mL/分で精製した。所望の生成物を含有するフラクションを集め、遠心式エバポレーションを介して乾燥させた。生成物の収量は14.3mgであり、LCMS分析により評価されるその純度は100%であった。1H NMR(500MHz、DMSO−d6)d 7.67−7.55(m,2H)、7.52−7.37(m,2H)、7.27(t,J=7.5Hz,1H)、7.18(d,J=7.3Hz,1H)、6.93(d,J=8.1Hz,1H)、6.79−6.73(m,2H)、5.28(s,2H)、4.29(s,4H)、3.87(d,J=13.2Hz,1H)、3.51(d,J=13.6Hz,3H)、2.86(br.s.,1H)、2.26−2.22(m,1H)、2.21(s,3H)、1.80(br.s.,1H)、1.70(d,J=9.2Hz,1H)、1.50(d,J=18.7Hz,3H)、1.37(br.s.,1H)
2−[({5−[(2−メチル−3−フェニルフェニル)メトキシ]チオフェン−2−イル}メチル)アミノ]エタン−1−オール
2−[({5−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−2−イル}メチル)アミノ]エタン−1−オール
N1−(2,6−ジメトキシ−4−((2−メチル−[1,1’−ビフェニル]−3−イル)メトキシ)ベンジル)−N1−メチルエタン−1,2−ジアミン
中間体190Aであるtert−ブチル (2−((2,6−ジメトキシ−4−((2−メチル−[1,1’−ビフェニル]−3−イル)メトキシ)ベンジル)(メチル)アミノ)エチル)カルバマート(0.6g、1.15ミリモル)をジエチルエーテル中0.5N塩酸(5mL)に溶かした。室温で1時間攪拌した。エーテルで希釈し、窒素をその反応物に10分間通した。溶媒をロータリーエバポレーションに付して除去した。該反応物を減圧下に一夜置いた。
1−(2−((2,6−ジメトキシ−4−((2−メチル−[1,1’−ビフェニル]−3−イル)メトキシ)ベンジル)(メチル)アミノ)エチル)−3−フェニルウレア
N−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)(メチル)アミノ]エチル}−2−オキソ−2H−クロメン−6−スルホンアミド
N−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)(メチル)アミノ]エチル}プロパ−2−エナミド
エチル (2E)−3−({2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)(メチル)アミノ]エチル}カルバモイル)プロパ−2−エノアート
N−{2−[({3−シアノ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}アセトアミド
シアン化銅(i)(18mg、0.201ミリモル)および3−ブロモ−4−((2−メチル−[1,1’−ビフェニル]−3−イル)メトキシ)ベンズアルデヒド(50mg、0.131ミリモル)をアルゴン下のDMF(1311μl)中で合わせた。密封し、120℃で72時間加熱した。濾過し、溶液を水素化トリアセトキシホウ素ナトリウム(84mg、0.394ミリモル)およびN−(2−アミノエチル)アセトアミド(26.8mg、0.263ミリモル)とDMF(657μl)中で直接合わせた。室温で一夜攪拌し、0.45μmのPVPFホワットマン(Whatman)シリンジフィルターを介して濾過した。その粗物質をプレパラティブLC/MSを介して次の条件:カラム:XBridge C18、19x200mm、5μm粒子;移動相A:5:95 アセトニトリル:水+10mM 酢酸アンモニウム;移動相B:95:5 アセトニトリル:水+10mM 酢酸アンモニウム;勾配:20分間にわたり35−75%Bとし、次に100%Bで5分間保持する;流速:20mL/分で精製した。所望の生成物を含有するフラクションを集め、遠心式エバポレーションを介して乾燥させた。生成物の収量は16.1mgであり、LCMS分析により評価されるその純度は91%であった。1H NMR(500MHz、DMSO−d6)δ 7.80(br.s.,1H)、7.69(s,1H)、7.63(d,J=8.4Hz,1H)、7.53−7.44(m,3H)、7.42−7.36(m,2H)、7.34−7.28(m,3H)、7.23(d,J=7.7Hz,1H)、5.33(s,2H)、3.66(s,2H)、3.38(d,J=11.7Hz,2H)、3.18−3.06(m,2H)、2.23(s,3H)、1.79(s,3H)
N−(2−((4−((3−(2,3−ジヒドロベンゾ[b][1,4]ジオキシン−6−イル)−2−メチルベンジル)オキシ)−2,5−ジフルオロベンジル)アミノ)エチル)アセトアミド
N−(2−アミノエチル)アセトアミド(12.37mg、0.121ミリモル)および4−((3−(2,3−ジヒドロベンゾ[b][1,4]ジオキシン−6−イル)−2−メチルベンジル)オキシ)−2,5−ジフルオロベンズアルデヒド(40mg、0.101ミリモル)の混合物をジクロロエタン(505μl)中で合わせた。固体は溶解しなかった。水素化トリアセトキシホウ素ナトリウム(42.8mg、0.202ミリモル)を加え、その混合物を室温で一夜攪拌した。大部分の固体が溶解した。LCMSは、生成物:不純物:出発物質:ジアルキル化物(1:1:5:2)の混合物を示唆した。10当量のN−(2−アミノエチル)アセトアミド(100mg、1ミリモル)およびシアノ水素化ホウ素ナトリウムを加え、2時間攪拌した。LCMSは所望の生成物だけを示した:その粗物質をプレパラティブLC/MSを介して次の条件:カラム:XBridge C18、19xmm、5μm粒子;移動相A:5:95 アセトニトリル:水+10mM 酢酸アンモニウム;移動相B:95:5 アセトニトリル:水+10mM 酢酸アンモニウム;勾配:15分間にわたって30−80%Bとし、次に100%Bで5分間保持する;流速:20mL/分で精製した。所望の生成物を含有するフラクションを集め、遠心式エバポレーションを介して乾燥させた。生成物の収量は29.6mgであり、LCMS分析により評価されるその純度は96%であった。1H NMR(500MHz、DMSO−d6)δ 7.79(br.s.,1H)、7.42(d,J=7.7Hz,1H)、7.36−7.23(m,3H)、7.19(d,J=7.0Hz,1H)、6.93(d,J=8.1Hz,1H)、6.78(s,1H)、6.76(d,J=8.1Hz,1H)、5.21(s,2H)、4.29(s,4H)、3.12(q,J=6.1Hz,2H)、2.21(s,3H)、1.92(br.s.,2H)、1.82−1.74(m,3H);2本の水素のピークの喪失はDMSOまたは水のピークの下にあると思われる。
N−{2−[({2−メトキシ−6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)アミノ]エチル}アセトアミド
シアノ水素化ホウ素ナトリウム(20mg、0.318ミリモル)、N−(2−アミノエチル)アセトアミド(25mg、0.245ミリモル)、および2−メトキシ−6−((2−メチル−[1,1’−ビフェニル]−3−イル)メトキシ)ニコチンアルデヒド粗製物(20mg、0.060ミリモル)をDMF(2mL)および酢酸(0.100mL)中にて1:00pmで合わせた。室温で一夜攪拌した。LC/MSは生成物:3.5分、M+1=420.3、EM=419.2であることを示した。その粗物質をプレパラティブLC/MSを介して次の条件:カラム:XBridge C18、19x200mm、5μm粒子;移動相A:5:95 アセトニトリル:水+10mM 酢酸アンモニウム;移動相B:95:5 アセトニトリル:水+10mM 酢酸アンモニウム;勾配:15分間にわたって35−75%Bとし、次に100%Bで5分間保持する;流速:20mL/分で精製した。所望の生成物を含有するフラクションを集め、遠心式エバポレーションを介して乾燥させた。生成物の収量は11.0mgであり、LCMS分析により評価されるその純度は96%であった。1H NMR(600MHz、DMSO−d6)δ 7.80(br.s.,1H)、7.62(d,J=8.1Hz,1H)、7.48−7.43(m,3H)、7.41−7.36(m,1H)、7.31(d,J=7.3Hz,2H)、7.26(t,J=7.5Hz,1H)、7.18(d,J=7.7Hz,1H)、6.42(d,J=7.7Hz,1H)、5.41(s,2H)、3.89(s,3H)、3.58(s,1H)、3.18−3.05(m,2H)、2.22(s,3H)、1.82−1.72(m,3H);ジアミノアセトアミドのメチレンは2.5ppmでDMSOの下にあると考えられた。
(2R)−2−{[(4−{[3−(3−フルオロ−5−メトキシフェニル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル]アミノ}プロパン酸
中間体227B、(S)−2−(((3’−ブロモ−3,5−ジメトキシ−2’−メチル−[1,1’−ビフェニル]−4−イル)メチル)アミノ)プロパン酸(714mg、1.8ミリモル)をジオキサン(35mL)に溶かした。炭酸セシウム(1.7gm、5.3ミリモル)を水(3.5mL)に溶かした。(3−フルオロ−5−メトキシフェニル)ボロン酸(18mg、0.1ミリモル)を秤量し、(S)−2−(((3’−ブロモ−3,5−ジメトキシ−2’−メチル−[1,1’−ビフェニル]−4−イル)メチル)アミノ)プロパン酸溶液(1mL、0.052ミリモル)、炭酸セシウム溶液(100μL)および1,1’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム(II)ジクロリド・ジクロロメタン複合体(4.25mg、0.0052ミリモル)を含む0.5−2mLのマイクロウェーブバイアルに入れた。反応物を、予め20秒間攪拌し、一定の保持時間を用いるバイオタージ・イニシエータ(登録商標)(Biotage Initiator)(400W)マイクロウェーブで15分間にわたり150℃で加熱した。中身を(メタノールで調節された)6mLのMP−チオールSPEカートリッジに移した。反応バイアルを2x500μLのメタノールで濯ぎ、その濯ぎ液をSPEカートリッジに移した。生成物を4mLのメタノールで溶出した。サンプルをザイマーク(Zymark)タブレットップ乾燥器にて40℃で1時間ブローダウンさせた。DMF(1mL)を各バイアルに加えた。中身を16x48mmのネジ式バイアルに移した。培養管を各々500μLのDMFで濯いだ。その粗物質をプレパラティブLC/MSを介して次の条件:カラム:XBridge C18、19xmm、5μm粒子;移動相A:5:95 メタノール:水+10mM 酢酸アンモニウム;移動相B:95:5 メタノール:水+10mM 酢酸アンモニウム;勾配:18分間にわたって10−100%Bとし、次に100%Bで7分間保持する;流速:20mL/分で精製した。所望の生成物を含有するフラクションを集め、遠心式エバポレーションを介して乾燥させた。生成物の収量は8.1mgであり、LCMS分析により評価されるその純度は100%であった。1H NMR(500MHz、DMSO−d6)d 7.52(d,J=7.9Hz,1H)、7.29(d,J=7.3Hz,1H)、7.24(d,J=7.9Hz,1H)、6.86(d,J=11.3Hz,1H)、6.76−6.68(m,2H)、6.44(s,2H)、5.20(s,2H)、3.97(br.s.,2H)、3.82(d,J=3.7Hz,9H)、3.05(d,J=6.7Hz,1H)、2.23(s,3H)、1.27(d,J=6.7Hz,3H)
3−[3−(4−{[(2−ヒドロキシエチル)アミノ]メチル}−3,5−ジメトキシフェノキシメチル)−2−メチルフェニル]フェノール
4−((3−ブロモ−2−メチルベンジル)オキシ)−2,6−ジメトキシベンズアルデヒド(310mg、850マイクロモル)のDCE(8.5mL)中溶液を調製した。別に、2−アミノエタノール(77μL、1.3ミリモル)のDCE(7.5mL)中溶液を調製した。各溶液のアリコート(0.5mL)を反応バイアルに入れた。酢酸(2.86μl、50.0マイクロモル)を該バイアルに加え、栓をし、40℃で1時間振盪させた。溶媒をザイマークタブレットップ乾燥器にて40℃で1時間にわたって除去した。トルエン(0.5mL)を加え、溶媒をザイマークタブレットップ乾燥器にて40℃で1時間にわたって除去した。水素化トリアセトキシホウ素テトラメチルアンモニウム(672mg、2.6ミリモル)のDCE(17mL)中溶液を調製し、1mLを該反応バイアルに添加した。該反応バイアルに栓をし、室温で一夜震盪させた。中身を(メタノールで調節された)6mLのPL−SO3HSPEカートリッジに移した。反応バイアルを500μLのメタノールで濯ぎ、その濯ぎ液をSPEカートリッジに移した。カートリッジを4mLのメタノールで洗浄した。生成物をメタノール中1Nアンモニア(4mL)で溶出した。溶媒をザイマークタブレットップ乾燥器にて35℃で1時間にわたって除去した。残渣をジオキサン(1mL)に溶かし、(3−ヒドロキシフェニル)ボロン酸(13.8mg、0.1ミリモル)含有のバイアルに移した。炭酸セシウム(831mg、2.6ミリモル)の水(1.7mL)中溶液(0.1mL)および固体の1,1’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム(II)ジクロリド・ジクロロメタン複合体(4.08mg、0.005ミリモル)を添加した。反応物を100℃で攪拌しながら一夜加熱した。反応体の中身を(メタノールで調節された)6mLのPL−チオールSPEカートリッジに移した。反応バイアルをメタノール(0.5mL)で濯ぎ、その濯ぎ液をSPEカートリッジに添加した。生成物をメタノール(4mL)で溶出した。溶媒をザイマークタブレットップ乾燥器にて35℃で2時間にわたって除去した。その粗物質をプレパラティブLC/MSを介して次の条件:カラム:XBridge C18、19xmm、5μm粒子;移動相A:5:95 メタノール:水+10mM 酢酸アンモニウム;移動相B:95:5 メタノール:水+10mM 酢酸アンモニウム;勾配:15分間にわたって50−90%Bとし、次に100%Bで5分間保持する;流速:20mL/分で精製した。所望の生成物を含有するフラクションを集め、遠心式エバポレーションを介して乾燥させた。生成物の収量は2.4mgであり、LCMS分析により評価されるその純度は96%であった。1H NMR(500MHz、DMSO−d6)δ 7.47(d,J=7.3Hz,1H)、7.30−7.22(m,2H)、7.18(d,J=7.3Hz,1H)、6.78(d,J=8.2Hz,1H)、6.71(d,J=7.3Hz,1H)、6.68(br.s.,1H)、6.38(s,2H)、5.16(s,2H)、3.91(s,1H)、3.78(s,6H)、3.67(br.s.,2H)、3.47−3.43(m,2H)、2.56−2.53(m,2H)、2.22(s,3H)
(3S)−3−ヒドロキシ−4−[({5−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−2−イル}メチル)アミノ]ブタン酸
N−(2−{[(3−クロロ−4−{[2−メチル−3−(チオフェン−3−イル)フェニル]メトキシ}フェニル)メチル]アミノ}エチル)アセトアミド
(3−((2−クロロ−4−ホルミルフェノキシ)メチル)−2−メチルフェニル)ボロン酸(352mg、1.2ミリモル)のジオキサン(16mL)中溶液を窒素で脱気した。リン酸三カリウム(613mg、2.9ミリモル)を水(4mL)に溶かし、窒素で脱気した。反応バイアルに2−ブロモチオフェン(23.6mg、0.144ミリモル)、(3−((2−クロロ−4−ホルミルフェノキシ)メチル)−2−メチルフェニル)ボロン酸溶液(1mL)、リン酸三カリウム溶液(250μL)および固形の第二世代XPhosプレ触媒(2.84mg、3.61マイクロモル、CAS番号1310584−14−5)を充填した。該バイアルを密封し、室温で一夜震盪させた。反応混合物を(メタノールで調節された)6mLのPL−チオールSPEカートリッジに移した。反応バイアルをメタノール(500μL)で濯ぎ、その濯ぎ液を該SPEカートリッジに移した。中間体の生成物をメタノール(4mL)で溶出し、溶媒をザイマークタブレットップ乾燥器にて40℃で3時間にわたって除去した。中間体をさらに精製することなく用いた。
方法A:カラム:Waters BEH C18、2.0x50mm、1.7μm粒子;移動相A:5:95 アセトニトリル:水+10mM酢酸アンモニウム;移動相B:95:5 アセトニトリル:水+10mM酢酸アンモニウム;温度:40℃;勾配:0%Bで0.5分間保持し、4分間にわたって0−100%Bとし、次に100%Bで0.5分間保持する;流速:1mL/分
式(I)の化合物の、PD−L1と結合する能力を、PD−1/PD−L1のホモジニアス時間分解蛍光(HTRF)結合アッセイを用いて研究した。
すべての結合実験を、0.1%(容量)ウシ血清アルブミンおよび0.05%(v/v)ツィーン(Tween)20を補足したdPBSからなるHTRFアッセイバッファー中で行った。PD−1−Ig/PD−L1−His結合アッセイでは、阻害剤をPD−L1−His(最終10nM)と一緒にアッセイバッファー(4μl)中で15分間プレインキュベートし、つづいてPD−1−Ig(最終20nM)/アッセイバッファー(1μl)を加え、さらに15分間インキュベートした。ヒト、イヌまたはマウスのいずれかからのPD−L1を用いた。HTRF検出は、ユーロピウムクリプテート(crypate)標識抗Ig(最終1nM)およびアロフィコシアニン(APC)標識抗His(最終20nM)を用いて達成された。抗体をHTRF検出バッファーに希釈し、その5μlを結合反応の上部に分配した。反応混合物を30分間で平衡とし、シグナル(665nm/620nmの割合)をエン・ビジョン(EnVision)蛍光光度計を用いて得た。さらなる結合アッセイをPD−1−Ig/PD−L2−His(各々、20および5nM)、CD80−His/PD−L1−Ig(各々、100および10nM)およびCD80−His/CTLA4−Ig(各々、10および5nM)の間で確立した。ビオチニル化した配列番号:71と、ヒトPD−L1−Hisの間の競合実験を次のように行った。阻害剤をPD−L1−His(最終10nM)と一緒にアッセイバッファー(4μl)中で60分間プレインキュベートし、つづいてビオチニル化した配列番号:71(最終0.5nM)/アッセイバッファー(1μl)を加えた。結合を30分間で平衡とし、つづいてユーロピウムクリプテート標識ストレプトアビジン(Strepatavidin)(最終2.5pM)およびAPC標識抗His(最終20nM)/HTRFバッファー(5μl)を添加した。反応を30分間で平衡とし、シグナル(665nm/620nmの割合)をエン・ビジョン蛍光光度計を用いて得た。
Claims (12)
- 式(I):
環Bはフェニルまたはチエニルであり;
環Aは
ここで、A’’はCHまたはNであって、R1およびR2の一方はQであり、R1およびR2の他方はRbであり;
R3はHまたは−CH2C(O)OHであり;
R4は−NHCH2CH2NHC(O)CH3であり;
Qは
(i)
(ii)−CH2NH−Rxであり、ここでRxはシクロブチル、−(CH2)シクロブチル(2個のフッ素原子で置換されてもよい)、シクロプロピル、ヒドロキシシクロペンチル、シクロペンチル、シクロヘキシル、ヒドロキシシクロヘキシル、ヒドロキシテトラヒドロフラニル、N−メチルピペリジニル、N−エチルピペリジニル、ヒドロキシテトラヒドロチエニル、または
(iii)−CH2NRa−CRaRa−(CH2)n−Rxであり、ここでRxは水素、アゼチジノニル、シクロヘキシル、ヒドロキシフェニル、ピロリジノニル、ピペリジノニル、ピペラジノニル、モルホリニル、イミダゾリル、N−メチルイミダゾリル、−C(O)(モルホリニル)、ピペラジニル(メチル、フェニル、アルコキシフェニル、ヒドロキシフェニル、ピリジニル、ピリミジニル、または−C(O)OC(CH3)3基で置換されてもよい)、ピロリジニル、ピリジニル、チオモルホリンジオキシド、またはメチルトリアゾリルであるか;あるいは
(iv)−CHRa−NRa−CRaRa−(CHRa)n−Rxであり、ここでRxは−OH、−OCH3、−C(O)OH、−OPh、−CH(CO2H)−NHC(O)CH3、−O(CH2)2O(CH2)2OH、−O(CH2)2O(CH2)2O(CH2)2OH、−O(CH2)2O(CH2)2O(CH2)2O(CH2)2CO2H、−O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2CO2H、−C(O)CH3、−C(O)NRaRa、−C(O)NRqRq、−N(CH3)2、−NHC(O)CH3、−NHC(O)Ph、−C(O)NH(CH2)2−イミダゾリル、NHC(O)OCH2Ph、−N(CH3)S(O)2CH3、−NHC(O)CH=CH2、−NHC(O)CH=CHC(O)CH2CH3、−NHS(O)2CH3、または
Raは、各々、独立して、H、−CH(OH)CH3、OH、−(CH2)2OH、−CH2OH、−(CH2)2NH2、−CH2CH3、または−CH3であるか;
または、同じ炭素原子上にある2個のRa基が4員、5員または6員の炭素環式環、N−メチルピペリジニル環、またはピラニル環を形成することができ;
Rbは、各々、独立して、H、F、Cl、Br、−CF3、−CN、CH3、または−OCH3であり;
Rcは、各々、独立して、−OCH3、−OH、−OCH2CH3、−O(CH2)OCH3、−OCH2CH=CH2、−O(CH2)2CH3、−O(CH2)2−モルホリニル、またはFであるか;
または、隣接する炭素原子に結合した2個のRcは−O−(CH2)v−O−を形成し、ここでvは1または2であり;
Rqは、各々、水素、−CH2C(O)NHCH2CO2H、−(CH2)C(O)NHCH(CO2H)CH2CH(CH3)2、−CH(Bn)−C(O)NHCH(CO2H)(CH2)3NHC(NH)NH2より選択され;
mは0または1であり;
nは0、1、2または3であり;
pは、各々、独立して、0または1であり;および
qは0、1または2である]
で示される化合物またはその塩。 - 環Aが
- Qが
- Qが−CH2NH−Rxであって、ここでRxがシクロブチル、−(CH2)シクロブチル(2個のフッ素原子で置換されてもよい)、シクロプロピル、ヒドロキシシクロペンチル、シクロペンチル、シクロヘキシル、ヒドロキシシクロヘキシル、ヒドロキシテトラヒドロフラニル、N−メチルピペリジニル、N−エチルピペリジニル、ヒドロキシテトラヒドロチエニル、または
- Qが−CH2NRa−CRaRa−(CH2)n−Rxであって、ここでRxが水素、アゼチジノニル、シクロヘキシル、ヒドロキシフェニル、ピロリジノニル、ピペリジノニル、ピペラジノニル、モルホリニル、イミダゾリル、N−メチルイミダゾリル、−C(O)(モルホリニル)、ピペラジニル(メチル、フェニル、アルコキシフェニル、ヒドロキシフェニル、ピリジニル、ピリミジニル、または−C(O)OC(CH3)3基で置換されてもよい)、ピロリジニル、ピリジニル、チオモルホリンジオキシド、またはメチルトリアゾリルである、請求項2に記載の化合物またはその塩。
- Qが−CHRa−NRa−CRaRa−(CHRa)n−Rxであって、ここでRxが−OH、−OCH3、−C(O)OH、−OPh、−CH(CO2H)−NHC(O)CH3、−O(CH2)2O(CH2)2OH、−O(CH2)2O(CH2)2O(CH2)2OH、−O(CH2)2O(CH2)2O(CH2)2O(CH2)2CO2H、−O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2O(CH2)2CO2H、−C(O)CH3、−C(O)NRaRa、−C(O)NRqRq、−N(CH3)2、−NHC(O)CH3、−NHC(O)Ph、−C(O)NH(CH2)2−イミダゾリル、NHC(O)OCH2Ph、−N(CH3)S(O)2CH3、−NHC(O)CH=CH2、−NHC(O)CH=CHC(O)CH2CH3、−NHS(O)2CH3、または
- (S)−1−(2,6−ジメトキシ−4−((2−メチルビフェニル−3−イル)メトキシ)ベンジル)ピペリジン−2−カルボン酸(1);1−(4−((2’−フルオロ−2−メチルビフェニル−3−イル)メトキシ)ベンジル)アゼチジン(3);N−{2−[({3−ブロモ−2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}アセトアミド(4);({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)[2−メチル−1−(4−メチルピペラジン−1−イル)プロパン−2−イル]アミン(5);N−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}−N−メチルメタンスルホンアミド(6);1−({3−ブロモ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−カルボン酸(7);2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−1−(モルホリン−4−イル)エタン−1−オン(8);({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)[2−(4−メチルピペラジン−1−イル)エチル]アミン(9);1−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}ピペリジン−2−オン(10);1−{3−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロピル}ピロリジン−2−オン(11);4−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}ピペラジン−2−オン(12);({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)[2−(モルホリン−4−イル)エチル]アミン(13);1−({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−カルボン酸(14);2−[メチル({3−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]酢酸(15);N−({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)−1−エチルピペリジン−3−アミン(16);1−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}ピロリジン−2−オン(17);(2S,4R)−4−(アセチルオキシ)−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピロリジン−2−カルボン酸(18);N−(2−ヒドロキシエチル)−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−4−カルボキシアミド(19);({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)[1−(5−メチル−4H−1,2,4−トリアゾール−3−イル)エチル]アミン(20);N−{2−[({3−ブロモ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}アセトアミド(21);(2S,4R)−1−({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)−4−メトキシピロリジン−2−カルボン酸(22);N−{3−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロピル}アセトアミド(23);(1R,2R)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]シクロヘキサン−1−オール(24);N−({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)−1−メチルピペリジン−3−アミン(25);(2S)−1−({2−メトキシ−3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−カルボン酸(26);(2S)−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)−2−(プロパ−2−エン−1−イル)ピロリジン−2−カルボン酸(27);3−[({3−ブロモ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパンアミド(28);3−[({3−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパンアミド(29);4−({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)モルホリン−3−カルボン酸(30);3−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]ブタン酸(31);1−({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−4−カルボン酸(32);(2R)−1−({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−カルボン酸(33);(2S)−1−({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−カルボン酸(34);2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−N,N−ジメチルアセトアミド(35);N−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}アセトアミド(36);1−({2−メトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−カルボン酸(37);1−({3−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アゼチジン(38);(2S,4R)−4−メトキシ−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピロリジン−2−カルボン酸(39);1−({2,6−ジメチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−カルボン酸(40);1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アゼパン−2−カルボン酸(41);2−[1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−イル]酢酸(42);1−{3−[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロピル}ピロリジン−2−オン(43);N−{2−[(1−{3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}エチル)アミノ]エチル}アセトアミド(44);2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)(メチル)アミノ]酢酸(45);3−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパンアミド(46);(2S)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン酸(47);1−({3−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−カルボン酸(48);1−({3−フルオロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−カルボン酸(49);(2R,4R)−4−ヒドロキシ−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピロリジン−2−カルボン酸(50);(2R,4S)−4−ヒドロキシ−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピロリジン−2−カルボン酸(51);1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−カルボン酸(52);1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−3−カルボン酸(53);(3R)−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−3−カルボン酸(54);(2R,4R)−4−メチル−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピロリジン−2−カルボン酸(55);(2S)−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−カルボン酸(56);1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−4−カルボン酸(57);(2R)−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−カルボン酸(58);(2S)−1−({4−メチル−3−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−カルボン酸(59);1−{3−[({3−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロピル}ピロリジン−2−オン(60);1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)−1,2,5,6−テトラヒドロピリジン−3−カルボン酸(63);2−[({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−2−メチルプロパン酸(64);N−{2−[({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}アセトアミド(65);1−({3−ブロモ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アゼチジン(66);N−{2−[({2−メトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}アセトアミド(67);N−({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)シクロブタナミン(68);N−{2−[({2,6−ジメチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}アセトアミド(69);N−{2−[(1−{3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}エチル)アミノ]エチル}アセトアミド(70);(2S)−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピロリジン−2−カルボン酸(71);1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピロリジン−2−カルボン酸(72);(1R,2R)−2−[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]シクロヘキサン−1−オール(73);1−({4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピペリジン−2−カルボン酸(74);(2R)−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピロリジン−2−カルボン酸(75);5−{[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]メチル}ピロリジン−2−オン(76);(2S)−2−[({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン
酸(77);(2R)−2−[({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン酸(78);N−{2−[({3−フルオロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}アセトアミド(79);(2S)−2−[({2−メトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン酸(80);(2S)−2−[({3−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン酸(81);3−[({2−メトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパンアミド(82);1−({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アゼチジン(83);3−[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]ブタン酸(84);(2R)−2−[メチル({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン酸(85);3−[({2,6−ジメチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパンアミド(86);N−{2−[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}アセトアミド(87);N−{2−[({4−メチル−3−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}アセトアミド(88);[(2S)−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)ピロリジン−2−イル]メタノール(89);(2S)−1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アゼチジン−2−カルボン酸(90);5−{[({4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]メチル}ピロリジン−2−オン(91);5−{[({4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]メチル}ピロリジン−2−オン(92);(2S)−2−[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン酸(93);2−[メチル({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]酢酸(94);3−[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパンアミド(95);(2R)−2−[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン酸(96);1−({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アゼチジン(97);1−({2−メトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アゼチジン(98);1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アゼチジン(99);1−({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アゼチジン(100);2−[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エタン−1−オール(102);2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エタン−1−オール(103);(2S)−2−[({3−ブロモ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン酸(104);(2R)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン酸(105);(2R)−2−{[(2,6−ジメトキシ−4−{[3−(3−メトキシフェニル)−2−メチルフェニル]メトキシ}フェニル)メチル]アミノ}プロパン酸(106);(2R)−2−{[(4−{[3−(3−フルオロ−5−メトキシフェニル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル]アミノ}プロパン酸(107);(2R)−2−{[(4−{[3−(2H−1,3−ベンゾジオキソール−5−イル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル]アミノ}プロパン酸(108);2−(6−((2−メチル−[1,1’−ビフェニル]−3−イル)メトキシ)−3,4−ジヒドロイソキノリン−2(1H)−イル)酢酸(2);N−[2−({5−[(2−メチル−3−フェニルフェニル)メトキシ]−1,2,3,4−テトラヒドロナフタレン−1−イル}アミノ)エチル]アセトアミド(61);N−[2−({6−[(2−メチル−3−フェニルフェニル)メトキシ]−1,2,3,4−テトラヒドロナフタレン−1−イル}アミノ)エチル]アセトアミド(62);または6−[(2−メチル−3−フェニルフェニル)メトキシ]−1,2,3,4−テトラヒドロイソキノリン(101)より選択される、請求項1に記載の化合物またはその塩。 - N−[2−({4−[(2−メチル−3−フェニルフェニル)メトキシ]−2,3−ジヒドロ−1H−インデン−1−イル}アミノ)エチル]アセトアミド;
4−{[({3−メチル−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]メチル}アゼチジン−2−オン;
(3S)−4−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−3−ヒドロキシブタン酸;
(2S)−1−[(4−{[3−(2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル)−2−メチルフェニル]メトキシ}−3−(トリフルオロメチル)フェニル)メチル]ピペリジン−2−カルボン酸;
N−(2−{[(4−{[3−(2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル)−2−メチルフェニル]メトキシ}−3−(トリフルオロメチル)フェニル)メチル]アミノ}エチル)アセトアミド;
(3S)−4−{[(4−{[3−(2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル)−2−メチルフェニル]メトキシ}−3−(トリフルオロメチル)フェニル)メチル]アミノ}−3−ヒドロキシブタン酸;
(2R,3S)−2−[({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−3−ヒドロキシブタン酸;
(2R,3R)−2−[({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−3−ヒドロキシブタン酸;
(2S,3S)−2−[({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−3−ヒドロキシブタン酸;
2−[({5−[(2−メチル−3−フェニルフェニル)メトキシ]チオフェン−2−イル}メチル)アミノ]エタン−1−オール;
2−[({5−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−2−イル}メチル)アミノ]エタン−1−オール;
{1−[({5−[(2−メチル−3−フェニル フェニル)メトキシ]ピリジン−2−イル}メチル)アミノ]シクロペンチル}メタノール;
メチル({5−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−2−イル}メチル)アミン;
5−{[({5−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−2−イル}メチル)アミノ]メチル}ピロリジン−2−オン;
2−(3,5−ジメトキシ−4−{[(ピリジン−2−イルメチル)アミノ]メチル}フェノキシメチル)−6−フェニルベンゾニトリル;
2−{4−[(シクロプロピルアミノ)メチル]−3,5−ジメトキシフェノキシメチル}−6−フェニルベンゾニトリル;
2−{3,5−ジメトキシ−4−[(3−メチルピペリジン−1−イル)メチル]フェノキシメチル}−6−フェニルベンゾニトリル;
2−[3,5−ジメトキシ−4−({[2−(ピロリジン−1−イル)エチル]アミノ}メチル)フェノキシメチル]−6−フェニルベンゾニトリル;
2−{4−[(4−ヒドロキシピペリジン−1−イル)メチル]−3,5−ジメトキシフェノキシメチル}−6−フェニルベンゾニトリル;
2−[3,5−ジメトキシ−4−(モルホリン−4−イルメチル)フェノキシメチル]−6−フェニルベンゾニトリル;
2−(3,5−ジメトキシ−4−{[(ピリジン−3−イルメチル)アミノ]メチル}フェノキシメチル)−6−フェニルベンゾニトリル;
2−(3,5−ジメトキシ−4−{[(ピリジン−4−イルメチル)アミノ]メチル}フェノキシメチル)−6−フェニルベンゾニトリル;
2−[4−({[(3−ヒドロキシフェニル)メチル]アミノ}メチル)−3,5−ジメトキシフェノキシメチル]−6−フェニルベンゾニトリル;
2−[4−({[(2−ヒドロキシフェニル)メチル]アミノ}メチル)−3,5−ジメトキシフェノキシメチル]−6−フェニルベンゾニトリル;
2−[4−({[(4−ヒドロキシフェニル)メチル]アミノ}メチル)−3,5−ジメトキシフェノキシメチル]−6−フェニルベンゾニトリル;
2−{4−[(シクロブチルアミノ)メチル]−3,5−ジメトキシフェノキシメチル}−6−フェニルベンゾニトリル;
2−{4−[(シクロペンチルアミノ)メチル]−3,5−ジメトキシフェノキシメチル}−6−フェニルベンゾニトリル;
2−{4−[(シクロヘキシルアミノ)メチル]−3,5−ジメトキシフェノキシメチル}−6−フェニルベンゾニトリル;
2−[3,5−ジメトキシ−4−({[3−(2−オキソピロリジン−1−イル)プロピル]アミノ}メチル)フェノキシメチル]−6−フェニルベンゾニトリル;
2−(3,5−ジメトキシ−4−{[(プロパン−2−イル)アミノ]メチル}フェノキシメチル)−6−フェニルベンゾニトリル;
N−{2−[({4−[(2−シアノ−3−フェニルフェニル)メトキシ]−2,6−ジメトキシフェニル}メチル)アミノ]エチル}アセトアミド;
2−[4−({[2−(ジメチルアミノ)エチル]アミノ}メチル)−3,5−ジメトキシフェノキシメチル]−6−フェニルベンゾニトリル;
2−(3,5−ジメトキシ−4−{[(2−メトキシエチル)アミノ]メチル}フェノキシメチル)−6−フェニルベンゾニトリル;
2−(4−{[(2−ヒドロキシエチル)アミノ]メチル}−3,5−ジメトキシフェノキシメチル)−6−フェニルベンゾニトリル;
2−[4−({[1−(ヒドロキシメチル)シクロペンチル]アミノ}メチル)−3,5−ジメトキシフェノキシメチル]−6−フェニルベンゾニトリル;
2−(4−{[(4−ヒドロキシシクロヘキシル)アミノ]メチル}−3,5−ジメトキシフェノキシメチル)−6−フェニルベンゾニトリル;
3−[({4−[(2−シアノ−3−フェニルフェニル)メトキシ]−2,6−ジメトキシフェニル}メチル)アミノ]プロパンアミド;
2−{3,5−ジメトキシ−4−[(メチルアミノ)メチル]フェノキシメチル}−6−フェニルベンゾニトリル;
2−[3,5−ジメトキシ−4−({[2−(ピリジン−2−イル)エチル]アミノ}メチル)フェノキシメチル]−6−フェニルベンゾニトリル;
2−{3,5−ジメトキシ−4−[(2−メチルピロリジン−1−イル)メチル]フェノキシメチル}−6−フェニルベンゾニトリル;
2−{4−[(4−アセチルピペラジン−1−イル)メチル]−3,5−ジメトキシフェノキシメチル}−6−フェニルベンゾニトリル;
2−[3,5−ジメトキシ−4−(ピロリジン−1−イルメチル)フェノキシメチル]−6−フェニルベンゾニトリル;
2−(4−{[3−(ヒドロキシメチル)ピペリジン−1−イル]メチル}−3,5−ジメトキシフェノキシメチル)−6−フェニルベンゾニトリル;
N−[(3S)−1−({4−[(2−シアノ−3−フェニルフェニル)メトキシ]−2,6−ジメトキシフェニル}メチル)ピロリジン−3−イル]アセトアミド;
2−[4−(アゼチジン−1−イルメチル)−3,5−ジメトキシフェノキシメチル]−6−フェニルベンゾニトリル;
2−{4−[(4−アセチル−1,4−ジアゼパン−1−イル)メチル]−3,5−ジメトキシフェノキシメチル}−6−フェニルベンゾニトリル;
2−(4−{[エチル(ピリジン−4−イルメチル)アミノ]メチル}−3,5−ジメトキシフェノキシメチル)−6−フェニルベンゾニトリル;
2−(4−{[(2S)−2−(ヒドロキシメチル)ピロリジン−1−イル]メチル}−3,5−ジメトキシフェノキシメチル)−6−フェニルベンゾニトリル;
2−{4−[(2,5−ジメチルピロリジン−1−イル)メチル]−3,5−ジメトキシフェノキシメチル}−6−フェニルベンゾニトリル;
2−{4−[(3−ヒドロキシピペリジン−1−イル)メチル]−3,5−ジメトキシフェノキシメチル}−6−フェニルベンゾニトリル;
1−({4−[(2−シアノ−3−フェニルフェニル)メトキシ]−2,6−ジメトキシフェニル}メチル)ピペリジン−3−カルボン酸;
(2S)−1−({4−[(2−シアノ−3−フェニルフェニル)メトキシ]−2,6−ジメトキシフェニル}メチル)ピロリジン−2−カルボキシアミド;
(2S)−1−({4−[(2−シアノ−3−フェニルフェニル)メトキシ]−2,6−ジメトキシフェニル}メチル)ピペリジン−2−カルボン酸;
(6S)−5−({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)−1,2,5−トリアザスピロ[2.4]ヘプタ−1−エン−6−カルボン酸;
{2−[2−(2−アミノエトキシ)エトキシ]エチル}({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミン;
2−(2−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エトキシ}エトキシ)エタン−1−オール;
({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)({2−[4−(2−メトキシフェニル)ピペラジン−1−イル]エチル})アミン;
({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)({2−[4−(ピリジン−2−イル)ピペラジン−1−イル]エチル})アミン;
({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)({2−[4−(ピリミジン−2−イル)ピペラジン−1−イル]エチル})アミン;
tert−ブチル 4−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}ピペラジン−1−カルボキシラート;
4−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}−1λ6,4−チオモルホリン−1,1−ジオン;
ベンジル N−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}カルバマート;
({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)[3−(4−メチルピペラジン−1−イル)プロピル]アミン;
({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)[3−(モルホリン−4−イル)プロピル]アミン;
({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)[3−(1H−イミダゾール−1−イル)プロピル]アミン;
4−{[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]メチル}アゼチジン−2−オン;
3−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−N−[2−(1H−イミダゾール−4−イル)エチル]プロパンアミド;
2−({3−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロピル}(2−ヒドロキシエチル)アミノ)エタン−1−オール;
({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)(3−フェノキシプロピル)アミン;
4−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−2−ヒドロキシブタン酸;
3−(4−{3−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロピル}ピペラジン−1−イル)フェノール;
[2−(ベンジルオキシ)エチル]({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミン;
1−{2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}−5,8,11−トリオキサ−2−アザトリデカン−13−オール;
1−{2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}−5,8,11,14,17,20−ヘキサオキサ−2−アザトリコサン−23−オン酸;
1−{2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}−5,8,11,14−テトラオキサ−2−アザヘプタデカン−17−オン酸;
(2S)−5−カルバミミダミド−2−[(2R)−2−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]アセトアミド}−3−フェニルプロパンアミド]ペンタノン酸;
2−(2−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]アセトアミド}アセトアミド)酢酸;
(2S)−5−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−2−アセトアミドペンタノン酸;
[(3,3−ジフルオロシクロブチル)メチル]({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミン;
(シクロブチルメチル)({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミン;
(2S)−2−(2−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]アセトアミド}アセトアミド)−4−メチルペンタノン酸;
(2−アミノエチル)({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)メチルアミン;
3−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)(メチル)アミノ]エチル}−1−フェニルウレア;
N−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)(メチル)アミノ]エチル}−2−オキソ−2H−クロメン−6−スルホンアミド;
N−{2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)(メチル)アミノ]エチル}プロパ−2−エナミド;
エチル (2E)−3−({2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)(メチル)アミノ]エチル}カルバモイル)プロパ−2−エノアート;
(6S)−5−({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)−1,2,5−トリアザスピロ[2.4]ヘプタ−1−エン−6−カルボン酸;
2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−2−(ヒドロキシメチル)プロパン−1,3−ジオール;
(3S)−4−[({3−クロロ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−3−ヒドロキシブタン酸;
N−{2−[({3−シアノ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エチル}アセトアミド;
N−(2−{[(4−{[3−(2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル)−2−メチルフェニル]メトキシ}−2,5−ジフルオロフェニル)メチル]アミノ}エチル)アセトアミド;
(3S)−4−{[(4−{[3−(2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル)−2−メチルフェニル]メトキシ}−2,5−ジフルオロフェニル)メチル]アミノ}−3−ヒドロキシブタン酸;
(2S)−1−[(4−{[3−(2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル)−2−メチルフェニル]メトキシ}−2,5−ジフルオロフェニル)メチル]ピペリジン−2−カルボン酸;
N−{2−[({2−メトキシ−6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)アミノ]エチル}アセトアミド;
5−(アゼチジン−1−イルメチル)−2−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン;
N−({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)シクロブタナミン;
N−({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)シクロペンタンアミン;
1−{3−[({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)アミノ]プロピル}ピロリジン−2−オン;
({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)[2−(ピリジン−2−イル)エチル]アミン;
2−[(2−メチル−3−フェニルフェニル)メトキシ]−5−(ピロリジン−1−イルメチル)ピリジン;
[(2S)−1−({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)ピロリジン−2−イル]メタノール;
(2S)−1−({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)ピペリジン−2−カルボン酸;
1−({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)ピペリジン−3−カルボン酸;
[1−({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)ピペリジン−3−イル]メタノール;
1−({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)ピペリジン−4−オール;
2−[(2−メチル−3−フェニルフェニル)メトキシ]−5−[(2−メチルピロリジン−1−イル)メチル]ピリジン;
({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)(プロパン−2−イル)アミン;
メチル({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)アミン;
N−{2−[({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)アミノ]エチル}アセトアミド;
[2−(ジメチルアミノ)エチル]({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)アミン;
(2−メトキシエチル)({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)アミン;
2−[({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)アミノ]エタン−1−オール;
{1−[({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)アミノ]シクロペンチル}メタノール;
4−[({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)アミノ]シクロヘキサン−1−オール;
3−[({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)アミノ]プロパンアミド;
(2S)−2−[({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)アミノ]プロパン酸;
5−{[({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)アミノ]メチル}ピロリジン−2−オン;
N−[(3S)−1−({6−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−3−イル}メチル)ピロリジン−3−イル]アセトアミド;
(2R)−2−{[(4−{[3−(3−フルオロ−5−メトキシフェニル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル]アミノ}プロパン酸;
(2R)−2−{[(4−{[3−(2H−1,3−ベンゾジオキソール−5−イル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル]アミノ}プロパン酸;
3−[3−(4−{[(2−ヒドロキシエチル)アミノ]メチル}−3,5−ジメトキシフェノキシメチル)−2−メチルフェニル]フェノール;
2−{[(4−{[3−(2H−1,3−ベンゾジオキソール−5−イル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル]アミノ}エタン−1−オール;
2−{[(4−{[3−(3−エトキシフェニル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル]アミノ}エタン−1−オール;
2−[({2,6−ジメトキシ−4−[(2−メチル−3−{3−[2−(ピペリジン−1−イル)エトキシ]フェニル}フェニル)メトキシ]フェニル}メチル)アミノ]エタン−1−オール;
2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−2−メチルプロパン−1,3−ジオール;
(2S,3S)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−3−メチルペンタン−1−オール;
(2R)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−4−メチルペンタン−1−オール;
1−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン−2−オール;
{1−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]シクロペンチル}メタノール;
2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン−1,3−ジオール;
1−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]ブタン−2−オール;
(2S)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−4−メチルペンタン−1−オール;
(2R)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−3−メチルブタン−1−オール;
(2S)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−3−メチルブタン−1−オール;
(2R)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン−1−オール;
(2S)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]ブタン−1−オール;
2−{[(2,6−ジメトキシ−4−{[2−メチル−3−(3−プロポキシフェニル)フェニル]メトキシ}フェニル)メチル]アミノ}エタン−1−オール;
(2S)−3−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン−1,2−ジオール;
(2R)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−2−メチルブタン酸;
1−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−2−メチルプロパン−2−オール;
(2S)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]ペンタン−1−オール;
3−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]ブタン−2−オール;
(2R)−3−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン−1,2−ジオール;
(2R)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]ブタン−1−オール;
(2S)−1−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]プロパン−2−オール;
2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]シクロヘキサン−1−オール;
(1S,2R)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]シクロヘキサン−1−オール;
(3R,4S)−4−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]オキソラン−3−オール;
1−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−3−メチルブタン−2−オール;
({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)[3−(ジメチルアミノ)−2−ヒドロキシプロピル]アミン;
(2R)−2−シクロプロピル−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エタン−1−オール;
3−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−2−メチルブタン−2−オール;
(2R)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−2−フェニルエタン−1−オール;
1−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−2,3−ジヒドロ−1H−インデン−2−オール;
(1S)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−1−フェニルエタン−1−オール;
(3S)−4−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−3−ヒドロキシブタン酸;
4−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]チオラン−3−オール;
(1R)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−1−フェニルエタン−1−オール;
2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−1−(ピリジン−3−イル)エタン−1−オール;
2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−1−(ピリジン−4−イル)エタン−1−オール;
(2S)−2−シクロヘキシル−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]エタン−1−オール;
{4−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]オキサン−4−イル}メタノール;
2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−1−(1−メチル−1H−イミダゾール−2−イル)エタン−1−オール;
1−{[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]メチル}シクロヘキサン−1−オール;
(1R,2S)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]シクロペンタン−1−オール;
4−{[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]メチル}−1−メチルピペリジン−4−オール;
(1R,2R)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]シクロヘキサン−1−オール;
(1S,2S)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]シクロペンタン−1−オール;
(1R,2R)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]シクロペンタン−1−オール;
(2R,3S)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]ブタン−1,3−ジオール;
(2S,3R)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]ブタン−1,3−ジオール;
1−{[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]メチル}シクロブタン−1−オール;
(3R)−4−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−3−ヒドロキシブタン酸;
2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−2−エチルプロパン−1,3−ジオール;
(2S)−2−[({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)アミノ]−2−フェニルエタン−1−オール;
1−({2,6−ジメトキシ−4−[(2−メチル−3−フェニルフェニル)メトキシ]フェニル}メチル)−4−ヒドロキシピペリジン−4−カルボキシアミド;
N−(2−{[(2,6−ジメトキシ−4−{[3−(3−メトキシフェニル)−2−メチルフェニル]メトキシ}フェニル)メチル]アミノ}エチル)アセトアミド;
N−(2−{[(4−{[3−(3−エトキシフェニル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル]アミノ}エチル)アセトアミド;
N−(2−{[(4−{[3−(2H−1,3−ベンゾジオキソール−5−イル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル]アミノ}エチル)アセトアミド;
[(4−{[3−(2H−1,3−ベンゾジオキソール−5−イル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル][2−メチル−1−(4−メチルピペラジン−1−イル)プロパン−2−イル]アミン;
N−(2−{[(4−{[3−(2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル]アミノ}エチル)アセトアミド;
[(4−{[3−(3−エトキシフェニル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル][2−メチル−1−(4−メチルピペラジン−1−イル)プロパン−2−イル]アミン;
[(4−{[3−(2,3−ジヒドロ−1,4−ベンゾジオキシン−6−イル)−2−メチルフェニル]メトキシ}−2,6−ジメトキシフェニル)メチル][2−メチル−1−(4−メチルピペラジン−1−イル)プロパン−2−イル]アミン;
{[2,6−ジメトキシ−4−({3−[3−(メトキシメトキシ)フェニル]−2−メチルフェニル}メトキシ)フェニル]メチル}[2−メチル−1−(4−メチルピペラジン−1−イル)プロパン−2−イル]アミン;
{[2,6−ジメトキシ−4−({2−メチル−3−[3−(プロパ−2−エン−1−イルオキシ)フェニル]フェニル}メトキシ)フェニル]メチル}[2−メチル−1−(4−メチルピペラジン−1−イル)プロパン−2−イル]アミン;
{[4−({3−[2−フルオロ−5−(2−メトキシエトキシ)フェニル]−2−メチルフェニル}メトキシ)−2,6−ジメトキシフェニル]メチル}[2−メチル−1−(4−メチルピペラジン−1−イル)プロパン−2−イル]アミン;
(3S)−4−[({4−[(2−シアノ−3−フェニルフェニル)メトキシ]−2,6−ジメトキシフェニル}メチル)アミノ]−3−ヒドロキシブタン酸;
(3S)−3−ヒドロキシ−4−[({5−[(2−メチル−3−フェニルフェニル)メトキシ]ピリジン−2−イル}メチル)アミノ]ブタン酸;および
N−(2−{[(3−クロロ−4−{[2−メチル−3−(チオフェン−3−イル)フェニル]メトキシ}フェニル)メチル]アミノ}エチル)アセトアミド
より選択される、請求項1に記載の化合物またはその塩。 - 環Aが
- 請求項1に記載の化合物またはその医薬的に許容される塩、および医薬的に許容される担体を含む、医薬組成物。
- PD−1/PD−L1の相互作用の阻害に付随する、疾患または障害を治療する方法であって、請求項1に記載の化合物またはその医薬的に許容される塩を哺乳動物の患者に投与することを含む、方法。
- 疾患または障害がウイルス学的感染症またはがんである、請求項11に記載の方法。
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JP6417419B2 (ja) | 2018-11-07 |
PE20160432A1 (es) | 2016-05-11 |
EA029901B1 (ru) | 2018-05-31 |
BR112016004194A8 (pt) | 2020-02-11 |
CA2923184A1 (en) | 2015-03-12 |
IL244346B (en) | 2019-10-31 |
ES2642074T3 (es) | 2017-11-15 |
AU2014315457B2 (en) | 2018-05-10 |
KR20160048946A (ko) | 2016-05-04 |
MX2016002544A (es) | 2016-06-17 |
SG11201601225RA (en) | 2016-03-30 |
CN105705489A (zh) | 2016-06-22 |
EA201690316A1 (ru) | 2016-07-29 |
EP3041822B1 (en) | 2017-08-09 |
US9872852B2 (en) | 2018-01-23 |
KR102276644B1 (ko) | 2021-07-13 |
AU2014315457A1 (en) | 2016-04-28 |
HK1223366A1 (zh) | 2017-07-28 |
CL2018000150A1 (es) | 2018-05-11 |
IL244346A0 (en) | 2016-04-21 |
EP3041822A1 (en) | 2016-07-13 |
US20160194307A1 (en) | 2016-07-07 |
CL2016000508A1 (es) | 2016-11-04 |
CN105705489B (zh) | 2019-04-26 |
WO2015034820A1 (en) | 2015-03-12 |
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