TWI844602B - Kif18a抑制劑 - Google Patents
Kif18a抑制劑 Download PDFInfo
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- TWI844602B TWI844602B TW108147097A TW108147097A TWI844602B TW I844602 B TWI844602 B TW I844602B TW 108147097 A TW108147097 A TW 108147097A TW 108147097 A TW108147097 A TW 108147097A TW I844602 B TWI844602 B TW I844602B
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- TW
- Taiwan
- Prior art keywords
- compound
- group
- alkyl
- pharmaceutically acceptable
- azaspiro
- Prior art date
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Abstract
提供給了如本文定義的式 (I) 之化合物:
Description
本發明關於藥物試劑領域,更具體地,關於用於調節KIF18A的化合物和組成物以及用於管理細胞增殖和治療癌症之用途及方法。
背景技術
癌症係折磨人類最普遍的疾病之一,並且是世界範圍內的主要死亡原因。在努力尋找針對許多不同癌症中的一種或更多種的有效治療或治癒中,在過去的幾十年中,許多小組已經投入大量的時間、精力和財力。然而,迄今為止,在可用的癌症治療和療法中,只有少數提供相當程度的成功。
癌症的特徵通常在於不受調節的細胞增殖。對細胞途徑負責的一個或更多個基因(藉由細胞週期和中心體循環控制增殖的進展)的損壞可以引起細胞增殖的正常調節喪失。該等失調的基因可以編碼各種腫瘤抑制物或癌基因蛋白,它們參與一系列事件,導致未經檢查的細胞週期進展和細胞增殖。各種激酶和驅動蛋白已經被鑒定在正常分裂的細胞和癌細胞的細胞週期和有絲分裂調節和進展中起關鍵作用。
驅動蛋白係在細胞分裂和細胞內囊泡和細胞器運輸中起重要作用的分子馬達。有絲分裂驅動蛋白在紡錘體組件、染色體分離、中心體分離和動力學的多個方面起作用(在O. Rath和F. Kozielski,Nature Review Cancer
[自然癌症綜述], 12:527-39, 2012中評述的)。基於所謂的「馬達結構域」內的序列同源性,人驅動蛋白被分類為14個亞家族,該結構域ATP酶活性驅動沿著微管(MT)單向運動。該等蛋白質的非馬達結構域負責貨物附接;「貨物」可以包括各種不同的膜狀細胞器、訊息傳導支架系統和染色體中的任何一種。驅動蛋白使用ATP水解能量來沿著極化微管移動貨物。因此,驅動蛋白通常被稱為「正端」或「負端」定向馬達。
KIF18A
基因屬於驅動蛋白-8亞家族並且是一個正端定向馬達。KIF18A被認為影響著絲粒微管的正端的動力學以控制正確的染色體定位和紡錘體張力。人KIF18A的耗盡在HeLa子宮頸癌細胞中導致更長的紡錘體,在中期增加的染色體振盪(chromosome oscillation)以及有絲分裂紡錘體組裝檢查點的激活(MI Mayr等人,Current Biology
[當代生物學] 17, 488-98, 2007)。KIF18A似乎係癌症治療的可行靶標。KIF18A在多種類型的癌症中過表現,包括但不限於結腸癌、乳腺癌、肺癌、胰臟癌、前列腺癌、膀胱癌、頭癌、頸癌、子宮頸癌和卵巢癌。此外,在癌細胞系中,基因缺失或敲除或者KIF18A抑制影響有絲分裂紡錘體裝置。特別地,已發現抑制KIF18A來誘導有絲分裂細胞停滯,這係一種已知的弱點,其可以藉由凋亡、有絲分裂災變或多相驅動致死性或分裂間期中有絲分裂滑脫後的死亡來促進有絲分裂細胞死亡。因此,對尋找KIF18A蛋白的抑制劑存在著強烈的興趣。
因此,KIF18A ATP酶活性的抑制係一種有前途的開發新的抗癌劑之方法。
本發明提供了一類新的化合物,該化合物單獨或在與微管的結合複合物中用於調節KIF18A蛋白,用以治療KIF18A介導的病症和/或疾病,包括癌症、炎症或纖毛病理學。
本發明提供的化合物具有基於MT的KIF18A調節活性,特別地,具有KIF18A抑制活性。為此,本發明還提供了該等化合物及其藥學上可接受的鹽在製備和製造用於治療性、預防性、急性或慢性治療KIF18A介導的疾病和障礙(包括但不限於癌症)的藥物組成物或藥物中之用途。因此,本發明的化合物可用於製造抗癌藥物。本發明還提供了用於製備式I化合物之方法,以及在此類方法中可用的中間體。
在實施方式1中,本發明提供了一種式 (I) 化合物,一種式I化合物:(I);
或其任何藥學上可接受的鹽,其中:
X1
為N或-CR6
;
R1
為-CN或基團-Z-R12
,其中Z為-C0-4
烷基-、-NR11
-、-NR11
SO2
-、-SO2
NR11
-、-NR11
-S(=O)(=NH)、-S(=O)(=NH)-、-S-、-S(=O)-、-SO2
-、C0-4
烷基-O-、-(C=O)-、-(C=O)NR11
-、-C=N(OH)-或-NR11
(C=O);或
基團-Z-R12
為-N=S(=O)-(R12
)2
,其中兩個R12
對可以可替代地與它們各自附接的硫原子組合以形成含有0、1、2或3個N原子和0、1或2個選自O和S的原子的飽和或部分飽和的3員、4員、5員或6員單環;
R2
為鹵素或基團-Y-R13
,其中Y為-C0-4
烷基-、-N(C0-1
烷基)-C0-4
烷基-、-C(=O)NRa
Ra
(C1-4
烷基)、-O-C0-4
烷基-、S、S=O、S(=O)2
、-SO2
NR13
或-S(=O)(=NH)-;
R3
為H、C1-4
烷基或C1-4
鹵代烷基;
R4
為H、鹵素、R4a
或R4b
;
R5
為H、鹵素、C1-8
烷基或C1-4
鹵代烷基;
R6
為H、鹵素、C1-8
烷基、C1-4
鹵代烷基、-O-C1-8
烷基或-O-R6a
,其中R6a
為含有0、1、2或3個N原子和0、1或2個選自O和S的原子的飽和的或部分飽和的3員、4員、5員或6員單環;
R7
為H、鹵素、C1-8
烷基或C1-4
鹵代烷基;
R8
為H、鹵素、C1-8
烷基、C1-4
鹵代烷基、-OH、-O-R8a
或-O-R8b
;
R9
為H、鹵素、C1-8
烷基或C1-4
鹵代烷基;
Rx
選自由以下各項組成之群組:、、和;
R10a
、R10b
、R10c
、R10d
、R10e
、R10f
、R10g
、R10h
、R10i
和R10j
中的每一個為H、鹵素、R10k
或R10l
;
或者可替代地,R10a
和R10b
對、R10c
和R10d
對、R10e
和R10f
對、R10g
和R10h
對或R10i
和R10j
對中的每一個可以獨立地與它們各自附接的碳原子組合以形成螺接到Rx
環的飽和的或部分飽和的3員、4員、5員、6員單環;其中所述3員、4員、5員、6員單環含有0、1、2或3個N原子和0、1或2個選自O和S的原子,並且進一步地,其中所述3員、4員、5員、6員單環為被選自以下的0、1、2或3個基團取代:F、Cl、Br、C1-6
烷基、C1-4
鹵代烷基、-ORa
、-OC1-4
鹵代烷基、CN、-NRa
Ra
或側氧基;
R11
為H、R11a
或R11b
;
R12
為H、R12a
或R12b
;
R13
為R13a
或R13b
;
R4a
、R8a
、R10k
、R11a
、R12a
和R13a
在每種情況下獨立地選自由以下各項組成之群組:含有0、1、2或3個N原子和0、1或2個選自O和S的原子的飽和的、部分飽和的或不飽和的3員、4員、5員、6員或7員單環或者4員、5員、6員、7員、8員、9員、10員、11員或12員雙環,其被選自以下的0、1、2或3個基團取代:F、Cl、Br、C1-6
烷基、C1-4
鹵代烷基、-ORa
、-OC1-4
鹵代烷基、CN、-C(=O)Rb
、-C(=O)ORa
、-C(=O)NRa
Ra
、-C(=NRa
)NRa
Ra
、-OC(=O)Rb
、-OC(=O)NRa
Ra
、-OC2-6
烷基NRa
Ra
、-OC2-6
烷基ORa
、-SRa
、-S(=O)Rb
、-S(=O)2
Rb
、-S(=O)2
NRa
Ra
、-NRa
Ra
、-N(Ra
)C(=O)Rb
、-N(Ra
)C(=O)ORb
、-N(Ra
)C(=O)NRa
Ra
、-N(Ra
)C(=NRa
)NRa
Ra
、-N(Ra
)S(=O)2
Rb
、-N(Ra
)S(=O)2
NRa
Ra
、-NRa
C2-6
烷基NRa
Ra
、-NRa
C2-6
烷基ORa
、-C1-6
烷基NRa
Ra
、-C1-6
烷基ORa
、-C1-6
烷基N(Ra
)C(=O)Rb
、-C1-6
烷基OC(=O)Rb
、-C1-6
烷基C(=O)NRa
Ra
、-C1-6
烷基C(=O)ORa
、R14
和側氧基;
R4b
、R8b
、R10l
、R11b
、R12b
和R13b
在每種情況下獨立地選自由以下各項組成之群組:被選自F、Cl、Br、-ORa
、-OC1-4
鹵代烷基或CN的0、1、2、3、4或5個基團取代的C1-6
烷基;
R14
在每種情況下獨立地選自由以下各項組成之群組:含有0、1、2或3個N原子和0或1個選自O和S的原子的飽和的、部分飽和的或不飽和的3員、4員、5員、6員或7員單環或者4員、5員、6員、7員、8員、9員、10員、11員或12員雙環,其被選自以下的0、1、2或3個基團取代:F、Cl、Br、C1-6
烷基、C1-4
鹵代烷基、-ORa
、-OC1-4
鹵代烷基、CN、-C(=O)Rb
、-C(=O)ORa
、-C(=O)NRa
Ra
、-C(=NRa
)NRa
Ra
、-OC(=O)Rb
、-OC(=O)NRa
Ra
、-OC2-6
烷基NRa
Ra
、-OC2-6
烷基ORa
、-SRa
、-S(=O)Rb
、-S(=O)2
Rb
、-S(=O)2
NRa
Ra
、-NRa
Ra
、-N(Ra
)C(=O)Rb
、-N(Ra
)C(=O)ORb
,-N(Ra
)C(=O)NRa
Ra
、-N(Ra
)C(=NRa
)NRa
Ra
、-N(Ra
)S(=O)2
Rb
、-N(Ra
)S(=O)2
NRa
Ra
、-NRa
C2-6
烷基NRa
Ra
、-NRa
C2-6
烷基ORa
、-C1-6
烷基NRa
Ra
、-C1-6
烷基ORa
、-C1-6
烷基N(Ra
)C(=O)Rb
、-C1-6
烷基OC(=O)Rb
、-C1-6
烷基C(=O)NRa
Ra
、-C1-6
烷基C(=O)ORa
和側氧基;
Ra
在每種情況下獨立地為H或Rb
;並且
Rb
在每種情況下獨立地為C1-6
烷基、苯基或苄基,其中C1-6
烷基被選自以下的0、1、2或3個取代基取代:鹵素、-OH、-OC1-4
烷基、-NH2
、-NHC1-4
烷基、-OC(=O)C1-4
烷基或-N(C1-4
烷基)C1-4
烷基;並且苯基或苄基被選自以下的0、1、2或3個取代基取代:鹵素、C1-4
烷基、C1-3
鹵代烷基、-OH、-OC1-4
烷基、-NH2
、-NHC1-4
烷基、-OC(=O)C1-4
烷基或-N(C1-4
烷基)C1-4
烷基。
在實施方式2中,本發明提供了化合物,其中X1
為N;具有式 (Ia):(Ia)。
在實施方式3中,本發明提供了化合物,其中X1
為-CR6
;具有式 (Ib):(Ib)。
在實施方式4中,本發明提供了化合物,其中R3
為H或甲基;較佳的是,R3
為H。
在實施方式5中,本發明提供了化合物,其中R10c
、R10d
、R10e
、R10f
、R10g
、R10h
、R10i
和R10j
中的每一個為H、鹵素、C1-6
烷基或C1-4
鹵代烷基;並且R10a
和R10b
對中的每一個與它們各自附接的碳原子組合形成螺接到Rx
環的飽和3員、4員或5員單環;其中所述環含有0、1、2或3個N原子和0、1或2個選自O和S的原子。
在實施方式6中,本發明提供了化合物,其中R10c
、R10d
、R10e
、R10f
、R10g
、R10h
、R10i
和R10j
中的每一個為H、甲基或乙基;並且R10a
和R10b
對中的每一個與它們各自附接的碳原子組合形成螺接到Rx
環的環丙基、環丁基或環戊基環。
在實施方式7中,本發明提供了根據實施方式1至6的化合物或其藥學上可接受的鹽,其中該基團選自。
在實施方式8中,本發明提供了根據實施方式1至7的化合物或其藥學上可接受的鹽,其中該基團為。
在實施方式9中,本發明提供了根據實施方式1至8的化合物或其藥學上可接受的鹽,其中R1
為-CN或基團-Z-R12
,其中Z為鍵、-NH-、-NHSO2
-、-SO2
NH-、-S(=O)(=NH)-、-S-、-S(=O)-、-SO2
-、-(C=O)-、-(C=O)NH-或-NH(C=O)-;並且R12
選自:
(a) H;
(b) 環丙基、環丁基、環戊基、環己基、環氧乙烷基、氧雜環丁烷基、四氫呋喃基、氮雜環丁烷基、咪唑基、𠰌啉基、吡咯啶基、哌𠯤基、 、或;其中每個所述環被選自以下的0、1、2或3個基團取代:其中每個環被0、1、2或3個OH、F、甲基、-CH2
OH、-C(=O)OCH3
、-C(=O)OC(CH3
)3
、NH2
、CN和側氧基取代;或
(c) 被0、1、2或3個OH、F、-C(=O)OCH3
、-NH2
、-NH(CH3
)或-N(CH3)2
取代的C1-6
烷基。
在實施方式10中,本發明提供了根據實施方式1至9的化合物或其藥學上可接受的鹽,其中R1
為-CN或基團-Z-R12
,其中Z為無、-NH-、-NHSO2
-、-SO2
NH-、-S(=O)(=NH)-、-S-、-S(=O)-、-SO2
-、-(C=O)-、-(C=O)NH-或-NH(C=O)-;並且
(a) R12
為H;
(b) R12
為氧雜環丁烷基、環丙基;或
(c) R12
為被0、1、2或3個OH基團取代的C1-6
烷基。
在實施方式11中,本發明提供了根據實施方式1至10的化合物或其藥學上可接受的鹽,其中基團-Z-R12
為-N=S(=O)-(R12
)2
,其中兩個R12
對可以可替代地與它們各自附接的硫原子組合以形成含有0、1、2或3個N原子和0、1或2個選自O和S的原子的飽和的或部分飽和的3員、4員、5員或6員單環;其選自:、或。
在實施方式12中,本發明提供了根據實施方式1至11的化合物或其藥學上可接受的鹽,其中R1
為基團-Z-R12
,其中Z為-NHSO2
-或-SO2
NH-;並且R12
為氧雜環丁烷基、環丙基,或R12
為被0、1、2或3個OH基團取代的C1-6
烷基。
在實施方式13中,本發明提供了根據實施方式1至12的化合物或其藥學上可接受的鹽,其中R1
為基團-Z-R12
,其中Z為-NHSO2
-並且R12
為-CH2
-CH2
-OH。
在實施方式14中,本發明提供了根據實施方式1至13的化合物或其藥學上可接受的鹽,其中R2
為鹵素或基團-Y-R13
,其中Y為鍵、-NH-、-NH-(CH2
)0-4
-或-O-(CH2
)0-4
;並且R13
為含有0、1、2或3個N原子和0或1個選自O和S的原子的飽和的、部分飽和的或不飽和的3員、4員、5員、6員或7員單環或者4員、5員、6員、7員、8員、9員、10員、11員或12員雙環,其被選自以下的0、1、2或3個基團取代:F、Cl、Br、C1-6
烷基、C1-4
鹵代烷基、-OH、-OC1-4
鹵代烷基、CN、R14
和側氧基;或
R13
為被選自F、Cl、Br、-OH、-OC1-4
鹵代烷基或CN的0、1、2、3、4或5個基團取代的C1-6
烷基。
在實施方式15中,本發明提供了根據實施方式1至14的化合物或其藥學上可接受的鹽,其中R2
為飽和5員或6員單環,其中每個所述環含有0、1或2個N原子和0或1個O原子,並且其中每個所述環被選自以下的0、1、2或3個基團取代:F、Cl、Br、C1-6
烷基、C1-4
鹵代烷基、-OH、-OC1-4
鹵代烷基、CN、R14
和側氧基。
在實施方式16中,本發明提供了根據實施方式1至15的化合物或其藥學上可接受的鹽,其中R2
為 (a) 鹵素;(b)基團-Y-R13
,其中Y為鍵;並且R13
為𠰌啉基、哌啶基、氮雜環丁烷基、吡咯啶基、環丙基、環丁基、環戊基、環己基、哌𠯤基、四氫呋喃基、 ;
其中每個所述環被選自以下的0、1、2或3個基團取代:F、Cl、Br、甲基、CF3
、-OH、-OCHF2
、CN和側氧基;或(c) 基團-Y-R13
,其中Y為NH、-O-、-O-(CH2
)-、-O-(CH2
)-(CH2
)-或-O-(CH2
)-(CH2
)-(CH2
)-,並且其中R13
為、;;或R13
為被選自F、Cl、Br、甲基、CF3、-OH或CN的0、1、2、3、4或5個基團取代的C1-6
烷基。
在實施方式17中,本發明提供了根據實施方式1至16的化合物或其藥學上可接受的鹽,其中R2
為被選自F、Cl、Br、甲基、CF3
、-OH、-OCHF2
、CN和側氧基的0、1、2或3個基團取代的𠰌啉基或哌啶基。
在實施方式18中,本發明提供了根據實施方式1至17的化合物或其藥學上可接受的鹽,其中R2
為被1、2或3個甲基取代的𠰌啉基。
在實施方式19中,本發明提供了根據實施方式1至18的化合物或其藥學上可接受的鹽,其中R2
為被1、2或3個氟基團取代的哌啶基。
在實施方式20中,本發明提供了根據實施方式1至19的化合物或其藥學上可接受的鹽,其中R2
為。
在實施方式21中,本發明提供了根據實施方式1至20的化合物或其藥學上可接受的鹽,其中Z為鍵、-NH-、-NHSO2
-、-SO2
NH-、-N=S(=O)<(Ra
)2
(其中每個R11
獨立地選自由以下各項組成之群組:H、甲基或異丙基)、-S(=O)(=NH)-、-S-、-S(=O)-、-SO2
-、-(C=O)-、-(C=O)NH-或-NH(C=O)-。
在實施方式22中,本發明提供了根據實施方式1至21的化合物或其藥學上可接受的鹽,其中R12
選自 (a) H;(b) 被選自F、Cl、Br、-OH、-OCH3
或環丙基的0、1、2或3個基團取代的C1-6
烷基;或 (c) 含有0、1、2或3個N原子和0或1個選自O和S的原子的飽和的、部分飽和的或不飽和的3員、4員、5員、6員或7員單環,其被選自以下的0、1、2或3個基團取代:F、Cl、Br、C1-6
烷基、C1-4
鹵代烷基、-C1-6
烷基OH、-OH、-OCH3
、-NH2
或側氧基。
在實施方式23中,本發明提供了根據實施方式1至22的化合物或其藥學上可接受的鹽,其中R12
選自環丙基、環丁基、環戊基、氧雜環丁烷基、氮雜環丁烷基、四氫呋喃基或1,3,4-氧雜噻𠯤烷基。
在實施方式24中,本發明提供了根據實施方式1至23的化合物或其藥學上可接受的鹽,其中R4
選自 (a) H;(b) 被0、1、2或3個OH基團取代的C1-6
烷基;或 (c) 環丙基。
在實施方式25中,本發明提供了根據實施方式1至24的化合物或其藥學上可接受的鹽,其中R4
為甲基。
在實施方式26中,本發明提供了根據實施方式1至25的化合物或其藥學上可接受的鹽,其中R5
為H。
在實施方式27中,本發明提供了根據實施方式1至26的化合物或其藥學上可接受的鹽,其中R6
為H或F。
在實施方式28中,本發明提供了根據實施方式1至27的化合物或其藥學上可接受的鹽,其中R7
為H或F。
在實施方式29中,本發明提供了根據實施方式1至28的化合物或其藥學上可接受的鹽,其中R8
為H。
在實施方式30中,本發明提供了根據實施方式1至29的化合物或其藥學上可接受的鹽,其中R9
為H。
在實施方式31中,本發明提供了一種化合物或其藥學上可接受的鹽,選自:
或其任何藥學上可接受的鹽。
實例編號 | 化學結構 | 名稱 |
1 | N -(2-((1-羥基-2-甲基丙烷-2-基)胺基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
1-7 | N -(2-((1-羥基-2-甲基丙烷-2-基)胺基)-6-甲基嘧啶-4-基)-4-(N-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
2 | N -(2-(2-羥基丙烷-2-基)嘧啶-4-基)-4-(N -(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
2-4 | N -(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-4-(N -(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
2-8 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-甲基環丙烷)-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
3 | (R )-4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
4 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
5-1 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
5-2 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
6-7 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(乙基磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
7 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
8-1 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
8-2 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
10-1 | (R )-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
10-2 | (S )-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
12 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
13-1 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙烷-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
13-2 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙烷-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
14 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基-2-甲基丙烷-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
15 | N -(2-(4,4-二氟環己基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
16-1 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-氟-1-(羥基甲基)乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
16-2 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-氟-1-(羥基甲基)乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
17 | N -(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-4-(N-(2-羥基乙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
18-1 | 2-(6-氮雜螺[2.5]辛-6-基)-4-(R -環丙基磺醯亞胺基)-N -(2-(4,4-二氟-1-哌啶基)-6-甲基-4-嘧啶基)苯甲醯胺 | |
18-2 | 2-(6-氮雜螺[2.5]辛-6-基)-4-(S -環丙基磺醯亞胺基)-N -(2-(4,4-二氟-1-哌啶基)-6-甲基-4-嘧啶基)苯甲醯胺 | |
20 | (N1 -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)對苯二甲醯胺 | |
21 | 4-(氮雜環丁烷-3-基磺醯基)-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | |
22 | N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-甲基氮雜環丁烷-3-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 |
在子實施方式31a中,本發明提供了N
-(2-((1-羥基-2-甲基丙烷-2-基)胺基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31b中,本發明提供了N
-(2-((1-羥基-2-甲基丙烷-2-基)胺基)-6-甲基嘧啶-4-基)-4-(N-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31c中,本發明提供了N
-(2-(2-羥基丙烷-2-基)嘧啶-4-基)-4-(N
-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31d中,本發明提供了N
-(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-4-(N
-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31e中,本發明提供了N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-甲基環丙烷)-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31f中,本發明提供了(R
)-4-((2-羥基乙基)磺醯胺基)-N
-(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31g中,本發明提供了N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31h中,本發明提供了
(R
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31i中,本發明提供了
(S
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31j中,本發明提供了N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(乙基磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31k中,本發明提供了N
-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31l中,本發明提供了
(R
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31m中,本發明提供了
(S
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31n中,本發明提供了
(R
)-N
-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31o中,本發明提供了
(S
)-N
-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31p中,本發明提供了N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31q中,本發明提供了(S
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙烷-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31r中,本發明提供了(R
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙烷-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31s中,本發明提供了N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基羥基-2-甲基丙烷-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31t中,本發明提供了N
-(2-(4,4-二氟環己基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31u中,本發明提供了
(R
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-氟-1-(羥基甲基)乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31v中,本發明提供了
(S
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-氟-1-(羥基甲基)乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31w中,本發明提供了N
-(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-4-(N-(2-羥基乙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31x中,本發明提供了
2-(6-氮雜螺[2.5]辛-6-基)-4-(R-環丙基磺醯亞胺基)-N
-(2-(4,4-二氟-1-哌啶基)-6-甲基-4-嘧啶基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31y中,本發明提供了
2-(6-氮雜螺[2.5]辛-6-基)-4-(S-環丙基磺醯亞胺基)-N
-(2-(4,4-二氟-1-哌啶基)-6-甲基-4-嘧啶基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31z中,本發明提供了(N1
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)對苯二甲醯胺或其藥學上可接受的鹽。
在子實施方式31aa中,本發明提供了4-(氮雜環丁烷-3-基磺醯基)-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在子實施方式31ab中,本發明提供了
N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-甲基氮雜環丁烷-3-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺或其藥學上可接受的鹽。
在實施方式32中,本發明提供了一種藥物組成物,該藥物組成物包含根據實施方式1至31中任一個的化合物或其藥學上可接受的鹽以及藥學上可接受的稀釋劑或載體。
在實施方式33中,本發明提供了一種用於治療可用KIF18a抑制劑治療的病症之方法,該方法包括向有需要的患者投與治療有效量的根據實施方式1至31的化合物或根據實施方式31的組成物。
在實施方式34中,本發明提供了根據實施方式33的方法,其中所述病症為選自由以下各項組成之群組的癌症:(a) 選自以下癌症的實體瘤或血液源性腫瘤:膀胱癌、子宮內膜癌、肺鱗細胞癌、乳腺癌、結腸癌、腎癌、肝癌、肺癌、小細胞肺癌、食道癌、膽囊癌、腦癌、頭頸癌、卵巢癌、胰臟癌、胃癌、子宮頸癌、甲狀腺癌、前列腺癌和皮膚癌;(b) 選自以下的淋巴系的造血腫瘤:白血病、急性淋巴球性白血病、急性成淋巴球性白血病、B細胞淋巴瘤、T細胞淋巴瘤、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、毛細胞淋巴瘤和伯克特淋巴瘤;(c) 選自以下的骨髓系的造血腫瘤:急性和慢性骨髓性白血病、骨髓化生不良症候群和前髓細胞白血病;(d) 選自纖維肉瘤和橫紋肌肉瘤的間質來源的腫瘤;(e) 選自星形細胞瘤、神經母細胞瘤、神經膠質瘤和神經鞘瘤的中樞和周圍神經系統的腫瘤;或 (f) 黑素瘤、精原細胞瘤、畸胎癌、骨肉瘤、著色性乾皮病、角化棘皮瘤(keratoctanthoma)、甲狀腺濾泡癌或卡波西氏肉瘤。
在子實施方式34a中,本發明提供了根據實施方式33的方法,其中所述病症為選自由以下各項組成之群組的癌症:黑素瘤、前列腺癌、子宮頸癌、乳腺癌、結腸癌、肉瘤或白血病。參見:Zhang C.等人, 「Kif18A is involved in human breast carcinogenesis[Kif18A參與人乳腺癌的致癌作用]」, Carcinogenesis[癌症學], 2010.09; 31(9):1676-84. doi: 10.1093/carcin/bgq134.Epub 2010 Jul 1。還參見:(1) https: //www.proteinatlas.org/ENSG00000121621-KIF18A/pathology; (2) Nagahara, M.等人, 「Kinesin 18A expression: clinical relevance to colorectal cancer progression[驅動蛋白18A表現:與大腸癌進展的臨床相關性]」, Int. J. Cancer[國際癌症]: 129, 2543-2552 (2011) VC 2011 UIC;和 (3) Yu, Y.等人, 「The Role of Kinesin Family Proteins in Tumorigenesis and Progression - Potential Biomarkers and Molecular Targets for Cancer Therapy[驅動蛋白家族蛋白在腫瘤發生和發展中的作用-潛在的生物標誌物和分子靶標的癌症治療]」, Cancer[癌症] 2010;116:5150-60。VC 2010 American Cancer Society[美國癌症協會]。在子實施方式34b中,本發明提供了根據實施方式33的方法,其中所述病症為實施方式 (a)、(b)、(c)、(d)、(e) 或 (f) 中指定的癌症中任一種。
在實施方式35中,本發明提供了一種用於在受試者中減小實體瘤大小之方法,該方法包括向有需要的患者投與治療有效量的根據實施方式1至31中任一個的化合物或根據實施方式32的組成物。
在實施方式36中,本發明提供了一種用於在受試者中治療細胞增殖障礙之方法,該方法包括向有需要的患者投與治療有效量的根據實施方式1至31中任一個的化合物或根據實施方式32的組成物。
在實施方式37中,本發明提供了一種用於在細胞中抑制KIF18A 之方法,該方法包括使該細胞與根據實施方式1至31中任一個的化合物或其藥學上可接受的鹽或根據實施方式32的組成物接觸。
在實施方式38中,本發明提供了根據實施方式1至31中任一個的化合物或所述化合物的藥學上可接受的鹽、或根據實施方式32的藥物組成物在製備用於治療可用KIF18a抑制劑治療的病症的藥物中之用途。
在實施方式39中,本發明提供了根據實施方式38之用途,其中該病症為選自由以下各項組成之群組的癌症:(a) 選自以下癌症的實體瘤或血液源性腫瘤:膀胱癌、子宮內膜癌、肺鱗細胞癌、乳腺癌、結腸癌、腎癌、肝癌、肺癌、小細胞肺癌、食道癌、膽囊癌、腦癌、頭頸癌、卵巢癌、胰臟癌、胃癌、子宮頸癌、甲狀腺癌、前列腺癌和皮膚癌;(b) 選自以下的淋巴系的造血腫瘤:白血病、急性淋巴球性白血病、急性成淋巴球性白血病、B細胞淋巴瘤、T細胞淋巴瘤、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、毛細胞淋巴瘤和伯克特淋巴瘤;(c) 選自以下的骨髓系的造血腫瘤:急性和慢性骨髓性白血病、骨髓化生不良症候群和前髓細胞白血病;(d) 選自纖維肉瘤和橫紋肌肉瘤的間質來源的腫瘤;(e) 選自星形細胞瘤、神經母細胞瘤、神經膠質瘤和神經鞘瘤的中樞和周圍神經系統的腫瘤;或 (f) 黑素瘤、精原細胞瘤、畸胎癌、骨肉瘤、著色性乾皮病、角化棘皮瘤、甲狀腺濾泡癌或卡波西氏肉瘤。
在子實施方式39a中,本發明提供了根據實施方式33之用途,其中所述病症為實施方式 (a)、(b)、(c)、(d)、(e) 或 (f) 中指定的癌症中任一種。
在實施方式40中,本發明提供了根據實施方式1至31中任一個的化合物或所述化合物的藥學上可接受的鹽、或根據實施方式32的藥物組成物在製備用於在受試者中減小實體瘤大小的藥物中之用途。
在實施方式41中,本發明提供了根據實施方式1至31中任一個的化合物或所述化合物的藥學上可接受的鹽、或根據實施方式32的藥物組成物在製備用於在受試者中治療細胞增殖障礙的藥物中之用途。
在實施方式42中,本發明提供了根據實施方式1至31中任一個的化合物或所述化合物的藥學上可接受的鹽、或根據實施方式32的藥物組成物在製備用於在細胞中抑制KIF18A 的藥物中之用途。
在實施方式43中,本發明提供了一種用於製備如本文所述的式 (I) 化合物的方法。
在實施方式44中,本發明提供了一種在製備如本文所述的式 (I) 化合物的方法中使用的中間體化合物。
應理解,對任何實施方式的以上引用旨在包括其任何和所有子實施方式。例如,對實施方式31的引用包括對子實施方式31a至31ab的引用。
本發明包括本發明的所有藥學上可接受的同位素標記的化合物,其中一個或多個原子被具有相同原子數但原子質量或質量數不同於自然界通常發現的原子質量或質量數的原子替代。
適用於包含在本發明的化合物中的同位素的實例包括但不限於,氫的同位素,例如2
H和3
H;碳的同位素,例如11
C、13
C 和14
C;氯的同位素,例如38
Cl;氟的同位素,例如18
F;碘的同位素,例如123
I和125
I;氮的同位素,例如13
N和15
N;氧的同位素,例如15
O、17
O和18
O;磷的同位素,例如32
P和硫的同位素,例如35
S。
本發明的某些同位素標記的化合物,例如併入放射性同位素的化合物可用於藥物及/或底物組織分佈研究中。放射性同位素氚,即3
H,及碳-14,即14
C因其易於併入及現有檢測手段而特別適用於此目的。
用較重同位素(例如氘,即2
H)取代可以提供源自較高代謝穩定性的某些治療優勢(例如,延長的體內半衰期或降低的劑量要求),並且因此在一些情況下係較佳的。
用正電子發射同位素,諸如11
C、18
F、15
O及13
N取代可用於正電子發射斷層掃描(PET)研究中以檢查底物受體佔有率。
本發明的同位素標記的化合物一般可以藉由熟悉該項技術者已知的常規技術,或藉由所附實例及製備中所描述的方法類似的方法,使用適當同位素標記的試劑代替先前採用的未標記的試劑來製備。
根據本發明的藥學上可接受的溶劑包括其中結晶溶劑可以被同位素取代的那些,例如D2
O、d6
-丙酮、d6
-DMSO。
本發明的特定實施方式包括以下實例中示例的化合物以及它們的藥學上可接受的鹽、複合物、溶劑化物、多晶型物、立體異構物、代謝物、前驅藥及其其他衍生物。
除非另有說明,以下定義適用於本說明書和申請專利範圍中出現的術語:
「Cα-β
烷基」意指在支鏈或線性關係或這三者的任意組合中包含最小α個和最大β個碳原子的烷基,其中α和β表示整數。在該部分中描述的烷基還可以含有一個或兩個雙鍵或三鍵。C0
烷基的指定表示直連鍵。C1-6
烷基的實例包括但不限於以下:。
單獨或以組合的「苯并基團」意指二價基團C4
H4
=,其中一個表示係-CH=CH-CH=CH-,當鄰位附接到另一環時形成苯狀環——例如四氫萘、吲哚等。
術語「側氧基」和「硫代」分別表示=O(如羰基)和=S(如硫代羰基)。
「鹵代」或「鹵素」意指選自F、Cl、Br和I的鹵素原子。
「Cα-β
鹵代烷基」意指如上所述的烷基,其中,任意數量(至少一個)的附接到烷基鏈的氫原子被F、Cl、Br或I替代。
N(Ra
)Ra
基團等包括其中兩個Ra
基團一起形成環(視需要包含N、O或S原子)的取代基,並且包括以下基團,例如:。
基團N(Cα-β
烷基) Cα-β
烷基(其中α和β係如上文定義的)包括其中兩個Cα-β
烷基基因一起形成環(視需要包含N、O或S原子)的取代基,並且包括以下基團,例如:。
「雙環」意指具有兩個連接環的基團。雙環可以為碳環(所有環原子為碳原子)或雜環(除了碳原子之外,環原子包括例如1、2或3個雜原子,例如N、O或S)。這兩個環都可以是脂肪族的(例如萘烷和降冰片烷(norbornane)),或可以是芳香族(例如萘),或脂肪族和芳香族的組合(例如四氫化萘)。雙環包括 (a) 螺環化合物,其中兩個環只共用一個單原子(螺原子,其通常為季碳)。螺環化合物的實例包括但不限於:、、、、、;
(b) 稠合的雙環化合物,其中兩個環共用兩個相鄰原子。換句話說,環共用一個共價鍵,即橋頭原子直接連接(例如α-崖柏烯和萘烷)。稠合的雙環的實例包括但不限於:
;和 (c) 橋聯的雙環化合物,其中兩個環共用三個或更多個原子,並藉由包含至少一個原子的橋將兩個橋頭原子隔開。例如,降冰片烷,也稱為雙環[2.2.1]庚烷,可以被認為係一對環戊烷環,每個環共用它們的五個碳原子中的三個。橋聯的雙環的實例包括但不限於: 、 、 、 、 、 、 或 。
除非另有說明,「碳環」或「碳環的」意指本身或與其他術語組合包含的環,表示「Cα-β
烷基」的環狀形式。碳環的實例包括環戊基、環己基、1-環己烯基、3-環己烯基、環庚基、伸環丁基、伸環己基等。
「雜環」或「雜環的」意指包含至少一個碳原子和至少一個選自N、O和S的其他原子的環。可在申請專利範圍中出現的雜環的實例包括但不限於以下:
和。
「藥學上可接受的鹽」意指藉由常規方式製備的鹽,並且是熟悉該項技術者眾所周知的。「藥學上可接受的鹽」包括無機和有機酸的鹼性鹽,所述無機和有機酸包括但不限於鹽酸、氫溴酸、硫酸、磷酸、甲磺酸、乙磺酸、蘋果酸、乙酸、草酸、酒石酸、檸檬酸、乳酸、富馬酸、琥珀酸、馬來酸、水楊酸、苯甲酸、苯乙酸、苦杏仁酸等。當本發明的化合物包含酸性官能基如羧基時,然後羧基的合適的藥學上可接受的陽離子對係熟悉該項技術者眾所周知的,並且包括鹼金屬、鹼土金屬、銨、季銨陽離子等。對於另外的「藥學上可接受的鹽」的實例,參見下文和Berge等人,J. Pharm.Sci.[藥學科學雜誌] 66:1 (1977)。
「飽和的、部分飽和的或不飽和的」包括被氫飽和的取代基、完全被氫不飽和的取代基和部分被氫飽和的取代基。
「脫離基脫離基」通常是指容易被親核試劑置換的基團,例如胺、硫醇或醇親核試劑。此類脫離基脫離基係本領域眾所周知的。此類脫離基脫離基的實例包括但不限於N-羥基琥珀醯亞胺、N-羥基苯并三唑、鹵化物、三氟甲磺酸酯、甲苯磺酸酯等。較佳的脫離基脫離基在適當時在本文中指出。
「保護基團」通常是指本領域眾所周知的基團,其用於防止所選反應性基團例如羧基、胺基、羥基、巰基等發生不期望的反應,例如親核、親電、氧化、還原等。較佳的保護基團在適當時在本文中指出。胺基保護基團的實例包括但不限於芳烷基、經取代的芳烷基、環烯基烷基和經取代的環烯烷基、烯丙基、經取代的烯丙基、醯基、烷氧基羰基、芳烷氧基羰基、矽基等。芳烷基的實例包括但不限於苄基、鄰-甲基苄基、三苯甲基和二苯甲基,其可以視需要被鹵素、烷基、烷氧基、羥基、硝基、醯基胺基、醯基等以及鹽(例如磷鹽和銨鹽)取代。芳基的實例包括苯基、萘基、茚滿基、蒽基、9-(9-苯基茀基)、菲基、杜烯基等。環烯基烷基或經取代的環烯基烷基基團的實例較佳的是具有6至10個碳原子,包括但不限於環己烯基甲基等。合適的醯基、烷氧基羰基和芳烷氧基羰基包括苄氧羰基、三級丁氧基羰基、異丁氧羰基、苯甲醯基、經取代的苯甲醯基、丁醯基、乙醯基、三氟乙醯基、三氯乙醯基、鄰苯二甲醯基等。保護基團的混合物可以用於保護同一胺基,例如一級胺基可以被芳烷基和芳烷氧羰基二者保護。胺基保護基團也可以與與它們附接的氮形成雜環,例如,1,2-雙(亞甲基)苯、鄰苯二甲醯亞胺基、琥珀醯亞胺基、馬來醯亞胺基等,並且其中該等雜環基團可以進一步包含鄰接的芳基和環烷基環。此外,雜環基團可以是單-、二-或三-取代的的,例如硝基鄰苯二甲醯亞胺基。胺基也可以藉由形成加成鹽(例如鹽酸鹽、對甲苯磺酸、三氟乙酸等)防止不希望的反應,例如氧化。許多胺基保護基團也適用於保護羧基、羥基和巰基。例如,芳烷基。烷基也是適用於保護羥基和巰基的基團,例如三級丁基。
矽基保護基團係視需要被一個或更多個烷基、芳基和芳烷基取代的矽原子。合適的矽基保護基團包括但不限於三甲基矽基、三乙基矽基、三異丙基矽基、三級丁基二甲基矽基、二甲基苯基矽基、1,2-雙(二甲基矽基)苯、1,2-雙(二甲基矽基)乙烷和二苯基甲基矽基。胺基的矽烷化提供了單-或二-矽基胺基。胺基醇化合物的矽烷化可以導致N,N,O-三矽基衍生物。從矽基醚官能除去矽基官能容易藉由用例如金屬氫氧化物或氟化銨試劑的處理來完成,其作為單獨的反應步驟或在與醇基團反應期間原位進行。合適的矽烷化劑為例如三甲基矽基氯化物、三級丁基-二甲基矽基氯化物、苯基二甲基矽基氯化物、二苯基甲基矽基氯化物或其與咪唑或DMF的組合產物。用於胺的矽烷化並除去矽基保護基團的方法係熟悉該項技術者眾所周知的。用於從相應胺基酸、胺基酸醯胺或胺基酸酯製備該等胺衍生物的方法也是有機化學領域技術人員眾所周知的,包括胺基酸/胺基酸酯或胺基醇化學。
保護基團在不會影響分子剩餘部分的條件下被除去。該等方法係本領域眾所周知的,並且包括酸水解、氫解等。較佳的方法涉及除去保護基團,例如藉由利用在合適的溶劑系統(例如醇、乙酸等或其混合物)中的鈀碳氫解除去苄氧基羰基。三級丁氧基羰基保護基團可以利用在合適的溶劑系統(例如二㗁𠮿或二氯甲烷)中的無機或有機酸(例如HCl或三氟乙酸)除去。所得的胺基鹽可以容易地被中和以得到游離胺。羧基保護基團(例如甲基、乙基、苄基、三級丁基、4-甲氧基苯基甲基等)可以在熟悉該項技術者眾所周知的水解和氫解條件下被除去。
應注意,本發明的化合物可以含有可以互變異構形式存在的基團,例如環狀和非環狀的脒和胍基、經雜原子取代的雜芳基(Y' = O、S、NR)等,其在以下實例中說明:
儘管本文命名、描述、顯示和/或要求保護一種形式,但是所有互變異構形式都旨在固有地包括在此名稱、描述、顯示和/或要求保護中。
本發明還考慮了本發明的化合物的前驅藥。前驅藥係活性或非活性化合物,其在將前驅藥投與到患者後藉由體內生理作用例如水解、代謝等而被化學修飾成本發明化合物。涉及製備和使用前驅藥的適用性和技術係熟悉該項技術者眾所周知的。對於涉及酯的前驅藥的一般性討論,參見Svensson和Tunek, Drug Metabolism Reviews [藥物代謝綜述] 165 (1988) 和Bundgaard, Design of Prodrugs [前驅藥設計],Elsevier(1985)。掩蔽的羧酸根陰離子的實例包括多種酯,例如烷基(例如甲基、乙基)、環烷基(例如環己基)、芳烷基(例如苄基、對甲氧基苄基)和烷基羰基氧基烷基(例如新戊醯氧基甲基)。胺已被掩蔽為經芳基羰氧基甲基取代的衍生物,其在體內被酯酶裂解,釋放出游離的藥物和甲醛(Bungaard J. Med. Chem.[藥物化學雜誌] 2503 (1989))。同樣,含有酸性NH基團(例如咪唑、醯亞胺、吲哚等)的藥物已被N-醯氧基甲基掩蔽(Bundgaard Design of Prodrugs[前驅藥設計], Elsevier (1985))。羥基已被掩蔽為酯和醚。EP 039,051(Sloan和Little, 4/11/81)公開了曼尼希鹼異羥肟酸前驅藥、其製備和用途。
本說明書和申請專利範圍包含使用「選自……和……」和「為……或……」語言的種類列表(有時稱為馬庫什組)。當在本申請中使用該語言時,除非另有說明,否則意指包括該組作為整體,或其任何單個成員,或其任何子組。該語言的使用僅出於速記目的,並不意指以任何方式限制根據需要除去單個要素或子組。
藥物組成物、給藥及投與途徑
本文還提供了藥物組成物,該等藥物組成物包含如本文所揭露的化合物以及藥學上可接受的賦形劑,例如稀釋劑或載體。適用於本發明中的化合物及藥物組成物包括可以按有效量投與該化合物以實現其預定目的的那些化合物及藥物組成物。以下將更詳細地描述該化合物的投與。
適合藥物配製物可以由技術人員根據投與途徑及所需劑量決定。參見例如,Remington’s Pharmaceutical Sciences [雷明頓藥物科學], 1435-712(第18版, 賓夕法尼亞州伊斯頓市馬克出版公司(Mack Publishing Co), 1990)。配製物可以影響所投與的藥劑的物理狀態、穩定性、或體內釋放速率及活體內清除速率。取決於投與途徑,可以根據體重、體表面積或器官大小來計算適合劑量。熟悉該項技術者在不進行過度實驗的情況下,尤其根據本文所揭露的劑量資訊和測定以及可藉由動物或人類臨床試驗獲得的藥物動力學數據,以常規方式進行決定適當治療劑量所需計算的進一步精化。
短語「藥學上可接受的」或「藥理學上可接受的」係指在投與動物或人類時不產生不良反應、過敏反應或其他不利反應的分子實體和組成物。如本文所使用,「藥學上可接受」包括任何和所有溶劑、分散介質、包衣、抗細菌劑和抗真菌劑、等滲劑和吸收延遲劑等。此類賦形劑用於藥學活性物質的使用係本領域所熟知的。除了任何常規介質或劑與治療組成物不相容的情況外,其在治療組成物中的使用係有所考慮的。還可以將補充性活性成分摻入組成物中。在示例性實施方式中,配製物可以包含玉米糖漿固體、高油酸紅花油、椰子油、大豆油、L-亮胺酸、磷酸三鈣、L-酪胺酸、L-脯胺酸、乙酸L-賴胺酸、DATEM(乳化劑)、L-麩醯胺酸、L-纈胺酸、磷酸氫二鉀、L-異亮胺酸、L-精胺酸、L-丙胺酸、甘胺酸、L-天冬醯胺一水合物、L-絲胺酸、檸檬酸鉀、L-蘇胺酸、檸檬酸鈉、氯化鎂、L-組胺酸、L-甲硫胺酸、抗壞血酸、碳酸鈣、L-麩胺酸、L-胱胺酸二鹽酸鹽、L-色胺酸、L-天冬胺酸、氯化膽鹼、牛磺酸、m-肌醇、硫酸亞鐵、抗壞血酸棕櫚酸酯、硫酸鋅、L-肉鹼、α-生育酚乙酸酯、氯化鈉、菸醯胺、混合生育酚、泛酸鈣、硫酸酮、氯化硫胺素鹽酸鹽、維生素A棕櫚酸酯、硫酸錳、核黃素、鹽酸吡哆辛、葉酸、β-胡蘿蔔素、碘化鉀、葉綠醌、生物素、硒酸鈉、氯化鉻、鉬酸鈉、維生素D3和氰鈷胺。
化合物可以作為藥學上可接受的鹽存在於藥物組成物中。如本文所使用,「藥學上可接受的鹽」包括例如鹼加成鹽和酸加成鹽。
藥學上可接受的鹼加成鹽可以用金屬或胺(例如鹼金屬和鹼土金屬或有機胺)來形成。化合物的藥學上可接受的鹽也可以用藥學上可接受的陽離子來製備。適合的藥學上可接受的陽離子係熟悉該項技術者熟知的且包括鹼金屬、鹼土金屬、銨及四級銨陽離子。碳酸鹽或碳酸氫鹽也有可能。用作陽離子的金屬的實例係鈉、鉀、鎂、銨、鈣或三價鐵等。適合的胺的實例包括異丙胺、三甲胺、組胺酸、N,N'-二苄基乙二胺、氯普魯卡因、膽鹼、二乙醇胺、二環己胺、乙二胺、N-甲基葡糖胺和普魯卡因。
藥學上可接受的酸加成鹽包括無機酸鹽或有機酸鹽。適合的酸鹽的實例包括鹽酸鹽、甲酸鹽、乙酸鹽、檸檬酸鹽、水楊酸鹽、硝酸鹽、磷酸鹽。其他適合的藥學上可接受的鹽係熟悉該項技術者所熟知的並且包括例如甲酸、乙酸、檸檬酸、草酸、酒石酸或苦杏仁酸、鹽酸、氫溴酸、硫酸或磷酸;與有機羧酸、磺酸、磺酸基酸或磷酸基酸或N-取代的胺基磺酸,例如乙酸、三氟乙酸(TFA)、丙酸、乙醇酸、琥珀酸、馬來酸、羥基馬來酸、甲基馬來酸、富馬酸、蘋果酸、酒石酸、乳酸、草酸、葡糖酸、葡糖二酸、葡糖醛酸、檸檬酸、苯甲酸、肉桂酸、苦杏仁酸、水楊酸、4-胺基水楊酸、2-苯氧基苯甲酸、2-乙醯氧基苯甲酸、撲酸、菸酸或異菸酸的鹽;以及與胺基酸,例如在自然界中參與蛋白質合成所涉及的20種α胺基酸,例如麩胺酸或天冬胺酸,以及與苯乙酸、甲磺酸、乙磺酸、2-羥基乙磺酸、乙烷1,2-二磺酸、苯磺酸、4-甲基苯磺酸、萘2-磺酸、萘1,5-二磺酸、2-磷酸甘油酸或3-磷酸甘油酸、葡萄糖6-磷酸、N-環己基胺基磺酸(用於環己胺磺酸鹽的形成),或與其他酸性有機化合物,例如抗壞血酸的鹽。
含有本文所揭露的化合物的藥物組成物能以常規方式來製造,例如藉由常規混合、溶解、造粒、糖衣丸製備、磨細、乳化、囊封、捕集或凍乾製程。適當的配製物取決於所選的投與途徑。
對於口服投與,可以藉由將本文所揭露的化合物與本領域熟知的藥學上可接受的賦形劑(例如載體)組合來容易地配製適合的組成物。此類賦形劑和載體使得能將本發明化合物配製為片劑、丸劑、糖衣丸、膠囊、液體、凝膠、糖漿、漿液、懸浮液等,以供要治療的患者口服攝食。用於口服使用的藥物製劑可以藉由以下方式來獲得:向如本文所揭露的化合物添加固體賦形劑,視需要研磨所得混合物,並且在添加適合的輔助劑後(如果需要)加工顆粒混合物,獲得片劑或糖衣丸核心。適合賦形劑包括例如填充劑及纖維素製劑。必要時,可以添加崩解劑。用於各種類型的配製物的藥學上可接受的成分係熟知的,並且可以是例如用於各種配製物類型的黏合劑(例如,天然或合成聚合物)、潤滑劑、表面活性劑、甜味和矯味劑、包衣材料、防腐劑、染料、增稠劑、佐劑、抗微生物劑、抗氧化劑和載體。
在口服投與治療有效量的本文所揭露的化合物時,組成物典型地呈固體(例如,片劑、膠囊、丸劑、粉末或糖錠)或液體配製物(例如,水性懸浮液、溶液、酏劑或糖漿)的形式。
在以片劑形式投與時,組成物可以另外含有功能性固體和/或固體載體,例如明膠或佐劑。片劑、膠囊和粉末可以含有約1%至約95%化合物,並且較佳的是約15%至約90%化合物。
在以液體或懸浮液形式投與時,可以添加功能性液體和/或液體載體,例如水、石油或動物或植物來源的油。組成物的液體形式可以進一步含有生理鹽水溶液、糖醇溶液、右旋糖或其他糖溶液或二醇。在以液體或懸浮液形式投與時,組成物可以含有以重量計約0.5%至約90%的本文所揭露的化合物,並且較佳的是約1%至約50%的本文所揭露的化合物。在考慮到的一個實施方式中,液體載體係非水性的或基本上非水性的。對於以液體形式投與,組成物可以作為快速溶解的固體配製物來供應,用於在即將投與前溶解或懸浮。
在藉由靜脈內、經皮膚或皮下注射投與治療有效量的本文所揭露的化合物時,組成物呈無熱原、腸胃外可接受的水溶液的形式。此類腸胃外可接受的溶液的製備應充分考慮pH、等滲性、穩定性等,係在本領域技術範圍的。除了本文所揭露的化合物以外,用於靜脈內、經皮膚或皮下注射的較佳的組成物典型地含有等滲媒劑。此類組成物可以經製備用於作為與表面活性劑(例如羥丙基纖維素)適當混合的游離鹼或藥理學上可接受的鹽於水中的溶液來投與。還可以在甘油、液體聚乙二醇及其混合物中以及在油中製備分散液。在普通的儲存和使用條件下,該等製劑可以視需要含有防腐劑以防止微生物生長。
可注射組成物可以包括無菌水性溶液、懸浮液或分散液,以及用於臨時製備無菌可注射溶液、懸浮液或分散液的無菌粉末。在所有實施方式中,該形式必須係無菌的,並且流動性必須達到存在易可注射性的程度。其必須在製造和儲存條件下穩定,並且必須藉由視需要包括防腐劑來抵抗微生物(例如細菌和真菌)的污染作用。載體可以是溶劑或分散介質,其含有例如水、乙醇、多元醇(例如,甘油、丙二醇和液體聚乙二醇等)、其適合的混合物以及植物油。在考慮到的一個實施方式中,載體係非水性的或基本上非水性的。適當流動性可以例如藉由以下方式來維持:藉由使用包衣,例如卵磷脂;在分散液的實施方式中藉由維持化合物的所需粒徑;以及藉由使用表面活性劑。對微生物作用的防止可以藉由各種抗細菌劑和抗真菌劑來實現,例如對羥苯甲酸酯、氯丁醇、酚、山梨酸、硫柳汞等。在許多實施方式中,包括等滲劑(例如,糖或氯化鈉)將是較佳的。可注射組成物的延長吸收可以藉由在組成物中使用吸收延遲劑(例如,單硬脂酸鋁和明膠)來實現。
無菌可注射溶液藉由以下方式來製備:將活性化合物以所需量摻入視需要含有上文所列舉的各種其他成分的適當溶劑中,之後過濾滅菌。通常,分散液藉由以下方式來製備:將各種經滅菌活性成分摻入無菌媒劑中,該媒劑含有基礎分散介質和來自上文所列舉的那些的其他所需成分。在用於製備無菌可注射溶液的無菌粉末的實施方式中,較佳的製備方法係真空乾燥和冷凍乾燥技術,其產生活性成分加來自其預先經無菌過濾的溶液的任何所需的其他成分的粉末。
還可以製備緩慢釋放或持續釋放配製物,以實現在胃腸道中與體液接觸的活性化合物的受控釋放,並且在血漿中提供基本上恒定且有效的活性化合物水平。例如,可以藉由溶解、擴散和離子交換中的一種或多種來控制釋放。另外,緩慢釋放方法可以藉由胃腸道內的可飽和或限制途徑促進吸收。例如,出於這個目的,可以將化合物包埋於生物可降解聚合物、水溶性聚合物或二者的混合物以及視需要適合的表面活性劑的聚合物基質中。在這種情況下,包埋可以意指在聚合物基質中摻入微粒。還藉由經由已知的分散液或乳液包衣技術囊封經分散的微粒或經乳化的微滴來獲得受控釋放配製物。
對於藉由吸入投與,本發明的化合物便捷地以氣溶膠噴霧呈遞的形式從加壓包裝或霧化器使用適合的推進劑來遞送。在加壓氣溶膠的實施方式中,可以藉由提供閥來確定劑量單位,以遞送經計量的量。用於吸入器或吹入器的例如明膠的膠囊和藥筒可以經配製含有化合物與適合的粉末基質(例如乳糖或澱粉)的粉末混合物。
本文所揭露的化合物可以經配製用於藉由注射(例如,藉由推注或連續輸注)腸胃外投與。注射用配製物能以單位劑型(例如,於安瓿中或於多劑量容器中)呈現,並添加有防腐劑。組成物可以採取諸如以下等形式:於油性或水性媒劑中的懸浮液、溶液或乳液,並且可以含有配製劑,例如懸浮劑、穩定劑和/或分散劑。
用於腸胃外投與的藥物配製物包括呈水溶性形式的化合物的水溶液。另外,可以將化合物的懸浮液製備為適當的油性注射懸浮液。適合的親脂性溶劑或媒劑包括脂肪油或合成脂肪酸酯。水性注射懸浮液可以含有提高懸浮液黏度的物質。視需要,懸浮液還可以含有適合的穩定劑或提高化合物的溶解度並允許製備高度濃縮的溶液的劑。可替代地,本發明組成物可以呈粉末形式以供在使用前用適合的媒劑(例如,無菌無熱原水)構造。
本文所揭露的化合物還可以配製於直腸組成物中,例如栓劑或滯留型灌腸劑(例如,含有常規栓劑基質)。除了先前所述的配製物以外,還可以將化合物配製為長效製劑。此類長效配製物可以藉由植入(例如,皮下或肌內)或藉由肌內注射來投與。因此,例如,化合物可以用適合的聚合或疏水材料(例如,作為可接受的油中的乳液)或離子交換樹脂,或作為微溶衍生物(例如,作為微溶鹽)來配製。
特別地,本文所揭露的化合物能以含有賦形劑(例如澱粉或乳糖)的片劑的形式,或以單獨的或與賦形劑混合的膠囊或珠囊(ovule),或以含有矯味劑或著色劑的酏劑或懸浮液的形式,口服、經頰或舌下投與。此類液體製劑可以用藥學上可接受的添加劑(例如懸浮劑)來製備。還可以腸胃外注射化合物,例如靜脈內、肌內、皮下或冠狀動脈內。對於腸胃外投與,化合物最佳地以無菌水溶液的形式來使用,其可以含有其他物質,例如鹽或糖醇(例如甘露醇)或葡萄糖,以使溶液與血液等滲。
對於獸用,本文所揭露的化合物根據正規獸醫實踐作為適合地可接受的配製物來投與。獸醫可以容易地確定對於特定動物最合適的給藥方案和投與途徑。
在一些實施方式中,可以將用於使用如本文所揭露的化合物(單獨的或與傳統地用於治療這種疾病的另一種藥劑或干預組合的)治療KIF18A相關障礙的所有所需組分包裝至劑盒中。具體地,本發明提供了用於疾病的治療干預的劑盒,該劑盒包含經包裝的成套藥物,包括本文所揭露的化合物以及用於製備所述藥物的可遞送形式的緩衝液和其他組分;和/或用於遞送此類藥物的裝置;和/或用於與本文所揭露的化合物的組合療法的任何藥劑;和/或與藥物一起包裝的疾病治療說明書。說明書可以固定於任何可觸摸介質中,例如印刷紙張、或電腦可讀取的磁性或光學介質、或參考遠端電腦數據來源的說明,例如可藉由互聯網訪問的萬維網網頁。
「治療有效量」意指有效治療或預防所治療受試者的已有症狀的發展或減輕已有症狀的量。尤其根據本文所提供的詳細揭露,有效量的確定完全在熟悉該項技術者的能力範圍內。通常,「治療有效劑量」係指導致實現所需效果的化合物的量。例如,在一個較佳的實施方式中,本文所揭露的化合物的治療有效量使KIF18A活性相較於對照組降低至少5%、至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%、至少80%、至少85%或至少90%。
所投與的化合物的量可以取決於所治療的受試者、受試者的年齡、健康狀況、性別和體重、並行治療(如果有)的種類、病情的嚴重程度、所需效果的性質、治療的方式和頻率以及開處方醫師的判斷。給藥頻率亦可取決於針對動脈血氧壓力的藥效學作用。雖然個體需求不同,但化合物的有效量的最佳範圍的確定係在本領域技術範圍的。此類劑量能以單一劑量來投與,或者可以將其分為多個劑量。
當在本文中使用時,術語「癌症」和「癌性的」係指或描述在哺乳動物中通常以不受調節的細胞生長為特徵的生理病症。癌症的實例包括但不限於癌、淋巴瘤、肉瘤、母細胞瘤和白血病。此類癌症的更具體實例包括鱗狀細胞癌、肺癌、胰臟癌、子宮頸癌、膀胱癌、肝癌、乳腺癌、結腸癌以及頭頸癌、卵巢癌和子宮內膜癌。儘管如本文所使用,術語「癌症」不限於該疾病的任一特定形式,但是認為本發明的方法對於發現伴有不受調節的KIF18A水平或依賴於KIF18A的癌症特別有效,KIF18A用於哺乳動物中的正確進行染色體分離和存活。
如本文所使用,術語「治療(「treat」、「treating」和「treatment」)」係指療法,包括但不限於治癒性療法、預防性療法和預防性療法。預防性治療通常包括完全預防個體疾病的發作或延遲個體障礙的臨床前明顯階段的發作。
如本文所使用,術語「患者」、「受試者」或「哺乳動物」係指任何「患者」、「受試者」或「哺乳動物」,包括人、牛、馬、狗和貓。在本發明的一個實施方式中,哺乳動物為人。
術語「包括/包含」意指開放式的,包括所指出的一個或更多個組分,但不排除其他要素。
術語「式I」包括任何子式,例如 (Ia)、(Ib)、(Ic)、(Id) 等。
使用KIF18A抑制劑的方法
本揭露提供了一般性具有基於MT的KIF18A調節活性,特別是具有抑制活性的化合物。在本發明的一個實施方式中,提供了一種用於在受試者中調節KIF18A蛋白之方法,該方法包括向受試者投與有效劑量的式I化合物。因此,本發明的化合物可以用於治療細胞增殖障礙,包括不受控制的細胞生長、異常的細胞週期調節、中心體異常(結構和/或數量上,片段化)。與額外中心體(> 2)累積相關的其他疾病或障礙包括人乳頭瘤病毒(HPV)感染,包括與HPV相關的腫瘤。該等化合物還可用於纖毛相關疾病以及消融可用作男性避孕劑的單倍體生殖細胞群。
此外,本發明的化合物可用於但不限於預防或治療癌症和其他KIF18A介導的疾病或病症。例如,本發明的化合物可用於治療多種實體瘤或血液源性腫瘤,例如癌,包括但不限於膀胱癌、乳腺癌、結腸癌、腎癌、肝癌、肺癌(包括鱗狀細胞癌和小細胞肺癌)、食道癌、膽囊癌、卵巢癌、胰臟癌、胃癌、子宮頸癌、甲狀腺癌、前列腺癌和皮膚癌(包括鱗狀細胞癌);淋巴系的造血腫瘤(包括白血病、急性淋巴球性白血病、急性成淋巴球性白血病、B細胞淋巴瘤、T細胞淋巴瘤、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、毛細胞淋巴瘤和伯克特淋巴瘤);骨髓系的造血腫瘤(包括急性和慢性骨髓性白血病、骨髓化生不良症候群和前髓細胞白血病);間質來源的腫瘤(包括纖維肉瘤和橫紋肌肉瘤以及其他肉瘤,例如軟組織和骨);中樞和周圍神經系統腫瘤(包括星形細胞瘤、神經母細胞瘤、神經膠質瘤和神經鞘瘤);以及其他腫瘤(包括黑素瘤、精原細胞瘤、畸胎癌、骨肉瘤、著色性乾皮病、角化棘皮瘤、甲狀腺濾泡癌或卡波西氏肉瘤)。
本發明的化合物還可用於治療癌症相關適應症,例如實體瘤、肉瘤(特別是尤因氏肉瘤和骨肉瘤)、視網膜母細胞瘤、橫紋肌肉瘤、神經母細胞瘤、造血性惡性腫瘤(包括白血病和淋巴瘤)、腫瘤引起的胸膜或心包積液和惡性腹水。
基於調節驅動蛋白影響血管生成的能力,本發明的化合物也可用於增殖性疾病的治療和療法。特別地,該等化合物可以用於治療炎性疾病,尤其是治療運動器的表現,例如多種炎性類風濕性疾病,尤其是慢性多發性關節炎,包括類風濕性關節炎、青少年關節炎或牛皮癬關節炎;腫瘤伴隨綜合症或腫瘤引起的炎性疾病、渾濁的積液、膠原性疾病,例如全身性紅斑狼瘡、多發性肌炎、皮肌炎、系統性硬皮病或混合性膠原性疾病;感染後關節炎(在身體患處或其中找不到活的病原性生物)、血清陰性的脊椎關節炎,例如強直性脊椎炎;血管炎、類肉瘤病或關節病;或其進一步的任意組合。
本發明的化合物還可以用作針對此類病況的活性劑,如關節炎、動脈粥樣硬化、牛皮癬、血管瘤、心肌血管生成、冠狀動脈和腦側突、膠體局部缺血血管生成、傷口癒合、消化性潰瘍、幽門螺旋桿菌相關疾病、骨折、貓抓熱、潮紅、新生血管性青光眼和視網膜病(例如與糖尿病性視網膜病變或黃斑點退化相關的視網膜病)。此外,該等化合物中的一些可以用作針對實體瘤、惡性腹水、造血癌症和過度增生性障礙(例如甲狀腺增生(尤其是格雷夫斯病))和囊腫(例如卵巢基質的血管過度增生、多囊卵巢綜合症的特徵(Stein-Leventhal綜合症))的活性劑,因為此類疾病需要血管細胞增殖才能生長和/或轉移。
該等化合物除了可用於人治療外,還可用於獸醫治療伴侶動物、外來動物和農場動物,包括哺乳動物、齧齒類動物等。例如,可以用本發明提供的化合物治療包括馬、狗和貓的動物。
組合
儘管本發明的化合物可以作為唯一的活性藥物試劑進行給藥或投與,但是它們還可以與一種或更多種本發明的化合物組合使用或與其他試劑聯合使用。當組合投與時,可以將治療劑配製成分開的組成物,該等組成物同時投與或在不同時間依次投與,或者可以將治療劑作為單一組成物給予。
在定義本發明的化合物和另一種藥物試劑的使用中,短語「共同療法」(或「組合療法」)旨在包括以提供有益的藥物組合效果的方案以順序方式投與每種試劑,並且還旨在包括以基本上同時的方式共同投與該等試劑,例如以具有固定比例的該等活性試劑的單個膠囊或以每種試劑的多個單獨的膠囊。
具體地,本發明的化合物的投與可以與熟悉該項技術者已知的預防或治療癌症的其他療法聯合,例如放射療法、小分子靶向劑(例如PARP抑制劑、激酶抑制劑)、具有腫瘤或細胞毒性劑的治療性抗體(例如裸露的和與藥物偶合的)免疫療法抗體(檢查點抑制劑、雙特異性T細胞接合劑)。
如果配製成固定劑量,則此類組合產品在可接受的劑量範圍內採用本發明的化合物。當組合配製物不合適時,式I化合物也可以與已知的抗癌劑或細胞毒性劑依次投與。本發明不限於投與順序;本發明的化合物可以在已知的抗癌劑或細胞毒性劑投與之前、同時或之後投與。
存在大量的在商用上使用、在臨床評估和臨床前開發上可用的抗癌劑,它們可以藉由組合藥物化學療法被選擇用於治療腫瘤。此類藥劑分為幾大類,例如抗生素類藥劑、烷基化和類烷基化藥劑、抗有絲分裂劑、小分子靶向劑、抗代謝藥、激素劑、免疫劑、抗血管發生劑、干擾素類藥劑和雜項藥劑類。
本揭露還提供了用於組合療法之方法,其中將已知可調節其他途徑或相同途徑的其他組分、或甚至靶標酶的重疊集合的藥劑與本揭露的化合物或其藥學上可接受的鹽組合使用。在一個方面中,這種療法包括但不限於一種或多種本揭露的化合物與化學治療劑、治療性抗體、小分子靶向劑和輻射治療的組合,以提供協同或累加的治療效果。
許多化學治療劑目前係本領域已知的,並且可以與本揭露的化合物組合使用。在一些實施方式中,化學治療劑選自由以下各項組成之群組:抗有絲分裂劑、烷基化劑、抗代謝藥、嵌入抗生素、生長因子抑制劑、細胞週期抑制劑、酶、拓撲異構酶抑制劑、生物反應修飾劑、抗激素藥、血管發生抑制劑和抗雄激素。非限制性實例係化學治療劑、細胞毒性劑和非肽小分子,例如Gleevec®(甲磺酸伊馬替尼)、Kyprolis®(卡非佐米(carfilzomib))、Velcade®(硼替佐米(bortezomib))、Casodex(比卡魯胺)、Iressa®(吉非替尼(gefitinib))和阿黴素(Adriamycin)以及多種化學治療劑。化學治療劑的非限制性實例包括烷基化劑,例如噻替派(thiotepa)和環磷醯胺(CYTOXANTM);烷基磺酸酯,例如白消安(busulfan)、英丙舒凡(improsulfan)和哌泊舒凡(piposulfan);氮丙啶,例如苯佐替哌(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)和烏瑞替哌(uredopa);乙烯亞胺和甲基蜜胺(methylamelamine),包括六甲蜜胺、三伸乙基蜜胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺(triethylenethiophosphaoramide)和三羥甲基蜜胺(trimethylolomelamine);氮芥,例如苯丁酸氮芥、萘氮芥、氯磷醯胺(cholophosphamide)、雌氮芥、異環磷醯胺、二氯甲基二乙胺、鹽酸甲氧氮芥(mechlorethamine oxide hydrochloride)、美法侖(melphalan)、新恩比興(novembichin)、苯芥膽甾醇(phenesterine)、潑尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥;亞硝基脲,例如卡莫司汀(carmustine)、氯脲黴素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)、雷莫司汀(ranimustine);抗生素,例如阿克拉黴素(aclacinomysin)、放線菌素(actinomycin)、安麯黴素(authramycin)、重氮絲胺酸、博來黴素(bleomycins)、放線菌素(cactinomycin)、卡奇黴素(calicheamicin)、卡柔比星(carabicin)、洋紅黴素(carminomycin)、嗜癌菌素(carzinophilin)、CasodexTM、色黴素(chromomycins)、更生黴素(dactinomycin)、道諾黴素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-側氧基-L-正亮胺酸、多柔比星(doxorubicin)、表柔比星(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(mitomycins)、黴酚酸(mycophenolic acid)、諾加黴素(nogalamycin)、橄欖黴素(olivomycins)、培洛黴素(peplomycin)、泊非黴素(potfiromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑菌素(streptonigrin)、鏈脲黴素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他丁(zinostatin)、佐柔比星(zorubicin);抗代謝藥,例如胺甲喋呤和5-氟尿嘧啶(5-FU);葉酸類似物,例如二甲葉酸(denopterin)、胺甲喋呤、蝶羅呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤類似物,例如氟達拉濱、6-巰嘌呤、硫咪嘌呤、硫鳥嘌呤;嘧啶類似物,例如安西他濱(azacitidine)、阿紮胞苷(azacitidine)、6-氮雜尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二去氧尿苷、去氧氟尿苷、依諾他濱(enocitabine)、氟尿苷(floxuridine),雄激素例如卡普睾酮(calusterone)、屈他雄酮丙酸酯(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾內酯(testolactone);抗腎上腺藥,例如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);葉酸補充劑,例如亞葉酸(frolinic acid);醋葡醛內酯;醛磷醯胺糖苷;胺基乙醯丙酸;安吖啶(amsacrine);貝曲布昔(bestrabucil);比生群(bisantrene);伊達曲沙(edatraxate);地磷醯胺(defofamine);秋水仙胺;地吖醌(diaziquone);依氟鳥胺酸(elfomithine);依利醋銨(elliptinium acetate);依託格魯(etoglucid);硝酸鎵;羥基脲;香菇多糖(lentinan);氯尼達明(lonidamine);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);莫哌達醇(mopidamol);硝胺丙吖啶(nitracrine);噴司他汀(pentostatin);蛋胺氮芥(phenamet);吡柔比星(pirarubicin);鬼臼酸(podophyllinic acid);2-乙基醯肼;丙卡巴肼(procarbazine);PSK;丙亞胺;西佐喃(sizofiran);鍺螺胺(spirogermanium);細交鏈孢菌酮酸(tenuazonic acid);三亞胺醌(triaziquone);2,2',2''-三氯三乙胺;烏拉坦(urethan);長春地辛(vindesine);達卡巴𠯤(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴衛矛醇(mitolactol);哌泊溴烷(pipobroman);加賽特辛(gacytosine);阿拉伯糖苷(「Ara-C」);環磷醯胺;噻替派(thiotepa);紫杉烷,例如紫杉酚和多西他賽(docetaxel)、白蛋白結合型紫杉酚(Nab-paclitaxel);視黃酸;埃斯波黴素(esperamicins);卡培他濱(capecitabine);以及上述任何一種的藥學上可接受的鹽、酸或衍生物。
作為適合的化學治療性細胞調理劑還包括用於調節或抑制激素對腫瘤的作用的抗激素劑,例如抗雌激素藥,包括例如他莫昔芬(NolvadexTM)、雷洛昔芬(raloxifene)、芳香酶抑制性4(5)-咪唑、4-羥基他莫昔芬(4-hydroxytamoxifen)、曲沃昔芬(trioxifene)、可莫昔芬(keoxifene)、LY 117018、奧那司酮(onapristone)和托瑞米芬(toremifene)(法樂通(Fareston));和抗雄激素藥,例如氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、亮丙瑞林(leuprolide)和戈舍瑞林(goserelin);苯丁酸氮芥;吉西他濱(gemcitabine);6-硫鳥嘌呤;巰嘌呤;甲胺喋呤;鉑類似物,例如順鉑、奧沙利鉑(oxaliplatin)和卡鉑;依託泊苷(etoposide)(VP-16);異環磷醯胺;絲裂黴素C(mitomycin C);米托蒽醌(mitoxantrone);長春鹼(vinblastine )、長春新鹼(vincristine);長春瑞濱(vinorelbine);諾維本(navelbine);諾安托(novantrone);替尼泊苷(teniposide);道諾黴素(daunomycin);胺基蝶呤(aminopterin);希羅達(xeloda);伊班膦酸鹽(ibandronate);拓撲替康(topotecan);喜樹鹼-11(CPT-11);拓撲異構酶抑制劑RFS 2000;二氟甲基鳥胺酸(DMFO)。
如果需要,本揭露的化合物或藥物組成物可以與通常開具的抗癌藥物組合使用,例如Herceptin®、Avastin®、Erbitux®、Rituxan®、Taxol®、Abraxane、Arimidex®、Taxotere®、ABVD、阿維金(AVICINE)、阿巴伏單抗(Abagovomab)、吖啶羧醯胺(Acridine carboxamide)、阿德木單抗(Adecatumumab)、17-N-烯丙基胺基-17-去甲氧基格爾德黴素、阿法雷丁(Alpharadin)、阿瓦昔地(Alvocidib)、3-胺基吡啶-2-甲醛胺基硫脲、胺萘非特(Amonafide)、蒽二酮(Anthracenedione)、抗CD22免疫毒素、抗腫瘤藥、抗腫瘤發生草藥(Antitumorigenic herbs)、阿帕茲醌(Apaziquone)、阿替莫德(Atiprimod)、硫唑嘌呤(Azathioprine)、貝洛替康(Belotecan)、苯達莫司汀(Bendamustine)、BIBW 2992、比立考達(Biricodar)、伯斯塔利辛(Brostallicin)、苔蘚抑素(Bryostatin)、丁硫胺酸亞碸胺(Buthionine sulfoximine)、CBV(化學療法)、花萼海綿誘癌素(Calyculin)、細胞週期非特異性抗腫瘤劑、二氯乙酸、圓皮海綿內酯(Discodermolide)、依沙蘆星(Elsamitrucin)、依諾他濱(Enocitabine)、埃博黴素(Epothilone)、艾日布林(Eribulin)、依維莫司(Everolimus)、依沙替康(Exatecan)、依昔舒林(Exisulind)、鐵銹醇(Ferruginol)、氟羅德辛(Forodesine)、磷雌酚(Fosfestrol)、ICE化學治療方案、IT-101、伊美克(Imexon)、咪喹莫特(Imiquimod)、吲哚并咔唑(Indolocarbazole)、伊羅夫文(Irofulven)、拉尼喹達(Laniquidar)、拉洛他賽(Larotaxel)、來那度胺(Lenalidomide)、硫蒽酮(Lucanthone)、勒托替康(Lurtotecan)、馬磷醯胺(Mafosfamide)、米托唑胺(Mitozolomide)、萘福昔定(Nafoxidine)、奈達鉑(Nedaplatin)、奧拉帕尼(Olaparib)、他拉唑帕尼(Talazoparib)、尼拉帕利(Niraparib)、沃塔紫杉醇(Ortataxel)、PAC-1、木瓜(Pawpaw)、匹杉瓊(Pixantrone)、蛋白酶體抑制劑、蝴蝶黴素(Rebeccamycin)、瑞喹莫德(Resiquimod)、魯比特康(Rubitecan)、SN-38、鹽孢菌醯胺A(Salinosporamide A)、沙帕他濱(Sapacitabine)、斯坦福V(Stanford V)、苦馬豆素(Swainsonine)、他拉泊芬(Talaporfin)、塔利喹達(Tariquidar)、優福定(Tegafur-uracil)、特莫多(Temodar)、替司他賽(Tesetaxel)、四硝酸三鉑(Triplatin tetranitrate)、三(2-氯乙基)胺、曲沙他濱(Troxacitabine)、烏拉莫司汀(Uramustine)、瓦帝莫澤(Vadimezan)、長春氟寧(Vinflunine)、ZD6126或唑喹達(Zosuquidar)、CDK4/6抑制劑(帕博西林(Palbociclib),Ibrance;瑞博西林(Ribociclib),Kisqali;玻瑪西林(Abemaciclib),Verzenio)。
本揭露進一步關於使用本文所提供的化合物或藥物組成物與放射療法的組合在哺乳動物中抑制異常細胞生長或治療過度增生障礙的方法。投與放射療法的技術係本領域已知的,並且該等技術可以用於本文所述的組合療法中。這種組合療法中本揭露的化合物的投與可以如本文所述來確定。
放射療法可以藉由若干種方法之一或方法的組合來投與,包括但不限於外射束療法、內放射療法、植入物放射、立體定位性放射外科手術、全身放射療法、放射療法和永久性或臨時性間質近距離放射療法。如本文所使用,術語「近距離放射療法」係指藉由空間受限的放射性材料遞送的放射療法,該放射性材料係在腫瘤或其他增生性組織患病位點處或附近插入體內的。該術語意圖不受限制地包括暴露於放射性同位素(例如,At-211、I-131、I-125、Y-90、Re-186、Re-188、Sm-153、Bi-212、P-32和Lu的放射性同位素)。用作本揭露的細胞調理劑的適合的放射源包括固體和液體。藉由非限制性實例,放射源可以是放射性核素,例如作為固體來源的I-125、I-131、Yb-169、Ir-192,作為固體來源的I-125,或發射光子、β粒子、γ輻射或其他治療性射線的其他放射性核素。放射性材料還可以是從一種或多種放射性核素的任何溶液(例如,I-125或I-131的溶液)製備的流體,或者放射性流體可以使用含有固體放射性核素(例如Au-198、Y-90)的小顆粒的適合的流體的漿液產生。此外,可以將一種或多種放射性核素包埋於凝膠或放射性微球中。
本揭露的化合物或藥物組成物可以與一定量的一種或多種選自以下的物質組合使用:抗血管發生劑、訊息傳導抑制劑、抗增殖劑、糖酵解抑制劑或自體吞噬抑制劑。
抗血管發生劑可以結合本揭露的化合物和本文所述的藥物組成物使用,該等抗血管發生劑係例如MMP-2(基質金屬蛋白酶2)抑制劑、MMP-9(基質金屬蛋白酶9)抑制劑和COX-11(環氧酶11)抑制劑。抗血管發生劑包括例如雷帕黴素、替西羅莫司(temsirolimus,CCI-779)、依維莫司(everolimus)(RAD001)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)和貝伐單抗(bevacizumab)。有用COX-II抑制劑的實例包括阿來昔布(alecoxib)、伐地昔布(valdecoxib)和羅非昔布(rofecoxib)。有用基質金屬蛋白酶抑制劑的實例描述於以下專利中:WO 96/33172、WO 96/27583、歐洲專利公開案EP 0818442、歐洲專利公開案EP 1004578、WO 98/07697、WO 98/03516、WO 98/34918、WO 98/34915、WO 98/33768、WO 98/30566、歐洲專利公開案606046、歐洲專利公開案931 788、WO 90/05719、WO 99/52910、WO 99/52889、WO 99/29667、WO 1999007675、歐洲專利公開案EP 1786785、歐洲專利公開案號EP 1181017、美國公開案號US 20090012085、美國公開案US 5863 949、美國公開案US 5861 510和歐洲專利公開案EP 0780386,將所有該等專利藉由引用以其整體併入本文。較佳的MMP-2和MMP-9抑制劑係具有極小或無抑制MMP-1的活性的那些。更較佳的是相對於其他基質金屬蛋白酶(即,MAP-1、MMP-3、MMP-4、MMP-5、MMP-6、MMP-7、MMP-8、MMP-10、MMP-11、MMP-12和MMP-13)選擇性抑制MMP-2和/或AMP-9的那些。可用於本揭露中的MMP抑制劑的一些具體實例係AG-3340、RO 32-3555和RS 13-0830。
本發明化合物還可以用於與其他抗瘤劑的共同療法中,該等其他抗瘤劑係例如醋孟南(acemannan)、阿柔比星、阿地白介素、阿侖單抗(alemtuzumab)、阿利維A酸(alitretinoin)、六甲蜜胺、胺磷汀、胺基乙醯丙酸、胺柔比星、安吖啶、阿那格雷、阿那曲唑、ANCER、安西司亭(ancestim)、阿加來必(ARGLABIN)、三氧化二砷、BAM 002(諾夫洛斯公司(Novelos))、貝沙羅汀(bexarotene)、比卡魯胺、溴尿苷、卡培他濱、西莫白介素、西曲瑞克、克拉屈濱、克黴唑、阿糖胞苷十八烷基磷酸鹽(cytarabine ocfosfate)、DA 3030(Dong-A)、達克珠單抗(daclizumab)、地尼白介素(denileukin diftitox)、地洛瑞林(deslorelin)、右雷佐生、地拉卓(dilazep)、多西他賽、二十二醇、度骨化醇(doxercalciferol)、去氧氟尿苷、多柔比星、溴隱亭、卡莫司汀、阿糖胞苷、氟尿嘧啶、HIT雙氯酚酸、干擾素-α、道諾黴素、多柔比星、維甲酸、依地福新、依決洛單抗、依氟鳥胺酸(eflornithine)、乙嘧替氟、表柔比星、紅血球生成素β、磷酸依託泊苷、依西美坦、依昔舒林(exisulind)、法倔唑、非格司亭(filgrastim)、非那雄胺、磷酸氟達拉濱、福美司坦(formestane)、福莫司汀、硝酸鎵、吉西他濱、吉妥珠單抗奧唑米星(gemtuzumab zogamicin)、吉美拉西(gimeracil)/奧替拉西(oteracil)/替加氟組合、格萊克濱(glycopine)、戈舍瑞林、庚鉑(heptaplatin)、人絨毛膜促性腺素、人類胎兒甲胎蛋白、伊班膦酸、伊達比星、咪喹莫特、干擾素-α、干擾素-α、天然干擾素-α-2、干擾素-α-2a、干擾素-α-2b、干擾素-α-N1、干擾素-α-n3、干擾素alfacon-1、干擾素α、天然干擾素β、干擾素β-1a、干擾素β-1b、干擾素γ、天然干擾素γ-1a、干擾素γ-1b、白介素-1β、碘苄胍、伊立替康、伊索拉定(irsogladine)、蘭瑞肽(lanreotide)、LC 9018(養樂多集團(Yakult))、來氟米特、來格司亭(lenograstim)、硫酸香菇多糖、來曲唑、白血球α干擾素、亮丙瑞林、左旋咪唑 + 氟尿嘧啶、利阿唑(liarozole)、洛鉑、氯尼達明、洛伐他汀、馬索羅酚、美拉胂醇、甲氧氯普胺、米非司酮、米替福新、米立司亭、錯配雙股RNA、米托胍腙、二溴衛矛醇、米托蒽醌、莫拉司亭(molgramostim)、那法瑞林、納洛酮 + 噴他佐辛、那托司亭(nartograstim)、奈達鉑、尼魯米特(nilutamide)、那可丁、新穎紅血球生成刺激蛋白、NSC 631570奧曲肽、奧普瑞白介素(oprelvekin)、奧沙特隆、奧沙利鉑(oxaliplatin)、紫杉酚、帕米膦酸(pamidronic acid)、培門冬酶、聚乙二醇干擾素-α-2b、木聚硫鈉(pentosan polysulfate sodium)、噴司他丁、畢西巴尼(picibanil)、吡柔比星、兔抗胸腺細胞多株抗體、聚乙二醇干擾素-α-2a、卟吩姆鈉、雷洛昔芬、雷替曲塞、拉斯伯門特(rasburiembodiment)、羥乙膦酸錸(Re 186)、RII維甲醯酚胺(RII retinamide)、利妥昔單抗、羅莫肽、來昔決南釤(153 Sm)(samarium (153 Sm) lexidronam)、沙格司亭(sargramostim)、西佐喃、索布佐生、索納明(sonermin)、氯化鍶-89、蘇拉明、他索那明(tasonermin)、他紮羅汀、替加氟、替莫泊芬(temoporfin)、替莫唑胺、替尼泊苷、四氯十氧化物、沙利度胺、胸腺法新、促甲狀腺素α、托泊替康(topotecan)、托瑞米芬、托西莫單抗(tositumomab)-碘131、曲妥珠單抗、曲奧舒凡、維甲酸、曲洛司坦、三甲曲沙、曲普瑞林、腫瘤壞死因子α、天然烏苯美司、膀胱癌疫苗、丸山(Maruyama)疫苗、黑色素瘤裂解物疫苗、戊柔比星(valrubicin)、維替泊芬、長春瑞濱、維魯利秦(VIRULIZIN)、淨司他丁斯酯(zinostatin stimalamer)或唑來膦酸;阿巴瑞克;AE 941(依特納公司(Aeterna))、胺莫司汀(ambamustine)、反義寡核苷酸、bcl-2(珍塔公司(Genta))、APC 8015(丹德里昂公司(Dendreon))、西妥昔單抗、地西他濱(decitabine)、德胺魯米特(dexaminoglutethimide)、地吖醌、EL 532(義隆公司(Elan))、EM 800(英杜裡奇公司(Endorecherche))、恩尿嘧啶、依他硝唑、芬維A銨(fenretinide)、非格司亭SD01(美商安進公司(Amgen))、氟維司群、加洛他濱、胃泌素17免疫原、HLA-B7基因療法(偉科公司(Vical))、粒細胞-巨噬細胞群落刺激因子、組胺二鹽酸鹽、替伊莫單抗、伊洛馬司他、IM 862(興創公司(Cytran))、白介素-2、艾潑昔芬(iproxifene)、LDI 200(米克豪公司(Milkhaus))、來立司亭(leridistim)、林妥珠單抗(lintuzumab)、CA 125 MAb(巴米拉公司(Biomira))、癌症MAb(日本製藥發展公司(Japan Pharmaceutical Development))、HER-2和Fc MAb(梅達拉公司(Medarex))、獨特型105AD7 MAb(CRC技術公司(CRC Technology))、獨特型CEA MAb(特裡萊公司(Trilex))、LYM-1-碘131 MAb(特尼殖株公司(Techniclone))、多態性上皮黏液素-釔90 MAb(安特索瑪公司(Antisoma))、馬立馬司他(marimastat)、美諾立爾、米妥莫單抗(mitumomab)、莫特沙芬釓(motexafin gadolinium)、MX 6(高德美公司(Galderma))、奈拉濱(nelarabine)、諾拉曲塞(nolatrexed)、P 30蛋白、培維索孟(pegvisomant)、培美曲塞、泊非黴素(porfiromycin)、普馬司他(prinomastat)、RL 0903(夏爾公司(Shire))、魯吡替康、沙鉑(satraplatin)、苯乙酸鈉、斯帕磷酸(sparfosic acid)、SRL 172(SR製藥公司(SR Pharma))、SU 5416(蘇根公司(SUGEN))、TA 077(田邊公司(Tanabe))、四硫鉬酸鹽、厚果糖松草鹼(thaliblastine)、血小板生成素、本紫紅素乙酯錫(tin ethyl etiopurpurin)、替拉紮明、癌症疫苗(巴米拉公司)、黑色素瘤疫苗(紐約大學(New York University))、黑色素瘤疫苗(斯隆-凱特琳研究所(Sloan Kettering Institute))、黑色素瘤腫瘤裂解物疫苗(紐約醫學院(New York Medical College))、病毒黑色素瘤細胞裂解物疫苗(皇家紐卡斯爾醫院(Royal Newcastle Hospital))或伐司朴達(valspodar)。
本發明的化合物可以進一步與VEGFR抑制劑一起使用。以下專利和專利申請案中所述的其他化合物可以用於組合療法中:US 6,258,812、US 2003/0105091、WO 01/37820、US 6,235,764、WO 01/32651、US 6,630,500、US 6,515,004、US 6,713,485、US 5,521,184、US 5,770,599、US 5,747,498、WO 02/68406、WO 02/66470、WO 02/55501、WO 04/05279、WO 04/07481、WO 04/07458、WO 04/09784、WO 02/59110、WO 99/45009、WO 00/59509、WO 99/61422、US 5,990,141、WO 00/12089和WO 00/02871。
在一些實施方式中,該組合包含本發明的組成物與至少一種抗血管發生劑的組合。藥劑包括但不限於在體外以合成方式製備的化學組成物、抗體、抗原結合區、放射性核素及其組合和軛合物(conjugate)。藥劑可以是激動劑、拮抗劑、變構調節劑、毒素,或者更通常地,可以用於抑制或刺激其靶標(例如,受體或酶激活或抑制),並且由此促進細胞死亡或阻止細胞生長。
示例性抗血管發生劑包括ERBITUX™(IMC-C225)、KDR(激酶結構域受體)抑制劑(例如,特異性結合至激酶結構域受體的抗體和抗原結合區)、抗VEGF劑(例如,特異性結合VEGF的抗體或抗原結合區、或可溶VEGF受體或其配位基結合區)(例如AVASTIN™或VEGF-TRAP™)和抗VEGF受體劑(例如,與其特異性結合的抗體或抗原結合區)、EGFR抑制劑(例如,與其特異性結合的抗體或抗原結合區)(例如維克替比(Vectibix)(帕尼單抗)、IRESSA™(吉非替尼)、TARCEVA™(厄洛替尼)、抗Ang1劑和抗Ang2劑(例如,與其或與其受體(例如Tie2/Tek)特異性結合的抗體或抗原結合區)以及抗Tie2激酶抑制劑(例如,與其特異性結合的抗體或抗原結合區)。本發明的藥物組成物還可以包含一種或多種特異性結合生長因子並抑制生長因子的活性的藥劑(例如,抗體、抗原結合區或可溶受體),例如肝細胞生長因子(HGF,還稱為散射因子)的拮抗劑、以及特異性結合其受體「c-met」的抗體或抗原結合區。
其他抗血管發生劑包括阿侖單抗(Campath)、IL-8、B-FGF、Tek拮抗劑(Ceretti等人, 美國公開案號2003/0162712;美國專利案號6,413,932)、抗TWEAK劑(例如特異性結合抗體或抗原結合區、或可溶性TWEAK受體拮抗劑;參見,Wiley,美國專利案號6,727,225)、ADAM解整聯蛋白結構域拮抗整聯蛋白與其配位基的結合(Fanslow等人,美國公開案號2002/0042368)、特異性結合抗-eph受體和/或抗-ephrin抗體或抗原結合區(美國專利案號5,981,245、5,728,813、5,969,110、6,596,852、6,232,447、6,057,124及其專利家族成員)、抗PDGF-BB拮抗劑(例如,特異性結合抗體或抗原結合區)以及特異性結合PDGF-BB配位基的抗體或抗原結合區和PDGFR激酶抑制劑(例如,與其特異性結合的抗體或抗原結合區)。
其他抗血管發生/抗腫瘤劑包括:SD-7784(美國輝瑞公司(Pfizer, USA));西侖吉肽(cilengitide)(德國默克集團(Merck KGaA, Germany), EPO 770622);哌加他尼八鈉(pegaptanib octasodium)(美國吉利德科學公司(Gilead Sciences, USA));阿爾法他汀(Alphastatin)(英國BioActa公司(BioActa, UK));M-PGA(美國新基公司(Celgene, USA), US 5712291);伊洛馬司他(ilomastat)(美國愛瑞發公司(Arriva, USA), US 5892112);依馬西尼(emaxanib)(美國輝瑞公司(Pfizer, USA), US 5792783);瓦他拉尼(vatalanib)(瑞士諾華公司(Novartis, Switzerland));2-甲氧基雌二醇 (美國恩特爾公司(EntreMed, USA));TLC ELL-12(愛爾蘭義隆公司(Elan, Ireland));阿奈可他乙酸酯(anecortave acetate)(美國愛爾康公司(Alcon, USA));α-D148 Mab(美國美商安進公司(Amgen, USA));CEP-7055(美國塞法隆公司(Cephalon, USA));抗-Vn Mab(荷蘭克魯賽爾公司(Crucell, Netherlands))DAC: 抗血管發生劑(加拿大康古公司(ConjuChem, Canada));安吉西丁(Angiocidin)(美國英肯製藥公司(InKine Pharmaceutical, USA));KM-2550(日本協和發酵工業株式會社(Kyowa Hakko, Japan));SU-0879(美國輝瑞公司(Pfizer, USA));CGP-79787(瑞士諾華公司(Novartis, Switzerland), EP 970070);ARGENT技術(美國阿瑞雅德公司(Ariad, USA));YIGSR-Stealth(美國強生公司(Johnson & Johnson, USA));纖維蛋白原E片段 (英國BioActa公司(BioActa, UK));血管發生抑制劑(英國特雷根公司(Trigen, UK));TBC-1635(美國恩賽斯夫製藥公司(Encysive Pharmaceuticals, USA));SC-236(美國輝瑞公司(Pfizer, USA));ABT-567(美國雅培公司(Abbott, USA));轉移抑素(美國恩特爾公司(EntreMed, USA));血管發生抑制劑(瑞典特裡普公司(Tripep, Sweden));絲胺酸蛋白酶抑制劑(maspin)(日本創生公司(Sosei, Japan));2-甲氧基雌二醇(美國腫瘤科學公司(Oncology Sciences Corporation, USA));ER-68203-00(美國安維世公司(IVAX, USA));氟草胺(美國萊恩實驗室(Lane Labs, USA));Tz-93(日本津村公司(Tsumura, Japan));TAN-1120(日本武田公司(Takeda, Japan));FR-111142(日本藤澤公司(Fujisawa, Japan), JP 02233610);血小板因子4(美國瑞普利金公司(RepliGen, USA), EP 407122);血管內皮生長因子拮抗劑(丹麥波登公司(Borean, Denmark));貝伐單抗 (pINN)(美國基因泰克公司(Genentech, USA));血管發生抑制劑(美國蘇根公司(SUGEN, USA));XL 784(美國伊克力西斯公司(Exelixis, USA));XL 647(美國伊克力西斯公司(Exelixis, USA));MAb,α5β3整聯蛋白,第二代(美國應用分子進化公司(Applied Molecular Evolution, USA)和美國醫學免疫公司(MedImmune, USA));基因療法,視網膜病(英國牛津生物技術公司(Oxford BioMedica, UK));鹽酸澤蘭素(USAN)(美國禮來公司(Lilly, USA));CEP 7055(美國賽福龍公司(Cephalon, USA)和法國賽諾菲聖德拉堡(Sanofi-Synthelabo, France));BC 1(義大利熱那亞癌症研究院(Genoa Institute of Cancer Research, Italy));血管發生抑制劑(澳大利亞Alchemia公司(Alchemia, Australia));VEGF拮抗劑(美國再生元製藥公司(Regeneron, USA));rBPI 21和BPI-衍生的抗血管生成劑(XOMA, USA);PI 88(澳大利亞培羅成公司(Progen, Australia));西侖吉肽(cilengitide)(pINN)(德國默克集團(Merck KGaA, Germany);德國慕尼克工業大學(Munich Technical University, Germany);美國斯克裡普斯診所和研究基金會(Scripps Clinic and Research Foundation, USA));西妥昔單抗(cetuximab)(INN)(法國安萬特公司(Aventis, France));AVE 8062(日本味子素公司(Ajinomoto, Japan));AS 1404(紐西蘭癌症研究實驗室(Cancer Research Laboratory, New Zealand));SG 292(美國特留斯公司(Telios, USA));內皮他丁(Endostatin)(美國波士頓兒童醫院(Boston Childrens Hospital, USA));ATN 161(美國艾登公司(Attenuon, USA));血管抑制素(美國波士頓兒童醫院(Boston Childrens Hospital, USA));2-甲氧基雌二醇(美國波士頓兒童醫院(Boston Childrens Hospital, USA));ZD 6474(英國阿斯利康公司(AstraZeneca, UK));ZD 6126(英國Angiogene製藥公司(Angiogene Pharmaceuticals, UK));PPI 2458(美國普雷西斯公司(Praecis, USA));AZD 9935(英國阿斯利康公司(AstraZeneca, UK));AZD 2171(英國阿斯利康公司(AstraZeneca, UK));瓦他拉尼(pINN)(瑞士諾華公司(Novartis, Switzerland)和德國先靈製藥公司(Schering AG, Germany));組織因子途徑抑制劑(美國恩特爾公司(EntreMed, USA));哌加他尼(pegaptanib)(Pinn)(美國吉利德科學公司(Gilead Sciences, USA));束骨薑黃醇(韓國延世大學(Yonsei University, South Korea));疫苗,基於基因的,VEGF-2(美國斯克裡普斯診所和研究基金會(Scripps Clinic and Research Foundation, USA));SPV5.2(加拿大蘇拉特(Supratek, Canada));SDX 103(美國加州大學聖地牙哥分校(University of California at San Diego, USA));PX 478(美國派克斯公司(ProlX, USA));轉移抑素(美國恩特爾公司(EntreMed, USA));肌鈣蛋白(troponin)I(美國哈佛大學(Harvard University, USA));SU 6668(美國蘇根公司(SUGEN, USA));OXI 4503(OXiGENE, USA);o-胍類促進劑(美國三維製藥公司(Dimensional Pharmaceuticals, USA));莫麯黴胺C(motuporamine C)(加拿大不列顛哥倫比亞大學(British Columbia University, Canada));CDP 791(英國希爾泰克公司(Celltech Group, UK));阿替莫德(atiprimod)(pINN)(英國葛蘭素史克公司(GlaxoSmithKline, UK));E 7820(日本衛材公司(Eisai, Japan));CYC 381(美國哈佛大學(Harvard University, USA));AE 941(加拿大依特鈉公司(Aeterna, Canada));疫苗,血管發生抑制劑(美國恩特爾公司(EntreMed, USA));尿激酶致纖溶酶原活化物抑制劑(美國德拉瓦公司(Dendreon, USA));oglufanide (pINN)(Melmotte, USA);HIF-1α抑制劑(英國諾瓦公司(Xenova, UK));CEP 5214(美國賽福龍公司(Cephalon, USA));BAY RES 2622(德國拜耳公司(Bayer, Germany));安吉西丁(Angiocidin)(美國英肯公司(InKine, USA));A6(Angstrom, USA);KR 31372(韓國化學技術研究所(Korea Research Institute of Chemical Technology, South Korea));GW 2286(英國葛蘭素史克公司(GlaxoSmithKline, UK));EHT 0101(法國埃克森希特公司(ExonHit, France));CP 868596(美國輝瑞公司(Pfizer, USA));CP 564959(OSI, USA);CP 547632(美國輝瑞公司(Pfizer, USA));786034(英國葛蘭素史克公司(GlaxoSmithKline, UK));KRN 633(日本麒麟麥酒株式會社(Kirin Brewery, Japan));藥物遞送系統內,眼內,2-甲氧基雌二醇(美國恩特爾公司(EntreMed, USA));吡卡酯(anginex)(荷蘭馬斯特里赫特大學(Maastricht University, Netherlands)和美國明尼蘇達大學(Minnesota University, USA));ABT 510(美國雅培公司(Abbott, USA));AAL 993(瑞士諾華公司(Novartis, Switzerland));VEGI(美國ProteomTech公司(ProteomTech, USA));腫瘤壞死因子-α抑制劑(美國國家老齡研究所(National Institute on Aging, USA));SU 11248(美國輝瑞公司(Pfizer, USA)和美國蘇根公司(SUGEN, USA));ABT 518(美國雅培公司(Abbott, USA));YH16(中國煙台榮昌公司(Yantai Rongchang, China));S-3APG (美國波士頓兒童醫院(Boston Childrens Hospital, USA)和美國恩特爾公司(EntreMed, USA));MAb, KDR(美國英殖株公司(ImClone Systems, USA));MAb, α5β1(美國蛋白質設計(Protein Design, USA));KDR激酶抑制劑(英國希爾泰克公司(Celltech Group, UK)和美國強生公司(Johnson & Johnson, USA));GFB 116(美國南佛羅里達大學(South Florida University, USA)和美國耶魯大學(Yale University, USA));CS 706(日本三共株式會社(Sankyo, Japan));康他汀A4前驅藥(美國亞利桑那州立大學(Arizona State University, USA));軟骨素酶AC(IBEX, 加拿大(Canada));BAY RES 2690(德國拜耳公司(Bayer, Germany));AGM 1470(美國哈佛大學(Harvard University, USA)、日本武田公司(Takeda, Japan)和美國TAP公司(TAP, USA));AG 13925(美國阿古倫公司(Agouron, USA));四硫鉬酸鹽(Tetrathiomolybdate)(美國密西根大學(University of Michigan, USA));GCS 100(美國韋恩州立大學(Wayne State University, USA))CV 247(英國常青藤醫學團體(Ivy Medical, UK));CKD 732(韓國鐘根堂公司(Chong Kun Dang, South Korea));MAb,血管內皮生長因子(英國諾瓦公司(Xenova, UK));伊索拉定(irsogladine)(INN)(日本新藥株式會社(Nippon Shinyaku, Japan));RG 13577(法國安萬特公司(Aventis, France));WX 360(德國威爾克斯公司(Wilex, Germany));角鯊胺(squalamine)(pINN)(美國金納萊公司(Genaera, USA));RPI 4610(美國錫爾納公司(Sirna, USA));癌症療法(澳大利亞馬里諾娃公司(Marinova, Australia));類肝素酶抑制劑(以色列InSight公司(InSight, Israel));KL 3106(韓國科隆公司(Kolon, South Korea));和厚樸酚(Honokiol)(美國埃默里大學(Emory University, USA));ZK CDK(德國先靈公司(Schering AG, Germany));ZK Angio(德國先靈公司(Schering AG, Germany));ZK 229561(瑞士諾華公司(Novartis, Switzerland)和德國先靈公司(Schering AG, Germany));XMP 300(XOMA, USA);VGA 1102(日本大正公司(Taisho, Japan));VEGF受體調節劑(Pharmacopeia, USA[美國藥典]);VE-鈣黏著蛋白-2拮抗劑(美國英殖株公司(ImClone Systems, USA));血管形成抑制素(美國國立衛生研究院(National Institutes of Health, USA));疫苗,Flk-1(美國英殖株公司(ImClone Systems, USA));TZ 93(日本津村公司(Tsumura, Japan));腫瘤抑素(TumStatin)(美國貝斯以色列醫院(Beth Israel Hospital, USA));短的可溶性FLT 1(血管內皮生長因子受體1)(美國默克公司(Merck & Co, USA));Tie-2配位基(美國再生元製藥公司(Regeneron, USA));和血小板反應蛋白1抑制劑(美國阿勒格尼健康、教育和研究基金會(Allegheny Health, Education and Research Foundation, USA))。
自體吞噬抑制劑包括但不限於氯喹、3-甲基腺嘌呤、羥氯喹(Plaquenil™)、巴弗洛黴素A1(bafilomycin A1)、5-胺基-4-咪唑甲醯胺核糖核苷(AICAR)、岡田酸、抑制2A型或1型蛋白磷酸酶的自體吞噬抑制性海藻毒素、cAMP類似物以及升高cAMP水平的藥物例如腺苷、LY204002、N6-巰嘌呤核糖核苷和長春鹼。另外,還可以使用抑制蛋白質表現的反義或siRNA,該等蛋白質包括但不限於ATG5(其參與自體吞噬)。
可以用於治療癌症並且可以與本發明的一種或多種化合物組合使用的其他藥學活性化合物/藥劑包括:阿法依伯汀(epoetin alfa);阿法達貝泊汀(darbepoetin alfa);帕尼單抗;培非格司亭(pegfilgrastim);帕利夫明(palifermin);非格司亭;地諾單抗(denosumab);安西司亭;AMG 102;AMG 386;AMG 479;AMG 655;AMG 745;AMG 951;及AMG 706或其藥學上可接受的鹽。
在某些實施方式中,將本文所提供的組成物與化學治療劑聯合投與。適合的化學治療劑可以包括天然產物,例如長春花生物鹼(例如,長春鹼、長春新鹼和長春瑞濱)、紫杉酚、表鬼臼毒素(Epidipodophyllotoxin)(例如,依託泊苷和替尼泊苷)、抗生素(例如,更生黴素(放線菌素D)、道諾黴素、多柔比星和伊達比星)、蒽環類抗生素、米托蒽醌、博來黴素、普卡黴素(光輝黴素)、絲裂黴素、酶(例如,L-天冬醯胺酶,其系統性地代謝L-天冬醯胺並剝奪不具有合成自身天冬醯胺的能力的細胞)、抗血小板劑、抗增殖/抗有絲分裂烷基化劑(例如氮芥,例如,二氯甲基二乙胺、環磷醯胺和類似物、美法侖和苯丁酸氮芥)、乙烯亞胺和甲基蜜胺(例如,六甲基蜜胺(hexaamethylmelaamine)和噻替派)、CDK抑制劑(例如,塞利西利(seliciclib)、UCN-01、P1446A-05、PD-0332991、迪那西利(dinaciclib)、P27-00、AT-7519、RGB286638和SCH727965)、烷基磺酸酯(例如,白消安)、亞硝基脲(例如,卡莫司汀(BCNU)和類似物和鏈脲黴素)、三氮烯-達卡巴𠯤(Trazenes-dacarbazinine)(DTIC)、抗增殖/抗有絲分裂抗代謝藥例如葉酸類似物(例如,胺甲喋呤)、嘧啶類似物(例如,氟尿嘧啶、氟尿苷和阿糖胞苷)、嘌呤類似物和相關抑制劑(例如,巰嘌呤、硫鳥嘌呤、噴司他丁和2-氯去氧腺苷)、芳香酶抑制劑(例如,阿那曲唑、依西美坦和來曲唑)和鉑配位錯合物(例如,順鉑和卡鉑)、丙卡巴肼、羥基脲、米托坦、胺魯米特、組蛋白脫乙醯酶(HDAC)抑制劑(例如,曲古抑菌素、丁酸鈉、阿匹西坦(apicidan)、辛二醯苯胺異羥肟酸(hydroamic acid)、伏立諾他(vorinostat)、LBH 589、羅米地辛(romidepsin)、ACY-1215和帕比司他(panobinostat))、mTor抑制劑(例如,替西羅莫司、依維莫司、地磷莫司(ridaforolimus)和西羅莫司)、KSP(Eg5)抑制劑(例如,Array 520)、DNA結合劑(例如,紮利普斯(Zalypsis))、PI3Kδ抑制劑(例如,GS-1101和TGR-1202)、PI3Kδ和γ抑制劑(例如,CAL-130)、多激酶抑制劑(例如,TG02和索拉非尼)、激素(例如,雌激素)和激素激動劑例如黃體化激素釋放激素(LHRH)激動劑(例如,戈舍瑞林、亮丙瑞林和曲普瑞林)、BAFF中和性抗體(例如,LY2127399)、IKK抑制劑、p38MAPK抑制劑、抗IL-6(例如,CNTO328)、端粒酶抑制劑(例如,GRN 163L)、極光激酶抑制劑(例如,MLN8237、AMG 900、AZD-1152)、細胞表面單株抗體(例如,抗CD38(HUMAX-CD38)、抗CS1(例如,埃羅妥珠單抗(elotuzumab))、HSP90抑制劑(例如,17 AAG和KOS 953)、P13K/Akt抑制劑(例如,哌立福辛(perifosine))、Akt抑制劑(例如,GSK-2141795)、PKC抑制劑(例如,恩紮妥林)、FTI(例如,Zarnestra™)、抗CD138(例如,BT062)、Torc1/2特異性激酶抑制劑(例如,INK128)、激酶抑制劑(例如,GS-1101)、ER/UPR靶向劑(例如,MKC-3946)、cFMS抑制劑(例如,ARRY-382)、JAK1/2抑制劑(例如,CYT387)、PARP抑制劑(例如,奧拉帕尼、他拉唑帕尼(Talazoparib)、尼拉帕利(Niraparib)和維利帕尼(veliparib)(ABT-888))、BCL-2拮抗劑。其他化學治療劑可以包括二氯甲基二乙胺、喜樹鹼、異環磷醯胺、他莫昔芬、雷洛昔芬、吉西他濱、諾維本、索拉非尼或前述項的任何類似物或衍生物變體。
本發明化合物亦可與放射療法、激素療法、手術及免疫療法結合使用,該等療法係熟悉該項技術者熟知的。
在某些實施方式中,將本文所提供的藥物組成物與類固醇聯合投與。適合的類固醇可以包括但不限於21-乙醯氧基孕烯醇酮、阿氯米松、阿爾孕酮、安西奈德、倍氯米松(beclomethasone)、倍他米松、布地奈德、氯強體松(chloroprednisone)、氯倍他索(clobetasol)、氯可托龍、氯潑尼醇、皮質酮、可的松、可的伐唑、地夫可特、地奈德、去羥米松、地塞米松、二氟拉松(diflorasone)、二氟可龍(diflucortolone)、二氟孕甾丁酯(difuprednate)、甘草次酸、氟紮可特、氟氯奈德(flucloronide)、氟米松(flumethasone)、氟尼縮松、氟輕鬆(fluocinolone acetonide)、醋酸氟輕鬆、氟考丁酯(fluocortin butyl)、氟可龍、氟米龍(fluorometholone)、醋酸甲氟龍(fluperolone acetate)、醋酸氟潑尼定(fluprednidene acetate)、氟潑尼龍(fluprednisolone)、氟氫縮松(flurandrenolide)、丙酸氟替卡松、福莫可他(formocortal)、氯氟舒松(halcinonide)、丙酸鹵倍他索(halobetasol propionate)、鹵米松(halometasone)、氫化可的松(hydrocortisone)、依碳酸氯替潑諾(loteprednol etabonate)、馬潑尼酮、甲羥松、甲強體松、甲普賴蘇穠(methylprednisolone)、糠酸莫米松(mometasone furoate)、帕拉米松、潑尼卡酯、普賴蘇穠(prednisolone)、普賴蘇穠25-二乙胺基乙酸酯、普賴蘇穠磷酸鈉、強體松(prednisone)、普賴蘇穠戊酸酯(prednival)、潑尼立定(prednylidene)、利美索龍、替可的松(tixocortol)、曲安西龍(triamcinolone)、曲安奈德(triamcinolone acetonide)、苯曲安奈德(triamcinolone benetonide)、己曲安奈德(triamcinolone hexacetonide)及其鹽和/或衍生物。在一個特定實施方式中,本發明的化合物還可以與治療噁心的其他藥學活性劑組合使用。可以用於治療噁心的藥劑的實例包括:屈大麻酚(dronabinol)、格拉司瓊(granisetron)、甲氧氯普胺(metoclopramide)、昂丹司瓊(ondansetron)及丙氯拉𠯤(prochlorperazine)、或其藥學上可接受的鹽。
本揭露的化合物或藥物組成物還可以與一定量的一種或多種選自以下的物質組合使用:EGFR抑制劑、MEK抑制劑、PI3K抑制劑、AKT抑制劑、TOR抑制劑和免疫療法,包括抗PD-1、抗PDL-1、抗CTLA4、抗LAG1和抗OX40劑、GITR激動劑、CAR-T細胞和BiTE。
EGFR抑制劑包括但不限於小分子拮抗劑、抗體抑制劑或特定反義核苷酸或siRNA。有用的EGFR抗體抑制劑包括西妥昔單抗(愛必妥)、帕尼單抗(維克替比)、紮魯木單抗(zalutumumab)、尼妥珠單抗(nimotuzumab)和馬妥珠單抗(matuzumab)。EGFR的小分子拮抗劑包括吉非替尼、厄洛替尼(特羅凱(Tarceva))和最近的拉帕替尼(lapatinib)(泰克博(TykerB))。參見例如Yan L等人,Pharmacogenetics and Pharmacogenomics In Oncology Therapeutic Antibody Development[腫瘤治療抗體開發中的藥物遺傳學和藥物基因組學], BioTechniques[生物技術] 2005;39(4): 565-8和Paez J G等人,EGFR Mutations In Lung Cancer Correlation With Clinical Response To Gefitinib Therapy[肺癌中的EGFR突變與對吉非替尼療法的臨床反應的相關性], Science[科學] 2004; 304(5676): 1497-500。
小分子EGFR抑制劑的非限制性實例包括以下專利公開案中描述的任何EGFR抑制劑、以及所述EGFR抑制劑的所有藥學上可接受的鹽和溶劑化物:歐洲專利申請案EP 520722,1992年12月30日公開;歐洲專利申請案EP 566226,1993年10月20日公開;PCT國際公開案WO 96/33980,1996年10月31日公開;美國專利案號5,747,498,1998年5月5日授權;PCT國際公開案WO 96/30347,1996年10月3日公開;歐洲專利申請案EP 787772,1997年8月6日公開;PCT國際公開案WO 97/30034,1997年8月21日公開;PCT國際公開案WO 97/30044,1997年8月21日公開;PCT國際公開案WO 97/38994,1997年10月23日公開;PCT國際公開案WO 97/49688,1997年12月31日公開;歐洲專利申請案EP 837063,1998年4月22日公開;PCT國際公開案WO 98/02434,1998年1月22日公開;PCT國際公開案WO 97/38983,1997年10月23日公開;PCT國際公開案WO 95/19774,1995年7月27日公開;PCT國際公開案WO 95/19970,1995年7月27日公開;PCT國際公開案WO 97/13771,1997年4月17日公開;PCT國際公開案WO 98/02437,1998年1月22日公開;PCT國際公開案WO 98/02438,1998年1月22日公開;PCT國際公開案WO 97/32881,1997年9月12日公開;德國申請案DE 19629652,1998年1月29日公開;PCT國際公開案WO 98/33798,1998年8月6日公開;PCT國際公開案WO 97/32880,1997年9月12日公開;PCT國際公開案WO 97/32880,1997年9月12日公開;歐洲專利申請案EP 682027,1995年11月15日公開;PCT國際公開案WO 97/02266,197年1月23日公開;PCT國際公開案WO 97/27199,1997年7月31日公開;PCT國際公開案WO 98/07726,1998年2月26日公開;PCT國際公開案WO 97/34895,1997年9月25日公開;PCT國際公開案WO 96/31510',1996年10月10日公開;PCT國際公開案WO 98/14449,1998年4月9日公開;PCT國際公開案WO 98/14450,1998年4月9日公開;PCT國際公開案WO 98/14451,1998年4月9日公開;PCT國際公開案WO 95/09847,1995年4月13日公開;PCT國際公開案WO 97/19065,1997年5月29日公開;PCT國際公開案WO 98/17662,1998年4月30日公開;美國專利案號5,789,427,1998年8月4日授權;美國專利案號5,650,415,1997年7月22日授權;美國專利案號5,656,643,1997年8月12日授權;PCT國際公開案WO 99/35146,1999年7月15日公開;PCT國際公開案WO 99/35132,1999年7月15日公開;PCT國際公開案WO 99/07701,1999年2月18日公開;和PCT國際公開案WO 92/20642,1992年11月26日公開。小分子EGFR抑制劑的其他非限制性實例包括描述於Traxler, P., 1998, Exp. Opin. Ther. Patents [治療術專利專家評述] 8(12):1599-1625中的任何EGFR抑制劑。
基於抗體的EGFR抑制劑包括可以部分或完全阻斷EGFR被其天然配位基激活的任何抗EGFR抗體或抗體片段。基於抗體的EGFR抑制劑的非限制性實例包括以下文獻中描述的那些:Modjtahedi, H.等人, 1993, Br. J. Cancer [英國癌症雜誌] 67:247-253;Teramoto, T.等人, 1996, Cancer [癌症] 77:639-645;Goldstein等人, 1995, Clin. Cancer Res. [臨床癌症研究] 1:1311-1318;Huang, S. M.等人, 1999, Cancer Res. [癌症研究] 15:59(8):1935-40;和Yang, X.等人, 1999, Cancer Res. [癌症研究] 59:1236-1243。因此,EGFR抑制劑可以是單株抗體Mab E7.6.3(Yang, 1999,同上)、或Mab C225(ATCC登錄號HB-8508)、或具有其結合特異性的抗體或抗體片段。
MEK抑制劑包括但不限於CI-1040、AZD6244、PD318088、PD98059、PD334581、RDEA119、ARRY-142886、ARRY-438162和PD-325901。
PI3K抑制劑包括但不限於渥曼青黴素、WO 06/044453中描述的17-羥基渥曼青黴素類似物、4-[2-(1H-吲唑-4-基)-6-[[4-(甲磺醯基)哌𠯤-1-基]甲基]噻吩并[3,2-d]嘧啶-4-基]𠰌啉(還稱為GDC 0941,並且描述於PCT公開案號WO 09/036,082和WO 09/055,730中)、2-甲基-2-[4-[3-甲基-2-側氧基-8-(喹啉-3-基)-2,3-二氫咪唑并[4,5-c]喹啉-1-基]苯基]丙腈(還稱為BEZ 235或NVP-BEZ 235,並且描述於PCT公開案號WO 06/122806中)、(S)-1-(4-((2-(2-胺基嘧啶-5-基)-7-甲基-4-𠰌啉代噻吩并[3,2-d]嘧啶-6-基)甲基)哌𠯤-1-基)-2-羥基丙-1-酮(描述於PCT公開案號WO 2008/070740中)、LY294002(2-(4-𠰌啉基)-8-苯基-4H-1-苯并哌喃-4-酮,可從艾克松醫學化學公司(Axon Medchem)獲得)、PI 103鹽酸鹽(3-[4-(4-𠰌啉基吡啶并-[3',2':4,5]呋喃并[3,2-d]嘧啶-2-基]苯酚鹽酸鹽,可從艾克松醫學化學公司獲得)、PIK 75(N'-[(1E)-(6-溴代咪唑并[1,2-a]吡啶-3-基)亞甲基]-N,2-二甲基-5-硝基苯磺醯基-醯肼鹽酸鹽,可從艾克松醫學化學公司獲得)、PIK 90(N-(7,8-二甲氧基-2,3-二氫-咪唑并[1,2-c]喹唑啉-5-基)-菸醯胺,可從艾克松醫學化學公司獲得)、GDC-0941二甲磺酸鹽(2-(1H-吲唑-4-基)-6-(4-甲烷磺醯基-哌𠯤-1-基甲基)-4-𠰌啉-4-基-噻吩并[3,2-d]嘧啶二甲磺酸鹽,可從艾克松醫學化學公司獲得)、AS-252424(5-[1-[5-(4-氟-2-羥基-苯基)-呋喃-2-基]-甲-(Z)-亞基]-四氫噻唑-2,4-二酮,可從艾克松醫學化學公司獲得)以及TGX-221(7-甲基-2-(4-𠰌啉基)-9-[1-(苯基胺基)乙基]-4H-吡啶并-[1,2-a]嘧啶-4-酮,可從艾克松醫學化學公司獲得)、XL-765和XL-147。其他PI3K抑制劑包括去甲氧基綠膠黴素(demethoxyviridin)、哌立福辛、CAL101、PX-866、BEZ235、SF1126、INK1117、IPI-145、BKM120、XL147、XL765、帕羅米德529(Palomid 529)、GSK1059615、ZSTK474、PWT33597、IC87114、TG100-115、CAL263、PI-103、GNE-477、CUDC-907和AEZS-136。
AKT抑制劑包括但不限於Akt-1-1(抑制Akt1)(Barnett等人 (2005) Biochem. J. [生物化學雜誌], 385 (Pt. 2), 399-408);Akt-1-1,2(抑制Ak1和2)(Barnett等人 (2005) Biochem. J. [生物化學雜誌] 385 (Pt. 2), 399-408);API-59CJ-Ome(例如,Jin等人 (2004) Br. J. Cancer [英國癌症雜誌] 91, 1808-12);1-H-咪唑并[4,5-c]吡啶基化合物(例如,WO 05011700);吲哚-3-甲醇及其衍生物(例如,美國專利案號6,656,963;Sarkar和Li (2004) J Nutr.[營養雜誌]134(12增刊), 3493S-3498S);哌立福辛(perifosine)(例如,干擾Akt膜定位;Dasmahapatra等人, (2004) Clin. Cancer Res.[臨床癌症研究] 10(15), 5242-52, 2004);磷脂醯肌醇醚脂質類似物(例如Gills和Dennis (2004) Expert.Opin. Investig.Drugs[研究藥物專家評論] 13, 787-97);和曲西立濱(triciribine)(TCN或API-2或NCI鑒定劑:NSC 154020;Yang等人, 2004, Cancer Res. [癌症研究] 64:4394-9)。
TOR抑制劑包括但不限於,抑制劑包括AP-23573、CCI-779、依維莫司、RAD-001、雷帕黴素、替西羅莫司、ATP競爭性TORC1/TORC2抑制劑,包括PI-103、PP242、PP30和托林1(Torin 1)。其他TOR抑制劑包括FKBP12增強劑;雷帕黴素及其衍生物,包括:CCI-779(替西羅莫司)、RAD001(依維莫司;WO 9409010)和AP23573;雷帕黴素類似物(rapalog),例如如WO 98/02441和WO 01/14387中所揭露,例如AP23573、AP23464或AP23841;40-(2-羥乙基)雷帕黴素、40-[3-羥基(羥甲基)甲基丙酸酯]-雷帕黴素(還稱為CC1779)、40-表-(四唑基)-雷帕黴素(還稱為ABT578)、32-去氧雷帕黴素、16-戊炔氧基-32(S)-二氫雷帕黴素和WO 05005434中揭露的其他衍生物;以下專利中揭露的衍生物:美國專利案號5,258,389、WO 94/090101、WO 92/05179、美國專利案號5,118,677、美國專利案號5,118,678、美國專利案號5,100,883、美國專利案號5,151,413、美國專利案號5,120,842、WO 93/111130、WO 94/02136、WO 94/02485、WO 95/14023、WO 94/02136、WO 95/16691、WO 96/41807、WO 96/41807和美國專利案號5,256,790;含磷雷帕黴素衍生物(例如,WO 05016252);4H-1-苯并哌喃-4-酮衍生物(例如,美國臨時申請案號60/528,340)。
免疫療法包括但不限於抗PD-1劑、抗PDL-1劑、抗CTLA-4劑、抗LAG1劑和抗OX40劑。示例性抗PD-1抗體及其使用方法描述於以下文獻中:Goldberg等人, Blood [血液] 110(1):186-192 (2007);Thompson等人, Clin. Cancer Res. [臨床癌症研究] 13(6):1757-1761 (2007);和Korman等人, 國際申請案號PCT/JP 2006/309606(公開案號WO 2006/121168 A1),將其各自藉由引用明確併入本文。包括:Yervoy™(伊匹單抗(ipilimumab))或曲美目單抗(Tremelimumab)(針對CTLA-4)、加利昔單抗(galiximab)(針對B7.1)、BMS-936558(針對PD-1)、MK-3475(針對PD-1)、AMP224(針對B7DC)、BMS-936559(針對B7-H1)、MPDL3280A(針對B7-H1)、MEDI-570(針對ICOS)、AMG557(針對B7H2)、MGA271(針對B7H3)、IMP321(針對LAG-3)、BMS-663513(針對CD137)、PF-05082566(針對CD137)、CDX-1127(針對CD27)、抗OX40(普羅維登斯衛生服務(Providence Health Services))、huMAbOX40L(針對OX40L)、阿塞西普(Atacicept)(針對TACI)、CP-870893(針對CD40)、魯卡木單抗(Lucatumumab)(針對CD40)、達西珠單抗(Dacetuzumab)(針對CD40)、莫羅單抗-CD3(Muromonab-CD3)(針對CD3)、伊匹單抗(針對CTLA-4)。免疫療法還包括遺傳工程化的T細胞(例如,CAR-T細胞)和雙特異性抗體(例如,BiTE)。
GITR激動劑包括但不限於GITR融合蛋白和抗GITR抗體(例如二價抗GITR抗體),例如美國專利案號6,111,090box.c、歐洲專利案號:090505 B1、美國專利案號8,586,023、PCT公開號:WO 2010/003118和2011/090754中所述的GITR融合蛋白,或例如在以下中描述的抗GITR抗體:美國專利案號7,025,962、歐洲專利案號:1947183 B1、美國專利案號7,812,135、美國專利案號8,388,967、美國專利案號8,591,886、歐洲專利案號:EP 1866339、PCT公開號:WO 2011/028683、PCT公開號:WO 2013/039954、PCT公開號:WO 2005/007190、PCT公開號:WO 2007/133822、PCT公開號:WO 2005/055808、PCT公開號:WO 99/40196、PCT公開號:WO 2001/03720、PCT公開號:WO 99/20758、PCT公開號:WO 2006/083289、PCT公開號:WO 2005/115451、美國專利案號7,618,632和PCT公開號:WO 2011/051726。
本文所述的化合物可以與本文所揭露的藥劑或其他適合的藥劑組合使用,這取決於所治療的病症。因此,在一些實施方式中,本揭露的一種或多種化合物將與如上所述的其他藥劑共投與。在用於組合療法中時,本文所述的化合物與第二藥劑同時或分開投與。這種組合投與可以包括以相同劑型同時投與兩種藥劑、以單獨劑型同時投與和分開投與。也就係說,本文所述的化合物和上述任何藥劑可以一起配製於相同劑型中並同時投與。可替代地,本揭露的化合物和上述任何藥劑可以同時投與,其中兩種藥劑存在於單獨配製物中。在另一個替代方案中,可以在投與本揭露的化合物後立即投與上述任何藥劑,或反之亦然。在單獨投與方案的一些實施方式中,本揭露的化合物和上述任何藥劑的投與相隔幾分鐘,或相隔幾小時,或相隔幾天。
由於本發明的一個方面考慮了用可以分開投與的藥學活性化合物的組合治療疾病/病症,本發明進一步關於以套組(kit)形式組合單獨的藥物組成物。該套組包含兩種單獨的藥物組成物:本發明的化合物和第二藥物化合物。該套組包含用於容納單獨組成物的容器,例如分開的瓶子或分開的箔袋。容器的其他實例包括注射器、盒和袋。在一些實施方式中,該套組包含單獨組分的使用說明。在較佳的是以不同劑型(例如,口服和腸胃外)投與單獨組分時,以不同劑量間隔投與時,或在開方的醫護專業人員需要組合中個別組分的滴定時,套組形式特別有利。
實驗
縮寫:在本文可以使用以下縮寫:
ACN或MeCN | 乙腈 |
AcOH | 乙酸 |
aq或aq. | 水性 |
BOC或Boc | 三級丁氧基羰基 |
cataCXium® A | 外消旋-((3R ,5R ,7R )-金剛烷-1-基)((3S ,5S ,7S )-金剛烷-1-基)(丁基)膦 |
DABSO | 1,4-二氮雜雙環[2.2.2]辛烷雙(二氧化硫)加合物 |
DCE | 1,2-二氯乙烷 |
DCM | 二氯甲烷 |
DMAP | 4-二甲胺基吡啶 |
DMF | N,N -二甲基甲醯胺 |
DMSO | 二甲基亞碸 |
Dppf、DPPF或dppf | 1,1’-雙(二苯基膦基)二茂鐵 |
dppp | 1,3-雙(二苯基膦基)丙烷 |
eq或eq.或equiv. | 當量 |
ESI或ES | 電灑電離 |
Et | 乙基 |
Et2 O | 乙醚 |
EtOH | 乙醇 |
EtOAc | 乙酸乙酯 |
g | 克 |
h | 小時 |
HATU | 1-[雙(二甲基胺基)亞甲基]-1H -1,2,3-三唑并[4,5-b ]吡啶鎓3-氧化物六氟磷酸鹽 |
HPLC | 高壓液相層析 |
IPA | 異丙醇 |
iPr | 異丙基 |
iPr2 NEt或DIPEA | N- 乙基二異丙基胺(Hünig鹼) |
KOAc | 乙酸鉀 |
LDA | 二異丙基醯胺鋰 |
LC MS、LCMS、LC-MS或LC/MS | 液相層析質譜 |
LG | 脫離基脫離基(例如鹵素、甲磺酸酯、三氟甲磺酸酯) |
m/z | 質荷比 |
Me | 甲基 |
MeOH | 甲醇 |
Met | 用於交叉偶合的金屬種類(例如MgX、ZnX、SnR3 、SiR3 、B(OR)2 ) |
mg | 毫克 |
min | 分鐘 |
mL | 毫升 |
MS | 質譜 |
MsCl | 甲磺醯氯 |
MTBE | 三級丁基甲基醚 |
NMP | 1-甲基-2-吡咯啶 |
n -BuLi | N -丁基鋰 |
NMR | 核磁共振 |
Pd2 (dba)3 | 三(二亞苄基丙酮)二鈀(0) |
Pd(dppf)Cl2 ·DCM | [1,1'-雙(二苯基膦基)二茂鐵]二氯鈀(II)與二氯甲烷的錯合物 |
Pd(PPh3 )4 | 四(三苯基膦)鈀(0) |
Ph | 苯基 |
苯 | 1,10-鄰二氮雜菲 |
PR或PG或Prot.基團 | 保護基團 |
rbf | 圓底燒瓶 |
RP-HPLC | 反相高壓液相層析 |
RT或rt | 室溫 |
sat.或satd. | 飽和的 |
SFC | 超臨界流體層析 |
SPhos Pd G3或SPhos G3 | 甲磺酸(2-二環己基膦基-2',6'-二甲氧基聯苯基)[2-(2'-胺基-1,1'-聯苯)]鈀(II) |
TBAF | 四正丁基氟化銨 |
t-BuOH | 三級丁醇 |
TEA或Et3 N | 三甲胺 |
TFA | 三氟乙酸 |
THF | 四氫呋喃 |
TLC | 薄層層析法 |
T3 P | 2,4,6-三丙基-1,3,5,2,4,6-三氧雜三膦2,4,6-三氧化物 |
UV | 紫外 |
Xantphos | 4,5-雙(二苯基膦基)-9,9-二甲基呫噸 |
XtalFluor-M | 二氟(𠰌啉)四氟硼酸鋶 |
除非另有說明,否則所有材料均從市場供應商獲得,並且不經進一步純化即可使用。除非另有說明,所有份均以重量計,溫度以攝氏度為計。所有微波輔助反應均使用BiotageTM
的Smith SynthesizerTM
進行。所有化合物均顯示與其指定結構一致的NMR光譜。熔點係在Buchi裝置上確定的,並且未校正。質譜數據藉由電灑電離技術確定。如藉由高效液相層析法確定,所有實施方式均純化至 > 90%的純度。除非另有說明,否則反應在室溫下進行。
在合成本發明的化合物中,可以期望使用某些脫離基脫離基。術語「脫離基脫離基」(「LG」)通常是指可被親核試劑置換的基團。此類脫離基脫離基係本領域已知的。脫離基脫離基的實例包括但不限於鹵化物(例如I、Br、F、Cl)、磺酸鹽/酯例如甲磺酸鹽/酯、甲苯磺酸鹽/酯)、硫化物(例如SCH3
)、N-羥基琥珀醯亞胺、N-羥基苯并三唑等。親核試劑的實例包括但不限於胺、硫醇、醇、格氏試劑、陰離子種類(例如醇鹽、醯胺、碳負離子)等。
下文所呈現的實例說明本發明的具體實施方式。該等實例係代表性的,無意以任何方式限制申請專利範圍的範圍。
應注意,當關於液體使用百分比(%)時,這係相對於溶液的體積百分比。當與固體一起使用時,這係相對於固體組成物的百分比。從市場供應商獲得的材料通常不經進一步純化即可使用。涉及空氣或濕氣敏感試劑的反應通常在氮氣或氬氣氣氛下進行。純度使用高效液相層析法(HPLC)系統用在254 nm和215 nm處的UV檢測(系統A:Agilent Zorbax Eclipse XDB-C8 4.6 x 150 mm, 5 µm, 5%至100% CH3
CN(在含0.1% TFA的H2
O中),15 min,1.5 mL/min;系統B:Zorbax SB-C8,4.6 x 75 mm,10%至90% CH3
CN(在含0.1%甲酸的H2
O中),12 min,1.0 mL/min)(加利福尼亞州聖克拉拉市安捷倫科技公司(Agilent Technologies,Santa Clara,CA))來測量。矽膠層析法通常使用預裝的矽膠筒(瑞典烏普薩拉Biotage(Biotage, Uppsala, Sweden)或內布拉斯加州林肯Teledyne-Isco(Teledyne-Isco,Lincoln,NE))進行。1
H NMR光譜在環境溫度下在Bruker AV-400(400 MHz)光譜儀(威斯康辛州麥迪森布魯克公司(Bruker Corporation,Madison,WI))或Varian(加利福尼亞州聖克拉拉市安捷倫科技公司(Agilent Technologies,Santa Clara,CA))400 MHz光譜儀上記錄。所有觀察到的質子均以四甲基矽烷(TMS)或其他內部參照在指定的適當溶劑中的低磁場以百萬分率(ppm)報告。數據包告如下:化學位移、多重性(s = 單重峰,d = 雙重峰,t = 三重峰,q = 四重峰,br = 寬峰,m = 多重峰)、耦合常數和質子數。低分辨質譜(MS)數據係在Agilent 1100系列(加利福尼亞州聖克拉拉市安捷倫科技公司(Agilent Technologies,Santa Clara,CA))LC/MS上用在254 nm和215 nm處的UV檢測和低共振電灑模式(ESI)確定的。
在該一般合成部分中出於清楚目的,在本發明的發明內容中定義的式 (I) 化合物可以示意性地繪製以包含Ar1
環和Ar2
環,如下:;其中基團-NR3
-(C=O)-為連接基,Ar1
環位於連接基左側,並且Ar2
環位於連接基右側。
通常,式 (I) 化合物可以藉由以下三個一般步驟如下合成:
步驟1:製備環Ar1
化合物
步驟2:製備環Ar2化合物
步驟3:將環Ar1
化合物與環Ar2
化合物偶合
下文的一般方案A-E意指向普通合成化學家提供指導,他們將容易瞭解,可以視需要修改溶劑、濃度、試劑、保護基團、合成步驟的順序、時間、溫度等,該等完全在熟悉該項技術者的技術和判斷範圍內。
方案A
根據方案A,在一個實施方式中如本文所揭露的式 (I) 化合物可以如下合成:
步驟1a:製備環Ar1
化合物
步驟1a:製備環Ar1
化合物可以在合適的鹼存在下在合適的有機溶劑例如NMP、二㗁𠮿、乙腈、四氫呋喃、DMF、二氯甲烷等中將化合物A-1
(其中W1
為鹵素,例如氟或氯)與含R2
基團的試劑反應以形成化合物A-2
。化合物A-1
可商購獲得或可以由熟悉該項技術者藉由已知方法合成。化合物A-1
的實例包括但不限於2-氯嘧啶-4-胺、2-氯-6-甲基嘧啶-4-胺、2-氟-6-甲基吡啶-4-胺、2-氯吡啶-4-胺、2-氯-6-甲基吡啶-4-胺、2-氯-6-乙基嘧啶-4-胺或2-氯-6-環丙基嘧啶-4-胺。R2
試劑的實例包括但不限於(1)(R
)-2-甲基𠰌啉、(2) 4,4-二氟哌啶鹽酸鹽、(3) 3,3-二氟氮雜環丁烷鹽酸鹽或 (4) 3,3,3-三氟丙烷-1-醇。鹼的實例包括但不限於二異丙基乙胺、碳酸鉀或氫化鈉。
步驟1b:製備環Ar1
化合物
可替代地,可以藉由與合適的有機硼R2
試劑(R2
-BY2
,其中Y為有機官能基,例如2-(4,4-二氟環己-1-烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷或2-(4-氟環戊-1-烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧雜硼烷)和合適的鈀催化劑和鹼(例如PdCl2
(dppf)-DCM加合物和磷酸三鉀)進行鈴木交叉偶合反應將入步驟1a中定義的化合物A-1
轉化為如步驟1a中定義的化合物A-2
。該步驟之後,在氫氣存在下用合適的鈀催化劑和氫氣源(例如Pd/C)進行還原以形成化合物A-2 。
當R2
基團藉由碳-碳鍵與Ar1
環連接時,可以使用該可替代的鈴木反應。
步驟2a:製備環Ar2
化合物
在步驟2a中,可以在合適的有機溶劑(例如NMP、乙腈、四氫呋喃、DMF、二氯甲烷、DMSO等)中將化合物A-3
(其中W2
和W3
中每一個獨立地為鹵素,例如氟、氯、溴或碘)與Rx
試劑(例如 (1) 6-氮雜螺[2.5]辛烷鹽酸鹽、(2) 4,4-二甲基哌啶鹽酸鹽、(3) 3,4,4-三甲基哌啶鹽酸鹽、(4) 4-甲基-6-氮雜螺[2.5]辛烷鹽酸鹽或 (5) 7-氮雜螺[3.5]壬烷鹽酸鹽)反應以形成化合物A-4
。
步驟3a:將環Ar1
化合物與環Ar2
化合物偶合,隨後引入R1
:
在步驟3a中,可以在合適的有機溶劑(例如四氫呋喃、二氯甲烷等)中將從步驟2a獲得的化合物A-4
與活化劑(例如醯基氯(COCl)2
或SOCl2
)反應以形成醯基氯衍生物,然後可以將其與化合物A-2
反應形成化合物A-5
。可替代地,可以在偶合試劑(例如N,N'-二異丙基碳二亞胺、N-(3-二甲基胺基丙基)-N'-乙基碳二亞胺、苯并三唑-1-基-氧三吡咯啶基六氟磷酸鏻、O
-(苯并三唑-1-基)-N,N,N',N’四甲基脲六氟磷酸鹽、羰基二咪唑和多膦酸酐)存在下在合適的有機溶劑(例如乙腈、四氫呋喃、DMF、二氯甲烷等)中將化合物A-2
與從步驟2a獲得的化合物A-4
直接偶合。那些普通合成化學家將容易理解,可以使用其他偶合劑。可以藉由在合適的有機溶劑(例如DMSO、乙腈、四氫呋喃、DMF等)中在金屬催化劑和R1
試劑存在下的轉化反應(例如金屬催化的磺醯胺化、硫化或磺醯化)進一步處理鹵素基團W3
來形成化合物 (I),該R1
試劑例如 (1) 1-甲基環丙烷-1-磺醯胺、(2) 3-甲基氧雜環丁烷-3-胺、(3) 三級丁基3-巰基氮雜環丁烷-1-甲酸酯、(4) 2-胺磺醯基丙酸乙酯、(5) 2-羥基丙烷-1-磺醯胺、(6) 2-羥基乙烷-1-磺醯胺、(7) 碘乙酸乙酯、(8) 2-巰基丙烷-1-醇、(9) 2-巰基-2-甲基丙烷-1-醇、(10) 2-胺基乙-1-醇或 (11) 環丙烷硫醇。那些普通化學家將容易理解,偶合反應(例如如步驟3a所示的)可以在多種已知條件下進行。
方案B
步驟1a或1b:製備環Ar1
化合物參見以上方案A
步驟2b:製備環Ar2
化合物
方案B提供用於形成本文所揭露的式 (I) 之化合物的替代性方法。在如方案A中描述的步驟1a或步驟1b之後,可以可替代地將R1
基團在步驟2b中引入到環Ar2
中,而不是在方案A的步驟3a中引入。根據步驟2b,可以在鹼(例如碳酸鉀)存在下將化合物B-1
(其中W4
和W5
中每一個獨立地為鹵素,例如氟、氯、溴或碘)與適當的羧酸保護基團(PG1
試劑,例如碘甲烷)反應以形成甲酯或在合適的有機溶劑(例如NMP、乙腈、四氫呋喃、DMF、二氯甲烷等)中與其他合適的保護基團反應以形成其他酯(例如苄基酯),以形成化合物B-2
,其中W4
和W5
中每一個如化合物B-1
中定義的。然後,可以在合適的有機溶劑(例如NMP、乙腈、四氫呋喃、DMF、二氯甲烷、DMSO等)中將化合物B-2
與Rx
試劑(例如6-氮雜螺[2.5]辛烷)反應以形成化合物B-3
,其中W5
係如化合物B-1
中定義的。然後,可以在金屬催化劑(例如碘化銅、Pd2
(dba)3
)存在下在合適的有機溶劑(例如DMSO、乙腈、四氫呋喃、DMF等)中藉由轉化反應(例如金屬催化的磺醯胺化、硫化或磺醯化)將化合物B-3
與R1
試劑反應以形成化合物B-4
,然後可以將其與適當的羧酸脫保護劑進一步反應以形成化合物B-5
。適當的羧酸保護基團和脫保護劑係熟悉該項技術者已知的,例如如有機合成中的Greene保護基團中所討論的。
步驟3b:將環Ar1
化合物與環Ar2
化合物偶合
步驟3b與如以上在步驟3a中所述的偶合反應類似。
方案C
方案C提供用於形成本文所揭露的式 (I) 之化合物的另一替代性方法。根據方案C,步驟1a可以如在方案A中所述的進行,隨後進行如在方案B中所述的步驟2b。
步驟3c:將環Ar1
化合物與環Ar2
化合物偶合
在步驟3c中,可以在與以上步驟3a和3b類似的條件下在活化劑存在下將化合物A-1a
(其為方案A的化合物A-1
,其中X1
為N且W1
為鹵素,例如氟或氯)與從方案B的步驟2b獲得的化合物B-5
反應以形成化合物C-1
,其中W1
係如化合物A-1a
中定義的,然後可以在合適的鹼(例如二異丙基乙胺、碳酸鉀或氫化鈉)存在下在合適的有機溶劑(例如NMP、二㗁𠮿、乙腈、四氫呋喃、DMF、二氯甲烷等)中將其與含R2
基團的試劑反應以形成式 (I) 之化合物,該含R2
基團的試劑例如 (1) (R
)-2-甲基𠰌啉、(2) 4,4-二氟哌啶鹽酸鹽、(3) 3,3-二氟氮雜環丁烷鹽酸鹽或 (4) 3,3,3-三氟丙-1-醇。
方案D
方案D提供用於形成本文所揭露的式 (I) 之化合物的另一替代性方法。根據方案D,步驟1a或1b可以如在方案A中所述的進行,隨後進行如在方案B中所述的步驟2b。
步驟3d:將環Ar1
化合物與環Ar2
化合物偶合
在步驟3d中,可以在與以上步驟3a和3b類似的條件下在活化劑存在下將化合物A-1a
(其為方案A的化合物A-1
,其中X1
為N並且W1
為鹵素,例如氟或氯)可以與從方案A的步驟2a獲得的化合物B-5
反應以形成化合物D-1
,其中W1
係如化合物A-1a
中定義的並且W3
係如化合物B-5
中定義的,然後可以視需要在合適的鹼(例如二異丙基乙胺、碳酸鉀或氫化鈉)存在下在合適的有機溶劑(例如NMP、二㗁𠮿、乙腈、四氫呋喃、DMF、二氯甲烷等)中將其與含R2
基團的試劑(例如 (1) (R
)-2-甲基𠰌啉、(2) 4,4-二氟哌啶鹽酸鹽、(3) 3,3-二氟氮雜環丁烷鹽酸鹽或 (4) 3,3,3-三氟丙烷-1-醇)反應以形成化合物A-5a
,即化合物A-5
,其中X1
為N並且W3
係如化合物B-5
中定義的,然後可以在金屬催化劑的存在下在合適的有機溶劑(例如DMSO、乙腈、四氫呋喃、DMF等)中藉由轉化反應(例如金屬催化的磺醯胺化、硫化或磺醯化)將其與含R1
基團的試劑反應以形成式 (I) 化合物。
方案E
方案E提供用於形成本文所揭露的式 (I) 之化合物的另一替代性方法。根據方案E,步驟1a或1b可以如在方案A中所述的進行以製備化合物A-2
。化合物E-1
(其中W6
為鹵素,例如氟或氯,其包括但不限於2-氟-4-硝基苯甲酸、2,5-二氟-4-硝基苯甲酸或2,6-二氟-4-硝基苯甲酸)係可商購獲得的或可以由熟悉該項技術者根據已知方法合成。
步驟3e:將環Ar1化合物與環Ar2
化合物偶合
在步驟3e中,可以與以上步驟3a和3b類似的條件下在活化劑存在下將化合物A-2
與化合物E-1
反應以形成化合物E-2
,然後可以將其以與步驟2a中所述方式類似的方式與Rx
試劑反應以形成化合物E-3
。然後可以藉由與還原劑(其包括但不限於鈀碳和氫氣)反應將化合物E-4
上的硝基轉化為胺基以形成化合物E-4,然後可以在金屬催化劑的存在下在合適的有機溶劑(如DMSO、乙腈、四氫呋喃、DMF等)中藉由轉化反應(例如金屬催化的磺醯胺化、硫化或磺醯化)將其與R1
試劑反應以形成化合物 (I),該R1
試劑例如 (1) 1-甲基環丙烷-1-磺醯胺、(2) 3-甲基氧雜環丁烷-3-胺、(3) 三級丁基3-巰基氮雜環丁烷-1-甲酸酯、(4) 2-胺磺醯基丙酸乙酯、(5) 2-羥基丙烷-1-磺醯胺、(6) 2-羥基乙烷-1-磺醯胺、(7) 碘乙酸乙酯、(8) 2-巰基丙烷-1-醇、(9) 2-巰基-2-甲基丙烷-1-醇、(10) 2-胺基乙-1-醇或 (11) 環丙烷硫醇。
實例
合成中間體的製備
環AR1
中間體:
中間體1:(R
)-2-(2-甲基𠰌啉)嘧啶-4-胺
將在NMP(600 mL)中的2-氯嘧啶-4-胺(60.0 g,463 mmol,加利福尼亞聖地牙哥康比樂公司(Combi-Blocks, San Diego, CA))、(R
)-2-甲基𠰌啉(65.6 g,648 mmol,藥明康得公司(Wuxi Apptec))和DIPEA(243 mL,1389 mmol)置於高壓釜中,並在150°C下加熱36 h。將反應混合物冷卻至室溫,用水(1 L)淬滅並用乙酸乙酯(3 x 500 mL)萃取。將有機層用鹽水溶液(500 mL)洗滌,乾燥(Na2
SO4
),過濾並在減壓下濃縮,以得到呈棕黃色油的粗物質。將該粗物質吸附到矽膠塞上,並藉由柱層析法在矽膠(60-120目)上進行純化,用在己烷中的50%至100%乙酸乙酯梯度洗脫,以得到黃色固體。將該固體進一步用己烷(300 mL)研磨,過濾並在真空中乾燥,以得到呈淺黃色固體的標題化合物(70 g,78%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 7.75 (d,J
= 5.6 Hz, 1H), 6.42 (s, 2H), 5.75 (d,J
= 5.6 Hz, 1H), 4.26 - 4.49 (m, 2H), 3.83 (ddd,J
= 11.4, 3.6, 1.4 Hz, 1H), 3.31 - 3.50 (m, 2H), 2.78 (ddd,J
= 13.2, 11.8, 3.5 Hz, 1H), 2.42 - 2.48 (m, 1H), 1.11 (d,J
= 6.2 Hz, 3H)。m/z
(ESI): 195.2 (M+H)+
。
中間體2:(R
)-6-甲基-2-(2-甲基𠰌啉)嘧啶-4-胺
將2-氯-6-甲基嘧啶-4-胺(30.0 g,209 mmol,加利福尼亞聖地牙哥康比樂公司(Combi-Blocks, San Diego, CA))、(R
)-2-甲基𠰌啉(40.3 g,293 mmol,中國藥明康得公司(Wuxi Apptec, PR China))和DIPEA(109 mL,627 mmol)置於高壓釜(600 mL)中,並在150°C下加熱12 h。將反應混合物用水(500 mL)淬滅並用乙酸乙酯(2 x 1500 mL)萃取。將有機層用鹽水溶液(500 mL)洗滌,乾燥(Na2
SO4
),過濾並在減壓下濃縮。將粗殘餘物藉由柱層析法在矽膠(60-120目)上使用在己烷中的50%乙酸乙酯作為洗脫液進行純化,以得到呈黃色固體的標題化合物(25.0 g,57%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ 6.28 (s, 2H), 5.62 (s, 1H), 4.45 - 4.31 (m, 2H), 3.83 (ddd,J
= 11.4, 3.5, 1.3 Hz, 1H), 3.42 (ddt,J
= 14.4, 9.7, 2.8 Hz, 2H), 2.78 - 2.70 (m, 1H), 2.43 (dd,J
= 13.0, 10.3 Hz, 1H), 2.05 (s, 3H), 1.11 (d,J
= 6.2 Hz, 3H)。m/z
(ESI): 209.2 (M+H)+
。
中間體3:2-(4,4-二氟哌啶-1-基)嘧啶-4-胺
在玻璃微波反應容器中依次裝入在NMP(12 mL)中的2-氯-4-胺基嘧啶(1.0 g,7.7 mmol,加利福尼亞聖地牙哥康比樂公司(Combi-Blocks, San Diego, CA))、4,4-二氟哌啶鹽酸鹽(1.82 g,11.58 mmol,加利福尼亞聖地牙哥康比樂公司(Combi-Blocks, San Diego, CA))和DIPEA(4.04 mL,23.2 mmol)。將反應混合物攪拌並在200°C下微波加熱1 h。將該反應混合物用水(50 mL)稀釋,用乙酸乙酯(30 x 2 mL)萃取。有機萃取物用鹽水(30 x mL)洗滌,經Na2
SO4
乾燥,在真空中濃縮,以得到呈褐色黏稠液體的粗物質。將該粗物質吸附到矽膠塞上,並藉由快速層析法經Redi-Sep預填充矽膠柱(40 g)進行純化,用在庚烷中的0%至100%乙酸乙酯洗脫,以得到呈灰白色固體的標題化合物(6.02 g,91%)。1
H NMR (300 MHz, DMSO-d 6
) δ ppm 7.21 (d,J
= 5.6 Hz, 1H), 6.46 (br s, 2H), 5.77 (d,J
= 5.6 Hz, 1H), 3.80 (t,J
= 5.6 Hz, 4H), 1.85-1.90 (m, 4H)。m/z
(ESI): 215.2 (M+H)+
。
中間體4:2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-胺
將在NMP(460 mL,10.00 mL/g)中的2-氯-6-甲基嘧啶-4-胺(46 g,320 mmol,加利福尼亞聖地牙哥康比樂公司(Combi-Blocks, San Diego, CA))、4,4-二氟哌啶鹽酸鹽(76 g,481 mmol,加利福尼亞聖地牙哥康比樂公司(Combi-Blocks, San Diego, CA))和DIPEA(166 mL,961 mmol)置於高壓釜(1 L)中,並在180°C下加熱30 h。將反應混合物冷卻至室溫並用水(500 mL)淬滅,用乙酸乙酯(2 x 1000 mL)萃取。將有機層用鹽水(500 mL)洗滌,乾燥(Na2
SO4
),過濾並在減壓下濃縮。將該粗物質吸附到矽膠塞上,並藉由柱層析法在矽膠(60-120目)上進行純化,用在己烷中的50%至100%乙酸乙酯作為洗脫液洗脫,以得到產物。將其重溶解於乙酸乙酯(500 mL),用水(2 x 500 mL)洗滌。將有機層乾燥(Na2
SO4
),過濾並在減壓下濃縮。將黃色固體再次懸浮在己烷(400mL)中,並攪拌30 min。將漿料過濾,用己烷(100 mL)洗滌,在真空中乾燥,以提供呈淺黃色固體的標題化合物(58 g,79%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 6.33 (s, 2H), 5.63 (s, 1H), 3.80 - 3.78 (dd,J
= 6.8, 4.7 Hz, 4H), 2.06 (s, 3H), 1.95 - 1.85 (tt,J
= 14.2, 5.7 Hz, 4H)。m/z
(ESI): 229.2 (M+H)+
。
中間體5:2-(3,3-二氟氮雜環丁烷-1-基)嘧啶-4-胺
將在二㗁𠮿(25 mL)中的2-氯-4-胺基嘧啶(5.0 g,38.6 mmol,加利福尼亞聖地牙哥康比樂公司(Combi-Blocks, San Diego, CA))、3,3-二氟氮雜環丁烷鹽酸鹽(7.50 g,57.9 mmol,加利福尼亞聖地牙哥康比樂公司(Combi-Blocks, San Diego, CA))和碳酸鉀(5.33 g,38.6 mmol)在95°C下加熱16 h。將反應混合物冷卻至室溫並將懸浮液過濾。將該粗物質吸附到矽膠塞上,並藉由快速層析法經Redi-Sep預填充矽膠柱(40 g)進行純化,用在DCM中的10% MeOH洗脫,以提供呈淺棕色固體的標題化合物(6.1 g,85%)。1
H NMR (300 MHz, DMSO-d 6
) δ ppm 8.29-8.66 (m, 2H), 7.81 (d,J
= 7.05 Hz, 1H), 6.22 (d,J
= 7.26 Hz, 1H), 4.61 (t,J
= 12.23 Hz, 4H)。m/z
(ESI): 187.2 (M+H)+
。
中間體6:2-(4,4-二氟環己基)-6-甲基嘧啶-4-胺
步驟1:向在1,4-二㗁𠮿(560 mL)和水(210 mL)中的2-氯-6-甲基嘧啶-4-胺(70.0 g,488 mmol,加利福尼亞聖地牙哥康比樂公司(Combi-Blocks, San Diego, CA))溶液中添加2-(4,4-二氟環己-1-烯-1-基)-4,4,5,5-四甲基-1,3,2-二氧硼戊環(119 g,488 mmol,加利福尼亞聖地牙哥康比樂公司(Combi-Blocks, San Diego, CA))和磷酸三鉀(310 g,1463 mmol)。將反應混合物脫氣並用氮氣吹掃5 min。向該反應混合物中添加PdCl2
(dppf)-DCM加合物(39.8 g,48.8 mmol),並在100°C下攪拌16 h。通過CELITE®床過濾深色的不均勻混合物,並用乙酸乙酯(2 x 1000 mL)洗滌濾餅。將濾液用1N NaOH溶液(300 mL)洗滌,隨後用水(500 mL)洗滌。將有機層乾燥(Na2
SO4
),過濾並在減壓下濃縮。將粗殘餘物吸附到矽膠塞上,並藉由柱層析法在矽膠(60-120目)上進行純化,用在己烷中的50%至60%乙酸乙酯梯度洗脫,以得到呈淺黃色固體的2-(4,4-二氟環己-1-烯-1-基)-6-甲基嘧啶-4-胺(70 g,64%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 6.85 (br s, 1H), 6.59 (br s, 2H), 6.13 (s, 1H), 2.62 - 2.80 (m, 4H), 2.19 (s, 3H), 2.04 - 2.17 (m, 2H)。m/z
(ESI): 226.2 (M+H)+
。
步驟2:向在EtOH(700 mL)中的2-(4,4-二氟環己-1-烯-1-基)-6-甲基嘧啶-4-胺(70.0 g,311 mmol)溶液中在氮氣下添加在碳上的10% Pd(33.1 g,155 mmol)。將反應混合物在氫壓(1 atm)下在室溫下攪拌16 h。通過CELITE®床過濾反應混合物,並用乙酸乙酯和乙醇的混合物(1 : 1,500 mL)洗滌。將濾液在減壓下濃縮。將粗產物藉由柱層析法在矽膠(60-120目)上使用在己烷中的50%乙酸乙酯進行純化,以得到呈灰白色固體的標題化合物(58.5 g,83%產率)。1
H NMR (400 MHz, DMSO-d 6
)δ
ppm 6.61 (s, 2H), 6.09 (s, 1H), 2.56 - 2.67 (m, 1H), 2.16 (s, 3H), 1.72 - 2.10 (m, 8H)。m/z
(ESI): 228.1 (M+H)+
。
中間體
7
:
2-
甲基
-6-(3,3,3-
三氟丙氧基
)
吡啶
-4-
胺
在0°C下,向在30 mL THF中的3,3,3-三氟丙-1-醇(1.99 g,17.44 mmol,康比樂公司(Combi-Blocks))溶液中添加氫化鈉(在礦物油中的60重量%,0.79 g,19.82 mmol)。將混合物在室溫下攪拌30 min,然後用2-氟-6-甲基吡啶-4-胺(1.00 g,7.93 mmol,愛斯特公司(AstaTech Inc))處理。將混合物在油浴中在65°C下加熱5 h。將其冷卻至室溫,用水(10 mL)淬滅並用EtOAc(2 x 50 mL)萃取。將有機溶液經Na2
SO4
乾燥,過濾並在真空中濃縮,以得到呈黃色油的粗物質。將粗物質吸附到矽膠塞上,並在矽膠柱上(在庚烷中的15%至30% EtOAc)純化,以得到呈淺黃色油的2-甲基-6-(3,3,3-三氟丙氧基)吡啶-4-胺(0.47 g,2.13 mmol,27%產率)。m/z
(ESI): 221.1 (M+H)+
。
[表1]:以下中間體按照中間體7的類似程序來製備:
中間體編號 | 化學結構 | 名稱 | LRMS: (ESI+ve離子)m/z |
7-1 | 6-甲基-2-(3,3,3-三氟丙氧基)嘧啶-4-胺 | 222.0 |
中間體8:2-(4,4-二氟哌啶-1-基)吡啶-4-胺
將在NMP(6 mL)中的2-氯吡啶-4-胺(2.00 g,15.56 mmol,康比樂公司(Combi-Blocks))、DIPEA(6.03 g,46.70 mmol,西格瑪奧德里奇公司(Sigma-Aldrich))和4,4-二氟哌啶(2.45 g,20.22 mmol,恩納公司(Enamine))的混合物在200°C下微波加熱6 h。將反應混合物用水(20 mL)稀釋並用EtOAc (2 x 50 mL)萃取。將有機萃取物濃縮。殘餘物藉由矽膠層析法(在庚烷中的20%至70% EtOAc)純化,以提供呈淺黃色固體的2-(4,4-二氟哌啶-1-基)吡啶-4-胺(2.91 g,13.65 mmol,88%產率)。m/z
(ESI): (M+H)+
214.1。
[表2]:以下中間體按照如關於中間體8所述的類似程序來製備:
中間體編號 | 化學結構 | 名稱 | LRMS: (ESI+ve離子)m/z |
8-1 | 2-(4,4-二氟哌啶-1-基)-6-甲基吡啶-4-胺 | 228.2 | |
8-2 | 2-(4,4-二氟哌啶-1-基)-6-乙基嘧啶-4-胺 | 243.1 | |
8-3 | 6-環丙基-2-(4,4-二氟哌啶-1-基)嘧啶-4-胺 | 255.1 |
中間體9:2-(4,4-二氟哌啶-1-基)-3-氟-6-甲基吡啶-4-胺
步驟1:在-60°C下向在四氫呋喃(50 mL)中的二異丙基胺(5.85 mL,41.0 mmol)的溶液中逐滴添加正丁基鋰(在己烷中2 M,20.52 mL,41.0 mmol)。將反應混合物緩慢溫熱至0°C,並在相同溫度下攪拌45 min。在另一個圓底燒瓶中,在-78°C下向在四氫呋喃(50 mL)中的2-溴-3-氟-6-甲基吡啶(3.9 g,20.52 mmol)的溶液中逐滴添加以上製備的LDA溶液。將反應所得的反應混合物在相同溫度下攪拌45 min,然後逐滴添加在THF(40 mL)中的碘(10.42 g,41.0 mmol)。將反應混合物在相同溫度下攪拌1 h。反應完成後,將其用飽和氯化銨溶液淬滅,並用乙酸乙酯萃取。將有機層用硫代硫酸鈉溶液、水和鹽水洗滌,經Na2
SO4
乾燥,過濾並濃縮,以得到呈黃色固體的2-溴-3-氟-4-碘-6-甲基吡啶(6 g,18.99 mmol,93%產率)。產物不經進一步純化即可用於下一步驟。1
H NMR (400 MHz, 氯仿-d
) δ ppm 7.53 (d,J
= 3.8 Hz, 1 H), 2.52 (s, 3 H)。m/z
(ESI): 315.8, 317.8 (M+H)+
。
步驟2:將在1,4-二㗁𠮿(30 mL)中的2-溴-3-氟-4-碘-6-甲基吡啶(1.5 g,4.75 mmol)、(4-甲氧基苯基)甲胺(0.782 g,5.70 mmol)、碳酸銫(4.64 g,14.24 mmol)、Xantphos(0.549 g,0.950 mmol)和Pd2
(dba)3
(0.065 g,0.071 mmol)的混合物在環境溫度下攪拌16 h。然後將反應混合物通過CELITE®塞過濾,並用EtOAc稀釋濾液。將所得溶液用水、鹽水洗滌,經Na2
SO4
乾燥,過濾並濃縮。將濃縮物藉由快速柱層析法使用在石油醚中的0%至18%乙酸乙酯的梯度進行純化,以得到呈淺黃色固體的2-溴-3-氟-N
-(4-甲氧基苄基)-6-甲基吡啶-4-胺(0.7 g,2.15 mmol,45%產率)。1
H NMR (300 MHz, DMSO-d 6
)
δ ppm 7.38 (s, 1 H), 7.21 - 7.31 (m, 2 H), 6.84 - 6.95 (m, 2 H), 6.52 (d,J
= 6.0 Hz, 1 H), 4.32 (d,J
= 6.3 Hz, 2 H), 3.72 (s, 3 H), 2.20 (s, 3 H)。m/z
(ESI): 325.0, 327.0 (M+H)+
。
步驟3:將在1,4-二㗁𠮿(15 mL)中的2-溴-3-氟-N
-(4-甲氧基苄基)-6-甲基吡啶-4-胺(0.7 g,2.153 mmol)、4,4-二氟哌啶鹽酸鹽(0.407 g,2.58 mmol)、碳酸銫(2.81 g,8.61 mmol)、Xantphos(0.249 g,0.431 mmol)和Pd2
(dba)3
(0.030 g,0.032 mmol)的混合物在密封管中在100°C下攪拌16 h。然後將反應混合物通過CELITE®塞過濾,並用EtOAc稀釋濾液。將所得溶液用水、鹽水洗滌,經NNa2
SO4
乾燥,過濾並濃縮。將濃縮物藉由快速柱層析法使用在石油醚中的0%至6%乙酸乙酯的梯度進行純化,以得到呈淺黃色固體的2-(4,4-二氟哌啶-1-基)-3-氟-N
-(4-甲氧基苄基)-6-甲基吡啶-4-胺(0.67 g,1.83 mmol,85%產率)。1
H NMR (300 MHz, DMSO-d 6
)
δ ppm 7.19 - 7.29 (m, 2 H), 6.83 - 6.93 (m, 2 H), 6.75 (m, 1H), 6.13 (d,J
= 5.4 Hz, 1 H), 4.26 (d,J
=6 .3 Hz, 2 H), 3.72 (s, 3 H), 3.40 (d,J
= 11.5 Hz, 4 H), 1.92 - 2.14 (m, 7 H)。m/z
(ESI): 366.1 (M+H)+
。
步驟4:在環境溫度下向在二氯甲烷(3 mL)中的2-(4,4-二氟哌啶-1-基)-3-氟-N
-(4-甲氧基苄基)-6-甲基吡啶-4-胺(0.3 g,0.821 mmol)的溶液中添加苯甲醚(0.179 mL,1.642 mmol)和TFA(1.5 mL,19.47 mmol),並將反應混合物在50°C下攪拌2.5 h。然後將反應混合物用水淬滅,並用10%碳酸氫鈉溶液將pH調節至8,然後將其用乙酸乙酯萃取。將有機層用水和鹽水洗滌,經Na2
SO4
乾燥,過濾並濃縮。將濃縮物藉由快速柱層析法使用在石油醚中的20%乙酸乙酯的梯度進行純化,以得到呈黃色油的2-(4,4-二氟哌啶-1-基)-3-氟-6-甲基吡啶-4-胺(0.17 g,0.69 mmol,84%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 6.15 (d,J
=5.5 Hz, 1 H), 5.79 (s, 2 H), 3.40 (t,J
= 5.6 Hz, 4 H), 2.13 (s, 3 H), 2.02 (tt,J
= 14.2, 5.6 Hz, 4 H)。m/z
(ESI): 246.2 (M+H)+
。
中間體10:2-(6-胺基-2-(4,4-二氟哌啶-1-基)嘧啶-4-基)丙-2-醇
步驟1:在0°C下向在四氫呋喃(200 mL)中的2,6-二氯嘧啶-4-甲酸甲酯(20.00 g,97 mmol)的溶液中添加(3,5-二甲氧基苯基)甲胺(19.39 g,116 mmol)和DIPEA(33.7 mL,193 mmol)。然後將反應混合物在環境溫度下攪拌16 h,然後用水淬滅並用EtOAc萃取。將有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並濃縮。將濃縮物用DCM和己烷研磨,以得到呈灰白色固體的2-氯-6-((3,5-二甲氧基苄基)胺基)嘧啶-4-甲酸甲酯(19.5 g,57.7 mmol,59.8%產率)。1
H NMR(400 MHz, DMSO-d 6
) δ ppm 8.52 (t,J
= 5.5 Hz, 1 H), 7.16 (d,J
= 8.9 Hz, 2 H), 6.59 (d,J
= 2.4 Hz, 1 H), 6.50 (dd,J
= 8.4, 2.4 Hz, 1 H), 4.40 (d,J
= 5.4 Hz, 2 H), 3.82 (d,J
= 14.5 Hz, 6 H), 3.75 (d,J
= 5.8 Hz, 3 H).m/z
(ESI): 338.1 (M+H)+
。
步驟2:將在DMF(30 mL)中的2-氯-6-((2,4-二甲氧基苄基)胺基)嘧啶-4-甲酸甲酯(3 g,8.88 mmol)、4,4-二氟哌啶鹽酸鹽(2.10 g,13.32 mmol)和DIPEA(3.44 g,26.6 mmol)的溶液在密封管中在90°C下攪拌16 h。然後將反應混合物用水淬滅並用乙酸乙酯萃取。將有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並濃縮。將粗物質藉由快速柱層析法使用在石油醚中的50%至60%乙酸乙酯的梯度進行純化,以提供呈淺黃色固體的2-(4,4-二氟哌啶-1-基)-6-氟-((2,4-甲氧基苄基)胺基)嘧啶-4-甲酸甲酯(2.6 g,6.15 mmol,69.3%產率)。1
H NMR (300 MHz, DMSO-d 6
) δ ppm 7.74 (s, 1 H), 7.13 (d,J
= 8.3 Hz, 1 H), 6.55 (d,J
= 2.4 Hz, 1 H), 6.47 (dd,J
= 8.3, 2.4 Hz, 2 H), 4.39 (s, 2 H), 3.82 (s, 3 H), 3.79 (s, 3 H), 3.73 (s, 3 H), 3.33 (m, 4 H), 1.85 - 2.00 (m, 4 H)。
步驟3:在0°C下向在DCM(10 mL)中的2-(4,4-二氟哌啶-1-基)-6-((2,4-二甲氧基苄基)胺基)嘧啶-4-甲酸甲酯(1 g,2.367 mmol)的溶液中逐滴添加硫酸(0.126 mL,2.37 mmol)。然後使混合物溫熱至室溫,並藉由TLC監測反應進程。起始材料完成後,將反應混合物用冰水淬滅,並藉由使用10% NaHCO3
溶液將pH調節至9。然後,將反應混合物用乙酸乙酯萃取,有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並濃縮,以提供呈灰白色固體的6-胺基-2-(4,4-二氟哌啶-1-基)嘧啶-4-甲酸甲酯(0.45 g,1.653 mmol,69.8%產率)。1
H NMR (300 MHz, DMSO-d 6
) δ ppm 6.90 (br s, 2 H), 6.39 (s, 1 H), 3.85 - 3.83 (m, 4 H), 3.79 (s, 3 H), 1.99-1.35 (m, 4 H).m/z
(ESI): 273.1 (M+H)+
。
步驟4:在0°C下向在四氫呋喃(5 mL)中的6-胺基-2-(4,4-二氟哌啶-1-基)-嘧啶-4-甲酸甲酯(0.45 g,1.653 mmol)的溶液中添加甲基溴化鎂(2.0 M二乙醚 )(2.07 mL,4.13 mmol)並在室溫下攪拌2 h。起始材料消耗後,將反應混合物用冰水淬滅,並用乙酸乙酯萃取。將有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾並濃縮。將濃縮物藉由快速柱層析法使用在石油醚中的0%至90%乙酸乙酯的梯度進行純化,以提供呈淺黃色固體的2-(6-胺基-2-(4,4-二氟哌啶-1-基)嘧啶-4-基)丙-2-醇(0.35 g,1.28 mmol,78%產率)。m/z
(ESI): 273.1 (M+H)+
。
[表3]:以下中間體按照如關於中間體10所述的類似程序來製備
中間體編號 | 化學結構 | 名稱 | LRMS: (ESI+ve離子)m/z |
10-1 | (R )-2-(6-胺基-2-(2-甲基𠰌啉)嘧啶-4-基)丙-2-醇 | 252.2 |
中間體11:2-(4-胺基-6-甲基嘧啶-2-基)丙-2-醇
步驟1:在室溫下將在四氫呋喃(100 mL)中的2,4-二氯-6-甲基嘧啶(3.0 g,18.40 mmol,美國密蘇里州聖路易斯奧德里奇公司(Aldrich, St. Louis, MO, USA))、雙(4-甲氧基苄基)-胺(7.10 g,27.6 mmol,美國加利福尼亞聖地牙哥康比樂公司(Combi-Blocks Inc., San Diego, CA, USA))、碳酸鉀(7.63 g,55.2 mmol,美國密蘇里州聖路易斯奧德里奇公司(Aldrich, St. Louis, MO, USA))的混合物攪拌72 h。將反應混合物用水(50 mL)稀釋並然後用EtOAc(2 x 100 mL)萃取。然後將合併的有機萃取物經MgSO4
乾燥並在真空中濃縮。層析純化殘餘物(矽膠,0%至100% EtOAc/庚烷),提供呈灰白色固體的2-氯-N,N-雙(4-甲氧基苄基)-6-甲基嘧啶-4-胺(3.11 g,8.10 mmol,44.0%)。1
H NMR (DMSO-d6) δ ppm 7.16 (br d, J=6.2 Hz, 4H), 6.89 (d, J=8.7 Hz, 4H), 6.60 (s, 1H), 4.39-4.84 (m, 4H), 3.73 (s, 6H), 2.20 (s, 3H). m/z (ESI): 384.2 (M+H)+。
步驟2:使在乙醇(0.5 mL)中的2-氯-N,N-雙(4-甲氧基苄基)-6-甲基嘧啶-4-胺(1.0 g,2.61 mmol)、1,3-雙(二苯基膦基)丙烷(64.5 mg,0.156 mmol,美國密蘇里州聖路易斯奧德里奇公司(Aldrich, St. Louis, MO, USA))、草酸二乙酯(0.529 mL,3.91 mmol,美國密蘇里州聖路易斯奧德里奇公司(Aldrich, St. Louis, MO, USA))、反-二氯雙(三苯基膦)鈀(ii)(54.9 mg,0.078 mmol,美國麻塞諸塞州紐伯里波特斯特倫(Strem Chemicals Inc., Newburyport, MA, USA))和4-(二甲基胺基)吡啶(477 mg,3.91 mmol,美國密蘇里州聖路易斯奧德里奇公司(Aldrich, St. Louis, MO, USA))在140°C下經歷微波照射20 min。然後將反應混合物用水(50 mL)稀釋並然後用EtOAc(2 x 50 mL)萃取。然後將合併的有機萃取物經MgSO4
乾燥並在真空中濃縮。層析純化殘餘物(矽膠,0%至100% EtOAc/庚烷),提供呈淺黃色固體的4-(雙(4-甲氧基苄基)胺基)-6-甲基嘧啶-2-甲酸乙酯(274 g,0.650 mmol,24.95%產率)。1
H NMR (甲醇-d4) δ ppm 7.29 (br s, 4H), 6.97 (d,J
=8.5 Hz, 4H), 6.68 (s, 1H), 4.78-4.93 (m, 4H), 4.54 (q,J
=7.2 Hz, 2H), 3.88 (s, 6H), 2.43 (s, 3H), 1.53 (t,J
=7.0 Hz, 3H)。m/z (ESI): 422.1 (M+H)+。
步驟3:在N2
下於0°C下向在2-甲基四氫呋喃(7 mL)中的4-(雙(4-甲氧基苄基)胺基)-6-甲基嘧啶-2-甲酸乙酯(396 mg,0.940 mmol)的溶液中逐滴添加甲基溴化鎂(在2-甲基四氫呋喃中的3.4M)(0.829 mL,2.82 mmol,美國密蘇里州聖路易斯奧德里奇公司(Aldrich, St. Louis, MO, USA))。添加後,然後將混合物在0°C下攪拌3.5 h。然後將混合物用飽和NH4
Cl(10 mL)淬滅並然後用EtOAc(2 x 50 mL)萃取。然後將合併的有機萃取物經MgSO4
乾燥並在真空中濃縮。層析純化殘餘物(矽膠,0%至100% EtOAc/庚烷),提供呈黃色固體的2-(4-(雙(4-甲氧基苄基)胺基)-6-甲基嘧啶-2-基)丙-2-醇(307 mg,0.753 mmol,80%產率)。m/z (ESI): 408.2 (M+H)+。
步驟4:使在三氟乙酸(10 mL,美國密蘇里州聖路易斯奧德里奇公司(Aldrich, St. Louis, MO, USA))中的2-(4-(雙(4-甲氧基苄基)胺基)-6-甲基嘧啶-2-基)丙-2-醇(300 mg,0.736 mmol)的溶液在110°C下經歷微波照射30 min。然後將混合物在減壓下濃縮。然後將粗產物溶解於DCM(10 mL)中,並然後用飽和Na2CO3(15 mL)淬滅。然後將該混合物用EtOAc(2 x 50 mL)萃取。然後將合併的有機萃取物經MgSO4
乾燥並在真空中濃縮。層析純化殘餘物(矽膠,0%至100% EtOAc:EtOH(3 : 1)/庚烷)提供呈淺黃色固體的2-(4-胺基-6-甲基嘧啶-2-基)丙-2-醇(123 mg)。m/z (ESI):168.2 (M+H)+。
環Ar2
中間體的製備
中間體12:4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸
在20°C下向在DMSO(2.10 L)中的2-氟-4-碘苯甲酸(300 g,1.13 mol,加利福尼亞聖地牙哥康比樂公司(Combi-Blocks, San Diego, CA))的溶液中添加6-氮雜螺[2.5]辛烷鹽酸鹽(216 g,1.47 mol,藥明康得公司(Wuxi AppTec))。然後添加K2
CO3
(468 g,3.38 mol),並將反應溶液在N2
下於140°C下攪拌48 h。將反應溶液緩慢倒入冰水(4.20 L)中,然後用己烷(2.00 L x 3)萃取。分離水相,並用HCl(2.00 mol/L,水溶液)調節pH = 6。沈澱出固體並收集。用水(700 mL x 3)洗滌固體並過濾。將濕的固體散佈在大的觀察玻璃上,並在25°C下在空氣中乾燥72 h。獲得呈淺黃色固體的4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸(280 g,777 mmol,68.9%產率)。400 MHz DMSO-d6
δ ppm 8.07 (s, 1H), 7.76 - 7.66 (m, 2H), 3.10 (t,J
= 5.2 Hz, 4H), 1.55 (br s, 4H), 0.41 (s, 4H)。
[表4]:以下中間體按照中間體12的類似程序來製備:
中間體編號 | 化學結構 | 名稱 | LRMS: (ESI+ve離子)m/z |
12-1 | 4-溴-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸 | 310.2/312.2 | |
12-2 | 4-溴-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸甲酯 | 324.0/326.0 | |
12-3 | 4-碘-2-(7-氮雜螺[3.5]壬-7-基)苯甲酸 | 372.0 | |
12-4 | 2-(4,4-二甲基哌啶-1-基)-4-碘苯甲酸 | 360.0 |
中間體13:4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸
步驟1:在0°C下向在N,N
-二甲基甲醯胺(1.0 L)中的2-氟-4-(甲基磺醯基)苯甲酸(90.0 g,412.1 mmol)的溶液中添加苄基溴(78.1 g,454.0 mmol)和碳酸鈉(52.5 g,495 mmol)。將反應混合物在室溫下攪拌12 h。將反應混合物用水(1 L)淬滅並用MTBE(3 x 1 L)萃取。將合併的有機層用鹽水(1 L)洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗殘餘物藉由柱層析法在矽膠上使用在己烷中的0%至30%乙酸乙酯作為洗脫液進行純化,以得到呈白色固體的2-氟-4-(甲基磺醯基)苯甲酸苄酯(100 g,79%產率)。1
H NMR (300 MHz, DMSO-d 6
)δ
ppm 8.16 (dd,J
= 8.2, 6.9 Hz, 1H), 7.98 - 7.86 (m, 2H), 7.48 - 7.31 (m, 5H), 5.40 (s, 2H), 3.33 (s, 3H)。
步驟2:向在二甲基亞碸(550 mL)中的2-氟-4-(甲基磺醯基)苯甲酸苄酯(55 g,178 mmol)的溶液中添加DIPEA(57.6 g,446 mmol),隨後添加6-氮雜螺[2.5]辛烷(29.8 g,268 mmol),並將反應混合物在100°C下攪拌24 h。將反應混合物用水(1 L)淬滅並用MTBE(3 x 1 L)萃取。將合併的有機層用鹽水溶液(1 L)洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗產物藉由柱層析法在矽膠(230-400目)上使用在己烷中的0%至10%乙酸乙酯作為洗脫液進行純化,以得到呈白色固體的4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸苄酯(55 g,77%產率)。1
H NMR (400 MHz, DMSO-d 6
)δ
ppm 7.76 (d,J
= 8.0 Hz, 1H), 7.52 - 7.45 (m, 4H), 7.43 - 7.35 (m, 3H), 5.35 (s, 2H), 3.25 (s, 3H), 3.05 (t,J
= 5.3 Hz, 4H), 1.36 (t,J
= 5.3 Hz, 4H), 0.30 (s, 4H)。m/z
(ESI): 400.1 (M+H)+
。
步驟3:在60°C下向在四氫呋喃(108 mL)和甲醇(36 mL)中的4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸苄酯(65 g,163 mmol)的溶液中添加1N氫氧化鈉水溶液(407 mL,407 mmol),並將反應混合物攪拌12 h。在減壓下濃縮該反應混合物以除去THF和甲醇。將剩餘的水溶液用1.5N HCl溶液酸化至pH〜2。將沈澱出的固體過濾,用水(200 mL)洗滌,隨後用己烷(200 mL)洗滌,在真空中乾燥12 h,以得到呈灰白色固體狀的4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸(42 g,83%產率)。1
H NMR (400 MHz, DMSO-d 6
)δ
ppm 16.13 (s, 1H), 8.04 (d,J
= 8.0 Hz, 1H), 7.99 (s, 1H), 7.75 (d,J
= 8.0 Hz, 1H), 3.29 (s, 3H), 3.17 (b s, 4H), 1.55 (b s, 4H), 0.41 (s, 4H)。m/z
(ESI): 310.1 (M+H)+
。
中間體14:4-((1-甲基環丙烷)-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸
步驟1:在0°C下向在DMF(500 mL)中的4-溴-2-氟苯甲酸(50.0 g,228 mmol,中國氟化工公司(F Chemicals, China))的溶液中添加碳酸鈉(31.5 g,297 mmol),隨後添加苄基溴(43.0 g,251 mmol),並將反應混合物在室溫下攪拌24 h。將反應混合物用水(1000 mL)淬滅並用乙酸乙酯(3 x 2000 mL)萃取。將有機層經硫酸鈉乾燥,過濾並在減壓下濃縮。將粗殘餘物藉由柱層析法在矽膠上使用在己烷中的10%乙酸乙酯作為洗脫液進行純化,以得到呈無色黏稠油的4-溴-2-氟苯甲酸苄酯(65 g,92%產率)。1
H NMR (400 MHz, 氯仿-d
) δ ppm 7.91 (t,J
= 8.4 Hz, 1H), 7.47 (dt,J
= 6.0, 1.5 Hz, 2H), 7.43 (dd,J
= 6.8, 1.8 Hz, 1H), 7.41 (q,J
= 1.5 Hz, 1H), 7.39 - 7.35 (m, 1H), 7.02 (dd,J
= 8.7, 2.1 Hz, 1H), 6.79 (s, 1H), 5.38 (s, 2H)。m/z
(ESI): 310.2 (MH)+
。
步驟2:向在DMSO(200 mL)中的4-溴-2-氟苯甲酸苄酯(60.0 g,194 mmol)的溶液中添加在DMSO(200 mL)和DIPEA(30 g,291 mmol)中的6-氮雜螺[2.5]辛烷(32.4,291 mmol,藥明康得公司(Wuxi Apptec)),並在100°C下攪拌12 h。將反應混合物用水(2000 mL)淬滅並用乙酸乙酯(3 x 2000 mL)萃取。將有機層經硫酸鈉乾燥,過濾並在減壓下濃縮。將粗殘餘物藉由柱層析法在矽膠上使用在己烷中的10%乙酸乙酯進行純化,以得到呈黃色油的4-溴-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸苄酯(70 g,90%產率)。1
H NMR (400 MHz, 氯仿-d
)δ
ppm 7.60 (dd,J
= 8.4, 1.9 Hz, 1H), 7.50 - 7.45 (m, 2H), 7.49 - 7.28 (m, 3H), 7.20 (d,J
= 1.9 Hz, 1H), 7.07 (dd,J
= 8.3, 1.9 Hz, 1H), 5.36 (s, 2H), 3.12 - 3.02 (m, 4H), 1.47 (t,J
= 5.3 Hz, 4H), 0.33 (d,J
= 1.8 Hz, 4H)。m/z
(ESI): 398.1, 400.1 (M+H)+
。
步驟3:向250 mL的密封管中添加在1,4-二㗁𠮿(90 mL)中的4-溴-2-(6-氮雜螺[2.5]正辛-6-基)苯甲酸苄酯(9 g,22.48 mmol)、1-甲基環丙烷-1-磺醯胺(3.95 g,29.2 mmol,加利福尼亞聖地牙哥康比樂公司(Combi-Blocks, San Diego, CA))和K2
CO3
(6.21 g,45.0 mmol),使反應脫氣並用氮氣吹掃5 min。向該反應混合物中添加Xantphos(1.301 g,2.248 mmol),隨後添加Pd2
(dba)3
(1.03 g,1.12 mmol),將密封管關閉並在110°C下攪拌18 h。將反應混合物用水(250 mL)淬滅並用乙酸乙酯 (2 x 150 mL)萃取。將有機層用水(100 mL)洗滌,經Na2
SO4
乾燥,過濾並在減壓下濃縮。將粗殘餘物藉由柱層析法在矽膠上用在己烷中的0%至15%EtOAc的梯度洗脫進行純化,以得到呈橙色油的4-((1-甲基環丙烷)-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸苄酯(6.1 g,59%產率)。1
H NMR (400 MHz, DMSO-d 6
)δ
ppm 10.06 (s, 1H), 7.62 (d,J
= 8.5 Hz, 1H), 7.48 - 7.31 (m, 5H), 6.98 (s, 1H), 6.81 (d,J
= 8.5 Hz, 1H), 5.27 (s, 2H), 2.92 (t,J
= 4.96 Hz, 4H), 1.40 - 1.30 (m, 7H), 1.16 (dd,J
= 6.4, 4.7 Hz, 2H), 0.81 (dd,J
= 6.4, 4.7 Hz, 2H), 0.28 (s, 4H)。m/z
(ESI): 455.2 (M+H)+
。
步驟4:在氮氣氣氛下向在甲醇(20 mL)和乙酸乙酯(10 mL)中的4-((1-甲基環丙烷)-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸苄酯(2.1 g,4.62 mmol)的溶液中添加10% Pd-C(1.05 g,50% wt/wt)。使反應混合物脫氣並在氫壓(1 atm,氣球壓力)下攪拌4 h。通過CELITE®床過濾該反應混合物,並用甲醇(20 mL)洗滌。將濾液在減壓下濃縮。將殘餘物用Et2
O(50 mL)研磨,以得到呈灰白色固體的4-((1-甲基環丙烷)-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸(1.2 g,71%產率))。1
H NMR (400 MHz, DMSO-d 6
)δ
ppm 13.20 (s, 1H), 10.33 (s, 1H), 7.95 (d,J
= 8.6 Hz, 1H), 7.41 (s, 1H), 7.20 (d,J
= 8.6 Hz, 1H), 2.99 (s, 4H), 1.56 (s, 4H), 1.39 (s, 3H), 1.18 (t,J
= 4.8 Hz, 2H), 0.83 (t,J
= 4.7 Hz, 2H), 0.42 (s, 4H)。m/z
(ESI): 363.2 (M+H)+
。
中間體15:4-(N
-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸
步驟1:在0°C下向在DCM(200 mL)中的3-甲基-3-氧雜環丁胺鹽酸鹽(5.50 g,44.5 mmol)和N,N
-二異丙基乙胺(23.26 mL,134 mmol)的溶液中添加4-(氯磺醯基)-2-氟苯甲酸甲酯(12.37 g,49.0 mmol),並將混合物從0°C至室溫攪拌1 h。將該混合物用1.0 N HCl(200 mL)稀釋並用二氯甲烷(150 mL x 2)萃取。將合併的有機層用鹽水洗滌,經無水硫酸鈉乾燥,過濾並在減壓中濃縮以得到粗產物。將粗產物用Biotage SNAP 100 g柱用在庚烷中的0%至30% 3 : 1 EtOAc-EtOH洗脫進行純化,以得到呈白色固體的2-氟-4-(N
-(3-甲基氧雜環丁烷-3-基)胺磺醯基)苯甲酸甲酯(13.59 g,44.8 mmol,100%產率)。1
H NMR (500 MHz, DMSO-d6
) δ ppm 8.67 (s, 1H), 8.11 (t,J
= 7.37 Hz, 1H), 7.76-7.82 (m, 1H), 7.69-7.76 (m, 1H), 4.56 (d,J
= 6.23 Hz, 2H), 4.18 (d,J =
6.75 Hz, 2H), 3.90 (s, 3H), 1.42 (s, 3H)。
步驟2:將在無水1,4-二㗁𠮿中的N,N
-二異丙基乙胺(16.23 mL,93 mmol)、6-氮雜螺[2.5]辛烷(6.22 g,55.9 mmol)和2-氟-4-(N
-(3-甲基氧雜環丁-3-基)胺磺醯基)苯甲酸甲酯(14.13 g,46.6 mmol)的混合物 在100°C下攪拌20 h。將混合物冷卻至室溫,用水淬滅並用乙酸乙酯萃取。將合併的有機相用鹽水洗滌,乾燥並在減壓下蒸發至乾燥。將粗產物使用Biotage SNAP 340 g柱用在庚烷中的0%至40% 3 : 1 EtOAc-EtOH洗脫進行純化,以得到呈灰白色固體的4-(N
-(3-甲基氧雜環丁-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸甲酯(14.15 g,35.9 mmol,77%產率)。1
H NMR (500 MHz, DMSO-d 6
) δ ppm 8.42 (s, 1H), 7.72 (d,J
= 8.04 Hz, 1H), 7.47 (d,J
= 1.56 Hz, 1H), 7.36 (dd,J
= 1.82, 8.04 Hz, 1H), 4.55 (d,J
= 5.97 Hz, 2H), 4.14 (d,J
= 6.49 Hz, 2H), 3.85 (s, 3H), 3.02-3.09 (m, 4H), 1.44-1.50 (m, 4H), 1.42 (s, 3H), 0.35 (s, 4H)。
步驟3:將在THF-水-MeOH(1 : 1 : 1,300 mL)中的4-(N
-(3-甲基氧雜環丁-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛基-6-基)苯甲酸甲酯(14.15 g,35.9 mmol)和氫氧化鋰一水合物(22.58 g,538 mmol)的混合物在室溫下攪拌過夜。在減壓下濃縮該混合物以部分除去有機溶劑。用2N HCl將溶液酸化至pH < 3。將沈澱出的固體過濾並在空氣中乾燥,以得到呈白色固體的4-(N
-(3-甲基氧雜環丁-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸(9.94 g,26.1 mmol, 72.8%產率)。1
H NMR (500 MHz, DMSO-d 6
) δ ppm 8.51 (s, 1H), 8.04 (d,J
=8.04 Hz, 1H), 7.89 (d,J
=1.30 Hz, 1H), 7.66 (dd,J
=1.69, 8.17 Hz, 1H), 4.55 (d,J
=6.23 Hz, 2H), 4.09-4.17 (m, 2H), 3.06-3.19 (m, 4H), 1.56 (t,J
=5.19 Hz, 4H), 1.40 (s, 3H), 0.36-0.46 (s, 4H)。
中間體16:4-((1-(三級丁氧基羰基)氮雜環丁烷-3-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸
步驟1:將在1,4-二㗁𠮿中的4-溴-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸甲酯(10.50 g,32.4 mmol,中間體12-2)、DIPEA(8.37 mL,64.8 mmol)、Xantphos(1.874g,3.24 mmol)和Pd2
(dba)3
(2.97 g,3.24 mmol)的混合物中用氬氣鼓泡,然後添加3-巰基氮雜環丁烷-1-甲酸三級丁酯(7.66 mL,40.5 mmol)。將混合物在100°C下攪拌18 h。將混合物冷卻至室溫,濃縮並通過Biotage SNAP用在庚烷中的0%至25%的3 : 1 EtOAc-EtOH的梯度洗脫進行純化,以提供呈淺黃色黏性固體的3-((4-(甲氧基羰基)-3-(6-氮雜螺[2.5]辛-6-基)苯基)硫)氮雜環丁烷-1-甲酸三級丁酯(13.85 g,32.0 mmol,99%產率)。1
H NMR (500 MHz, DMSO-d 6
) δ ppm 7.55 (d,J
= 8.04 Hz, 1H), 6.79 (s, 1H), 6.76 (d,J
= 8.14 Hz, 1H), 4.34-4.43 (m, 2H), 4.27-4.34 (m, 1H), 3.79 (s, 3H), 3.70 (dd,J
= 4.67, 8.56 Hz, 2H), 2.97-3.04 (m, 4H), 1.41-1.51 (m, 4H), 1.38 (s, 9H), 0.29-0.37 (m, 4H)。
步驟2:向在1,4-二㗁𠮿(300 mL)中的3-((4-(甲氧基羰基)-3-(6-氮雜螺[2.5]辛-6-基)苯基)硫)氮雜環丁烷-1-甲酸三級丁酯(13.85 g,32.0 mmol)的溶液中添加在150 mL水中的Oxone單過硫酸氫鹽(39.4 g,64.0 mmol)。將混合物在室溫下攪拌5 h,並添加150 mL乙酸乙酯和150 mL水,將混合物攪拌10 min。分離有機層,並將水層用乙酸乙酯萃取。將合併的有機物用鹽水洗滌,乾燥,過濾並濃縮。粗產物通過Biotage SNAP 340 g柱用在庚烷中的0%至25% EtOAc-EtOH(3 : 1)洗脫進行純化,以得到呈灰白色固體的3-((4-(甲氧基羰基)-3-(6-氮雜螺[2.5]辛-6-基)苯基)磺醯基)氮雜環丁烷-1-甲酸三級丁酯(12.77 g,27.5 mmol,86%產率)。1
H NMR (500 MHz, DMSO-d 6
) δ 7.75 (d,J
= 8.04 Hz, 1H), 7.44-7.50 (m, 2 H), 4.48-4.55 (m, 1 H), 4.09 (br s, 2 H), 3.97-4.02 (m, 2H), 3.86 (s, 3H), 3.04-3.17 (m, 4 H), 1.42-1.51 (m, 4 H), 1.38 (s, 9 H), 0.35 (s, 4 H)。
步驟3:將在THF-水-MeOH(1 : 1 : 1,230 mL)中的3-((4-(甲氧基羰基)-3-(6-氮雜螺[2.5]辛-6-基)苯基)磺醯基)氮雜環丁烷-1-甲酸三級丁酯(12.77 g,27.5 mmol)和氫氧化鋰一水合物(11.53 g,275 mmol)的混合物在室溫下攪拌15 h。在減壓下濃縮該混合物以除去一些有機溶劑。用2N HCl將溶液酸化至pH < 3。將沈澱出的固體過濾並乾燥,以得到呈灰白色固體的4-((1-(三級丁氧基羰基)氮雜環丁烷-3-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸(10.6 g,23.53 mmol, 86%產率)。1
H NMR (500 MHz, DMSO-d 6
) δ ppm 8.03 (d,J
= 8.30 Hz, 1H), 7.93 (d,J
= 1.82 Hz, 1H), 7.72 (dd,J
= 1.69, 8.17 Hz, 1H), 4.48-4.60 (m, 1H), 4.10 (br. s., 2H), 3.99-4.06 (m, 3H), 3.14-3.22 (m, 4H), 1.49-1.59 (m, 4H), 1.38 (s, 9H), 0.41 (s, 4H)。
具有AR1
和AR2
環的中間體化合物
中間體17:N
-(2-氯-6-甲基嘧啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
將2,4,6-三丙基-1,3,5,2,4,6-三氧雜三膦烷2,4,6-三氧化物(在EtOAc中的50 wt%溶液,12.50 mL,21.00 mmol)和三乙胺(2.93 mL,21.00 mmol)添加到在DCE(20 mL)中的4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸(3.0 g,8.40 mmol,中間體12)和2-氯-6-甲基嘧啶-4-胺(1.45 g,10.08 mmol,奧蘭醫藥公司(Aurum Pharmtech Inc.))的懸浮液中。將混合物在85°C下加熱24 h,然後冷卻至室溫。添加水(10 mL),分離各層,並將水層用DCM(1 x 10 mL)萃取。將合併的有機萃取物經無水MgSO4
乾燥,過濾並在真空中濃縮,以得到固體。將固體懸浮在1 : 1 EtOAc/庚烷中並過濾,以提供呈灰白色固體的N
-(2-氯-6-甲基嘧啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(3.61 g,7.48 mmol,89%產率)。1
H NMR (400 MHz, 氯仿-d
) δ ppm 13.53 (br s, 1 H) 8.11 (s, 1 H) 7.92 (d,J
= 8.29 Hz, 1 H) 7.70 (s, 1 H) 7.65 - 7.69 (m, 1 H) 3.05 (t,J
= 5.39 Hz, 4 H) 2.53 (s, 3 H) 1.61 - 1.88 (m, 4 H) 0.44 (s, 4 H)。m/z
(ESI): 483.0 (M+H)+
。
中間體18:(R
)-4-溴-N
-(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
步驟1:向100 mL的圓底燒瓶中添加在DCM(8 mL)中的4-溴-2-(6-氮雜螺[2.5]辛基-6-基)苯甲酸(0.9 g,2.90 mmol,中間體12-1)、吡啶(0.657 mL,8.12 mmol)和2,2,2-三氟乙酸全氟苯基酯(0.717 g,3.77 mmol)。將所得混合物在室溫下攪拌16 h,並在真空中除去溶劑,以得到粗產物,將其不經純化即可用於下一步驟。m/z
(ESI): 476和478 (M+1)。
步驟2:向50 mL的圓底燒瓶中添加溶解於N,N
-二甲基甲醯胺(6 mL)中的(R
)-2-甲基-4-(4-甲基嘧啶-2-基)𠰌啉(0.223 g,1.15 mmol,中間體2),隨後在氮氣氣氛下在室溫下添加氫化鈉(0.084 g,2.1 mmol)。將該反應混合物攪拌10 min,然後將其在氮氣氣氛下在室溫下用4-溴-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸全氟苯基酯(0.5 g,1.050 mmol)處理。將所得反應混合物在室溫下再攪拌2 h。將該反應混合物用DCM(2 x 30 mL)萃取,分離,經無水硫酸鈉乾燥並蒸發至乾燥,以得到粗物質。然後將其吸附到矽膠塞上,並藉由矽膠快速柱層析法用30%至50% EtOAc/己烷洗脫進行純化,以提供呈白色固體的標題化合物(0.20 g,0.40 mmol,38%產率)。1
H NMR (300 MHz, DMSO-d 6
) δ ppm 13.19 (bs, 1H), 7.99 (d,J
= 8.4 Hz, 1H), 7.69 (s, 1H), 7.55 (d,J
= 8.4 Hz, 1H), 7.36 (s, 1H), 4.45 (t,J
= 12 Hz, 2H), 3.88 (m, 1H), 3.52-3.48 (m, 2H) 3.10-2.90 (m, 6H), 2.30 (s, 3H), 1.71-1.62 (m, 4H), 1.14 (d,J
= 6 Hz, 3H), 0.36 (s, 4H)。m/z
(ESI): 500和502 (M+1)。
中間體19:N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
在氬氣下將4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸(150.0 g,420 mmol,中間體12)懸浮於二氯甲烷(1000 mL)中。添加催化DMF(1.0 mL),隨後在10 min內逐滴添加在二氯甲烷(500 mL)中的亞硫醯氯(54.6 g,28 mL,459 mmol,西格瑪奧德里奇公司(Sigma-Aldrich Corporation))的溶液。在環境溫度下攪拌30 min後,將混合物在減壓下蒸發至乾燥。將該粗產物與甲苯(2 x 300 mL)共沸,並在氬氣下將其懸浮於二氯甲烷(300 mL)中。添加磷酸三鉀(267 g,1.26 mol,西格瑪奧德里奇公司(Sigma-Aldrich Corporation)),隨後添加在DCM(300 mL,在5 min內添加)中的2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-胺(100 g,438 mmol,中間體4)和N,N
-二異丙基乙胺(200 mL,1.14 mol,西格瑪奧德里奇公司(Sigma-Aldrich Corporation))的溶液。將黃色混合物在環境溫度下攪拌3 h,然後在減壓下蒸發至乾燥。將粗固體懸浮於二氯甲烷(1 L)中並攪拌10 min。將混合物通過玻璃料過濾,並將固體用另外的二氯甲烷(2 x 100mL)洗滌。丟棄固體,並將濾液在減壓下蒸發至乾燥。將粗殘餘物懸浮於乙腈(750 mL)中,並在環境溫度下攪拌15 min。將該懸浮液通過玻璃料過濾,並將固體用另外的乙腈(75 mL)洗滌。將固體在氮氣流下乾燥,以得到N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(186 g,328 mmol,78%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.38 (br s, 1 H) 7.72 - 7.87 (m, 3 H) 7.39 (s, 1 H) 3.91 (br s, 4 H) 2.99 - 3.06 (m, 4 H) 2.32 (s, 3 H) 1.92 - 2.07 (m, 4 H) 1.62 - 1.85 (m, 4 H) 0.38 (s, 4 H)。m/z
(ESI): 568.0 (M+H)+
。
中間體20:4-溴-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-氟-6-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
步驟1:向在THF(50 mL)中的4-溴-2,6-二氟苯甲酸(3.0 g,12.7 mmol,阿波羅科技有限公司(Apollo Scientific Ltd.))的溶液中添加草醯氯(1.7 mL,19.0 mmol),隨後添加1滴DMF。將混合物攪拌1 h,然後在真空中除去溶劑,以得到固體,其不經進一步表徵即可直接用於下一階段。將固體溶解於DCM(50 mL)和無水吡啶(4.31 mL,50.6 mmol)中,隨後添加2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-胺(2.89 g,12.7 mmol,中間體4),並將混合物在室溫攪拌16 h。添加EtOAc(200 mL),並將混合物用飽和NH4
Cl(1x)、水(1x)、鹽水(1x)洗滌,經無水MgSO4
乾燥,過濾並在真空中濃縮,以得到油。該油藉由矽膠層析法進行純化,用0%至40% EtOAc/庚烷洗脫,以提供呈白色固體的4-溴-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2,6-二氟苯甲醯胺(1.36 g,3.04 mmol,24%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 11.24 (s, 1 H) 7.64 (d,J
=7.05 Hz, 2 H) 7.19 - 7.37 (m, 1 H) 3.86 (br s, 4 H) 2.32 (s, 3 H) 1.98 (br d,J
=11.40 Hz, 4 H)。m/z
(ESI): 447.0, 449.0 (M+H)+
。
步驟2:將在DMSO(2.5 mL)中的4-溴-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2,6-二氟苯甲醯胺(0.65 g,1.45 mmol)、6-氮雜螺[2.5]辛烷(0.18 g,1.60 mmol,藥明康得公司(Wuxi App Tech))和DIPEA(0.31 mL,1.74 mmol)加熱至100°C持續8 h,然後冷卻至室溫。添加水,將所得懸浮液過濾,並將獲得的固體乾燥。該固體藉由矽膠層析法進行純化,用0%至15% EtOAc/庚烷洗脫,以提供呈白色固體的4-溴-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-氟-6-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.23 g,0.43 mmol,28.2%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 10.86 (br s, 1 H) 7.30 (br s, 1 H) 7.21 (br d,J
=9.12 Hz, 1 H) 7.10 (br s, 1 H) 3.88 (br s, 4 H) 3.05 (br s, 4 H) 2.32 (br s, 3 H) 1.77 - 2.04 (m, 4 H) 1.36 (br s, 4 H) 0.27 (s, 4 H)。19
F NMR (376 MHz, DMSO-d 6
) δ ppm -94.88 (s, 1 F) -113.60 (s, 1 F)。m/z
(ESI): 538.2, 540.2 (M+H)+
。
中間體21:4-胺基-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
步驟1:將三乙胺(3.11 mL,22.2 mmol)和2,4,6-三丙基-1,3,5,2,4,6-三氧雜三膦烷2,4,6-三氧化物(在EtOAc中的50 wt%,13.2 mL,22.2 mmol)添加到在DCE(15 mL)中的2,5-二氟-4-硝基苯羧酸(1.5 g,7.39 mmol,康比樂公司(Combi-Blocks Inc.))和2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-胺(1.69 g,7.39 mmol,中間體4)的溶液,將混合物加熱至85°C持續2 h,然後冷卻至室溫。添加水(15 mL),分離所得兩相混合物,將有機層經無水MgSO4
乾燥,過濾並在真空中濃縮,以得到固體。將該固體懸浮於DCM(15 mL)中,過濾並乾燥,以提供呈黃色固體的N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2,5-二氟-4-硝基苯甲醯胺(3.05 g,4.55 mmol,62%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 11.15 (s, 1 H) 8.27 (dd,J
=8.81, 5.91 Hz, 1 H) 7.99 (dd,J
=10.57, 5.39 Hz, 1 H) 7.23 (br s, 1 H) 3.85 (br s, 3 H) 2.33 (s, 4 H) 1.89 - 2.05 (m, 4 H)。19
F NMR (376 MHz, DMSO-d 6
) δ ppm -95.11 (s, 1 F) -123.35 (s, 1 F) -123.40 (s, 1 F)。m/z
(ESI): 414.2 (M+H)+
。
步驟2:將N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2,5-二氟-4-硝基苯甲醯胺(1.0 g,2.42 mmol)和鈀(在活性炭上的10wt%,0.45 g,0.42 mmol)置於氬氣氣氛下,然後添加EtOH(15 mL),隨後添加甲酸銨(0.76 g,12.1 mmol)。將混合物在75°C下攪拌10 min,然後冷卻至室溫。使用CELITE®過濾出鈀,並將濾液在真空中濃縮。將所得殘餘物溶解於EtOAc(10 mL)中,並將溶液用水(2 x 10 mL)、鹽水(1 x 10 mL)洗滌,經無水MgSO4
乾燥,過濾,並在真空中濃縮以提供呈白色固體的4-胺基-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2,5-二氟苯甲醯胺(0.93 g,2.19 mmol,91%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 9.68 - 9.80 (m, 1 H) 7.40 (dd,J
= 11.61, 6.84 Hz, 1 H) 7.28 (s, 1 H) 6.54 (dd,J
= 13.48, 7.26 Hz, 1 H) 6.26 (s, 2 H) 3.83 - 3.90 (m, 4 H) 2.30 (s, 3 H) 1.92 - 2.05 (m, 4 H)。19
F NMR (376 MHz, DMSO-d 6
) δ ppm -95.07 (s, 1 F) -116.10 (s, 1 F) -140.24 (s, 1 F)。m/z
(ESI): 384.2 (M+H)+
。
步驟3:將在NMP(4 mL)中的4-胺基-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2,5-二氟苯甲醯胺(0.80 g,2.09 mmol)、6-氮雜螺[2.5]辛烷(0.70 g,6.26 mmol,藥明康得公司(Wuxi App Tech))和DIPEA(1.1 mL,6.26 mmol)在微波反應器中加熱至200°C持續4 h。添加水(4 mL),並將所得懸浮液攪拌30 min,過濾,將收集的固體乾燥以得到白色固體。將該固體溶解於DCM中,熔於矽膠並藉由矽膠層析法進行純化,用0%至50% EtOAc/庚烷洗脫,以提供呈白色固體的4-胺基-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(702 g,1.48 mmol,70.9%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.77 (s, 1 H) 7.64 (d,J
= 12.85 Hz, 1 H) 7.38 (s, 1 H) 6.83 (d,J
= 8.09 Hz, 1 H) 6.04 (s, 2 H) 3.90 (br t,J
= 5.39 Hz, 4 H) 2.91 (br s, 4 H) 2.29 (s, 3 H) 1.88 - 2.04 (m, 4 H) 0.37 (s, 4 H)。(注意:4個質子未觀察到)19
F NMR (376 MHz, DMSO-d 6
) δ ppm -94.73 (s, 1 F) -138.31 (s, 1 F)。m/z
(ESI): 475.2 (M+H)+
。
[表5]:中間體21-1至21-20按照中間體17至21的類似程序來製備:
中間體編號 | 化學結構 | 名稱 | LRMS: (ESI+ve離子)m/z |
21-1 | (R )-4-溴-N -(2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 486.1/488.1 | |
21-2 | (R )-4-碘-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 548.2 | |
21-3 | 4-溴-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 520.1/522.1 | |
21-4 | 4-溴-N -(2-(4,4-二氟哌啶-1-基)-6-(2-羥基丙烷-2-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 564.1/566.1 | |
21-5 | 4-溴-N -(2-(4,4-二氟哌啶-1-基)-6-乙基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 534.2/536.2 | |
21-6 | 4-溴-N -(6-環丙基-2-(4,4-二氟哌啶-1-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 546.1/548.1 | |
21-7 | 4-溴-5-氯-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 553.0/555.0 | |
21-8 | 4-溴-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-甲基-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 534.2/536.2 | |
21-9 | (R )-4-胺基-5-氟-N -(2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 441.2 | |
21-10 | (R )-4-胺基-5-氟-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 455.2 | |
21-11 | 4-胺基-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-甲氧基-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 487.4 | |
21-12 | 4-溴-N -(2-(4,4-二氟哌啶-1-基)-3-氟-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 537.1/539.1 | |
21-13 | 4-溴-N -(2-(4,4-二氟環己基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 519.1/521.1 | |
21-14 | N -(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 553.1 | |
21-15 | 4-溴-N -(2-(4,4-二氟哌啶-1-基)-6-甲基吡啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 519.1/521.1 | |
21-16 | 4-碘-N -(6-甲基-2-(3,3,3-三氟丙氧基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 561.0 | |
21-17 | 4-溴-N -(2-氯-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 435.0/437.0 | |
21-18 | N -(2-氯-6-甲基嘧啶-4-基)-4-硝基-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 402.2 | |
21-19 | N -(2-氯-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 434.4 | |
21-20 | N -(2-氯-6-甲基嘧啶-4-基)-4-(N -(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 506.1 |
中間體22:2-胺磺醯基丙酸乙酯
步驟1:在-78°C下向在四氫呋喃(4000 mL)中的N,N
-雙(4-甲氧基苄基)乙烷磺醯胺(200.0 g,572.0 mmol)的溶液中緩慢添加nBuLi(在己烷中1.6 M,608.0 mL,973.0 mmol),並攪拌30 min。向反應混合物中添加在THF(50 mL)中的乙基氯甲酸酯(92.0 mL,973.0 mmol),並在-78°C下攪拌1 h。將反應混合物用HCl(1.5 N, 3000 mL)淬滅並用EtOAc(2 x 3000 mL)萃取。將有機萃取物經硫酸鈉乾燥,過濾並在減壓下濃縮,以得到呈黃色油的2-(N,N-雙(4-甲氧基苄基)胺磺醯基)丙酸乙酯(250.0 g,60%純度)的粗物質。1
H-NMR顯示期望的峰,並且不經任何純化即可進行下一步驟。
步驟2:向在三氟乙酸(2.50 L,32.45 mol)中的2-(N,N
-雙(4-甲氧基苄基)胺磺醯基)丙酸乙酯(600.0 g,1.4 mol)的溶液中添加苯甲醚(500.0 mL,4.57 mol)並在室溫下攪拌3 h。將反應混合物在減壓下濃縮,用10%冷的NaHCO3
水溶液(3 L)淬滅並用EtOAc(2 x 3 L)萃取。將有機層經硫酸鈉乾燥,過濾並在減壓下濃縮。粗殘餘物藉由柱層析法在矽膠上使用在己烷中的25%乙酸乙酯進行純化,以得到淺黃色固體(168 g),將其溶解於DCM(1 L)中並藉由添加己烷(3000 mL)進行沈澱。將固體過濾,在真空中乾燥,以得到呈白色固體的標題化合物(109.0 g,42%產率)。1
H NMR (400 MHz, DMSO-d 6
)δ
ppm 7.14 (s, 2H), 4.15 (q,J
= 7.1 Hz, 2H), 3.98 (q,J
= 7.0 Hz, 1H), 1.45 (d,J
= 7.0 Hz, 3H), 1.21 (t,J
= 7.1 Hz, 3H)。m/z
(ESI): 180.1 (M+H)+
。
中間體23:2-羥基丙烷-1-磺醯胺
步驟1:在5 min內將甲磺醯氯(1.73 mL,22.3 mmol)逐滴添加至在DCM(40 mL)中的雙(4-甲氧基苄基)胺(5.0 g,19.4 mmol,康比樂公司(Combi-Blocks Inc.))和三乙胺(8.12 mL,58.3 mmol)的0°C溶液中。然後將混合物在室溫下攪拌2 h,然後添加1N HCl(50 mL)。分離各層,並將有機層用鹽水(1 x 50 mL)洗滌,經無水MgSO4
乾燥,過濾並然後在真空中濃縮,以得到棕色油。將該油溶解於MeOH(50 mL)中,並在真空中部分濃縮直到形成濃稠的懸浮液。將懸浮液攪拌30 min,過濾並將收集的固體在真空中乾燥,以提供呈白色固體的N
,N
-雙(4-甲氧基苄基)甲磺醯胺(5.11 g,15.2 mmol,78%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 7.19 (d,J
=8.50 Hz, 4 H) 6.90 (d,J
=8.50 Hz, 4 H) 4.19 (s, 4 H) 3.75 (s, 6 H) 2.89 (s, 3 H)。
步驟2:在-78°C下將正丁基鋰(4.10 mL,6.56 mmol)逐滴添加至在THF(15 mL)中的N
,N
-雙(4-甲氧基苄基)甲磺醯胺(2.0 g,5.96 mmol)的溶液中。將混合物攪拌10 min,之後逐滴添加乙醛(0.37 mL,6.56 mmol)。將該混合物在-78°C下攪拌5 min,然後用0°C浴代替-78°C浴。將混合物攪拌15 min並然後將反應用飽和NH4
Cl淬滅。添加EtOAc,分離所得兩相混合物,將有機層經無水MgSO4
乾燥,過濾並在真空中濃縮,以得到油。該油藉由矽膠層析法進行純化,用0%至70% EtOAc/庚烷梯度洗脫,以提供呈油的2-羥基-N,N
-雙(4-甲氧基苄基)丙烷-1-磺醯胺(1.84 g,4.85 mmol,81%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 7.16 (d,J
=8.50 Hz, 4 H) 6.80 - 6.92 (m, 4 H) 4.99 (d,J
=5.18 Hz, 1 H) 4.15 - 4.28 (m, 4 H) 4.01 - 4.13 (m, 1H) 3.74 (s, 6 H) 3.16 (dd,J
=13.99, 6.53 Hz, 1 H) 3.04 (dd,J
=13.89, 5.39 Hz, 1 H) 1.12 - 1.27 (m, 3 H)。m/z
(ESI): 402.2 (M+Na)+
。
步驟3:將在TFA(10 mL)中的2-羥基-N,N
-雙(4-甲氧基苄基)丙烷-1-磺醯胺(1.84 g,4.85 mmol)和苯甲醚(1.06 mL,9.70 mmol)的混合物在室溫下攪拌2 h,然後在真空中除去揮發物。所得油藉由矽膠層析法進行純化,用0%至100% EtOAc/庚烷梯度洗脫,以提供呈無色油的2-羥基丙烷-1-磺醯胺(592 g,4.25 mmol,88%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 6.70 (s, 2 H) 4.02 - 4.13 (m, 1 H) 3.50 - 3.25 (br s, 1H) 3.07 - 3.15 (m, 1 H) 2.98 - 3.06 (m, 1 H) 1.20 (d,J
=6.22 Hz, 3 H)。
實例1:N
-(2-((1-羥基-2-甲基丙烷-2-基)胺基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
將在NMP(1 mL)中的N
-(2-氯-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(200 mg,0.46 mmol,中間體21-19)、2-胺基-2-甲基-1-丙醇(180 uL,1.80 mmol,密蘇里州聖路易斯西格瑪奧德里奇公司(Aldrich, St. Louis, MO))和DIPEA(200 uL,1.14 mmol)的混合物在130°C下加熱60 h。將反應混合物冷卻至室溫並用水(10 mL)淬滅,用乙酸乙酯(2 x 10 mL)萃取。將有機層用鹽水(500 mL)洗滌,乾燥(Na2
SO4
),過濾並在減壓下濃縮。將粗物質吸附到矽膠塞上,並藉由柱層析法在矽膠(60-120目)上進行純化,用在己烷中的0%至70%乙酸乙酯洗脫,以得到呈灰白色固體的標題化合物(111 mg,49%)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 11.65-11.96 (m, 1H), 8.07-8.25 (m, 1H), 7.82-7.87 (m, 1H), 7.75-7.81 (m, 1H), 7.32-7.41 (m, 1H), 6.13-6.24 (m, 1H), 4.73-4.91 (m, 1H), 3.42-3.54 (m, 2H), 3.30-3.33 (m, 3H), 3.01-3.16 (m, 4H), 2.18-2.28 (m, 3H), 1.55-1.75 (m, 4H), 1.25-1.42 (m, 6H), 0.27-0.40 (m, 4H)。m/z
(ESI): 487.4 (M+H)+
。
[表6]:實例1-1至1-7按照如關於實例1所述的類似程序來製備:
實例編號 | 化學結構 | 名稱 | LRMS: (ESI+ve離子)m/z |
1-1 | (R )-N -(2-((1-羥基丙烷-2-基)胺基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 474.0 | |
1-2 | (S )-N -(2-((1-羥基丙烷-2-基)胺基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 474.0 | |
1-3 | N -(2-((2-羥基乙基)胺基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 460.4 | |
1-4 | (R )-N -(2-((2-羥基丙基)胺基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 474.4 | |
1-5 | (S)-N -(2-((2-羥基丙基)胺基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 474.4 | |
1-6 | N -(6-甲基-2-(3,3,3-三氟丙氧基)嘧啶-4-基)-4-(N-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 584.2 | |
1-7 | N -(2-((1-羥基-2-甲基丙烷-2-基)胺基)-6-甲基嘧啶-4-基)-4-(N-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 559.4 |
實例2:N
-(2-(2-羥基丙烷-2-基)嘧啶-4-基)-4-(N
-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
在0°C下向在二氯甲烷(2.6 mL)中的4-(N
-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸(150 mg,0.394 mmol,中間體15)和2-(4-胺基嘧啶-2-基)丙烷-2-醇(91 mg,0.591 mmol,美國賓夕法尼亞州布里斯托爾愛斯特公司(AstaTech, Bristol, PA, USA)的溶液中添加1-丙烷膦酸酐(在乙酸乙酯中的50%,0.469 mL,0.789 mmol,奧德里奇公司(Aldrich)),隨後添加DIPEA(0.207 mL,1.18 mmol,奧德里奇公司(Aldrich))。然後將所得混合物在室溫下攪拌過夜。然後將混合物用飽和NaHCO3
水溶液(2 mL)稀釋,隨後用飽和NH4
Cl(7 mL)稀釋。然後將該混合物用EtOAc(2 x 15 mL)萃取。然後將合併的有機萃取物經MgSO4
乾燥並濃縮。層析純化殘餘物(矽膠,0%至100% EtOAc/庚烷),以提供呈淺黃色固體的N
-(2-(2-羥基丙烷-2-基)嘧啶-4-基)-4-(N
-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(45 mg,0.087 mmol)。1
H NMR (DMSO-d6
) δ ppm 13.52 (br s, 1H), 8.76 (d,J
= 5.6 Hz, 1H), 8.54 (br d,J
= 3.5 Hz, 1H), 8.24 (d,J
= 8.1 Hz, 1H), 8.08 (br d,J
= 5.4 Hz, 1H), 7.86 (d,J
= 1.0 Hz, 1H), 7.74 (dd,J
= 8.1, 1.5 Hz, 1H), 4.96 (s, 1H), 4.55 (d,J
= 6.0 Hz, 2H), 4.13 (d,J
= 6.4 Hz, 2H), 3.08 (br t,J
= 5.2 Hz, 4H), 1.70 (br s, 4H), 1.51 (s, 6H), 1.41 (s, 3H), 0.38 (s, 4H)。m/z (ESI): 516.2 (M+H)+。
[表7]:實例2-1至2-8按照如關於實例2所述的類似程序來製備:
實例編號 | 化學結構 | 名稱 | LRMS: (ESI+ve離子)m/z |
2-1 | N -(2-(2-羥基丙烷-2-基)-6-甲基嘧啶-4-基)-4-(N -(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 530.2 | |
2-2 | (R )-N -(2-(2-甲基𠰌啉)嘧啶-4-基)-4-(N -(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 557.2 | |
2-3 | (R )-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-4-(N -(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 571.2 | |
2-4 | N -(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-4-(N -(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 576.2 | |
2-5 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(N-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 591.2 | |
2-6 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 520.0 | |
2-7 | (R )-N -(2-(2-甲基𠰌啉)嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 486.1 | |
2-8 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-甲基環丙烷)-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 575.4 |
實例3:(R
)-4-((2-羥基乙基)磺醯胺基)-N
-(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
將磷酸三鉀(9.89 g,46.6 mmol,西格瑪奧德里奇公司(Sigma-Aldrich))、碘化亞銅 (I)(0.710 g,3.73 mmol,西格瑪奧德里奇公司(Sigma-Aldrich))、2-羥基乙烷-1-磺醯胺(1.166 g,9.32 mmol,中國藥明康得公司(Wuxi Apptec, China))、肌胺酸(0.830 g,9.32 mmol)和(R
)-4-碘-N
-(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(5.1 g,9.32 mmol,中間體21-2)在氬氣下合併在三頸燒瓶中。添加乾燥的脫氣的DMF(20 mL),並在架空攪拌下將混合物加熱至110°C持續45 min。將反應混合物冷卻至環境溫度,並添加飽和的氯化銨(75 mL)、水(200 mL)和乙酸乙酸(200 mL)。混合並分離各相,有機層用鹽水(75 mL)乾燥,然後在減壓下蒸發至乾燥。將粗固體在沸騰的乙醇(15 mL)中攪拌10 m攪拌機,然後冷卻至環境溫度,並通過燒結的玻璃料過濾。將固體在玻璃料上乾燥,然後懸浮於水(75 mL)中,並加熱至80°C。10 min後,將混合物冷卻至環境溫度,並通過燒結的玻璃料過濾。將固體在氮氣流下乾燥,以得到呈灰白色固體的標題化合物(3.3 g,6.06 mmol,65.0%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.23 (bs, 1H), 10.26 (bs, 1H), 8.05 (m, 1H), 7.37 (s, 1H), 7.26 (s, 1H), 7.13 (s, 1H), 4.95 (bs, 1H), 4.50-4.42 (m, 2H), 3.84 (m, 1H), 3.76-3.74 (m, 2H), 3.51-3.45 (m, 2H), 3.00-2.82 (m, 6H), 2.61-2.58 (m, 2H), 2.31 (s, 3H), 1.91-1.65 (m, 4H), 1.17 (d,J
= 6.0 Hz, 3H), 0.39 (s, 4H). m/z (ESI): 545.2 (M+H)+。
實例4:N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
將在100 mL的圓底燒瓶中的2-羥基乙烷-1-磺醯胺(1.28 g,10.3 mmol,藥明康得公司(Wuxi AppTec))、碘化亞銅 (I)(0.49 g,2.56 mmol)、磷酸三鉀(5.44 g,25.6 mmol)和肌胺酸(0.48 g,5.13 mmol)的混合物置於氬氣氣氛下。添加無水DMF(20 mL),並將混合物溫熱至50°C持續5 min。添加固體的N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(2.91 g,5.13 mmol,中間體19),並將混合物加熱至100°C,攪拌2 h,然後冷卻至室溫。添加EtOAc(20 mL)和水(20 mL),分離所得兩相混合物,並將水層用EtOAc(3x)萃取。然後將合併的有機萃取物用水(2x)、9 : 1 NH4
Cl/NH4
OH(水溶液)、鹽水洗滌,經無水MgSO4
乾燥,過濾並在真空中濃縮,以得到油。該油藉由矽膠層析法進行純化,用0%至50% EtOAc/庚烷梯度洗脫,然後用50% EtOAc/庚烷等度洗脫,以提供灰白色固體。將該固體懸浮於甲醇中,過濾,並乾燥,以得到白色固體。然後將該固體懸浮於水中,攪拌24 h,過濾並在真空中乾燥以提供呈白色固體的N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(1.55 g,2.75 mmol,54%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.37 (s, 1 H) 10.03 - 10.52 (m, 1 H) 8.06 (d,J
= 8.71 Hz, 1 H) 7.41 (s, 1 H) 7.28 (d,J
= 1.87 Hz, 1 H) 7.15 (dd,J
= 8.71, 1.87 Hz, 1 H) 4.73 - 5.14 (m, 1 H) 3.92 (br t,J
= 5.39 Hz, 4 H) 3.77 (t,J
= 6.43 Hz, 2 H) 3.34 - 3.40 (m, 2 H) 2.98 (br t,J
= 4.56 Hz, 4 H) 2.32 (s, 3 H) 1.93 - 2.07 (m, 4 H) 1.58 - 1.85 (m, 4 H) 0.40 (s, 4 H)。19
F NMR (376 MHz, DMSO-d 6
) δ ppm -94.74 (s, 1 F)。m/z
(ESI): 565.2 (M+H)+
。
實例 5-1 和 5-2 :
(R
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺和(S
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
步驟1:將在DMF(15 mL)中的2-胺磺醯基丙酸乙酯(1.44 g,7.93 mmol,中間體22)、碘化亞銅 (I)(0.503 g,2.64 mmol,斯特倫公司(Strem))、肌胺酸(0.47 g,5.29 mmol,西格瑪奧德里奇公司(Sigma-Aldrich Corporation))和磷酸鉀(4.49 g,21.2 mmol)的混合物置於氬氣氣氛下,並溫熱至50°C持續5 min。添加N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(3.0 g,5.29 mmol,中間體19),並將混合物加熱至100°C持續3 h,然後冷卻至室溫。添加EtOAc(50 mL)、IPA(5 mL)和水(50 mL),並將混合物劇烈攪拌5 min。將所得兩相混合物轉移至分液漏斗且分離各層。有機層用EtOAc(2 x 20 mL)萃取,然後將合併的萃取物用水(2 x 50 mL)、9 : 1 NH4
Cl/NH4
OH(1 x 50 mL)洗滌,經無水MgSO4
乾燥,過濾並在真空中濃縮,以得到油。該粗油藉由矽膠層析法使用Redi-Sep預裝矽膠柱(80 g)進行純化,用0%至50% EtOAc/庚烷梯度洗脫,以提供呈白色固體的2-(N
-(4-((2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)胺基甲醯基)-3-(6-氮雜螺[2.5]辛-6-基)苯基)胺磺醯基)丙酸乙酯(2.76 g,4.45 mmol ,84%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.35 (s, 1 H) 10.69 (br s, 1 H) 8.07 (d,J
=8.71 Hz, 1 H) 7.40 (s, 1 H) 7.31 (d,J
=1.87 Hz, 1 H) 7.17 (dd,J
= 8.60, 1.97 Hz, 1 H) 4.06 (qd,J
=7.08, 4.87 Hz, 2 H) 3.92 (br t,J
=5.49 Hz, 4 H) 2.98 (br t,J
=4.77 Hz, 4 H) 2.32 (s, 3 H) 1.85 - 2.06 (m, 5 H) 1.73 (br s, 4 H) 1.48 (d,J
=6.84 Hz, 3 H) 1.14 (t,J
=7.05 Hz, 3 H) 0.39 (s, 4 H)。19
F NMR (376 MHz, DMSO-d 6
) δ ppm -94.75 (s, 1 F)。m/z
(ESI): 621.2 (M+H)+
。
步驟2:向250 mL的圓底燒瓶中添加在THF(100 mL)中的2-(N
-(4-((2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)胺基甲醯基)-3-(6-氮雜螺[2.5]辛-6-基)苯基)胺磺醯基)丙酸乙酯(10.39 g,16.74 mmol)和硼氫化鋰溶液(在THF中2.0M,16.7 mL,33.5 mmol,西格瑪奧德里奇公司(Sigma-Aldrich Corporation))。在5 min內緩慢添加甲醇(4.29 mL,134 mmol),並將所得溶液在室溫下攪拌30 min。緩慢添加1 N HCl(20 mL),隨後添加EtOAc(20 mL),並將所得兩相混合物轉移至分液漏斗中,分離各相。有機層用EtOAc(1 x 25 mL)萃取,並將合併的萃取物用飽和的NaHCO3
(1 x 50 mL)、鹽水(1 x 50 mL)洗滌,經無水MgSO4
乾燥,過濾並濃縮,以得到8.9 g的外消旋混合物。藉由製備型SFC使用Chiral Tech AD柱(250 X 30 mm,5 mm)用150 mL/min流速的85%液態CO2
和具有0.2% TEA的15% MeOH的流動相分離該物質,以得到:
實例5-1:(R
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺。第一個洗脫峰(3.50 g,6.05 mmol,36.1%產率,> 99%ee)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.36 (s, 1 H) 8.05 (d,J
= 8.50 Hz, 1 H) 7.40 (s, 1 H) 7.31 (d,J
= 1.87 Hz, 1 H) 7.17 (dd,J
= 8.71, 2.07 Hz, 1H) 3.88 - 3.97 (m, 4 H) 3.84 (dd,J
=10.99, 4.35 Hz, 1 H) 3.37 - 3.54 (m, 1 H) 3.25 - 3.30 (m, 1 H) 2.97 (br t,J
= 4.77 Hz, 4 H) 2.32 (s, 3 H) 1.84 -2.06 (m, 4 H) 1.57 - 1.84 (br s, 4 H) 1.30 (d,J
=6.84 Hz, 3 H) 0.39 (s, 4 H)。2個可交換的質子未觀察到。19
F NMR (376 MHz, DMSO-d 6
) δ ppm -94.74 (s, 1 F)。m/z
(ESI): 579.2 (M+H)+
。
實例5-2:(S
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺。第二個洗脫峰(2.66 g,4.60 mmol,27.5%產率,98.9%ee)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.35 (s, 1 H) 8.05 (d,J
=8.50 Hz, 1 H) 7.40 (s, 1 H) 7.31 (d,J
=2.07 Hz, 1 H) 7.17 (dd,J
=8.60, 1.97 Hz, 1H) 3.88 - 3.97 (m, 4 H) 3.84 (dd,J
=10.99, 4.35 Hz, 1 H) 3.50 (dd,J
=10.99, 7.46 Hz, 1 H) 3.25 - 3.32 (m, 1 H) 2.97 (br t,J
=4.77 Hz, 4 H) 2.31 (s, 3H) 1.83 - 2.06 (m, 4 H) 1.73 (br s, 4 H) 1.30 (d,J
=6.84 Hz, 3 H) 0.39 (s, 4 H)。2個可交換的質子未觀察到。19
F NMR (376 MHz, DMSO-d 6
) δ ppm -94.75 (s, 1 F)。m/z
(ESI): 579.2 (M+H)+
。立體化學係任意確定的。
[表8]:實例6-1至6-40按照實例3至5-2的類似程序來製備:
實例編號 | 化學結構 | 名稱 | LRMS: (ESI+ve離子)m/z |
6-1 | 4-((氟甲基)磺醯胺基)-N -(2-(4-氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 535.3 | |
6-2 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((氟甲基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 553.3 | |
6-3 | (R )-4-((氟甲基)磺醯胺基)-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 533.2 | |
6-4 | (R )-4-((2-羥基乙基)磺醯胺基)-N-(2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 531.2 | |
6-5 | (R )-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 515.2 | |
6-6 | (R )-4-(乙基磺醯胺基)-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 529.2 | |
6-7 | N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(乙基磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 549.2 | |
6-8 | (R )-4-((3-羥基丙基)磺醯胺基)-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 559.2 | |
6-9 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(3,3-二氧化-1,3,4-氧雜噻𠯤-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 577.2 | |
6-10 | 4-(環戊烷磺醯胺基)-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 589.3 | |
6-11 | 4-(環丁烷磺醯胺基)-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 575.2 | |
6-12 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(氧雜環丁烷-3-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 577.2 | |
6-13 | 4-(環丁烷磺醯胺基)-N-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 547.2 | |
6-14 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1,1-二甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 577.3 | |
6-15 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((3-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 579.2 | |
6-16 | 4-(環丙烷磺醯胺基)-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 561.2 | |
6-17 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-甲氧基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 579.9 | |
6-18 | 4-((環丙基甲基)磺醯胺基)-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 575.2 | |
6-19 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(((3-羥基氧雜環丁烷-3-基)甲基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 607.2 | |
6-20 | (N )-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1,1-二甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 593.2 | |
6-21 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(甲基磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 535.2 | |
6-22 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 563.2 | |
6-23-1 | 4-(((S )-2-羥基-1-甲基乙基)磺醯胺基)-N -(6-甲基-2-((R )-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 559.2 | |
6-23-2 | 4-(((R )-2-羥基-1-甲基乙基)磺醯胺基)-N -(6-甲基-2-((R )-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 559.2 | |
6-24-1 | 4-(((S )-2-羥基-1-甲基乙基)磺醯胺基)-N -(2-((R )-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 545.2 | |
6-24-2 | 4-(((R)-2-羥基-1-甲基乙基)磺醯胺基)-N -(2-((R )-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 545.2 | |
6-25-1 | (S )-N -(2-(4-氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 561.2 | |
6-25-2 | (R )-N -(2-(4-氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 561.2 | |
6-26-1 | (S )-N -(2-(4,4-二氟哌啶-1-基)嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 565.2 | |
6-26-2 | (R )-N -(2-(4,4-二氟哌啶-1-基)嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 565.2 | |
6-27-1 | 4-(((R )-2-羥基丙基)磺醯胺基)-N -(6-甲基-2-((R)-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 559.2 | |
6-27-2 | 4-(((S )-2-羥基丙基)磺醯胺基)-N -(6-甲基-2-((R)-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 559.2 | |
6-28-1 | (R )-4-((2-羥基丙基)磺醯胺基)-N -(6-甲基-2-(3,3,3-三氟丙氧基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 572.2 | |
6-28-2 | (S )-4-((2-羥基丙基)磺醯胺基)-N -(6-甲基-2-(3,3,3-三氟丙氧基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 572.2 | |
6-29 | N -(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 550.2 | |
6-30 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基吡啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 564.2 | |
6-31-1 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-(1-羥基乙基)環丙烷)-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 605.2 | |
6-31-2 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-(1-羥基乙基)環丙烷)-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 605.2 | |
6-32-1 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 579.1 | |
6-32-2 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 579.1 | |
6-33-1 | 4-(((S )-2-羥基丙基)磺醯胺基)-N -(2-((R)-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 545.2 | |
6-33-2 | 4-(((R )-2-羥基丙基)磺醯胺基)-N -(2-((R)-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 545.2 | |
6-34 | 5-氯-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 599.2 | |
6-35 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-5-甲基-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 579.2 | |
6-36 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-5-甲氧基-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 595.2 | |
6-37 | N -(2-(4,4-二氟哌啶-1-基)-6-(2-羥基丙-2-基)嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 609.1 | |
6-38 | N -(2-(4,4-二氟哌啶-1-基)-6-乙基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 579.2 | |
6-39 | N -(6-環丙基-2-(4,4-二氟哌啶-1-基)嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 591.2 | |
6-40 | (R )-4-((2-羥基乙基)磺醯胺基)-N-(6-(2-羥基丙-2-基)-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 589.3 |
實例
7
:
N
-(2-(3,3-
二氟氮雜環丁烷
-1-
基
)-6-
甲基嘧啶
-4-
基
)-4-((2-
羥基乙基
)
磺醯胺基
)-2-(6-
氮雜螺
[2.5]
辛
-6-
基
)
苯甲醯胺
步驟1:將在DMF(0.5 mL)和乙醇(1 mL)中的N
-(2-氯-6-甲基嘧啶-4-基)-4-硝基-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.3 mg,0.747 mmol,中間體21-18)、3,3-二氟氮雜環丁烷鹽酸鹽(0.145 g,1.120 mmol,康比樂公司(Combi-Blocks))和DIPEA(0.261 mL,1.49 mmol)的溶液在80°C下加熱4 h。然後將反應混合物用水(50 mL)淬滅並用乙酸乙酯(3 x 50 mL)萃取。合併的有機層用鹽水(50 mL)洗滌,經Na2
SO4
乾燥,過濾並濃縮。濃縮物藉由快速柱層析法用在石油醚中的30%至50%乙酸乙酯洗脫進行純化,以提供呈黃色固體的N
-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-硝基-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(180 g,0.393 mmol,52.6%產率)。1
H NMR (400 MHz, 氯仿-d
) δ ppm 8.47 (d,J
= 8.7 Hz, 1 H), 8.25 (d,J
= 2.2 Hz, 1 H), 8.17 (dd,J
= 8.7, 2.2 Hz, 1 H), 7.68 (s, 1 H), 3.79 - 3.66 (m, 4 H), 3.17 (t,J
= 5.4 Hz, 4 H), 2.60 (s, 3 H), 1.28 (s, 4 H), 0.50 (s, 4 H)。m/z
(ESI): 459.2 (M+H)+
。
步驟2:向在乙醇(8 mL)和水(8 mL)中的N-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-硝基-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.18 g,0.39 mmol)的溶液中添加鐵粉(0.066 g,1.18 mmol)和氯化銨(0.063 g,1.18 mmol)。然後將混合物在90°C下加熱3 h,然後將其通過CELITE®床過濾並用乙酸乙酯(3 × 100 mL)洗滌。濾液用鹽水洗滌,經Na2
SO4
乾燥,過濾並濃縮,以提供呈淺黃色固體的4-胺基-N
-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.12 g,0.280 mmol,71.3%產率)。其不經進一步純化即直接用於下一步驟中。m/z
(ESI): 429.2 (M+H)+
。
步驟3:在0°C下向在DCM(5 mL)中的4-胺基-N
-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.120 g,0.280 mmol)的溶液中添加Et3
N(0.078 mL,0.560 mmol)和2-(氯磺醯基)乙酸甲酯(0.058 g,0.336 mmol,康比樂公司(Combi-Blocks))。將混合物在室溫下攪拌4 h,然後將其用水(50 mL)淬滅並用DCM(3 × 50 mL)萃取。合併的有機層用鹽水(50 mL)洗滌,經Na2
SO4
乾燥,過濾並濃縮,以得到呈淺黃色固體的2-(N
-(4-((2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)胺基甲醯基)-3-(6-氮雜螺[2.5]辛-6-基)苯基)胺磺醯基)乙酸甲酯(140 g,0.25 mmol,89%產率)。其不經進一步純化即用於下一步驟中。m/z
(ESI): 565.2 (M+H)+
。
步驟4:在-30°C下將在THF(5 mL)中的2-(N
-(4-((2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)胺基甲醯基)-3-(6-氮雜螺[2.5]辛-6-基)苯基)胺磺醯基)乙酸甲酯(130 mg,0.230 mmol)的溶液用LiBH4
(230 µl,0.460 mmol)處理。將反應混合物在0°C下攪拌30 min,然後將其在0°C下用飽和NH4
Cl水溶液(50 mL)淬滅並用EtOAc(2 x 10 mL)萃取。合併的有機層用鹽水(5 mL)洗滌,經Na2
SO4
乾燥,過濾並濃縮。濃縮物藉由快速柱層析法用在己烷中的20%至100% EtOAc梯度洗脫進行純化,以提供呈白色固體的N
-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(60 mg,0.112 mmol,48.6%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.55 (s, 1 H), 10.28 (s, 1 H), 8.05 (d,J
=8.7 Hz, 1 H), 7.51 (s, 1 H), 7.28 (d,J
= 2.2 Hz, 1 H), 7.14 (dd,J
=8.6, 2.2 Hz, 1 H), 4.95 (s, 1 H), 4.45 (d,J
=12.3 Hz, 4 H), 3.76 (t,J
=6.4 Hz, 2 H), 3.64 (s, 1 H), 3.57 (s, 1 H), 2.97 (t,J
=5.4 Hz, 4 H), 2.34 (s, 3 H), 1.74 (br s, 4 H), 0.40 (s, 4 H)。m/z
(ESI): 537.2 (M+H)+
。
實例 8-1 和 8-2 :
(R
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺和(S
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
步驟1:在0°C下向在DCM(3 mL)中的4-胺基-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.41 g,0.86 mmol,中間體21)和三乙胺(0.18 mL,1.30 mmol)的溶液中添加2-(氯磺醯基)丙酸甲酯(177 mg,0.95 mmol,恩納公司(Enamine))。將混合物攪拌1 h,然後在真空中濃縮混合物,藉由矽膠層析法使用Redi-Sep預裝矽膠柱(12 g)進行純化,用25% EtOAc/庚烷梯度洗脫,以提供呈白色固體的2-(N-(4-((2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)胺基甲醯基)-2-氟-5-(6-氮雜螺[2.5]辛-6-基)苯基)胺磺醯基)丙酸甲酯(0.54 g,0.48 mmol,54.8%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.71 (s, 1 H) 10.66 (br s, 1 H) 7.88 (d,J
=11.61 Hz, 1 H) 7.60 (d,J
=7.26 Hz, 1 H) 7.39 (s, 1 H) 4.38 (d,J
=7.05 Hz, 1 H) 3.88 - 3.96 (m, 4 H) 3.57 (s, 3 H) 2.98 (br t,J
=4.56 Hz, 4 H) 2.33 (s, 3 H) 1.92 - 2.07 (m, 4 H) 1.57 - 1.91 (m, 4 H) 1.52 (d,J
=6.84 Hz, 3 H) 0.40 (s, 4 H)。19
F NMR (376 MHz, DMSO-d 6
) δ ppm -94.77 (s, 1 F) -126.39 (s, 1 F)。m/z
(ESI): 625.2 (M+H)+
。
步驟2:向2-(N
-(4-((2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)胺基甲醯基)-2-氟-5-(6-氮雜螺[2.5]辛-6-基)苯基)胺磺醯基)丙酸甲酯(192 mg,0.31 mmol)和硼氫化鋰(在THF中2.0 M,0.35 mL,0.69 mmol)的THF(2.5 mL)溶液中逐滴添加甲醇(0.10 mL,2.52 mmol)。將混合物攪拌30 min,然後添加水性NH4
Cl。將產物萃取到EtOAc(2x)中,並將合併的萃取物用無水MgSO4
乾燥,過濾並在真空中濃縮,以得到固體的外消旋產物。藉由製備型SFC使用OD柱(250 X 21 mm,5 mm)和OD柱(150 X 21 mm,5 mm)用80 mL/min流速的90%液態CO2
和10% EtOH/0.2%三乙胺的流動相分離該物質,以得到:
實例8-1:(R
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺。第一個洗脫峰(94 mg,0.16 mmol,33.2%產率,> 99%ee)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.74 (s, 1 H) 7.82 (d,J
=11.82 Hz, 1 H) 7.58 (d,J
=7.26 Hz, 1 H) 7.39 (s, 1 H) 3.77 - 3.96 (m, 6 H) 3.37 -3.54 (m, 1 H) 3.22 - 3.30 (m, 1 H) 2.88 - 3.05 (m, 4 H) 2.32 (s, 3 H) 1.92 - 2.05 (m, 4 H) 1.73 (br s, 4 H) 1.31 (d,J
=6.84 Hz, 3 H) 0.40 (s, 4 H)。19
F NMR (376 MHz, DMSO-d 6
) δ ppm -94.77 (s, 1 F) -127.36 (s, 1 F)。m/z
(ESI): 597.2 (M+H)+
。
實例8-2:(S
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺。第二個洗脫峰(102 mg,0.17 mmol,36.1%產率,> 98.4%ee)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.74 (s, 1 H) 7.82 (d,J
=11.82 Hz, 1 H) 7.58 (d,J
=7.26 Hz, 1 H) 7.39 (s, 1 H) 3.77 - 3.96 (m, 6 H) 3.37 -3.54 (m, 1 H) 3.22 - 3.30 (m, 1 H) 2.88 - 3.05 (m, 4 H) 2.32 (s, 3 H) 1.92 - 2.05 (m, 4 H) 1.73 (br s, 4 H) 1.31 (d,J
=6.84 Hz, 3 H) 0.40 (s, 4 H)。19
F NMR (376 MHz, DMSO-d 6
) δ ppm -94.76 (s, 1 F) -127.73 (s, 1 F)。m/z
(ESI): 597.2 (M+H)+
。立體化學係任意確定的。
[表9]:實例9-1至9-2按照實例8-1和8-2的類似程序來製備:
實例編號 | 化學結構 | 名稱 | LRMS: (ESI+ve離子)m/z |
9-1 | (R )-5-氟-4-((2-羥基乙基)磺醯胺基)-N-(2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 549.2 | |
9-2 | (R )-5-氟-4-((2-羥基乙基)磺醯胺基)-N-(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 563.2 |
實例10-1和10-2:(R
)-N
-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺和(S
)-N
-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
步驟1:將在NMP(10 mL)中的N
-(2-氯-6-甲基嘧啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(2.0 mg,4.14 mmol,中間體17)、3,3-二氟氮雜環丁烷鹽酸鹽(1.07 g,8.29 mmol,康比樂公司(Combi-Blocks Inc.))和碳酸鉀(1.72 g,12.4 mmol,康比樂公司(Combi-Blocks Inc.))的溶液加熱至90°C持續24 h。將混合物冷卻至室溫,添加EtOAc(10 mL),然後用水(1 x 10 mL)、1N HCl(1 x 10 mL)和鹽水(1 x 10 mL)洗滌混合物。然後將混合物經無水MgSO4
乾燥,過濾並在真空中濃縮,以得到固體。然後將該固體懸浮於MeOH中,過濾並在真空中乾燥以提供淺棕色固體的N
-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(1.16 g,2.15 mmol,51.9%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.53 (br s, 1 H) 7.79 - 7.86 (m, 2 H) 7.73 - 7.77 (m, 1 H) 7.49 (s, 1 H) 4.43 (t,J
=12.44 Hz, 4 H) 3.02 (br t,J
= 5.08 Hz, 4 H) 2.31 - 2.38 (m, 3 H) 1.65 - 1.82 (m, 4 H) 0.39 (s, 4 H)。19
F NMR (376 MHz, DMSO-d 6
) δ ppm -99.09 (s, 1 F)。m/z
(ESI): 540.0 (M+H)+
。
步驟2:將2-羥基丙烷-1-磺醯胺(206 mg,1.48 mmol,中間體23)、碘化亞銅 (I)(71 mg,0.37 mmol)、肌胺酸(66 mg,0.74 mmol)和磷酸鉀(787 mg,3.71 mmol)置於氬氣氣氛下,溶於無水DMF(3 mL)中,並溫熱至50°C持續5 min。一次添加N
-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.40 g,0.74 mmol),並將混合物加熱至100°C持續2.5 h,然後冷卻至室溫。添加水且將產物萃取到EtOAc(2x)中。然後將合併的萃取物用水(2x)、9 : 1飽和NH4
Cl/NH4
OH(1x)洗滌,經無水MgSO4
乾燥,過濾並在真空中濃縮,以得到呈油的外消旋產物。藉由製備型SFC使用IF柱(250 X 301 mm,5 mm)用130 mL/min流速的75%液態CO2
和25% MeOH的流動相分離該物質,以得到:
實例10-1:(R
)-N
-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺。第一個洗脫峰(88 mg,0.16 mmol,21.6%產率,> 99%ee)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.54 (s, 1 H) 8.05 (d,J
= 8.71 Hz, 1 H) 7.51 (s, 1 H) 7.27 (d,J
= 1.87 Hz, 1 H) 7.14 (dd,J
= 8.71, 1.87 Hz, 1H) 4.44 (t,J
= 12.44 Hz, 4 H) 4.07 - 4.15 (m, 1 H) 3.22 - 3.29 (m, 2 H) 2.97 (br t,J
= 4.87 Hz, 4 H) 2.34 (s, 3 H) 1.74 (br s, 4 H) 1.19 (d,J
= 6.22 Hz, 3H) 0.40 (s, 4 H)。2個可交換的質子未觀察到。19
F NMR (376 MHz, DMSO-d 6
) δ ppm -99.08 (s, 1 F)。m/z
(ESI): 551 (M+H)+
。
實例10-2:(S
)-N
-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺。第二個洗脫峰(89 mg,0.162 mmol,21.8%產率,> 99%ee)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.55 (s, 1 H) 8.05 (d,J
=8.71 Hz, 1 H) 7.51 (s, 1 H) 7.26 (d,J
= 1.87 Hz, 1 H) 7.14 (dd,J
= 8.71, 1.87 Hz, 1H) 4.43 (t,J
= 12.44 Hz, 4 H) 4.11 (d,J
= 6.01 Hz, 1 H) 3.21 - 3.31 (m, 2 H) 2.97 (br t,J
= 4.87 Hz, 4 H) 2.34 (s, 3 H) 1.53 - 2.01 (m, 4 H) 1.19 (d,J
= 6.43 Hz, 3 H) 0.40 (s, 4 H)。2個可交換的質子未觀察到。19
F NMR (376 MHz, DMSO-d 6
) δ ppm -99.09 (s, 1 F)。m/z
(ESI): 551 (M+H)+
。立體化學係任意確定的。
[表10]:實例11-1至11-83按照實例10的類似程序來製備:
實例編號 | 化學結構 | 名稱 | LRMS: (ESI+ve離子)m/z |
11-1 | (S )-4-((2-羥基乙基)磺醯胺基)-N-(2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 531.2 | |
11-2 | 4-((2-羥乙基)磺醯胺基)-N-(2-異丙基-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 488.1 | |
11-3 | N -(2-環丙基-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 486.1 | |
11-4 | N -(2-環丁基-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 516.2 | |
11-5 | N -(2-(3-氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 519.2 | |
11-6 | N -(2-(3-氟氮雜環丁烷-1-基)嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 505.1 | |
11-7 | N -(2-(3,3-二氟氮雜環丁烷-1-基)嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 523.1 | |
11-8 | 4-((2-羥基乙基)磺醯胺基)-N-(6-甲基-2-(2-氧雜-6-氮雜螺[3.3]庚-6-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 543.2 | |
11-9 | 4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(6-氧雜-1-氮雜螺[3.3]庚-1-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 543.2 | |
11-10 | N -(2-(3-(二氟甲氧基)氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 567.2 | |
11-11 | N -(2-(1,1-二氟-5-氮雜螺[2.3]己-5-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 563.2 | |
11-12 | 4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(3-(三氟甲基)氮雜環丁烷-1-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 569.2 | |
11-13 | N -(2-(3-氰基氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 526.2 | |
11-14 | 4-((2-羥基乙基)磺醯胺基)-N -(2-(3-(2-羥基丙-2-基)氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 559.2 | |
11-15 | N -(2-(3-羥基-3-甲基氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 531.2 | |
11-16 | N -(2-(3-環丙基-3-羥基氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 557.2 | |
11-17 | 4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(5-氮雜螺[2.3]己-5-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 527.2 | |
11-18 | N -(2-(3-羥基-3-(三氟甲基)氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 585.2 | |
11-19 | N -(2-(氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 501.2 | |
11-20 | N -(2-(3-羥基氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 517.2 | |
11-21 | (S )-N -(2-(3-(1-羥基乙基)氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 545.2 | |
11-22 | 4-(環丙烷磺醯胺基)-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 533.2 | |
11-23 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-(氧雜環丁烷-3-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 549.2 | |
11-24 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-(甲基磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 507.1 | |
11-25 | 4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(5-氮雜螺[2.4]庚-5-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 541.2 | |
11-26 | (R)4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(吡咯啶-1-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 515.2 | |
11-27 | (R )-N -(2-(3-氟-3-羥基吡咯啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 547.3 | |
11-28 | N -(2-(2-氮雜雙環[3.1.0]己-2-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 527.2 | |
11-29 | N -(2-((1R ,5S )-3-氮雜雙環[3.1.0]己-3-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 527.2 | |
11-30 | N -(2-(3,3-二氟吡咯啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 551.2 | |
11-31 | 4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(6-氮雜螺[2.5]辛-6-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 555.2 | |
11-32 | N -(2-((1R )-1-羥基-3-氮雜雙環[3.1.0]己-3-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 543.2 | |
11-33 | N -(2-(4-氰基哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 554.2 | |
11-34 | (R )-N -(2-(3-氰基哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 554.2 | |
11-35 | (S )-N -(2-(3-氰基哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 554.2 | |
11-36 | 4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(哌啶-1-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 529.3 | |
11-37 | 4-((2-羥基乙基)磺醯胺基)-N -(2-(4-羥基哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 545.2 | |
11-38 | N -(2-(4-羥基-4-甲基哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 559.2 | |
11-39 | N -(2-(3,3-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 565.2 | |
11-40 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(7-氮雜螺[3.5]壬-7-基)苯甲醯胺 | 579.2 | |
11-41 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(4,4-二甲基哌啶-1-基)-4-((2-羥基乙基)磺醯胺基)苯甲醯胺 | 567.2 | |
11-42 | N -(2-((1R )-1-羥基-3-氮雜雙環[4.1.0]庚-3-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 557.2 | |
11-43 | N -(2-((1R ,6R )-3-氮雜雙環[4.1.0]庚-3-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 541.2 | |
11-44 | N -(2-((1S,6R)-2-氮雜雙環[4.1.0]庚-2-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 541.2 | |
11-45 | (S )-4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 545.2 | |
11-46 | N -(2-(2,2-二甲基𠰌啉)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 559.3 | |
11-47 | 4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(4-氧雜-7-氮雜螺[2.5]辛-7-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 557.3 | |
11-48 | N -(2-((3S ,5R )-3,5-二甲基𠰌啉)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 559.3 | |
11-49 | N -(2-((3S,5S)-3,5-二甲基𠰌啉)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 559.3 | |
11-50 | N -(2-((3R ,5R )-3,5-二甲基𠰌啉)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 559.3 | |
11-51 | N -(2-(4-氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 547.2 | |
11-52 | N -(2-(4-氟-4-甲基哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 561.3 | |
11-53 | (S )-4-((2-羥基乙基)磺醯胺基)-N -(2-(3-羥基哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 545.2 | |
11-54 | (R )-4-((2-羥基乙基)磺醯胺基)-N -(2-(3-羥基哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 545.2 | |
11-55 | (R )-N -(2-(3-氟-3-甲基哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 561.2 | |
11-56 | N -(2-(4-氟哌啶-1-基)嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 533.2 | |
11-57 | N -(2-(4,4-二氟哌啶-1-基)嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 551.2 | |
11-58 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-氟-4-((2-羥基乙基)磺醯胺基)-6-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 583.2 | |
11-59 | 4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)-N-(2-(3,3,3-三氟丙氧基)吡啶-4-基)苯甲醯胺 | 543.2 | |
11-60 | 4-((2-羥基丙基)磺醯胺基)-N -(2-甲基-6-(3,3,3-三氟丙氧基)吡啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 557.2 | |
11-61 | 4-((2-羥基丙基)磺醯胺基)-N -(6-甲基-2-(3,3,3-三氟丙氧基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 558.2 | |
11-62 | N -(2-((1-羥基-2-甲基丙-2-基)胺基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 533.2 | |
11-63 | N -(2-(4,4-二氟哌啶-1-基)-3-氟吡啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 568.2 | |
11-64 | N -(2-(4,4-二氟哌啶-1-基)-3-氟-6-甲基吡啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 582.2 | |
11-65 | (R )-4-((2-羥基乙基)磺醯胺基)-N-(2-(2-甲基𠰌啉)吡啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 530.2 | |
11-66 | (R )-4-((2-羥基乙基)磺醯胺基)-N -(2-甲基-6-(2-甲基𠰌啉)吡啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 544.3 | |
11-67 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 583.4 | |
11-68 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基甲基)環丙烷-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 563.2 | |
11-69 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基甲基)環丙烷-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 591.2 | |
11-70 | (S )-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)-4-((四氫呋喃)-3-磺醯胺基)苯甲醯胺 | 563.2 | |
11-71 | (R )-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)-4-((四氫呋喃)-3-磺醯胺基)苯甲醯胺 | 563.2 | |
11-72 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)-4-((四氫呋喃)-3-磺醯胺基)苯甲醯胺 | 591.3 | |
11-73 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)-4-((四氫呋喃)-3-磺醯胺基)苯甲醯胺 | 591.3 | |
11-74 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((1-甲基環丙烷)-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 547.2 | |
11-75 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 535.2 | |
11-76 | (R )-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 551.2 | |
11-77 | (S )-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 551.2 | |
11-78 | 4-((環丙基甲基)磺醯胺基)-N-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 547.2 | |
11-79 | 4-((2-羥乙基)磺醯胺基)-N-(2-異丙氧基-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 504.2 | |
11-80 | (R )-4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-((四氫呋喃-3-基)氧)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 532.2 | |
11-81 | N -(2-(4-氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(甲基磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 517.2 | |
11-82 | 4-(乙基磺醯胺基)-N -(2-(4-氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 531.2 | |
11-83 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((1,1-二甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 549.2 |
實例12:N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
步驟1:將在二甲基亞碸(3 mL)中的N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺( 500 mg,0.881 mmol,中間體19)、三苯基膦(34.7 mg,0.132 mmol,美國密蘇里州聖路易斯奧德里奇公司(Aldrich, St. Louis, MO USA))、1,10-二氮雜菲(23.82 mg,0.132 mmol,美國密蘇里州聖路易斯奧德里奇公司(Aldrich, St. Louis, MO USA))、乙酸鈀(II)(9.89 mg,0.044 mmol,美國麻塞諸塞州紐伯里波特斯特倫(Strem Chemicals Inc., Newburyport, MA USA))、甲酸鈉(132 mg,1.939 mmol,美國紐約州格蘭德艾蘭的賽默飛世爾科技公司(Thermo Fisher Scientific, Grand Island, NY USA))和四丁基溴化銨(426 mg,1.322 mmol,美國密蘇里州聖路易斯奧德里奇公司(Aldrich, St. Louis, MO USA))的混合物在N2下於70°C下攪拌45 min。然後,將混合物冷卻至室溫,並添加碘乙酸乙酯(0.157 mL,1.322 mmol,美國密蘇里州聖路易斯奧德里奇公司(Aldrich, St. Louis, MO USA))。然後將混合物在室溫下攪拌10 min。然後將反應混合物用水(20 mL)稀釋並然後用EtOAc (2 x 40 mL)萃取。然後將合併的有機萃取物經MgSO4
乾燥並濃縮。層析純化殘餘物(矽膠,0%至100% EtOAc/庚烷),以提供呈淺黃色固體的2-((4-((2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)胺基甲醯基)-3-(6-氮雜螺[2.5]辛-6-基)苯基)磺醯基)乙酸乙酯(330 mg,0.558 mmol)。1
H NMR (DMSO-d6
) δ 13.14 (br s, 1H), 8.27 (br d,J
= 8.1 Hz, 1H), 7.97 (s, 1H), 7.84 (br d,J
= 7.7 Hz, 1H), 7.40 (s, 1H), 4.80 (s, 2H), 4.05 (q,J
= 7.2 Hz, 2H), 3.92 (br s, 4H), 3.03-3.13 (m, 4H), 2.34 (s, 3H), 1.90-2.07 (m, 4H), 1.71 (br s, 4H), 1.07 (t,J
= 7.0 Hz, 3H), 0.39 (s, 4H)。m/z (ESI): 592.3 (M+H)+。
步驟2:在N2
下於0°C下向在2-甲基四氫呋喃(3.5 mL)中的2-((4-((2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)胺基甲醯基)-3-(6-氮雜螺[2.5]辛-6-基)苯基)磺醯基)乙酸乙酯(320 mg,0.541 mmol)的溶液中逐滴添加硼氫化鋰溶液(在四氫呋喃中2.0M,0.541 mL,1.082 mmol,美國密蘇里州聖路易斯奧德里奇公司(Aldrich, St. Louis, MO USA))。添加後,將混合物在室溫下攪拌過夜。然後,將混合物用飽和NH4
Cl(18 mL)淬滅並在室溫下攪拌15 min。然後將該混合物用EtOAc(2 x 30 mL)萃取。然後將合併的有機萃取物經MgSO4
乾燥並濃縮。層析純化殘餘物(矽膠,0%至100% EtOAc/庚烷),以提供N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(60 mg,0.109 mmol,20%產率),呈白色固體的N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(60 mg,0.109 mmol)。1
H NMR (DMSO-d6
) δ ppm 13.17 (br s, 1H), 8.25 (br d,J
= 8.3 Hz, 1H), 7.93 (br s, 1H), 7.82 (br d,J
= 8.3 Hz, 1H), 7.40 (br s, 1H), 4.91 (br t,J
= 5.0 Hz, 1H), 3.92 (br s, 4H), 3.68-3.77 (m, 2H), 3.52-3.60 (m, 2H), 3.09 (br s, 4H), 2.34 (s, 3H), 1.87-2.08 (m, 4H), 1.70 (br d,J
= 1.0 Hz, 4H), 0.39 (s, 4H)。19
F NMR (DMSO-d6
) δ ppm -94.76 (s, 2F)。m/z (ESI): 550.1 (M+H)+。
實例13-1和13-2:(S
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺和(R
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
步驟1:將在4 mL DMSO中的N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(1.08 g,1.90 mmol,中間體19)、2-巰基丙-1-醇(0.48 g,5.21 mmol,Enamine)和碳酸鉀(0.237 mL,3.91 mmol)的溶液在密封瓶中於90°C下加熱4 h。將混合物冷卻至室溫,添加50 mL乙酸乙酯和10 mL鹽水。將有機層分離,用鹽水洗滌,乾燥並蒸發。將所得產物吸附到矽膠塞上,並藉由矽膠層析法進行純化(在庚烷中的0%至30% EtOAc),以得到呈黃色固體的N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙-2-基)硫)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺。1
H NMR (400 MHz, 氯仿-d) δ ppm 0.39 - 0.44 (m, 4 H) 1.37 - 1.43 (m, 3 H) 1.55 - 1.60 (m, 4 H) 1.96 - 2.04 (m, 4 H) 2.35 - 2.41 (m, 3 H) 3.01 - 3.11 (m, 4 H) 3.46 - 3.78 (m, 3 H) 3.96 - 4.05 (m, 4 H) 7.28 - 7.36 (m, 2 H) 7.48 - 7.53 (m, 1 H) 8.12 - 8.32 (m, 1 H) 13.01 - 13.37 (m, 1 H)。m/z
(ESI): 531.4 (M+H)+
。
步驟2:向在15mL THF中的N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙-2-基)硫)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.62 g,1.17 mmol)中添加在5 mL水中的oxone(r) 單過硫酸氫鹽化合物(0.72 g,1.17 mmol)。攪拌1.5 h後,LCMS顯示形成了碸和亞碸的混合物。添加另外的在3 mL水中的0.4g oxone。再攪拌2 h後,向反應混合物中添加EtOAc(50 mL)和鹽水(20 mL),並收集有機層,用鹽水洗滌,乾燥並蒸發。粗產物藉由製備型SFC使用 (S,S) Whelk-01(250 X 21 mm,5 mm)柱用80 mL/min流速的60%液態CO2
和40% MeOH的流動相進行純化,以得到N
-(5-氯-2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(337 mg,0.58 mmol,50%產率)。1
H NMR (400 MHz, 氯仿-d) δ ppm 0.30 - 0.57 (m, 4 H) 1.27 - 1.37 (m, 3 H) 1.59 - 1.72 (m, 4 H) 1.94 - 2.10 (m, 4 H) 2.40 - 2.54 (m, 3 H) 2.55 - 2.97 (m, 1 H) 3.05 - 3.23 (m, 4 H) 3.28 - 3.41 (m, 1 H) 3.84 - 4.06 (m, 6 H) 7.63 - 7.86 (m, 2 H) 8.13 - 8.37 (m, 1 H) 11.08 - 11.59 (m, 1 H)。m/z
(ESI): 598.3 (M+H)+
。藉由製備型SFC使用OD(250 X 21 mm,5 mm)用90 mL/min流速的85%液態CO2
和15% iPrOH的流動相分離該外消旋混合物,以產生:
實例13-1:(S
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙烷-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺。第一洗脫峰(85 mg,> 99%ee)。1
H NMR (400 MHz, 氯仿-d) δ ppm 12.74 - 13.01 (m, 1 H), 8.36 - 8.54 (m, 1 H), 7.69 - 8.03 (m, 2 H), 7.41 - 7.58 (m, 1 H), 3.83 - 4.06 (m, 6 H), 3.25 - 3.43 (m, 1 H), 3.03 - 3.17 (m, 4 H), 2.50 - 2.81 (m, 1 H), 2.31 - 2.42 (m, 3 H), 1.93 - 2.10 (m, 4 H), 1.61 - 1.90 (m, 4 H), 1.28 - 1.36 (m, 3 H), 0.35 - 0.50 (m, 4 H)。m/z
(ESI): 563.2 (M+H)+
。
實例13-2:(R
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙烷-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺。第二洗脫峰(84 mg,97%ee)。1
H NMR (400 MHz, 氯仿-d) δ ppm 12.71 - 13.05 (m, 1 H), 8.39 - 8.56 (m, 1 H), 7.74 - 8.03 (m, 2 H), 7.38 - 7.54 (m, 1 H), 3.81 - 4.04 (m, 6 H), 3.26 - 3.39 (m, 1 H), 3.03 - 3.19 (m, 4 H), 2.48 - 2.83 (m, 1 H), 2.33 - 2.41 (m, 3 H), 1.92 - 2.10 (m, 4 H), 1.60 - 1.90 (m, 4 H), 1.28 - 1.33 (m, 3 H), 0.36 - 0.46 (m, 4 H)。m/z
(ESI): 563.2 (M+H)+
。立體化學係任意確定的。
實例14:N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基-2-甲基丙烷-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
步驟1:將在3 mL二㗁𠮿中的N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.55 g,0.967 mmol,中間體19)、4,5-雙(二苯基膦)-9,9-二甲基-呫噸(0.034 g,0.058 mmol)、三(二亞苄基丙酮)二鈀 (0) 氯仿加合物(0.035 g,0.034 mmol)、DIPEA(0.4 mL,2.29 mmol)和2-巰基-2-甲基丙-1-醇(0.134 g,1.29 mmol)在密封管中通入N2
5min。將混合物在90°C下加熱3 h並冷卻至室溫。將所得粗產物吸附到矽膠塞上,並藉由矽膠層析法進行純化(在DCM中的0%至7% EtOAc),以得到N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基-2-甲基丙-2-基)硫)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺。1
H NMR (400 MHz, 氯仿-d) δ ppm 0.38 - 0.47 (m, 4 H) 1.25 - 1.31 (m, 6 H) 1.56 - 1.56 (m, 4 H) 1.94 - 2.04 (m, 4 H) 2.35 - 2.41 (m, 3 H) 3.03 - 3.12 (m, 4 H) 3.31 - 3.38 (m, 2 H) 3.95 - 4.04 (m, 4 H) 7.41 - 7.47 (m, 2 H) 7.48 - 7.52 (m, 1 H) 8.14 - 8.32 (m, 1 H) 12.96 - 13.41 (m, 1 H)。4H與水峰重疊。m/z
(ESI):546.2 (M+H)+
。
步驟2:向冷卻至0°C的在THF(15 mL)中的N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基-2-甲基丙-2-基)硫)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.36 g,0.66 mmol)添加在水(5 mL)中的oxone(r) 單過硫酸氫鹽化合物(0.52 g,0.85 mmol)。將混合物在從0°C至室溫下攪拌2.5 h。添加另外的0.35g oxone。1 h後,Icms顯示亞碸幾乎被消耗。添加乙酸乙酯(40 mL)和鹽水(20 mL),分離有機層,乾燥並蒸發。粗混合物藉由製備型SFC使用 (S,S
) Whelk-01(250 x 21 mm,5 mm)用80 mL/min流速的60%液態CO2
和40%MeOH的流動相進行純化,以得到N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基-2-甲基丙-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺。1
H NMR (400 MHz, 氯仿-d) δ ppm 8.15 - 8.73 (m, 1 H), 7.64 - 7.90 (m, 2 H), 7.41 - 7.52 (m, 1 H), 3.94 - 4.07 (m, 4 H), 3.70 - 3.83 (m, 2 H), 3.04 - 3.20 (m, 4 H), 2.34 - 2.47 (m, 3 H), 1.96 - 2.12 (m, 4 H), 1.47 - 1.95 (m, 4 H), 1.30 - 1.41 (m, 6 H), 0.37 - 0.52 (m, 4 H)。19
F NMR (376 MHz, 氯仿-d) δ ppm -96.68 (br s, 1 F)。m/z
(ESI): 578.2 (M+H)+
。
[表11]:實例14-1至14-8按照實例12至14的類似程序來製備:
實例編號 | 化學結構 | 名稱 | LRMS: (ESI+ve離子)m/z |
14-1 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(氧雜環丁烷-3-基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 562.3 | |
14-2 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(乙基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 534.2 | |
14-3 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(異丙基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 548.2 | |
14-4 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-2-甲基丙基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 578.2 | |
14-5 | 4-(環丙基磺醯基)-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 546.2 | |
14-6 | 4-(三級丁基磺醯基)-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 562.3 | |
14-7 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(((3R ,4R )-4-羥基四氫呋喃-3-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 592.2 | |
14-8 | N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(((3S,4S)-4-羥基四氫呋喃-3-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 592.2 | |
14-9 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)--4-(((1R,2R)-2-羥基環戊基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 590.2 |
實例15:N
-(2-(4,4-二氟環己基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
將在DMF(1.5 mL)中的4-溴-N-(2-(4,4-二氟環己基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲(0.055 g,0.106 mmol,中間體21-13)、2-羥基乙烷-1-磺醯胺(0.020 g,0.159 mmol,藥明康得公司(Wuxi))、磷酸三鉀(0.045 g,0.212 mmol)、碘化亞銅 (I) (0.020 g,0.106 mmol)和(1R,2R
)-N,N'-二甲基-1,2-環己二胺(7.53 mg,0.053 mmol,康比樂公司(Combi-Blocks))的混合物在90°C下加熱16 h。然後將反應混合物通過CELITE®墊的墊過濾,並用EtOAc稀釋濾液。將所得溶液用水和鹽水洗滌,經Na2
SO4
乾燥,過濾並濃縮。殘餘物藉由反相HPLC使用在水(0.1% TFA)中的60% ACN梯度進行純化,以得到呈白色固體的N
-(2-(4,4-二氟環己基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.025 g,0.044 mmol,42%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.70 (s, 1 H), 8.04 (d,J
= 8.8 Hz, 1 H), 7.92 (s, 1 H), 7.25 (d,J
= 2.2 Hz, 1 H), 7.16 - 7.08 (m, 1 H), 3.75 (t,J
= 6.3 Hz, 2 H), 3.03 - 2.85 (m, 6 H), 2.44 (d,J
= 4.5 Hz, 5 H), 2.05 (s, 5 H), 1.92 (d,J
= 11.7 Hz, 4 H), 1.72 (s, 4 H), 0.38 (s, 4 H)。m/z
(ESI): 564.1 (M+H)+。
實例16-1和16-2:(S
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-氟-1-(羥基甲基)乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺和(R
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-氟-1-(羥基甲基)乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
步驟1:在室溫下向在THF中的1-(苄氧基)-3-((三級丁基二甲基矽基)氧)丙烷-2-磺醯胺(0.803 g,2.23 mmol)的溶液中添加四丁基氟化銨溶液(2.75 mL,2.75 mmol,在THF中的1M)。將反應攪拌1 h,然後在減壓下濃縮。所得物質立即用於下一步驟。
步驟2:向裝有前一步驟的磺醯胺的壓力釋放瓶中添加碘化亞銅(I)(0.196 g,1.03 mmol)、甲基甘胺酸(0.128 g,1.440 mmol)、磷酸三鉀(0.934 g,4.40 mmol)和N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.975 g,1.72 mmol,中間體19)。將該瓶密封並抽空/用氮氣回填,然後添加DMF(7 mL)。蓋上蓋子,並將反應在預熱的100°C油浴中攪拌16 h。將反應混合物在飽和NH4
Cl : NH4
OH(9 : 1)和EtOAc之間分配。將有機相分離,用鹽水洗滌並在真空中濃縮。該物質藉由矽膠層析法(在庚烷中的20%至100% EtOAc)進行純化,以得到4-((2-(苄氧基)-1-(羥基甲基)乙基)磺醯胺基)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛基-6-基)苯甲醯胺(0.635 g,0.927 mmol,54.0%產率)。1
H NMR (400 MHz, 氯仿-d) δ ppm 13.11 (br dd, J=4.66, 2.38 Hz, 1 H) 8.14 (d, J=8.50 Hz, 1 H) 7.49 (br s, 1 H) 7.31 - 7.44 (m, 5 H) 7.13 (d, J=1.87 Hz, 1 H) 6.83 (dd, J=8.60, 2.18 Hz, 2 H) 4.49 - 4.62 (m, 2 H) 4.08 (dt, J=11.77, 5.83 Hz, 1 H) 3.94 - 4.03 (m, 5 H) 3.88 - 3.93 (m, 1 H) 3.95 (br s, 1 H) 3.45 - 3.55 (m, 1 H) 2.96 (br t, J=4.98 Hz, 4 H) 2.29 - 2.49 (m, 4 H) 1.95 - 2.07 (m, 4 H) 1.57 (br s, 4 H) 1.18 - 1.35 (m, 2 H) 0.85 - 0.91 (m, 1 H) 0.40 (s, 4 H)。m/z
(ESI, +ve離子): 683.8 (M+H)+
。
步驟3:在鹽水/冰浴中向在DCM(6 mL)中的xtalfluor-m(0.351 g,1.446 mmol)的溶液中藉由加料漏斗逐滴添加三乙胺三氟化氫(0.262 mL,1.61 mmol),隨後添加在DCM(10 mL)中的4-((2-(苄氧基)-1-(羥基甲基)乙基)磺醯胺基)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛基-6-基)苯甲醯胺(0.55 g,0.803 mmol)。將反應逐漸溫熱至室溫並攪拌16 h。將反應用飽和碳酸氫鈉(水溶液)淬滅,並用水和DCM稀釋。將有機相分離,用鹽水洗滌,經硫酸鎂乾燥並在真空中濃縮。粗物質藉由矽膠層析法(在庚烷中的20%至100% EtOAc)進行純化,以得到外消旋-4-((2-(苄氧基)-1-(氟甲基)乙基)磺醯胺基)-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺和4-((1-((苄氧基)甲基)乙烯基)磺醯胺基)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺的1 : 0.8混合物(265 mg)。該混合物不經進一步純化即繼續使用。
步驟4:向在EtOH(20 mL)中的265 mg來自前一步驟的產物混合物和在碳上的氫氧化鈀(0.135 g,0.193 mmol)的懸浮液中添加AcOH(0.033 mL,0.579 mmol)。將反應在55 psi氫氣下在室溫下氫化24 h。用氮氣沖洗反應後,添加另外部分的在碳上的氫氧化鈀(0.135 mL,0.193 mmol),隨後添加另外的AcOH(0.033 mL,0.579 mmol)。將反應容器用N2
沖洗,然後用55 psi氫氣置換氣氛。將反應在室溫下繼續另外的48 h。將反應用氮氣沖洗,然後經CELITE®過濾並在真空中濃縮濾液。藉由製備型SFC使用IE(250 x 21 mm,5 mm)用80%液態CO2
和20% MeOH的流動相(80 mL/min的流速)分離外消旋混合物,以得到:
實例16-1:(S
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-氟-1-(羥基甲基)乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺。第一洗脫峰1
H NMR (400 MHz, DMSO-d6
) δ ppm 13.35 (s, 1 H), 10.21 - 10.84 (m, 1 H), 8.06 (d,J
= 8.50 Hz, 1 H) 7.40 (s, 1 H), 7.29 (d, J=2.07 Hz, 1 H), 7.16 (dd, J=8.50, 2.07 Hz, 1 H), 5.12 - 5.38 (m, 1 H), 4.88 - 4.97 (m, 1 H) 4.71 - 4.84 (m, 1 H), 3.85 - 4.01 (m, 5 H), 3.74 (dd,J
= 11.30, 7.98 Hz, 1 H), 3.51 - 3.63 (m, 1 H) 2.98 (br t,J
= 4.77 Hz, 4 H), 2.32 (s, 3 H), 1.93 - 2.07 (m, 4 H), 1.51 - 1.91 (m, 4 H), 0.40 (s, 4 H)。m/z
(ESI, +ve離子): 597.2 (M+H)+
。
實例16-2:(R
)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-氟-1-(羥基甲基)乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺。第二洗脫峰。1
H NMR (400 MHz, DMSO-d6
) δ ppm 13.35 (s, 1 H) 10.32 - 10.70 (m, 1 H) 8.05 (d,J
= 8.71 Hz, 1 H) 7.40 (s, 1 H) 7.29 (d,J
= 2.07 Hz, 1 H) 7.16 (dd,J
= 8.71, 2.07 Hz, 1 H) 5.14 - 5.40 (m, 1 H) 4.85 - 4.97 (m, 1 H) 4.73 - 4.84 (m, 1 H) 3.87 - 3.98 (m, 5 H), 3.74 (dd,J
= 11.09, 7.98 Hz, 1 H) 3.48。m/z
(ESI, +ve離子): 597.2 (M+H)+
。立體化學係任意確定的。
實例17:N
-(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-4-(N-(2-羥基乙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
在玻璃管中將在IPA(3 mL)中的N-(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(212 mg,0.384 mmol,中間體21-14)、1,4-二氮雜雙環[2.2.2]辛烷雙(二氧化硫)加合物(DABSO)(55 mg,0.23 mmol,西格瑪奧德里奇公司(Sigma-Aldrich Corporation))、二乙醯氧基鈀(13 mg,0.06 mmol,斯特倫公司(Strem))、((3R,5R,7R)-金剛烷-1-基)((3S,5S,7S)金剛烷-1-基)(丁基)膦(cataCXium®A)(28 mg,0.08 mmol,斯特倫公司(Strem))和三乙胺(107 uL,0.77 mmol)的混合物脫氣3 min。將該管密封,然後在油浴中於85°C加熱3 h。將非均相混合物冷卻至室溫,用2-胺基乙-1-醇(47 mg,0.77 mmol,西格瑪奧德里奇公司(Sigma-Aldrich))處理,隨後用次氯酸鈉溶液(10 wt%,571 mg,0.77 mmol,西格瑪奧德里奇公司(Sigma-Aldrich))處理,並在室溫下攪拌18 h。將混合物用2-胺基乙-1-醇(23 mg)處理,隨後用次氯酸鈉溶液(10 wt%,275 mg)處理,然後在室溫下攪拌5 h。向非均相混合物中添加EtOAc(20 mL)和水(5 mL),並濾出不溶性固體。將濾餅用水(2 x 2 mL)洗滌,隨後用EtOAc(2 x 4 mL)洗滌。取有機溶液並在真空中濃縮。殘餘物藉由矽膠層析法(在庚烷中的10%至60% EtOAc)進行純化,以得到呈灰白色固體的N
-(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-4-(N-(2-羥基乙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(100 mg,0.18 mmol,47%產率)。1
H NMR (400 MHz, 甲醇-d4
) δ ppm 7.99-8.14 (m, 2H), 7.79 (s, 1H), 7.68 (d,J
= 7.88 Hz, 1H), 7.47 (s, 1H), 7.01 (d,J
= 4.77 Hz, 1H), 3.76 (t,J
=5.29 Hz, 4H), 3.58 (t,J
= 5.91 Hz, 2H), 3.16 (t,J
= 5.08 Hz, 4H), 3.02 (t,J
= 5.80 Hz, 2H), 1.98-2.11 (m, 4H), 1.62 (s, 4H), 0.42 (s, 4H)。m/z
(ESI): (M+H)+
550.1。
[表12]:實例17-1至17-8按照實例17的類似程序來製備:
實例編號 | 化學結構 | 名稱 | LRMS: (ESI+ve離子)m/z |
17-1 | 4-((2-羥基乙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)-N-(2-(3,3,3-三氟丙氧基)嘧啶-4-基)苯甲醯胺 | 544.2 | |
17-2 | 4-(N -(2-羥基丙基)胺磺醯基)-N -(6-甲基-2-(3,3,3-三氟丙氧基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 558.2 | |
17-3 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)4-(N -(2-羥基乙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 565.2 | |
17-4 | N -(2-(4,4-二氟哌啶-1-基)嘧啶-4-基)-4-(N-(2-羥基乙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 551.2 | |
17-5 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)4-(N -(2-羥基乙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 537.2 | |
17-6 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙烷-2-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 579.4 | |
17-7 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙烷-2-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 579.4 | |
17-8 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(N -(2-羥基-2-甲基丙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 593.4 |
實例18-1和18-2:2-(6-氮雜螺[2.5]辛-6-基)-4-(R
-環丙基磺醯亞胺基)-N
-(2-(4,4-二氟-1-哌啶基)-6-甲基-4-嘧啶基)苯甲醯胺和2-(6-氮雜螺[2.5]辛-6-基)-4-(S
-環丙基磺醯亞胺基)-N
-(2-(4,4-二氟-1-哌啶基)-6-甲基-4-嘧啶基)苯甲醯胺
步驟1:將N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-碘-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(1.00 g,1.762 mmol,中間體19)<autotext key="1B5C19C3" name="[Reactants]" index="1" field="Reactants" type="field" length="125" />、三(二亞苄基丙酮)二鈀(0)(0.161 g,0.176 mmol)<autotext key="1B5C19C4" name="[Reactants]" index="3" field="Reactants" type="field" length="65" />和4,5-雙(二苯基膦)-9,9-二甲基-𠮿口星(0.102 g,0.176 mmol)<autotext key="1B5C19C5" name="[Reactants]" index="4" field="Reactants" type="field" length="71" />,隨後1,4-二㗁𠮿(10 mL)<autotext key="1B5C19C6" name="[Solvents]" index="1" field="Solvents" type="field" length="19" />置於20 mL微波容器中。將所得混合物攪拌並用氮氣吹掃5 min,然後在氮氣下添加1,1'-二甲基三乙胺(0.616 mL,3.52 mmol)<autotext key="1B5C19C8" name="[Reactants]" index="5" field="Reactants" type="field" length="48" />,隨後添加環丙烷硫醇(0.142 mL,1.939 mmol)<autotext key="1B5C19C9" name="[Reactants]" index="2" field="Reactants" type="field" length="40" />。將容器密封並再次經受微波條件(10 h,90°C)。將粗混合物直接負載到矽膠預柱上,並在40-g ISCO金柱上進行combi-快速柱層析法,用MeOH/DCM(5 min在0%,25 min從0%至6%)洗脫兩次,以得到呈灰白色固體的4-(環丙基硫)-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.92 g,1.791 mmol,102%產率)<autotext key="1B5C19CA" name="[Products]" index="1" field="Products" type="field" length="150" />。1
H NMR (400 MHz, 二氯甲烷-d2
) δ ppm 13.33 (s, 1H), 8.15 (d,J
=8.29 Hz, 1H), 7.48 (s, 1H), 7.22-7.35 (m, 2H), 3.91-4.09 (m, 4H), 3.06 (br t,J
=5.18 Hz, 4H), 2.35 (s, 3H), 2.17-2.28 (m, 1H), 1.62-2.10 (m, 6H), 1.52 (s, 2H), 1.13-1.21 (m, 2H), 0.68-0.76 (m, 2H), 0.40 (s, 4H)。m/z
(ESI): 514.1 (M+H)+
。
步驟2:向在MeOH(4.5 mL)和二氯甲烷(9.0 mL)中的4-(環丙基硫)-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.89 g,1.733 mmol)和碳酸銨(0.250 g,2.60 mmol)溶液中一次添加固體(乙醯氧基)(苯基)-碘乙酸酯(1.284 g,3.99 mmol)。將所得混合物在開放空氣下在室溫下攪拌18 h。將所得混合物直接負載到矽膠預柱(25 g)上,並在40-g ISCO金柱上進行combi-快速柱層析法,用MeOH/DCM(3 min在0%,25 min從0%至14%)洗脫,以得到呈灰白色固體的4-(環丙烷磺醯亞胺基)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺的外消旋混合物(0.95 g,1.744 mmol,101%產率)。藉由製備型SFC使用Regis (S,S) Whelk-01(250 X 21 mm,5 mm)用60 mL/min流速的50%液態CO2
和50% MeOH的流動相分離鏡像異構物,以產生:
實例18-1:2-(6-氮雜螺[2.5]辛-6-基)-4-(R
-環丙基磺醯亞胺基)-N
-(2-(4,4-二氟-1-哌啶基)-6-甲基-4-嘧啶基)苯甲醯胺。第一洗脫峰,1
H NMR (400 MHz, 氯仿-d) δ ppm 13.20 (br d, J=3.73 Hz, 1H), 8.44 (d,J
=8.29 Hz, 1H), 7.96 (d, J=1.45 Hz, 1H), 7.87 (dd, J=1.66, 8.29 Hz, 1H), 7.52 (s, 1H), 4.03 (br s, 4H), 3.14 (t, J=5.29 Hz, 4H), 2.53-2.63 (m, 1H), 2.44 (br s, 3H), 1.95-2.10 (m, 4H), 1.53-1.89 (m, 5H), 1.45 (tdd, J=5.08, 6.92, 10.29 Hz, 1H), 1.20-1.30 (m, 1H), 1.07-1.17 (m, 1H), 0.93-1.03 (m, 1H), 0.44 (s, 4H)。m/z
(ESI): 545.2 (M+H)+
。
實例18-2:2-(6-氮雜螺[2.5]辛-6-基)-4-(R
-環丙基磺醯亞胺基)-N
-(2-(4,4-二氟-1-哌啶基)-6-甲基-4-嘧啶基)苯甲醯胺第二洗脫峰。1
H NMR (400 MHz, 氯仿-d) δ ppm 13.20 (br d, J=3.73 Hz, 1H), 8.44 (d, J=8.29 Hz, 1H), 7.96 (d, J=1.45 Hz, 1H), 7.87 (dd, J=1.66, 8.29 Hz, 1H), 7.52 (s, 1H), 4.03 (br s, 4H), 3.14 (t, J=5.29 Hz, 4H), 2.53-2.63 (m, 1H), 2.44 (br s, 3H), 1.95-2.10 (m, 4H), 1.53-1.89 (m, 5H), 1.45 (tdd, J=5.08, 6.92, 10.29 Hz, 1H), 1.20-1.30 (m, 1H), 1.07-1.17 (m, 1H), 0.93-1.03 (m, 1H), 0.44 (s, 4H)。m/z
(ESI): 545.2(M+H)+ 。
立體化學確定係任意的。
[表13]:實例19-1至19-9按照關於實例18-1和18-2所述的程序來製備:
實例編號 | 化學結構 | 名稱 | LRMS: (ESI+ve離子)m/z |
19-1 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(氧雜環丁烷-3-磺醯亞胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 561.2 | |
19-2 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(甲基磺醯亞胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 519.2 | |
19-3 | 2-(6-氮雜螺[2.5]辛-6-基)-N -(2-(4,4-二氟-1-哌啶基)-6-甲基-4-嘧啶基)-4-(S -乙基磺醯亞胺基)苯甲醯胺 | 533.2 | |
19-4 | 2-(6-氮雜螺[2.5]辛-6-基)-N -(2-(4,4-二氟-1-哌啶基)-6-甲基-4-嘧啶基)-4-(R -乙基磺醯亞胺基)苯甲醯胺 | 533.2 | |
19-5 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(丙-2-基磺醯亞胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 547.3 | |
19-6 | 4-(環丙烷磺醯亞胺基)-N -(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 530.0 | |
19-7 | 2-(6-氮雜螺[2.5]辛-6-基)-4-(S -環丙基磺醯亞胺基)-N -(6-甲基-2-((2R)-2-甲基-4-𠰌啉基)-4-嘧啶基)苯甲醯胺 | 525.2 | |
19-8 | 2-(6-氮雜螺[2.5]辛-6-基)-4-(R -環丙基磺醯亞胺基)-N -(6-甲基-2-((2R )-2-甲基-4-𠰌啉基)-4-嘧啶基)苯甲醯胺 | 525.2 | |
19-9 | 4-(環丙烷磺醯亞胺基)-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 517.3 |
實例20:(N1
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)對苯二甲醯胺
步驟1:向在DMF(2.5 mL)中的4-溴-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(250 mg,0.48 mmol,中間體21-3)的溶液中添加Pd(PPh3
)4
(6 mg,4.8 µmol)和Zn(CN)2
(113 mg,0.961 mmol),並將反應混合物在100°C下攪拌16 h。然後將反應混合物用EtOAc稀釋並通過CELITE®床過濾。將濾液用水和鹽水洗滌,經Na2
SO4
乾燥,過濾並濃縮,並藉由快速柱狀層析法使用在石油醚中的30% EtOAc梯度進行純化,以提供呈灰白色固體的4-氰基-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(160 mg,0.343 mmol,71.4%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.20 (s, 1 H), 8.18 (d,J
=8.1 Hz, 1 H), 8.03 (s, 1 H), 7.79 (d,J
=8.1 Hz, 1 H), 7.39 (s, 1 H), 4.00 - 3.80 (m, 4 H), 3.07 (t,J
=5.2 Hz, 4 H), 2.34 (s, 3 H), 1.99 (tt,J
=13.3, 5.7 Hz, 4 H), 1.69 (s, 4 H), 0.38 (s, 4 H)。m/z
(ESI): 467.2 (M+H)+
。
步驟2:在0°C下向在二甲亞碸(2 mL)中的4-氰基-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(110 mg,0.236 mmol)的溶液中添加K2
CO3
(6.52 mg,0.047 mmol)和H2
O2
(103 µL,1.179 mmol),並將反應混合物攪拌1 h,然後將其用水淬滅並用EtOAc(2 x 20 mL)萃取。將合併的有機層用鹽水洗滌,經Na2
SO4
乾燥,過濾,濃縮並藉由快速柱狀層析法使用在二氯甲烷中的10%甲醇梯度進行純化,以提供呈灰白色固體的N1
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)對苯二甲醯胺(108 mg,0.223 mmol,95%產率)。1
H NMR (400 MHz, DMSO-d 6
) δ ppm 13.75 (s, 1 H), 8.26 (m, 1 H), 8.17 (m, 1 H), 8.00 (s, 1 H), 7.89 - 7.78 (m, 1 H), 7.61 (s, 1 H), 7.42 (s, 1 H), 3.94 (d,J
=5.8 Hz, 4 H), 3.06 (d,J
=6.0 Hz, 4 H), 2.34 (d,J
=2.3 Hz, 3 H), 2.01 (q,J
=8.5, 8.1 Hz, 4 H), 1.74 (s, 4 H), 0.41 (d,J
=2.3 Hz, 4 H)。m/z
(ESI): 485.2 (M+H)+
。
實例21:4-(氮雜環丁烷-3-基磺醯基)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
向在DMF(35 mL)中的4-((1-(三級丁氧基羰基)氮雜環丁烷-3-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲酸(2.54 g,5.64 mmol,中間體16)和HATU(3.22 g,8.46 mmol,坎佩公司(ChemPep))的溶液中添加2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-胺(1.93 g,8.46 mmol,中間體4)和DIPEA(2.46 mL,14.09 mmol)。將混合物在室溫下攪拌18 h。用飽和Na2
CO3
和EtOAc稀釋混合物。分離有機物,並用Na2
CO3
、水和鹽水洗滌,經Na2
SO4
乾燥並在真空中濃縮。粗產物藉由矽膠層析法進行純化:在庚烷中的0%至30%至60% EtOAc。m/z
(ESI): 661.3 (M+H)+
。將殘餘物在室溫下用DCM(8 mL)和TFA(4 mL)處理30 min,並在真空中濃縮。將所得固體懸浮於EtOAc中,並用1N NaOH溶液洗滌,將混合物用EtOAc萃取。將有機萃取物用水和鹽水洗滌,經Na2
SO4
乾燥並在真空中濃縮。粗產物藉由矽膠層析法進行純化:具有2% NH4OH的DCM中的0%至20% MeOH,以得到呈白色固體的標題化合物。1
H NMR (400 MHz, 甲醇-d4
) δ ppm 8.35 (d,J
=8.09 Hz, 1H), 7.90 (d,J
=1.24 Hz, 1H), 7.81 (dd,J
=1.66, 8.09 Hz, 1H), 7.46 (s, 1H), 4.46-4.60 (m, 1H), 3.97-4.06 (m, 6H), 3.76-3.86 (m, 2H), 3.10-3.21 (m, 4H), 2.37 (s, 3H), 1.93-2.01 (m, 4H), 1.73-1.88 (m, 4H), 0.45 (s, 4H)。m/z
(ESI): 561.2 (M+H)+
。
實例22:4- N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-甲基氮雜環丁烷-3-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺
向4-(氮雜環丁烷-3-基磺醯基)-N
-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺(0.045 g,0.080 mmol,實例21)、MeOH(1 mL)和具有10%至15% MeOH的甲醛(0.016 g,0.482 mmol,飛世爾公司(Fisher))的混合物中添加AcOH(0.037 mL,0.642 mmol,奧德里奇公司(Aldrich)),隨後添加三乙醯氧基硼氫化鈉(0.204 g,0.963 mmol,奧德里奇公司(Aldrich))。將混合物在室溫下攪拌18 h,並在真空中濃縮。用1N NaOH溶液中和酸,並將混合物用EtOAc萃取。將有機相用水和鹽水洗滌,經Na2
SO4
乾燥並在真空中濃縮。藉由矽膠層析法純化:庚烷中的0%至100% EtOAc/EtOH(3/1),以得到呈白色固體的標題化合物。1
H NMR (400 MHz, 氯仿-d) δ ppm 12.82 (br s, 1H), 8.44 (d,J
=8.29 Hz, 1H), 7.82 (d,J
=1.66 Hz, 1H), 7.73 (dd,J
=1.76, 8.19 Hz, 1H), 7.46 (s, 1H), 3.97-4.11 (m, 5H), 3.60-3.90 (m, 4H), 3.12 (t,J
=5.29 Hz, 4H), 2.44-2.57 (m, 3H), 2.39 (s, 3H), 1.68-2.06 (m, 8H), 0.43 (s, 4H)。m/z
(ESI): 575.3 (M+H)+
。
生物學實例
以下測定法用於測試本發明的示例性化合物。根據下述程序測試的那些實例的數據示於下表A中。
KIF18A酶測定:使用微管刺激的ATP酶活性測定測量用化合物處理後的KIF18A酶活性。在22個濃度點範圍內,將化合物在DMSO(西格瑪公司(Sigma Inc))中連續稀釋2倍。使用桿狀病毒系統表現重組人KIF18A(1-467 His-標記的)蛋白,並藉由美商安進公司(Amgen Inc.)的親和層析法進行純化。使用ADP-GloTM
激酶/ATP酶測定套組(普羅米加公司(Promega Inc))對反應中的KIF18A蛋白、微管(MT)和ATP的濃度進行優化以進行標準化的同質酶測定。該測定測量由ATP酶反應形成的ADP。製備反應緩衝液[(15 mM Tris,pH 7.5(泰克諾瓦公司(Teknova Inc)),10 mM MgCl2(JT貝克公司(JT Baker Inc)),0.01% Pluronic F-68(生命技術公司(Life Technologies Inc)),1 µM紫杉醇(Cytoskeleton公司(Cytoskeleton Inc))和30 µg/mL豬微管(Cytoskeleton公司(Cytoskeleton Inc))]。向製備的反應緩衝液中添加化合物和KIF18A蛋白(30 nM)並在室溫下孵育15 min,接下來向反應混合物中添加ATP(Km
,75 µM),在室溫下再孵育15 min。將5 µl的ADP-GloTM
試劑和2.5 µl的反應混合物混合並在室溫下孵育40 min。添加10 µl ADP-GloTM
檢測試劑,並在室溫下孵育40 min。使用帶有超發光模組(珀金埃爾默公司(Perkin Elmer Inc))的EnVision酶標儀(microplate reader)讀取發光。使用帶有四參數邏輯回歸擬合模型的基因數據篩選(Genedata Screener)軟體(版本15.0.1,基因數據公司(Genedata Inc))進行濃度-反應曲線擬合和IC50
確定。
表A提供了本申請及其優先權文件中示例的化合物的數據,作為本發明的代表性化合物,如下:化合物名稱和生物學數據。(如果有的話,IC50
以µM計。Ex.#係指實例編號)
表A:生物學數據
實例編號 | 化合物名稱 | KIF18A ATP酶 IC50 (µM) |
1 | N -(2-((1-羥基-2-甲基丙烷-2-基)胺基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.186 |
1-1 | (R )-N -(2-((1-羥基丙烷-2-基)胺基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.216 |
1-2 | (S )-N -(2-((1-羥基丙烷-2-基)胺基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.491 |
1-3 | N -(2-((2-羥基乙基)胺基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.849 |
1-4 | (R )-N -(2-((2-羥基丙基)胺基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.580 |
1-5 | (S)-N -(2-((2-羥基丙基)胺基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.451 |
1-6 | N -(6-甲基-2-(3,3,3-三氟丙氧基)嘧啶-4-基)-4-(N-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.032 |
1-7 | N -(2-((1-羥基-2-甲基丙烷-2-基)胺基)-6-甲基嘧啶-4-基)-4-(N-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.168 |
2 | N -(2-(2-羥基丙烷-2-基)嘧啶-4-基)-4-(N -(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.143 |
2-1 | N -(2-(2-羥基丙烷-2-基)-6-甲基嘧啶-4-基)-4-(N-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.065 |
2-2 | (R )-N -(2-(2-甲基𠰌啉)嘧啶-4-基)-4-(N -(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.068 |
2-3 | (R )-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-4-(N-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.115 |
2-4 | N -(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-4-(N -(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.029 |
2-5 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(N-(3-甲基氧雜環丁烷-3-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.103 |
2-6 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.260 |
2-7 | (R )-N -(2-(2-甲基𠰌啉)嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.240 |
2-8 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-甲基環丙烷)-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.713 |
3 | (R )-4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.057 |
4 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.071 |
5-1 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.062 |
5-2 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.070 |
6-1 | 4-((氟甲基)磺醯胺基)-N -(2-(4-氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.062 |
6-2 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((氟甲基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.042 |
6-3 | (R )-4-((氟甲基)磺醯胺基)-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.079 |
6-4 | (R )-4-((2-羥基乙基)磺醯胺基)-N-(2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.032 |
6-5 | (R )-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-4-(甲基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.120 |
6-6 | (R )-4-(乙基磺醯胺基)-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.067 |
6-7 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(乙基磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.122 |
6-8 | (R )-4-((3-羥基丙基)磺醯胺基)-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.107 |
6-9 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(3,3-二氧化-1,3,4-氧雜噻𠯤-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.246 |
6-10 | 4-(環戊烷磺醯胺基)-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 2.42 |
6-11 | 4-(環丁烷磺醯胺基)-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.127 |
6-12 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(氧雜環丁烷-3-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.040 |
6-13 | 4-(環丁烷磺醯胺基)-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.052 |
6-14 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1,1-二甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.413 |
6-15 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((3-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.086 |
6-16 | 4-(環丙烷磺醯胺基)-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.052 |
6-17 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-甲氧基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.032 |
6-18 | 4-((環丙基甲基)磺醯胺基)-N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.085 |
6-19 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(((3-羥基氧雜環丁烷-3-基)甲基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.039 |
6-20 | (N )-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1,1-二甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.049 |
6-21 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(甲基磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.039 |
6-22 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.151 |
6-23-1 | 4-(((S )-2-羥基-1-甲基乙基)磺醯胺基)-N -(6-甲基-2-((R )-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.039 |
6-23-2 | 4-(((R )-2-羥基-1-甲基乙基)磺醯胺基)-N -(6-甲基-2-((R )-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.0373 |
6-24-1 | 4-(((S )-2-羥基-1-甲基乙基)磺醯胺基)-N -(2-((R )-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.0174 |
6-24-2 | 4-(((R)-2-羥基-1-甲基乙基)磺醯胺基)-N-(2-((R)-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.028 |
6-25-1 | (S )-N -(2-(4-氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.047 |
6-25-2 | (R )-N -(2-(4-氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.041 |
6-26-1 | (S )-N -(2-(4,4-二氟哌啶-1-基)嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.031 |
6-26-2 | (R )-N -(2-(4,4-二氟哌啶-1-基)嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.021 |
6-27-1 | 4-(((R )-2-羥基丙基)磺醯胺基)-N-(6-甲基-2-((R)-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.162 |
6-27-2 | 4-(((S )-2-羥基丙基)磺醯胺基)-N-(6-甲基-2-((R)-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.151 |
6-28-1 | (R )-4-((2-羥基丙基)磺醯胺基)-N-(6-甲基-2-(3,3,3-三氟丙氧基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.068 |
6-28-2 | (S )-4-((2-羥基丙基)磺醯胺基)-N-(6-甲基-2-(3,3,3-三氟丙氧基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.071 |
6-29 | N -(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.017 |
6-30 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基吡啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.0384 |
6-31-1 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-(1-羥基乙基)環丙烷)-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.324 |
6-31-2 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-(1-羥基乙基)環丙烷)-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.281 |
6-32-1 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.112 |
6-32-2 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.141 |
6-33-1 | 4-(((S )-2-羥基丙基)磺醯胺基)-N -(2-((R)-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.115 |
6-33-2 | 4-(((R )-2-羥基丙基)磺醯胺基)-N -(2-((R)-2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.086 |
6-34 | 5-氯-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.0922 |
6-35 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-5-甲基-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.144 |
6-36 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-5-甲氧基-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.114 |
6-37 | N -(2-(4,4-二氟哌啶-1-基)-6-(2-羥基丙-2-基)嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.125 |
6-38 | N -(2-(4,4-二氟哌啶-1-基)-6-乙基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.060 |
6-39 | N -(6-環丙基-2-(4,4-二氟哌啶-1-基)嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.225 |
6-40 | (R )-4-((2-羥基乙基)磺醯胺基)-N-(6-(2-羥基丙-2-基)-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.161 |
7 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.023 |
8-1 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.091 |
8-2 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.073 |
9-1 | (R )-5-氟-4-((2-羥基乙基)磺醯胺基)-N -(2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.078 |
9-2 | (R )-5-氟-4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.158 |
10-1 | (R )-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.083 |
10-2 | (S )-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基丙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.073 |
11-1 | (S )-4-((2-羥基乙基)磺醯胺基)-N -(2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.037 |
11-2 | 4-((2-羥乙基)磺醯胺基)-N -(2-異丙基-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.027 |
11-3 | N -(2-環丙基-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.049 |
11-4 | N -(2-環丁基-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.018 |
11-5 | N -(2-(3-氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.032 |
11-6 | N -(2-(3-氟氮雜環丁烷-1-基)嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.068 |
11-7 | N -(2-(3,3-二氟氮雜環丁烷-1-基)嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.023 |
11-8 | 4-((2-羥基乙基)磺醯胺基)-N-(6-甲基-2-(2-氧雜-6-氮雜螺[3.3]庚-6-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.640 |
11-9 | 4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(6-氧雜-1-氮雜螺[3.3]庚-1-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.128 |
11-10 | N -(2-(3-(二氟甲氧基)氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.192 |
11-12 | N -(2-(1,1-二氟-5-氮雜螺[2.3]己-5-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.093 |
11-13 | 4-((2-羥基乙基)磺醯胺基)-N-(6-甲基-2-(3-(三氟甲基)氮雜環丁烷-1-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.067 |
11-14 | N -(2-(3-氰基氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.172 |
11-15 | 4-((2-羥基乙基)磺醯胺基)-N-(2-(3-(2-羥基丙-2-基)氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.935 |
11-16 | N -(2-(3-羥基-3-甲基氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 1.01 |
11-17 | N -(2-(3-環丙基-3-羥基氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 1.09 |
11-18 | 4-((2-羥基乙基)磺醯胺基)-N-(6-甲基-2-(5-氮雜螺[2.3]己-5-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.064 |
11-19 | N -(2-(3-羥基-3-(三氟甲基)氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.205 |
11-20 | N -(2-(氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.0483 |
11-21 | (S )-N -(2-(3-(1-羥基乙基)氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.704 |
11-22 | 4-(環丙烷磺醯胺基)-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.788 |
11-23 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-(氧雜環丁烷-3-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.0489 |
11-24 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-(甲基磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.0551 |
11-25 | 4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(5-氮雜螺[2.4]庚-5-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.0176 |
11-26 | (R)4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(吡咯啶-1-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.0716 |
11-27 | (R )-N -(2-(3-氟-3-羥基吡咯啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.020 |
11-28 | N -(2-(2-氮雜雙環[3.1.0]己-2-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.059 |
11-29 | N -(2-((1R ,5S )-3-氮雜雙環[3.1.0]己-3-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.020 |
11-30 | N -(2-(3,3-二氟吡咯啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.033 |
11-31 | 4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(6-氮雜螺[2.5]辛-6-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.146 |
11-32 | N -(2-((1R )-1-羥基-3-氮雜雙環[3.1.0]己-3-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.193 |
11-33 | N -(2-(4-氰基哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.088 |
11-34 | (R )-N -(2-(3-氰基哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.092 |
11-35 | (S )-N -(2-(3-氰基哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.043 |
11-36 | (R)4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(哌啶-1-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.082 |
11-37 | 4-((2-羥基乙基)磺醯胺基)-N -(2-(4-羥基哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.144 |
11-38 | N -(2-(4-羥基-4-甲基哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.065 |
11-39 | N -(2-(3,3-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.045 |
11-40 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(7-氮雜螺[3.5]壬-7-基)苯甲醯胺 | 0.109 |
11-41 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(4,4-二甲基哌啶-1-基)-4-((2-羥基乙基)磺醯胺基)苯甲醯胺 | 0.127 |
11-42 | N -(2-((1R )-1-羥基-3-氮雜雙環[4.1.0]庚-3-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.034 |
11-43 | N -(2-((1R ,6R )-3-氮雜雙環[4.1.0]庚-3-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.035 |
11-44 | N -(2-((1S,6R)-2-氮雜雙環[4.1.0]庚-2-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.033 |
11-45 | (S )-4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(2-甲基𠰌啉)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.035 |
11-46 | N -(2-(2,2-二甲基𠰌啉)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.150 |
11-47 | 4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-(4-氧雜-7-氮雜螺[2.5]辛-7-基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.095 |
11-48 | N -(2-((3S ,5R )-3,5-二甲基𠰌啉)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.095 |
11-49 | N -(2-((3S,5S)-3,5-二甲基𠰌啉)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.245 |
11-50 | N -(2-((3R ,5R )-3,5-二甲基𠰌啉)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.187 |
11-51 | N -(2-(4-氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.020 |
11-52 | N -(2-(4-氟-4-甲基哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.063 |
11-53 | (S )-4-((2-羥基乙基)磺醯胺基)-N -(2-(3-羥基哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.105 |
11-54 | (R )-4-((2-羥基乙基)磺醯胺基)-N -(2-(3-羥基哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.074 |
11-55 | (R )-N -(2-(3-氟-3-甲基哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.041 |
11-56 | N -(2-(4-氟哌啶-1-基)嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.022 |
11-57 | N -(2-(4,4-二氟哌啶-1-基)嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.022 |
11-58 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-氟-4-((2-羥基乙基)磺醯胺基)-6-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.071 |
11-59 | 4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)-N-(2-(3,3,3-三氟丙氧基)吡啶-4-基)苯甲醯胺 | 0.058 |
11-60 | 4-((2-羥基丙基)磺醯胺基)-N -(2-甲基-6-(3,3,3-三氟丙氧基)吡啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.084 |
11-61 | 4-((2-羥基丙基)磺醯胺基)-N -(6-甲基-2-(3,3,3-三氟丙氧基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.070 |
11-62 | N -(2-((1-羥基-2-甲基丙-2-基)胺基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.018 |
11-63 | N -(2-(4,4-二氟哌啶-1-基)-3-氟吡啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.022 |
11-64 | N -(2-(4,4-二氟哌啶-1-基)-3-氟-6-甲基吡啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.054 |
11-65 | (R )-4-((2-羥基乙基)磺醯胺基)-N-(2-(2-甲基𠰌啉)吡啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.151 |
11-66 | (R )-4-((2-羥基乙基)磺醯胺基)-N -(2-甲基-6-(2-甲基𠰌啉)吡啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.148 |
11-67 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-5-氟-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.034 |
11-68 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基甲基)環丙烷-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.053 |
11-69 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基甲基)環丙烷-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.099 |
11-70 | (S )-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)-4-((四氫呋喃)-3-磺醯胺基)苯甲醯胺 | 0.072 |
11-71 | (R )-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)-4-((四氫呋喃)-3-磺醯胺基)苯甲醯胺 | 0.042 |
11-72 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)-4-((四氫呋喃)-3-磺醯胺基)苯甲醯胺 | 0.135 |
11-73 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)-4-((四氫呋喃)-3-磺醯胺基)苯甲醯胺 | 0.079 |
11-74 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((1-甲基環丙烷)-1-磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.094 |
11-75 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.056 |
11-76 | (R )-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.020 |
11-77 | (S )-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-1-甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.034 |
11-78 | 4-((環丙基甲基)磺醯胺基)-N-(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.125 |
11-79 | 4-((2-羥乙基)磺醯胺基)-N-(2-異丙氧基-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.057 |
11-80 | (R )-4-((2-羥基乙基)磺醯胺基)-N -(6-甲基-2-((四氫呋喃-3-基)氧)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.117 |
11-81 | N -(2-(4-氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(甲基磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.060 |
11-82 | 4-(乙基磺醯胺基)-N -(2-(4-氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.051 |
11-83 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-4-((1,1-二甲基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.098 |
12 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.076 |
13-1 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙烷-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.057 |
13-2 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙烷-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.064 |
14 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基-2-甲基丙烷-2-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.122 |
14-1 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(氧雜環丁烷-3-基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.182 |
14-2 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(乙基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.108 |
14-3 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(異丙基磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.128 |
14-4 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-羥基-2-甲基丙基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.806 |
14-5 | 4-(環丙基磺醯基)-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.826 |
14-6 | 4-(三級丁基磺醯基)-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 1.88 |
14-7 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(((3R ,4R )-4-羥基四氫呋喃-3-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.094 |
14-8 | N-(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(((3S,4S)-4-羥基四氫呋喃-3-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.097 |
14-9 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)--4-(((1R,2R)-2-羥基環戊基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.195 |
15 | N -(2-(4,4-二氟環己基)-6-甲基嘧啶-4-基)-4-((2-羥基乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.017 |
16-1 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-氟-1-(羥基甲基)乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.089 |
16-2 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((2-氟-1-(羥基甲基)乙基)磺醯胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.096 |
17 | N -(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-4-(N-(2-羥基乙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.023 |
17-1 | 4-((2-羥基乙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)-N-(2-(3,3,3-三氟丙氧基)嘧啶-4-基)苯甲醯胺 | 0.027 |
17-2 | 4-(N -(2-羥基丙基)胺磺醯基)-N -(6-甲基-2-(3,3,3-三氟丙氧基)嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.042 |
17-3 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)4-(N -(2-羥基乙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.063 |
17-4 | N -(2-(4,4-二氟哌啶-1-基)嘧啶-4-基)-4-(N-(2-羥基乙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.023 |
17-5 | N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)4-(N -(2-羥基乙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.133 |
17-6 | (R )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙烷-2-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.127 |
17-7 | (S )-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-羥基丙烷-2-基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.147 |
17-8 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(N -(2-羥基-2-甲基丙基)胺磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.286 |
18-1 | 2-(6-氮雜螺[2.5]辛-6-基)-4-(R -環丙基磺醯亞胺基)-N -(2-(4,4-二氟-1-哌啶基)-6-甲基-4-嘧啶基)苯甲醯胺 | 0.064 |
18-2 | 2-(6-氮雜螺[2.5]辛-6-基)-4-(S -環丙基磺醯亞胺基)-N -(2-(4,4-二氟-1-哌啶基)-6-甲基-4-嘧啶基)苯甲醯胺 | 0.057 |
19-1 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(氧雜環丁烷-3-磺醯亞胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.163 |
19-2 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(S -甲基磺醯亞胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.438 |
19-3 | 2-(6-氮雜螺[2.5]辛-6-基)-N -(2-(4,4-二氟-1-哌啶基)-6-甲基-4-嘧啶基)-4-(S -乙基磺醯亞胺基)苯甲醯胺 | 0.078 |
19-4 | 2-(6-氮雜螺[2.5]辛-6-基)-N -(2-(4,4-二氟-1-哌啶基)-6-甲基-4-嘧啶基)-4-(R -乙基磺醯亞胺基)苯甲醯胺 | 0.035 |
19-5 | N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-(丙-2-基磺醯亞胺基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.175 |
19-6 | 4-(環丙烷磺醯亞胺基)-N -(2-(4,4-二氟哌啶-1-基)吡啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.042 |
19-7 | 2-(6-氮雜螺[2.5]辛-6-基)-4-(S -環丙基磺醯亞胺基)-N -(6-甲基-2-((2R)-2-甲基-4-𠰌啉基)-4-嘧啶基)苯甲醯胺 | 0.195 |
19-8 | 2-(6-氮雜螺[2.5]辛-6-基)-4-(R -環丙基磺醯亞胺基)-N -(6-甲基-2-((2R )-2-甲基-4-𠰌啉基)-4-嘧啶基)苯甲醯胺 | 0.078 |
19-9 | 4-(環丙烷磺醯亞胺基)-N -(2-(3,3-二氟氮雜環丁烷-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.069 |
20 | (N1 -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)對苯二甲醯胺 | 0.119 |
21 | 4-(氮雜環丁烷-3-基磺醯基)-N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.040 |
22 | 4- N -(2-(4,4-二氟哌啶-1-基)-6-甲基嘧啶-4-基)-4-((1-甲基氮雜環丁烷-3-基)磺醯基)-2-(6-氮雜螺[2.5]辛-6-基)苯甲醯胺 | 0.406 |
出於清楚和理解的目的,已經通過說明和實例的方式詳細地描述了前述發明。熟悉該項技術者理解,可以在所附申請專利範圍的範圍內進行改變和修改。因此,應理解,以上描述旨在係說明性的而非限制性的。因此,本發明的範圍不應參考上文的描述來確定,而應參考以下所附申請專利範圍以及此申請專利範圍所賦予的等同方案的全部範圍來確定。
出於所有目的,本文引用的所有專利案、專利申請案和出版物在此藉由引用整體併入本文,其程度就好像每個單獨的專利案、專利申請案或出版物被如此單獨地表示。
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Claims (36)
- 一種化合物或其任何藥學上可接受的鹽,其中該化合物為式(I)的化合物:
- 如申請專利範圍第1項所述之化合物或其藥學上可接受的鹽,其中R10c、R10d、R10e、R10f、R10g、R10h、R10i和R10j中的每一個為H、鹵素、C1-6烷基或C1-4鹵代烷基;並且R10a和R10b對中的每一個與它們各自附接的碳原子組合形成螺接到Rx環的飽和3員、4員或5員單環;其中所述環含有0、1、2或3個N原子和0、1或2個選自由O和S組成之群組的原子。
- 如申請專利範圍第1項所述之化合物或其藥學上可接受的鹽,其中R10c、R10d、R10e、R10f、R10g、R10h、R10i和R10j中的每一個為H、甲基或乙基;並且R10a和R10b對中的每一個與它們各自附接的碳原子組合形成螺接到Rx環的環丙基、環丁基或環戊基環。
- 如申請專利範圍第1至7項中任一項所述之化合物或其藥學上可接受的鹽,其中Z為-NHSO2-、-SO2NH-、-S(=O)(=NH)-、-SO2-或-(C=O)NH-;並且 (a)R12為H;(b)R12為氧雜環丁烷基或環丙基;或(c)R12為被0、1、2或3個OH基團取代的C1-6烷基。
- 如申請專利範圍第1至7項中任一項所述之化合物或其藥學上可接受的鹽,其中Z為-NHSO2-或-SO2NH-;並且R12為氧雜環丁烷基、環丙基、或被0、1、2或3個OH基團取代的C1-6烷基。
- 如申請專利範圍第1至7項中任一項所述之化合物或其藥學上可接受的鹽,其中Z為-NHSO2-並且R12為-CH2-CH2-OH。
- 如申請專利範圍第1至7項中任一項所述之化合物或其藥學上可接受的鹽,其中Y為鍵、-NH-(CH2)0-4-或-O-(CH2)0-4-;並且R13為含有0、1、2或3個N原子和0或1個選自由O和S組成之群組的原子的飽和的、部分飽和的或不飽和的3員、4員、5員、6員或7員單環或者5員、6員、7員、8員、9員、10員、11員或12員雙環,其被0、1、2或3個選自由以下各項組成之群組的基團取代:F、Cl、Br、C1-6烷基、C1-4鹵代烷基、-OH、-OC1-4鹵代烷基、CN、R14和側氧基;或者R13為被0、1、2、3、4或5個選自由F、Cl、Br、-OH、-OC1-4鹵代烷基及CN組成之群組的基團取代的C1-6烷基。
- 如申請專利範圍第1至7項中任一項所述之化合物或其藥學上可接受的鹽,其中R2為飽和5員或6員單環,其中每個所述環含有0、1或2個N原子和0或1個O原子,並且其中每個所述環被0、1、2或3個選自由以下各項組成之群組的基團取代:F、Cl、Br、C1-6烷基、C1-4鹵代烷基、-OH、-OC1-4鹵代烷基、CN、R14和側氧基。
- 如申請專利範圍第1至7項中任一項所述之化合物或其藥學上可接受的鹽,其中R2為被1、2或3個氟基團取代的哌啶基。
- 如申請專利範圍第1至7項中任一項所述之化合物或其藥學上可接受的鹽,其中Z為-NHSO2-、-SO2NH-、-S(=O)(=NH)-、-SO2-或-(C=O)NH-。
- 如申請專利範圍第1至7項中任一項所述之化合物或其藥學上可接受的鹽,其中R12選自(a)H;(b)被0、1、2或3個選自由F、Cl、Br、-OH及-OCH3組成之群組的基團取代的C1-6烷基;或(c)含有0、1、2或3個N原子和0或1個選自由O和S組成之群組的原子的飽和的、部分飽和的或不飽和的3員、4員、5員、6員或7員單環,其被0、1、2或3個選自由以下各項組成之群組的基團取代:F、Cl、Br、C1-6烷基、C1-4鹵代烷基、-C1-6烷基OH、-OH、-OCH3、-NH2及側氧基。
- 如申請專利範圍第1至7項中任一項所述之化合物或其藥學上可接受的鹽,其中R4選自由以下各項組成之群組:(a)H;(b)C1-6烷基;及(c)環丙基。
- 如申請專利範圍第1至7項中任一項所述之化合物或其藥學上可接受的鹽,其中R4為H或甲基。
- 如申請專利範圍第1或3項所述之化合物或其藥學上可接受的鹽,其中R6為H或F。
- 如申請專利範圍第1至7項中任一項所述之化合物或其藥學上可接受的鹽,其中R7為H或F。
- 如申請專利範圍第1至7項中任一項所述之化合物或其藥學上可接受的鹽,其中R8為H。
- 一種藥物組成物,該藥物組成物包含如申請專利範圍第1至28項中任一項所述之化合物或其藥學上可接受的鹽、及藥學上可接受的稀釋劑或載體。
- 一種如申請專利範圍第1至28項中任一項所述之化合物或其藥學上可接受的鹽、或如申請專利範圍第29項所述之藥物組成物在製備用於治療可用KIF18a抑制劑治療的病症的藥物中之用途。
- 如申請專利範圍第30項所述之用途,其中該病症為選自由以下各項組成之群組之癌症:(a)選自由以下各項組成之群組的實體瘤或血液源性腫瘤:膀胱癌、子宮內膜癌、乳腺癌、結腸癌、腎癌、肝癌、肺癌、食道癌、膽囊癌、腦癌、頭頸癌、卵巢癌、胰臟癌、胃癌、子宮頸癌、甲狀腺癌、前列腺癌或皮膚癌;(b)選自由以下各項組成之群組的淋巴系的造血性腫瘤:白血病、B細胞淋巴瘤、T細胞淋巴瘤、何杰金氏淋巴瘤、非何杰金氏淋巴瘤、毛細胞淋巴瘤和伯克特淋巴瘤;(c)選自由以下各項組成之群組的骨髓系的造血性腫瘤:急性和慢性骨髓性白血病、骨髓化生不良症候群和前髓細胞白血病;(d)選自由纖維肉瘤和橫紋肌肉瘤組成之群組的間質來源的腫瘤;(e)選自由星形細胞瘤、神經母細胞瘤、神經膠質瘤和神經鞘瘤組成之群組的中樞和周圍神經系統的腫瘤;及(f)黑素瘤、精原細胞瘤、畸胎癌、骨肉瘤、著色性乾皮病、角化棘皮瘤、甲狀腺濾泡癌及卡波西氏肉瘤。
- 如申請專利範圍第31項之用途,其中該病症為肺鱗細胞癌或小細胞肺癌。
- 如申請專利範圍第31項之用途,其中該病症為急性淋巴球性白血病或急性成淋巴球性白血病。
- 一種如申請專利範圍第1至28項中任一項所述之化合物或其藥學上可接受的鹽、或如申請專利範圍第29項所述之藥物組成物在製備用於在受試者中減小實體瘤大小的藥物中之用途。
- 一種如申請專利範圍第1至28項中任一項所述之化合物或其藥學上可接受的鹽、或如申請專利範圍第29項所述之藥物組成物在製備用於在受試者中治療細胞增殖障礙的藥物中之用途。
- 一種如申請專利範圍第1至28項中任一項所述之化合物或其藥學上可接受的鹽、或如申請專利範圍第29項所述之藥物組成物在製備用於在細胞中抑制KIF18A的藥物中之用途。
Applications Claiming Priority (2)
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