TW202300486A - Lpa受體拮抗劑及其用途 - Google Patents
Lpa受體拮抗劑及其用途 Download PDFInfo
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- TW202300486A TW202300486A TW111117740A TW111117740A TW202300486A TW 202300486 A TW202300486 A TW 202300486A TW 111117740 A TW111117740 A TW 111117740A TW 111117740 A TW111117740 A TW 111117740A TW 202300486 A TW202300486 A TW 202300486A
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- alkyl
- compound
- pharmaceutically acceptable
- acceptable salt
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Abstract
本揭露大致上係關於結合至溶血磷脂酸受體1 (LPAR1)並作為LPAR1之拮抗劑的化合物。本揭露進一步係關於一種該等化合物用於製備用於透過結合LPAR1來治療疾病及/或病況之藥劑的用途,該疾病及/或病況包括纖維化及肝病,諸如非酒精性脂肪肝炎(NASH)、間質性肺病(ILD)、或慢性腎病(CKD)。
Description
相互申請案之交互參照
本申請案依據35 U.S.C. §119(e)主張2021年5月13日申請之美國臨時專利申請案第63/188,281號之權益,其全部內容特此以引用方式全文併入本文中。
本揭露係關於結合至溶血磷脂酸(LPA)受體(諸如LPAR1)並作為其拮抗劑的化合物。本揭露進一步係關於一種該等化合物用於治療及/或預防與一或多種LPA受體相關之疾病及/或病況(例如LPAR1相關疾病或病況)的用途。
溶血磷脂酸(單醯基-甘油-3-磷酸鹽,LPA)為可由溶血磷脂醯膽鹼(LPC)產生(例如,藉由酶自毒素(autotaxin))之一類生物活性磷脂質。典型的LPA具有甘油、在
sn-1位置之酯聯脂肪酸,及在
sn-3位置之磷酸鹽頭部基團。已辨識出具有各種脂肪酸的LPA,包括棕櫚醯基LPA (16:0)、硬脂醯基LPA (18:0)、油醯基LPA (18:1)、亞油醯基LPA (18:2)、及花生四烯基LPA (20:4)。LPA通過視紫質樣G蛋白偶聯受體(GPCR)家族影響廣泛範圍之細胞反應,諸如增生、分化、存活、遷移、黏附性、侵襲、及形態發生。已表徵六種LPA受體,且發現其組織分佈、及下游信號傳導路徑的不同。此六種LPA受體通常可互換地指LPAR1-6(基因)或LPA1-6(蛋白質)。LPA受體介導之信號傳導已顯示影響許多生物程序,諸如傷口癒合、免疫、致癌作用、血管新生、及神經新生。
涉及LPA受體缺乏小鼠之體內研究、或某些工具化合物已暗示LPA受體作為包括癌症、纖維化、發炎、疼痛、及心血管疾病之多種疾病之可能藥物靶標的潛力。最近,LPAR1拮抗劑已進行與纖維化疾病狀態相關之臨床研究,諸如特發性肺纖維化(IPF)、及全身性硬化症。
仍需要具有所欲之選擇性、效力、代謝穩定性、或減少不利影響之LPA拮抗劑。
本揭露提供可用作溶血磷脂酸受體1 (LPAR1)之抑制劑的化合物。本揭露進一步係關於一種該等化合物用於透過該等化合物結合LPAR1來治療及/或預防疾病及/或病況的用途。
在一個實施例,本文提供一種式(I)之化合物,
(I)
或其醫藥上可接受之鹽,
其中:
R
1係氫、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-10環烷基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、或具有1至4個獨立地選自氮、氧、及硫之雜原子的5至10員雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基、或雜芳基可選地經1至4個R
1A取代,該等取代基可相同或不同,其中各R
1A係獨立地選自鹵素、氰基、硝基、側氧基、C
1-4烷基、C
3-10環烷基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、具有1至4個獨立地選自氮、氧、或硫之雜原子的5至10員雜芳基、–N(R
1B1)(R
1B2)、-O-R
1B1、-S-R
1B1、–C(O)N(R
1B1) (R
1B2)、–N(R
1B1)C(O)R
1B2、-N(R
1B1)C(O)N(R
1B2)(R
1B3)、–S(O)
0-2R
1B1、–S(O)
2N(R
1B1) (R
1B2)、及–N(R
1B1)S(O)
2R
1B2,其中各R
1B1、R
1B2、及R
1B3獨立地係氫、C
1-6烷基、或C
3-6環烷基,
其中各R
1A烷基、環烷基、雜環基、芳基、及雜芳基可選地經1至4個R
1C取代,該等取代基可相同或不同,且其中各R
1C獨立地係C
1-4烷基、鹵素、氰基、-O-R
1D1、或-N(R
1D1)(R
1D2),其中各R
1D1及R
1D2獨立地係氫或C
1-6烷基,且
其中各R
1B1、R
1B2、及R
1B3烷基及環烷基可選地經1至3個鹵素取代;或
R
2係氫或可選地經1至3個取代基取代之C
1-6烷基,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C
1-4烷氧基、及C
3-10環烷基;或
R
2係可選地經1至3個取代基取代之C
3-6環烷基,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C
1-4烷氧基、及C
1-6烷基;
R
3係選自氫、氘、鹵素、C
1-6烷基、C
3-6環烷基、-O-R
3A1、及-N(R
3A1)(R
3A2),其中C
1-6烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C
1-4烷氧基及鹵素,且其中各R
3A1及R
3A2獨立地係氫或可選地經1至3個鹵素取代之C
1-3烷基,該等鹵素可相同或不同;
各R
4係獨立地選自氘、鹵素、C
1-6烷基、C
3-6環烷基、-O-R
3A1、及-N(R
4A1)(R
4A2),其中C
1-6烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C
1-4烷氧基及鹵素,且其中各R
4A1及R
4A2獨立地係氫或可選地經1至3個鹵素取代之C
1-3烷基,該等鹵素可相同或不同;
n係0、1、或2;
R
5係可選地經1至3個取代基取代之C
1-6烷基,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C
1-4烷氧基、-C(O)N(R
5A1)、及-N(R
5A1)(R
5A2),其中各R
5A1及R
5A2獨立地係H、C
1-6烷基、或C
3-10環烷基;或
R
5係C
3-6環烷基或具有1或2個獨立地選自氮、氧、及硫之雜原子的3至6員雜環基,其中該環烷基或雜環基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C
1-4烷基、及C
1-4烷氧基;
各Y
1及Y
2獨立地係氫、氘、或可選地經1至3個取代基取代之C
1-6烷基,該等取代基可相同或不同,且獨立地選自氘、鹵素、氰基、C
2-3炔基、C
1-4烷氧基、及-C(O)NH-(C
1-4H
3-9);及
Z係C
1-8烷基、C
1-6烷氧基、C
3-6環烷基、C
6-12芳基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至12員雜環基、或具有1至4個獨立地選自氮、氧、及硫之雜原子的5至12員雜芳基,其中該烷基、烷氧基、環烷基、芳基、雜環基、或雜芳基各可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C
1-4烷基、C
1-4烷氧基、及C
3-6環烷基,其中該C
1-4烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且選自C
1-4烷氧基及鹵素;或
Y
1及Z與其等所附接之碳一起形成C
3-6環烷基、C
6-12芳基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至12員雜環基、或具有1至4個獨立地選自氮、氧、及硫之雜原子的5至12員雜芳基,其中該環烷基、芳基、雜環基、或雜芳基各可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自氰基、C
1-4烷基、C
1-4烷氧基、C
6-10芳基、及鹵素,其中該C
1-4烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C
1-4烷氧基及鹵素,且其中該C
6-10芳基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C
1-4烷基、C
1-4烷氧基、及鹵素,且Y
2係氫或氘。
在一些實施例中,本文提供醫藥組成物,其包含本文所提供之化合物、或其醫藥上可接受之鹽、及醫藥上可接受之賦形劑或載劑。在一些實施例中,醫藥組成物包含治療有效量的本文所提供之化合物或其醫藥上可接受之鹽、及醫藥上可接受之賦形劑或載劑。
在一些實施例中,本文所提供之醫藥組成物進一步包含一或多種(例如一、二、三、四、一或二、一至三、或一至四種)額外治療劑或其醫藥上可接受之鹽。在一些實施例中,醫藥組成物進一步包含治療有效量的一或多種(例如一、二、三、四、一或二、一至三、或一至四種)額外治療劑或其醫藥上可接受之鹽。
在一些實施例中,本揭露提供在有需要之對象中抑制LPAR1活性之方法,其包含向該對象投予治療有效量的本文所提供之化合物(例如,式(I)、(Ia)、(II)、或(IIa)之化合物)或其醫藥上可接受之鹽、或本文所提供之醫藥組成物。
在一些實施例中,本揭露提供治療具有LPAR1介導之病況之患者的方法,其包含向該患者投予治療有效量之本文所提供之化合物(例如,式(I)、(Ia)、(II)、或(IIa)之化合物)或其醫藥上可接受之鹽、或本文所提供之醫藥組成物。
本揭露係關於LPA受體拮抗劑,諸如LPAR1之拮抗劑。本揭露亦關於與LPAR1拮抗劑相關之組成物及方法、以及此類化合物於治療及/或預防LPAR1介導之疾病及病況的應用。本揭露亦關於治療及/或預防肝病之組成物及方法,其包括LPAR1拮抗劑與一或多種額外治療劑組合。
通常咸信患有某些LPAR1介導之疾病(諸如癌症、纖維化、發炎、疼痛、及心血管疾病)或肝病(包括非酒精性脂肪肝病(NAFLD)及非酒精性脂肪肝炎(NASH))的患者可受益於以LPAR1拮抗劑及可選地之一或多種額外治療劑之治療。
定義及一般參數
以下描述係在理解本揭露被視為所請標的之示例下做出的,且不意欲將隨附申請專利範圍限制於所說明之具體實施例。本揭露通篇所使用之標題為了方便而提供,且不應被解讀為以任何方式限制申請專利範圍。在任何標題下說明之實施例可與在任何其他標題下說明之實施例組合。
除非另有定義,否則本文中所使用之所有技術及科學用語具有與所屬技術領域中具有通常知識者一般理解的意義相同。應注意,如本文中及隨附申請專利範圍中所使用,單數形式「一(a/an)」及「該(the)」皆包括複數指稱,除非上下文另有明確說明。因此,例如提及「該化合物(the compound)」包括複數個此類化合物,而提及「該檢定(the assay)」包括提及所屬技術領域中具有通常知識者已知之一或多種檢定及其等效物等等。
如本說明書中所使用,下列用語及片語通常旨在具有以下之含義,除非在使用彼等之上下文中另有說明。
不在兩個字母或符號之間的破折號(「-」)用於指示取代基之附接點。例如,-CONH
2透過碳原子附接。化學基團前面或末端之破折號係爲了方便起見;化學基團可用或不用一或多個破折號描繪,而不失去其通常意義。透過結構中之線繪製之波浪線指示基團之附接點。除非在化學或結構上有要求,否則化學基團之書寫或命名順序不會指示或暗示方向性。從環中心出來的實線指示在環上之取代基的附接點可在任何環原子處。例如,在以下結構中之R
a可附接至五個碳環原子之任一者或R
a可置換附接至氮環原子之氫:
。
前綴「C
u-v」指示後述基團具有u至v個碳原子。例如,「C
1-6烷基」指示烷基具有1至6個碳原子。同樣地,用語「x至y員(x-y membered)」環,其中x及y係數值範圍(諸如「3至12員雜環基」),係指含有x至y個原子(例如,3至12)之環,其中至多80%可係諸如N、O、S、P之雜原子,而其餘原子係碳。
此外,可使用或可不使用某些常用替代化學名稱。例如,諸如二價「烷基」、二價「芳基」等之二價基團亦可各別稱為「伸烷基(alkylene/alkylenyl/alkylyl)」、「伸芳基(arylene/arylenyl/arylyl)」。
「本文所揭示之化合物」或「本揭露之化合物」或「本文所提供之化合物」或「本文所述之化合物」係指式(I)、(Ia)、(II)、或(IIa)之化合物。亦包括本文所提供之特定化合物1至66(例如,實例1至18)。
本文提及「約」值或參數包括(且描述)針對該值或參數本身的實施例。在某些實施例中,用語「約(about)」包括指示之量± 10%。在其他實施例中,用語「約(about)」包括指示之量± 5%。在某些其他實施例中,用語「約(about)」包括指示之量± 1%。此外,對用語「約X (about X)」包含「X」之描述。此外,單數形式「一(a)」及「該(the)」包括複數的指稱,除非上下文另有明確說明。因此,例如提及「該化合物(the compound)」包括複數個此類化合物,而提及「該檢定(the assay)」包括提及所屬技術領域中具有通常知識者已知之一或多種檢定及其等效物。
「烷基(alkyl)」係指非支鏈或支鏈飽和烴鏈。如本文中所使用,烷基具有1至20個碳原子(亦即,C
1-20烷基)、1至8個碳原子(亦即,C
1-8烷基)、1至6個碳原子(亦即,C
1-6烷基)、1至4個碳原子(亦即,C
1-4烷基)、或1至3個碳原子(亦即,C
1-3烷基)。烷基之實例包括甲基、乙基、丙基、異丙基、正丁基、二級丁基、異丁基、三級丁基、戊基、2-戊基、異戊基、新戊基、己基、2-己基、3-己基、及3-甲基戊基。當具有特定碳數之烷基殘基被化學名稱命名或由分子式確定時,可涵蓋具有該碳數的所有位置的異構物;因此,例如「丁基(butyl)」包括正丁基(亦即,-(CH
2)
3CH
3)、二級丁基(亦即,-CH(CH
3)CH
2CH
3)、異丁基(亦即,-CH
2CH(CH
3)
2)、及三級丁基(亦即,-C(CH
3)
3);及「丙基(propyl)」包括正丙基(亦即,-(CH
2)
2CH
3)及異丙基(亦即,-CH(CH
3)
2)。
「烯基(alkenyl)」係指含有至少一個碳-碳雙鍵且具有2至20個碳原子之脂族基團(亦即,C
2-20烯基)、或2至8個碳原子(亦即,C
2-8烯基)、或2至6個碳原子(亦即,C
2-6烯基)、或2至4個碳原子(亦即,C
2-4烯基)。烯基之實例包括乙烯基、丙烯基、丁二烯基(包括1,2-丁二烯基及1,3-丁二烯基)。
「炔基(Alkynyl)」係指含有至少一個碳-碳參鍵且具有2至20個碳原子之脂族基團(亦即,C
2-20炔基)、或2至8個碳原子(亦即,C
2-8炔基)、或2至6個碳原子(亦即,C
2-6炔基)、或2至4個碳原子(亦即,C
2-4炔基)。用語「炔基(alkynyl)」亦包括具有一個三鍵及一個雙鍵之基團者。
「烷氧基(alkoxy)」係指基團「烷基-O-(alkyl-O-)」。烷氧基之實例包括甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、三級丁氧基、二級丁氧基、正戊氧基、正己氧基、及1,2-二甲基丁氧基。
「醯基(acyl)」係指基團-C(=O)R,其中R係氫、烷基、環烷基、雜環基、芳基、雜烷基、或雜芳基;其各自可係可選地經取代,如本文所定義。醯基之實例包括甲醯基、乙醯基、環己基羰基、環己基甲基-羰基、及苯甲醯基。
「胺基(amino)」係指-NR
yR
z,其中R
y及R
z係獨立地選自由下列所組成之群組:氫、烷基、鹵烷基、芳基、雜芳基、環烷基、或雜環基;其各自可係可選地經取代。
「芳基(aryl)」係指具有單個環(例如單環)或多個環(例如雙環或三環)之芳族碳環基團,其包括稠合系統。如本文中所使用,芳基具有6至20個環碳原子(即C
6-20芳基)、6至12個碳環原子(即C
6-12芳基)、或6至10個碳環原子(即C
6-10芳基)。芳基之實例包括苯基、萘基、茀基、及蒽基。然而,芳基並未涵蓋以下定義之雜芳基或以任何方式與其重疊。若一或多個芳基與雜芳基環稠合,則得到的環系統是雜芳基。
「氰基(cyano)」或「甲腈(carbonitrile)」係指基團-CN。
「環烷基(cycloalkyl)」係指具有單個環或多個環之飽和或部分飽和環狀烷基,多個環包括稠合、橋聯、及螺環系統。用語「環烷基(cycloalkyl)」包括環烯基(亦即具有至少一個雙鍵之環狀基團)。如本文中所使用,環烷基具有3至20個環碳原子(亦即C
3-20環烷基)、3至12個環碳原子(亦即C
3-12環烷基)、3至10個環碳原子(亦即C
3-10環烷基)、3至8個環碳原子(亦即C
3-8環烷基)、或3至6個環碳原子(亦即C
3-6環烷基)。環烷基之實例包括環丙基、環丁基、環戊基、及環己基。
「橋聯(bridged)」係指其中環上之不相鄰原子藉由二價取代基(諸如伸烷基、或含有一或兩個雜原子之伸烷基、或單一雜原子)接合的環稠合。
啶基及金剛烷基係橋聯環系統之實例。在一些實施例中,橋聯環係雙環戊基(雙環[1.1.1]戊烷基])、或雙環辛烷基(雙環[2.2.2]辛烷)。在一些實施例中,該橋聯環係
、
、
、
、
、
、
、
、
、
、
、或
。
「螺(spiro)」係指藉由在相同碳原子處之兩個鍵接合的環取代基。螺基之實例包括1,1-二乙基環戊烷、二甲基-二氧雜環戊烷、及4-苄基-4-甲基哌啶,其中該環戊烷及哌啶分別係螺取代基。在一些實施例中,螺取代基係螺戊烷基(螺[a.b]戊烷基)、螺己烷基、螺庚烷基、或螺癸烷基。在一些實施例中,螺取代基係
、
、
、
、
、
、
、
、
、
、
、
、
、或
。
「鹵素(halogen)」或「鹵基(halo)」包括氟基、氯基、溴基、及碘基。
「雜芳基(heteroaryl)」係指具有單個環、多個環、或多個稠環之芳族基團,其具有一或多個獨立地選自氮、氧、及硫之環雜原子。如本文所使用,雜芳基包括1至20個碳環原子(亦即,C
1-20雜芳基)、3至12個碳環原子(亦即,C
3-12雜芳基)、或3至8個碳環原子(亦即,C
3-8雜芳基);且1至5個環雜原子、1至4個環雜原子、1至3個環雜原子、1至2個環雜原子、或1個環雜原子獨立地選自氮、氧、及硫。雜芳基之實例包括嘧啶基、嘌呤基、吡啶基、嗒
基、苯并噻唑基、及吡唑基。雜芳基並未涵蓋如上所定義之芳基或與其重疊。
「雜環基(heterocyclyl)」或「雜環(heterocyclic ring/heterocycle)」係指具有一或多個獨立地選自氮、氧、及硫之環雜原子之非芳族環烷基。除非另有指示,否則如本文所使用,「雜環基」或「雜環」係指飽和或部分飽和之環,例如,在一些實施例中,「雜環基」或「雜環」在指定之情況下係指部分飽和之環。用語「雜環基(heterocyclyl)」或「雜環(heterocyclic ring/heterocycle)」包括雜環烯基(亦即,具有至少一個雙鍵之雜環基)。雜環基可係單環或多環,其中多環可係稠合、橋聯、或螺環接的。如本文所使用,雜環基具有2至20個碳環原子(亦即,C
2-20雜環基)、2至12個碳環原子(亦即,C
2-12雜環基)、2至10個碳環原子(亦即,C
2-10雜環基)、2至8個碳環原子(亦即,C
2-8雜環基)、3至12個碳環原子(亦即,C
3-12雜環基)、3至8個碳環原子(亦即,C
3-8雜環基)、或3至6個碳環原子(亦即,C
3-6雜環基);具有1至5個環雜原子、1至4個環雜原子、1至3個環雜原子、1至2個環雜原子、或1個環雜原子獨立地選自氮、硫、或氧。雜環基之實例包括吡咯啶基、哌啶基、哌
基、氧呾基、二氧雜環戊烷基(dioxolanyl)、吖呾基、及
啉基。如本文所使用,用語「雜環(heterocycle)」、「雜環基(heterocyclyl)」、及「雜環(heterocyclic ring)」可互換使用。
「羥基(hydroxy/hydroxyl)」係指基團-OH。
「側氧基(oxo)」係指基團(=O)或(O)。
「磺醯基(sulfonyl)」係指基團-S(O)
2R
c,其中R
c係烷基、雜環基、環烷基、雜芳基、或芳基。磺醯基之實例係甲磺醯基、乙磺醯基、苯磺醯基、及甲苯磺醯基。
除非另有指示,否則每當基團之圖形表示以單鍵結氮原子結束時,該基團表示-NH
2基團。類似地,除非以其他方式表示,否則根據所屬技術領域中具有通常知識者之知識,氫原子在必要時暗示為且視為存在以使價數完整或提供穩定性。
用語「可選的(optional)」或「可選地(optionally)」意指隨後描述的事件或情形可發生或可不發生,且該描述包括該事件或情形發生的情況及不發生的情況。此外,用語「可選地經取代之(optionally substituted)」意謂指定原子或基團上之任一或多個氫原子可經或可不經除氫以外之部分置換。
用語「經取代之(substituted)」意指指定原子或基團上之任一或多個氫原子經除氫以外之一或多個取代基置換,其限制條件為不超過指定原子之正常價。一或多個取代基包括但不限於烷基、烯基、炔基、烷氧基、醯基、胺基、醯胺基、甲脒基、芳基、疊氮基、胺甲醯基、羧基、羧基酯、氰基、胍基、鹵基、鹵烷基、雜烷基、雜芳基、雜環基、羥基、肼基、亞胺基、側氧基、硝基、烷基亞磺醯基、磺酸、烷基磺醯基、硫氰酸酯、硫醇、硫酮、或其組合。藉由用無限地附加之其他取代基(例如,具有經取代之烷基的經取代之芳基,該經取代之烷基本身經經取代之芳基取代,該經取代芳基進一步由經取代之雜烷基等等取代)定義取代基所獲得之聚合物或類似的無限結構並不意欲包括在本文中。除非另有說明,否則本文所述之化合物中的連續取代之最大數目係三。例如,用兩個其他經取代之芳基連續取代的經取代之芳基限於經(經(經取代之芳基)取代之芳基)取代之芳基。類似地,以上定義並不意欲包括不許可之取代模式(例如,經5個氟取代之甲基或具有兩個相鄰氧環原子之雜芳基)。此類不許可之取代模式為所屬技術領域具有通常知識者眾所週知的。當用於修飾化學基團時,用語「經取代之(substituted)」可描述本文所定義之其他化學基團。例如,用語「經取代之芳基(substituted aryl)」包括但不限於「烷芳基(alkylaryl)」。除非另有說明,否則當基團被描述為可選地經取代時,該基團之任何取代基本身皆是未經取代的。
在一些實施例中,用語「經取代之烷基(substituted alkyl)」係指具有一或多個取代基(包括羥基、鹵基、胺基、烷氧基、環烷基、雜環基、芳基、及雜芳基)之烷基。在額外實施例中,「經取代之環烷基(substituted cycloalkyl)」係指具有一或多個取代基(包含烷基、鹵烷基、環烷基、雜環基、芳基、雜芳基、胺基、烷氧基、鹵基、側氧基、及羥基)之環烷基;「經取代之雜環基(substituted heterocyclyl)」係指具有一或多個取代基(包括烷基、胺基、鹵烷基、雜環基、環烷基、芳基、雜芳基、烷氧基、鹵基、側氧基、及羥基)之雜環基;「經取代之芳基(substituted aryl)」係指具有一或多個取代基(包括鹵基、烷基、胺基、鹵烷基、環烷基、雜環基、雜芳基、烷氧基、及氰基)之芳基;「經取代之雜芳基(substituted heteroaryl)」係指具有一或多個取代基(包括鹵基、胺基、烷基、鹵烷基、環烷基、芳基、雜環基、雜芳基、烷氧基、及氰基)之雜芳基,且「經取代之磺醯基(substituted sulfonyl)」係指基團-S(O)
2R,其中R係經一或多個取代基(包括烷基、環烷基、雜環基、芳基、及雜芳基)取代。在其他實施例中,該一或多個取代基可進一步經鹵基、烷基、鹵烷基、羥基、烷氧基、環烷基、雜環基、芳基、或雜芳基取代,其中之各者係經取代。在其他實施例中,該取代基可進一步經鹵基、烷基、鹵烷基、烷氧基、羥基、環烷基、雜環基、芳基、或雜芳基取代,其中之各者未經取代。
在一些實施例中,經取代之環烷基、經取代之雜環基、經取代之芳基、及/或經取代之雜芳基包括具有於環原子上之取代基的環烷基、雜環基、芳基、及/或雜芳基,該於環原子上之取代基使環烷基、雜環基、芳基、及/或雜芳基附接至化合物之其餘部分。例如,在以下部分中,環丙基係經甲基取代:
。
本文中說明性地描述之揭露內容可適當地在不存在本文未特定揭示之任意元件或複數個元件、限制或複數個限制下實施。因此,例如,用語「包含(comprising)」、「包括(including)」、「含有(containing)」等應廣泛地讀取且不被限制。另外,本文中所採用之用語及表述係用於描述而非限制,且不意欲使用此類用語及表述排除任意所示及描述之特徵或其部分的等效物,但應認識到,在本揭露所請之範圍內各種修飾係可能的。
本揭露之化合物可呈醫藥上可接受之鹽的形式。用語「醫藥上可接受之鹽(pharmaceutically acceptable salts)」係指由醫藥上可接受之非毒性鹼或酸(包括無機鹼或酸、及有機鹼或酸)所製備之鹽。本揭露之化合物可呈醫藥上可接受之鹽的形式。用語「醫藥上可接受之鹽(pharmaceutically acceptable salts)」係指由醫藥上可接受之非毒性鹼或酸(包括無機鹼或酸、及有機鹼或酸)所製備之鹽。在本揭露之化合物含有一或多種酸性或鹼性基團的情況下,本揭露亦包含其對應之醫藥上或毒理上可接受之鹽,尤其是其醫藥上可用之鹽。因此,含有酸性基團之本揭露之化合物可存在於此等基團上,且可根據本揭露使用,例如,作為鹼金屬鹽、鹼土金屬鹽、或銨鹽。此類鹽之更精確實例包括鈉鹽、鉀鹽、鈣鹽、鎂鹽、或具有氨或有機胺之鹽,諸如乙胺、乙醇胺、三乙醇胺、胺基酸、或所屬技術領域中具有通常知識者已知的其他鹼基。含有一或多個鹼基之本揭露之化合物,亦即,可質子化、可呈現、且可根據本揭露以其具有無機或有機酸之額外鹽形式使用之基團。合適酸之實例包括氯化氫、溴化氫、磷酸、硫酸、硝酸、甲磺酸、對甲苯磺酸、萘二磺酸、草酸、乙酸、酒石酸、乳酸、水楊酸、苯甲酸、甲酸、丙酸、三甲基乙酸、二乙基乙酸、丙二酸、琥珀酸、庚二酸、富馬酸、馬來酸、蘋果酸、胺基磺酸、苯丙酸、葡萄糖酸、抗壞血酸、異菸鹼酸、檸檬酸、己二酸、及其他所屬技術領域中具有通常知識者已知的酸。
若本揭露之化合物在分子中同時含有酸性及鹼性基團,則本揭露亦包括(除所提及之鹽形式以外的)內鹽或甜菜鹼(兩性離子)。各別鹽可藉由所屬技術領域中具有通常知識者已知之習用方法來獲得,例如藉由將此等與有機或無機酸或鹼在溶劑或分散劑中接觸,或藉由與其他鹽進行陰離子交換或陽離子交換。
本揭露亦包括本揭露之化合物之所有鹽類,其由於低生理相容性而不直接適合在藥品中使用,但可用於例如作為化學反應之中間物、或用於製備醫藥上可接受之鹽。可用於與下方化合物反應以形成醫藥上可接受之鹽的酸及鹼(分別為酸加成鹽或鹼加成鹽)係所屬技術領域中具有通常知識者已知的。類似地,來自下方化合物(一旦揭露)之醫藥上可接受之鹽的製備方法係所屬技術領域中具有通常知識者已知的,且係揭示於例如Berge, at al. Journal of Pharmaceutical Science, Jan. 1977 vol. 66, No.1、及其他來源中。
此外,本文中所揭示之化合物可以為互變異構物。其中可發生化合物或其前藥之互變異構物,例如,酮-烯醇互變異構物,其個別形式,例如酮及烯醇形式,各自在本揭露之範圍內、以及其任何比率之混合物。相同地適用於立體異構物,例如鏡像異構物、順/反異構物、非鏡像異構物、構形異構物、及類似物。
用語「保護基(protecting group)」係指化合物之部份,其遮罩或改變官能基之性質或整個化合物之性質。化學保護基及用於保護/去保護之策略係所屬技術領域中熟知的。參見例如Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991。保護基通常用以遮罩某些官能基之反應性,以幫助所欲化學反應之效率,例如以有序及有計劃之方式製造及破壞化學鍵。用語「去保護(deprotecting)」係指移除保護基。
熟習此項技術者應瞭解,當替代取代基之清單包括因為其價要求或其他原因不能用以替代特定群組的成員,所述清單意欲使用熟習此項技術者之知識來讀取,以僅包括適合於取代特定群組之清單之該等成員。
此外,本揭露之化合物可以溶劑合物之形式存在,諸如包括溶劑合物水或醫藥上可接受之溶劑合物,諸如醇,尤其乙醇。「溶劑合物(solvate)」係藉由溶劑與化合物之交互作用形成。
在某些實施例中,提供本文所述之化合物或其醫藥上可接受之鹽、或其混合物的光學異構物、外消旋物、或其其他混合物。若需要,可藉由本領域中熟知之方法分離異構物,例如,藉由液相層析法。在彼等情况下,單獨之鏡像異構物或非鏡像異構物;亦即,光學活性形式可藉由不對稱合成或藉由解析獲得。解析可例如藉由習知方法來完成,諸如在光學分割劑存在下結晶、或在層析法中使用例如對掌性高壓液相層析(HPLC)管柱。
「立體異構物(stereoisomer)」係指由相同鍵所鍵結之相同原子構成但具有不同三維結構的化合物,該等化合物係不可互換的。本發明設想各種立體異構物及其混合物且包括「鏡像異構物(enantiomer)」,其係指兩個立體異構物的分子係彼此之不可重疊鏡像。「非鏡像異構物(Diastereomer)」係具有至少兩個非對稱原子,但彼此不為鏡像之立體異構物。
本文所揭示之化合物、及其醫藥上可接受之鹽可在一些實施例中包括不對稱中心,並因此可產生鏡像異構物、非鏡像異構物、及其他立體異構形式,其等可依絕對立體化學定義為(
R)-或(
S)-、或針對胺基酸定義為(D)-或(L)-。在一些實施例中包括所有此類可能的異構物、以及其外消旋及光學純形式。光學活性(+)及(-)、(
R)-及(
S)-、或(D)-及(L)-異構物可使用掌性合成組元(synthon)或掌性試劑製備,或使用例如層析法及分段結晶之習知技術解析。用於製備/單離個別鏡像異構物的習知技術包括使用例如掌性高壓液相層析法(high pressure liquid chromatography, HPLC),由合適的光學純前驅物進行掌性合成或解析外消旋物(或鹽或衍生物的外消旋物)。當本文所述之化合物含有烯烴雙鍵或其他幾何不對稱中心時,除非另有指明,否則意指該等化合物包括E及Z幾何異構物兩者。
本文所提供之組成物包括本文所描述之化合物或其醫藥學上可接受之鹽、異構物、或其混合物,其可包括外消旋混合物、或含有鏡像異構物之混合物,其超過單個鏡像異構物或單獨之非鏡像異構物、或非鏡像異構物之混合物。此等化合物之所有此類異構形式係明確地包括於本文中,如同其各自與每一異構形式係特定地且單獨地列出。
本文所給出之任何式或結構亦意欲表示化合物之未經標記之形式以及經同位素標記之形式。經同位素標示之化合物具有由本文中給出之式繪示的結構,除了一或多個原子係由具有所選原子質量或質量數之原子置換。可併入至本揭露之化合物中之同位素之實例包括氫、碳、氮、氧、磷、氟及氯之同位素,諸如但不限於
2H(氘,D)、
3H(氚)、
11C、
13C、
14C、
15N、
18F、
31P、
32P、
35S、
36Cl、及
125I。本揭露之各種經同位素標示之化合物,例如其中併入放射性同位素(諸如
3H、
13C、及
14C)者。此類經同位素標示之化合物可用於代謝研究、反應動力學研究、偵測或造影技術(諸如正電子發射斷層造影(PET)或單光子發射電腦斷層造影(SPECT)),包括藥物或受質組織分布檢定,或用於患者之放射性治療。本揭露之經同位素標示之化合物及其前藥通常可藉由進行下述方案或實例及製備中所揭示之程序,並藉由用可輕易取得的經同位素標示之試劑取代未經同位素標示之試劑來製備。
本揭露亦包括本文所揭示之化合物之「氚化類似物」,其中1至n個附接至碳原子之氫係由氘置換,其中n係分子中氫的數目。此類化合物可展現對代謝之抗性增加,且因此用於增加任何式(I)之化合物在投予至哺乳動物(例如人類)時的半衰期。參見例如Foster, 「Deuterium Isotope Effects in Studies of Drug Metabolism,」 Trends Pharmacol. Sci. 5(12):524-527 (1984)。此類化合物係藉由所屬技術領域中眾所週知之手段合成,例如藉由採用其中一或多個氫原子已經氘置換的起始材料。
本揭露之經氘標記或取代之治療性化合物可對DMPK(藥物代謝及藥物動力學)性質具有益處,該等性質與分布、代謝、及排泄(ADME)相關。用較重同位素(諸如氘)進行取代可提供某些由較高代謝穩定性所致之治療性優點,例如體內半衰期增加、劑量需求減少、及/或治療指數改善。經
18F標記之化合物可用於PET或SPECT研究。
此較重同位素(具體而言為氘)之濃度可藉由同位素富集因子定義。在本揭露之化合物中,未具體指定為特定同位素之任何原子意欲代表該原子之任何穩定同位素。除非另有陳述,當將一個位置具體指定為「H」或「氫」時,該位置係理解為以氫之天然豐度同位素組成具有氫。因此,在本揭露之化合物中,具體指定為氘(D)之任何原子意欲代表氘。
此外,本揭露提供包括醫藥組成物,其包含作為活性成分之本揭露之化合物、或其前藥化合物、或其醫藥上可接受之鹽、或其溶劑合物,其與醫藥上可接受之載劑一起。
「醫藥組成物(Pharmaceutical composition)」意指一或多種活性成分、及一或多種構成載劑之惰性成分、以及任意產物,該產物係由任何二或更多種成分之組合、錯合、或聚集直接或間接地造成、或自一或更多種成分中解離、或由一或更多種成分之其他類型之反應或相互作用而造成。因此,本揭露之醫藥組成物可涵蓋藉由混合本揭露之至少一種化合物及醫藥上可接受之載劑所製成之任意組成物。
如本文所用,「醫藥上可接受之載劑(pharmaceutically acceptable carrier)」包括賦形劑、或劑,諸如溶劑、稀釋劑、分散介質、塗層、抗細菌劑、及抗真菌劑、等張及吸收延遲劑、及不會危害所揭示之化合物或其應用的其類似物。此類載劑及劑於製備醫藥上活性物質之組成物的應用係此項技術中所熟知的(參見例如,Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, PA 17th Ed.(1985);及Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed.(G.S.Banker & C.T. Rhodes, Eds.)。
「IC
50」、或「EC
50」係指達成最大所欲效果之50%所需的抑制濃度。在許多情況下,最大所欲效果係LPA誘導之LPAR1活化之抑制。此用語係使用體外分析(諸如鈣移動分析)來獲得,評估LPA誘導之LPAR1活性之濃度依賴性抑制。
「治療(treatment/treating)」係用於獲得包括臨床結果之有益或所欲結果之方法。有益或所欲臨床結果可包括下列中之一或多者:a)抑制疾病或病況(例如,降低起因於疾病或病況之一或多個症狀、及/或縮小疾病或病況的程度);b)減緩或阻止與疾病或病況相關之一或多種臨床症狀的發展(例如,使疾病或病況穩定、預防或延遲疾病或病況之惡化或進展、及/或預防或延遲疾病或病況之擴散(例如,轉移));及/或c)減輕疾病,亦即使臨床症狀消退(例如,改善疾病狀態、提供疾病或病況之部分或總體緩解、增強另一藥物之作用、延遲疾病之進展、提高生命品質、及/或延長存活期。在一些實施例中,用語「治療(treatment/treating」意指為以下目的投予式(I)、(Ia)、(II)、或(II)之化合物或醫藥上可接受之鹽:(i)延緩疾病之發作,亦即,導致疾病之臨床症狀不能發展或延遲其發展;(ii)抑制疾病,亦即阻止臨床症狀之發展;及/或(iii)減輕疾病,亦即造成臨床症狀或其嚴重程度之消退。
「預防(prevention/preventing)」意指造成疾病或病況之臨床症狀不發展的疾病或病況之任何治療。在一些實施例中,化合物可投予至對象(包括人類),該對象處於風險或具有疾病或病況之家族病史。
「對象(subject)」係指已成為或將成為治療、觀察、或實驗標的的動物,諸如哺乳動物(包括人類)。本文所述之方法可用於人類療法及/或獸醫應用。在一些實施例中,對象係哺乳動物。在一些實施例中,對象係人類。
本文所述之化合物、或其醫藥上可接受之鹽、互變異構物、立體異構物、立體異構物之混合物、前藥、或其氘化類似物之用語「治療有效量(therapeutically effective amount)」或「有效量(effective amount)」意指在向對象投予時足以有效治療以提供供治療效益(諸如改善症狀或減緩疾病進展)之量。例如,治療有效量可為足以降低對LPAR1拮抗劑具有反應之疾病或病況之症狀的量。治療有效量可視所治療之對象及疾病或病況、對象之體重及年齡、疾病或病況之嚴重度、及投予方式而變化,其可容易地由所屬技術領域中具有通常知識者判定。
縮寫及頭字語之清單
縮寫 | 意義 |
ACN或MeCN | 乙腈 |
aq. | 水性 |
Bn | 苄基 |
COPD | 慢性阻塞性肺病 |
DCM | 二氯甲烷 |
DIEA | N,N-二異丙基乙基胺 |
DMF | N,N-二甲基甲醯胺 |
DMSO | 二甲基亞碸 |
DPPA | 疊氮磷酸二苯酯 |
EA | 乙酸乙酯 |
EDTA | 乙二胺四乙酸 |
ESI | 電灑離子化法 |
Et | 乙基 |
Et 2O | 二乙醚 |
EtOAc | 乙酸乙酯 |
h或hr(s) | 小時 |
HBSS | 漢克斯平衡鹽溶液 |
HCC | 肝細胞癌 |
HPLC | 高效液相層析法 |
LCMS或LC/MS | 液相層析質譜法 |
LPA | 溶血磷脂酸 |
LPC | 溶血磷脂醯膽鹼 |
Me | 甲基 |
MeOH | 甲醇 |
MS | 質譜法 |
m/z | 質荷比 |
NADPH | 二氫菸鹼醯胺-腺嘌呤二核苷酸磷酸 |
NAFLD | 非酒精性脂肪肝病 |
NASH | 非酒精性脂肪肝炎 |
NMR | 核磁共振光譜法 |
PBC | 原發性膽汁性肝硬化 |
PE | 石油醚 |
PSC | 原發性硬化性膽管炎 |
Rpm | 每分鐘轉數 |
RT或rt | 室溫 |
sat. | 飽和 |
TEMPO | 2,2,6,6- 四甲基哌啶 1- 氧基 |
TFA | 三氟乙酸 |
THF | 四氫呋喃 |
T3P | 丙烷膦酸酐 |
如本文所用,「LPAR1拮抗劑(LPAR1 antagonist)」係指能夠結合及抑制LPAR1之任意藥劑。LPAR1,亦稱為LPA
1,係結合脂質信號傳導分子溶血磷脂酸(LPA)之GPCR。LPAR1之例示性參考序列包括NCBI參考序列NP_001392(人類蛋白)、NP_001277415(小鼠蛋白)、NM_001401(人類mRNA)、及NM_001290486(小鼠mRNA)。LPAR1拮抗劑可作為全部或部分LPAR1促效劑之競爭性抑制劑,或作為反向促效劑。LPAR拮抗劑之活性可藉由本領域已知之方法來測量,諸如改等描述且引用於Castelino
et al., 2010 Arthritis Rheum. 2011 May; 63(5): 1405–1415、或Swaney
et al., J Pharmacol Exp Ther. 2011 Mar; 336(3):693-700。
如本文所用,「ACC抑制劑(ACC inhibitor)」係指能夠結合及抑制乙醯CoA羧酶(ACC)之任意藥劑。ACC抑制劑可作為ACC之抑制劑或部分抑制劑。藥劑可係化學化合物或生物分子(例如,蛋白或抗體)。ACC抑制劑之活性可藉由本領域已知之方法來測量,諸如該等描述及引用於美國專利第8,969,557號及/或美國專利第10,208,063號中者,該等專利皆以全文引用之方式併入本文中。
如本文中所提及,「ASK1抑制劑(ASK1 inhibitor)」可為能夠使細胞凋亡信號調節激酶1 (ASK1)蛋白失活之任意藥劑。藥劑可係化學化合物或生物分子(例如,蛋白或抗體)。ASK1蛋白活性可藉由數種不同方法來測量。例如,可基於ASK1蛋白磷酸化受質蛋白之能力來判定ASK1蛋白之活性。識別ASK1抑制劑之方法係已知者(參見例如,U.S. 2007/0276050)。例示性ASK1受質蛋白包括MAPKK3、MAPKK4、MAPKK6、MAPKK7、或其片段。ASK1蛋白活性亦可藉由ASK1蛋白之磷酸化程度來測量,例如,在ASK1蛋白中之蘇胺酸殘跡的磷酸化程度,該蘇胺酸殘跡對應於人類全長ASK1蛋白之蘇胺酸838 (T838)、或小鼠全長ASK1蛋白之蘇胺酸845 (T845)。例如,其中ASK1蛋白包含全長人類ASK1蛋白序列,ASK1抑制劑可衰減在全長人類ASK1蛋白序列中之T838的磷酸化。針對人類ASK1 T838或小鼠ASK1 T845之位點特異性抗體可用以偵測磷酸化程度。
如本文所用,「FXR促效劑(FXR agonist)」係指能夠結合及活化可稱為膽酸受體(BAR)或NR1H4(核受體子族1,基團H,成員4)受體之類法尼醇X受體的任意藥劑。FXR促效劑可作為FXR之促效劑或部分促效劑。藥劑可係化學化合物或生物分子(例如,蛋白或抗體)。FXR促效劑之活性可藉由數種不同方法來測量,例如,在體外分析中使用螢光共振能量轉移(FRET)細胞游離分析,如描述於Pellicciari, et al. Journal of Medicinal Chemistry, 2002 vol. 15, No. 45:3569-72.般。
化合物
在一個實施例,本文提供一種式(I)之化合物,
(I)
或其醫藥上可接受之鹽,
其中:
R
1係氫、C
1-6烷基、C
2-6烯基、C
2-6炔基、C
3-10環烷基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、或具有1至4個獨立地選自氮、氧、及硫之雜原子的5至10員雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基、或雜芳基可選地經1至4個R
1A取代,該等取代基可相同或不同,其中各R
1A係獨立地選自鹵素、氰基、硝基、側氧基、C
1-4烷基、C
3-10環烷基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、具有1至4個獨立地選自氮、氧、或硫之雜原子的5至10員雜芳基、–N(R
1B1)(R
1B2)、-O-R
1B1、-S-R
1B1、–C(O)N(R
1B1) (R
1B2)、–N(R
1B1)C(O)R
1B2、-N(R
1B1)C(O)N(R
1B2)(R
1B3)、–S(O)
0-2R
1B1、–S(O)
2N(R
1B1) (R
1B2)、及–N(R
1B1)S(O)
2R
1B2,其中各R
1B1、R
1B2、及R
1B3獨立地係氫、C
1-6烷基、或C
3-6環烷基,
其中各R
1A烷基、環烷基、雜環基、芳基、及雜芳基可選地經1至4個R
1C取代,該等取代基可相同或不同,且其中各R
1C獨立地係C
1-4烷基、鹵素、氰基、-O-R
1D1、或-N(R
1D1)(R
1D2),其中各R
1D1及R
1D2獨立地係氫或C
1-6烷基,且
其中各R
1B1、R
1B2、及R
1B3烷基及環烷基可選地經1至3個鹵素取代;或
R
2係氫或可選地經1至3個取代基取代之C
1-6烷基,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C
1-4烷氧基、及C
3-10環烷基;或
R
2係可選地經1至3個取代基取代之C
3-6環烷基,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C
1-4烷氧基、及C
1-6烷基;
R
3係選自氫、氘、鹵素、C
1-6烷基、C
3-6環烷基、-O-R
3A1、及-N(R
3A1)(R
3A2),其中C
1-6烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C
1-4烷氧基及鹵素,且其中各R
3A1及R
3A2獨立地係氫或可選地經1至3個鹵素取代之C
1-3烷基,該等鹵素可相同或不同;
各R
4係獨立地選自氘、鹵素、C
1-6烷基、C
3-6環烷基、-O-R
4A1、及-N(R
4A1)(R
4A2),其中C
1-6烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C
1-4烷氧基及鹵素,且其中各R
4A1及R
4A2獨立地係氫或可選地經1至3個鹵素取代之C
1-3烷基,該等鹵素可相同或不同;
n係0、1、或2;
R
5係可選地經1至3個取代基取代之C
1-6烷基,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C
1-4烷氧基、-C(O)N(R
5A1)、及-N(R
5A1)(R
5A2),其中各R
5A1及R
5A2獨立地係H、C
1-6烷基、或C
3-10環烷基;或
R
5係C
3-6環烷基或具有1或2個獨立地選自氮、氧、及硫之雜原子的3至6員雜環基,其中該環烷基或雜環基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C
1-4烷基、及C
1-4烷氧基;
各Y
1及Y
2獨立地係氫、氘、或可選地經1至3個取代基取代之C
1-6烷基,該等取代基可相同或不同,且獨立地選自氘、鹵素、氰基、C
2-3炔基、C
1-4烷氧基、及-C(O)NH-(C
1-4H
3-9);及
Z係C
1-8烷基、C
1-6烷氧基、C
3-6環烷基、C
6-12芳基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至12員雜環基、或具有1至4個獨立地選自氮、氧、及硫之雜原子的5至12員雜芳基,其中該烷基、烷氧基、環烷基、芳基、雜環基、或雜芳基各可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C
1-4烷基、C
1-4烷氧基、及C
3-6環烷基,其中該C
1-4烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且選自C
1-4烷氧基及鹵素;或
Y
1及Z與其等所附接之碳一起形成C
3-6環烷基、C
6-12芳基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至12員雜環基、或具有1至4個獨立地選自氮、氧、及硫之雜原子的5至12員雜芳基,其中該環烷基、芳基、雜環基、或雜芳基各可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自氰基、C
1-4烷基、C
1-4烷氧基、C
6-10芳基、及鹵素,其中該C
1-4烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C
1-4烷氧基及鹵素,且其中該C
6-10芳基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C
1-4烷基、C
1-4烷氧基、及鹵素,且Y
2係氫或氘。
在式(I)或(Ia)之化合物或其醫藥上可接受之鹽之一些實施例中,R
2係氫。
在式(I)或(Ia)之化合物或其醫藥上可接受之鹽之一些實施例中,各Y
1及Y
2獨立地係氫、氘、或可選地經1至3個取代基取代之C
1-6烷基,該等取代基可相同或不同,且各獨立地選自鹵素、氰基、C
2-3炔基、C
1-4烷氧基、及-C(O)NH-(C
1-4H
3-9)。
在式(I)或(Ia)之化合物或其醫藥上可接受之鹽之一些實施例中,Y
1係可選地經1至3個取代基取代之C
1-4烷基,該等取代基可相同或不同,且各獨立地選自鹵素、氰基、及C
1-4烷氧基,且Y
2係氫。
在式(I)或(Ia)之化合物或其醫藥上可接受之鹽之一些實施例中,Y
1係可選地經1至3個取代基取代之甲基,該等取代基可相同或不同,且各獨立地選自-F、-Cl、-CN、及-O-CH
3。
在式(I)或(Ia)之化合物或其醫藥上可接受之鹽之一些實施例中,Y
1係-CH
3。
在式(I)或(Ia)之化合物或其醫藥上可接受之鹽之一些實施例中,Y
2係氫。
在式(I)或(Ia)之化合物或其醫藥上可接受之鹽之一些實施例中,Z係具有1至3個獨立地選自氮、氧、及硫之雜原子的5或6員雜芳基,其中該雜芳基可選地經1至3個取代基取代,該等取代基可相同或不同,且各獨立地選自鹵素及C
1-4烷基。
在式(I)或(Ia)之化合物或其醫藥上可接受之鹽之一些實施例中,Z係吡啶基,其可選地經1或2個取代基取代,各獨立地選自-F、及-Cl。
在式(I)或(Ia)之化合物或其醫藥上可接受之鹽之一些實施例中,R
5係可選地經1至3個取代基取代之C
1-6烷基,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C
1-4烷氧基、-C(O)N(R
5A1)、及-N(R
5A1)(R
5A2),其中各R
5A1及R
5A2獨立地係H、C
1-6烷基、或C
3-10環烷基。
在式(I)或(Ia)之化合物或其醫藥上可接受之鹽之一些實施例中,R
5係-CH
3。
在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
1係可選地經1至4個R
1A取代之C
3-10環烷基,該等取代基可相同或不同,其中各R
1A係獨立地選自鹵素、氰基、側氧基、硝基、C
1-4烷基、C
3-10環烷基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、具有1至4個獨立地選自氮、氧、或硫之雜原子的5至10員雜芳基、–N(R
1B1)(R
1B2), -O-R
1B1、-S-R
1B1、–C(O)N(R
1B1)(R
1B2)、–N(R
1B1)C(O)R
1B2、-NR
1B1C(O)N(R
1B2)(R
1B3)、–S(O)
0-2R
1B1、–S(O)
2N(R
1B1)(R
1B2)、及–N(R
1B1)S(O)
2R
1B2,其中各R
1B1、R
1B2、及R
1B3獨立地係氫、C
1-6烷基、或-C
3-6環烷基,其中各R
1A烷基、環烷基、雜環基、芳基、及雜芳基可選地經1至4個R
1C取代,該等取代基可相同或不同,且其中各R
1C獨立地係C
1-4烷基、鹵素、氰基、-O-R
1D1、或-N(R
1D1)(R
1D2),其中各R
1D1及R
1D2獨立地係氫或C
1-6烷基,且其中各R
1B1及R
1B2烷基及環烷基可選地經1至3個鹵素取代。
在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
1係環丙基或環丁基,其各可選地經1或2個R
1A取代,該等取代基獨立地選自-F及苯基,其中各苯基可選地經1至4個R
1C取代,該等取代基可相同或不同,且其中各R
1C獨立地係C
1-4烷基、鹵素。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
1係
、
、或
。
在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
1C
3-10環烷基係C
5-10雙環環烷基。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,C
5-10雙環環烷基係C
5-8橋聯雙環環烷基。
在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,C
5-8橋聯雙環環烷基係雙環戊基,其各可選地經1至3個取代基取代,該等取代基可相同或不同,且各獨立地選自-F、-Cl、-CN、-CH
3、-CH
2-OH、-CHF
2、-CF
3、-O-CH
3、-CO
2-CH
3、-SO
2-CH
3、及苯基。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,C
5-8橋聯雙環環烷基係
、
、
、
、
、
、
、
、
、
、
、
、或
。
在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
1係具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基,其可選地經1至4個R
1A取代,該等取代基可相同或不同,其中各R
1A係獨立地選自鹵素、氰基、側氧基、硝基、C
1-4烷基、C
3-10環烷基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員查雜環基、6至10員芳基、具有1至4個獨立地選自氮、氧、或硫之雜原子的5至10員雜芳基、–N(R
1B1)(R
1B2)、-O-R
1B1、-S-R
1B1、–C(O)N(R
1B1)(R
1B2)、–N(R
1B1)C(O)R
1B2、-N(R
1B1)C(O)N(R
1B2)(R
1B3)、–S(O)
0-2R
1B1、–S(O)
2N(R
1B1)(R
1B2)、及–N(R
1B1)S(O)
2R
1B2,其中各R
1B1、R
1B2、及R
1B3獨立地係氫、C
1-6烷基、或-C
3-6環烷基,其中各R
1A烷基、環烷基、雜環基、芳基、及雜芳基可選地經1至4個R
1C取代,該等取代基可相同或不同,且其中各R
1C獨立地係C
1-4烷基、鹵素、氰基、-O-R
1D1、或-N(R
1D1) (R
1D2),其中各R
1D1及R
1D2獨立地係氫或C
1-6烷基,其中各R
1B1及R
1B2烷基及環烷基可選地經1至3個鹵素取代。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
1係可選地經1至4個R
1A取代之四氫哌喃基,該等取代基可相同或不同,且各獨立地選自-F、-Cl、-OH、-CN、-CH
3、-CH
2F、-CHF
2、-CF
3、及-O-CH
3。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
1係
。
在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
1係可選地經1至4個R
1A取代之6至10員芳基,該等取代基可相同或不同,其中各R
1A係獨立地選自鹵素、氰基、側氧基、硝基、C
1-4烷基、C
3-10環烷基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、具有1至4個獨立地選自氮、氧、或硫之雜原子的5至10員雜芳基、–N(R
1B1)(R
1B2)、-O-R
1B1、-S-R
1B1、–C(O)N(R
1B1)(R
1B2)、–N(R
1B1)C(O)R
1B2、-N(R
1B1)C(O)N(R
1B2)(R
1B3)、–S(O)
0-2R
1B1、–S(O)
2N(R
1B1)(R
1B2)、及–NR
1B1S(O)
2R
1B2,其中各R
1B1、R
1B2、及R
1B3獨立地係氫、C
1-6烷基、或-C
3-6環烷基,其中各R
1A烷基、環烷基、雜環基、芳基、及雜芳基可選地經1至4個R
1C取代,該等取代基可相同或不同,且其中各R
1C獨立地係C
1-4烷基、鹵素、氰基、-O-R
1D1、或-N(R
1D1)(R
1D2),其中各R
1D1及R
1D2獨立地係氫或C
1-6烷基,其中各R
1B1及R
1B2烷基及環烷基可選地經1至3個鹵素取代。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
1係可選地經1至4個R
1A取代之苯基,該等取代基可相同或不同,其中各R
1A係獨立地選自鹵素、氰基、C
1-3烷基、C
1-4烷氧基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、或具有1至4個獨立地選自氮、氧、或硫之5至10員雜芳基,其中各烷基、雜環基、及雜芳基可選地經1至4個R
1C取代,該等取代基可相同或不同,且其中各R
1C獨立地係氰基、鹵素、或C
1-4烷基。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
1係可選地經1至4個R
1A取代之苯基,該等取代基可相同或不同,其中各R
1A係獨立地選自氰基、-CF
3、-F、-Cl、
啉基、苯基、吡啶基、
二唑基、其中各
啉基、苯基、吡啶基、及
二唑基可選地經1至4個R
1C取代,該等取代基可相同或不同,且其中各R
1C獨立地係氰基、鹵素、或C
1-4烷基。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
1係
、
、
、
、
、
、
、
、或
。
在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
1係具有1至4個獨立地選自氮、氧、及硫之雜原子的5至10員雜芳基,其可選地經1至4個R
1A取代,該等取代基可相同或不同,其中各R
1A係獨立地選自鹵素、氰基、側氧基、硝基、C
1-4烷基、C
3-10環烷基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、具有1至4個獨立地選自氮、氧、或硫之雜原子的5至10員雜芳基、–N(R
1B1)(R
1B2)、-O-R
1B1、-S-R
1B1、–C(O)N(R
1B1)(R
1B2)、–N(R
1B1)C(O)R
1B2、-N(R
1B1)C(O)N(R
1B2)(R
1B3)、–S(O)
0-2R
1B1、–S(O)
2N(R
1B1)(R
1B2)、及–NR
1B1S(O)
2R
1B2,其中各R
1B1、R
1B2、及R
1B3獨立地係氫、C
1-6烷基、或-C
3-6環烷基,其中各R
1A烷基、環烷基、雜環基、芳基、及雜芳基可選地經1至4個R
1C取代,該等取代基可相同或不同,且其中各R
1C獨立地係C
1-4烷基、鹵素、氰基、-O-R
1D1、或-N(R
1D1)(R
1D2),其中各R
1D1及R
1D2獨立地係氫或C
1-6烷基,其中各R
1B1及R
1B2烷基及環烷基可選地經1至3個鹵素取代。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
1係噻唑基、
唑基、吡啶基、嘧啶基、或嗒
基,其各可選地經1至4個R
1A取代,該等取代基可相同或不同,其中各R
1A係獨立地選自鹵素、氰基、側氧基、C
1-4烷基、C
3-10環烷基、具有1至4個獨立地選自氮、及氧之雜原子的3至10員雜環基、–N(R
1B1)(R
1B2)、-O-R
1B1、及–S(O)
0-2R
1B1,其中各R
1B1及R
1B2獨立地係氫、或C
1-6烷基,其中各R
1A烷基、環烷基、及雜環基可選地經1至4個R
1C取代,可相同或不同,且其中各R
1C獨立地係C
1-4烷基、鹵素、或氰基,其中各R
1B1及R
1B2烷基及環烷基可選地經1至3個鹵素取代。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
1係
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、或
。
在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
3係氫。
在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
3係選自氘、鹵素、C
1-6烷基、C
3-6環烷基、-O-R
3A1、及-N(R
3A1)(R
3A2),其中C
1-6烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C
1-4烷氧基及鹵素,且其中各R
3A1及R
3A2獨立地係氫或可選地經1至3個鹵素取代之C
1-4烷基,該等鹵素可相同或不同。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
3係選自鹵素或可選地經1至3個鹵素取代之C
1-3烷基。在一些實施例中,鹵素係-F。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
3係選自-F、-Cl、-CH
3、或-CF
3。
在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,各R
4係獨立地選自氘、鹵素、C
1-6烷基、C
3-6環烷基、-O-R
4A1、及-N(R
4A1)(R
4A2),其中C
1-6烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C
1-4烷氧基及鹵素,且其中各R
4A1及R
4A2獨立地係氫或可選地經1至3個鹵素取代之C
1-4烷基,該等鹵素可相同或不同。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,各R
4係鹵素。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,各R
4係-F。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,n係0、1、或2。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,n係0。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,n係1。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,n係2。
在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
6係氫、鹵素、氰基、C
1-4烷基、C
1-4烷氧基、或C
3-6環烷基,其中C
1-4烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且選自C
1-4烷氧基及鹵素。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
6係鹵素。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,-F或-Cl。
在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
7係氫、鹵素、氰基、C
1-4烷基、C
1-4烷氧基、或C
3-6環烷基,其中C
1-4烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且選自C
1-4烷氧基及鹵素。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
7係氫或鹵素。在式(I)、(Ia)、(II)、及(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,R
7係氫或-F。
在式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽之一些實施例中,係選自由下列所組成之群組:
、
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、
、
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、
、
、
、
、
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、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
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、
、
、
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、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、
、及
,
或其醫藥上可接受之鹽。
此外,本揭露提供醫藥組成物,該醫藥組成物包含作為活性成分之至少一種本揭露之化合物、或其前藥化合物、或其醫藥學上可接受之鹽或溶劑合物,其與醫藥上可接受之載劑一起。
本揭露之醫藥組成物可額外包含作為活性成分之一或多種其他化合物,像是前藥化合物、或其他酶抑制劑。
組成物適合於口服、直腸、局部、腸胃外(包括皮下、肌肉內、及靜脈內)、眼睛(眼內)、肺(鼻或頰吸入)、或鼻內投予,儘管在任何給定情況中最適合之途徑將取決於所治療之病況之性質及嚴重程度、及活性成分之性質。其可方便地以單位劑型呈現,且可藉由藥學技術領域中已知的任何方法製備。
在實際使用中,本揭露之化合物可作為活性成分與根據習知醫藥化合物技術之醫藥載劑密切混合而組合。該載劑可取決於所欲投予(例如,口服或腸胃外(包括靜脈內))之製備形式而成各種廣泛形式。在製備用於口服劑型之組成物,可採用任意常見醫藥媒介物,諸如,例如在口服液體製劑(諸如,例如懸浮液、酏劑、及溶液)的情況下,可採用水、二醇、油、醇、調味劑、防腐劑、著色劑、及類似物;或在口服固體製劑(諸如,例如粉末、硬質及軟質膠囊、及錠劑)的情況下,可採用載劑,諸如澱粉、糖、微晶纖維素、稀釋劑、造粒劑、潤滑劑、黏合劑、崩散劑、及類似物,其中固體口服製劑較液體製劑為佳。
因為其易於投予,錠劑及膠囊代表最有利的口服劑量單位形式,其中採用固體醫藥載劑。若需要,錠劑可藉由標準水性或非水性技術塗佈。此類組成物及製劑應含有至少0.1百分比之活性化合物。此等組成物中之活性化合物之百分比當然可變化,且可方便地在單位重量之約2重量百分比至約60重量百分比之間變化。此類治療有用之組成物中之活性化合物之量係使得將獲得有效劑量的量。活性化合物亦可以鼻內投予,例如液滴或噴霧。
錠劑、丸劑、膠囊、及類似物亦可含有黏合劑,諸如膠狀龍膠、阿拉伯膠、玉米澱粉、或明膠;賦形劑,諸如磷酸二鈣;崩散劑,諸如玉米澱粉、馬鈴薯澱粉、藻酸;潤滑劑,諸如硬脂酸鎂;及甜味劑,諸如蔗糖、乳糖、或糖精。當劑量單位形式為膠囊,除了上述類型之材料外,其可含有液體載劑,諸如脂肪油。
各種其他材料可作為塗層存在、或修飾劑量單位之物理形式。舉例而言,錠劑可塗佈有蟲膠、糖、或二者。糖漿或酏劑除了活性成分以外,可含有蔗糖作為甜味劑、甲基及丙基對羥苯甲酸酯作為防腐劑、染料、及調味劑(諸如櫻桃或橘子風味)。
在一些實施例中,本揭露之化合物亦可用作具有各種相對陽離子(countercation)之鹽,以產生可口服調配物。
本揭露之化合物亦可腸胃外投予。此等活性化合物之溶液或懸浮液可在水中適當地與界面活性劑(諸如羥基-丙基纖維素)混合。分散液亦可在甘油、液體聚乙二醇、及其在油中之混合物中製備。在一般儲存及使用條件下,此等製劑含有防腐劑以防止微生物生長。
適用於可注射用途之醫藥形式包括無菌水溶液或分散液、及用於無菌可注射溶液或分散液之即時製備的無菌粉末。在所有情況下,該形式必須為無菌,且必須在容易注射性存在的情況下為流體。其必須在製造及儲存條件下穩定,且必須在對抗微生物(諸如細菌及真菌)汙染作用下保存。載劑可係含有例如水、乙醇、多元醇(例如甘油、丙二醇、及液體聚乙二醇)、其適合混合物、及植物油之溶劑或分散媒介物。
可採用任意適合之投予途徑,以提供哺乳動物(尤其是人類)有效劑量之本揭露之化合物。例如,可採用口服、直腸、局部、腸胃外、眼、肺、鼻、及類似者。劑型包括錠劑、片劑、分散液、懸浮液、溶液、膠囊、乳膏、軟膏、霧劑、及類似物。在一些實施例中,本揭露之化合物係口服投予。
套組
本文亦提供一種套組,其包括本揭露之化合物或其醫藥上可接受之鹽、互變異構物、立體異構物、立體異構物之混合物、前藥、或氘化類似物、及適合的包裝。在一個實施例中,套組進一步包括使用說明。在一個態樣中,套組包括本揭露之化合物或其醫藥上可接受之鹽、互變異構物、立體異構物、立體異構物之混合物、前藥、或氘化類似物、及化合物在治療適應症(包括本文所述之疾病或病況)中的標籤及/或使用說明。
本文亦提供一種製品,其在合適的容器中包括本文所述之化合物或其醫藥上可接受之鹽、互變異構物、立體異構物、立體異構物之混合物、前藥、或氘化類似物。容器可係小瓶、罐子、安瓿、預載注射器、及靜脈內袋。
處理方法及用途
本揭露進一步係關於本文所揭示之化合物用於藉由該等化合物結合LPAR1來治療及/或預防疾病及/或病況的用途。此外,本揭露係關於一種該等化合物用於製備用於透過該等化合物結合LPAR1來治療及/或預防疾病及/或病況之藥劑的用途。
如本文中所指之藥劑可藉由習知程序製備,包括根據本揭露之化合物與醫藥上可接受之載劑的組合。
在一些實施例中,本文提供一種在有需要之患者中治療及/或預防LPAR1介導之疾病或病況的方法,其包含向該患者投與治療有效量之式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽、或包含式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽的組成物。
在一些實施例中,LPAR1介導之疾病或病況包括彼等其中存在及/或觀測到絕對或相對過量之LPA者。
在一些實施例中,LPAR1介導之疾病或病況包括纖維化、傷口癒合、癌症、疼痛、呼吸病症、過敏性病症、神經系統病症、心血管病症、或發炎性病症。
在一些實施例中,LPAR1介導之疾病或病況係間質性肺病(ILD)。在一些實施例中,間質性肺病(ILD)係非特異性間質性肺炎(NSIP)、類肉瘤病、石綿肺症(與職業暴露相關之ILD)、漸進性纖維化ILD、特發性間質性肺炎(IIP)、結締組織疾病相關之間質性肺病(CTD-ILD)、類風濕性關節炎相關ILD、硬皮症相關ILD、或外因性肺泡肺泡炎。
在一些實施例中,LPAR1介導之疾病或病況係慢性腎病(CKD)。在一些實施例中,慢性腎病係補體腎絲球病變、膜性腎絲球病變、多囊性腎病、IgA腎病變、局部節段性腎絲球硬化症(FSGS)、或亞伯氏症候群(Alport syndrome)。
在一些實施例中,LPAR1介導之疾病或病況包括纖維化。在一些實施例中,纖維化包括肺纖維化、腎纖維化、肝纖維化、眼纖維化、或心臟纖維化。
在一些實施例中,LPAR1介導之疾病或病況包括肺纖維化。在一些實施例中,肺纖維化包括特發性肺纖維化(IPF)。在一些實施例中,肺纖維化包括漸進性纖維化間質性肺病(PF-ILD)。在一些實施例中,肺纖維化包括肺纖維化繼發於全身性發炎性疾病,諸如類風濕性關節炎、硬皮症、狼瘡、隱原性纖維化肺泡炎、輻射誘導之纖維化、慢性阻塞性肺病(COPD)、硬皮症、慢性氣喘、矽肺病、石棉誘導之肺或胸膜纖維化、急性肺損傷及急性呼吸窘迫(包括細菌性肺炎誘導、創傷誘導、病毒肺炎誘導、呼吸器誘導、非肺部敗血症誘導、及吸入誘導)。
在一些實施例中,LPAR1介導之疾病或病況包括腎纖維化。在一些實施例中,腎纖維化包括與損傷/纖維化(腎纖維化)相關之慢性腎病變,例如腎絲球腎炎繼發於全身性發炎性疾病,諸如狼瘡及硬皮症、糖尿病、腎絲球腎炎、局部節段性腎絲球硬化症、IgA腎病變、高血壓、異體移植及亞伯氏;腸道纖維化,例如硬皮症、及輻射誘導之腸道纖維化。
在一些實施例中,LPAR1介導之疾病或病況包括肝纖維化。在一些實施例中,肝纖維化包括肝臟硬化、酒精誘發肝纖維化、非酒精性脂肪肝炎(NASH)、膽道損傷、原發性膽汁性肝硬化、感染或病毒誘導肝纖維化(例如慢性HCV感染)、及自體免疫肝炎。
在一些實施例中,LPAR1介導之疾病或病況包括頭頸纖維化,例如輻射誘導。
在一些實施例中,LPAR1介導之疾病或病況包括角膜疤痕,例如,由於LASIK(雷射輔助原位角膜磨削術)、角膜移植、或小樑切除術。在一些實施例中,式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽係用於改善由諸如角膜手術(諸如LASIK或白內障手術)所引起之角膜敏感性減少、由角膜退化所引起之角膜敏感性減少、及由此所引起之乾眼症狀。在一些實施例中,式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽係用於治療或預防眼睛發炎及過敏性結膜炎、春季結膜炎、及乳頭性結膜炎。在一些實施例中,式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽係用於治療或預防伴隨有乾眼之休格倫氏病、或發炎性疾病。
在一些實施例中,LPAR1介導之疾病或病況包括另一纖維化病況,諸如增生性疤痕及蟹足腫,例如,燙傷誘導或手術性、類肉瘤病、硬皮症、脊髓損傷/纖維化、骨髓纖維化、血管再狹窄、動脈粥樣硬化、動脈硬化、華格納氏肉芽病、混合結締組織疾病、及佩洛尼氏病。
在一些實施例中,LPAR1介導之疾病或病況包括疼痛。在一些實施例中,疼痛包括神經病理性疼痛。在一些實施例中,疼痛包括急性疼痛。在一些實施例中,疼痛包括慢性疼痛。
在一些實施例中,LPAR1介導之疾病或病況包括癌症。在一些實施例中,癌症包括卵巢癌、結腸癌、前列腺癌、乳癌、黑色素瘤、頭頸癌、腸癌(結腸直腸癌)、及甲狀腺癌。在一些實施例中,癌症包括實體腫瘤,諸如(諸如膀胱、腸道、腦、乳房、子宮內膜、心臟、腎臟、肺、淋巴球組織(淋巴瘤)、卵巢、胰臟、或其他內分泌器官(甲狀腺)、前列腺、皮膚(黑色素瘤、或基底細胞癌)或血液腫瘤(諸如白血病),在該疾病的任意階段轉移或不轉移。在一些實施例中,癌症包括急性淋巴母細胞白血病、急性骨髓性白血病、腎上腺皮質癌、肛門癌、闌尾癌、星狀細胞瘤、非典型畸胎/橫紋肌樣腫瘤、基底細胞瘤、膽管癌、膀胱癌、骨癌(骨肉瘤、及惡性纖維組織細胞瘤)、腦幹神經膠質瘤、腦腫瘤、腦部及脊髓腫瘤、乳癌、支氣管腫瘤、勃兒基特氏淋巴瘤、子宮頸癌、慢性淋巴球性白血病、慢性骨髓性白血病、結腸癌、結腸直腸癌、顱咽管瘤、皮膚T細胞淋巴癌、胚胎細胞瘤、子宮內膜癌、室管膜母細胞瘤、室管膜瘤、食道癌、尤文氏肉瘤家族腫瘤、眼癌、視網膜母細胞瘤、膽囊癌、胃部(胃)癌、胃腸類癌、胃腸道基質瘤(GIST)、胃腸道基質細胞瘤、生殖細胞瘤、神經膠質瘤、毛細胞白血病、頭頸癌、肝細胞(肝)癌、霍奇金氏淋巴瘤、下咽癌、眼球內黑色素瘤、胰島細胞腫瘤(內分泌胰腺)、卡波西氏肉瘤、腎癌、蘭格罕細胞組織球增多症、喉頭癌、白血病、急性淋巴母細胞性白血病、急性骨髓性白血病、慢性淋巴球性白血病、慢性骨髓性白血病、毛)細胞白血病、肝癌、非小細胞肺癌、小細胞肺癌、勃兒基特氏淋巴瘤、皮膚T細胞淋巴癌、霍奇金氏淋巴瘤、非霍奇金氏淋巴瘤、淋巴瘤、華氏巨球蛋白血症、神經管胚細胞瘤、髓上皮瘤、黑色素瘤、間皮瘤、口腔癌、慢性骨髓性白血病、骨髓性白血病、多發性骨髓瘤、鼻咽癌、神經母細胞瘤、非霍奇金氏淋巴瘤、非小細胞肺癌、口腔癌、口咽癌、骨肉瘤、骨頭之惡性纖維組織細胞瘤、卵巢癌、卵巢上皮細胞癌、卵巢生殖細胞瘤、卵巢低惡性度腫瘤、胰臟癌、乳頭狀瘤症、副甲狀腺癌、陰莖癌、咽癌、中度分化之松果體實質瘤、松果體母細胞瘤及幕上神經外胚層母細胞瘤(supratentorial primitive neuroectodermal tumors)、腦下垂體腫瘤、漿細胞瘤/多發性骨髓瘤、胸膜肺母細胞瘤、原發性中樞神經系統淋巴瘤、前列腺癌、直腸癌、腎細胞(腎臟)癌、網膜芽細胞瘤、橫紋肌肉瘤、唾液腺癌、肉瘤、尤文氏肉瘤家族腫瘤、肉瘤、卡波西、塞扎萊症候群(Sezary syndrome)、皮膚癌、小細胞肺癌、小腸癌、軟組織肉瘤、鱗狀細胞癌、胃(胃部)癌、幕上神經外胚層母細胞瘤、T細胞淋巴瘤、睾丸癌、咽喉癌症、胸腺瘤及胸腺癌、甲狀腺癌、尿道癌、子宮癌、子宮肉瘤、陰道癌、陰門癌、華氏巨球蛋白血症、及威爾姆氏腫瘤。
在一些實施例中,LPAR1介導之疾病或病況包括呼吸或過敏病症。在一些實施例中,呼吸或過敏病症包括氣喘、支氣管周圍纖維化、閉塞性細支氣管炎、及慢性阻塞性肺病(COPD)。在一些實施例中,COPD包括慢性支氣管炎或肺氣腫、肺部高血壓、間質肺纖維化及/或氣道發炎、及囊性纖維變性。在一些實施例中,呼吸疾病包括成人呼吸窘迫症候群及過敏性(外因)氣喘、非過敏性(內因)氣喘、急性嚴重氣喘、慢性氣喘、臨床氣喘、夜間氣喘、過敏原誘導之氣喘、阿斯匹靈敏感性氣喘、運動誘導之氣喘、等二氧化碳過度換氣、兒童發病氣喘、成人發病氣喘、咳嗽變異型氣喘、職業型氣喘、類固醇抗性氣喘、季節性氣喘、季節性過敏性鼻炎、長期過敏性鼻炎、及缺氧。
在一些實施例中,LPAR1介導之疾病或病況包括神經系統病症。在一些實施例中,神經系統病症包括阿茲海默氏症、腦水腫、腦缺血、中風、多發性硬化症、神經病變、帕金森式症、在鈍器或手術創傷之後發現的神經病況(包括手術後認知功能異常、以及脊髓或腦幹損傷)、以及病症之神經方面,諸如椎間盤退變性疾病及坐骨神經痛。
在一些實施例中,LPAR1介導之疾病或病況包括心血管病症。在一些實施例中,心血管病症包括心律不整(心房或心室或兩者);動脈粥樣硬化及其後遺症;心絞痛;心節律不整;心肌缺氧;心肌梗塞;心臟或血管動脈瘤;脈管炎;中風;肢體、器官、或組織之周邊阻塞性動脈病變;在腦部、心臟、或其他器官或組織之缺血後再灌流損傷;內毒素、手術、或創傷性休克;高血壓;心臟瓣膜疾病;心臟衰竭;異常血壓;休克;血管收縮(包括與偏頭痛相關者);限於單一器官或組織之血管異常及心血管功能不全。
在一些實施例中,LPAR1介導之疾病或病況包括肺纖維化、腎纖維化、肝纖維化、疤痕、氣喘、鼻炎、慢性阻塞性肺病(COPD)、肺部高血壓、間質性肺纖維化、關節炎、過敏、牛皮癬、發炎性腸病、成人呼吸窘迫症候群、心肌梗塞、動脈瘤、中風、癌症、疼痛、增殖性病症、及發炎性病況。
在一些實施例中,LPAR1介導之疾病或病況係肝病。在一些實施例中,肝病係C型肝炎、肝癌、家族性混合型高脂血症、非酒精性脂肪肝病(NAFLD)、進行性家族性肝內膽汁鬱滯症、原發性膽汁性肝硬化(PBC)或(PSC)。在一些實施例中,肝病係PSC。在一些實施例中,肝病包含門脈高壓。在一些實施例中,肝癌包含肝細胞癌(HCC)、膽管癌、血管肉瘤(angiosarcoma或hemangiosarcoma)。在一些實施例中,肝癌包含HCC。在一些實施例中,NAFLD包含脂肪變性。在一些實施例中,NAFLD包含NASH。在一些實施例中,NAFLD或NASH包含肝纖維化。在一些實施例中,NAFLD或NASH包含肝硬化。在一些實施例中,NAFLD或NASH包含代償性肝硬化。在一些實施例中,NAFLD或NASH包含代償不全之肝纖維化。在一些實施例中,NAFLD包含HCC。在一些實施例中,肝病係NASH。
在一些實施例中,本文提供一種在有需要之患者中治療及/或預防NAFLD或NASH的方法,其包含向該患者投與治療有效量之式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽、或包含式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽的組成物。在一些實施例中,NAFLD或NASH包含肝纖維化。在一些實施例中,NAFLD或NASH包含肝硬化。在一些實施例中,肝硬化係代償性肝硬化。在一些實施例中,肝硬化係代償不全之肝硬化。在一些實施例中,NAFLD或NASH包含HCC。
在一些實施例中,本文提供一種在有需要之患者中治療及/或預防肝病或病況的方法,其包含向該患者投與治療有效量之式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽、或包含式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽的組成物。在一些實施例中,肝病或病況係肝纖維化。在一些實施例中,肝病或病況係肝硬化。在一些實施例中,肝硬化係代償性肝硬化。在一些實施例中,肝硬化係代償不全之肝硬化。在一些實施例中,肝病或病況係HCC。
在一些實施例中,本揭露係關於一種根據式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽於製備用於預防及/或治療本文所揭示之LPAR1介導之疾病或病況之藥劑中的用途。
劑量
所採用之活性成分之有效劑量可依所採用之特定化合物、投予模式、治療之病況、及治療之病況的嚴重程度而變化。此類劑量可藉由所屬技術領域中具有通常知識者來容易地確定。
當本揭露之化合物係表示治療或預防LPAR1介導之疾病或病況,當本揭露之化合物以每公斤動物體重約0.1毫克至約300毫克之每日劑量投予時,通常獲得了令人滿意的結果。在一些實施例中,本揭露之化合物係以單獨每日劑量給予、或以一天兩次至六次之分開劑量給予,或以持續釋放形式給予。對於大多數哺乳動物,日總劑量係約1毫克至約1000毫克,或約1毫克至約50毫克。在70kg成人人類之情況下,日總劑量通常為約0.1毫克至約200毫克。可調整此劑量方案以提供最適治療反應。在一些實施例中,日總劑量為約1毫克至約900毫克、約1毫克至約800毫克、約1毫克至約700毫克、約1毫克至約600毫克、約1毫克至約400毫克、約1毫克至約300毫克、約1毫克至約200毫克、約1毫克至約100毫克、約1毫克至約50毫克、約1毫克至約20毫克、或約1毫克至約10毫克。
本申請之化合物或其組成物可使用任何上述合適的模式每天投予一、二、三、或四次。此外,投予化合物或用化合物治療可持續數天;例如,針對一個治療週期,通常治療將持續至少7天、14天、或28天。治療週期經常在週期之間以約1至28天、通常約7天或約14天的休息期交替。在其他實施例中,治療週期亦可係連續的。
在一些實施例中,本文所提供之方法包含向對象投予約1至800mg之初始每日劑量的本文所述之化合物,並藉由增量增加劑量直到達成臨床療效。可使用約5、10、25、50、或100mg之增量來增加劑量。劑量可每天、每隔一天、每週兩次、或每週一次增加。
組合
在一些實施例中,本文提供之式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽係與一或多種額外治療劑組合投予,以治療或預防本文所揭示之疾病或病況。在一些實施例中,一或多種額外治療劑係一、二、三、或四種額外治療劑。在一些實施例中,一或多種額外治療劑係一種額外治療劑。在一些實施例中,一或多種額外治療劑係二種額外治療劑。在一些實施例中,一或多種額外治療劑係三種額外治療劑。在一些實施例中,一或多種額外治療劑係四種額外治療劑。
在一些實施例中,本文提供之醫藥組成物具有式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽、及一或多種額外治療劑。在一些實施例中,一或多種額外治療劑係一、二、三、或四種額外治療劑。在一些實施例中,一或多種額外治療劑係一種額外治療劑。在一些實施例中,一或多種額外治療劑係二種額外治療劑。在一些實施例中,一或多種額外治療劑係三種額外治療劑。在一些實施例中,一或多種額外治療劑係四種額外治療劑。
在一些實施例中,一或多種額外治療劑係選自血管收縮素轉化酶(ACE)抑制劑、腺苷A3受體促效劑、脂聯素受體促效劑、AKT蛋白激酶抑制劑、AMP激酶活化劑、AMP活化蛋白激酶(AMPK)活化劑、澱粉素受體促效劑、血管收縮素II AT-1受體拮抗劑、雄性激素受體拮抗劑、細胞凋亡信息調節激素1 (ASK1)抑制劑、ATP檸檬酸裂解酶抑制劑、載脂蛋白C3 (APOC3)拮抗劑、自噬蛋白調節劑、自毒素抑制劑、Axl酪胺酸激酶受體抑制劑、Bax蛋白刺激劑、生物活性脂質、抑鈣素促效劑、大麻素受體調節劑、凋亡蛋白酶抑制劑、凋亡蛋白酶-3刺激劑、細胞自溶酵素抑制劑(例如,細胞自溶酵素B抑制劑)、窖蛋白1抑制劑(Caveolin 1 inhibitor)、CCR2趨化因子拮抗劑、CCR3趨化因子拮抗劑、CCR5趨化因子拮抗劑、CD3拮抗劑、氯通道刺激劑、膽固醇增溶劑、CNR1抑制劑、週期蛋白D1抑制劑、細胞色素P450 7A1抑制劑、細胞色素P450 2E1 (CYP2E1)抑制劑、二醯基甘油O醯基轉移酶1抑制劑(DGAT1)抑制劑、CXCR4趨化因子拮抗劑、二肽基肽酶IV抑制劑、內皮唾酸蛋白調節劑(Endosialin modulator)、內皮一氧化氮合成酶刺激劑、伊紅趨素配體抑制劑、胞外基質蛋白調節劑、類法尼醇X受體促效劑、脂肪酸合成酶抑制劑、FGF1受體促效劑、纖維母細胞活化蛋白(FAP)抑制劑、纖維母細胞生長因子受體配體(例如FGF-15、FGF-19、FGF-21)、魚油、半乳糖凝集素-3抑制劑、升糖素受體促效劑、類升糖素胜肽1受體拮抗劑、糖皮質素受體拮抗劑、葡萄糖6-磷酸鹽1-去氫酶抑制劑、麩胺酸酶抑制劑、麩胺基硫前驅物、G-蛋白偶聯之膽酸受體1促效劑、G-蛋白偶聯受體84拮抗劑、刺蝟蛋白(Hh)調節劑、C型肝炎病毒NS3蛋白酶抑制劑、肝細胞核因子4α調節劑(HNF4A)、肝細胞生長因子調節劑、組蛋白去乙醯酶抑制劑、HMG CoA還原酶抑制劑、11β-羥類固醇去氫酶(11β-HSD1)抑制劑、缺氧誘導型因子-2α抑制劑、IL-1β拮抗劑、IL-6受體促效劑、IL-10促效劑、IL-11拮抗劑、IL-17拮抗劑、迴腸鈉膽酸共運輸蛋白抑制劑、胰島素增敏劑、胰島素配體促效劑、胰島素受體促效劑、整合素調節劑、整合素拮抗劑、介白素-1受體-相關激酶4(IRAK4)抑制劑、Jak2酪胺酸激酶抑制劑、己酮糖激酶(KHK)抑制劑、克洛素β刺激劑、瘦素、瘦素類似物、5-脂氧合酶抑制劑、脂蛋白脂酶抑制劑、肝臟X受體、LPL基因刺激劑、溶血磷脂-1受體(Lysophosphatidate-1 receptor, LPAR-1)拮抗劑、賴胺醯氧化酶同源物2 (LOXL2)抑制劑、LXR反向促效劑、巨噬細胞甘露糖受體1調節劑、基質金屬蛋白酶(MMP)抑制劑、MCH受體-1拮抗劑、MEKK-5蛋白激酶抑制劑、膜銅胺氧化酶(VAP-1)抑制劑、甲硫胺酸胺基肽酶-2抑制劑、甲基CpG結合蛋白2調節劑、微小RNA-132 (miR-132)拮抗劑、微小RNA-21 (miR-21)抑制劑、粒線體解聯劑、混合譜系激酶-3抑制劑、髓磷脂鹼性蛋白刺激劑、NACHT LRR PYD域蛋白3 (NLRP3)抑制劑、NAD依賴性去乙醯酶sirtuin-1刺激劑、NADPH氧化酶抑制劑(NOX)、菸鹼酸受體1促效劑、P2X7嘌呤受體調節劑、P2Y13嘌呤受體刺激劑、PDE 3抑制劑、PDE 4抑制劑、PDE 5抑制劑、PDGF受體β調節劑、肽基-脯胺醯基順反異構酶A刺激劑、苯丙胺酸羥化酶刺激劑、磷脂酶C抑制劑、PPARα促效劑、PPARγ促效劑、PPARδ促效劑、PPARγ調節劑、PPARα/δ促效劑、PPARα/γ/δ促效劑、蛋白酶活化受體-2拮抗劑、蛋白激酶調節劑、Rho相關蛋白激酶2 (ROCK2)抑制劑、S-亞硝基麩胱甘肽還原酶(Snitrosoglutathione reductase, GSNOR)酶抑制劑、鈉葡萄糖轉運蛋白-2 (SGLT2)抑制劑、SREBP轉錄因子抑制劑、STAT-1抑制劑、STAT-3調節劑、硬脂醯基CoA去飽和酶-1抑制劑、S-亞硝基麩胱甘肽還原酶(GSNOR)酶抑制劑、細胞介素信號-1刺激劑之抑制因子、細胞介素信號-3刺激劑之抑制因子、脾臟酪胺酸激酶(SYK)抑制劑、轉變生長因子β(TGF-β)、TGF-β拮抗劑(例如,TGF-β1拮抗劑、TGF-β2拮抗劑、TGF-β3拮抗劑、潛伏TGFβ錯合物調節劑)、TGF-β受體拮抗劑、轉變生長因子β活化激酶1(TAK1)、甲狀腺激素受體β促效劑、類鐸受體(TLR)-4拮抗劑、轉麩醯胺酸酶抑制劑、腫瘤壞死因子α(TNFα)配體抑制劑、腫瘤進展基因座2(Tpl2)激酶抑制劑、酪胺酸激酶受體調節劑、GPCR調節劑、核激素受體調節劑、WNT調節劑、YAP/TAZ調節劑、及解連蛋白抑制劑。
一或多種額外治療劑之非限制性實例包括:
ACE抑制劑,諸如依那普利(enalapril);
乙醯CoA羧化酶(ACC)抑制劑,諸如NDI-010976(費索司他(firsocostat))、DRM-01、賈卡賓尼(gemcabene)、PF-05175157、QLT-091382、或PF-05221304;
乙醯CoA羧化酶/二醯基甘油O醯基轉移酶2抑制劑,諸如PF-07055341;
乙醛去氫酶抑制劑,諸如ADX-629;
腺苷受體促效劑,諸如CF-102(納莫德森(namodenoson))、CF-101、CF-502、或CGS21680;
脂聯素受體促效劑,諸如ADP-355、或ADP-399;
澱粉素/抑鈣素受體促效劑,諸如KBP-042、或KBP-089;
AMP活化蛋白激酶刺激劑,諸如PXL-770、或O-304;
AMP激酶活化劑/ATP檸檬酸裂解酶抑制劑,諸如貝培多酸(bempedoic acid)(ETC-1002, ESP-55016);
AMP活化蛋白激酶/內皮一氧化氮合成酶/NAD依賴性去乙醯酶sirtuin-1刺激劑,諸如NS-0200(白胺酸+二甲雙胍(metformin) +西地那非(sildenafil));
雄性激素受體促效劑,諸如LPCN-1144;
血管收縮素II AT-1受體拮抗劑,諸如艾比沙坦(irbesartan);
促血管生成素相關蛋白3抑制劑,諸如IONIS-ANGPTL3-LRx;
自毒素抑制劑,諸如PAT-505、PAT-048、GLPG-1690、X-165、PF-8380、AM-063、或BBT-877;
Axl酪胺酸激酶受體抑制劑,諸如貝西替尼(bemcentinib) (BGB-324、R-428);
Bax蛋白刺激劑,諸如CBL-514;
生物活性脂質,諸如DS-102;
大麻素受體第1型(CNR1)抑制劑,諸如那馬席單抗(namacizumab)、GWP-42004、REV-200、或CRB-4001;
凋亡蛋白酶抑制劑,諸如恩利卡生(emricasan);
泛組織蛋白酶B抑制劑,諸如VBY-376;
泛組織蛋白酶抑制劑,諸如VBY-825;
CCR2/CCR5趨化因子拮抗劑,諸如森尼維若(cenicriviroc)、馬拉韋羅(maraviroc)、CCX-872、或WXSH-0213;
CCR2趨化因子拮抗劑,諸如丙帕鍺(propagermanium);
CCR2趨化因子/血管收縮素II AT-1受體拮抗劑,諸如DMX-200、DMX-250;
CCR2/CCR5趨化因子拮抗劑及FXR促效劑,諸如LJC-242(曲匹氟索(tropifexor)+塞尼維羅克(cenivriviroc));CCR3趨化因子拮抗劑,諸如柏替木單抗(bertilimumab);
氯通道刺激劑,諸如考柔斯同(cobiprostone)、及魯比前列酮(lubiprostone);
CD3拮抗劑,諸如NI-0401(弗拉魯單抗(foralumab));
CXCR4趨化因子拮抗劑,諸如AD-214;
雙甘油酯醯基轉移酶1 (DGAT1)抑制劑,諸如GSK-3008356;
二醯基甘油O醯基轉移酶1(DGAT1)/細胞色素P450 2E1抑制劑(CYP2E1),諸如SNP-610;
二酸甘油酯醯基轉移酶2 (DGAT2)抑制劑,諸如IONIS-DGAT2Rx、或PF-06865571;
二肽基肽酶IV抑制劑,諸如利拉利汀(linagliptin)、依格列汀(evogliptin);
伊紅趨素配體抑制劑,諸如柏替木單抗(bertilimumab)、CM-101;
胞外基質蛋白調節劑,諸如CNX-024;
類法尼醇X受體(FXR)促效劑,諸如AGN-242266、AGN-242256、EP-024297、RDX-023、BWL-200、AKN-083、EDP-305、GNF-5120、GS-9674、LMB-763、奧貝膽酸(obeticholic acid)、Px-102、Px-103、M790、M780、M450、M-480、MET-409、PX20606、EYP-001、TERN-101、TC-100、INT-2228;
類法尼醇X受體(FXR)/G蛋白偶聯膽酸受體1 (TGR5)促效劑,諸如INT-767;
脂肪酸合成酶抑制劑,諸如TVB-2640;
FGF受體促效劑/克洛素β刺激劑,諸如BFKB-8488A (RG-7992);
纖維母細胞生長因子19 (rhFGF19)/細胞色素P450 (CYP) 7A1抑制劑,諸如NGM-282;
纖維母細胞生長因子21 (FGF-21)配體,諸如BMS-986171、BIO89-100、B-1344、或BMS-986036;
纖維母細胞生長因子21 (FGF-21)/升糖素類胜肽1(GLP-1)促效劑,諸如YH-25723 (YH-25724; YH-22241)、或AKR-001;
魚油組成物,諸如二十碳五烯酸乙酯(Vascepa
®);
半乳糖凝集素-3抑制劑,諸如GR-MD-02、GB-1107 (Gal-300)、或GB1211 (Gal-400);
類升糖素肽1受體(GLP1R)促效劑,諸如AC-3174、利拉魯肽(liraglutide)、可妥度肽(cotadutide) (MEDI-0382)、艾塞那肽(exenatide)、SAR-425899、LY-3305677、HM-15211、YH-25723、YH-GLP1、RPC-8844、PB-718、或索馬魯肽(semaglutide);
糖皮質素受體拮抗劑,諸如CORT-118335(米瑞蘭特(miricorilant));
葡萄糖6-磷酸1-去氫酶抑制劑,諸如ST001;
G蛋白偶聯膽酸受體1 (TGR5)促效劑,諸如RDX-009、或INT-777;
熱休克蛋白47 (HSP47)抑制劑,諸如ND-L02-s0201;
HMG CoA還原酶抑制劑,諸如阿托伐他汀、氟伐他汀、匹伐他汀、普伐他汀、羅伐他汀、或辛伐他汀;
缺氧誘導因子-2α抑制劑,諸如PT-2567;
IL-10促效劑,諸如peg-伊洛白介素(peg-ilodecakin);
迴腸鈉膽酸共轉運蛋白抑制劑,諸如奧维昔巴特(odevixibat)(A-4250)、沃利席貝特(volixibat)乙醇鉀水合物(SHP-262)、GSK2330672、CJ-14199、依洛昔巴特(A-3309);
胰島素增敏劑,諸如KBP-042、MSDC-0602K、MSDC-5514、Px-102、RG-125 (AZD4076)、VVP-100X、CB-4211、或ETI-101;
胰島素配體/ds胰島素受體促效劑,諸如ORMD-0801;
整合素拮抗劑,諸如IDL-2965;
IL-6受體促效劑,諸如KM-2702;
酮己糖激酶(KHK)抑制劑,諸如PF-06835919;
β克洛素(KLB)- FGF1c促效劑,諸如MK-3655 (NGM-313);
5-脂氧合酶抑制劑,諸如泰魯司特(tipelukast) (MN-001)、DS-102 (AF-102);
脂蛋白脂酶抑制劑,諸如CAT-2003;
LPL基因刺激劑,諸如阿利潑金替帕波維(alipogene tiparvovec);
肝臟X受體(LXR)調節劑,諸如PX-L603、PX-L493、BMS-852927、T-0901317、GW-3965、或SR-9238;
溶血磷脂-1受體拮抗劑,諸如BMT-053011、UD-009 (CP-2090)、AR-479、ITMN-10534、BMS-986020、或KI-16198;
賴胺醯氧化酶同源物2抑制劑,諸如西妥珠單抗(simtuzumab)、或PXS-5382A (PXS-5338);
巨噬細胞甘露糖受體1調節劑,諸如泰曼諾西普(tilmanocept)-Cy3(鎝Tc 99m泰曼諾西普);
膜銅胺氧化酶(VAP-1)抑制劑,諸如TERN-201;
MEKK-5蛋白質激酶(ASK-1)抑制劑,諸如GS-4997、SRT-015、或GS-444217、GST-HG-151;
MCH受體-1拮抗劑,諸如CSTI-100 (ALB-127158);
甲硫胺酸胺基肽酶-2抑制劑,諸如ZGN-839、ZGN-839、或ZN-1345;
甲基CpG結合蛋白2調節劑,諸如巰乙胺(mercaptamine);
粒線體解聯劑,諸如2,4-二硝基酚、或HU6;
混合譜系激酶-3抑制劑,諸如URMC-099-C;
髓磷脂鹼性蛋白刺激劑,諸如奧利索西(olesoxime);
NADPH氧化酶1/4抑制劑,諸如GKT-831、或APX-311;
菸鹼酸受體1促效劑,諸如ARI-3037MO;
硝唑尼特(nitazoxinide);
NACHT LRR PYD域蛋白3 (NLRP3)抑制劑,諸如KDDF-201406-03、NBC-6、IFM-514、或JT-194 (JT-349);
核受體調節劑,諸如DUR-928 (DV-928);
P2X7嘌呤受體調節劑,諸如SGM-1019;
P2Y13嘌呤受體刺激劑,諸如CER-209;
PDE 3/4抑制劑,諸如泰魯司特(tipelukast) (MN-001);
PDE 5抑制劑,諸如西地那非、或MSTM-102;
PDGF受體β調節劑,諸如BOT-191、或BOT-509;
肽基-脯胺醯基順反異構酶抑制劑,諸如CRV-431 (CPI-432-32)、NVP-018、或NV-556 (NVP-025);
苯丙胺酸羥化酶刺激劑,諸如HepaStem;
PPAR促效劑(包括PPARα促效劑、PPARα/δ促效劑、PPARα/δ/γ促效劑、PPARδ促效劑),諸如依拉菲貝諾(elafibranor)(GFT-505)、MBX-8025、氘化皮利酮-R-鏡像異構物、皮利酮、DRX-065、沙羅格列扎(saroglitazar)、或IVA-337;PPARα促效劑,諸如克氯吩貝鋁、苯扎貝特(bezafibrate)、環丙貝特(ciprofibrate)、非諾貝特膽鹼(choline fenofibrate)、克利貝特(clinofibrate)、克氯吩貝、氯貝胺(clofibride)、非諾貝特、吉非貝齊(gemfibrozil)、培馬貝特(pemafibrate)、羅尼貝特(ronifibrate)、雙貝特(simfibrate)、ω-3脂肪酸(魚油,例如二十碳五烯酸乙酯(Vascepa
®)、或二十二碳六烯酸)、匹立尼酸、GW409544、AZ 242、LY518674、NS-220、AVE8134、BMS-711939、阿格列扎(aleglitazar)、莫格列扎(muraglitzar)、或沙羅格列扎;
PPARα/δ促效劑,諸如依拉菲貝諾;
PPARα/δ/γ促效劑,諸如拉尼非貝諾(lanifibranor);
PPARδ促效劑,諸如司拉德帕(seladelpar);
蛋白酶活化受體-2拮抗劑,諸如PZ-235;
蛋白激酶調節劑,諸如CNX-014;
Rho相關蛋白激酶(ROCK)抑制劑,諸如REDX-10178 (REDX-10325)、或KD-025;
半卡肼-敏感胺氧化酶/血管黏附蛋白-1(SSAO/VAP-1)抑制劑,諸如PXS-4728A;
S-亞硝基麩胱甘肽還原酶(GSNOR)酶抑制劑,諸如SL-891;
鈉葡萄糖轉運蛋白-2 (SGLT2)抑制劑,諸如伊格列淨(ipragliflozin)、瑞格列淨(remogliflozin etabonate)、艾托格列淨(ertugliflozin)、達格列淨(dapagliflozin)、托格列淨(tofogliflozin)、或所格列淨(sotagliflozin);
SREBP轉錄因子抑制劑,諸如CAT-2003、或MDV-4463;
硬脂醯CoA去飽和酶-1抑制劑,諸如阿拉克爾(aramchol);
甲狀腺荷爾蒙受體(THR)β促效劑,諸如瑞司特羅姆(resmetriom) (MGL-3196)、MGL-3745、VK-2809;
TLR-2/TLR-4拮抗劑,諸如VB-201 (CI-201);
TLR-4拮抗劑,諸如JKB-121;
酪胺酸激酶受體調節劑,諸如CNX-025、或GFE-2137(再利用硝唑尼特);
GPCR調節劑,諸如CNX-023;
核激素受體調節劑,諸如Px-102;
黃嘌呤氧化酶/尿酸鹽陰離子交換劑1 (URAT1)抑制劑,諸如RLBN-1001、RLBN-1127;及
解連蛋白抑制劑,諸如乙酸拉瑞唑來(lorazotide acetate) (INN-202)。
一或多種額外治療劑之額外非限制性實例包括
ACE抑制劑,諸如貝那普利(benazepril)、咪達普利(imidapril);
腺苷A3受體拮抗劑,諸如FM-101;
阿德羅平刺激劑,諸如RBT-2;
白蛋白調節劑,諸如SYNT-002;
醛固酮/礦皮質素受體拮抗劑,諸如MT-3995;
異體骨髓衍生之間質幹細胞療法,諸如ORBCEL-M;
異體擴增脂肪衍生之幹細胞療法,諸如Elixcyte™;
AMP活化蛋白激酶刺激劑/前蛋白轉化酶PC9抑制劑,諸如O-304;
AMP活化蛋白激酶刺激劑,諸如DZCY-01、MK-8722、PXL-770;
血管收縮素II AT-1受體/CCR2趨化因子拮抗劑,諸如DMX-200;
血管收縮素II AT-2受體促效劑,諸如MOR-107、艾比沙坦;
血管收縮素II受體拮抗劑,諸如氯沙坦(losartan);
血管收縮素原配體抑制劑,諸如ALN-AGT;
抗C1抗體,諸如BIVV-009(蘇替莫單抗(sutimlimab));
抗CB1抗體,諸如GFB-024;
抗CX3CR1奈米抗體,諸如BI-655088;
抗IL-6抗體,諸如COR-001;
抗VEGF-B抗體,諸如CSL-346;
APOA1基因刺激劑/含有蛋白2之溴結構域/含有蛋白4之溴結構域,諸如阿帕他隆(apabetalone);
骨成形性蛋白-7配體調節劑,諸如BMP-7;
鈣通道抑制劑,諸如TBN(席同坤(xiaotongqin));
大麻素CB1受體拮抗劑,諸如JNJ-2463;
CB1反向促效劑,諸如CRB-4001;
凝乳酶抑制劑,諸如氟卡司他(fulacimstat)(BAY-1142524);
環氧合酶1抑制劑,諸如GLY-230;
環氧合酶2/環氧化物水解酶抑制劑,諸如COX-2/可溶性環氧化物水解酶;
細胞色素P450 11B2抑制劑,諸如醛固酮合成酶抑制劑;
外核苷酸焦磷酸酶-PDE-2抑制劑,諸如BLD-0409;
內皮素ET-A/內皮素ET-B受體拮抗劑,諸如愛普替坦(aprocitentan);
腸激酶抑制劑,諸如SCO-792;
紅血球生成素受體拮抗劑,諸如EPO-018B;
類法尼醇X受體促效劑,諸如LMB-763;
FGF/PDGF/β受體拮抗劑/p38 MAP激酶抑制劑,諸如吡非尼酮(pirfenidone);
GHR/IGF1基因抑制劑,諸如阿特西多森鈉(atesidorsen sodium);
GPR40促效劑/GPR84拮抗劑,諸如PBI-4050;
G-蛋白β次單元抑制劑,諸如加利恩(galleon);
G蛋白偶聯受體84調節劑,諸如PBI-4425;
生長激素配體/生長激素受體促效劑,諸如Jintropin AQ™;
生長激素受體促效劑,諸如LAT-8881;
鳥苷酸環化酶受體促效劑/鳥苷酸環化酶刺激劑,諸如帕利西哌(praliciguat);
鳥苷酸環化酶刺激劑,諸如MRL-001、瑞卡昔(runcaciguat);
血基質加氧酶1調節劑,諸如RBT-1;
HIF脯胺醯基羥化酶抑制劑,諸如TRGX-154;
胰島素增敏劑/血管舒緩素(Kallikrein) 1調節劑,諸如DM-199;
整合素α-V/β-3拮抗劑,諸如VPI-2690B;
介白素33配體抑制劑,諸如MEDI-3506;
Kelch樣ECH相關蛋白1調節劑/核紅血球2相關因子2刺激劑,諸如SFX-01;
LDHA基因抑制劑,諸如那朵昔蘭(nedosiran);
5-脂氧合酶活化蛋白抑制劑,諸如AZD-5718;
溶血磷脂-1受體拮抗劑,諸如BMS-002、EPGN-696;
基質胞外磷酸糖蛋白調節劑/降磷素受體促效劑,諸如TPX-200;
MEKK-5蛋白激酶抑制劑,諸如司隆色替(selonsertib);
膜銅胺氧化酶抑制劑,諸如UD-014;
中期因子配體抑制劑,諸如CAB-101;
礦皮質素受體拮抗劑,諸如AZD-9977、艾沙利酮(esaxerenone)、非奈利酮(finerenone)、KBP-5074;
肌凝蛋白2抑制劑,諸如DeciMab™;
NADPH氧化酶1抑制劑/NADPH氧化酶4抑制劑,諸如西他那昔布(setanaxib);
NADPH氧化酶抑制劑,諸如APX-115;
NK1受體拮抗劑/類鴉片受體κ促效劑/類鴉片受體µ拮抗劑,諸如AV-104;
核紅血球2相關因子2刺激劑/TGFβ配體抑制劑,諸如CU01-1001;
核因子κB抑制劑,諸如美氟尼酮(mefunidone)、甲基巴多索隆(bardoxolone methyl)(NSC-713200);
PDE 4抑制劑,諸如ART-648、PCS-499;
PDGF受體β調節劑,諸如BOT-191;
PDGF/VEGF受體拮抗劑,諸如ANG-3070;
PR84拮抗劑/GPR40 (FFAR1)/GPR120 (FFAR4)促效劑/及過氧化體增殖活化受體(PPAR)之部分活化劑,諸如PBI-4547;
PRKAA2基因刺激劑/AMPK活化劑,諸如PF-06679142、PF-06685249;
前列腺環素(PGI2)促效劑,諸如YS-1402;
蛋白C活化劑/醣蛋白Ib (GPIb)拮抗劑,諸如AB-002;
蛋白NOV同源物調節劑,諸如BLR-200;
蛋白酪胺酸磷酸酶-1B抑制劑,諸如MSI-1436;
活性氧物種調節劑抑制劑,諸如SUL-121;
腎素抑制劑,諸如鹽酸伊馬利克倫(imarikiren hydrochloride);
Rho相關蛋白激酶2抑制劑,諸如ANG-4201、RXC-007;
鈉葡萄糖轉運蛋白-2抑制劑,諸如坎格列淨、達格列淨、丙二醇、恩格列淨(empagliflozin);
血栓素A2受體拮抗劑/血栓素合成抑制劑,諸如SER-150;
組織轉麩醯胺酸酶抑制劑,諸如ZED-1227;
TRP陽離子通道C5抑制劑,諸如GFB-887;
TRP陽離子通道C6抑制劑,諸如ALGX-2224;
細胞黏附分子抑制劑,諸如糖苷細菌黏附拮抗劑;
尿酸鹽陰離子交換劑1 (URAT1)/SLC22A12抑制劑,諸如維立諾雷(verinurad) (RDEA3170);
VIP 1/VIP 2受體促效劑,諸如LBT-3627;及
黃嘌呤氧化酶抑制劑,諸如TMX-049、TMX-049DN。
在一些實施例中,一或多種額外治療劑係選自A-4250、AC-3174、乙醯水楊酸、AK-20、阿利潑金、AMX-342、AN-3015、阿拉克爾、ARI-3037MO、ASP-8232、AZD-2693、柏替木單抗、無水甜菜鹼、BI-1467335、BMS-986036、BMS-986171、BMT-053011、BOT-191、BTT-1023、CAT-2003、森尼維若、CBW-511、CER-209、CF-102、CGS21680、CNX-014、CNX-023、CNX-024、CNX-025、考柔斯同、考來維侖、達格列淨、DCR-LIV1、氘化吡格列酮R-鏡像異構物、2,4-二硝基苯酚、DRX-065、DS-102、DUR-928、EDP-305、埃拉佛蘭諾(GFT-505)、恩利卡生、依那普利、艾托格列淨、依格列汀、F-351、夫斯特隆(fluasterone) (ST-002)、FT-4101、GKT-831、GNF-5120、GRI-0621、GR-MD-02、GS-300、GS-4997、GS-9674、HTD-1801、HST-202、HST-201、氫氯噻嗪、埃扣賽伯特(icosabutate) (PRC-4016)、二十碳五烯乙酸乙酯、IMM-124-E、INT-767、INV-240、IONIS-DGAT2Rx、伊格列淨、伊貝沙坦(Irbesarta)、丙帕鍺、IVA-337、JKB-121、KB-GE-001、KBP-042、KD-025、M790、M780、M450、二甲雙胍、西地那非、LC-280126、利拉利汀、利拉魯肽、LJN-452(特洛皮非若)、LM-011、LM-002 (CVI-LM-002)、LMB-763、LYN-100、MBX-8025、MDV-4463、巰乙胺、MGL-3196、MGL-3745、MP-301、MSDC-0602K、納馬單抗、NC-101、NDI-010976、ND-L02-s0201 (BMS-986263)、NGM-282、NGM-313、NGM-386、NGM-395、NP-160、去甲熊去氧膽酸(norursodeoxycholic acid)、NVP-022、O-304、奧貝膽酸(OCA)、25HC3S、奧利索西、PAT-505、PAT-048、PBI-4547、peg-伊洛白介素、吡格列酮、哌非尼酮(pirfenidone)、PRI-724、PX20606、Px-102、PX-L603、PX-L493、PXS-4728A、PZ-235、RDX-009、瑞格列淨、RG-125 (AZD4076)、RPI-500、沙羅格列扎、索馬魯肽、西妥珠單抗、索利霉素(solithromycin)、所格列淨、他汀類(阿托伐他汀、氟伐他汀、匹伐他汀、普伐他汀、瑞舒伐他汀、辛伐他汀)、共生、TCM-606F、TEV-45478、TQA-3526、泰魯司特(MN-001)、TLY-012、TRX-318、TVB-2640、UD-009、熊去氧膽酸(ursodeoxycholic acid)、VBY-376、VBY-825、VK-2809、維莫德吉、沃利席貝特乙醇鉀水合物(SHP-626)、VVP-100X、WAV-301、WNT-974、XRx-117、ZGN-839、ZG-5216、ZSYM-008、及ZYSM-007。
在一些實施例中,本文所提供之方法及醫藥組成物包括治療有效量之細胞凋亡信號-調節激酶1 (ASK1)抑制劑、及治療有效量之LPAR1拮抗劑,其中LPAR1拮抗劑係本文所提供之式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽。
在本文所揭示之方法及醫藥組成物之一些實施例中,ASK1抑制劑係GS-4997(司隆色替(selonsertib),SEL)。
ASK1抑制劑可使用所屬技術領域中具有通常知識者已知之方法合成及表徵,諸如該等描述於美國2007/0276050、美國2011/0009410、及美國2013/0197037中者。
在一些實施例中,本文所提供之方法及醫藥組成物包括治療有效量之乙醯-CoA羧化酶(ACC)抑制劑、及治療有效量之LPAR1拮抗劑,其中該LPAR1拮抗劑係本文所提供之式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽。
在本文所揭示之方法及醫藥組成物之一些實施例中,ACC抑制劑係GS-0976(費索司他,FIR)。
ACC抑制劑可使用所屬技術領域中具有通常知識者已知之方法合成及表徵,諸如該等描述於美國專利第9,453,026號、及美國專利第10,183,951號中者。
在一些實施例中,本文所提供之方法及組成物包括治療有效量之PPAR促效劑(例如PPARα促效劑、PPARα/δ促效劑、PPARα/δ/γ促效劑、PPARδ促效劑)或魚油、治療有效量之乙醯CoA羧化酶(ACC)抑制劑(諸如GS-0976(費索司他,FIR))、及治療有效量之LPAR1拮抗劑,其中該LPAR1拮抗劑係本文所提供之式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽。在一些實施例中,PPAR促效劑係PPARα促效劑。在一些實施例中,PPARα促效劑係選自克氯吩貝鋁、苯扎貝特、環丙貝特、非諾貝特膽鹼、克利貝特、克氯吩貝、氯貝胺、非諾貝特、吉非貝齊、培馬貝特、羅尼貝特、雙貝特、匹立尼酸、GW409544、AZ 242、LY518674、NS-220、AVE8134、BMS-711939、阿格列扎、莫格列扎、或沙羅格列扎。在一些實施例中,PPAR促效劑(例如,PPARα促效劑)係纖維酸鹽類(fibrate)。在一些實施例中,PPAR促效劑(例如,PPARα促效劑)係非諾貝特。在一些實施例中,PPAR促效劑係PPARα/δ促效劑(例如,依拉菲貝諾)。在一些實施例中,PPAR促效劑係PPARα/δ/γ促效劑(例如,拉尼非貝諾)。在一些實施例中,PPAR促效劑係PPARδ促效劑(例如,司拉德帕)。在一些實施例中,魚油係ω-3脂肪酸、或二十二碳六烯酸。在一些實施例中,魚油係二十碳五烯酸乙酯(例如,Vascepa
®)。
在一些實施例中,本文所提供之方法及組成物包括治療有效量之類法尼醇X受體(FXR)促效劑、及治療有效量之LPAR1拮抗劑,其中LPAR1拮抗劑係本文所提供之式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽。
在本文所揭示之方法及醫藥組成物之一些實施例中,FXR促效劑係GS-9674(希勒氟索(cilofexor),CILO)。
在一些實施例中,本文所提供之方法及組成物包括治療有效量之GLP-1受體促效劑、及治療有效量之LPAR1拮抗劑,其中LPAR1拮抗劑係本文所提供之式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽。在一些實施例中,GLP-1受體促效劑係利拉魯肽、或索馬魯肽。在一些實施例中,GLP-1受體促效劑係索馬魯肽。
在一些實施例中,本文所提供之方法及組成物包括治療有效量之TGFβ拮抗劑、及治療有效量之LPAR1拮抗劑,其中LPAR1拮抗劑係本文所提供之式(I)、(Ia)、(II)、或(IIa)之化合物或其醫藥上可接受之鹽。在一些實施例中,TGFβ拮抗劑係TGFβ-特異性抗體。TGFβ-特異性抗體可使用所屬技術領域中具有通常知識者已知之方法製備及表徵,諸如該等描述於PCT國際申請公開案第WO 2018/129329號、及美國專利第9,518,112號中者。在一些實施例中,TGFβ拮抗劑結合至TGFβ潛在相關肽(LAP),例如,TGFβ1-LAP。TGFβ1-LAP-特異性抗體可使用所屬技術領域中具有通常知識者已知之方法製備及表徵,諸如該等描述於美國專利第8,198,412號、或美國專利第10,017,567號中者。在一些實施例中,TGFβ拮抗劑係以獨立於上下文之方式(例如獨立於TGFβ在特定組織或器官中之存在)結合至TGFβ(例如TGFβ1)。在一些實施例中,TGFβ拮抗劑係以上下文依賴性方式結合至TGFβ(例如,TGFβ1)。在一些實施例中,TGFβ拮抗劑阻斷潛在TGF之活化β(例如,潛在TGFβ1),其位於細胞外基質中,例如,在肝臟之結締組織中。在一些實施例中,TGFβ拮抗劑阻斷潛在TGF之活化β(例如,潛在TGFβ1),其位於胸腺、淋巴結、或腫瘤微環境中,例如,在患有肝癌之患者中。在一些實施例中,TGFβ拮抗劑藉由潛伏在TGFβ結合蛋白(LTBP)阻斷潛在TGF之活化β(例如,潛在TGFβ1)。在一些實施例中,TGFβ拮抗劑藉由醣蛋白-A重複優勢蛋白(Glycoprotein-A Repetitions Predominant protein, GARP)阻斷潛在TGF之活化β(例如,潛在TGFβ1),如描述於例如美國專利第10,000,572號中者。在一些實施例中,TGFβ拮抗劑係ARGX-115。在一些實施例中,TGFβ拮抗劑係特異性結合至LAP-TGFβ錯合物之抗潛在相關肽(LAP)抗體。在一些實施例中,抗LAP抗體在胞外基質(ECM)(例如,在肝臟之結締組織)中特異性結合至LAP-TGFβ錯合物。在一些實施例中,抗LAP抗體在某些免疫抑制細胞類型(諸如調節性T細胞(Tregs)、腫瘤相關巨噬細胞、或骨髓衍生之抑制細胞)之表面上特異性結合至LAP-TGFβ錯合物,例如,在腫瘤微環境中。在一些實施例中,抗LAP抗體係TLS-01抗體。在一些實施例中,抗LAP抗體在任何上下文中特異性結合至LAP-TGFβ錯合物。在一些實施例中,抗LAP抗體係TLS-02抗體。在一些實施例中,TGFβ拮抗劑包含TGFβ受體。在一些實施例中,TGFβ拮抗劑係TGFβ受體-Fc融合蛋白。在一些實施例中,TGFβ拮抗劑係包含TGFβ受體之抗體。TGFβ拮抗劑,其包含TGFβ可用於與本文所提供之組成物及方法相關的受體已描述於,例如,在PCT國際公開案第WO 2019/113123 A1、及WO 2019/113464 A1中。
在一些實施例中,本文所提供之方法及組成物包括治療有效量之LPAR1拮抗劑、及選自以下之額外治療劑:ACE抑制劑、腺苷A3受體拮抗劑、阿德羅平刺激劑、AMP活化蛋白激酶刺激劑、血管收縮素II AT-2受體促效劑、血管收縮素II受體拮抗劑、血管收縮素原配體抑制劑、APOA1基因刺激劑、載脂蛋白L1調節劑、骨成形性蛋白-7配體調節劑、含有蛋白2之溴結構域抑制劑、含有蛋白4之溴結構域抑制劑、鈣通道抑制劑、大麻素CB1受體拮抗劑、CB1反向促效劑、CCR2趨化因子拮抗劑、凝乳酶抑制劑、補體C1s次組份抑制劑、CX3CR1趨化因子拮抗劑、環氧化酶1抑制劑、環氧化酶2抑制劑、細胞色素P450 11B2抑制劑、外核苷酸焦磷酸酶-PDE-2抑制劑、內皮素ET-A受體拮抗劑、內皮素ET-B受體拮抗劑、腸激酶抑制劑、環氧化物水解酶抑制劑、紅血球生成素受體拮抗劑、類法尼醇X受體促效劑、FGF受體拮抗劑、遊離脂肪酸受體1促效劑、GHR基因抑制劑、醣蛋白Ib (GPIb)拮抗劑、GPR40促效劑、GPR84拮抗劑、G-蛋白β次單元抑制劑、G-蛋白偶聯受體120促效劑、G-蛋白偶聯受體84調節劑、生長激素配體、生長激素受體促效劑、鳥苷酸環化酶受體促效劑、鳥苷酸環化酶刺激劑、血基質加氧酶1調節劑、HIF脯胺醯基羥化酶抑抑制劑、IGF1基因抑制劑、IgG受體FcRn大次單元p51調節劑、IL-6受體拮抗劑、整合素α-V/ β-3拮抗劑、介白素33配體抑制劑、Kelch樣ECH相關蛋白1調節劑、LDHA基因抑制劑、5-脂氧合酶活化蛋白抑制劑、溶血磷脂-1受體拮抗劑、基質胞外磷酸糖蛋白調節劑、膜銅胺氧化酶抑制劑、中期因子配體抑制劑、礦皮質素受體拮抗劑、肌凝蛋白2抑制劑、NADPH氧化酶1抑制劑、NADPH氧化酶4抑制劑、NADPH氧化酶抑制劑、NK1受體拮抗劑、核紅血球2相關因子2刺激劑、核因子κB抑制劑、類鴉片受體κ促效劑、類鴉片受體µ拮抗劑、p38 MAP激酶抑制劑、PDE4抑制劑、PDGF受體拮抗劑、PDGF受體β調節劑、降磷素受體促效劑、PRKAA2基因刺激劑、前蛋白轉化酶PC9抑制劑、前列腺環素(PGI2)促效劑、蛋白C活化劑、蛋白NOV同源物調節劑、蛋白酪胺酸磷酸酶-1B抑制劑、活性氧物種調節劑抑制劑、腎素抑制劑、Rho相關蛋白激酶2抑制劑、SLC22A12抑制劑、鈉葡萄糖轉運蛋白-2抑制劑、溶質載體家族抑制劑、TGFβ配體抑制劑、TGFβ受體拮抗劑、血栓素A2受體拮抗劑、血栓素合成抑制劑、組織轉麩醯胺酸酶抑制劑、TRP陽離子通道C5抑制劑、TRP陽離子通道C6抑制劑、色胺酸酶抑制劑、非特異細胞黏合分子抑制劑、尿酸鹽陰離子交換劑1抑制劑、血管加壓素V1a受體拮抗劑、VEGF受體拮抗劑、VIP 1受體促效劑、VIP 2受體促效劑、及黃嘌呤氧化酶抑制劑。
在一些實施例中,本文所提供之方法及組成物包括治療有效量之LPAR1拮抗劑、及選自下列之額外治療劑:VEGFR抑制劑、FGFR抑制劑、PDGFR抑制劑、自毒素(autaxin)抑制劑、GPR84促效劑、PASK抑制劑、CFTR促效劑、JAK1抑制劑、ADAMTS5抑制劑、TOL2/3抑制劑、CTGF抑制劑、可溶性PTX2、抗半乳糖凝集素-3抗體、整合素-α
V-β
6/α
V-β
1拮抗劑、JNK1抑制劑、礦皮質素受體拮抗劑、Nrf2活化劑、凝乳酶抑制劑、PDE抑制劑、NOX1/4抑制劑、白三烯/血栓素受體拮抗劑、SLC22A12抑制劑、sGC抑制劑、及黃嘌呤氧化酶抑制劑。
在一些實施例中,本文所提供之方法及組成物包括治療有效量之LPAR1拮抗劑、及選自以下之額外治療劑:尼達尼布、吡非尼酮、帕莫樂單抗(pamrevlumab)、PRM-151、GB-0139、PLN-74809、CC-90001、非奈利酮、BAY1142524、PCS-499、西他那昔布、SER150、RDEA3170、帕利西哌、TMX-049、GLPG1690、GLPG1205、GLPG1972、GLPG4059、GLPG2737、GLPG3970、及非戈替尼(filgotinib)。
在一些實施例中,本文所提供之方法及組成物包括治療有效量之LPAR1拮抗劑、及選自以下的額外治療劑:A-717、ACF-TEI、丙胺醯基-麩醯胺、ALLN-346、抗SCF248抗體、抗TAGE單株抗體、抗TGFβ抗體、AST-120、BAY-2327949、BI-685509、DP-001、DZ-4001、GDT-01、LNP-1892、MEDI-8367、微小RNA-標靶反股寡核苷酸療法、MK-2060、MPC-300-IV、NAV-003、Neo-Kidney Augment™ (NKA)、NP-135、NP-160、NP-251、NRF-803、PBI-4610、PHN-033、R-HSC-010、丹參酸、SGF-3、SPD-01、Sugaheal變異體、SZ-005、TCF-12、UMC119-06、VAR-400、韋佛莫(veverimer)、VS-105、及XRx-221。
實例
包括以下實例以證明本揭露之具體實施例。所屬技術領域中具有通常知識者應瞭解,實例中所揭示之技術代表在本揭露之實施中能夠充分運作的技術,且因此可視為構成其實施之具體模式。然而,鑒於本揭露,所屬技術領域中具有通常知識者應瞭解此等實例係例示性的且非全面性的。在所揭示之具體實施例中可做出許多改變,且仍獲得一樣或類似之結果,而不脫離本揭露之精神及範疇。
本文所揭示之化合物可使用適當的材料根據以下流程及實例之程序來製備,且藉由以下具體實例進一步例示。此外,藉由利用本文所描述之程序,結合所屬技術領域中具有通常知識者,本文所主張之本揭露的額外化合物可容易地製備。實例進一步說明用於製備本揭露之化合物的細節。所屬技術領域中具有通常知識者將易於理解,可使用以下製備程序之條件及程序的已知變化來製備此等化合物。為了合成本揭露中所描述之具體實例的化合物,待合成之化合物的結構之檢驗將提供各取代基之識別。在一些情況下,可藉由檢驗方法識別必要起始物質使最終產物之識別顯而易見,本文列出實例。化合物可以其醫藥上可接受之鹽(諸如上文所描述者)的形式單離。本文所述之化合物一般係穩定的且在室溫及壓力下係可單離的。
下文顯示本文所揭示之化合物之製備的說明。除非另有指示,否則變數具有如上文所描述者之相同含義。下文所呈現之實例意欲說明本揭露之具體實施例。如下文所描述之適合的起始材料、建立方塊、及合成中所採用之試劑可購自,例如AbovChem、Acros Organics、Astatech、Combi Blocks、Oakwood Chemical、或Sigma-Aldrich,或可藉由文獻中所描述之程序例行地製備,該等文獻係例如「March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure」, 5
thEdition;John Wiley & Sons or T. Eicher, S. Hauptmann「The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Application」, 2
ndedition, Wiley-VCH 2003;Fieser et al. 「Fiesers´ Reagents for organic Synthesis」 John Wiley & Sons 2000。
一般方案 方案 A
方案 A :提供三唑胺甲酸酯雜芳基醯胺(
VII)之一般合成。在本文所揭示之方案中,「A」可係鹵素,諸如Cl、Br、或I。「W」可係小烷基,諸如甲基、或乙基。步驟一描述雜芳基三唑羧酸(
III)經由交叉偶合反應之一般合成。雜芳基酯鹵化物(
I)可首先轉換成對應的硼酯,諸如經由宮浦硼化轉換為
硼酸鹽,且接著與溴三唑羧酸(
II)經受鈴木反應條件以供給所需雜芳基三唑羧酸(
III)。或者,溴三唑羧酸(
II)可首先經由鋰-鹵素交換、及以氯化鋅捕捉來轉化為有機鋅物種。接著,與雜芳基鹵化物(
I)根岸交叉偶合,提供所需雜芳基三唑羧酸(
III)。
步驟二描述雜芳基三唑胺甲酸酯(
V)之一般合成。當雜芳基三唑羧酸(
II)以二苯基磷酸疊氮(DPPA)處理時經歷柯提斯重排,或替代地以1-丙烷膦酸酐(T3P)溶液、及疊氮基三甲基矽烷處理。接著以醇(
IV)捕捉中間物異氰酸酯,以提供所需雜芳基三唑胺甲酸酯(
V)。
步驟三描述雜芳基三唑胺甲酸酯(
VI)之一般合成。雜芳基三唑胺甲酸酯(
V)可藉由鹼基(諸如氫氧化鈉、或氫氧化鋰)處理水解,以提供對應之雜芳基三唑胺甲酸酯羧酸(
VI)。
步驟四描述三唑胺甲酸酯芳基-及雜芳基-醯胺(
VII)之一般合成。雜芳基三唑胺甲酸酯羧酸(
VI)可以標準肽偶合試劑(諸如1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(EDC)、或(1-[雙(二甲胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化六氟磷酸鹽(HATU)與醯胺之組合)來處理,以提供對應之三唑胺甲酸酯雜芳基醯胺(
VII)。或者,雜芳基三唑胺甲酸酯羧酸(
VI)可首先例如藉由以氯化磷醯處理轉換成酸氯化物,並接著與所需醯胺偶合,以提供對應之三唑胺甲酸酯雜芳基醯胺(
VII)。
方案 B
方案 B :提供雜芳基三唑胺甲酸酯(
VII)之一般替代性合成。步驟一描述含溴三唑之胺甲酸酯(
VIII)之一般合成。當溴三唑羧酸(
II)與二苯基磷酸疊氮(DPPA)反應時經歷柯提斯重排,或替代地與1-丙烷膦酸酐(T3P)溶液、及疊氮基三甲基矽烷反應。接著以醇(
V)捕捉中間物異氰酸酯,以提供所需溴三唑胺甲酸酯(
VIII)。
步驟二描述三唑胺甲酸酯芳基-及雜芳基-酯或酸(
V)經由交叉偶合反應之一般合成。溴三唑胺甲酸酯(
VIII)可首先經由鋰-鹵素交換、及以氯化鋅捕捉來轉化為有機鋅物種。接著,與雜芳基鹵化物(
I)根岸交叉偶合,提供所需雜芳基三唑胺甲酸酯(
V)。或者,雜芳基鹵化物(
I)可首先轉換成對應的硼酯,諸如經由宮浦硼化轉換為
硼酸鹽,且接著與溴三唑胺甲酸鹽
VIII經受鈴木反應條件以供給所需雜芳基三唑胺甲酸鹽(
V)。在Y=H的情況中,步驟三可跳過。
步驟三描述雜芳基三唑胺甲酸酯(
VI)之一般合成。雜芳基三唑胺甲酸酯(
V)可藉由鹼基(諸如氫氧化鈉、或氫氧化鋰)處理水解,以提供對應之雜芳基三唑胺甲酸酯羧酸(
VI)。
步驟四描述三唑胺甲酸酯芳基-及雜芳基-醯胺(
VII)之一般合成。雜芳基三唑胺甲酸酯羧酸(VI)可以肽偶合試劑(諸如1-乙基-3-(3-二甲基胺基丙基)碳二亞胺(EDC)、或(1-[雙(二甲胺基)亞甲基]-1H-1,2,3-三唑并[4,5-b]吡啶鎓3-氧化六氟磷酸鹽(HATU)與醯胺之組合)來處理,以提供對應之三唑胺甲酸酯雜芳基醯胺(
VII)。或者,雜芳基三唑胺甲酸酯羧酸(
VI)可首先例如藉由以氯化磷醯處理轉換成酸氯化物,並接著與所需醯胺偶合,以提供對應之三唑胺甲酸酯雜芳基醯胺(
VII)。
實例 1 : 4- 溴 -1- 甲基 -1H-1,2,3- 三唑 -5- 羧酸(中間物 1 )的製備: 步驟 1 : 4,5- 二溴 -2H-1,2,3- 三唑
將溴(2.8mol)在40℃下添加至2H-1,2,3-三唑(1.4mol)於水(600mL)中之溶液中。將反應混合物在40℃下攪拌2小時。冷卻至室溫後,藉由過濾收集沉澱物。將固體用水(2x 300mL)洗滌,且在真空下乾燥,以給出4,5-二溴-2H-1,2,3-三唑。
步驟 2 : 4,5- 二溴 -1- 甲基 -1H-1,2,3- 三唑
向在THF (1000mL)中之4,5-二溴-2H-1, 2, 3-三唑(704mmol)及K
2CO
3(1.4mol)之混合物添加碘甲烷(1.0mol)。將混合物在室溫下攪拌12h。過濾混合物,並將濾餅用乙酸乙酯(2x 500mL)洗滌,將濾液在40℃下濃縮,以得到粗產物,其藉由管柱層析法純化,以給出4,5-二溴-1-甲基-1H-1,2,3-三唑。
步驟 3 : 4- 溴 -1- 甲基 -1H-1,2,3- 三唑 -5- 糖醛
在-10℃下向4,5-二溴-1-甲基-1H-1,2,3-三唑(168.0mmol)於THF(600mL)中之溶液中添加異丙基氯化鎂(252.0mmol)。將混合物攪拌15min,添加DMF(840mmol)。1h後,用250mL飽和氯化銨處理混合物,且用DCM (2x 350mL)萃取。經合併之有機物用250mL鹽水洗滌,以Na
2SO
4乾燥,過濾且濃縮,以給出4-溴-1-甲基-1H-1,2,3-三唑-5-糖醛。
步驟 4 : 4- 溴 -1- 甲基 -1H-1,2,3- 三唑 -5- 羧酸
將Oxone (651mmol)添加至4-溴-1-甲基-1H-1, 2, 3-三唑-5-糖醛(536mmol)於DMF (800mL)中之溶液中,且將所得懸浮液在室溫下攪拌隔夜。將混合反應物用H
2O (1000mL)稀釋,用1N HCl調整至pH 3,且用乙酸乙酯(3 × 800mL)萃取水相。經合併之有機物係用飽和Na
2CO
3(2 × 500mL)洗滌,用1N HCl將水相調整至pH 3。藉由過濾單離沈澱物且在減壓下乾燥,以提供4-溴-1-甲基-1H-1,2,3-三唑-5 -羧酸(中間物1)。
實例 2 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4- 溴 -1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯(中間物 2B )的製備:
4-溴-1-甲基-1H-1,2,3-三唑-5-羧酸(95mmol)、50% 1-丙烷膦酸酐溶液(143mmol)於DMF中、及疊氮三甲基矽烷(143mmol)係在氬氣氛圍下懸浮於THF (350mL)中。添加三乙胺(143mmol)且使所得溶液攪拌30min。添加(R)-1-(2-氯吡啶-3 -基)乙-1-醇(143mmol),且將混合物在回流下加熱,與次級鼓泡機接觸以允許排氣,進行12小時。將反應混合物冷卻至室溫,且在真空中移除THF。將所得粗材料溶解於500mL之乙酸乙酯中,並用300mL之水萃取三次。接著將粗混合物以硫酸鈉乾燥,過濾並將濾液濃縮。將粗產物藉由矽膠管柱層析法純化,以提供(R)-1-(2-氯吡啶-3-基)乙基(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(中間物2B)。
實例 3 : (R)-1-(2- 氟吡啶 -3- 基 ) 乙基 (4- 溴 -1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯(中間物 2C )之製備:
依照實例3中所述用於合成(R)-1-(2-氯吡啶-3-基)乙基(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(中間物2B)之程序,但使用(R)-1-(2-氟吡啶-3-基)乙-1-醇(143mmol)取代(R)-1-(2-氯吡啶-3-基)乙-1-醇,得到(R)-1-(2-氟吡啶-3-基)乙基(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(中間物2C)。
實例 4 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (1- 甲基 -4-(5-( 吡啶 -4- 基胺甲醯基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯(化合物 1 ) 步驟 1 :甲基 (R)-6-(5-(((1-(2- 氯吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 ) 菸鹼酸酯的製備
將溶解於四氫呋喃(8mL)中之(R)-1-(2-氯吡啶-3-基)乙基(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(1.11mmol)冷卻至-78℃,並用1M鋰雙(三甲基矽基)醯胺溶液(1.30mmol)處理。將反應混合物在-78℃下攪拌15min,之後添加1.6M正丁基鋰溶液(2.40mmol)。在-78℃下繼續攪拌額外的30min之後,添加1.9M氯化鋅溶液(3.23mmol)。在5min後,將反應混合物溫熱至室溫。接著將甲基6-溴菸鹼酸酯(1.11mmol)添加至反應混合物中,接著添加XPhos Pd G3 (0.118mmol)。將反應混合物在70℃下加熱2h。在冷卻至室溫後,將反應混合物用1N HCl溶液淬熄,並用乙酸乙酯萃取。接著用鹽水洗滌有機層,以硫酸鈉乾燥,並濃縮。將殘餘物藉由管柱層析法純化,以給出甲基(R)-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼酸酯。
步驟 2 : (R)-6-(5-(((1-(2- 氯吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 ) 菸鹼酸(中間物 3A )之製備
將溶解於四氫呋喃(3mL)中之甲基(R)-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼酸酯(0.432mmol)以2M氫氧化鋰溶液(1.40mmol)處理。將反應混合物在室溫下攪拌2h。將反應混合物用乙酸乙酯稀釋,並用1N HCl溶液洗滌。接著用鹽水洗滌有機層,以硫酸鈉乾燥,並濃縮,以給出粗(R)-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼酸(中間物3A)。
步驟 3 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (1- 甲基 -4-(5-( 吡啶 -4- 基胺甲醯基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯之製備(方法 A )
將溶解於二氯甲烷(1mL)中之(R)-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼酸(0.0621mmol)用吡啶-4-醯胺(0.159mmol)、HATU (0.106mmol)、及N,N-二異丙基乙胺(0.172mmol)處理。將反應混合物在室溫下攪拌1h。將反應混合物濃縮。將殘餘物藉由HPLC純化,以給出(R)-1-(2-氯吡啶-3-基)乙基(1-甲基-4-(5-(吡啶-4-基胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯。1H NMR (400MHz,甲醇-d4) δ 9.15 (dd, J = 2.4, 0.8Hz, 1H), 8.75 – 8.68 (m, 2H), 8.47 – 8.38 (m, 3H), 8.33 (s, 1H), 8.18 (dd, J = 8.4, 0.9Hz, 1H), 8.07 (d, J = 18.7Hz, 1H), 7.47 (s, 1H), 6.11 (q, J = 6.6Hz, 1H), 4.03 (s, 3H), 1.63 (s, 3H)。LCMS m/z 479.1 M+1。
實例 5 :化合物 2 至 17 之製備
化合物2至17通常根據方案B步驟4、使用
方法 A 、 B 、或 C來合成。例如,(R)-1-(2-氯吡啶-3-基)乙基(4-(5-((3-氯雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(化合物2)係藉由如下之
方法 A來製備。
將溶解於二氯甲烷(1mL)中之(R)-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼酸(0.0745mmol)用3-氯雙環[1.1.1]戊-1-醯胺鹽酸鹽(0.149mmol)、HATU (0.149mmol)、及N,N-二異丙基乙胺(0.230mmol)處理。將反應混合物在室溫下攪拌16h。將反應混合物濃縮。將殘餘物藉由HPLC純化,以給出(R)-1-(2-氯吡啶-3-基)乙基(4-(5-((3-氯雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(化合物2)。1H NMR (400MHz,甲醇-d4) δ 9.04 – 8.92 (m, 1H), 8.38 – 8.29 (m, 1H), 8.25 (dd, J = 8.4, 2.2Hz, 1H), 8.06 (d, J = 8.3Hz, 2H), 7.44 (s, 1H), 6.08 (q, J = 6.6Hz, 1H), 4.00 (s, 3H), 2.54 (s, 6H), 1.61 (s, 3H)。LCMS m/z 502.1 M+1。
化合物2至17(表1)係藉由將
(中間物 3A )(實例5)與列於表1之試劑(取代3-氯雙環[1.1.1]戊-1-醯胺鹽酸鹽)使用所述方法反應,根據方案B步驟4類似地製備。
表 1 :根據方案 B 步驟 4 製備之化合物。
實例 6 : (R)-1-(2,5- 二氟吡啶 -3- 基 ) 乙基 (4-(5-((3- 氰基雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯(化合物 18 )之合成 步驟 1 : 4-(5-( 甲氧基羰基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 羧酸
化合物 | 結構 | 試劑 | 方法 | LCMS m/z | 1H NMR |
化合物2 (R)-1-(2-氯吡啶-3-基)乙基(4-(5-((3-氯雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 502.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.04 – 8.92 (m, 1H), 8.38 – 8.29 (m, 1H), 8.25 (dd, J = 8.4, 2.2Hz, 1H), 8.06 (d, J = 8.3Hz, 2H), 7.44 (s, 1H), 6.08 (q, J = 6.6Hz, 1H), 4.00 (s, 3H), 2.54 (s, 6H), 1.61 (s, 3H)。 | ||
化合物3 (R)-1-(2-氯吡啶-3-基)乙基(4-(5-((3,3-二氟環丁基) 胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3 -三唑-5-基)胺甲酸酯 | A | 492.0 | 1H NMR (400 MHz,甲醇- d 4) δ 9.02 (d, J = 2.2Hz, 1H), 8.33 (s, 1H), 8.26 (dd, J = 8.3, 2.3Hz, 1H), 8.08 (dd, J = 8.3, 0.9Hz, 1H), 7.47 (s, 1H), 6.09 (d, J = 6.7Hz, 1H), 4.45 – 4.33 (m, 1H), 4.01 (s, 3H), 3.77 – 3.63 (m, 1H), 3.12 – 2.97 (m, 2H), 2.85 – 2.67 (m, 2H), 1.63 (s, 3H)。 | ||
化合物4 (R)-1-(2-氯吡啶-3-基)乙基(4-(5-((3-氟雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 486.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.04 (s, 1H), 8.45 (d, J= 28.7Hz, 1H), 8.34 (s, 1H), 8.17 – 7.94 (m, 2H), 7.48 (s, 1H), 6.11 (q, J= 6.5Hz, 1H), 4.08 – 3.96 (m, 3H), 2.51 (d, J= 2.1Hz, 5H), 1.64 (s, 3H)。 | ||
化合物5 (R)-1-(2-氯吡啶-3-基)乙基(4-(5-((3-氰基雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 493.1 | 1H NMR (400 MHz,甲醇-d4) δ 8.99 (d, J = 2.2Hz, 1H), 8.32 (d, J = 8.7Hz, 2H), 8.08 (dd, J = 8.4, 0.9Hz, 2H), 7.46 (s, 1H), 6.10 (q, J = 6.5Hz, 1H), 4.01 (s, 3H), 2.68 (s, 6H), 1.62 (s, 3H)。 | ||
化合物6 (R)-1-(2-氯吡啶-3-基)乙基(4-(5-((3-(二氟甲基)雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 518.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.01 (d, J = 1.7Hz, 1H), 8.41 – 8.26 (m, 2H), 8.08 (d, J = 8.3Hz, 2H), 7.46 (s, 1H), 6.09 (t, J = 6.6Hz, 1H), 5.91 (d, J = 56.5Hz, 1H), 4.01 (s, 3H), 2.30 (s, 6H), 1.62 (s, 3H)。 | ||
化合物7 (R)-1-(2-氯吡啶-3-基)乙基(1-甲基-4-(5-(吡啶-3-基胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 479.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.34 (s, 1H), 9.14 (d, J = 2.3Hz, 1H), 8.55 (dd, J = 11.7, 7.0Hz, 2H), 8.42 (d, J = 9.1Hz, 1H), 8.33 (s, 3H), 8.16 (d, J = 8.3Hz, 1H), 7.94 – 7.79 (m, 2H), 6.11 (d, J = 6.6Hz, 1H), 4.03 (s, 3H), 1.63 (s, 3H)。 | ||
化合物8 (R)-1-(2-氯吡啶-3-基)乙基(1-甲基-4-(5-((3-甲基雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 482.1 | 1H NMR (400 MHz,甲醇-d4) δ 8.98 (s, 1H), 8.32 (s, 1H), 8.24 (dd, J = 8.3, 2.3Hz, 1H), 8.06 (d, J = 8.3Hz, 2H), 7.46 (s, 1H), 6.09 (q, J = 6.6Hz, 1H), 4.00 (s, 3H), 2.08 (s, 6H), 1.62 (s, 3H), 1.30 (s, 3H)。 | ||
化合物9 (R)-1-(2-氯吡啶-3-基)乙基(4-(5-((6-氟吡啶-3-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 497.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.18 (s, 1H), 8.70 – 8.52 (m, 2H), 8.37 (ddd, J = 9.5, 7.0, 2.8Hz, 2H), 8.22 – 7.99 (m, 2H), 7.49 (s, 1H), 7.16 (dd, J = 8.9, 3.0Hz, 1H), 6.12 (q, J = 6.6Hz, 1H), 4.04 (d, J = 1.0Hz, 3H), 1.65 (s, 3H)。 | ||
化合物10 (R)-1-(2-氯吡啶-3-基)乙基(4-(5-(雙環[1.1.1]戊-1-基胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 468.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.05 – 8.95 (m, 1H), 8.38 – 8.25 (m, 2H), 8.07 (d, J = 8.3Hz, 2H), 7.46 (s, 1H), 6.10 (q, J = 6.6Hz, 1H), 4.01 (s, 3H), 2.53 (s, 1H), 2.23 (s, 6H), 1.62 (s, 3H)。 | ||
化合物11 (R)-1-(2-氯吡啶-3-基)乙基(4-(5-((3-甲氧基雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 498.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.02 (s, 1H), 8.41 (d, J = 8.4Hz, 1H), 8.33 (d, J = 4.3Hz, 1H), 8.08 (d, J = 8.4Hz, 2H), 7.47 (s, 1H), 6.10 (q, J = 6.6Hz, 1H), 4.02 (s, 3H), 3.36 (s, 3H), 2.32 (s, 6H), 1.63 (s, 3H)。 | ||
化合物12 (R)-甲基3-(6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼醯胺)雙環[1.1.1]戊烷-1-羧酸酯 | A | 526.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.02 (s, 1H), 8.39 (s, 1H), 8.37 – 8.29 (m, 1H), 8.09 (d, J = 8.4Hz, 2H), 7.47 (s, 1H), 6.10 (q, J = 6.6Hz, 1H), 4.02 (s, 3H), 3.72 (s, 3H), 2.47 (s, 6H), 1.63 (s, 3H)。 | ||
化合物13 (R)-1-(2-氯吡啶-3-基)乙基(4-(5-((3-(羥甲基)雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 498.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.02 – 8.94 (m, 1H), 8.32 (s, 1H), 8.26 (dd, J = 8.3, 2.2Hz, 1H), 8.06 (d, J = 8.3Hz, 2H), 7.42 (d, J = 30.5Hz, 1H), 6.10 (q, J = 6.6Hz, 1H), 4.01 (s, 3H), 3.68 (s, 2H), 2.13 (s, 6H), 1.62 (s, 3H)。 | ||
化合物14 (R)-1-(2-氯吡啶-3-基)乙基(1-甲基-4-(5-(苯基胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 478.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.12 (s, 1H), 8.43 (dd, J = 8.3, 2.3Hz, 1H), 8.33 (d, J = 4.1Hz, 1H), 8.13 (d, J = 8.3Hz, 2H), 7.82 – 7.63 (m, 2H), 7.57 – 7.29 (m, 3H), 7.27 – 7.14 (m, 1H), 6.11 (q, J = 6.6Hz, 1H), 4.02 (s, 3H), 1.63 (s, 3H)。 | ||
化合物15 (R)-1-(2-氯吡啶-3-基)乙基(1-甲基-4-(5-((3-(三氟甲基)雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 536.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.00 (d, J = 2.2Hz, 1H), 8.33 (s, 1H), 8.26 (dd, J = 8.4, 2.2Hz, 1H), 8.08 (d, J = 8.3Hz, 2H), 7.45 (s, 1H), 6.10 (q, J = 6.6Hz, 1H), 4.01 (s, 3H), 2.44 (s, 6H), 1.62 (s, 3H)。 | ||
化合物16 (R)-1-(2-氯吡啶-3-基)乙基(1-甲基-4-(5-((四氫-2H-哌喃-4-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 486.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.00 (d, J = 2.2Hz, 1H), 8.37 – 8.24 (m, 2H), 8.17 – 7.88 (m, 2H), 7.45 (s, 1H), 6.10 (q, J = 6.6Hz, 1H), 4.16 (tt, J = 11.3, 4.3Hz, 1H), 4.03 (dd, J = 6.1, 4.0Hz, 2H), 4.01 (s, 3H), 3.56 (td, J = 11.9, 2.1Hz, 2H), 2.01 – 1.91 (m, 2H), 1.78 – 1.67 (m, 2H), 1.64 (d, J = 19.3Hz, 3H)。 | ||
化合物17 (R)-1-(2-氯吡啶-3-基)乙基(1-甲基-4-(5-((4- 啉基苯基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 563.2 | 1H NMR (400 MHz,甲醇- d 4) δ 9.10 (s, 1H), 8.37 (dd, J = 8.4, 2.2Hz, 1H), 8.32 (d, J = 4.8Hz, 1H), 8.12 (d, J = 8.3Hz, 2H), 7.84 – 7.76 (m, 2H), 7.47 (s, 1H), 7.35 – 7.28 (m, 2H), 6.11 (q, J = 6.6Hz, 1H), 4.02 (s, 3H), 4.00 – 3.94 (m, 4H), 3.45 – 3.39 (m, 4H), 1.63 (s, 3H)。 |
將4-溴-1-甲基-1H-1,2,3-三唑-5-羧酸(49mmol)溶解於500mL四氫呋喃中,且在–78℃之浴中浸泡15min。在氮氣下,在15min內逐滴添加在四氫呋喃(53mmol)中之1M鋰雙(三甲基矽基)醯胺溶液。在20min內逐滴添加在己烷中之2.5M正丁基鋰溶液(102mmol,並使其再攪拌額外的1h。在15min內逐滴添加在2-甲基四氫呋喃中之1.9M氯化鋅溶液(102mmol)。將反應混合物浸泡在水浴中加溫至環境溫度,並使其攪拌30min。將所得混合物用氬氣鼓泡10min,且隨後添加6-溴吡啶-3-羧酸酯(53mmol)、及與二氯甲烷錯合之[1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)(5mmol)。將反應物在75℃下加熱5h,且隨後冷卻至環境溫度。將反應用100mL飽和碳酸氫鈉水溶液、及100mL水淬滅,並劇烈攪拌。逐滴添加200mL之MTBE,且產物崩裂。過濾產物,並用MTBE及水洗滌。粗產物未經進一步純化直接用於下一步驟。
步驟 2 :甲基 (R)-6-(5-(((1-(2,5- 二氟吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 ) 菸鹼酸酯
將4-(5-(甲氧基羰基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-羧酸(11.6mmol)懸浮於THF (100mL)中,並將於THF中之50% 1-丙烷膦酸酐溶液(14.5mmol)、三乙胺(58mmol)、及疊氮三甲基矽烷(10.4mmol)裝入反應中。使所得溶液在室溫下攪拌30min。將反應物加熱至70C達30分鐘,之後在相同溫度下添加(1R)-1-(2,5-二氟-3-吡啶基)乙醇(23.2mmol)。將反應物在70℃下加熱24h。將反應物溫熱,且在乙酸異丙酯中稀釋,用飽和碳酸氫鈉水溶液洗滌,以硫酸鈉乾燥,濃縮並藉由矽膠層析法純化。
步驟 3 : (R)-6-(5-(((1-(2,5- 二氟吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 ) 菸鹼酸(中間物 3B )
將甲基(R)-6-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼酸酯(6.5mmol)溶解於THF(25mL)中,並添加1M NaOH (30mL),且劇烈攪拌15min。將反應混合物用MTBE (25mL)稀釋,並丟棄有機物。隨後,水相係被以下所酸化:濃縮HCl,直至將pH調節至4。過濾所得沈澱物,並在真空中乾燥以提供所需產物
(中間物 3B )。
步驟 4 : (R)-1-(2,5- 二氟吡啶 -3- 基 ) 乙基 (4-(5-((3- 氰基雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺基甲酸酯(藉由方法 A )
將溶解於二氯甲烷(3mL)中之(R)-6-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼酸(0.25mmol)用3-胺基雙環[1.1.1]戊烷-1-甲腈處理。(0.32mmol)、HATU (0.37mmol)、及N,N-二異丙基乙胺(0.75mmol)。將反應混合物在室溫下攪拌1h。將反應混合物濃縮。將殘餘物藉由HPLC純化,以提供標題化合物。1H NMR (400MHz,甲醇-d4) δ 9.05 – 8.91 (m, 1H), 8.35 (dd, J = 8.4, 2.2Hz, 1H), 8.15 – 8.00 (m, 2H), 7.88 (s, 1H), 5.96 (q, J = 6.7Hz, 1H), 4.02 (s, 3H), 2.68 (s, 6H), 1.63 (s, 3H)。LCMS m/z 495.1 M+1。
實例 7 :化合物 19 至 44 之製備
化合物19至44通常根據方案A步驟4、使用
方法 A 、 B 、或 C來合成。例如,(R)-1-(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-((2-(三氟甲基)吡啶-4 -基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯(化合物19)係藉由如下之
方法 B來製備。
將懸浮於吡啶(3mL)中之(R)-6-(5-(((1-(2,5-二氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼酸(0.371mmol)用2-(三氟甲基)吡啶-4-醯胺(0.493mmol)處理,接著用EDCI (0.742mmol)處理。將反應混合物在50℃下加熱隔夜。將反應混合物濃縮。將殘餘物藉由HPLC純化,以給出(R)-1-(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-((2-(三氟甲基)吡啶-4-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯。1H NMR (400MHz,甲醇-d4) δ 9.13 (s, 1H), 8.65 (d, J = 5.6Hz, 1H), 8.43 (dd, J = 8.3, 2.2Hz, 1H), 8.33 (d, J = 2.0Hz, 1H), 8.17 (d, J = 8.4Hz, 1H), 8.06 (dd, J = 5.7, 2.2Hz, 2H), 7.89 (s, 1H), 5.97 (q, J = 6.6Hz, 1H), 4.03 (s, 3H), 1.64 (s, 3H)。LCMS m/z 549.1 M+1。
化合物19至44(表2)係藉由將
(中間物 3B )(實例6)與列於表2之試劑(取代2-(三氟甲基)吡啶-4-醯胺)使用所述方法反應,根據方案A步驟4類似地製備。
表 2 :根據方案 A 步驟 4 製備之化合物。
實例 8 :化合物 45 至 54 之製備
化合物 | 結構 | 試劑 | 方法 | LCMS m/z | 1H NMR |
化合物19 (R)-1-(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-((2-(三氟甲基)吡啶-4-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 549.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.13 (s, 1H), 8.65 (d, J = 5.6Hz, 1H), 8.43 (dd, J = 8.3, 2.2Hz, 1H), 8.33 (d, J = 2.0Hz, 1H), 8.17 (d, J = 8.4Hz, 1H), 8.06 (dd, J = 5.7, 2.2Hz, 2H), 7.89 (s, 1H), 5.97 (q, J = 6.6Hz, 1H), 4.03 (s, 3H), 1.64 (s, 3H)。 | ||
化合物20 (R)-1-(2,5-二氟吡啶-3-基)乙基(4-(5-((3-氟雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 488.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.04 – 8.93 (m, 1H), 8.31 (dd, J = 8.4, 2.3Hz, 1H), 8.13 – 8.01 (m, 2H), 7.87 (s, 1H), 5.96 (q, J = 6.7Hz, 1H), 4.02 (s, 3H), 2.50 (d, J = 2.1Hz, 6H), 1.63 (s, 3H)。 | ||
化合物21 (R)-1-(2,5-二氟吡啶-3-基)乙基(4-(5-((3-氯雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 504.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.02 – 8.90 (m, 1H), 8.26 (dd, J = 8.3, 2.3Hz, 1H), 8.12 – 7.99 (m, 2H), 7.87 (s, 1H), 5.96 (q, J = 6.7Hz, 1H), 4.07 – 3.99 (m, 3H), 2.55 (d, J = 0.8Hz, 6H), 1.62 (s, 3H)。 | ||
化合物22 (R)-1-(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-((3-(三氟甲基)雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 538.1 | 1H NMR (400 MHz,甲醇- d 4) δ 8.99 (s, 1H), 8.29 (dd, J= 8.4, 2.2Hz, 1H), 8.14 – 8.01 (m, 2H), 7.87 (s, 1H), 5.96 (q, J | ||
化合物23 (R)-1-(2,5-二氟吡啶-3-基)乙基(4-(5-((3-(二氟甲基)雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 520.1 | 1H NMR (400 MHz,甲醇-d4) δ 8.97 (d, J = 2.3Hz, 1H), 8.23 (dd, J = 8.3, 2.3Hz, 1H), 8.11 – 8.00 (m, 2H), 7.86 (d, J = 8.6Hz, 1H), 6.14 – 5.82 (m, 2H), 4.01 (s, 3H), 2.30 (s, 6H), 1.62 (s, 3H)。 | ||
化合物24 (R)-1 -(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-((2-(三氟甲基)嘧啶-5-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 550.0 | 1H NMR (400 MHz,甲醇- d 4) δ 9.41 (s, 2H), 9.16 (s, 1H), 8.45 (dd, J = 8.4, 2.5Hz, 1H), 8.18 (d, J = 8.4Hz, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 5.98 (d, J = 7.3Hz, 1H), 4.03 (s, 3H), 1.64 (s, 3H)。 | ||
化合物25 (R)-1-(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-((6-(三氟甲基)吡啶-3-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | $549.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.14 (d, J = 2.2Hz, 1H), 9.07 (d, J = 2.4Hz, 1H), 8.55 (dd, J = 8.7, 2.5Hz, 1H), 8.44 (dd, J = 8.4, 2.3Hz, 1H), 8.17 (d, J = 8.3Hz, 1H), 8.05 (s, 1H), 7.88 (d, J = 8.6Hz, 2H), 5.98 (q, J = 6.7Hz, 1H), 4.03 (s, 3H), 1.64 (s, 3H)。 | ||
化合物26 (R)-1-(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-((3-苯基雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 546.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.07 – 8.97 (m, 1H), 8.30 (dd, J = 8.4, 2.3Hz, 1H), 8.13 – 8.02 (m, 2H), 7.89 (s, 1H), 7.36 – 7.20 (m, 5H), 5.97 (q, J = 6.6Hz, 1H), 4.02 (s, 3H), 2.48 (s, 6H), 1.63 (s, 3H)。 | ||
化合物27 (R)-1-(2,5-二氟吡啶-3-基)乙基(4-(5-((2-氟吡啶-4-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 499.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.11 (s, 1H), 8.41 (dd, J= 8.4, 2.3Hz, 1H), 8.25 – 8.10 (m, 2H), 8.05 (s, 1H), 7.89 (s, 1H), 7.71 – 7.53 (m, 2H), 6.04 – 5.91 (m, 1H), 4.02 (d, J= 7.5Hz, 3H), 1.63 (s, 3H)。 | ||
化合物28 (R)-1-(2,5-二氟吡啶-3-基)乙基(4-(5-((6-環丙基吡啶-3-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 521.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.27 (d, J = 2.5Hz, 1H), 9.11 (d, J = 2.3Hz, 1H), 8.49 (dd, J = 9.0, 2.5Hz, 1H), 8.40 (dd, J = 8.4, 2.3Hz, 1H), 8.14 (d, J = 8.3Hz, 1H), 8.04 (s, 1H), 7.99 – 7.73 (m, 1H), 7.63 (d, J = 9.0Hz, 1H), 5.97 (q, J = 6.6Hz, 1H), 4.02 (s, 3H), 2.35 (tt, J = 8.4, 4.9Hz, 1H), 1.63 (s, 3H), 1.45 – 1.35 (m, 2H), 1.20 (dt, J = 7.5, 4.8Hz, 2H)。 | ||
化合物29 (R)-1-(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-((3-(甲基磺醯基)雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 548.017 | 1H NMR (400 MHz,甲醇- d 4) δ 8.97 (d, J = 2.1Hz, 1H), 8.32 – 7.51 (m, 4H), 5.95 (d, J = 6.7Hz, 1H), 4.01 (s, 3H), 3.01 (s, 3H), 2.64 (s, 6H), 1.62 (s, 3H)。 | ||
化合物30 (R)-1-(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-((3-(三氟甲基)苯基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 548.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.18 – 9.03 (m, 1H), 8.43 (dd, J= 8.3, 2.3Hz, 1H), 8.19 (d, J= 2.0Hz, 1H), 8.14 (d, J= 8.3Hz, 1H), 8.05 (s, 1H), 7.98 (dt, J= 8.2, 1.3Hz, 1H), 7.89 (s, 1H), 7.59 (t, J= 8.0Hz, 1H), 7.52 – 7.44 (m, 1H), 5.98 (q, J= 6.6Hz, 1H), 4.03 (s, 3H), 1.64 (s, 3H)。 | ||
化合物31 (R)-1-(2,5-二氟吡啶-3-基)乙基(4-(5-((2-(二氟甲基)吡啶-4-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 531.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.13 (s, 1H), 8.60 (d, J= 5.7Hz, 1H), 8.42 (dd, J= 8.3, 2.3Hz, 1H), 8.22 (d, J= 2.1Hz, 1H), 8.17 (d, J= 8.3Hz, 1H), 8.10 – 8.00 (m, 2H), 7.89 (s, 1H), 6.79 (t, J= 55.1Hz, 1H), 5.97 (q, J= 6.7Hz, 1H), 4.03 (s, 3H), 1.64 (s, 3H)。 | ||
化合物32 (R)-1-(2,5-二氟吡啶-3-基)乙基(4-(5-((2甲氧基吡啶-4-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 511.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.16 – 9.04 (m, 1H), 8.42 (dd, J= 8.3, 2.4Hz, 1H), 8.24 – 8.13 (m, 2H), 8.05 (s, 1H), 7.88 (d, J= 1.9Hz, 2H), 7.61 (dd, J= 6.6, 2.0Hz, 1H), 5.97 (q, J= 6.7Hz, 1H), 4.16 (s, 3H), 4.04 (s, 3H), 1.63 (s, 3H)。 | ||
化合物33 (R)-1-(2,5-二氟吡啶-3-基)乙基(4-(5-((2-(二氟甲氧基)吡啶-4-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 547.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.10 (s, 1H), 8.40 (dd, J= 8.3, 2.3Hz, 1H), 8.19 – 8.13 (m, 2H), 8.05 (s, 1H), 7.59 – 7.52 (m, 2H), 7.55 (m, 1H), 5.97 (d, J= 6.9Hz, 1H), 4.03 (s, 3H), 1.64 (s, 3H)。 | ||
化合物34 (R)-1-(2,5-二氟吡啶-3-基)乙基(4-(5-((4-氰基-3-(三氟甲基)苯基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | C | 573.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.13 (d, J= 2.3Hz, 1H), 8.43 (dd, J= 8.3, 2.3Hz, 2H), 8.24 (dd, J= 8.6, 2.1Hz, 1H), 8.16 (d, J= 8.3Hz, 1H), 8.03 (t, J= 9.2Hz, 2H), 7.89 (s, 1H), 5.97 (q, J= 6.7Hz, 1H), 4.03 (s, 3H), 1.64 (s, 3H)。 | ||
化合物35 (R)-1-(2,5-二氟吡啶-3-基)乙基(4-(5-((2-氯-3-氟吡啶-4-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | C | 533.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.09 (s, 1H), 8.41 (dd, J = 8.4, 2.3Hz, 1H), 8.30 (t, J = 5.4Hz, 1H), 8.25 – 8.14 (m, 2H), 8.05 (s, 1H), 7.90 (s, 1H), 5.97 (q, J = 6.7Hz, 1H), 4.03 (s, 3H), 1.64 (s, 3H)。 | ||
化合物36 (R)-1-(2,5-二氟吡啶-3-基)乙基(4-(5-([1,1'-聯苯]-4-基胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 556.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.12 (s, 1H), 8.42 (dd, J = 8.3, 2.3Hz, 1H), 8.15 (d, J = 8.2Hz, 1H), 8.06 (s, 1H), 7.98 – 7.79 (m, 3H), 7.72 – 7.61 (m, 4H), 7.46 (dd, J = 8.4, 7.0Hz, 2H), 7.39 – 7.31 (m, 1H), 5.98 (q, J = 6.6Hz, 1H), 4.04 (s, 3H), 1.64 (s, 3H)。 | ||
化合物37 (R)-1 -(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-(((1R,2S)-2-苯基環丙基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 520.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.01 (s, 1H), 8.37 – 8.24 (m, 1H), 8.08 (d, J = 18.9Hz, 2H), 7.88 (s, 1H), 7.30 (t, J = 7.6Hz, 2H), 7.28 – 7.15 (m, 3H), 5.96 (q, J = 6.6Hz, 1H), 4.02 (s, 3H), 3.11 (ddd, J = 7.9, 4.7, 3.5Hz, 1H), 2.24 (ddd, J = 9.8, 6.4, 3.5Hz, 1H), 1.63 (s, 3H), 1.46 – 1.30 (m, 2H)。 | ||
化合物38 (R)-1-(2,5-二氟吡啶-3-基)乙基(4-(5-((6-氯吡啶-4-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | C | 516.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.41 (d, J= 2.2Hz, 1H), 9.13 (s, 1H), 8.43 (td, J= 4.2, 3.7, 2.3Hz, 2H), 8.18 (d, J= 8.3Hz, 1H), 8.06 (s, 1H), 7.89 (s, 1H), 5.97 (d, J= 6.7Hz, 1H), 4.03 (s, 3H), 1.64 (s, 3H)。 | ||
化合物39 (R)-1-(2,5-二氟吡啶-3-基)乙基(1-甲基-4 -(5-((4-(5-甲基-1,3,4- 二唑-2-基)苯基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 562.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.12 (s, 1H), 8.42 (dd, J = 8.3, 2.3Hz, 1H), 8.16 (d, J = 8.3Hz, 1H), 8.11 – 8.03 (m, 3H), 8.03 – 7.96 (m, 2H), 7.91 (s, 1H), 5.98 (q, J = 6.6Hz, 1H), 4.03 (s, 3H), 2.65 (s, 3H), 1.64 (s, 3H)。 | ||
化合物40 (R)-1-(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-((4-(吡啶-3-基)苯基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 557.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.19 (d, J = 2.1Hz, 1H), 9.10 (d, J = 2.2Hz, 1H), 8.91 (ddd, J = 8.3, 2.2, 1.3Hz, 1H), 8.80 (dt, J = 5.4, 1.1Hz, 1H), 8.49 – 8.27 (m, 2H), 8.24 – 8.09 (m, 2H), 8.11 – 7.95 (m, 3H), 7.95 – 7.77 (m, 2H), 5.97 (q, J = 6.7Hz, 1H), 4.02 (d, J = 6.8Hz, 3H), 1.64 (s, 3H)。 | ||
化合物41 (R)-1-(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-((4-(吡啶-4-基)苯基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 557.2 | 1H NMR (400 MHz,甲醇- d 4) δ 9.11 (d, J = 2.2Hz, 1H), 8.83 – 8.73 (m, 2H), 8.41 (dd, J = 8.3, 2.4Hz, 1H), 8.37 – 8.28 (m, 2H), 8.16 (dd, J = 8.2, 0.9Hz, 1H), 8.07 (s, 5H), 7.88 (s, 1H), 5.98 (q, J = 6.5Hz, 1H), 4.04 (s, 3H), 1.64 (s, 3H)。 | ||
化合物42 (R)-1-(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-((2-(三氟甲基)噻唑-5-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | C | 554.96 | 1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 9.98 (bs, 1H), 9.06 (dd, J = 2.3, 0.8Hz, 1H), 8.45 (dd, J = 8.4, 2.3Hz, 1H), 8.32-7.51 (m, 4H), 5.80 (bs, 1H), 3.93 (s, 3H), 1.56 (bs, 3H)。 | ||
化合物43 (R)-1-(2,5-二氟吡啶-3-基)乙基(4-(5-((2-氯-6-(三氟甲基)吡啶-4-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | C | 583.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.13 (d, J = 2.2Hz, 1H), 8.43 (dd, J = 8.3, 2.3Hz, 1H), 8.22 – 8.12 (m, 3H), 8.05 (s, 1H), 7.89 (s, 1H), 5.97 (q, J = 6.6Hz, 1H), 4.03 (s, 3H), 1.64 (s, 3H)。 | ||
化合物44 (R)-1-(2,5-二氟吡啶-3-基)乙基(1-甲基-4-(5-((3-苯基環丁基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 534.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.05 – 8.95 (m, 1H), 8.35 – 8.23 (m, 2H), 8.12 – 8.06 (m, 1H), 7.88 (d, J = 8.0Hz, 1H), 6.04 (q, J = 6.6Hz, 1H), 4.02 (s, 3H), 2.50 (d, J = 2.1Hz, 6H), 1.62 (s, 3H)。 |
化合物45至54通常根據方案A、使用方法A、B、或C來合成。例如,(R)-1-(2-氯-5-氟吡啶-3-基)乙基(1-甲基-4-(5-((2-(三氟甲基)吡啶-4-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯(化合物45)係如下般製備。
步驟 1 :甲基 (R)-6-(5-(((1-(2- 氯 -5- 氟吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 ) 菸鹼酸酯
將4-(5-(甲氧基羰基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-羧酸(11.6mmol)懸浮於THF (100mL)中,並將於THF中之50% 1-丙烷膦酸酐溶液(14.5mmol)、三乙胺(58mmol)、及疊氮三甲基矽烷(10.4mmol)裝入反應中。使所得溶液在室溫下攪拌30min。將反應物加熱至70C達30分鐘,之後在相同溫度下添加(R)-1-(2-氯-5-氟吡啶-3-基)乙-1-醇(23.2mmol)。將反應物在70℃下加熱24h。將反應物溫熱,且在乙酸異丙酯中稀釋,用飽和碳酸氫鈉水溶液洗滌,以硫酸鈉乾燥,濃縮並藉由矽膠層析法純化。
步驟 2 : (R)-6-(5-(((1-(2- 氯 -5- 氟吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4 - 基 ) 菸鹼酸(中間物 3C )
將甲基(R)-6-(5-(((1-(2-氯-5-氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼酸酯(6.5mmol)溶解於THF (25mL)中,並添加1M NaOH (30mL),且劇烈攪拌15min。將反應混合物用MTBE(25mL)稀釋,並丟棄有機物。隨後,水相係被以下所酸化:濃縮HCl,直至將pH調節至4。過濾所得沈澱物,並在真空中乾燥以提供所需產物。
步驟 3 : (R)-1-(2- 氯 -5- 氟吡啶 -3- 基 ) 乙基 (1- 甲基 -4-(5-((2-( 三氟甲基 ) 吡啶 -4- 基 ) 胺甲醯基 ) 吡啶 -2- 基 )-1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯(方法 C )
將懸浮於二氯甲烷(1mL)中之(R)-6-(5-(((1-(2-氯-5-氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4 -基)菸鹼酸(0.095mmol)用2-(三氟甲基)吡啶-4-醯胺(0.123mmol)處理,然後用吡啶(0.496mmol)處理,並緩慢逐滴添加氯化磷醯(0.235mmol)。將反應混合物在室溫下攪拌30min。藉由緩慢添加飽和碳酸氫鈉溶液來淬滅反應混合物。隨後將其用二氯甲烷稀釋,並分離層。接著用鹽水洗滌有機層,以硫酸鈉乾燥,並濃縮。將殘餘物藉由HPLC純化,以給出(R)-1-(2-氯-5-氟吡啶-3-基)乙基(1-甲基-4-(5-((2-(三氟甲基)吡啶-4-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯。1H NMR (400MHz,甲醇-d4) δ 9.16 (d, J = 2.3Hz, 1H), 8.65 (d, J = 5.6Hz, 1H), 8.44 (dd, J = 8.3, 2.3Hz, 1H), 8.36 – 8.23 (m, 2H), 8.21 – 8.13 (m, 1H), 8.05 (dd, J = 5.6, 2.1Hz, 1H), 7.89 (s, 1H), 6.06 (q, J = 6.6Hz, 1H), 4.03 (s, 3H), 1.63 (s, 3H)。LCMS m/z 565.1 M+1。
化合物45至54(表3)係藉由將
(中間物 3C )(實例6)與列於表2之試劑(取代2-(三氟甲基)吡啶-4-醯胺)使用
方法 A 、 B 、或 C反應,根據方案A步驟4類似地製備。
表 3 :根據方案 A 步驟 4 製備之化合物。
實例 9 :化合物 55 至 57 之製備
化合物 | 結構 | 試劑 | 方法 | LCMS m/z | 1H NMR |
化合物45 (R)-1-(2-氯-5-氟吡啶-3-基)乙基(1-甲基-4-(5-((2-(三氟甲基)吡啶-4-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | C | 565.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.16 (d, J= 2.3Hz, 1H), 8.65 (d, J= 5.6Hz, 1H), 8.44 (dd, J= 8.3, 2.3Hz, 1H), 8.36 – 8.23 (m, 2H), 8.21 – 8.13 (m, 1H), 8.05 (dd, J= 5.6, 2.1Hz, 1H), 7.89 (s, 1H), 6.06 (q, J= 6.6Hz, 1H), 4.03 (s, 3H), 1.63 (s, 3H)。 | ||
化合物46 (R)-1-(2-氯-5-氟吡啶-3-基)乙基(4-(5-((3-氟雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1 -甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 504.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.05 – 8.95 (m, 1H), 8.35 – 8.23 (m, 2H), 8.12 – 8.06 (m, 1H), 7.88 (d, J= 8.0Hz, 1H), 6.04 (q, J= 6.6Hz, 1H), 4.02 (s, 3H), 2.50 (d, J= 2.1Hz, 6H), 1.62 (s, 3H)。 | ||
化合物47 (R)-1-(2-氯-5-氟吡啶-3-基)乙基(4-(5-((3-氰基雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 511.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.05 – 8.92 (m, 1H), 8.37 – 8.23 (m, 2H), 8.09 (d, J= 8.3Hz, 1H), 7.89 (s, 1H), 6.04 (q, J= 6.6Hz, 1H), 4.02 (s, 3H), 2.68 (s, 6H), 1.62 (s, 3H)。 | ||
化合物48 (R)-1-(2-氯-5-氟吡啶-3-基)乙基(4-(5-((3-(二氟甲基)雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 536.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.08 – 8.91 (m, 1H), 8.42 – 8.17 (m, 2H), 8.09 (dd, J= 8.3, 0.9Hz, 1H), 8.04 – 7.61 (m, 1H), 6.18 – 5.78 (m, 2H), 4.02 (s, 3H), 2.30 (s, 6H), 1.62 (s, 3H)。 | ||
化合物49 (R)-1-(2-氯-5-氟吡啶-3-基)乙基(4-(5-((4-氰基苯基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 521.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.12 (d, J= 2.2Hz, 1H), 8.40 (dd, J= 8.3, 2.3Hz, 1H), 8.32 – 8.23 (m, 1H), 8.15 (d, J= 8.3Hz, 1H), 8.02 – 7.95 (m, 2H), 7.90 (s, 1H), 7.81 – 7.73 (m, 2H), 6.06 (q, J= 6.6Hz, 1H), 4.03 (s, 3H), 1.63 (s, 3H)。 | ||
化合物50 (R)-1-(2-氯-5-氟吡啶-3-基)乙基(4-(5-((2-氰基吡啶-4-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | C | 522.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.19 – 9.10 (m, 1H), 8.63 (d, J = 5.7Hz, 1H), 8.41 (dd, J = 8.4, 2.3Hz, 1H), 8.35 (d, J = 2.1Hz, 1H), 8.28 (s, 1H), 8.17 (d, J = 8.3Hz, 1H), 8.04 (dd, J = 5.7, 2.2Hz, 1H), 7.89 (s, 1H), 6.06 (q, J = 6.6Hz, 1H), 4.03 (s, 3H), 1.63 (s, 3H)。 | ||
化合物51 (R)-1-(2-氯-5-氟吡啶-3-基)乙基(4-(5-((2,6-二氯吡啶-4-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | C | 567.0 | 1H NMR (400 MHz,甲醇- d 4) δ 9.12 (d, J= 2.2Hz, 1H), 8.40 (dd, J= 8.4, 2.4Hz, 1H), 8.28 (s, 1H), 8.17 (d, J= 8.4Hz, 1H), 7.89 (s, 3H), 6.06 (q, J= 6.5Hz, 1H), 4.03 (s, 3H), 1.63 (s, 3H)。 | ||
化合物52 (R)-1-(2-氯-5-氟吡啶-3-基)乙基(1-甲基-4-(5-((4-(三氟甲基)噁唑-2-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | C | 555.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.18 – 9.07 (m, 1H), 8.40 (dd, J = 8.3, 2.3Hz, 1H), 8.37 – 8.22 (m, 2H), 8.17 (dd, J = 8.4, 0.9Hz, 1H), 7.88 (s, 1H), 6.06 (q, J = 6.7Hz, 1H), 4.03 (s, 3H), 1.63 (s, 3H)。 | ||
化合物53 (R)-1-(2-氯-5-氟吡啶-3-基)乙基(1-甲基-4-(5-((5-(三氟甲基)噻唑-2-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | C | 571.0 | 1H NMR (400 MHz,甲醇- d 4) δ 9.21 (s, 1H), 8.48 (dd, J= 8.3, 2.4Hz, 1H), 8.28 (s, 2H), 8.20 (d, J= 8.6Hz, 1H), 7.98 (d, J= 1.5Hz, 1H), 6.06 (d, J= 6.4Hz, 1H), 4.03 (s, 3H), 1.63 (s, 3H)。 | ||
化合物54 (R)-1-(2-氯-5-氟吡啶-3-基)乙基(4-(5-((3-乙炔基雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | B | 510.1 | 1H NMR (400 MHz,甲醇-d4) δ 9.17 (s, 1H), 8.98 (s, 1H), 8.28 (s, 1H), 8.21 (dd, J = 8.4, 2.3Hz, 1H), 8.08 (d, J = 8.4Hz, 1H), 6.04 (d, J = 6.8Hz, 1H), 4.02 (s, 3H), 2.55 (s, 1H), 2.45 (s, 6H), 1.62 (s, 3H)。 |
化合物55至57通常根據方案B、使用
方法 A 、 B 、或 C 合成來合成。例如,(R)-1-(2-氟吡啶-3-基)乙基(4-(5-((3-氯雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(化合物55)係如下般製備。
步驟 1 :甲基 (R)-6-(5-(((1-(2- 氟吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 ) 菸鹼酸酯
將溶解於四氫呋喃(30mL)中之(R)-1-(2-氟吡啶-3-基)乙基(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(4.36mmol)冷卻至-78℃,並用1M鋰雙(三甲基矽基)醯胺溶液(4.80mmol)處理。將反應混合物在-78℃下攪拌15min,之後添加1.6M正丁基鋰溶液(9.12mmol)。在-78℃下繼續攪拌額外的30min之後,添加1.9M氯化鋅溶液(12.5mmol)。在5min後,將反應混合物溫熱至室溫。接著將甲基6-溴菸鹼酸酯(4.17mmol)添加至反應混合物中,接著添加XPhos Pd G3 (0.443mmol)。將反應混合物在70℃下加熱1h。在冷卻至室溫後,將反應混合物用1N HCl溶液淬熄,並用乙酸乙酯萃取。接著用鹽水洗滌有機層,以硫酸鈉乾燥,並濃縮。將殘餘物藉由管柱層析法純化,以給出甲基(R)-6-(5-(((1-(2-氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼酸酯。
步驟 2 : (R)-6-(5-(((1-(2- 氟吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 ) 菸鹼酸(中間物 3D )
將甲基(R)-6-(5-(((1-(2-氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼酸酯(0.157mmol)溶解於THF (2mL)中,並添加2M氫氧化鋰溶液(0.500mmol),且在室溫下攪拌隔夜。將反應混合物用乙酸乙酯稀釋,並用1N HCl溶液洗滌。將有機層用鹽水洗滌,以硫酸鈉乾燥,並濃縮以得到粗(R)-6-(5-(((1-(2-氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼酸。
步驟 3 : (R)-1-(2- 氟吡啶 -3- 基 ) 乙基 (4-(5-((3- 氯雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯
將溶解於二氯甲烷(1mL)中之(R)-6-(5-(((1-(2-氟吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼酸(0.155mmol)用3-氯雙環[1.1.1]戊-1-醯胺鹽酸鹽(0.214mmol)、HATU (0.255mmol)、及N,N-二異丙基乙胺(0.459mmol)處理。將反應混合物在室溫下攪拌隔夜。將反應混合物濃縮。將殘餘物藉由HPLC純化,以提供標題化合物。1H NMR (400MHz,甲醇-d4) δ 9.01 – 8.91 (m, 1H), 8.28 (d, J = 8.5Hz, 1H), 8.16 (s, 1H), 8.07 (d, J = 8.3Hz, 2H), 7.35 (s, 1H), 6.00 (q, J = 6.6Hz, 1H), 4.01 (s, 3H), 2.55 (s, 6H), 1.63 (s, 3H)。LCMS m/z 486.1 M+1。
化合物55至57(表4)係藉由將
(中間物 3D )(實例 9 )與列於表4之試劑(取代3-氯雙環[1.1.1]戊-1-醯胺鹽酸鹽)使用
方法 A 、 B 、或 C反應,根據方案B步驟4類似地製備。
表 4 :根據方案 A 步驟 4 製備之化合物。
實例 10 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(5-((3- 氯雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 )-6- 甲基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯(化合物 58 )之合成 步驟 1 :甲基 (R)-6-(5-(((1-(2- 氯吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 )-2- 甲基菸鹼酸酯
化合物 | 結構 | 試劑 | 方法 | LCMS m/z | 1H NMR |
化合物55 (R)-1-(2-氟吡啶-3-基)乙基(4-(5-((3-氯雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 486.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.01 – 8.91 (m, 1H), 8.28 (d, J= 8.5Hz, 1H), 8.16 (s, 1H), 8.07 (d, J= 8.3Hz, 2H), 7.35 (s, 1H), 6.00 (q, J= 6.6Hz, 1H), 4.01 (s, 3H), 2.55 (s, 6H), 1.63 (s, 3H)。 | ||
化合物56 (R)-1-(2-氟吡啶-3-基)乙基(1-甲基-4-(5-((3-(三氟甲基)雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 520.1 | 1H NMR (400 MHz,甲醇- d 4) δ 8.97 (s, 1H), 8.25 (dd, J = 8.3, 2.2Hz, 1H), 8.16 (s, 1H), 8.07 (d, J = 8.3Hz, 2H), 7.35 (s, 1H), 6.00 (q, J = 6.6Hz, 1H), 4.00 (s, 3H), 2.44 (s, 6H), 1.63 (s, 3H)。 | ||
化合物57 (R)-1-(2-氟吡啶-3-基)乙基(4-(5-((3-氟雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯 | A | 470.1 | 1H NMR (400 MHz,甲醇- d 4) δ 9.01 (s, 1H), 8.42 (s, 1H), 8.17 (s, 1H), 8.09 (d, J = 8.4Hz, 2H), 7.34 (d, J = 22.2Hz, 1H), 6.01 (q, J = 6.6Hz, 1H), 4.02 (d, J = 1.1Hz, 3H), 2.51 (d, J = 2.1Hz, 6H), 1.63 (d, J = 10.7Hz, 3H)。 |
將溶解於四氫呋喃(7mL)中之(R)-1-(2-氯吡啶-3-基)乙基(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(1.11mmol)冷卻至-78℃,並用鋰雙(三甲基矽基)醯胺溶液(1.20mmol)處理。將反應混合物在-78℃下攪拌15min,之後添加正丁基鋰溶液(2.24mmol)。在-78℃下繼續攪拌額外的30min之後,添加氯化鋅溶液(3.23mmol)。在5min後,將反應混合物溫熱至室溫。接著將甲基6-溴-2-甲基菸鹼酸酯(1.09mmol)添加至反應混合物中,接著添加XPhos Pd G3 (0.115mmol)。將反應混合物在70℃下加熱1h。在冷卻至室溫後,將反應混合物用1N HCl溶液淬熄,並用乙酸乙酯萃取。接著用鹽水洗滌有機層,以硫酸鈉乾燥,並濃縮。將殘餘物藉由管柱層析法純化,以給出甲基(R)-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)-2-甲基菸鹼酸酯。
步驟 2 : (R)-6-(5-(((1-(2- 氯吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 )-2- 甲基菸鹼酸
將甲基(R)-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)-2-甲基菸鹼酸酯(0.302mmol)溶解於THF (2mL)、及甲醇(500µL)中,並添加2M氫氧化鋰溶液(0.960mmol),且在室溫下攪拌隔夜。將反應混合物濃縮。將殘餘物用乙酸乙酯稀釋,並用1N HCl溶液洗滌。將有機層用鹽水洗滌,以硫酸鈉乾燥,並濃縮以給出粗(R)-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)-2-甲基菸鹼酸。
步驟 3 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(5-((3- 氯雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 )-6- 甲基吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯
將溶解於二氯甲烷(1mL)中之(R)-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)-2-甲基菸鹼酸(0.098mmol)用3-氯雙環[1.1.1]戊-1-醯胺鹽酸鹽(0.214mmol)、HATU (0.162mmol)、及N,N-二異丙基乙胺(0.287mmol)處理。將反應混合物在室溫下攪拌1h。將反應混合物濃縮。將殘餘物藉由HPLC純化,以提供標題化合物。1H NMR (400MHz,甲醇-d4) δ 8.33 (s, 1H), 8.10 – 7.83 (m, 3H), 7.44 (s, 1H), 6.11 (d, J = 6.8Hz, 1H), 4.02 (s, 3H), 2.64 (s, 3H), 2.54 (s, 6H), 1.61 (s, 3H)。LCMS m/z 516.1 M+1。
實例 11 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(5-((3- 氰基雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 )-3- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯(化合物 59 )之製備 步驟 1 : (R)-6-(5-(((1-(2- 氯吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 )-5 - 氟菸鹼酸
將100mL圓底燒瓶在氬氣氛圍下裝入(R)-1-(2-氯吡啶-3-基)乙基(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(1.4mmol)、30mL THF,並冷卻至-78℃。保持低於-70℃之溫度的同時,逐滴添加LiHMDS(3.4ml,1M於THF中),在逐滴添加正BuLi(2.3mL,2.5M於己烷中)之前使其攪拌5min。在攪拌額外之5min之後,逐滴添加ZnCl
2(3.1mL,1.9M於2-Me-THF中)。完成添加後,將反應混合物在冰/水浴中溫熱至0℃,並攪拌10min。接著將甲基6-溴-5-氟菸鹼酸酯(3.1mmol)、(R)-1-(2-氯吡啶-3-基)乙基(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(1.4mmol)、及Pd-Xphos G2 (0.28mmol)添加入反應混合物中,接著在65℃下加熱2h。隨後將反應物冷卻至室溫,添加二氧化矽(15質量等效物),並將粗混合物在真空中濃縮至乾燥,然後通過矽膠管柱層析法(DCM/MeOH 0至25%)進行純化。隨後將純化材料溶解於4mL THF中,向其添加NaOH (12mL, 0.5M)溶液,且使其攪拌1h。在酯之水解完成後,用4M HCl酸化溶液至pH 3。接著將溶液用20mL水、及20mL鹽水稀釋,並用30mL EtOAc萃取三次。合併有機萃取物,以硫酸鈉乾燥,過濾並在真空中濃縮至乾燥,提供所需酸。
步驟 2 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(5-((3- 氰基雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 )-3- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯
向(R)-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)-5-氟菸鹼酸(0.08mmol)在吡啶(0.5mL)之混合物中添加3-胺基雙環[1.1.1]戊烷-1-甲腈(0.17mmol)、及N'-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.17mmol)。將反應混合物以磁性攪拌2h,在該時間點添加水(1mL),並藉由HPLC純化粗混合物。1H NMR (400MHz,甲醇-d4) δ 8.82 (t, J = 1.6Hz, 1H), 8.51 – 8.25 (m, 1H), 7.99 (dd, J = 10.9, 1.8Hz, 2H), 7.46 (s, 1H), 6.03 (q, J = 6.6Hz, 1H), 4.02 (s, 3H), 2.68 (s, 6H), 1.59 (s, 3H)。LCMS m/z 511.079 M+1。
實例 12 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(6- 氯 -5-((3- 氟雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯(化合物 60 )之製備 步驟 1 : (R)-2- 氯 -6-(5-(((1-(2- 氯吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4 - 基 ) 菸鹼酸
將100mL圓底燒瓶在氬氣氛圍下裝入(R)-1-(2-氯吡啶-3-基)乙基(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(2.77mmol)、20mL THF,並冷卻至-78℃。保持低於-70℃之溫度的同時,逐滴添加LiHMDS(3.4ml,1M於THF中),在逐滴添加正BuLi(2.4mL,2.5M於己烷中)之前使其攪拌5min。在攪拌額外之5min之後,逐滴添加ZnCl
2(3.1mL,1.9M於2-Me-THF中)。完成添加後,將反應混合物在冰/水浴中溫熱至0℃,並攪拌10min。接著將甲基6-溴-2-氯菸鹼酸酯(2.77mmol)、及Pd-Xphos G2 (0.28mmol)添加入反應混合物中,接著在65℃下加熱2h。隨後將反應物冷卻至室溫,添加二氧化矽(15質量等效物),並將粗混合物在真空中濃縮至乾燥,然後通過矽膠管柱層析法(DCM/MeOH 0至25%)進行純化。隨後將純化材料溶解於4mL THF中,向其添加NaOH (12mL, 0.5M)溶液,且使其攪拌1h。在酯之水解完成後,用4M HCl酸化溶液至pH 3。接著將溶液用20mL水、及20mL鹽水稀釋,並用30mL EtOAc萃取三次。合併有機萃取物,以硫酸鈉乾燥,過濾並在真空中濃縮至乾燥,提供所需酸。
步驟 2 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(6- 氯 -5-((3- 氟雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯
向(R)-2-氯-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)菸鹼酸(0.06mmol)在吡啶(0.5mL)之混合物中添加3-氟雙環[1.1.1]戊-1-醯胺(0.11mmol)、及N'-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.07mmol)。將反應混合物以磁性攪拌2h,在該時間點添加水(1mL),並藉由製備型HPLC純化粗混合物。1H NMR (400MHz,甲醇-d4) δ 8.32 (d, J = 4.6Hz, 1H), 8.22 – 7.83 (m, 3H), 7.45 (s, 1H), 6.13 (q, J = 6.6Hz, 1H), 4.00 (s, 3H), 2.49 (d, J = 2.1Hz, 6H), 1.63 (s, 3H)。LCMS m/z 519.998 M+1。
實例 13 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(5-((3- 氰基雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 )-4- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯(化合物 61 )之製備 步驟 1 : (R)-6-(5-(((1-(2- 氯吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 )-4 - 氟菸鹼酸
將100mL圓底燒瓶在氬氣氛圍下裝入(R)-1-(2-氯吡啶-3-基)乙基(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(1.4mmol)、10mL THF,並冷卻至-78℃。保持低於-70℃之溫度的同時,逐滴添加LiHMDS(1.7ml,1M於THF中),在逐滴添加正BuLi(1.2mL,2.5M於己烷中)之前使其攪拌5min。在攪拌額外之5min之後,逐滴添加ZnCl
2(1.5mL,1.9M於2-Me-THF中)。完成添加後,將反應混合物在冰/水浴中溫熱至0℃,並攪拌10min。接著將甲基6-氯-4-氟菸鹼酸酯(1.53mmol)、及Pd-Xphos G2 (0.1mmol)添加入反應混合物中,接著在65℃下加熱2h。隨後將反應物冷卻至室溫,添加二氧化矽(15質量等效物),並將粗混合物在真空中濃縮至乾燥,然後通過矽膠管柱層析法(DCM/MeOH 0至25%)進行純化。隨後將純化材料溶解於4mL THF中,向其添加NaOH (12mL, 0.5M)溶液,且使其攪拌1h。在酯之水解完成後,用4M HCl酸化溶液至pH 3。接著將溶液用20mL水、及20mL鹽水稀釋,並用30mL EtOAc萃取三次。合併有機萃取物,以硫酸鈉乾燥,過濾並在真空中濃縮至乾燥,提供所需酸。
步驟 3 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(5-((3- 氰基雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 )-4- 氟吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯
向(R)-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)-4-氟菸鹼酸(0.08mmol)在吡啶(0.5mL)之混合物中添加3-胺基雙環[1.1.1]戊烷-1-甲腈(0.17mmol)、及N'-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.17mmol)。將反應混合物以磁性攪拌2h,在該時間點添加水(1mL),並藉由HPLC純化粗混合物。1H NMR (400MHz,甲醇-d4) δ 8.79 (d, J = 10.0Hz, 1H), 8.44 – 8.22 (m, 1H), 7.82 (d, J = 11.4Hz, 2H), 7.46 (s, 1H), 6.09 (q, J = 6.4Hz, 1H), 3.99 (s, 3H), 2.68 (s, 6H), 1.61 (s, 3H)。LCMS m/z 511.062 M+1。
實例 14 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(5-((3- 氰基雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 )-6-( 三氟甲基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯(化合物 62 )之製備 步驟 1 : (R)-6-(5-(((1-(2- 氯吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 )-2-( 三氟甲基 ) 菸鹼酸
將100mL圓底燒瓶在氬氣氛圍下裝入(R)-1-(2-氯吡啶-3-基)乙基(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(2.77mmol)、20mL THF,並冷卻至-78℃。保持低於-70℃之溫度的同時,逐滴添加LiHMDS(3.4ml,1M於THF中),在逐滴添加正BuLi(2.4mL,2.5M於己烷中)之前使其攪拌5min。在攪拌額外之5min之後,逐滴添加ZnCl
2(3.1mL,1.9M於2-Me-THF中)。完成添加後,將反應混合物在冰/水浴中溫熱至0℃,並攪拌10min。接著將甲基6-氯-2-(三氟甲基)吡啶-3-羧酸酯(2.77mmol)、及Pd-Xphos G2 (0.28mmol)添加入反應混合物中,接著在65℃下加熱2h。隨後將反應物冷卻至室溫,添加二氧化矽(15質量等效物),並將粗混合物在真空中濃縮至乾燥,然後通過矽膠管柱層析法(DCM/MeOH 0至25%)進行純化。隨後將純化材料溶解於4mL THF中,向其添加NaOH (12mL, 0.5M)溶液,且使其攪拌1h。在酯之水解完成後,用4M HCl酸化溶液至pH 3。接著將溶液用20mL水、及20mL鹽水稀釋,並用30mL EtOAc萃取三次。合併有機萃取物,以硫酸鈉乾燥,過濾並在真空中濃縮至乾燥,提供所需酸。
步驟 2 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(5-((3- 氰基雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 )-6-( 三氟甲基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯
向(R)-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)-2-(三氟甲基)菸鹼酸(0.06mmol)在吡啶(0.5mL)之混合物中添加3-胺基雙環[1.1.1]戊烷-1-甲腈(0.11mmol)、及N'-乙基-N'-(3-二甲胺基丙基)碳二亞胺鹽酸鹽(0.07mmol)。將反應混合物以磁性攪拌2h,在該時間點添加水(1mL),並藉由製備型HPLC純化粗混合物。1H NMR (400MHz,甲醇-d4) δ 8.31 (d, J = 8.2Hz, 2H), 8.03 (d, J = 8.1Hz, 2H), 7.44 (s, 1H), 6.09 (q, J = 6.6Hz, 1H), 4.01 (s, 3H), 2.66 (s, 6H), 1.61 (s, 3H).。LCMS m/z 561.037 M+1。
實例 15 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(6- 氟 -5-((3- 氟雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯(化合物 63 )之製備 步驟 1 : (R)-6-(5-(((1-(2- 氯吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 )-2- 氟菸鹼酸
將40mL小瓶在氮氣氛圍下裝入(R)-1-(2-氯吡啶-3-基)乙基(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(1mmol)、15mL THF,並冷卻至-78℃。保持低於-70℃之溫度的同時,逐滴添加LiHMDS(1.2ml,1M於THF中),在逐滴添加正BuLi(1.1mL,2.5M於己烷中)之前使其攪拌5min。在攪拌額外之5min之後,逐滴添加ZnCl
2(1.3mL,1.9M於2-Me-THF中)。完成添加後,將反應混合物在冰/水浴中溫熱至0℃,並攪拌10min。接著將6-溴-2-氟菸鹼酸(1.2mmol)、及Pd(dppf)Cl
2-DCM (0.28mmol)添加至反應混合物中,接著在765℃加熱2h。隨後將反應物冷卻至室溫,並藉由添加乙酸(2mL)及10%甲醇(於二氯甲烷中)溶液(10mL)淬滅。將粗反應物經由矽塞過濾,並在真空中濃縮至乾燥,且未經進一步純化即用於下一步驟中。
步驟 2 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(6- 氟 -5-((3- 氟雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯
向(R)-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)-2-氟菸鹼酸(0.1mmol)於DCM (0.5mL)中之混合物添加3-氟雙環[1.1.1]戊-1-醯胺(0.2mmol)、HATU (0.14mmol)、及N,N-二異丙基乙胺(0.3mmol)。將反應混合物用磁力攪拌16h,並接著用乙酸乙酯稀釋,且用以下洗滌:飽和碳酸氫鈉、及鹽水。將有機層分離,以硫酸鈉乾燥,濃縮,並藉由逆相HPLC純化。1H NMR (400MHz,甲醇-d4) δ 8.42 – 8.29 (m, 1H), 8.25 (dd, J = 9.4, 7.8Hz, 1H), 8.19 – 7.93 (m, 2H), 7.58 – 7.32 (m, 1H), 6.11 (q, J = 6.5Hz, 1H), 3.99 (s, 3H), 2.50 (d, J = 2.1Hz, 6H), 1.63 (s, 3H)。LCMS m/z 503.95 M+1。
實例 16 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(3- 氟 -5-((3- 氟雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯(化合物 64 )之製備 步驟 1 : (R)-6-(5-(((1-(2- 氯吡啶 -3- 基 ) 乙氧基 ) 羰基 ) 胺基 )-1- 甲基 -1H-1,2,3- 三唑 -4- 基 )-5 - 氟菸鹼酸
將40mL小瓶在氮氣氛圍下裝入(R)-1-(2-氯吡啶-3-基)乙基(4-溴-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(1mmol)、15mL THF,並冷卻至-78℃。保持低於-70℃之溫度的同時,逐滴添加LiHMDS(1.2ml,1M於THF中),在逐滴添加正BuLi(1.1mL,2.5M於己烷中)之前使其攪拌5min。在攪拌額外之5min之後,逐滴添加ZnCl
2(1.3mL,1.9M於2-Me-THF中)。完成添加後,將反應混合物在冰/水浴中溫熱至0℃,並攪拌10min。接著將6-溴-2-氟菸鹼酸(1.2mmol)、及Pd(dppf)Cl
2-DCM (0.28mmol)添加至反應混合物中,接著在765℃加熱2h。隨後將反應物冷卻至室溫,並藉由添加乙酸(2mL)及10%甲醇(於二氯甲烷中)溶液(10mL)淬滅。將粗反應物經由矽塞過濾,並在真空中濃縮至乾燥,且未經進一步純化即用於下一步驟中。
步驟 2 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(3- 氟 -5-((3- 氟雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯
向(R)-6-(5-(((1-(2-氯吡啶-3-基)乙氧基)羰基)胺基)-1-甲基-1H-1,2,3-三唑-4-基)-2-氟菸鹼酸(0.1mmol)於DCM (0.5mL)中之混合物添加3-氟雙環[1.1.1]戊-1-醯胺(0.2mmol)、HATU (0.14mmol)、及N,N-二異丙基乙胺(0.3mmol)。將反應混合物用磁力攪拌16h,並接著用乙酸乙酯稀釋,且用以下洗滌:飽和碳酸氫鈉、及鹽水。將有機層分離,以硫酸鈉乾燥,濃縮,並藉由逆相HPLC純化。1H NMR (400MHz,甲醇-d4) δ 8.85 (s, 1H), 8.33 (d, J = 4.7Hz, 1H), 8.01 (dd, J = 10.9, 1.8Hz, 2H), 7.47 (s, 1H), 6.04 (q, J = 6.6Hz, 1H), 4.03 (s, 3H), 2.51 (d, J = 2.1Hz, 6H), 1.59 (s, 3H)。LCMS m/z 503.98 M+1。
實例 17 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(6- 氯 -5-((3- 氰基雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯(化合物 65 )之製備
依照實例12中所描述之用於合成(R)-1-(2-氯吡啶-3-基)乙基(4-(6-氯-5-((3-氟雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(化合物60)的程序,但使用3-胺基雙環[1.1.1]戊-1-甲腈(0.114mmol)取代3-氟雙環[1.1.1]戊-1-醯胺,得到(R)-1-(2-氯吡啶-3-基)乙基(4-(6-氯-5-((3-氰基雙環[1.1.1]戊-1-基)胺甲醯基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(化合物65)。1H NMR (400MHz,甲醇-d4) δ 8.32 (d, J = 4.6Hz, 1H), 7.98 (dd, J = 49.0, 7.9Hz, 3H), 7.45 (s, 1H), 6.12 (q, J = 6.6Hz, 1H), 3.99 (s, 3H), 2.67 (s, 6H), 1.63 (s, 3H)。LCMS m/z 526.99 M+1。
實例 18 : (R)-1-(2- 氯吡啶 -3- 基 ) 乙基 (4-(5-((3- 氟雙環 [1.1.1] 戊 -1- 基 ) 胺甲醯基 )-6-( 三氟甲基 ) 吡啶 -2- 基 )-1- 甲基 -1H-1,2,3- 三唑 -5- 基 ) 胺甲酸酯(化合物 66 )之製備
依照實例14中所描述之用於合成(R)-1-(2-氯吡啶-3-基)乙基(4-(5-((3-氰基雙環[1.1.1]戊-1-基)胺甲醯基)-6-(三氟甲基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(化合物62)的程序,但使用3-氟雙環[1.1.1]戊-1-醯胺(0.106mmol)取代3-胺基雙環[1.1.1]戊-1-甲腈,得到(R)-1-(2-氯吡啶-3-基)乙基(4-(5-((3-氟雙環[1.1.1]戊-1-基)胺甲醯基)-6-(三氟甲基)吡啶-2-基)-1-甲基-1H-1,2,3-三唑-5-基)胺甲酸酯(化合物66)。LCMS m/z 554.037 M+1。
1H NMR (400MHz,甲醇-
d
4 ) δ 8.32 (d, J = 8.1Hz, 2H), 8.04 (d, J = 8.2Hz, 2H), 7.44 (s, 1H), 6.10 (q, J = 6.6Hz, 1H), 4.01 (s, 3H), 2.48 (d, J = 2.1Hz, 6H), 1.61 (s, 3H)。
實例 19 :鈣分析
體外LPAR1活性係在細胞內鈣移動分析中測量。
表現人類LPAR1 (NM_001401.3)之CHO-K1 EDG2細胞(DiscoverX cat# 93-0644C2)係以總體積為25µL之含有10%胎牛血清、300µg/ml濕黴素、及800µg/ml G418的杜氏修飾伊格爾培養基(DMEM)、以15,000個細胞/孔種至384孔組織培養盤(Grenier # 781091)中,並在37℃下培養隔夜。在測試之前,25µL鈣負載染料組分A(FLIPR Calcium 6 Assay Kit Molecular Device # R8190)、及在漢克平衡鹽溶液(Corning # 21-023-CV)中之2.5 mM丙磺舒(Invitrogen # P36400,新鮮製備)、20 mM HEPES (Corning # 25-060-CI)、0.1%牛血清白蛋白(Sigma-Aldrich # A7906-500G)係在37℃下添加至細胞60分鐘。
記錄LPA 18:2(Avanti Polar Lipids cat# 857138,0.5nM至10 µM)之促效劑劑量曲線,以確定用於後續拮抗劑分析之LPA 18:2 EC
80。對於促效劑劑量曲線,在染料負載後2小時移除細胞,並轉移至FLIPR Tetra儀器(Molecular Devices, San Jose, CA)。監測鈣移動5分鐘,並於分析中添加10µL 6X LPA in HBSS / 20 mM Hepes / 0.1%牛血清白蛋白(BSA)至細胞5秒。
為確定測試化合物之LPAR1拮抗活性,將細胞與測試化合物以0.5 nM至10 µM之劑量範圍內進行預培養,接著與LPA以EC
80濃度(100 nM)進行預培養。在染料負載之後,將細胞自培育箱中移除,並添加0.3µL之200X拮抗劑。將細胞在37℃下培養60分鐘。在FLIPR Tetra上測量拮抗劑活性。監測鈣移動3.5分鐘,並於分析中添加10µL之於HBSS中的6X EC
80LPA、20 mM HEPES、及0.1%BSA至細胞5秒。信號振幅(最大減最小)值係使用Dose Response Tool (Gilead Sciences Inc.)對拮抗劑濃度之log
10繪製以確定EC
50。
評定例示性化合物之拮抗潛力,針對化合物1至66在LPAR1鈣移動分析中測定EC
50值。結果係顯示於表5中(LPAR1 EC
50)。化合物編號對應於實例1至18中之化合物編號。N/A =不適用。
表 5
* * *
化合物 | LPAR1(EC 50; nM) |
化合物1 | 75.8 |
化合物2 | 8.1 |
化合物3 | 1,416.6 |
化合物4 | 141.8 |
化合物5 | 42.9 |
化合物6 | 56.1 |
化合物7 | 334.2 |
化合物8 | 30.4 |
化合物9 | 324.9 |
化合物10 | 438.8 |
化合物11 | 62.7 |
化合物12 | 26.5 |
化合物13 | 250.5 |
化合物14 | 255.7 |
化合物15 | 26.2 |
化合物16 | 3,588.1 |
化合物17 | 649.2 |
化合物18 | 91.2 |
化合物19 | 16.6 |
化合物20 | 313.5 |
化合物21 | 44.8 |
化合物22 | 84.8 |
化合物23 | 159.3 |
化合物24 | 221.6 |
化合物25 | 363.7 |
化合物26 | <4.6 |
化合物27 | 42.8 |
化合物28 | 426.7 |
化合物29 | 3,418.0 |
化合物30 | 93.0 |
化合物31 | 14.9 |
化合物32 | 55.9 |
化合物33 | 273.3 |
化合物34 | 47.5 |
化合物35 | 140.1 |
化合物36 | 15.6 |
化合物37 | 196.1 |
化合物38 | 24.4 |
化合物39 | 9.1 |
化合物40 | 7.6 |
化合物41 | 61.0 |
化合物42 | 10.1 |
化合物43 | 9.0 |
化合物44 | 272.7 |
化合物45 | <4.6 |
化合物46 | 88.1 |
化合物47 | <4.6 |
化合物48 | 80.7 |
化合物49 | 74.3 |
化合物50 | 8.7 |
化合物51 | <4.6 |
化合物52 | 280.9 |
化合物53 | 19.4 |
化合物54 | <4.6 |
化合物55 | 58.1 |
化合物56 | 139.2 |
化合物57 | 716.6 |
化合物58 | 48.3 |
化合物59 | 23.2 |
化合物60 | 93.4 |
化合物61 | 232.6 |
化合物62 | 14.5 |
化合物63 | 144.6 |
化合物64 | 93.5 |
化合物65 | <4.6 |
化合物66 | 210.1 |
除非另行定義,否則本文所使用之所有技術及科學用語具有本揭露所屬技術領域中具有通常知識者所經常瞭解之相同意義。
因此,應理解,儘管本揭露已藉由較佳實施例及可選的揭示特徵具體,本文中所揭示之揭示內容之修改、改良、及變化可被所屬技術領域中具有通常知識者所採用,且此類修改、改良、及變化被視為在本揭露之範疇內。本文提供之材料、方法、及實例係代表較佳實施例,其係例示性的且不意欲作為本揭露之範疇上之限制。
本揭露已廣泛且通用地描述於本文中。在通用揭露內容中之各較窄種類及次通用群組亦形成本揭露之部分。此包括本揭露之通用描述,其前提或負限制係自屬中移除任何標的,無論排除材料是否具體引用於本文中。
另外,當本揭露之特徵或態樣係以馬庫西群組之形式來描述,所屬技術領域中具有通常知識者將認識到,本揭露亦因此以馬庫西群組中之任何個別成員或成員之子群組之形式來描述。
應理解,雖然本揭露已結合上述實施例來描述,但前述描述及實例意欲說明而非限制本揭露之範疇。本揭露之範疇內之其他態樣、優點、及修改對於本揭露之技術領域中具有通常知識者將係顯而易見的。
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Claims (100)
- 一種式(I)之化合物, (I) 或其醫藥上可接受之鹽, 其中: R 1係氫、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-10環烷基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、或具有1至4個獨立地選自氮、氧、及硫之雜原子的5至10員雜芳基,其中各烷基、烯基、炔基、環烷基、雜環基、芳基、或雜芳基可選地經1至4個R 1A取代,該等取代基可相同或不同,其中各R 1A係獨立地選自鹵素、氰基、硝基、側氧基、C 1-4烷基、C 3-10環烷基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、具有1至4個獨立地選自氮、氧、或硫之雜原子的5至10員雜芳基、–N(R 1B1)(R 1B2)、-O-R 1B1、-S-R 1B1、–C(O)N(R 1B1) (R 1B2)、–N(R 1B1)C(O)R 1B2、-N(R 1B1)C(O)N(R 1B2)(R 1B3)、–S(O) 0-2R 1B1、–S(O) 2N(R 1B1) (R 1B2)、及–N(R 1B1)S(O) 2R 1B2,其中各R 1B1、R 1B2、及R 1B3獨立地係氫、C 1-6烷基、或C 3-6環烷基, 其中各R 1A烷基、環烷基、雜環基、芳基、及雜芳基可選地經1至4個R 1C取代,該等取代基可相同或不同,且其中各R 1C獨立地係C 1-4烷基、鹵素、氰基、-O-R 1D1、或-N(R 1D1)(R 1D2),其中各R 1D1及R 1D2獨立地係氫或C 1-6烷基,且 其中各R 1B1、R 1B2、及R 1B3烷基及環烷基可選地經1至3個鹵素取代;或 R 2係氫或可選地經1至3個取代基取代之C 1-6烷基,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C 1-4烷氧基、及C 3-10環烷基;或 R 2係可選地經1至3個取代基取代之C 3-6環烷基,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C 1-4烷氧基、及C 1-6烷基; R 3係選自氫、氘、鹵素、C 1-6烷基、C 3-6環烷基、-O-R 3A1、及-N(R 3A1)(R 3A2),其中該C 1-6烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C 1-4烷氧基及鹵素,且其中各R 3A1及R 3A2獨立地係氫或可選地經1至3個鹵素取代之C 1-3烷基,該等鹵素可相同或不同; 各R 4係獨立地選自氘、鹵素、C 1-6烷基、C 3-6環烷基、-O-R 4A1、及-N(R 4A1)(R 4A2),其中該C 1-6烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C 1-4烷氧基及鹵素,且其中各R 4A1及R 4A2獨立地係氫或可選地經1至3個鹵素取代之C 1-3烷基,該等鹵素可相同或不同; n係0、1、或2; R 5係可選地經1至3個取代基取代之C 1-6烷基,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C 1-4烷氧基、-C(O)N(R 5A1)、及-N(R 5A1)(R 5A2),其中各R 5A1及R 5A2獨立地係氫、C 1-6烷基、或C 3-10環烷基;或 R 5係C 3-6環烷基或具有1或2個獨立地選自氮、氧、及硫之雜原子的3至6員雜環基,其中該環烷基或雜環基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C 1-4烷基、及C 1-4烷氧基; 各Y 1及Y 2獨立地係氫、氘、或可選地經1至3個取代基取代之C 1-6烷基,該等取代基可相同或不同,且獨立地選自氘、鹵素、氰基、C 2-3炔基、C 1-4烷氧基、及-C(O)NH-(C 1-4H 3-9);及 Z係C 1-8烷基、C 1-6烷氧基、C 3-6環烷基、C 6-12芳基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至12員雜環基、或具有1至4個獨立地選自氮、氧、及硫之雜原子的5至12員雜芳基,其中該烷基、烷氧基、環烷基、芳基、雜環基、或雜芳基各可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C 1-4烷基、C 1-4烷氧基、及C 3-6環烷基,其中該C 1-4烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且選自C 1-4烷氧基及鹵素;或 Y 1及Z與其等所附接之碳一起形成C 3-6環烷基、C 6-12芳基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至12員雜環基、或具有1至4個獨立地選自氮、氧、及硫之雜原子的5至12員雜芳基,其中該環烷基、芳基、雜環基、或雜芳基各可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自氰基、C 1-4烷基、C 1-4烷氧基、C 6-10芳基、及鹵素,其中該C 1-4烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C 1-4烷氧基及鹵素,且其中該C 6-10芳基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C 1-4烷基、C 1-4烷氧基、及鹵素,且Y 2係氫或氘。
- 如請求項1或2之化合物或其醫藥上可接受之鹽,其中R 2係氫。
- 如請求項1至3中任一項之化合物或其醫藥上可接受之鹽,其中各Y 1及Y 2獨立地係氫、氘、或可選地經1至3個取代基取代之C 1-6烷基,該等取代基可相同或不同,且各獨立地選自鹵素、氰基、C 2-3炔基、C 1-4烷氧基、及-C(O)NH-(C 1-4H 3-9)。
- 如請求項1至4中任一項之化合物或其醫藥上可接受之鹽,其中Y 1係可選地經1至3個取代基取代之C 1-4烷基,該等取代基可相同或不同,且各獨立地選自鹵素、氰基、及C 1-4烷氧基,且Y 2係氫。
- 如請求項1至5中任一項之化合物或其醫藥上可接受之鹽,其中Y 1係可選地經1至3個取代基取代之甲基,該等取代基可相同或不同,且各獨立地選自-F、-Cl、-CN、及-O-CH 3。
- 如請求項1至6中任一項之化合物或其醫藥上可接受之鹽,其中Y 1係-CH 3。
- 如請求項1至4及6至7中任一項之化合物或其醫藥上可接受之鹽,其中Y 2係氫。
- 如請求項1至8中任一項之化合物或其醫藥上可接受之鹽,其中Z係具有1至3個獨立地選自氮、氧、及硫之雜原子的5或6員雜芳基,其中該雜芳基可選地經1至3個取代基取代,該等取代基可相同或不同,且各獨立地選自鹵素及C 1-4烷基。
- 如請求項1至9中任一項之化合物或其醫藥上可接受之鹽,其中Z係吡啶基,其可選地經1或2個取代基取代,該等取代基各獨立地選自-F及-Cl。
- 如請求項1至12中任一項之化合物或其醫藥上可接受之鹽,其中R 5係可選地經1至3個取代基取代之C 1-6烷基,該等取代基可相同或不同,且獨立地選自鹵素、氰基、C 1-4烷氧基、-C(O)N(R 5A1)、及-N(R 5A1)(R 5A2),其中各R 5A1及R 5A2獨立地係H、C 1-6烷基、或C 3-10環烷基。
- 如請求項1至13中任一項之化合物或其醫藥上可接受之鹽,其中R 5係-CH 3。
- 如請求項1至14中任一項之化合物或其醫藥上可接受之鹽,其中R 1係可選地經1至4個R 1A取代之C 3-10環烷基,該等取代基可相同或不同,其中各R 1A係獨立地選自鹵素、氰基、側氧基、硝基、C 1-4烷基、C 3-10環烷基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、具有1至4個獨立地選自氮、氧、或硫之雜原子的5至10員雜芳基、–N(R 1B1)(R 1B2)、-O-R 1B1、-S-R 1B1、–C(O)N(R 1B1)(R 1B2)、–N(R 1B1)C(O)R 1B2、-NR 1B1C(O)N(R 1B2)(R 1B3)、–S(O) 0-2R 1B1、–S(O) 2N(R 1B1)(R 1B2)、及–N(R 1B1)S(O) 2R 1B2,其中各R 1B1、R 1B2、及R 1B3獨立地係氫、C 1-6烷基、或-C 3-6環烷基, 其中各R 1A烷基、環烷基、雜環基、芳基、及雜芳基可選地經1至4個R 1C取代,該等取代基可相同或不同,且其中各R 1C獨立地係C 1-4烷基、鹵素、氰基、-O-R 1D1、或-N(R 1D1)(R 1D2),其中各R 1D1及R 1D2獨立地係氫或C 1-6烷基,且 其中各R 1B1及R 1B2烷基及環烷基可選地經1至3個鹵素取代。
- 如請求項1至17中任一項之化合物或其醫藥上可接受之鹽,其中R 1係環丙基或環丁基,其各可選地經1或2個R 1A取代,該等取代基獨立地選自-F及苯基,其中各苯基可選地經1至4個R 1C取代,該等取代基可相同或不同,且其中各R 1C獨立地係C 1-4烷基、鹵素。
- 如請求項1至17中任一項之化合物或其醫藥上可接受之鹽,其中該C 3-10環烷基係C 5-10雙環環烷基。
- 如請求項20之化合物或其醫藥上可接受之鹽,其中該C 5-10雙環環烷基係C 5-8橋聯雙環環烷基。
- 如請求項21之化合物或其醫藥上可接受之鹽,其中該C 5-8橋聯雙環環烷基係雙環戊基,其各可選地經1至3個取代基取代,該等取代基可相同或不同,且各獨立地選自-F、-Cl、-CN、-CH 3、-CH 2-OH、-CHF 2、-CF 3、-O-CH 3、-CO 2-CH 3、-SO 2-CH 3、及苯基。
- 如請求項1至16中任一項之化合物或其醫藥上可接受之鹽,其中R 1係具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基,其可選地經1至4個R 1A取代,該等取代基可相同或不同,其中各R 1A係獨立地選自鹵素、氰基、側氧基、硝基、C 1-4烷基、C 3-10環烷基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、具有1至4個獨立地選自氮、氧、或硫之雜原子的5至10員雜芳基、–N(R 1B1)(R 1B2)、-O-R 1B1、-S-R 1B1、–C(O)N(R 1B1)(R 1B2)、–N(R 1B1)C(O)R 1B2、-NR 1B1C(O)N(R 1B2)(R 1B3)、–S(O) 0-2R 1B1、–S(O) 2N(R 1B1)(R 1B2)、及–N(R 1B1)S(O) 2R 1B2,其中各R 1B1、R 1B2、及R 1B3獨立地係氫、C 1-6烷基、或-C 3-6環烷基, 其中各R 1A烷基、環烷基、雜環基、芳基、及雜芳基可選地經1至4個R 1C取代,該等取代基可相同或不同,且其中各R 1C獨立地係C 1-4烷基、鹵素、氰基、-O-R 1D1、或-N(R 1D1) (R 1D2),其中各R 1D1及R 1D2獨立地係氫或C 1-6烷基, 其中各R 1B1及R 1B2烷基及環烷基可選地經1至3個鹵素取代。
- 如請求項1至16及24中任一項之化合物或其醫藥上可接受之鹽,其中R 1係可選地經1至4個R 1A取代之四氫哌喃基,該等取代基可相同或不同,且各獨立地選自-F、-Cl、-OH、-CN、-CH 3、-CH 2F、-CHF 2、-CF 3、及-O-CH 3。
- 如請求項1至16中任一項之化合物或其醫藥上可接受之鹽,其中R 1係可選地經1至4個R 1A取代之6至10員芳基,該等取代基可相同或不同,其中各R 1A係獨立地選自鹵素、氰基、側氧基、硝基、C 1-4烷基、C 3-10環烷基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、具有1至4個獨立地選自氮、氧、或硫之雜原子的5至10員雜芳基、–N(R 1B1)(R 1B2)、-O-R 1B1、-S-R 1B1、–C(O)N(R 1B1)(R 1B2)、–N(R 1B1)C(O)R 1B2、-NR 1B1C(O)N(R 1B2)(R 1B3)、–S(O) 0-2R 1B1、–S(O) 2N(R 1B1)(R 1B2)、及–N(R 1B1)S(O) 2R 1B2,其中各R 1B1、R 1B2、及R 1B3獨立地係氫、C 1-6烷基、或-C 3-6環烷基, 其中各R 1A烷基、環烷基、雜環基、芳基、及雜芳基可選地經1至4個R 1C取代,該等取代基可相同或不同,且其中各R 1C獨立地係C 1-4烷基、鹵素、氰基、-O-R 1D1、或-N(R 1D1)(R 1D2),其中各R 1D1及R 1D2獨立地係氫或C 1-6烷基, 其中各R 1B1及R 1B2烷基及環烷基可選地經1至3個鹵素取代。
- 如請求項1至16及27中任一項之化合物或其醫藥上可接受之鹽,其中R 1係可選地經1至4個R 1A取代之苯基,該等取代基可相同或不同,其中各R 1A係獨立地選自鹵素、氰基、C 1-3烷基、C 1-4烷氧基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、或具有1至4個獨立地選自氮、氧、或硫之5至10員雜芳基,其中各烷基、雜環基、及雜芳基可選地經1至4個R 1C取代,該等取代基可相同或不同,且其中各R 1C獨立地係氰基、鹵素、或C 1-4烷基。
- 如請求項1至16中任一項之化合物或其醫藥上可接受之鹽,其中R 1係具有1至4個獨立地選自氮、氧、及硫之雜原子的5至10員雜芳基,其可選地經1至4個R 1A取代,該等取代基可相同或不同,其中各R 1A係獨立地選自鹵素、氰基、側氧基、硝基、C 1-4烷基、C 3-10環烷基、具有1至4個獨立地選自氮、氧、及硫之雜原子的3至10員雜環基、6至10員芳基、具有1至4個獨立地選自氮、氧、或硫之雜原子的5至10員雜芳基、–N(R 1B1)(R 1B2)、-O-R 1B1、-S-R 1B1、–C(O)N(R 1B1)(R 1B2)、–N(R 1B1)C(O)R 1B2、-NR 1B1C(O)N(R 1B2)(R 1B3)、–S(O) 0-2R 1B1、–S(O) 2N(R 1B1)(R 1B2)、及–N(R 1B1)S(O) 2R 1B2,其中各R 1B1、R 1B2、及R 1B3獨立地係氫、C 1-6烷基、或-C 3-6環烷基, 其中各R 1A烷基、環烷基、雜環基、芳基、及雜芳基可選地經1至4個R 1C取代,該等取代基可相同或不同,且其中各R 1C獨立地係C 1-4烷基、鹵素、氰基、-O-R 1D1、或-N(R 1D1)(R 1D2),其中各R 1D1及R 1D2獨立地係氫或C 1-6烷基, 其中各R 1B1及R 1B2烷基及環烷基可選地經1至3個鹵素取代。
- 如請求項1至16及31中任一項之化合物或其醫藥上可接受之鹽,其中R 1係噻唑基、 唑基、吡啶基、嘧啶基、或嗒 基,其各可選地經1至4個R 1A取代,該等取代基可相同或不同,其中各R 1A係獨立地選自鹵素、氰基、側氧基、C 1-4烷基、C 3-10環烷基、具有1至4個獨立地選自氮及氧之雜原子的3至10員雜環基、–N(R 1B1)(R 1B2)、-O-R 1B1、及–S(O) 0-2R 1B1,其中各R 1B1及R 1B2獨立地係氫或C 1-6烷基, 其中各R 1A烷基、環烷基、及雜環基可選地經1至4個R 1C取代,該等取代基可相同或不同,且其中各R 1C獨立地係C 1-4烷基、鹵素、或氰基, 其中各R 1B1及R 1B2烷基及環烷基可選地經1至3個鹵素取代。
- 如請求項1至34中任一項之化合物或其醫藥上可接受之鹽,其中R 3係氫。
- 如請求項1至34中任一項之化合物或其醫藥上可接受之鹽,其中R 3係選自氘、鹵素、C 1-6烷基、C 3-6環烷基、-O-R 3A1、及-N(R 3A1)(R 3A2),其中該C 1-6烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C 1-4烷氧基及鹵素,且其中各R 3A1及R 3A2獨立地係氫或可選地經1至3個鹵素取代之C 1-4烷基,該等鹵素可相同或不同。
- 如請求項1至34中任一項之化合物或其醫藥上可接受之鹽,其中R 3係選自鹵素或可選地經1至3個鹵素取代之C 1-3烷基。
- 如請求項1至34中任一項之化合物或其醫藥上可接受之鹽,其中R 3係選自–F、-Cl、-CH 3、或-CF 3。
- 如請求項1至38中任一項之化合物或其醫藥上可接受之鹽,其中各R 4係獨立地選自氘、鹵素、C 1-6烷基、C 3-6環烷基、-O-R 4A1、及-N(R 4A1)(R 4A2),其中該C 1-6烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且獨立地選自C 1-4烷氧基及鹵素,且其中各R 4A1及R 4A2獨立地係氫或可選地經1至3個鹵素取代之C 1-4烷基,該等鹵素可相同或不同。
- 如請求項1至39中任一項之化合物或其醫藥上可接受之鹽,其中各R 4係鹵素。
- 如請求項1至40中任一項之化合物或其醫藥上可接受之鹽,其中各R 4係-F。
- 如請求項1至41中任一項之化合物或其醫藥上可接受之鹽,其中n係0、1、或2。
- 如請求項42之化合物或其醫藥上可接受之鹽,其中n係0。
- 如請求項42之化合物或其醫藥上可接受之鹽,其中n係1。
- 如請求項42之化合物或其醫藥上可接受之鹽,其中n係2。
- 如請求項1至45中任一項之化合物或其醫藥上可接受之鹽,其中R 6係氫、鹵素、氰基、C 1-4烷基、C 1-4烷氧基、或C 3-6環烷基,其中該C 1-4烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且選自C 1-4烷氧基及鹵素。
- 如請求項1至46中任一項之化合物或其醫藥上可接受之鹽,其中R 6係鹵素。
- 如請求項1至46中任一項之化合物或其醫藥上可接受之鹽,其中R 6係-F或-Cl。
- 如請求項1至48中任一項之化合物或其醫藥上可接受之鹽,其中R 7係氫、鹵素、氰基、C 1-4烷基、C 1-4烷氧基、或C 3-6環烷基,其中該C 1-4烷基可選地經1至3個取代基取代,該等取代基可相同或不同,且選自C 1-4烷氧基及鹵素。
- 如請求項1至49中任一項之化合物或其醫藥上可接受之鹽,其中R 7係氫或鹵素。
- 如請求項1至49中任一項之化合物或其醫藥上可接受之鹽,其中R 7係氫或-F。
- 一種醫藥組成物,其包含治療有效量的如請求項1至57中任一項之化合物或其醫藥上可接受之鹽、及醫藥上可接受之賦形劑。
- 如請求項58之醫藥組成物,其進一步包含額外治療劑。
- 一種治療、穩定LPAR1介導之疾病或病況、或減輕其嚴重性或進展的方法,其包含向有需要之患者投予治療有效量的如請求項1至47中任一項之化合物或其醫藥上可接受之鹽、或如請求項58或59之醫藥組成物。
- 如請求項60之方法,其中該LPAR1介導之疾病或病況係選自由下列所組成之群組:傷口癒合、癌症、疼痛、呼吸道病症、過敏性病症、神經系統病症、心血管病症、及發炎性病症。
- 如請求項60之方法,其中該LPAR1介導之疾病或病況係間質性肺病(ILD)。
- 如請求項62之方法,其中該間質性肺病(ILD)係非特異性間質性肺炎(NSIP)、類肉瘤病、石綿肺症(與職業暴露相關之ILD)、漸進性纖維化ILD、特發性間質性肺炎(IIP)、結締組織疾病相關之間質性肺病(CTD-ILD)、類風濕性關節炎相關ILD、硬皮症相關ILD、或外因性肺泡肺泡炎。
- 如請求項60之方法,其中該LPAR1介導之疾病或病況係慢性腎病(CKD)。
- 如請求項64之方法,其中該CKD係補體腎絲球病變、膜性腎絲球病變、多囊性腎病、IgA腎病變、局部節段性腎絲球硬化症(FSGS)、或亞伯氏症候群(Alport syndrome)。
- 如請求項64或65之方法,其中該LPAR1介導之疾病或病況包含纖維化。
- 如請求項66之方法,其中該纖維化係肺纖維化、腎纖維化、肝纖維化、眼部纖維化、心臟纖維化、或全身性硬化症。
- 如請求項67之方法,其中該肺纖維化係特發性肺纖維化(IPF)或漸進性纖維化間質性肺病(PF-ILD)。
- 如請求項67之方法,其中該肺纖維化係繼發於全身性發炎性疾病。
- 如請求項69之方法,其中該全身性發炎性疾病係類風濕性關節炎、硬皮症、狼瘡、隱原性纖維化肺泡炎、輻射誘導之纖維化、慢性阻塞性肺病(COPD)、硬皮症、慢性氣喘、矽肺病、石棉誘導之肺或胸膜纖維化、急性肺損傷、或急性呼吸窘迫。
- 如請求項67之方法,其中該腎纖維化係與糖尿病腎病相關。
- 如請求項60之方法,其中該LPAR1介導之疾病或病況係肝病。
- 如請求項72之方法,其中該肝病包含肝纖維化。
- 如請求項72或73之方法,其中該肝病包含非酒精性脂肪肝病(NAFLD)。
- 如請求項72至74中任一項之方法,其中該肝病包含脂肪變性。
- 如請求項72至75中任一項之方法,其中該肝病包含非酒精性脂肪肝炎(NASH)。
- 如請求項72至76中任一項之方法,其中該肝病包含肝硬化。
- 如請求項77之方法,其中該肝硬化係代償性肝硬化。
- 如請求項77之方法,其中該肝硬化係代償不全之肝硬化。
- 如請求項72至79中任一項之方法,其中該肝病包含肝細胞癌(HCC)。
- 如請求項72至79中任一項之方法,其中該肝病包含原發性膽汁性肝硬化(PBC)或原發性硬化性膽管炎(PSC)。
- 如請求項72至79中任一項之方法,其中該肝病包含門脈高壓。
- 如請求項60至82中任一項之方法,其中該化合物或其醫藥上可接受之鹽係與額外治療劑組合投予。
- 如請求項59之醫藥組成物或如請求項83之方法,其中該額外治療劑係一、二、三、或四種額外治療劑。
- 如請求項59之醫藥組成物或如請求項83或84之方法,其中該額外治療劑包含乙醯CoA羧化酶(ACC)抑制劑、細胞凋亡信號調節激酶(ASK-1)抑制劑、類法尼醇X受體(FXR)促效劑、魚油、類升糖素肽-1受體促效劑、過氧化體增殖活化受體α (PPARα)促效劑、或TGFβ拮抗劑。
- 如請求項85之醫藥組成物或方法,其中該ACC抑制劑係費索司他(firsocostat)。
- 如請求項85之醫藥組成物或方法,其中該ASK1抑制劑係司隆色替(selonsertib)。
- 如請求項85之醫藥組成物或方法,其中該FXR促效劑係希勒氟索(cilofexor)。
- 如請求項85之醫藥組成物或方法,其中該PPARα促效劑係纖維酸鹽類(fibrate)。
- 如請求項85之醫藥組成物或方法,其中該魚油係二十碳五烯酸乙酯(icosapent ethyl)。
- 如請求項85之醫藥組成物或方法,其中該GLP-1受體促效劑係利拉魯肽(liraglutide)或索馬魯肽(semaglutide)。
- 如請求項85之醫藥組成物或方法,其中該TGFβ拮抗劑係抗TGFβ1特異性抗體。
- 如請求項85之醫藥組成物或方法,其中該TGFβ拮抗劑係TGFβ受體。
- 如請求項85之醫藥組成物或方法,其中該額外治療劑包含費索司他及希勒氟索。
- 如請求項85之醫藥組成物或方法,其中該額外治療劑包含費索司他、及利拉魯肽或索馬魯肽。
- 如請求項85或86之醫藥組成物或方法,其中該額外治療劑包含纖維酸鹽類或二十碳五烯酸乙酯。
- 如請求項85之醫藥組成物或方法,其中該額外治療劑包含希勒氟索、及利拉魯肽或索馬魯肽。
- 如請求項59之醫藥組成物或如請求項83或84之方法,其中該額外治療劑包含VEGFR抑制劑、FGFR抑制劑、PDGFR抑制劑、自毒素(autaxin)抑制劑、GPR84促效劑、PASK抑制劑、CFTR促效劑、JAK1抑制劑、ADAMTS5抑制劑、TOL2/3抑制劑、CTGF抑制劑、可溶性PTX2、抗半乳糖凝集素-3抗體、整合素-α V-β 6/α V-β 1拮抗劑、JNK1抑制劑、礦皮質素受體拮抗劑、Nrf2活化劑、凝乳酶抑制劑、PDE抑制劑、NOX1/4抑制劑、白三烯/血栓素受體拮抗劑、SLC22A12抑制劑、sGC抑制劑、或黃嘌呤氧化酶抑制劑。
- 如請求項59之醫藥組成物或如請求項83或84之方法,其中該額外治療劑係選自由下列所組成之群組:尼達尼布(nintedanib)、吡非尼酮(pirfenidone)、帕莫樂單抗(pamrevlumab)、PRM-151、GB-0139、PLN-74809、CC-90001、非奈利酮(finerenone)、BAY1142524、PCS-499、西他那昔布(setanaxib)、SER150、RDEA3170、帕利西哌(praliciguat)、TMX-049、GLPG1690、GLPG1205、GLPG1972、GLPG4059、GLPG2737、GLPG3970、及非戈替尼(filgotinib)。
- 一種如請求項1至57中任一項之化合物或其醫藥上可接受之鹽於用於製造用於治療LPAR1介導之疾病或病況之藥劑中的用途。
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