如本文本中所提及之術語具有以下含義： 如本文所用之術語「ATR激酶抑制劑(inhibitor of ATR kinase/ATR kinase inhibitor)」意謂抑制ATR激酶之任何化合物。此類化合物之實例描述於下文(「組合中之組分A」)。 術語「鹵素原子」、「鹵基- (halo-/Hal-)」應理解為意謂氟、氯、溴或碘原子。 術語「C1
-C6
-烷基」應理解為意謂具有1、2、3、4、5或6個碳原子之直鏈或分支鏈飽和單價烴基，例如甲基、乙基、丙基、丁基、戊基、己基、異丙基、異丁基、第二丁基、第三丁基、異戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基，或其異構體。特別是，該基團具有1、2、3或4個碳原子(「C1
-C4
-烷基」)，例如甲基、乙基、丙基、丁基、異丙基、異丁基、第二丁基、第三丁基，更特別是具有1、2或3個碳原子(「C1
-C3
-烷基」)，例如甲基、乙基、正丙基或異丙基。 術語「C1
-C6
-鹵烷基」應理解為意謂直鏈或分支鏈飽和單價烴基，其中術語「C1
-C6
-烷基」如上文所定義，且其中一或多個氫原子相同或不同地經鹵素原子置換，亦即一個鹵素原子獨立於另一鹵素原子。特別是，該鹵素原子為F。該C1
-C6
-鹵烷基為例如-CF3
、-CHF2
、-CH2
F、-CF2
CF3
或-CH2
CF3
。 術語「C1
-C4
-羥烷基」應理解為意謂直鏈或分支鏈飽和單價烴基，其中術語「C1
-C4
-烷基」如上文所定義，且其中一或多個氫原子經羥基置換，例如羥基甲基、1-羥基乙基、2-羥基乙基、1,2-二羥基乙基、3-羥基丙基、2-羥基丙基、2,3-二羥丙基、1,3-二羥基丙-2-基、3-羥基-2-甲基-丙基、2-羥基-2-甲基-丙基、1-羥基-2-甲基-丙基。 術語「C1
-C6
-烷氧基」應理解為意謂具有式-O-烷基之直鏈或分支鏈飽和單價烴基，其中術語「烷基」如上文所定義，例如甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、異丁氧基、第三丁氧基、第二丁氧基、戊氧基、異戊氧基或正己氧基或其異構體。特別是，該「C1
-C6
-烷氧基」可含有1、2、3、4或5個碳原子(「C1
-C5
-烷氧基)」，較佳1、2、3或4個碳原子(「C1
-C4
-烷氧基」)。 術語「C1
-C6
-鹵烷氧基」應理解為意謂如上文所定義之直鏈或分支鏈飽和單價C1
-C6
-烷氧基，其中一或多個氫原子相同或不同地經鹵素原子置換。特別是，該鹵素原子為F。該C1
-C6
-鹵烷氧基為例如-OCF3
、-OCHF2
、-OCH2
F、-OCF2
CF3
或-OCH2
CF3
。 術語「C2
-C6
-烯基」應理解為意謂直鏈或分支鏈單價烴基，其含有一或多個雙鍵，且其具有2、3、4、5或6個碳原子或2、3或4個碳原子(「C2
-C4
烯基」)，特別是2或3個碳原子(「C2
-C3
-烯基」)，應理解，在該烯基含有多於一個雙鍵之情況下，則該等雙鍵可彼此分離或彼此共軛。該烯基為例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、高烯丙基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、異丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-異丙基乙烯基、4-甲基戊-4-烯基、3-甲基戊-4-烯基、2-甲基戊-4-烯基、1-甲基戊-4-烯基、4-甲基戊-3-烯基、(E)-3-甲基戊-3-烯基、(Z)-3-甲基戊-3-烯基、(E)-2-甲基戊-3-烯基、(Z)-2-甲基戊-3-烯基、(E)-1-甲基戊-3-烯基、(Z)-1-甲基戊-3-烯基、(E)-4-甲基戊-2-烯基、(Z)-4-甲基戊-2-烯基、(E)-3-甲基戊-2-烯基、(Z)-3-甲基戊-2-烯基、(E)-2-甲基戊-2-烯基、(Z)-2-甲基戊-2-烯基、(E)-1-甲基戊-2-烯基、(Z)-1-甲基戊-2-烯基、(E)-4-甲基戊-1-烯基、(Z)-4-甲基戊-1-烯基、(E)-3-甲基戊-1-烯基、(Z)-3-甲基戊-1-烯基、(E)-2-甲基戊-1-烯基、(Z)-2-甲基戊-1-烯基、(E)-1-甲基戊-1-烯基、(Z)-1-甲基戊-1-烯基、3-乙基丁-3-烯基、2-乙基丁-3-烯基、1-乙基丁-3-烯基、(E)-3-乙基丁-2-烯基、(Z)-3-乙基丁-2-烯基、(E)-2-乙基丁-2-烯基、(Z)-2-乙基丁-2-烯基、(E)-1-乙基丁-2-烯基、(Z)-1-乙基丁-2-烯基、(E)-3-乙基丁-1-烯基、(Z)-3-乙基丁-1-烯基、2-乙基丁-1-烯基、(E)-1-乙基丁-1-烯基、(Z)-1-乙基丁-1-烯基、2-丙基丙-2-烯基、1-丙基丙-2-烯基、2-異丙基丙-2-烯基、1-異丙基丙-2-烯基、(E)-2-丙基丙-1-烯基、(Z)-2-丙基丙-1-烯基、(E)-1-丙基丙-1-烯基、(Z)-1-丙基丙-1-烯基、(E)-2-異丙基丙-1-烯基、(Z)-2-異丙基丙-1-烯基、(E)-1-異丙基丙-1-烯基、(Z)-1-異丙基丙-1-烯基、(E)-3,3-二甲基丙-1-烯基、(Z)-3,3-二甲基丙-1-烯基、1-(1,1-二甲基乙基)乙烯基、丁-1,3-二烯基、戊-1,4-二烯基、己-1,5-二烯基或甲基己二烯基。特別是，該基團為乙烯基或烯丙基。 術語「C3
-C10
-環烷基」應理解為意謂含有3、4、5、6、7、8、9或10個碳原子(「C3
-C10
-環烷基」)之飽和單價單環或雙環烴環。該C3
-C10
-環烷基為例如單環烴環，例如環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環壬基或環癸基，或為雙環烴環，例如全氫并環戊二烯或十氫萘環。特 定言之，該環含有3、4、5或6個碳原子(「C3
-C6
-環烷基」)，較佳環丙基。 術語「3員至10員雜環烷基」應理解為意謂飽和單價單環或雙環烴環，其含有2、3、4、5、6、7、8或9個碳原子及選自C(=O)、O、S、S(=O)、S(=O)2
、NRa
之一或多個含雜原子基團，其中Ra
表示氫原子或C1
-C6
-烷基或C1
-C6
-鹵烷基；該雜環烷基有可能經由碳原子或氮原子(若存在)中之任一者連接至分子其餘部分。 特別是，該3員至10員雜環烷基可含有2、3、4或5個碳原子及上述含雜原子基團(「3員至6員雜環烷基」)中之一或多者，更特別是該雜環烷基可含有4或5個碳原子及上述含雜原子基團(「5員至6員雜環烷基」)中之一或多者。 特別是且並非限制性的，該雜環烷基可為例如4員環，諸如氮雜環丁烷基、氧雜環丁烷基；或5員環，諸如四氫呋喃基、二氧戊環基(dioxolinyl)、吡咯啶基、咪唑啶基、吡唑啶基、吡咯啉基；或6員環，諸如四氫哌喃基、哌啶基、嗎啉基、二噻烷基、硫代嗎啉基、哌嗪基或三噻烷基；或7員環，諸如二氮雜環庚烷基環。視情況，該雜環烷基可經苯并稠合。較佳地，3員至6員雜環烷基為四氫呋喃基、四氫哌喃基或哌嗪基。 該雜環烷基可為雙環，諸如但不限於5,5-員環，例如六氫環戊二烯并[c]吡咯-2(1H)-基環；或5,6-員雙環，例如六氫吡咯并[1,2-a]吡嗪-2(1H)-基環。 如上文所提及，該含氮原子環可為部分不飽和的，亦即例如其可含有一或多個雙鍵，諸如但不限於2,5-二氫-1H-吡咯基環、4H-[1,3,4]噻二嗪基環、4,5-二氫噁唑基環或4H-[1,4]噻嗪基環；或例如其可經苯并稠合，諸如但不限於二氫異喹啉基環。 具有式-O-雜環烷基之術語「3員至10員雜環烷氧基」(其中術語「雜環烷基」如上文所定義)應理解為意謂飽和單價單環或雙環烴環，其含有2、3、4、5、6、7、8或9個碳原子及選自C(=O)、O、S、S(=O)、S(=O)2
、NRa
之一或多個含雜原子基團，其中Ra
表示氫原子、C1
-C6
烷基或C1
-C6
鹵烷基，且其經由氧原子連接至分子其餘部分，例如吡咯啶氧基、四氫呋喃氧基或四氫哌喃氧基。 術語「4員至10員雜環烯基」應理解為意謂不飽和單價單環或雙環烴環，其含有3、4、5、6、7、8或9個碳原子及選自C(=O)、O、S、S(=O)、S(=O)2
、NRa
之一或多個含雜原子基團，其中Ra
表示氫原子或C1
-C6
烷基或C1
-C6
鹵烷基；該雜環烯基有可能經由碳原子或氮原子(若存在)中之任一者連接至分子其餘部分。該雜環烯基之實例可含有一或多個雙鍵，例如4H-哌喃基、2H-哌喃基、3,6-二氫-2H-哌喃-4-基、3,6-二氫-2H-硫哌喃-4-基、1,2,3,6-四氫吡啶-4-基、3H-二氮雜環丙烯基、2,5-二氫-1H-吡咯基、[1,3]間二氧雜環戊烯基、4H-[1,3,4]噻二嗪基、2,5-二氫呋喃基、2,3-二氫呋喃基、2,5-二氫噻吩基、2,3-二氫噻吩基、4,5-二氫噁唑基、4H-[1,4]噻嗪基或5,6-二氫咪唑并[1,2-a]吡嗪-7(8H)-基，或其可經苯并稠合。 術語「雜芳基」理解為意謂具有5、6、7、8、9、10、11、12、13或14個環原子(「5員至14員雜芳基」)、5或6或9或10個環原子(「5員至10員雜芳基」)、或特別是5或6個環原子(「5員至6員雜芳基」)之單價單環、雙環或三環芳環系統，且其含有至少一個可相同或不同之雜原子，該雜原子為諸如氧、氮或硫，且另外在各情況下可經苯并縮合。特別是，雜芳基係選自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、異噁唑基、異噻唑基、噁二唑基、三唑基、噻二唑基、硫-4H-吡唑基等及其苯并衍生物，諸如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并異噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、異吲哚基等；或吡啶基、噠嗪基、嘧啶基、吡嗪基、三嗪基等及其苯并衍生物，諸如喹啉基、喹唑啉基、異喹啉基等；或吖㖕基、吲哚嗪基、嘌呤基等及其苯并衍生物；或㖕啉基、酞嗪基、喹唑啉基、喹喏啉基、㖠吡啶基、喋啶基、咔唑基、吖啶基、啡嗪基、啡噻嗪基、啡噁嗪基、𠮿基、氧呯基或1H-吡咯并[2,3-b]吡啶-4-基等。 一般而言且除非另外說明，否則雜芳基或伸雜芳基包括其所有可能存在之異構形式，例如其位置異構體。因此，就一些說明性非限制性實例而言，術語吡啶基或伸吡啶基包括吡啶-2-基、伸吡啶-2-基、吡啶-3-基、伸吡啶-3-基、吡啶-4-基及伸吡啶-4-基；或術語噻吩基或伸噻吩基包括噻吩-2-基、伸噻吩-2-基、噻吩-3-基及伸噻吩-3-基。 例如在「C1
-C6
-烷基」、「C1
-C6
-鹵烷基」、「C1
-C6
-烷氧基」或「C1
-C6
-鹵烷氧基」之定義之上下文中，如貫穿本文中所使用之術語「C1
-C6
」應理解為意謂具有1至6個之有限數目個碳原子，亦即1、2、3、4、5或6個碳原子之烷基。應進一步理解，該術語「C1
-C6
」應解釋為其中包含之任何子範圍，例如C1
-C6
、C2
-C5
、C3
-C4
、C1
-C2
、C1
-C3
、C1
-C4
、C1
-C5
；特別是C1
-C2
、C1
-C3
、C1
-C4
、C1
-C5
、C1
-C6
；更特別是C1
-C4
；在「C1
-C6
-鹵烷基」或「C1
-C6
-鹵烷氧基」之情況下，甚至更特別是C1
-C2
。 類似地，如本文所用，例如在「C2
-C6
-烯基」及「C2
-C6
-炔基」之定義之上下文中，如貫穿本文中所使用之術語「C2
-C6
」應理解為意謂具有2至6個之有限數目個碳原子，亦即2、3、4、5或6個碳原子之烯基或炔基。應進一步理解，該術語「C2
-C6
」應解釋為其中包含之任何子範圍，例如C2
-C6
、C3
-C5
、C3
-C4
、C2
-C3
、C2
-C4
、C2
-C5
；特別是C2
-C3
。 另外，如本文所用，例如在「C3
-C6
-環烷基」之定義之上下文中，如貫穿本文中所使用之術語「C3
-C6
」應理解為意謂具有3至6個之有限數目個碳原子，亦即3、4、5或6個碳原子之環烷基。應進一步理解，該術語「C3
-C6
」應解釋為其中包含之任何子範圍，例如C3
-C6
、C4
-C5
、C3
-C5
、C3
-C4
、C4
-C6
、C5
-C6
；特別是C3
-C6
。 另外，如本文所用，例如在「C2
-C4
-烯基」之上下文中，如貫穿本文中所使用之術語「C2
-C4
」應理解為意謂具有2至4個之有限數目個碳原子，亦即2、3或4個碳原子之烯基。應進一步理解，該術語「C2
-C4
」應解釋為其中包含之任何子範圍，例如C2
-C4
、C2
-C3
、C3
-C4
。 術語「經取代」意謂在指定原子上之一或多個氫經指定基團中之選擇置換，其限制條件為在現有情形下不超出指定原子的正常原子價，且該取代產生穩定化合物。取代基及/或變數之組合僅在此類組合產生穩定化合物時為容許的。 術語「視情況經取代」意謂視情況經指定基團、基或部分取代。 環系統取代基意謂連接至芳環系統或非芳環系統之取代基，其例如置換環系統上之可用氫。 「穩定化合物」或「穩定結構」意謂足夠穩固以經受住自反應混合物分離至適用純度且調配為有效治療劑之化合物。 如本文所用，例如在本發明之通式化合物之取代基之定義中，術語「一或多個」應理解為意謂「一個、兩個、三個、四個或五個，特別是一個、兩個、三個或四個，更特別是一個、兩個或三個，甚至更特別是一個或兩個」。 本發明亦包括組分A之化合物，特別是化合物A之所有適合同位素變體。組分A之化合物之同位素變體定義為至少一個原子經具有相同原子數但原子質量不同於自然界中通常或主要存在之原子質量的原子置換的化合物。可併入組分A之化合物中之同位素之實例包括氫、碳、氮、氧、磷、硫、氟、氯、溴及碘之同位素，分別諸如2
H (氘)、3
H (氚)、11
C、13
C、14
C、15
N、17
O、18
O、32
P、33
P、33
S、34
S、35
S、36
S、18
F、36
Cl、82
Br、123
I、124
I、129
I及131
I。組分A之化合物之某些同位素變體，例如併入一或多種放射性同位素(諸如3H或14
C)之彼等同位素變體適用於藥物及/或受質組織分佈研究。氚化及碳-14(亦即14
C)同位素因其易於製備及偵測而尤其較佳。另外，經諸如氘之同位素取代可獲得由較大代謝穩定性產生之某些治療優勢，例如活體內半衰期增加或劑量需求減少，且因此在某些情況下可為較佳的。組分A之化合物之同位素變體通常可藉由為熟習此項技術者已知之習知程序，諸如藉由說明性方法或藉由下文實例中所描述之製備，使用適合試劑之適當同位素變體來製備。 在本文中使用字詞化合物、鹽、多晶型物、水合物、溶劑合物及其類似物之複數形式時，亦用以意謂單個化合物、鹽、多晶型物、異構體、水合物、溶劑合物或其類似物。 視各種所要取代基之位置及性質而定，組分A之化合物可含有一或多個不對稱中心。不對稱碳原子可以(R)或(S)組態存在，在單個不對稱中心之情況下產生外消旋混合物，且在多個不對稱中心之情況下產生非對映異構體混合物。在某些情況下，亦可由於圍繞既定鍵(例如與指定化合物之兩個經取代芳族環鄰接之中心鍵)受限旋轉而存在不對稱性。 組分A之化合物可含有具有以下結構之不對稱硫原子(諸如不對稱亞碸或磺醯亞胺基團)：，例如其中*指示可結合至分子其餘部分之原子。 環上之取代基亦可以順式或反式存在。預期所有此類組態(包括對映異構體及非對映異構體)均包括在本發明之範疇內。 組分A之較佳化合物為產生更需要之生物活性者，尤佳為化合物A。組分A之化合物之經分離、純或部分純化異構體及立體異構體或外消旋或非對映異構體混合物亦包括在本發明之範疇內。此物質之純化及分離可藉由此項技術中已知之標準技術實現。 光學異構體可藉由外消旋混合物根據習知方法解析，例如藉由使用光活性酸或鹼形成非對映異構鹽，或形成共價非對映異構體來獲得。適當酸之實例為酒石酸、二乙醯基酒石酸、二甲苯醯基酒石酸及樟腦磺酸。非對映異構體之混合物可藉由此項技術中已知之方法(例如藉由層析或分步結晶)基於其物理及/或化學差異分離成其個別非對映異構體。接著自經分離之非對映異構體鹽釋放光活性鹼或酸。一種用於分離光學異構體之不同方法涉及使用對掌性層析(例如對掌性HPLC管柱)，進行或不進行習知衍化，經最佳選擇以使對映異構體之分離最大。適合之對掌性HPLC管柱由Daicel 製造，例如Chiracel OD及Chiracel OJ等，均可常規選用。在進行或不進行衍化之情況下，酶分離亦適用。本發明之光學活性化合物同樣可藉由利用光學活性起始物質之對掌性合成獲得。 為了限制彼此不同異構體類型，請參考IUPAC規則E章節(Pure Appl Chem 45, 11-30, 1976)。 本發明包括組分A之化合物之所有可能立體異構體，呈單一立體異構體，或呈該等立體異構體(例如R或S異構體，或E或Z異構體)之任何比率之任何混合物。組分A之化合物之單一立體異構體(例如單一對映異構體或單一非對映異構體)之分離可藉由任何適合之現有技術方法，諸如層析，尤其例如對掌性層析來達成。 另外，組分A，特別是化合物A之化合物，可以互變異構體存在。舉例而言，例如含有吡唑部分作為雜芳基之組分A之任何化合物可以1H互變異構體、或2H互變異構體或甚至任何量之兩種互變異構體之混合物存在，或者例如含有三唑部分作為雜芳基之組分A之任何化合物可以1H互變異構體、2H互變異構體，或4H互變異構體，或甚至任何量之該1H、該2H及該4H互變異構體之混合物存在，即：。 本發明組合包括組分A之化合物之所有可能互變異構體，特別是化合物A之㖠啶中心之8位中之吡唑-5-基的1H互變異構體或2H互變異構體，其呈單一互變異構體形式或呈該等互變異構體之任何比率之任何混合物形式。 另外，組分A之化合物，特別是化合物A可以N-氧化物之形式存在，其定義為本發明化合物之至少一個氮經氧化。本發明組合包括組分A之所有此類可能存在之N-氧化物。 本發明組合亦涵蓋如本文中所揭示之化合物之適用形式，諸如代謝物、水合物、溶劑合物、前藥、鹽，特別是醫藥學上可接受之鹽，及共沈澱物。 本發明組合之化合物可以水合物或以溶劑合物之形式存在，其中本發明組合之化合物含有極性溶劑，特別是水、甲醇或乙醇，例如作為化合物之晶格的結構元素。極性溶劑，特別是水，之量可以化學計量或非化學計量比率存在。在化學計量溶劑合物(例如水合物)之情況下，半(hemi-/semi-)、單、倍半、二、三、四、五等溶劑合物或水合物分別係可能的。本發明組合包括所有此類水合物或溶劑合物。 另外，本發明組合之化合物可以游離形式，例如游離鹼或游離酸或兩性離子形式存在或可以鹽形式存在。該鹽可為藥劑學中慣用之任何鹽，有機或無機加成鹽，特別是，醫藥學上可接受之任何有機或無機加成鹽。 本發明包括本發明組合中之組分之所有可能鹽，其呈單一鹽形式或呈任何比率之該等鹽之任何混合物形式。 此外，本發明包括本發明組合中之組分之化合物的所有可能結晶形式或多晶型物形式，其呈單一多晶型物形式或呈任何比率之多於一種多晶型物之混合物形式。 除非另外規定，否則當本發明組合之化合物中之基團經取代時，基團可經單或多取代。在本發明之上下文中，所有出現多於一次之基團彼此獨立地定義。經一個、兩個或三個相同或不同取代基取代為較佳的。 在本發明之上下文中，術語「治療(treatment/treating)」包括抑制、遲緩、抑止、減輕、緩解、限制、減少、遏制、排斥或治癒疾病或發展、病程或此類病狀及/或此類病狀之症狀之進展。 術語「疾病」包括但不限於病況、病症、損傷或健康問題。 術語「療法」在此處理解為與術語「治療」同義。 術語「預防(prevention/prophylaxis/preclusion)」在本發明之上下文中同義使用且係指避免或降低感染、經歷、罹患或患有疾病或此類病況及/或此類病況之症狀發展或進展之風險。 疾病之治療或預防可為部分或完全的。組合中之組分 A
組分A可選自特異性或一般揭示於以下公開案中之ATR激酶抑制劑：J. Med. Chem. 2013, 56, 2125-2138；Exp. Rev. Mol. Med. 16, e10, 2014；WO2010054398A1；WO2010071837A1；WO2010073034A1；WO2011143399A1；WO2011143419A1；WO2011143422A1；WO2011143423A2；WO2011143425A2；WO2011143426A1；WO2011154737A1；WO2011163527A1；WO2012138938A1；WO2012178123A1；WO2012178124A1；WO2012178125A1；WO2013049719A1；WO2013049720A1；WO2013049722A1；WO2013049859A1；WO2013071085A1；WO2013071088A1；WO2013071090A1；WO2013071093A1；WO2013071094A1；WO2013152298A1；WO2014062604A1；WO2014089379A1；WO2014143240；WO 2014143241；WO 2014143242；ACS Med. Chem. Lett. 2015. 6, 37-41；ACS Med. Chem. Lett. 2015. 6, 42-46；WO 2015085132；WO 2015187451。已揭示先前技術中所提及之ATR激酶抑制劑用於治療或預防不同疾病，尤其癌症。 在本發明之另一實施例中，該組分A係選自VX-803、VX-970、AZD-6738及通式(I)化合物其中： R1
表示選自以下之基團：， 其中*指示該基團與分子其餘部分連接之點； R2
表示氫、鹵素、-NR7
R8
、CN、C1
-C6
-烷基、C1
-C6
-烷氧基、3員至10員雜環烷氧基、C2
-C6
-烯基、C3
-C6
-環烷基、3員至10員雜環烷基、4員至10員雜環烯基、苯基、雜芳基、-(CO)OR7
、-(CO)NR7
R8
、-(SO2
)R9
、-(SO)R9
、-SR9
、-(SO2
)NR7
R8
、-NR7
(SO2
)R9
、-((SO)=NR11
)R10
、-N=(SO)R9
R10
、-SiR10
R11
R12
、-(PO)(OR7
)2
、-(PO)(OR7
)R10
或-(PO)(R10
)2
， 其中各C1
-C6
-烷基、C1
-C6
-烷氧基、3員至10員雜環烷氧基、C2
-C6
-烯基、C3
-C6
-環烷基、3員至10員雜環烷基、苯基或雜芳基視情況彼此獨立地經以下取代一或多次：鹵素、OH、-NR7
R8
、視情況經羥基或苯基取代一或多次之C1
-C6
-烷基、C1
-C6
-鹵烷基、C1
-C6
-烷氧基、C3
-C6
-環烷基、3員至6員雜環烷基、苯基、-(CO)OR7
、-(CO)NR7
R8
、-NR7
(CO)R10
、-NR8
(CO)OR7
、-NR8
(CO)NR7
R8
、-(SO2
)R9
、-(SO)R9
、-SR9
、-(SO2
)R7
R8
、-NR7
(SO2
)R9
、-((SO)=NR11
)R10
、-N=(SO)R9
R10
、-(PO)(OR7
)2
、-(PO)(OR7
)R10
、-(PO)(R10
)2
或視情況經C1
-C4
-烷基取代一或多次之雜芳基； 其中各4員至10員雜環烯基視情況彼此獨立地經C1
-C4
-烷基取代一或多次； R3
、R4
彼此獨立地表示氫或甲基； R7
、R8
彼此獨立地表示氫、C1
-C6
-烷基、C3
-C6
-環烷基或苯基，該苯基視情況經鹵素取代一或多次；或 R7
及R8
一起表示4員、5員、6員或7員環胺基團，其視情況彼此獨立地經選自C1
-C6
-烷基、C1
-C6
-鹵烷基之取代基取代一或多次，該4員、5員、6員或7員環胺基團視情況含有選自由O、N及S組成之群的另外一個雜原子； R9
表示C1
-C4
-烷基或苯基，其中各C1
-C4
-烷基或苯基視情況彼此獨立地經R13
取代一或多次； R10
表示C1
-C4
-烷基；或 在-N=(SO)R9
R10
基團之情況下R9
及R10
一起表示5員至8員雜環烷基； R11
表示氫、C1
-C4
-烷基、-(CO)OR7
、-(CO)NR7
R8
或CN； R12
表示氫或C1
-C4
-烷基； R13
表示鹵素、OH、-NR7
R8
、CN、NO2
、C1
-C6
-烷基、C1
-C6
-鹵烷基、C1
-C6
-烷氧基、C1
-C6
-鹵烷氧基、C2
-C6
-烯基、C3
-C6
-環烷基、-(CO)OR7
或-(CO)NR7
R8
； 或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽。 在本發明之上下文中，術語「VX-803」意謂2-胺基-6-氟-N-[5-氟-4-(4-{[4-(氧雜環丁-3-基)哌嗪-1-基]羰基}哌啶-1-基)吡啶-3-基]吡唑并[1,5-a]嘧啶-3-甲醯胺。其具有以下結構：。 在本發明之上下文中，術語「VX-970」意謂3-(3-{4-[(甲胺基)甲基]苯基}-1,2-噁唑-5-基)-5-[4-(丙-2-基磺醯基)苯基]吡嗪-2-胺。其具有以下結構：。 在本發明之上下文中，術語「AZD-6738」意謂4-{4-[(3R)-3-甲基嗎啉-4-基]-6-[1-(S-甲磺醯亞胺基)環丙基]嘧啶-2-基}-1H-吡咯并[2,3-b]吡啶。其具有以下結構：。 在本發明組合之另一實施例中，該組分A係選自VX-803、VX-970、AZD-6738及通式(Ib)化合物， 其中R1
、R2
、R4
、R7
、R8
、R9
、R10
、R11
、R12
及R13
如上文對於通式(I)化合物所定義。 在本發明之另一實施例中，該組分A為通式(Ib)化合物，其中 R1
表示：， 其中*指示該基團與分子其餘部分連接之點； R2
表示氫、氟、氯、CN、甲基、C1
-C4
-烷氧基、C2
-C3
-烯基、環丙基、3員至6員雜環烷基、4員至6員雜環烯基、苯基、吡啶基、噻唑基、-(SO2
)R9
、-SR9
、-((SO)=NR11
)R10
、-N=(SO)R9
R10
，其中各甲基、C1
-C4
-烷氧基、C2
-C3
-烯基、環丙基、3至6員雜環烷基、苯基、吡啶基或噻唑基視情況彼此獨立地經以下取代一或多次：氟、氯、OH、-NR7
R8
、甲基、5員雜環烷基、-NR8
(CO)OR7
、-(SO2
)R9
、-((SO)=NR11
)R10
、-(PO)(OR7
)2
或選自以下之基團：， 其中*指示該基團與分子其餘部分連接之點； 其中各4員至6員雜環烯基視情況經甲基取代一或多次； R4
表示氫或甲基； R7
、R8
彼此獨立地表示氫或C1
-C4
-烷基； R9
表示C1
-C4
-烷基； R10
表示C1
-C4
-烷基；或 在-N=(SO)R9
R10
基團之情況下R9
及R10
一起表示6員雜環烷基； R11
表示氫、甲基、-(CO)OR7
； 或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽。 在另一實施例中，該組分A為選自由以下組成之群的化合物： 4-[(2-(嗎啉-4-基)-8-[2H-吡唑-3-基]-[1,7]㖠啶-4-基]苯基-N-乙氧羰基-S-甲基亞磺醯亞胺 4-[(2-(嗎啉-4-基)-8-(2H-吡唑-3-基)-[1,7]㖠啶-4-基]苯基-S-甲基亞磺醯亞胺 4-[6-(甲磺醯基)吡啶-3-基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3,6-二氫-2H-哌喃-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶 4-[4-(N,S-二甲磺醯亞胺基)苯基]-2-[嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[4-甲基-6-(甲磺醯基)吡啶-3-基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(4-甲烷磺醯基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]-㖠啶 4-(2-甲烷磺醯基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶鹽酸鹽 {4-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯基}膦酸二甲酯 4-異丙烯基-2-(嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶 2-(嗎啉-4-基)-4-苯基-8-(1H-吡唑-3-基)-[1,7]㖠啶 4-[4-(S-乙基磺醯亞胺基)苯基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 3-[(2-(嗎啉-4-基)-8-[2H-吡唑-3-基]-[1,7]㖠啶-4-基]苯基-N-乙氧羰基-S-甲基亞磺醯亞胺 4-(1-甲基-1,2,3,6-四氫吡啶-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3-甲烷磺醯基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶 4-[5-甲基-6-(甲磺醯基)吡啶-3-基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(1,2,3,6-四氫吡啶-4-基)-1,7-㖠啶 4-環丙基-2-(嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶 3-[(2-(嗎啉-4-基)-8-(2H-吡唑-3-基)-[1,7]㖠啶-4-基]苯基-S-甲基亞磺醯亞胺 4-甲基-2-(嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶鹽酸鹽 4-[2-(甲磺醯基)-1,3-噻唑-4-基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]吡啶-2(1H)-酮 5-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]吡啶-2(1H)-酮 4-[2-氟-4-(甲磺醯基)苯基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-4-{4-[S-(丙-2-基)磺醯亞胺基]苯基}-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(4-甲烷磺醯基苯基)-2-((R)-3-甲基嗎啉-4-基)-8-(2H-吡唑-3-基)-[1,7]㖠啶 2-((R)-3-甲基嗎啉-4-基)-4-苯基-8-(2H-吡唑-3-基)-[1,7]㖠啶 4-(3-甲烷磺醯基苯基)-2-((R)-3-甲基嗎啉-4-基)-8-(2H-吡唑-3-基)-[1,7]㖠啶 4-環丙基-2-((R)-3-甲基嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]-㖠啶 4-[2-((R)-3-甲基嗎啉-4-基)-8-(2H-吡唑-3-基)-[1,7]㖠啶-4-基]苯基-S-甲基亞磺醯亞胺 3-[2-((R)-3-甲基嗎啉-4-基)-8-(2H-吡唑-3-基)-[1,7]㖠啶-4-基]苯基-S-甲基亞磺醯亞胺 4-甲烷磺醯基-2-(嗎啉-4-基)-8-[2-(四氫哌喃-2-基)-2H-吡唑-3-基]-[1,7]㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(甲磺醯基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶-4-甲腈 2-((R)-3-甲基嗎啉-4-基)-8-(2H-吡唑-3-基)-[1,7]㖠啶-4-甲腈 2-嗎啉-4-基-8-(1H-吡唑-3-基)-[1,7]㖠啶-4-甲醯胺 4-甲烷磺醯基甲基-2-嗎啉-4-基-8-(2H-吡唑-3-基)-[1,7]㖠啶 [2-(嗎啉-4-基)-8-(2H-吡唑-3-基)-[1,7]㖠啶-4-基]甲醇 4-(1-甲烷磺醯基環丙基)-2-(嗎啉-4-基)-8-(2H-吡唑-3-基)-[1,7]㖠啶 4-異丙氧基-2-(嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶 2-(嗎啉-4-基)-4-(丙-2-基氧基)-8-(1H-吡咯-2-基)-1,7-㖠啶 4-[3-(S-甲磺醯亞胺基)丙氧基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-乙氧基-2-(嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶 4-甲氧基-2-(嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶 2-甲基-1-{[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]氧基}丙-2-醇 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(四氫呋喃-2-基甲氧基)-1,7-㖠啶 3-{[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]氧基}二氫呋喃-2(3H)-酮 4-[(3-甲基-1,2-噁唑-5-基)甲氧基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[(5-甲基-1,2-噁唑-3-基)甲氧基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-苯甲氧基-2-(嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶 4-異丙氧基-2-((R)-3-甲基嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶 [4-({2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}氧基)丁基]胺基甲酸第三丁酯 4-甲氧基-2-((R)-3-甲基嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶 [3-({2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}氧基)丙基]胺基甲酸第三丁酯 2-({2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}氧基)乙胺 [2-({2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}氧基)乙基]胺基甲酸第三丁酯 4-({2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}氧基)丁-1-胺 2-[(3R,5S)-3,5-二甲基嗎啉-4-基]-4-異丙氧基-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R,5R)-3,5-二甲基嗎啉-4-基]-4-異丙氧基-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(四氫-2H-哌喃-4-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶鹽酸鹽 4-氯-2-嗎啉-4-基-8-(1H-吡唑-3-基)-[1,7]㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(甲基硫基(sulfanyl))-8-(1H-吡唑-5-基)-1,7-㖠啶 N-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}-1,4λ4
-氧硫𠮿-4-亞胺4-氧化物 4-{[二甲基(側氧基)-λ6
-亞硫基]胺基}-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(哌嗪-1-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-異丙氧基-2-((S)-3-甲基嗎啉-4-基)-8-(1H-吡唑-3-基)-[1,7]㖠啶 2-(嗎啉-4-基)-4-(丙-2-基氧基)-8-(1H-吡咯-3-基)-1,7-㖠啶 4-(1-乙基-1H-吡唑-5-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1-甲基-1H-咪唑-5-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯胺 4-(2,3-二氟苯基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[2-甲基-6-(甲磺醯基)吡啶-3-基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[2-氟-4-(甲磺醯基)苯基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-氟-2-[2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯胺 4-(1-苯甲基-1H-咪唑-5-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-氟苯基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(2-甲基-1,3-噻唑-5-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[4-甲基-6-(甲磺醯基)吡啶-3-基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1-環丙基-1H-吡唑-5-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[2-氟-4-(哌嗪-1-基)苯基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-[4-(甲磺醯基)哌嗪-1-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 N-(2,2-二甲基丙基)-N-甲基-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-胺 (1-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}哌啶-4-基)甲醇 N-環丙基-N-甲基-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-胺 4-(5,6-二氫咪唑并[1,2-a]吡嗪-7(8H)-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 N-(4-氟苯基)-N-甲基-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-胺 2-[(3R)-3-甲基嗎啉-4-基]-4-(6-甲基吡啶-3-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-氟吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-氟-4-甲基吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(1-甲基-1H-吡咯-2-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(6-氟-5-甲基吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-氟-6-甲基吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(6-氟吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(6-甲氧基吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(6-甲氧基-5-甲基吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(6-氟-2-甲基吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-[1-甲基-3-(三氟甲基)-1H-吡唑-5-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(3-甲基-2-噻吩基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(5-甲基-2-噻吩基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(4-甲基-3-噻吩基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3-氯-2-噻吩基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(2-甲基-3-噻吩基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-4-(1H-吡咯并[2,3-b]吡啶-4-基)-1,7-㖠啶 4-(3,5-二甲基-1,2-噁唑-4-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3-氯-2-甲氧基吡啶-4-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-4-(四氫-2H-哌喃-4-基)-1,7-㖠啶 4-(3,6-二氫-2H-硫哌喃-4-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(4-甲基哌啶-1-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1-第三丁基-1H-吡唑-5-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(1-甲基-1H-吡唑-5-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(3-甲基-1,2-噁唑-5-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1-乙基-3-甲基-1H-吡唑-5-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1,4-二甲基-1H-吡唑-5-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[2-甲基-6-(甲基硫基)吡啶-3-基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[2-甲基-6-(S-甲磺醯亞胺基)吡啶-3-基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(1-丙基-1H-吡唑-5-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(6,7-二氫-5H-吡咯并[1,2-a]咪唑-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[1-乙基-3-(三氟甲基)-1H-吡唑-5-基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 5-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}-1H-吡咯-2-甲酸甲酯 2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-4-(1,2-噻唑-5-基)-1,7-㖠啶 N,N-二甲基-2-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}苯胺 4-(2,4-二氟苯基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1-異丙基-1H-吡唑-5-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 甲基{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}亞膦酸乙酯 4-{[二乙基(側氧基)-λ6
-亞硫基]胺基}-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 {2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}亞膦酸異丁酯甲酯 2-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}丙-2-醇 3-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}戊-3-醇 4-(5-氯吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 5-氟-2-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}苯胺 4-[2-氟-3-(甲磺醯基)苯基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-[1-(氧雜環丁-3-基)-1H-吡唑-5-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[2-氟-4-(吡咯啶-1-基)苯基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[3-(甲氧基甲基)-5-甲基-1,2-噁唑-4-基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(5-甲基-1,3,4-噁二唑-2-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 N-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}四氫-1H-1λ4
-噻吩-1-亞胺1-氧化物 4-{[(4-氟苯基)(甲基)側氧基-λ6
-亞硫基]胺基}-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶，2種非對映異構體之混合物 4-{[(2-氟苯基)(甲基)側氧基-λ6
-亞硫基]胺基}-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶，2種非對映異構體之混合物 4-{[(R)(2-氟苯基)(甲基)側氧基-λ6
-亞硫基]胺基}-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶，非對映異構體 4-{[(S)(2-氟苯基)(甲基)側氧基-λ6
-亞硫基]胺基}-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶，非對映異構體 4-(二甲基磷醯基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(二乙基磷醯基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 異丁基{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}亞膦酸乙酯 2-[(3R)-3-甲基嗎啉-4-基]-4-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1-異丁基-1H-吡唑-5-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[5-氟-6-(甲磺醯基)吡啶-3-基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[(3R)-3-甲基嗎啉-4-基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(4-甲基-1H-吡唑-5-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[2-氟-5-(甲磺醯基)苯基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[4-(異丙基磺醯基)苯基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(6-氟吡啶-2-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1-乙基-1H-咪唑-4-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 1-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}脯胺醯胺 3-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}吡啶-2-胺 2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-4-[1-(2,2,2-三氟乙基)-1H-吡唑-5-基]-1,7-㖠啶 1-甲基-4-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}哌嗪-2-酮 4-[1-(2-氟乙基)-1H-吡唑-3-基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[1-(2-氟乙基)-1H-吡唑-5-基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(3-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}-1H-吡唑-1-基)乙醇 2-甲基-1-(3-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}-1H-吡唑-1-基)丙-2-醇 4-[(2R)-2-甲基嗎啉-4-基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(5-氟吡啶-2-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(6-甲基吡啶-2-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(3-甲基吡啶-2-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 N-(2-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}苯基)乙醯胺 3-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}吡啶-2-醇 2-(3-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}苯基)丙-2-醇 4-(5,6-二氫咪唑并[1,2-a]吡嗪-7(8H)-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[(2S)-2-甲基嗎啉-4-基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[(反式)-2-甲基環丙基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(二氟甲氧基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]丙-2-醇 2-(嗎啉-4-基)-4-(3-氧雜-8-氮雜雙環[3.2.1]辛-8-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-4-(吡咯啶-1-基)-1,7-㖠啶 4-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]哌嗪-2-酮 4-(二甲基磷醯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[(反式)-2,5-二甲基哌嗪-1-基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[(順式)-3,5-二甲基哌嗪-1-基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 1-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]-3-(三氟甲基)氮雜環丁-3-醇 甲基氫{4-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯基}膦酸酯 4-(4-甲基哌嗪-1-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-[(3aR,6aS)-四氫-1H-呋喃并[3,4-c]吡咯-5(3H)-基]-1,7-㖠啶 4-(3-甲氧基-3-甲基氮雜環丁-1-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-4-[(1S,4S)-2-氧-5-氮雜雙環[2.2.1]庚-5-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-[(甲基硫基)甲基]-8-(1H-吡唑-5-基)-1,7-㖠啶 N,N-二甲基-5-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]吡啶-2-胺 4-(2-甲基吡啶-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 1-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}環己醇 2-氟-6-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}苯胺 (甲基{4-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯基}側氧基-λ6
-亞硫基)氰胺 1-乙基-3-(甲基{4-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯基}側氧基-λ6
-亞硫基)脲 3-({2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}氧基)丙-1-胺 4-(4-環丙基-1H-1,2,3-三唑-5-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-乙基亞磺醯基-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-4-[丙-2-基亞磺醯基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-[3-(甲磺醯基)丙氧基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-4-(苯基磺醯基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-4-(丙-2-基磺醯基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(乙基磺醯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-4-(苯基亞磺醯基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(甲基亞磺醯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-[1-側氧基四氫-2H-硫哌喃-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1,1-二側氧基四氫-2H-硫哌喃-4-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4,8-二(1H-吡唑-5-基)-1,7-㖠啶 N,N-二甲基-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-胺 2-(嗎啉-4-基)-4-(苯基硫基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-N-(丙-2-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-胺 4-(乙基硫基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-4-(丙-2-基硫基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(1H-吡咯-2-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(1H-吡咯-3-基)-1,7-㖠啶 4-[(4-甲氧基苯基)硫基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(5-甲基-1H-吡唑-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 1-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]吡咯啶-2-酮 4-(1,1-二側氧基-1,2-噻唑啶-2-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 1-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]哌啶-2-酮 2-[(3R)-3-甲基嗎啉-4-基]-4-(2-甲基吡啶-3-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-[2-(丙-2-基氧基)吡啶-3-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-甲氧基吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(吡啶-4-基)-1,7-㖠啶 4-[(4-甲氧基苯基)硫基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[3-氟-2-(嗎啉-4-基)吡啶-4-基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(6-氟-5-甲基吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 3-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]-1,3-氧氮雜環己-2-酮 3-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]-1,3-噁唑啶-2-酮 4-(3-甲氧基吡啶-4-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2,6-二氟吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(5-氯-2-氟吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3-氟吡啶-4-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-氯-6-甲基吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(5,6-二甲基吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(5-氟-6-甲基吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(5-甲基噻吩-3-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3-甲氧基噻吩-2-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-氯噻吩-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(異喹啉-4-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(5-氯噻吩-2-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(4-甲基噻吩-2-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2,5-二甲基噻吩-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-4-(四氫-2H-硫哌喃-4-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(1-甲基-1,2,5,6-四氫吡啶-3-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(1-甲基-1,2,3,6-四氫吡啶-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-[1-甲基哌啶-3-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-4-(1,2,3,6-四氫吡啶-4-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-4-[1-(四氫-2H-哌喃-4-基)-1H-吡唑-3-基]-1,7-㖠啶 4-(4,6-di氟吡啶-3-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(1-甲基-1H-吡唑-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1,3-二甲基-1H-吡唑-4-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1,5-二甲基-1H-吡唑-4-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(哌啶-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-4-[3-(三氟甲基)-1H-吡唑-4-基]-1,7-㖠啶 4-(1-環丁基-1H-吡唑-4-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1-環丙基-1H-吡唑-4-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-[1-(丙-2-基)-1H-吡唑-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[1-(二氟甲基)-1H-吡唑-4-基]-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1-第三丁基-1H-吡唑-4-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-4-(1,3,5-三甲基-1H-吡唑-4-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-[1-甲基-3-(三氟甲基)-1H-吡唑-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(4-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}-1H-吡唑-1-基)乙醇 4-(1-乙基-1H-吡唑-4-基)-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(1-甲基-1H-吡咯-3-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-[1-(丙-2-基)-1H-吡唑-3-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-4-(1,2,5-三甲基-1H-吡咯-3-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(1-苯基-1H-吡唑-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(3-甲基-1H-吡唑-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-胺 2-[(3R)-3-甲基嗎啉-4-基]-4-[1-(2-甲基丙基)-1H-吡唑-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(1H-吡唑-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[(3R)-3-甲基嗎啉-4-基]-4-(1,3-噁唑-2-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1,3-二甲基-1H-吡唑-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1,5-二甲基-1H-吡唑-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(1,3,5-三甲基-1H-吡唑-4-基)-1,7-㖠啶 4-{[(2-甲氧基乙基)(甲基)側氧基-λ6
-亞硫基]胺基}-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-{[(4-溴苯基)(側氧基)丙-2-基-λ6
-亞硫基]胺基}-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(甲基-N-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}磺醯亞胺基)苯酚 4-{[(4-溴苯基)(甲基)側氧基-λ6
-亞硫基]胺基}-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-{[第三丁基(甲基)側氧基-λ6
-亞硫基]胺基}-2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 甲酸、N-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]-1,4λ4
-氧硫𠮿-4-亞胺4-氧化物(1:1) N-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]六氫-1λ4
-硫哌喃-1-亞胺1-氧化物 3-甲基-2-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}丁-2-醇 1-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}-1-(四氫-2H-哌喃-4-基)乙醇 3,3-二甲基-2-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}丁-2-醇 2-{2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基}己-2-醇 2-[(3R)-3-甲基嗎啉-4-基]-8-(1H-吡唑-3-基)-1,7-㖠啶-4-甲醯胺 2-[(3R)-3-甲基嗎啉-4-基]-4-[1-(甲磺醯基)環丙基]-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(四氫-2H-哌喃-4-基甲氧基)-1,7-㖠啶 N,N-二甲基-3-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯甲醯胺 {4-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯基}(哌啶-1-基)甲酮 N,N-二甲基-2-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯甲醯胺 N-環丙基-4-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯甲醯胺 4-(4-甲基吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1H-吲哚-6-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1H-吲哚-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 3-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯甲醯胺 4-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯甲醯胺 N-甲基-3-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯甲醯胺 4-(3-氟苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(5-氯噻吩-2-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-甲氧基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-[2-(三氟甲基)苯基]-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-[4-(三氟甲基)苯基]-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-[3-(三氟甲基)苯基]-1,7-㖠啶 4-(3-氯苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 N-{3-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯基}乙醯胺 4-(3-甲氧基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3,5-二甲氧基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3-甲基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(4-甲氧基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(呋喃-2-基甲基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2,6-二甲基-4-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯酚 4-(2,3-二甲基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 {3-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯基}甲醇 4-(4-氟苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(4-甲基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(4-氯苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-氟-3-甲氧基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-甲基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2,3-二甲氧基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 N,N-二甲基-3-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯胺 N,N-二甲基-2-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯胺 N-{2-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯基}甲磺醯胺 N-{4-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯基}甲磺醯胺 N,N-二甲基-4-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯甲醯胺 2-(嗎啉-4-基)-4-[(1E)-丙-1-烯-1-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯酚 4-(2-氟苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 {3-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯基}(哌啶-1-基)甲酮 2-(嗎啉-4-基)-4-[4-(丙-2-基)苯基]-8-(1H-吡唑-5-基)-1,7-㖠啶 N-環丙基-3-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯甲醯胺 4-(聯苯-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2,4-二甲氧基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-氯苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2,5-二甲基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 3-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯胺 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-[3-(1H-吡唑-1-基)苯基]-1,7-㖠啶 3-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯酚 4-(2-氟-5-甲氧基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(5-氟-2-甲氧基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2,4-二氟苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2,3-二氟苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2,6-二甲氧基苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]苯胺 4-(3,5-二氯苯基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(聯苯-2-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-氯吡啶-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1-苯并噻吩-2-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1-甲基-1H-吡唑-5-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(喹啉-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(吡啶-3-基)-1,7-㖠啶 4-(2-甲氧基吡啶-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(5-甲基吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(5-甲氧基吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(喹啉-3-基)-1,7-㖠啶 2-(嗎啉-4-基)-4-[1-(苯基磺醯基)-1H-吲哚-2-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-氯吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(6-氯吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 {5-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]噻吩-2-基}甲醇 4-(2-氟吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(6-氟吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-氯-6-甲基吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-甲氧基吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(異喹啉-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3-氯吡啶-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3-氟吡啶-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2,6-二氟吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1-甲基-1H-吡唑-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 5-甲氧基-2-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]-1H-吲哚-1-甲酸第三丁酯 2-(嗎啉-4-基)-4-[6-(嗎啉-4-基)吡啶-3-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(4-甲基噻吩-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(噻吩-2-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(噻吩-3-基)-1,7-㖠啶 4-(3-甲基噻吩-2-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-氯-5-甲基吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(4-甲氧基吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(5-氯-2-甲氧基吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 5-甲基-2-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]-1H-吲哚-1-甲酸第三丁酯 4-(5-氯-2-氟吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3,5-二甲基-1,2-噁唑-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(喹啉-8-基)-1,7-㖠啶 4-(5-甲基噻吩-2-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(6-乙氧基吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(2-乙氧基吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(喹啉-6-基)-1,7-㖠啶 4-(2-氯噻吩-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 5-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]吡啶-2-胺 2-(嗎啉-4-基)-4-(1H-吡唑-3-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(6-甲基吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1-甲基-1H-吡咯-2-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 5-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]吡啶-2-醇 4-(5-氯吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3-氯-2-甲氧基吡啶-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3-氯噻吩-2-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(5-氟吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[2-(甲基硫基)嘧啶-5-基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 N-環丙基-5-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]嘧啶-2-胺 4-(異喹啉-5-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 N-甲基-5-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]吡啶-2-甲醯胺 N-第三丁基-5-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]吡啶-3-甲醯胺 4-[5-(甲基硫基)吡啶-3-基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-(1H-吡咯并[2,3-b]吡啶-4-基)-1,7-㖠啶 3-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]吡啶-2-胺 4-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]噻吩-2-甲酸甲酯 4-[2-甲氧基-5-(三氟甲基)吡啶-3-基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-4-[2-(丙-2-基氧基)吡啶-3-基]-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(5-氯-6-乙氧基吡啶-3-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1-第三丁基-1H-吡唑-4-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-4-(哌啶-1-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 1-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]哌啶-4-醇 N-甲基-2-(嗎啉-4-基)-N-苯基-8-(1H-吡唑-5-基)-1,7-㖠啶-4-胺 {1-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]吡咯啶-2-基}甲醇 N-甲基-2-(嗎啉-4-基)-N-丙基-8-(1H-吡唑-5-基)-1,7-㖠啶-4-胺 4-(氧雜環庚烷-1-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3-甲基哌啶-1-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(4-甲基哌啶-1-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 1-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]哌啶-3-甲醯胺 4-(2,5-二氫-1H-吡咯-1-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3,4-二氫喹啉-1(2H)-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3,4-二氫異喹啉-2(1H)-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(1,3-二氫-2H-異吲哚-2-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-4-[1,3,3-三甲基-6-氮雜雙環[3.2.1]辛-6-基]-1,7-㖠啶 1-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]-脯胺酸第三丁酯 N-甲基-N-(2-甲基丙基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-胺 N-(3-氟苯基)-N-甲基-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-胺 4-(1,1-二側氧基-1-硫雜(thia)-6-氮雜螺[3.3]庚-6-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-(3-氟哌啶-1-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 N-(2-氟苯基)-N-甲基-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-胺 1-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]-脯胺醯胺 {1-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]哌啶-4-基}甲醇 4-(4-甲氧基哌啶-1-基)-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 N-(4-氟苯基)-N-甲基-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-胺 N-甲基-1-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]-脯胺醯胺 4-[4-(乙基磺醯基)哌嗪-1-基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 4-[4-(甲磺醯基)哌嗪-1-基]-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶 N-環丙基-N-甲基-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-胺 N-(2,2-二甲基丙基)-N-甲基-2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-胺 {1-[2-(嗎啉-4-基)-8-(1H-吡唑-5-基)-1,7-㖠啶-4-基]哌啶-3-基}甲醇 或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽。 上文所列之組分A之通式(I)或(Ib)化合物之合成描述於國際專利公開案WO2016020320 (A1)中。 在一較佳實施例中，該組分A為2-[(3R)-3-甲基嗎啉-4-基]-4-(1-甲基-1H-吡唑-5-基)-8-(1H-吡唑-5-基)-1,7-㖠啶(「化合物A」)、其互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽。 在一較佳實施例中，該組分A為具有以下結構之化合物A。 化合物A之合成描述於WO2016020320 (A1)之實例111中。 術語組分A，特別是化合物A之「醫藥學上可接受之鹽」係指本發明化合物之相對無毒、無機或有機酸加成鹽。舉例而言，參見S. M. Berge等人「Pharmaceutical Salts,」 J. Pharm. Sci. 1977, 66, 1-19。醫藥學上可接受之鹽包括藉由使充當鹼之主要化合物與無機或有機酸反應以形成鹽來獲得之彼等鹽，例如鹽酸鹽、硫酸鹽、磷酸鹽、甲磺酸鹽、樟腦磺酸鹽、草酸鹽、順丁烯二酸鹽、琥珀酸鹽及檸檬酸鹽。醫藥學上可接受之鹽亦包括其中主要化合物充當酸且與適當鹼反應以形成例如鈉鹽、鉀鹽、鈣鹽、鎂鹽、銨鹽及氯鹽之彼等鹽。熟習此項技術者將進一步認識到，所主張之化合物之酸加成鹽可藉由使化合物與適當無機或有機酸經由多種已知方法中之任一者反應來製備。或者，本發明之酸性化合物的鹼金屬鹽及鹼土金屬鹽藉由使本發明化合物與適當鹼經由多種已知方法反應來製備。 本發明之組分A之代表性鹽包括習知無毒鹽及例如藉由此項技術中熟知之手段由無機或有機酸或鹼形成之四級銨鹽。舉例而言，此類酸加成鹽包括：乙酸鹽、己二酸鹽、海藻酸鹽、抗壞血酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、硫酸氫鹽、丁酸鹽、檸檬酸鹽、樟腦酸鹽、樟腦磺酸鹽、肉桂酸鹽、環戊烷丙酸鹽、二葡糖酸鹽、十二烷基硫酸鹽、乙磺酸鹽、反丁烯二酸鹽、葡糖庚酸鹽、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、氯鹽、溴鹽、碘鹽、2-羥基乙烷磺酸鹽、伊康酸鹽、乳酸鹽、順丁烯二酸鹽、杏仁酸鹽、甲磺酸鹽、2-萘磺酸鹽、菸鹼酸鹽、硝酸鹽、草酸鹽、雙羥萘酸鹽、果膠酸鹽、過氧硫酸鹽、3-苯基丙酸鹽、苦味酸鹽、特戊酸鹽、丙酸鹽、琥珀酸鹽、磺酸酯、硫酸鹽、酒石酸鹽、硫氰酸鹽、甲苯磺酸鹽及十一烷酸鹽。 鹼鹽包括鹼金屬鹽，諸如鉀鹽及鈉鹽；鹼土金屬鹽，諸如鈣鹽及鎂鹽；及與諸如二環己胺及N-甲基-D-葡糖胺之有機鹼形成之銨鹽。另外，鹼性含氮基團可經諸如以下之試劑四級銨化：低碳數烷基鹵化物，諸如甲基、乙基、丙基及丁基氯化物、溴化物及碘化物；硫酸二烷酯，如硫酸二甲酯、硫酸二乙酯、硫酸二丁酯或硫酸二戊酯；長鏈鹵化物，諸如癸基、月桂基、肉豆蔻基及硬脂基氯化物、溴化物及碘化物；芳烷基鹵化物，如苯甲基及苯乙基溴化物；及其他。 該組分A可呈醫藥調配物形式，其準備好用於與組分B及視情況組分C同時、並行、分開或依序投與，如下文進一步所描述。組分A及B及視情況組分C可藉由經口、靜脈內、局部、局部裝置、腹膜內或經鼻途徑彼此獨立地投與。 如上文所揭示之清單之特定化合物較佳為組合中之組分A，最佳為用於實驗部分中之「化合物A」。 應理解，本發明亦係關於上文所描述之組分A之實施例之任何組合。組合中之組分 B
組分B為鹼土放射性核種鐳-223之醫藥學上可接受之鹽。 鐳-223之醫藥學上可接受之鹽可為例如與以下之酸形成之酸加成鹽：諸如，無機酸，例如鹽酸、氫溴酸、氫碘酸、硫酸、重硫酸、磷酸或硝酸；或有機酸，例如甲酸、乙酸、乙醯乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、柳酸、2-(4-羥苯甲醯基)苯甲酸、樟腦酸、肉桂酸、環戊丙酸、二葡萄糖酸、3-羥基-2-萘甲酸、菸鹼酸、撲酸、果膠酯酸、過硫酸、3-苯基丙酸、苦酸、特戊酸、2-羥基乙磺酸鹽、伊康酸、胺磺酸、三氟甲磺酸、十二基硫酸、乙磺酸、苯磺酸、對甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟腦磺酸、檸檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、蘋果酸、肥酸、褐藻酸、順丁烯二酸、反丁烯二酸、D葡萄糖酸、杏仁酸、抗壞血酸、葡糖庚酸、甘油磷酸、天冬胺酸、磺柳酸、半硫酸或硫氰酸。 鐳-223之較佳醫藥學上可接受之鹽為二氯化物(223
RaCl2
)。 用於製備包含鐳-223之醫藥學上可接受之溶液的方法揭示於例如WO 2000/40275(A2)、WO 2011/134671(A1)及WO 2011/134672(A1)中。 包含鐳-223之醫藥學上可接受之溶液展示用作靶向放射性藥物之獨特機制。該等溶液代表基於天然趨骨性核種鐳-223之新一代發射α之治療性藥物。較佳地，使用靜脈內注射用、無菌及不含細菌內毒素之氯化鐳-223 (223
RaCl2
)之水溶液。 較佳地，溶液具等張性，含有至生理pH之檸檬酸鈉緩衝鹽水。 氯化鐳-223注射劑之較佳給藥方案為以由6次注射組成之療程形式每間隔4週給予50 kBq/kg體重。在I期臨床試驗中評估達至250 kBq/kg體重之單次鐳-223劑量。在此劑量下觀測到之不良反應為下痢及可逆性骨髓抑制(包括一個3級嗜中性白血球減少症病例(1/5))。 作為一實例，二氯化鐳-223水溶液可在含有6 ml填充量之單次劑量10 ml小瓶中提供。此產品之鐳-223放射性濃度為1,000 kBq/mL (0.03 mCi/mL)，對應於在參考日期之0.53 ng/mL鐳。活性部分為α粒子放射核種鐳-223 (半衰期為11.4天)，表現為二價陽離子(223
Ra2 +
)。自鐳-223及其子體發射為α粒子之能量分數為95.3%，發射為β粒子之分數為3.6%，且發射為γ輻射之分數為1.1%。來自由鐳-223及其子核種之完全衰變而發射之輻射的組合能量為28.2 MeV。 鐳-223將由專業人員以緩慢推注注射形式靜脈內投與。應使用靜脈內進入管線以用於投與鐳-223。在注射鐳-223之前及之後必須用等張鹽水沖洗該管線。 鐳-223選擇性地靶向如骨轉移中增加之骨轉換區域，且藉由與羥磷灰石形成複合物來濃縮。α發射貢獻約93%總輻射吸收劑量。高線性能量α粒子輻射誘導雙鏈DNA斷裂，從而在含有轉移性癌細胞之目標區域中產生強力且局部化的細胞毒性效果。α粒子之短路徑長度(小於100微米)使對鄰近健康組織(諸如骨髓)之效果最小化。組合
根據另一態樣，本發明提供至少兩種組分、較佳兩種組分之組合，其包含組分A及組分B，組分A為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及組分B為鹼土放射性核種鐳-223之醫藥學上可接受之鹽。 根據另一態樣，本發明涵蓋一種本文中所提及之任何組分A與本文中所提及之任何組分B，視情況與本文中所提及之任何組分C的組合。 根據另一態樣，本發明涉及至少兩種組分A及B、較佳兩種組分之組合，其包含為ATR激酶抑制劑，特別是化合物A的組分A及為鹼土放射性核種鐳-223之醫藥學上可接受之鹽的組分B。根據另一態樣，本發明提供至少兩種組分A及B、較佳兩種組分之組合，其包含為ATR激酶抑制劑，特別是化合物A或其醫藥學上可接受之鹽的組分A及為鹼土放射性核種鐳-223之醫藥學上可接受之無機鹽的組分B。根據另一態樣，本發明提供至少兩種組分、較佳兩種組分之組合，其包含如上文所描述之組分A及如上文所描述之組分B，組分A為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及組分B為鹼土放射性核種鐳-223之醫藥學上可接受之鹽。 如本文所描述及定義之包含至少兩種組分A及B、較佳兩種組分之組合亦稱為「本發明組合」。 本文證實本發明組合與尤其揭示於實例部分中之ATR激酶抑制劑中之一者(「化合物A」)之協同行為。 此外，包含如上文所提及之化合物A及鐳-223之醫藥學上可接受之鹽，特別是223
RaCl2
的本發明組合為本發明之一較佳態樣。 在另一態樣中，本發明組合包含化合物A或其醫藥學上可接受之鹽及鹼土放射性核種鐳-223之醫藥學上可接受之鹽，較佳鐳-223之二氯化物鹽。 在一較佳實施例中，本發明組合包含化合物A或其醫藥學上可接受之鹽及鐳-223之二氯化物鹽。 另外，本發明涵蓋一種套組，其包含： 組分A：一或多種、較佳一種如上文所描述之ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽； 組分B：如上文所描述之鹼土放射性核種鐳-223之醫藥學上可接受之鹽或其溶劑合物或水合物。 在該套組中，視情況上述組合之任一者中該組分A及該組分B之任一者或兩者呈醫藥組合物形式，其準備用於同時、並行、分開或依序投與。組分A及B可彼此獨立地藉由經口、靜脈內、局部、局部裝置、腹膜內或經鼻途徑投與。較佳地，組分A藉由經口途徑投與且組分B藉由靜脈內途徑投與。 另外，本發明涵蓋一種套組，其包含： 組分A：一或多種、較佳一種如上文所描述之ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽； 組分B：如上文所描述之鹼土放射性核種鐳-223之醫藥學上可接受之鹽或其溶劑合物或水合物；及視情況， 組分C：一或多種，較佳一種，其他醫藥劑， 其中視情況，上述組合之任一者中該組分A、該組分B及該組分C之任一者或全部呈醫藥組合物形式，其準備用於同時、並行、分開或依序投與。組分A及B，視情況組分C可藉由經口、靜脈內、局部、局部裝置、腹膜內或經鼻途徑彼此獨立地投與。 至少一種醫藥劑之術語「組分C」包括有效化合物自身以及其醫藥學上可接受之鹽、溶劑合物、水合物或立體異構體以及包含此有效化合物或其醫藥學上可接受之鹽、溶劑合物、水合物或立體異構體之醫藥組合物。組分C之醫藥劑之清單進一步提供於下文。 本發明之組分A及組分B之組合可以單獨醫藥劑或與一或多種其他醫藥劑C組合投與，其中組分A、B及C所產生之組合不會造成不可接受之不良影響。舉例而言，本發明之組分A及B之組合可與組分C組合，該組分C亦即一或多種其他醫藥劑，諸如已知抗血管生成劑、抗過度增生劑、消炎劑、鎮痛劑、免疫調節劑、利尿劑、抗心律不整劑、抗高膽固醇血症劑、抗異常血脂症劑、抗糖尿病劑或抗病毒劑及類似者，以及其摻和物及組合。 可作為組分C添加至組分A及B之組合的可選醫藥劑可為一或多種諸如以下之醫藥劑：131I-chTNT、阿巴瑞克(abarelix)、阿比特龍(abiraterone)、阿柔比星(aclarubicin)、恩他新阿多-曲妥珠單抗(ado-trastuzumab emtansine)、阿法替尼(afatinib)、阿柏西普(aflibercept)、阿地介白素(aldesleukin)、艾樂替尼(alectinib)、阿侖妥珠單抗(alemtuzumab)、阿侖膦酸(alendronic acid)、亞利崔托寧(alitretinoin)、六甲蜜胺、阿米福汀(amifostine)、胺格魯米特(aminoglutethimide)、胺基乙醯丙酸己酯、胺柔比星(amrubicin)、安吖啶(amsacrine)、阿那曲唑(anastrozole)、安西司亭(ancestim)、大茴香腦、二硫雜環戊二烯硫酮、拉夫坦辛阿內圖單抗(anetumab ravtansine)、血管收縮素II、抗凝血酶III、阿瑞匹坦(aprepitant)、阿西莫單抗(arcitumomab)、阿格拉賓(arglabin)、三氧化二砷、天冬醯胺酶、阿西替尼(axitinib)、阿紮胞苷(azacitidine)、巴利昔單抗(basiliximab)、貝洛替康(belotecan)、苯達莫司汀(bendamustine)、貝索單抗(besilesomab)、貝林諾他(belinostat)、貝伐單抗(bevacizumab)、貝瑟羅汀(bexarotene)、比卡魯胺(bicalutamide)、比生群(bisantrene)、博萊黴素(bleomycin)、布林莫單抗(blinatumomab)、硼替佐米(bortezomib)、布舍瑞林(buserelin)、伯舒替尼(bosutinib)、貝倫妥單抗維多汀(brentuximab vedotin)、白消安(busulfan)、卡巴利他索(cabazitaxel)、卡博替尼(cabozantinib)、降鈣素(calcitonine)、亞葉酸鈣、左亞葉酸鈣、卡培他濱(capecitabine)、卡羅單抗(capromab)、卡鉑(carboplatin)、卡波醌(carboquone)、卡非佐米(carfilzomib)、卡莫氟(carmofur)、卡莫司汀(carmustine)、卡妥索單抗(catumaxomab)、塞內昔布(celecoxib)、西莫介白素(celmoleukin)、色瑞替尼(ceritinib)、西妥昔單抗(cetuximab)、氯芥苯丁酸(chlorambucil)、氯地孕酮(chlormadinone)、雙氯乙基甲胺(chlormethine)、西多福韋(cidofovir)、西那卡塞(cinacalcet)、順鉑(cisplatin)、克拉屈濱(cladribine)、氯膦酸、氯法拉濱(clofarabine)、考比替尼(cobimetinib)、考班昔布(copanlisib)、克立他酶(crisantaspase)、克卓替尼(crizotinib)、環磷醯胺(cyclophosphamide)、環丙孕酮(cyproterone)、阿糖胞苷(cytarabine)、達卡巴嗪(dacarbazine)、放線菌素、達土木單抗(daratumumab)、阿法達貝泊汀(darbepoetin alfa)、達拉非尼(dabrafenib)、達沙替尼(dasatinib)、道諾黴素(daunorubicin)、地西他濱(decitabine)、地加瑞克(degarelix)、迪夫托斯地尼介白素(denileukin diftitox)、德諾單抗(denosumab)、地普奧肽(depreotide)、德舍瑞林(deslorelin)、衛康醇(dianhydrogalactitol)、右雷佐生(dexrazoxane)、二溴螺氯銨(dibrospidium chloride)、雙氯芬酸(diclofenac)、迪奴圖單抗(dinutuximab)、多西他賽(docetaxel)、多拉司瓊(dolasetron)、去氧氟尿苷(doxifluridine)、多柔比星(doxorubicin)、多柔比星+雌酮、屈大麻酚(dronabinol)、依庫麗單抗(eculizumab)、依決洛單抗(edrecolomab)、依利醋銨(elliptinium acetate)、埃羅妥珠單抗(elotuzumab)、艾曲波帕(eltrombopag)、內皮生長抑素、依諾他濱(enocitabine)、恩雜魯胺(enzalutamide)、表柔比星(epirubicin)、環硫雄醇、阿法依泊汀(epoetin alfa)、倍他依泊汀(epoetin beta)、澤塔依伯汀(epoetin zeta)、依鉑(eptaplatin)、艾瑞布林(eribulin)、埃羅替尼(erlotinib)、埃索美拉唑(esomeprazole)、雌二醇、雌莫司汀(estramustine)、炔雌醇、依託泊苷(etoposide)、依維莫司(everolimus)、依西美坦(exemestane)、法屈唑(fadrozole)、芬太尼(fentanyl)、非格司亭(filgrastim)、氟羥甲基睾酮、氟尿苷(floxuridine)、氟達拉賓(fludarabine)、氟尿嘧啶、氟他胺(flutamide)、醛葉酸、福美司坦(formestane)、福沙匹坦(fosaprepitant)、福莫司汀(fotemustine)、氟維司群(fulvestrant)、釓布醇(gadobutrol)、釓特醇(gadoteridol)、釓特酸葡甲胺(gadoteric acid meglumine)、釓弗塞胺(gadoversetamide)、釓塞酸(gadoxetic acid)、硝酸鎵(gallium nitrate)、加尼瑞克(ganirelix)、吉非替尼(gefitinib)、吉西他濱(gemcitabine)、吉妥單抗(gemtuzumab)、谷卡匹酶(Glucarpidase)、氧化型谷胱甘肽(glutoxim)、GM-CSF、戈舍瑞林(goserelin)、格拉司瓊(granisetron)、粒細胞群落刺激因子、二氫氯化組胺(histamine dihydrochloride)、組胺瑞林(histrelin)、羥基脲、I-125晶種、蘭索拉唑(lansoprazole)、伊班膦酸(ibandronic acid)、替坦異貝莫單抗(ibritumomab tiuxetan)、依魯替尼(ibrutinib)、艾達黴素(idarubicin)、異環磷醯胺、伊馬替尼(imatinib)、咪喹莫特(imiquimod)、英丙舒凡(improsulfan)、吲地司瓊(indisetron)、英卡膦酸(incadronic acid)、巨大戟醇甲基丁烯酸酯(ingenol mebutate)、干擾素α、干擾素β、干擾素γ、碘比醇(iobitridol)、碘苄胍(iobenguane) (123I)、碘美普爾(iomeprol)、伊派利單抗(ipilimumab)、伊立替康(irinotecan)、伊曲康唑(Itraconazole)、伊沙匹隆(ixabepilone)、依薩唑米(ixazomib)、蘭瑞肽(lanreotide)、拉帕替尼(lapatinib)、艾索膽鹼(Iasocholine)、來那度胺(lenalidomide)、樂伐替尼(lenvatinib)、來格司亭(lenograstim)、磨菇多糖、來曲唑(letrozole)、亮丙瑞林(leuprorelin)、左旋咪唑(levamisole)、左炔諾孕酮(levonorgestrel)、左旋甲狀腺素鈉、麥角乙脲(lisuride)、洛鉑(lobaplatin)、洛莫司汀(lomustine)、氯尼達明(lonidamine)、馬索羅酚(masoprocol)、甲羥孕酮、甲地孕酮、美拉胂醇(melarsoprol)、美法侖(melphalan)、美雄烷(mepitiostane)、巰嘌呤(mercaptopurine)、美司鈉(mesna)、美沙酮(methadone)、甲胺喋呤(methotrexate)、甲氧沙林(methoxsalen)、胺基乙醯丙酸甲酯、甲潑尼龍(methylprednisolone)、甲睾酮、甲酪胺酸、米伐木肽(mifamurtide)、米替福新(miltefosine)、米鉑(miriplatin)、二溴甘露醇(mitobronitol)、米托胍腙(mitoguazone)、二溴衛矛醇(mitolactol)、絲裂黴素、米托坦(mitotane)、米托蒽醌(mitoxantrone)、莫格利珠單抗(mogamulizumab)、莫拉司亭(molgramostim)、莫哌達醇(mopidamol)、鹽酸嗎啡(morphine hydrochloride)、硫酸嗎啡(morphine sulfate)、納比隆(nabilone)、納比系莫耳(nabiximols)、那法瑞林(nafarelin)、納洛酮+戊唑星(naloxone + pentazocine)、納曲酮(naltrexone)、那托司亭(nartograstim)、萊西單抗(necitumumab)、奈達鉑(nedaplatin)、奈拉濱(nelarabine)、奈立膦酸(neridronic acid)、奈妥吡坦/帕洛諾司瓊(netupitant/palonosetron)、尼魯單抗噴曲肽(nivolumabpentetreotide)、尼羅替尼(nilotinib)、尼魯胺(nilutamide)、尼莫唑(nimorazole)、尼妥珠單抗(nimotuzumab)、尼莫司汀(nimustine)、尼達尼布(nintedanib)、二胺硝吖啶(nitracrine)、納武單抗(nivolumab)、歐比托珠單抗(obinutuzumab)、奧曲肽(octreotide)、奧伐木單抗(ofatumumab)、奧拉帕尼(olaparib)、奧馬他辛美匹辛雷(omacetaxine mepesuccinate)、奧美拉唑(omeprazole)、昂丹司瓊(ondansetron)、奧普瑞介白素(oprelvekin)、奧古蛋白(orgotein)、奧瑞洛替莫德(orilotimod)、奧希替尼(osimertinib)、奧沙利鉑(oxaliplatin)、羥考酮(oxycodone)、羥次甲氫龍(oxymetholone)、奧佐米星(ozogamicine)、p53基因療法、太平洋紫杉醇(paclitaxel)、帕博希布(palbociclib)、帕利夫明(palifermin)、鈀-103晶種、帕洛諾司瓊(palonosetron)、帕米膦酸(pamidronic acid)、帕尼單抗(panitumumab)、帕比諾他(panobinostat)、泮托拉唑(pantoprazole)、帕佐泮尼(pazopanib)、培門冬酶(pegaspargase)、PEG-倍他依泊汀(甲氧基PEG-倍他依泊汀)、派立珠單抗(pembrolizumab)、派非格司亭(pegfilgrastim)、聚乙二醇化干擾素α-2b、培美曲塞(pemetrexed)、戊唑星、噴司他丁(pentostatin)、培洛黴素(peplomycin)、全氟正丁烷、培磷醯胺(perfosfamide)、帕妥珠單抗(Pertuzumab)、畢西巴尼(picibanil)、匹魯卡品(pilocarpine)、吡柔比星(pirarubicin)、匹蒽醌(pixantrone)、普樂沙福(plerixafor)、普卡黴素(plicamycin)、聚胺葡糖、聚磷酸雌二醇、聚乙烯吡咯啶酮+玻尿酸鈉、多醣-K、泊馬度胺(pomalidomide)、普納替尼(ponatinib)、卟吩姆鈉(porfimer sodium)、普拉曲沙(pralatrexate)、潑尼莫司汀(prednimustine)、潑尼松(prednisone)、丙卡巴肼(procarbazine)、丙考達唑(procodazole)、普萘洛爾(propranolol)、喹高利特(quinagolide)、雷貝拉唑(rabeprazole)、拉克莫單抗(racotumomab)、拉多替尼(radotinib)、雷洛昔芬(raloxifene)、雷替曲塞(raltitrexed)、拉莫司瓊(ramosetron)、雷莫蘆單抗(ramucirumab)、雷莫司汀(ranimustine)、拉布立酶(rasburicase)、雷佐生(razoxane)、瑞法美替尼(refametinib)、瑞戈非尼(regorafenib)、利塞膦酸(risedronic acid)、依替膦酸錸-186 (rhenium-186 etidronate)、利妥昔單抗(rituximab)、羅拉匹坦(rolapitant)、羅米地辛(romidepsin)、羅米司亭(romiplostim)、羅莫肽(romurtide)、羅尼西克萊伯(roniciclib)、來昔決南釤(153Sm) (samarium (153Sm) lexidronam)、沙格司亭(sargramostim)、沙妥莫單抗(satumomab)、胰泌素、思圖昔單抗(siltuximab)、西普亮塞-T (sipuleucel-T)、西索菲蘭(sizofiran)、索布佐生(sobuzoxane)、甘胺雙唑鈉(sodium glycididazole)、索尼蒂吉伯(sonidegib)、索拉非尼(sorafenib)、司坦唑醇(stanozolol)、鏈脲佐菌素(streptozocin)、舒尼替尼(sunitinib)、他拉泊芬(talaporfin)、塔里穆尼拉赫帕雷普韋克(talimogene laherparepvec)、他米巴羅汀(tamibarotene)、他莫昔芬(tamoxifen)、他噴他多(tapentadol)、他索納明(tasonermin)、替西介白素(teceleukin)、美噴坦諾非單抗鍀(99mTc) (technetium (99mTc) nofetumomab merpentan)、99mTc-HYNIC-[Tyr3]-奧曲肽、喃氟啶(tegafur)、喃氟啶+吉美拉西(gimeracil) +奧特拉西(oteracil)、替莫泊芬(temoporfin)、替莫唑胺(temozolomide)、替西羅莫司(temsirolimus)、替尼泊苷(teniposide)、睪酮、替曲膦(tetrofosmin)、沙立度胺(thalidomide)、噻替派(thiotepa)、胸腺法新(thymalfasin)、促甲狀腺素α、硫鳥嘌呤(tioguanine)、托西利單抗(tocilizumab)、拓朴替康(topotecan)、托瑞米芬(toremifene)、托西莫單抗(tositumomab)、曲貝替定(trabectedin)、曲美替尼(trametinib)、曲馬多(tramadol)、曲妥珠單抗(trastuzumab)、恩他新曲妥珠單抗(trastuzumab emtansine)、曲奧舒凡(treosulfan)、維甲酸、曲氟尿苷(trifluridine) +替吡嘧啶(tipiracil)、曲洛司坦(trilostane)、曲普瑞林(triptorelin)、曲磷胺(trofosfamide)、血小板生成素、色胺酸、烏苯美司(ubenimex)、伐拉替尼(valatinib)、伐柔比星(valrubicin)、凡德他尼(vandetanib)、伐普肽(vapreotide)、維羅非尼(vemurafenib)、長春鹼(vinblastine)、長春新鹼(vincristine)、長春地辛(vindesine)、長春氟寧(vinflunine)、長春瑞賓(vinorelbine)、維莫德吉(vismodegib)、伏立諾他(vorinostat)、伏羅唑(vorozole)、釔-90玻璃微球粒、淨司他丁(zinostatin)、淨司他丁司他美(zinostatin stimalamer)、唑來膦酸(zoledronic acid)、佐柔比星(zorubicin)或其組合。 可作為組分C添加至組分A及B之組合的較佳可選醫藥劑為選自恩雜魯胺、比卡魯胺、氟他胺、尼魯胺及/或阿比特龍之一或多種藥劑。 一般而言，作為組分C與本發明之組分A及B之組合組合使用細胞毒素及/或細胞生長抑制劑可用於： (1) 相較於單獨投與任一藥劑，在減少腫瘤生長及/或轉移或甚至消除腫瘤及/或轉移上獲得更佳療效， (2) 提供減少量的所投與之化學治療劑的投與， (3) 提供在患者中良好耐受、具有相較於使用單一藥劑化學療法及某些其他組合療法所觀測更少的有害藥理學併發症的化學治療， (4) 對哺乳動物、尤其人類之較廣譜不同癌症類型提供治療， (5) 在所治療患者中獲得較高反應速率， (6) 相較於標準化學療法在所治療患者中獲得更長存活時間， (7) 使得腫瘤進展時間延長，及/或 (8) 相較於其他癌症藥劑組合產生拮抗作用之已知情形，產生至少與單獨使用藥劑一樣好的療效及耐受性結果。 另外，本發明涵蓋一種醫藥組合物，其包含如上文所描述之本發明組合以及一或多種醫藥學上可接受之賦形劑。 另外，本發明涵蓋一種醫藥組合物，其包含至少兩種組分、組分A及組分B之組合，組分A為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及組分B為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，以及一或多種醫藥學上可接受之賦形劑。 另外，本發明涵蓋一種醫藥組合物，其包含至少兩種組分，組分A及組分B，視情況與本文中所提及之任何組分C之組合，組分A為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及組分B為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，以及一或多種醫藥學上可接受之賦形劑。 在另一實施例中，組分A及B及視情況組分C存在於各別調配物中。 在另一實施例中，組分A及B及視情況組分C存在於聯合調配物中。 醫藥學上可接受之賦形劑為無毒的，較佳地其為無毒且為惰性的。醫藥學上可接受之賦形劑尤其包括 · 填充劑及賦形劑(例如纖維素、微晶纖維素，諸如Avicel®、乳糖、甘露醇、澱粉、磷酸鈣，諸如Di-Cafos®)， · 軟膏基質(例如石油膏、石蠟、甘油三酯、蠟、毛絨蠟、毛絨蠟醇、羊毛蠟、親水性軟膏、聚乙二醇)， · 栓劑用基質(例如聚乙二醇、可可脂、硬脂肪)， · 溶劑(例如水、乙醇、異丙醇、丙三醇、丙二醇、中鏈長甘油三酯脂肪油、液體聚乙二醇、石蠟)， · 界面活性劑、乳化劑、分散劑或潤濕劑(例如十二烷基硫酸鈉、卵磷脂、磷脂、脂肪醇(諸如Lanette®)、脫水山梨糖醇脂肪酸酯(諸如Span®)、聚氧乙烯脫水山梨糖醇脂肪酸酯(諸如Tween®)、聚氧乙烯脂肪酸甘油酯(諸如Cremophor®)、聚氧乙烯脂肪酸酯、聚氧乙烯脂肪醇醚、甘油脂肪酸酯、泊洛沙姆(poloxamer，諸如Pluronic®))， · 緩衝劑以及酸及鹼(例如磷酸鹽、碳酸鹽、檸檬酸、乙酸、鹽酸、氫氧化鈉溶液、碳酸銨、胺丁三醇、三乙醇胺)， · 等張劑(例如葡萄糖、氯化鈉)， · 吸附劑(例如高分散二氧化矽)， · 增黏劑、凝膠形成劑、增稠劑及/或黏合劑(例如聚乙烯吡咯啶酮、甲基纖維素、羥丙基甲基纖維素、羥基丙基纖維素、羧基甲基纖維素鈉、澱粉、卡波姆(carbomer)、聚丙烯酸(諸如Carbopol®)、海藻酸鹽、明膠)， · 崩解劑(例如改質澱粉、羧基甲基纖維素鈉、羥基乙酸澱粉鈉(諸如Explotab®)、交聯聚乙烯吡咯啶酮、交聯羧甲纖維素鈉(諸如AcDiSol®))， · 流量調節劑、潤滑劑、滑動劑及脫模劑(例如硬脂酸鎂、硬脂酸、滑石、高分散二氧化矽(諸如Aerosil®))， · 包衣材料(例如糖、蟲膠)及快速或以經調節之方式溶解的用於膜或擴散膜之成膜劑(例如聚乙烯吡咯啶酮(諸如Kollidon®)、聚乙烯醇、羥基丙基甲基纖維素、羥基丙基纖維素、乙基纖維素、鄰苯二甲酸羥基丙基甲基纖維素、乙酸纖維素、鄰苯二甲酸乙酸纖維素、聚丙烯酸酯、聚甲基丙烯酸酯(諸如Eudragit®))， · 膠囊材料(例如明膠、羥基丙基甲基纖維素)， · 合成聚合物(例如聚乳酸交酯、聚乙交酯、聚丙烯酸酯、聚甲基丙烯酸酯(諸如Eudragit®)、聚乙烯吡咯啶酮(諸如Kollidon®)、聚乙烯醇、聚乙烯乙酸酯、聚氧乙烯、聚乙二醇及其共聚物與嵌段共聚物)， · 塑化劑(例如聚乙二醇、丙二醇、甘油、三醋酸甘油酯、檸檬酸三乙醯酯、鄰苯二甲酸二丁酯)， · 穿透增強劑， · 穩定劑(例如抗氧化劑，諸如抗壞血酸、抗壞血酸棕櫚酸酯、抗壞血酸鈉、丁基羥基苯甲醚、丁基羥基甲苯、沒食子酸丙酯)， · 防腐劑(例如對羥苯甲酸酯、山梨酸、硫柳汞、苯紮氯銨、氯己定乙酸酯、苯甲酸鈉)， · 著色劑(例如無機顏料，諸如氧化鐵、二氧化鈦)， · 調味劑、甜味劑、味道及/或氣味遮蔽劑。 其他賦形劑及程序描述於以下參考文獻(各自以引用的方式併入本文中)中：Powell, M.F.等人, 「Compendium of Excipients for Parenteral Formulations」 PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311；Strickley, R.G 「Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1」 PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349；及Nema, S.等人, 「Excipients and Their Use in Injectable Products」 PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171。 組分A、B及C可藉由經口、靜脈內、局部、局部裝置、腹膜內或經鼻途徑彼此獨立地投與。 組分A經靜脈內、腹膜內投與，較佳其經口投與。組分B較佳藉由靜脈內途徑投與。組分C經靜脈內、腹膜內投與，較佳其經口投與。 醫藥組合物(調配物)根據投與途徑而變化。 可將本發明組分與習知錠劑基質(諸如乳糖、蔗糖及玉米澱粉)組合以下各物一起製成錠劑：黏合劑，諸如阿拉伯膠(acacia)、玉米澱粉或明膠；旨在投藥後有助於錠劑分解及溶解之崩解劑，諸如馬鈴薯澱粉、海藻酸、玉米澱粉及瓜爾膠(guar gum)、黃蓍膠、阿拉伯膠；旨在改良錠劑顆粒之流動且防止錠劑材料黏附於錠劑壓模及衝頭表面的潤滑劑，例如滑石、硬脂酸或硬脂酸鎂、硬脂酸鈣或硬脂酸鋅；旨在增強錠劑之美觀品質且使其更易於患者接受之染料、著色劑及調味劑，諸如胡椒薄荷、冬青油或櫻桃調味劑。適用於口服液體劑型之賦形劑包括磷酸二鈣；及稀釋劑，諸如水及醇，例如乙醇、苄醇及聚乙烯醇，其中添加或不添加醫藥學上可接受之界面活性劑、懸浮劑或乳化劑。各種其他材料可以包衣形式存在或以其他方式改變劑量單位之物理形式。舉例而言，錠劑、丸劑或膠囊可用蟲膠、糖或二者包覆。 分散性散劑及粒劑適用於製備水性懸浮液。其提供與分散劑或濕潤劑、懸浮劑及一或多種防腐劑混合之活性成分。適合之分散劑或潤濕劑及懸浮劑由上文已提及之試劑例示。亦可存在額外賦形劑，例如上文所描述之彼等甜味劑、調味劑及著色劑。 本發明組分亦可呈水包油乳液形式。油相可為植物油(諸如液體石蠟)或植物油之混合物。適合的乳化劑可為(1)天然存在之樹膠，諸如阿拉伯膠及黃蓍膠；(2)天然存生之磷脂，諸如大豆及卵磷脂；(3)衍生自脂肪酸及己醣醇酐之酯或偏酯，例如脫水山梨糖醇單油酸酯；(4)該等偏酯與氧化乙烯之縮合產物，例如聚氧乙烯脫水山梨糖醇單油酸酯。乳液亦可含有甜味劑及調味劑。 油性懸浮液可藉由使活性成分懸浮於植物油(諸如花生油、橄欖油、芝麻油或椰子油)中或礦物油(諸如液體石蠟)中來調配。油性懸浮液可含有增稠劑，諸如蜂臘、硬石蠟或十六烷醇。懸浮液亦可含有一或多種防腐劑，例如對羥苯甲酸乙酯或對羥苯甲酸正丙酯；一或多種著色劑；一或多種調味劑；及一或多種甜味劑，諸如蔗糖或糖精。 糖漿及酏劑可用諸如甘油、丙二醇、山梨糖醇或蔗糖之甜味劑來調配。此類調配物亦可含有緩和劑及防腐劑(諸如對羥苯甲酸甲酯及對羥苯甲酸丙酯)及調味劑以及著色劑。 本發明組分亦可非經腸(亦即皮下、靜脈內、眼內、滑膜內、肌肉內或腹膜內)投與，呈化合物於較佳地醫藥學上可接受之稀釋劑與醫藥載劑中的可注射劑型投與，該醫藥載劑可為添加或未添加醫藥學上可接受之界面活性劑(諸如皂或清潔劑)、懸浮劑(諸如果膠、卡波姆、甲基纖維素、羥丙基甲基纖維素或羧甲基纖維素)或乳化劑及其他醫藥佐劑的無菌液體或液體混合物，諸如水、鹽水、右旋糖水溶液及相關糖溶液；醇，諸如乙醇、異丙醇或十六烷醇；二醇，諸如丙二醇或聚乙二醇；甘油縮酮，諸如2,2-二甲基-1,1-二氧雜環戊烷-4-甲醇；醚，諸如聚(乙二醇) 400；油、脂肪酸、脂肪酸酯或脂肪酸甘油酯或乙醯化脂肪酸甘油酯。 可用於本發明之非經腸調配物中之說明性油為石油、動物油、植物油或合成來源之油，例如花生油、大豆油、芝麻油、棉籽油、玉米油、橄欖油、石蠟脂及礦物油。適合的脂肪酸包括油酸、硬脂酸、異硬脂酸及肉豆蔻酸。適合的脂肪酸酯為例如油酸乙酯及肉豆蔻酸異丙酯。適合之皂包括脂肪酸鹼金屬鹽、銨鹽及三乙醇胺鹽；且適合之清潔劑包括：陽離子型清潔劑，例如二甲基二烷基銨鹵化物、烷基吡錠鹵化物及烷基胺乙酸鹽；陰離子型清潔劑，例如烷基、芳基及烯烴磺酸酯，烷基、烯烴、醚及單甘油脂硫酸酯及磺基丁二酸酯；非離子型清潔劑，例如脂肪胺氧化物、脂肪酸烷醇醯胺及聚(氧乙烯-氧丙烯)，或氧化乙烯或氧化丙烯共聚物；及兩性清潔劑，例如烷基-β-胺基丙酸酯及2-烷基咪唑啉四級銨鹽；以及混合物。 本發明之非經腸組合物將典型地在溶液中含有約0.5重量%至約25重量%之活性成分。亦宜使用防腐劑及緩衝劑。為了使注射部位處之刺激降至最低或消除，此類組合物可含有親水親油平衡值(HLB)較佳為約12至約17之非離子型界面活性劑。此類調配物中界面活性劑之量較佳在約5重量%至約15重量%範圍內。界面活性劑可為具有上述HLB之單一組分或可為具有所要HLB之兩種或更多種組分的混合物。 用於非經腸調配物中之說明性界面活性劑為聚乙烯脫水山梨糖醇脂肪酸酯類(例如脫水山梨糖醇單油酸酯)及氧化乙烯與藉由氧化丙烯與丙二醇縮合所形成之疏水性基質的高分子量加成物。 本發明醫藥組合物可呈無菌可注射水性懸浮液形式。此類懸浮液可根據已知方法使用以下來調配：適合的分散劑或濕潤劑及懸浮劑，諸如羧甲基纖維素鈉、甲基纖維素、羥丙基甲基纖維素、海藻酸鈉、聚乙烯吡咯啶酮、黃蓍膠及阿拉伯膠；分散劑或濕潤劑，其可為天然存在之磷脂，諸如卵磷脂；環氧烷與脂肪酸之縮合產物，例如聚氧乙烯硬脂酸酯；環氧乙烷與長鏈脂族醇之縮合產物，例如十七伸乙氧基十六醇；環氧乙烷與衍生自脂肪酸與己醣醇之偏酯的縮合產物，諸如聚氧乙烯山梨糖醇單油酸酯；或環氧乙烷與衍生自脂肪酸與己糖醇酐之偏酯的縮合產物，例如聚氧乙烯脫水山梨糖醇單油酸酯。 無菌可注射製劑亦可為於無毒非經腸可接受之稀釋劑或溶劑中之無菌可注射溶液或懸浮液。可使用之稀釋劑及溶劑為例如水、林格氏溶液(Ringer's solution)、等張氯化鈉溶液及等張葡萄糖溶液。另外，無菌不揮發性油習知用作溶劑或懸浮介質。出於此目的，可採用包括合成單甘油酯或二甘油酯之任何溫和的不揮發性油。另外，諸如油酸之脂肪酸亦可用於製備可注射劑。 本發明組分亦可以用於經直腸投與藥物之栓劑形式投與。可藉由將藥物與適合無刺激賦形劑混合來製備此等組分，該賦形劑在常溫下為固體，但在直腸溫度下為液體且因此將在直腸中融化而釋放藥物。此類材料為例如可可脂及聚乙二醇。 本發明方法中所用的另一種調配物使用經皮遞送裝置(「貼片」)。此類經皮貼片可用於提供以控制量連續或非連續輸注本發明化合物。遞送醫藥劑之經皮貼片之構築及用途在此項技術中熟知(參見例如1991年6月11日頒佈之美國專利第5,023,252號，其以引用的方式併入本文中)。此類貼片可經構築以用於連續、脈衝式或按需求遞送醫藥劑。 用於非經腸投藥之控制釋放型調配物包括此項技術中已知之脂質體、聚合物微球體及聚合物凝膠調配物。 可能需要或必需經由機械遞送裝置向患者引入患者本發明組分。用於遞送醫藥劑之機械遞送裝置的構築及用途在此項技術中熟知。用於例如將藥物直接投與腦之直接技術之直接技術通常包括將藥物遞送導管置入患者之腦室系統中以繞過血腦障壁。一種用於將藥劑輸送至身體之特定解剖學區域的此類可植入式遞送系統描述於1991年4月30日頒佈之美國專利第5,011,472號中。 根據另一態樣，本發明涉及如本文所描述之本發明組合之用途，其用於治療或預防疾病，較佳如下文所描述之過度增生性疾病及/或其轉移，較佳骨轉移。 根據另一態樣，本發明涉及如本文所描述之套組，其用於治療或預防疾病，較佳如下文所描述之過度增生性疾病及/或其轉移，較佳骨轉移。 根據另一態樣，本發明涉及如上文所描述之醫藥組合物，其用於治療或預防疾病，較佳如下文所描述之過度增生性疾病及/或其轉移，較佳骨轉移。 根據另一態樣，本發明涵蓋如上文所描述之此類組合之用途，其用於製備用以治療或預防疾病，較佳如下文所描述之過度增生性疾病及/或其轉移，較佳骨轉移之藥劑。 根據另一態樣，本發明涵蓋如上文所描述之此類套組之用途，其用於製備用以治療或預防疾病，較佳如下文所描述之過度增生性疾病及/或其轉移，較佳骨轉移之藥劑。 根據另一態樣，本發明涵蓋如上文所描述之此類醫藥組合物之用途，其用於製備用以治療或預防疾病，較佳如下文所描述之過度增生性疾病及/或其轉移，較佳骨轉移之藥劑。 根據另一態樣，本發明涉及使用有效量之如上文所描述之組合治療及/或預防疾病，較佳如下文所描述之過度增生性疾病及/或其轉移，較佳骨轉移的方法。 根據另一態樣，本發明涉及使用有效量之如上文所描述之套組或醫藥組合物治療及/或預防疾病，較佳如下文所描述之過度增生性疾病及/或其轉移，較佳骨轉移的方法。 根據另一態樣，本發明涉及一種治療患者之疾病，較佳如下文所描述之過度增生性疾病及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及 b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分A及B同時、並行、分開或依序投與。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分A及B並行投與。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分B係在組分A之前投與。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分B係在組分A之前2小時至96小時投與。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分B係在組分A之前6小時至84小時投與。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分B係在組分A之前12小時至72小時投與。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分B係在組分A之前24小時至48小時投與。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分B係在組分A之前18小時至30小時投與。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分B係在組分A之前20小時至28小時投與。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分B係在組分A之前22小時至26小時投與。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分B係在組分A之前42小時至54小時投與。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分B係在組分A之前44小時至52小時投與。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分B係在組分A之前46小時至50小時投與。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分B係在組分A之前24小時投與。根據另一態樣，本發明涉及一種治療前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，其中組分B係在組分A之前48小時投與。根據另一態樣，本發明涉及一種治療患者之疾病，較佳如下文所描述之過度增生性疾病及/或其轉移，較佳骨轉移之方法，其包含 a) 投與組分A，其為ATR激酶抑制劑，特別是化合物A，或其立體異構體、互變異構體、N-氧化物、水合物、溶劑合物或醫藥學上可接受之鹽，及b) 投與組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽，及視情況c) 投與組分C，其為如下文所描述之醫藥劑。因此，本發明之組合、套組或醫藥組合物可用於治療或預防過度增生性疾病，包括不可控細胞生長、增殖及/或存活、不當細胞免疫反應或不當細胞發炎性反應之疾病；或伴有不可控細胞生長、增殖及/或存活、不當細胞免疫反應或不當細胞發炎反應之疾病，尤其其中不可控細胞生長、增殖及/或存活、不當細胞免疫反應或不當細胞發炎反應，諸如血液腫瘤及/或其轉移、實體腫瘤及/或其轉移(例如白血病、其多發性骨髓瘤及骨髓發育不良症候群)、惡性淋巴瘤(包括乳房腫瘤及其骨轉移)、胸部腫瘤(包括非小細胞及小細胞肺腫瘤及其骨轉移)、胃腸腫瘤、內分泌腫瘤、乳腺及其他婦科腫瘤及其骨轉移、泌尿腫瘤(包括腎、膀胱及前列腺腫瘤)、皮膚腫瘤及肉瘤，及/或其轉移。 如本文所用，術語「不當」在本發明之情形內，尤其在「不當細胞免疫反應或不當細胞發炎性反應」之情形下，應理解為較佳意謂反應低於或高於正常，且關聯、造成或引起該疾病病變。 詳言之，本發明涵蓋治療肺癌(尤其小細胞肺癌)、結腸直腸癌、膀胱癌、淋巴瘤(尤其彌漫性大型B細胞淋巴瘤(DLBC)及套細胞淋巴瘤(MCL))、前列腺癌(尤其去勢抵抗性前列腺癌)、神經膠質瘤及卵巢癌。在一個實施例中，本發明涵蓋如上文所描述之組合、套組或醫藥組合物，其包含用於治療癌症適應症，特別是形成骨轉移之此類癌症類型的組分A或其醫藥學上可接受之鹽及組分B，其為鹼土放射性核種鐳-223之醫藥學上可接受之鹽。此類癌症類型為例如乳癌、前列腺癌、肺癌多發性骨髓瘤、腎癌或甲狀腺癌。 本發明之另一態樣涉及根據本發明之組合、套組或醫藥組合物，其用於治療或預防過度增生性疾病及/或其轉移。 根據另一態樣，本發明涉及根據本發明之組合、套組或醫藥組合物，其用於治療或預防前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移，其中組分A及B同時、並行、分開或依序投與。根據另一態樣，本發明涉及根據本發明之組合、套組或醫藥組合物，其用於治療或預防前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移，其中組分A及B並行投與。 根據另一態樣，本發明涉及根據本發明之組合、套組或醫藥組合物，其用於治療或預防前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移，其中組分B係在組分A之前投與。根據另一態樣，本發明涉及根據本發明之組合、套組或醫藥組合物，其用於治療或預防前列腺癌，特別是去勢抵抗性前列腺癌及/或其轉移，較佳骨轉移，其中組分B係在組分A之前2小時至96小時、或6小時至84小時、或12小時至72小時、或24小時至48小時、或18小時至30小時、或20小時至28小時、或22小時至26小時、或42小時至54小時、或44小時至52小時、或46小時至50小時、或24小時、或48小時投與。 另一實施例涵蓋一種根據本發明之組合、套組或醫藥組合物之用途，其用於製備用以治療或預防乳癌、前列腺癌、多發性骨髓瘤、非小細胞肺癌及/或其轉移，尤其其中該轉移為骨轉移之藥劑。 在一個實施例中，本發明涵蓋一種治療或預防個體之癌症，特別是乳癌、前列腺癌、多發性骨髓瘤、肝細胞癌、肺癌(尤其非小細胞肺癌)、結腸直腸癌、黑素瘤或胰臟癌的方法，其包含向該個體投與治療有效量之根據本發明之組合。 在另一實施例中，本發明涵蓋一種治療或預防個體之癌症，特別是乳癌、前列腺癌、多發性骨髓瘤、肝細胞癌、肺癌(尤其非小細胞肺癌)、結腸直腸癌、黑素瘤或胰臟癌的方法，其包含向該個體投與治療有效量之根據本發明之組合。 在另一實施例中，本發明涵蓋一種治療或預防個體之癌症，特別是乳癌、前列腺癌、多發性骨髓瘤、肝細胞癌、肺癌(尤其非小細胞肺癌)、結腸直腸癌、黑素瘤或胰臟癌及/或其轉移的方法，其包含向該個體投與治療有效量之根據本發明之組合。 本發明組合之較佳用途係關於治療前列腺癌。 如本文所用之術語「前列腺癌」意謂任何組織學類型之前列腺癌，包括但不限於腺泡腺癌、乳腺管腺癌、移行細胞(或尿道上皮)癌、鱗狀細胞癌、類癌、小細胞癌、肉瘤及肉瘤樣癌，特別是腺泡腺癌、M0級去勢抵抗性前列腺癌(M0 CRPC)或M1級去勢抵抗性前列腺癌(M1 CRPC)，較佳M1去勢抵抗性前列腺癌(M1 CRPC)。 根據由美國癌症聯合委員會(American Joint Committee on Cancer)研發用於前列腺癌之「TNM分級系統」使用術語「M0」及「M1」(包括M1a、M1b、M1c)，如「TNM CLASSIFICATION OF MALIGNANT TUMORS」,第7版,James D.Brierley, Mary K. Gospodarowicz, Christian Wittekind編, UICC出版, 2011中進一步所描述。根據TNM分類，術語「M0」意謂不存在遠距離轉移且癌症尚未擴散至身體其他部位。「M1」意謂存在遠距離轉移且癌症已擴散至身體之遠距離部位。 本發明組合之較佳用途為治療去勢抵抗性前列腺癌(CRPC)，特別是M1級CRPC，較佳M1b級去勢抵抗性前列腺癌(M1b CRPC)或M1c級去勢抵抗性前列腺癌(M1c CRPC)。 如本文所用之術語「M1b CRPC」意謂去勢抵抗性前列腺癌已擴散至骨骼。 如本文所用之術語「M1c CRPC」意謂去勢抵抗性前列腺癌已擴散至其他器官，諸如肺、肝或腦(在擴散或未擴散至骨骼之情況下)。 本發明組合之較佳用途為治療前列腺癌，尤其去勢抵抗性前列腺癌(CRPC)，較佳具有症狀性骨轉移且無已知之內臟轉移性疾病之CRPC。 一個較佳實施例為一種本發明之組合、套組或醫藥組合物之用途，其用於治療前列腺癌，尤其具有症狀性骨轉移且無已知之內臟轉移性疾病之去勢抵抗性前列腺癌(CRPC)。 在另一實施例中，本發明之組合、套組或醫藥組合物之用途涉及治療個體之去勢抵抗性前列腺癌(M0 CRPC)或M1去勢抵抗性前列腺癌(M1 CRPC),其中該個體未經化學療法治療。 如本文所用之術語「未經化學療法治療」意謂個體在用本發明之組合、套組或醫藥組合物治療之前尚未接受化學療法。 在另一實施例中，本發明之組合、套組或醫藥組合物之用途涉及治療個體之去勢抵抗性前列腺癌(M0 CRPC)或M1去勢抵抗性前列腺癌(M1 CRPC)，其中該個體在用本發明之組合、套組或醫藥組合物治療之前已接受化學療法。 如本文所用之術語「化學療法」意謂一種癌症治療之類別，其使用一或多種化學治療劑作為標準化化學療法方案之部分。化學治療劑實際上為非特異性藥劑，諸如烷基化劑、蒽環黴素、紫杉烷、埃博黴素(epothilone)、組蛋白去乙醯酶抑制劑、拓樸異構酶I (topoisomerase I)抑制劑、拓樸異構酶II抑制劑、核苷酸類似物、鉑類藥劑、長春花生物鹼等。 本發明之另一實施例涉及一種本發明組合之用途，其用於治療乳癌，尤其具有骨轉移之乳癌(Amol Takalkar等人, Exp Hematol Oncol. 2014; 3: 23. 「Radium-223 dichloride bone-targeted alpha particle therapy for hormone-refractory breast cancer metastatic to bone」；Suominen等人, J Natl Cancer Inst. 2013 Jun 19;105(12):908-16. 「Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis」)。 在另一實施例中，本發明涉及一種本發明組合之用途，其用於治療多發性骨髓瘤。 本發明之組合、套組或醫藥組合物可用於抑制、阻斷、減少、降低細胞增殖及/或細胞分裂等，及/或產生細胞凋亡。 本發明包括一種方法，其包含向有需要之哺乳動物(包括人類)投與一定量之本發明組分A及一定量之本發明組分B或其醫藥學上可接受之鹽、異構體、多晶型物、代謝物、水合物、溶劑合物或酯，其對治療疾病為有效地。 過度增生性疾病包括但不限於例如牛皮癬、瘢痕瘤及影響皮膚之其他增殖、良性前列腺增殖(BPH)以及惡性贅瘤。可用根據本發明化合物治療之惡性贅瘤之實例包括實體腫瘤及血液腫瘤。實體腫瘤可例示為乳房瘤、膀胱瘤、骨瘤、腦瘤、中樞及周邊神經系統瘤、結腸瘤、肛門瘤、內分泌腺(例如甲狀腺及腎上腺皮質)瘤、食道瘤、子宮內膜瘤、生殖細胞瘤、頭頸瘤、腎瘤、肝瘤、肺瘤、喉及下咽瘤、間皮瘤、卵巢瘤、胰臟瘤、前列腺瘤、直腸瘤、腎瘤、小腸瘤、軟組織瘤、睪丸瘤、胃瘤、皮膚瘤、輸尿管瘤、陰道及外陰瘤。惡性贅瘤包括遺傳性癌症，例如視網膜母細胞瘤及威爾姆斯腫瘤(Wilms tumor)。此外，惡性贅瘤包括該等器官之原發性腫瘤及遠距離器官之對應繼發性腫瘤(「腫瘤轉移」)。血液腫瘤可例示為白血病及淋巴瘤之侵襲性及惰性形式，亦即非霍奇金氏病(non-Hodgkins disease)、慢性骨髓性白血病及急性骨髓性白血病(CML/AML)、急性淋巴母細胞白血病(ALL)、霍奇金氏病、多發性骨髓瘤及T細胞淋巴瘤。亦包括骨髓發育不良症候群、漿細胞瘤形成、副腫瘤症候群、及未知原發性位點之癌症以及AIDS相關之惡性病。 乳癌之實例包括但不限於侵襲性乳腺管癌、侵襲性小葉癌、原位乳腺管癌及原位小葉癌，特別是具有骨轉移之該等乳癌。 呼吸道癌之實例包括但不限於小細胞肺癌及非小細胞肺癌，以及支氣管腺瘤及胸膜肺母細胞瘤。 腦癌之實例包括但不限於腦幹及下丘腦神經膠質瘤、小腦及大腦星形細胞瘤、神經膠母細胞瘤、神經管胚細胞瘤、室管膜瘤以及神經外胚層及松果體腫瘤。 男性生殖器官腫瘤包括但不限於前列腺及睾丸癌症。女性生殖器官腫瘤包括但不限於子宮內膜癌、子宮頸癌、卵巢癌、陰道癌及外陰癌以及子宮肉瘤。 消化道腫瘤包括但不限於肛門癌、結腸癌、結腸直腸癌、食道癌、膽囊癌、胃癌、胰臟癌、直腸癌、小腸癌及唾液腺癌。 泌尿道腫瘤包括但不限於膀胱癌、陰莖癌、腎癌、腎盂癌、輸尿管癌、尿道癌及人類乳頭狀腎癌。 眼癌包括但不限於眼內黑色素瘤及視網膜母細胞瘤。 肝癌之實例包括但不限於肝細胞癌(具有或不具有纖維板層變異之肝細胞癌)、膽管癌(肝內膽管癌)及混合型肝細胞膽管癌。 皮膚癌包括但不限於鱗狀細胞癌、卡波西氏肉瘤(Kaposi's sarcoma)、惡性黑色素瘤、梅克爾細胞皮膚癌(Merkel cell skin cancer)及非黑色素瘤皮膚癌。 頭頸癌包括但不限於喉癌、下咽癌、鼻咽癌、口咽癌、唇及口腔癌及鱗狀細胞癌。淋巴瘤包括但不限於AIDS相關淋巴瘤、非霍奇金氏淋巴瘤、皮膚T細胞淋巴瘤、伯基特淋巴瘤(Burkitt lymphoma)、霍奇金氏病及中樞神經系統之淋巴瘤。 肉瘤包括但不限於軟組織肉瘤、骨肉瘤、惡性纖維組織細胞瘤、淋巴肉瘤及橫紋肌肉瘤。 白血病包括但不限於急性骨髓性白血病、急性淋巴母細胞白血病、慢性淋巴細胞白血病、慢性骨髓性白血病及毛細胞白血病。 此等疾病在人類中已進行良好表徵，且在其他哺乳動物中亦以類似病源學存在，且可藉由投與本發明之醫藥組合物來治療。 本發明組合亦可用於治療與過度及/或異常血管生成相關之疾病。 血管生成之不當及異位表現可能對生物體有害。多種病理性病況與額外血管生長相關。此等病況包括例如糖尿病性視網膜病變、局部缺血性視網膜靜脈閉塞及早產兒視網膜病變[Aiello等人 New Engl. J. Med. 1994, 331, 1480；Peer等人 Lab. Invest. 1995, 72, 638]、年齡相關之黃斑變性[AMD；參見Lopez等人 Invest. Opththalmol. Vis. Sci. 1996, 37, 855]、新生血管性青光眼、牛皮癬、晶狀體後纖維組織增生、血管纖維瘤、發炎、類風濕性關節炎(RA)、再狹窄、支架內再狹窄、血管移植再狹窄等。此外，與癌性及贅生性組織相關之血液供應增加促進生長，導致腫瘤快速增大及轉移。此外，腫瘤中新血管及淋巴管之生長向反叛細胞提供逃脫途徑，從而促進癌轉移及隨後之癌擴散。因此，本發明組合可用於治療及/或預防前述血管生成疾病中之任一者，例如藉由抑制及/或減少血管形成；藉由抑制、阻斷、減少、降低內皮細胞增殖或涉及血管生成之其他類型等，以及促使此類細胞類型發生細胞死亡或細胞凋亡。劑量及投與 組分 A
基於已知評估適用於治療過度增生性疾病及血管生成疾病之化合物的標準實驗室技術，藉由標準毒性測試及藉由用於判定哺乳動物之如上所鑑別之病狀之治療之標準藥理學分析，且藉由比較此等結果與用於治療此等病狀之已知藥劑之結果，可容易地判定本發明化合物用於治療各種所要適應症的有效劑量。治療此等病狀中之一者所投與之活性成分之量可根據諸如以下考慮因素而極大地變化：所用特定組分及劑量單位、投與模式、治療期、所治療患者之年齡及性別，及所治療病狀之性質及程度。 所投與之活性成分之總量之範圍通常將為每日約0.001 mg/kg至約200 mg/kg體重，且較佳每日約0.01 mg/kg至約50 mg/kg體重。臨床上適用之化合物給藥時程的範圍將為一日給藥一至三次至每四週給藥一次。此外，「藥物假期」(在一定時間段內不給與患者藥物)可有益於藥理學效應與耐受性之間的整體平衡。單位劑量可含有約0.5 mg至約1500 mg活性成分且可每日投與一或多次或少於一日一次。藉由注射(包括靜脈內、肌肉內、皮下及非經腸注射)及使用輸注技術投與之每日平均劑量較佳為每公斤總體重0.01至200 mg。平均每天直腸給藥方案較佳為每公斤總體重0.01至200 mg。平均每天陰道給藥方案較佳為每公斤總體重0.01至200 mg。平均每天局部給藥方案較佳為0.1至200 mg，每天投與次數介於一次至四次之間。經皮濃度較佳為維持0.01至200 mg/kg日劑量所必需之濃度。平均每天吸入給藥方案較佳為每公斤總體重0.01至100 mg。組分 B
鐳-223注射劑之較佳給藥方案為以由6次注射組成之療程形式每間隔4週給予50 kBq/kg體重。在I期臨床試驗中評估達至250 kBq/kg體重之單次鐳-223劑量。在此劑量下觀測到之不良反應為下痢及可逆性骨髓抑制(包括一個3級嗜中性白血球減少症病例(1/5))。作為一實例，二氯化鐳-223水溶液可在含有6 ml填充量之單次劑量10 ml小瓶中提供。此產品之鐳-223放射性濃度為1,000 kBq/mL (0.03 mCi/mL)，對應於在參考日期之0.53 ng/mL鐳。 鐳-223將由專業人員以緩慢推注注射形式靜脈內投與。應使用靜脈內進入管線投與鐳-223。在注射鐳-223之前及之後必須用等張鹽水沖洗該管線。 當然，各患者之特定初始及連續給藥方案將根據如主治診斷醫師所判定之病狀性質及嚴重程度、所用特定化合物之活性、患者之年齡及一般狀況、投與時間、投與途徑、藥物之排泄速率、藥物組合及其類似因素而變化。所要治療模式及本發明化合物或其醫藥學上可接受之鹽或酯或組合物之劑量次數可由熟習此項技術者使用習知治療測試來確定。實驗部分 實例 1 化合物 A 及二氯化鐳 - 223 之組合之協同效應 組分 A ：
在此實驗部分及圖式中，術語「化合物A」為組分A之實例。化合物A描述於國際專利申請案WO2016020320 (A1)之實例111中。如本文所示，化合物A為具有以下結構之2-[(3R)-3-甲基嗎啉-4-基]-4-(1-甲基-1H-吡唑-5-基)-8-(1H-吡唑-5-基)-1,7-㖠啶： 化合物 A 組分 B ：
在此實驗部分及圖式中，組分B為二氯化鐳-223，其合成揭示於WO2000/040275中，該申請案以全文引用之方式併入本文中。測試系統 / 活體內模型 ( 應用於 實驗 1 、 2 及 3 中 ) ：
在雄性NOD/Scid小鼠之骨母細胞及混合性前列腺癌骨轉移模型LNCaP-luc中研究化合物A與二氯化鐳-223 (Ra-223)組合之療效(Minhong Zou等人, ONCOLOGY REPORTS 30: 615-622, 2013; Multiple metastases in a novel LNCaP model of human prostate cancer)。LNCaP為在DNA損害或錯配修復基因中(APCR2714C, ARID1Afs, ATG5fs, ATMA1119V/K1572N, ATRXEE2264-2265E, BRCA2fs, CHEK2T430N, ERCC3A740T;R391W, ERCC5L1023I, FANCAE369D,Q652*, HDAC2A62V, MLH3I541V, MSH3PPA66-68-;fs, POLBfs, POLHD631G, PRKDCfs, PTENfs, RAD50fs, RAD54LL532M, RB1splice_acceptor, SLX4S605N, TDP2T308S, TP53BP1R639Q;Q111*, TRRAPR2665W;P3554L, WDR48G107*, XRCC3P87L, XRCC4L70M)以及在誘導複製應力之基因或致癌基因中(ATRK1379N, ERBB3K177N, MYCN45S,TOP2Afs, TOP2BG323*/V889A)具有若干突變/缺失之雄激素受體(AR)陽性CRPC細胞株(fs：框移；del：缺失 ；*：終止密碼子；amp：基因擴增)。LNCaP細胞分泌前列腺特異性抗原(PSA)且已知在接種至骨髓腔時形成骨母細胞及混合性病變。因此，此模型可有效地用於測試候選癌症藥物對骨中前列腺癌細胞之生長之效果。在此實驗中，經螢光素酶轉染之LNCaP細胞株(LNCaP-luc)已用於允許藉由生物發光成像(BLI)進行額外腫瘤生長監測(Ruxana T. Sadikot及Timothy S. Blackwell; Proc Am Thorac Soc Vol 2. pp 537-540, 2005; Bioluminescence Imaging)。 小鼠在開始研究時為5-8週齡。在第0天，對小鼠脛骨內接種LNCaP-luc人類前列腺癌細胞。在開始給藥之前及3週間隔之後藉由X射線成像監測骨母細胞病變之進展。藉由繪製射線不透區域及射線可透區域之輪廓用MetaMorph影像分析軟體(Molecular Devices LLC, Sunnyvale, CA, USA)自影像判定後肢之病變面積。藉由使由LNCaP-luc細胞發射之生物發光成像而定量腫瘤負荷。使用Living Image®軟體(PerkinElmer, Waltham, MA, USA) 4.2版本分析所獲得資料。自接種脛骨判定平均輻射率(p/s/cm2/sr)。自第四週開始每兩週採集血液樣本且每三週對動物進行放射照相。在第五週，根據BLI信號、PSA及放射照相術將動物分級為治療組(n=10-20)並開始給藥。一週兩次測定體重。體重變化為治療相關毒性之量度(＞10%=臨界，停止治療直至恢復，＞20%=毒性，終止)。在開始給藥之後六週或七週殺死動物。在血漿中量測作為腫瘤生長及骨形成之標記之PSA及I型N端原膠原(PINP)。使用Human PSA ELISA分析(R&D Systems)來量測PSA (Hsing AW, Chokkalingam AP. Prostate cancer epidemiology. Front Biosci. 2006;11:1388-413；Schröder FH, Wildhagen MF. Rotterdam Study Group of the 『 European Randomised Study of Screening for Prostate Cancer』 (ERSPC) Screening for prostate cancer: Evidence and perspectives. BJU Int. 2001;88:811-7)，使用VICTOR2 Multilabel Counter (PerkinElmer, Waltham, MA, USA)測定PINP之含量(N. Koopmans等人, THE JOURNAL OF UROLOGY, 第178卷, 849-853, 2007年9月. Serum Bone Turnover Markers (PINP and ICTP) for the Early Detection of Bone Metastases in Patients With Prostate Cancer: A Longitudinal Approach；Windy Dean-Colomb等人; Breast Cancer Res Treat. 2013年1月; 137(2). Elevated serum P1NP predicts development of bone metastasis and survival in early-stage breast cancer)。使用單因素方差分析(single-factor ANOVA)及藉助於逐對比較分析(鄧奈特測試(Dunnett's test))或斯圖登氏t測試(student's t-test)將其與對照組比較來實現統計學分析。實驗 1 ：
分析以下實驗組： 1)用於Ra-223之媒劑：28 mmol/L檸檬酸鈉，5 ml/kg，iv(=靜脈內)，每4週(q4w) 2) Ra-223：300 kBq/kg，5 ml/kg，iv，q4w 3)化合物A劑量1：20 mg/kg，2天給藥/5天停藥，po(=經口)，每天一次(qd)+Ra-223之媒劑，28 mmol/L檸檬酸鈉，5 mL/kg，iv，q4w 4)化合物A劑量2：50 mg/kg，2天給藥/5天停藥，po qd+用於Ra-223之媒劑，28 mmol/L檸檬酸鈉，5 ml/kg，iv，q4w 5)組合Ra-223+化合物A劑量1：Ra-223 (300 kBq/kg，5 ml/kg，iv，q4W)+化合物A (20 mg/kg，2天給藥/5天停藥，po qd，在腫瘤細胞接種之後第4週開始) 6)組合Ra-223+化合物A劑量2：Ra-223 (300 kBq/kg，5 ml/kg，iv，q4W，在腫瘤細胞接種之後第4週開始)+化合物A (50 mg/kg，2天給藥/5天停藥，po qd，在腫瘤細胞接種之後第4週開始)實驗 1 之結果 ：
經媒劑處理之對照組之腫瘤生長導致血漿中PSA含量增加，骨中BLI信號增加及骨病變面積擴大。然而，BLI分析揭露經媒劑處理之對照組之高偏差，由此已在最終研究分析中排除此參數。Ra-223單藥劑相較於經媒劑處理之對照組降低血漿中之PINP含量。化合物A單獨治療對腫瘤負荷不具有顯著效果，如藉由PSA或PINP所分析。組合療法在降低血漿中之PSA (參見圖1A)及PINP (參見圖1B)含量上比媒劑、單獨Ra-223或單獨各別測試劑量之化合物A明顯(P ＜ 0.05)更有效。治療具有良好耐受性，無臨界體重損失＞10%之記錄(參見圖2)。 概言之，吾人之資料指示ATR抑制劑化合物A及鐳-223在抑制前列腺癌骨轉移模型LNCaP-luc之腫瘤生長中之協同效應，從而指示其作為未來治療患有骨轉移之CRPC患者之強大潛能。 為了評估化合物A與二氯化鐳-223之組合之協同性，根據布利斯模型(Bliss model)計算期望相加性(C=A+B-A*B；其中C為藥物A及藥物B(若其以相加方式起作用)之組合的期望T/C，A為藥物A之T/C，B為藥物B之T/C)。假定超出於期望相加效果＞10%指示兩種藥物之協同作用，假定期望相加效果小於10%指示拮抗作用(Bliss, C.I., The toxicity of poisons applied jointly. Ann. Appl. Biol. 26, 585-615, 1939) (參見表1)：表 1 ：
化合物A與Ra-223在NOD/Scid小鼠之LNCaP-luc人類前列腺癌骨轉移異種移植模型中之抗腫瘤活性
* 相較於媒劑對照組，P ＜ 0.05#
相較於Ra-223，P ＜ 0.05 a) T/C=在研究結束時治療組與對照組的PSA含量之比率。 b) T/C=在研究結束時治療組與對照組的PINP含量之比率。實驗 2 ：
為了評估化合物A在Ra-223組合治療中之不同給藥時程，在實驗2中分析以下實驗組： 1)用於Ra-223之媒劑：28 mmol/L檸檬酸鈉，5 ml/kg，iv(=靜脈內)，每4週(q4w) 2) Ra-223：150 kBq/kg，5 ml/kg，iv，q4w 3) 化合物A：20 mg/kg，2天給藥/5天停藥，po(=經口)，每天一次(qd) 4)組合Ra-223 (150 kBq/kg，5 ml/kg，iv，q4w) +化合物A (20 mg/kg，2天給藥/5天停藥，po，qd，與Ra-223並行開始) 5)組合Ra-223 (150 kBq/kg，5 ml/kg，iv，q4w) +化合物A (20 mg/kg，2天給藥/5天停藥，po，qd，在Ra-223之後24小時開始) 6)組合Ra-223 (150 kBq/kg，5 ml/kg，iv，q4w) +化合物A (20 mg/kg，2天給藥/5天停藥，po，qd，在Ra-223之後48小時開始) 7)組合Ra-223 (150 kBq/kg，5 ml/kg，iv，q4w) +化合物A (20 mg/kg，2天給藥/26天停藥，po，qd，在Ra-223之後24小時開始)實驗 2 之結果 ：
經媒劑處理之對照組之腫瘤生長導致血漿中PSA含量增加，骨中BLI信號增加及骨病變面積擴大。Ra-223或化合物A單藥劑治療相較於經媒劑處理之對照組對腫瘤負荷不具有顯著效果，如藉由血漿中之PSA含量、BLI信號及總骨病變面積所分析。在化合物A應用於2天給藥及5天停藥之每週循環中，與Ra-223並行開始或在Ra-223之後24 h或48 h開始時，組合療法在降低血漿中之PSA含量上相較於媒劑對照組明顯(P ＜ 0.05)更有效(參見圖3A)。在化合物A應用於2天給藥及5天停藥之每週循環中，與Ra-223並行開始或在Ra-223之後24 h開始時，組合療法中之總骨病變面積相較於媒劑對照組明顯減少(參見圖3B)。藉由全部經測試組合治療方案，藉由骨中之BLI信號所測定之腫瘤負荷相較於媒劑對照組明顯減少(參見圖3C)。總體而言，治療具有良好耐受性。無治療相關之臨界體重損失(＞10%)或毒性/死亡之記錄(資料未示出)。 概言之，吾人之資料指示，基於腫瘤負荷(PSA，BLI)及骨病變，在Ra-223第一次給藥之後24 h開始且應用於持續的每週循環中之化合物A治療在前列腺癌骨轉移模型LNCaP-luc中之Ra-223組合治療中實現最佳抗腫瘤活性。然而，並行開始或在Ra-223第一次給藥之後48 h開始且應用於持續的每週循環中之化合物A治療以及Ra-223每次給藥之後24 h開始，應用於4週循環中之化合物A治療亦顯示與Ra-223之組合治療中LNCaP-luc骨腫瘤生長之抑制效果。表 2 ：
NOD/Scid小鼠之LNCaP-luc人類前列腺癌骨轉移異種移植模型中之化合物A與Ra-223之組合治療的不同給藥時程的抗腫瘤活性
*相較於媒劑對照組，P ＜ 0.05 b) T/C=在研究結束時治療組與對照組的PSA含量之比率。 b) T/C=在研究結束時治療組與對照組的總骨病變面積之比率。 c) T/C=在研究結束時治療組與對照組的BLI信號之比率。實驗 3 ：
為了評估化合物A在Ra-223組合治療中之不同劑量，在實驗3中分析以下實驗組： 1)用於Ra-223之媒劑：28 mmol/L檸檬酸鈉，5 ml/kg，iv(=靜脈內)，每4週(q4w) 2) Ra-223：150 kBq/kg，5 ml/kg，iv，q4w 3) 化合物A：20 mg/kg，2天給藥/5天停藥，po(=經口)，每天一次(qd) 4)組合Ra-223 (150 kBq/kg，5 ml/kg，iv，q4w) +化合物A (5 mg/kg，2天給藥/5天停藥，po，qd，在Ra-223之後24小時開始) 5)組合Ra-223 (150 kBq/kg，5 ml/kg，iv，q4w) +化合物A (10 mg/kg，2天給藥/5天停藥，po，qd，在Ra-223之後24小時開始) 6)組合Ra-223 (150 kBq/kg，5 ml/kg，iv，q4w) +化合物A (20 mg/kg，2天給藥/5天停藥，po，qd，在Ra-223之後24小時開始) 7)組合Ra-223 (150 kBq/kg，5 ml/kg，iv，q4w) +化合物A(40 mg/kg，1天給藥/6天停藥，po，qd，在Ra-223之後24小時開始)實驗 3 之結果 ：
經媒劑處理之對照組之腫瘤生長導致血漿中PSA含量增加，骨中BLI信號增加及骨病變面積擴大。Ra-223或化合物A單藥劑治療相較於經媒劑處理之對照組對腫瘤負荷不具有顯著效果，如藉由血漿中之PSA含量、BLI信號及總骨病變面積所分析，血漿中骨生長標記PINP之評估揭露相較於經媒劑處理之對照組藉由單獨Ra-223之減少。與Ra-223組合所評估之全部經測試化合物A劑量相較於媒劑對照組達成血清PSA或PINP含量、BLI信號及骨病變面積之顯著(P ＜ 0.05)減少(參見表3，圖4A至圖4D)，除Ra-223+化合物A 5 mg/kg關於PSA未達成顯著性外(參見圖4A)。總體而言，治療具有良好耐受性。無治療相關之臨界體重損失(＞10%)或毒性/死亡之記錄(資料未示出)。 概言之，吾人之資料指示，基於腫瘤負荷(PSA，BLI)、骨生長(PINP)及骨病變，應用每天一次，2天給藥及5天停藥，在Ra-223第一次給藥24 h之後開始且在持續的每週循環中給予的高5 mg/kg之化合物A劑量，說明組合治療在前列腺癌骨轉移模型LNCaP-luc中之抗腫瘤活性且改良各別單藥療法之療效。總體而言，在良好耐受性下之最佳抗腫瘤活性用在Ra-223第一次給藥之後24 h開始，每天一次20 mg/kg，2天給藥及5天停藥或每天一次40 mg/kg，1天給藥及6天停藥且在持續的每週循環中給予之化合物A劑量來達成。表 3 ：
NOD/Scid小鼠之LNCaP-luc人類前列腺癌骨轉移異種移植模型中之化合物A與Ra-223之組合治療的不同劑量之抗腫瘤活性
*相較於媒劑對照組，P ＜ 0.05#
相較於Ra-223，P ＜ 0.05 a)T/C=在研究結束時治療組與對照組的PSA含量之比率。 b)T/C=在研究結束時治療組與對照組的PINP含量之比率。 c)T/C=在研究結束時治療組與對照組的總骨病變面積之比率。 d)T/C=在研究結束時治療組與對照組的BLI信號之比率。The term as referred to in this text has the following meaning: As used herein, the term "inhibitor of ATR kinase/ATR kinase inhibitor" means any compound that inhibits ATR kinase. Examples of such compounds are described below ("Component A in Combination"). The terms "halogen-atoms" and "halo-/Hal-" are understood to mean fluorine, chlorine, bromine or iodine atoms. The term "C1
-C6
-alkyl" is understood to mean a straight or branched chain saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, Hexyl, isopropyl, isobutyl, t-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-di Methylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-B Butyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl , 1,3-dimethylbutyl or 1,2-dimethylbutyl, or an isomer thereof. In particular, the group has 1, 2, 3 or 4 carbon atoms ("C1
-C4
-alkyl"), for example methyl, ethyl, propyl, butyl, isopropyl, isobutyl, t-butyl, tert-butyl, more particularly having 1, 2 or 3 carbon atoms "C1
-C3
-alkyl"), for example methyl, ethyl, n-propyl or isopropyl. The term "C1
-C6
-haloalkyl" is understood to mean a straight or branched chain saturated monovalent hydrocarbon radical, wherein the term "C"1
-C6
-Alkyl" is as defined above, and wherein one or more hydrogen atoms are replaced identically or differently by a halogen atom, that is, one halogen atom is independent of the other halogen atom. In particular, the halogen atom is F. The C1
-C6
-haloalkyl is, for example, -CF3
, -CHF2
, -CH2
F, -CF2
CF3
Or -CH2
CF3
. The term "C1
-C4
-Hydroxyalkyl" is understood to mean a straight or branched chain saturated monovalent hydrocarbon radical, wherein the term "C"1
-C4
-alkyl" is as defined above, and wherein one or more hydrogen atoms are replaced by a hydroxy group, such as hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 3-hydroxy Propyl, 2-hydroxypropyl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl, 3-hydroxy-2-methyl-propyl, 2-hydroxy-2-methyl -propyl, 1-hydroxy-2-methyl-propyl. The term "C1
-C6
-Alkoxy" is understood to mean a straight-chain or branched-chain saturated monovalent hydrocarbon radical of the formula -O-alkyl, wherein the term "alkyl" is as defined above, for example methoxy, ethoxy, n-propoxy Base, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, second butoxy, pentyloxy, isopentyloxy or n-hexyloxy or isomers thereof. In particular, the "C1
-C6
-alkoxy" may contain 1, 2, 3, 4 or 5 carbon atoms ("C1
-C5
- alkoxy)", preferably 1, 2, 3 or 4 carbon atoms ("C1
-C4
- alkoxy"). The term "C1
-C6
-haloalkoxy" is understood to mean a linear or branched chain saturated monovalent C as defined above.1
-C6
An alkoxy group in which one or more hydrogen atoms are replaced by a halogen atom identically or differently. In particular, the halogen atom is F. The C1
-C6
-haloalkoxy is, for example, -OCF3
-OCHF2
-OCH2
F, -OCF2
CF3
Or -OCH2
CF3
. The term "C2
-C6
-Alkenyl" is understood to mean a straight or branched chain monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5 or 6 carbon atoms or 2, 3 or 4 carbon atoms ("C2
-C4
Alkenyl"), especially 2 or 3 carbon atoms ("C2
-C3
-Alkenyl"), it is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or conjugated to each other. The alkenyl group is, for example, a vinyl group, an allyl group, (E)-2-methylvinyl group, (Z)-2-methylvinyl group, homoallyl group, (E)-but-2-enyl group, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl , (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pentyl 1-enyl, hex-5-alkenyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)- Hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl , isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl, (E)-1-methylprop-1- Alkenyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl , 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methyl But-2-enyl, (Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-ene , (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z) -1-methylbut-1-enyl, 1,1-dimethylprop-2-ene , 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl, 3-methylpent-4-enyl, 2 -methylpent-4-enyl, 1-methylpent-4-enyl, 4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z) 3-methylpent-3-enyl, (E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl, (E)-1-methyl Pent-3-enyl, (Z)-1-methylpent-3-enyl, (E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-ene , (E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl, (E)-2-methylpent-2-enyl, (Z) -2-methylpent-2-enyl, (E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl, (E)-4-methyl Pent-1-enyl, (Z)-4-methylpent-1-enyl, (E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-ene , (E)-2-methylpent-1-enyl, (Z)-2-methylpent-1-enyl, (E)-1-methylpent-1-enyl, (Z) -1-methylpent-1-enyl, 3-ethylbut-3-enyl, 2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3 -ethylbut-2-enyl, (Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbutyl- 2-alkenyl, (E)-1-ethylbut-2-enyl, (Z)-1-ethylbutyl- 2-alkenyl, (E)-3-ethylbut-1-enyl, (Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)- 1-ethylbut-1-enyl, (Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl, 2- Isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl, (Z)-2-propylprop-1-ene , (E)-1-propylprop-1-enyl, (Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl, (Z -2-isopropylpropan-1-enyl, (E)-1-isopropylpropan-1-enyl, (Z)-1-isopropylpropan-1-enyl, (E)- 3,3-Dimethylprop-1-enyl, (Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)vinyl, butyl- 1,3-Dienyl, pent-1,4-dienyl, hex-1,5-dienyl or methylhexadienyl. In particular, the group is a vinyl or allyl group. The term "C3
-C10
-cycloalkyl" is understood to mean 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms ("C3
-C10
a saturated monovalent monocyclic or bicyclic hydrocarbon ring of a cycloalkyl group. The C3
-C10
a cycloalkyl group is, for example, a monocyclic hydrocarbon ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl or cyclodecyl, or a bicyclic hydrocarbon ring, for example Perhydrocyclopentadiene or decahydronaphthalene ring. Specifically, the ring contains 3, 4, 5 or 6 carbon atoms ("C3
-C6
-cycloalkyl"), preferably cyclopropyl. The term "3 to 10 membered heterocycloalkyl" is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and selected from C. (=O), O, S, S(=O), S(=O)2
NRa
One or more hetero atom-containing groups, wherein Ra
Represents a hydrogen atom or C1
-C6
-alkyl or C1
-C6
-haloalkyl; it is possible that the heterocycloalkyl group is attached to the remainder of the molecule via either a carbon atom or a nitrogen atom, if any. In particular, the 3 to 10 membered heterocycloalkyl group may have one or more of 2, 3, 4 or 5 carbon atoms and the above hetero atom-containing group ("3 to 6 membered heterocycloalkyl"). More particularly, the heterocycloalkyl group may contain one or more of 4 or 5 carbon atoms and the above hetero atom-containing group ("5 to 6 membered heterocycloalkyl"). Particularly, and not by way of limitation, the heterocycloalkyl group can be, for example, a 4-membered ring, such as azetidinyl, oxetanyl; or a 5-membered ring, such as tetrahydrofuranyl, dioxolanyl ( Dioxolinyl), pyrrolidinyl, imidazolidinyl, pyrazolyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl , piperazinyl or trithiaalkyl; or a 7-membered ring, such as a diazepanyl ring. Optionally, the heterocycloalkyl group can be benzofused. Preferably, the 3- to 6-membered heterocycloalkyl group is tetrahydrofuranyl, tetrahydropyranyl or piperazinyl. The heterocycloalkyl group can be a bicyclic ring such as, but not limited to, a 5,5-membered ring, such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring; or a 5,6-membered bicyclic ring, for example Hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring. As mentioned above, the nitrogen-containing atomic ring may be partially unsaturated, that is, for example, it may contain one or more double bonds such as, but not limited to, 2,5-dihydro-1H-pyrrolyl ring, 4H- [1,3,4]thiadiazinyl ring, 4,5-dihydrooxazolyl ring or 4H-[1,4]thiazinyl ring; or for example, it may be benzofused, such as but not limited to Dihydroisoquinolinyl ring. The term "3 to 10 membered heterocycloalkoxy" having the formula -O-heterocycloalkyl (wherein the term "heterocycloalkyl" is as defined above) is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring. , which contains 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and is selected from C(=O), O, S, S(=O), S(=O)2
NRa
One or more hetero atom-containing groups, wherein Ra
Represents hydrogen atom, C1
-C6
Alkyl or C1
-C6
Haloalkyl, and which is attached to the remainder of the molecule via an oxygen atom, such as pyrrolidinyloxy, tetrahydrofuranyloxy or tetrahydropyranyloxy. The term "4 to 10 membered heterocycloalkenyl" is understood to mean an unsaturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3, 4, 5, 6, 7, 8 or 9 carbon atoms and selected from C ( =O), O, S, S(=O), S(=O)2
NRa
One or more hetero atom-containing groups, wherein Ra
Represents a hydrogen atom or C1
-C6
Alkyl or C1
-C6
Haloalkyl; it is possible that the heterocyclenyl group is attached to the remainder of the molecule via either a carbon atom or a nitrogen atom, if any. Examples of the heterocycloalkenyl group may contain one or more double bonds, such as 4H-piperidyl, 2H-piperidyl, 3,6-dihydro-2H-piperidin-4-yl, 3,6-di Hydrogen-2H-thiopiperazin-4-yl, 1,2,3,6-tetrahydropyridin-4-yl, 3H-diazacyclopropenyl, 2,5-dihydro-1H-pyrrolyl, [ 1,3]dioxolyl, 4H-[1,3,4]thiadiazinyl, 2,5-dihydrofuranyl, 2,3-dihydrofuranyl, 2,5-di Hydrothienyl, 2,3-dihydrothiophenyl, 4,5-dihydrooxazolyl, 4H-[1,4]thiazinyl or 5,6-dihydroimidazo[1,2-a]pyridyl Pyrida-7(8H)-yl, or it may be benzofused. The term "heteroaryl" is understood to mean 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms ("5 to 14 membered heteroaryl"), 5 or 6 or Monovalent monocyclic, bicyclic or tricyclic aromatics of 9 or 10 ring atoms ("5 to 10 membered heteroaryl"), or especially 5 or 6 ring atoms ("5 to 6 heteroaryl") A ring system and which contains at least one hetero atom which may be the same or different, such as oxygen, nitrogen or sulfur, and additionally may be benzocondensed in each case. In particular, the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, Thiadiazolyl, sulfur-4H-pyrazolyl and the like and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzene And a triazolyl group, a carbazolyl group, a fluorenyl group, an isodecyl group, etc.; or a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, etc., and a benzo derivative thereof, such as a quinolyl group, a quinazolinyl group, an isoquinolyl group or the like; or a fluorenyl group, a pyridazinyl group, a fluorenyl group or the like and a benzo derivative thereof; or a porphyrin group, a pyridazinyl group, a quinazolinyl group, a quinoxaline group, Pyridyl, acridinyl, oxazolyl, acridine, cyanozinyl, phenothiazine, phenoxazinyl, fluorenyl, oxonyl or 1H-pyrrolo[2,3-b]pyridine 4-base and the like. In general and unless otherwise stated, a heteroaryl or heteroaryl group includes all possible isomeric forms thereof, such as positional isomers thereof. Thus, for some illustrative, non-limiting examples, the term pyridyl or extended pyridyl includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridine-4 - and pyridyl-4-yl; or the term thienyl or thienyl includes thiophen-2-yl, thiophen-2-yl, thiophen-3-yl and thiophen-3-yl. For example, in "C1
-C6
-alkyl", "C1
-C6
-haloalkyl", "C1
-C6
-alkoxy" or "C1
-C6
In the context of the definition of -haloalkoxy, as the term "C" is used throughout1
-C6
"It should be understood to mean an alkyl group having from 1 to 6 of a limited number of carbon atoms, that is, 1, 2, 3, 4, 5 or 6 carbon atoms. It should be further understood that the term "C1
-C6
Should be interpreted as any subrange contained in it, such as C1
-C6
, C2
-C5
, C3
-C4
, C1
-C2
, C1
-C3
, C1
-C4
, C1
-C5
Especially C1
-C2
, C1
-C3
, C1
-C4
, C1
-C5
, C1
-C6
More especially C1
-C4
; in "C1
-C6
-haloalkyl" or "C1
-C6
-haloalkoxy", even more particularly C1
-C2
. Similarly, as used herein, for example, in "C2
-C6
-alkenyl" and "C2
-C6
In the context of the definition of -alkynyl, as the term "C is used throughout"2
-C6
"It is understood to mean an alkenyl or alkynyl group having from 2 to 6 of a limited number of carbon atoms, ie 2, 3, 4, 5 or 6 carbon atoms. It should be further understood that the term "C2
-C6
Should be interpreted as any subrange contained in it, such as C2
-C6
, C3
-C5
, C3
-C4
, C2
-C3
, C2
-C4
, C2
-C5
Especially C2
-C3
. Also, as used herein, for example in "C3
-C6
In the context of the definition of -cycloalkyl, as the term "C" is used throughout3
-C6
"It should be understood to mean a cycloalkyl group having from 3 to 6 of a limited number of carbon atoms, that is, 3, 4, 5 or 6 carbon atoms. It should be further understood that the term "C3
-C6
Should be interpreted as any subrange contained in it, such as C3
-C6
, C4
-C5
, C3
-C5
, C3
-C4
, C4
-C6
, C5
-C6
Especially C3
-C6
. Also, as used herein, for example in "C2
-C4
In the context of -alkenyl, as the term "C is used throughout"2
-C4
"It should be understood to mean an alkenyl group having a finite number of carbon atoms of 2 to 4, that is, 2, 3 or 4 carbon atoms. It should be further understood that the term "C2
-C4
Should be interpreted as any subrange contained in it, such as C2
-C4
, C2
-C3
, C3
-C4
. The term "substituted" means that one or more hydrogens on a given atom are replaced by a selected one of the specified groups, with the proviso that the normal valence of the specified atom is not exceeded in the prior art and that the substitution results in a stable compound. Combinations of substituents and/or variables are only permissible when such combinations result in stable compounds. The term "optionally substituted" means replaced by a designated group, radical or moiety, as appropriate. Ring system substituent means a substituent attached to an aromatic ring system or a non-aromatic ring system which, for example, replaces the available hydrogen on the ring system. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to withstand separation from the reaction mixture to the appropriate purity and formulated as an effective therapeutic. As used herein, for example, in the definition of a substituent of a compound of the formula of the present invention, the term "one or more" is understood to mean "one, two, three, four or five, especially one, Two, three or four, more particularly one, two or three, even more specifically one or two." The invention also includes compounds of component A, in particular all suitable isotopic variations of compound A. An isotopic variation of a compound of component A is defined as a compound in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass normally or predominantly present in nature. Examples of isotopes which may be incorporated into the compound of component A include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as2
H (氘),3
H (氚),11
C,13
C,14
C,15
N,17
O,18
O,32
P,33
P,33
S,34
S,35
S,36
S,18
F,36
Cl,82
Br,123
I,124
I,129
I and131
I. Certain isotopic variations of a compound of component A, for example, incorporating one or more radioisotopes (such as 3H or14
The isotopic variants of C) are suitable for drug and/or matrix distribution studies. Deuterated and carbon-14 (ie14
C) Isotope is especially preferred for its ease of preparation and detection. In addition, certain therapeutic advantages resulting from greater metabolic stability can be obtained by isotopic substitutions such as hydrazine, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in certain circumstances. Isotopic variants of the compound of component A can generally be prepared using suitable isotopic variants of suitable reagents by conventional procedures known to those skilled in the art, such as by illustrative methods or by the methods described in the examples below. To prepare. As used herein, the plural forms of the word compounds, salts, polymorphs, hydrates, solvates, and analogs thereof, are also meant to mean individual compounds, salts, polymorphs, isomers, hydration. , solvate or the like. Depending on the location and nature of the various substituents, the compound of component A may contain one or more asymmetric centers. Asymmetric carbon atoms may be present in the (R) or (S) configuration, producing a racemic mixture in the case of a single asymmetric center, and producing a mixture of diastereomers in the case of multiple asymmetric centers. In some cases, there may also be asymmetry due to limited rotation around a given bond (eg, a central bond adjacent to two substituted aromatic rings of a given compound). The compound of component A may contain an asymmetric sulfur atom (such as an asymmetric amidene or a sulfonium imine group) having the following structure:For example, where * indicates an atom that can bind to the rest of the molecule. Substituents on the ring may also be present in cis or trans form. All such configurations, including enantiomers and diastereomers, are contemplated to be within the scope of the invention. Preferred compounds of component A are those which produce more desirable biological activity, particularly preferably compound A. Isolated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the components of component A are also included within the scope of the invention. Purification and isolation of this material can be accomplished by standard techniques known in the art. Optical isomers can be resolved by conventional methods by racemic mixtures, for example by formation of diastereomeric salts using photoactive acids or bases, or formation of covalent diastereomers. Examples of suitable acids are tartaric acid, diethyl tartaric acid, xylyl tartaric acid and camphorsulfonic acid. Mixtures of diastereomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art (for example by chromatography or fractional crystallization). The photoactive base or acid is then released from the separated diastereomeric salt. A different method for separating optical isomers involves the use of a palm chromatography (e.g., a palmitic HPLC column) with or without conventional derivatization, optimally selected to maximize separation of the enantiomers. . Suitable palm-shaped HPLC columns are manufactured by Daicel, such as Chiracel OD and Chiracel OJ. Enzyme separation is also applicable with or without derivatization. The optically active compounds of the invention can likewise be obtained by the palmar synthesis using optically active starting materials. In order to limit the different isomer types to each other, please refer to the IUPAC Rules E section (Pure Appl Chem 45, 11-30, 1976). The invention includes all possible stereoisomers of the compound of component A, either as a single stereoisomer, or as any of such stereoisomers (eg, R or S isomers, or E or Z isomers) Any mixture of ratios. Separation of a single stereoisomer (e.g., a single enantiomer or a single diastereomer) of a compound of Component A can be by any suitable prior art method, such as chromatography, especially for example, for the palm layer Analyze to achieve. Further, component A, particularly a compound of compound A, may exist as a tautomer. For example, any compound containing, for example, a pyrazole moiety as component A of the heteroaryl group may be present as a 1H tautomer, or a 2H tautomer or even a mixture of two tautomers in any amount, or for example Any compound containing a triazole moiety as component A of the heteroaryl group may be a 1H tautomer, a 2H tautomer, or a 4H tautomer, or even any amount of the 1H, the 2H, and the 4H tautomer A mixture of structures exists, namely:. Combinations of the invention include all possible tautomers of the compound of component A, in particular the pyrazole-5-yl 1H tautomer or 2H tautomer in the 8 position of the acridine center of compound A, It is in the form of a single tautomer or in any mixture of any ratio of such tautomers. Alternatively, the compound of component A, in particular compound A, may be present in the form of an N-oxide, which is defined as the oxidation of at least one nitrogen of the compound of the invention. The combinations of the invention include all such N-oxides that may be present of component A. Combinations of the invention also encompass suitable forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, prodrugs, salts, especially pharmaceutically acceptable salts, and coprecipitates. The compounds of the combinations according to the invention may be present in the form of hydrates or solvates, wherein the compounds of the combinations according to the invention contain polar solvents, in particular water, methanol or ethanol, for example as structural elements of the crystal lattice of the compounds. The polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios. In the case of stoichiometric solvates (e.g., hydrates), hemi-/semi-, mono-, sesqui-, di-, tri-, tetra-, penta-, etc. solvates or hydrates are possible, respectively. Combinations of the invention include all such hydrates or solvates. Additionally, the compounds of the combinations of the invention may be present in free form, such as the free base or free acid or zwitterionic form or may be in the form of a salt. The salt may be any salt, organic or inorganic addition salt conventionally used in pharmacy, in particular any pharmaceutically acceptable organic or inorganic addition salt. The invention includes all possible salts of the components of the combinations of the invention in the form of a single salt or any mixture of such salts in any ratio. Furthermore, the invention includes all possible crystalline or polymorphic forms of the compounds of the components of the combinations of the invention in the form of a single polymorph or a mixture of more than one polymorph in any ratio. . Unless otherwise specified, when a group in a compound of the combination of the invention is substituted, the group may be mono- or polysubstituted. In the context of the present invention, all groups which occur more than once are defined independently of one another. Substitution with one, two or three identical or different substituents is preferred. In the context of the present invention, the term "treatment/treating" includes inhibiting, retarding, inhibiting, alleviating, alleviating, limiting, reducing, suppressing, repressing or curing a disease or progression, a course of disease or such a condition and/or Progress in the symptoms of the disease. The term "disease" includes, but is not limited to, a condition, disorder, injury, or health problem. The term "therapy" is understood herein to be synonymous with the term "treatment." The term "prevention/prophylaxis/prevention" is used synonymously in the context of the present invention and refers to the avoidance or reduction of infection, experience, affliction or disease or the development or progression of symptoms of such conditions and/or such conditions. risk. The treatment or prevention of the disease can be partial or complete.Components in the combination A
Component A can be selected from ATR kinase inhibitors that are specific or generally disclosed in the following publications: J. Med. Chem. 2013, 56, 2125-2138; Exp. Rev. Mol. Med. 16, e10, 2014; WO2010054398A1; WO2010071837A1; WO2010073034A1; WO2011143399A1; WO2011143419A1; WO2011143422A1; WO2011143423A2; WO2011143425A2; WO2011143426A1; WO2011154737A1; WO2011163527A1; WO2012138938A1; WO2012178123A1; WO2012178124A1; WO2012178125A1; WO2013049719A1; WO2013049720A1; WO2013049722A1; WO2013049859A1; WO2013071085A1; WO2013071088A1; WO2013071090A1; WO2013071093A1; WO2013071094A1; WO2013152298A1; WO2014062604A1; WO2014089379A1; WO2014143240; WO 2014143241; WO 2014143242; ACS Med. Chem. Lett. 2015. 6, 37-41; ACS Med. Chem. Lett. 2015. 6, 42-46; WO 2015085132; WO 2015187451. ATR kinase inhibitors mentioned in the prior art have been disclosed for use in the treatment or prevention of various diseases, particularly cancer. In another embodiment of the present invention, the component A is selected from the group consisting of VX-803, VX-970, AZD-6738, and a compound of the formula (I)Where: R1
Represents a group selected from the following:, where * indicates the point at which the group is attached to the rest of the molecule; R2
Represents hydrogen, halogen, -NR7
R8
, CN, C1
-C6
-alkyl, C1
-C6
- alkoxy, 3 to 10 membered heterocycloalkoxy, C2
-C6
-alkenyl, C3
-C6
-cycloalkyl, 3 to 10 membered heterocycloalkyl, 4 to 10 membered heterocycloalkenyl, phenyl, heteroaryl, -(CO)OR7
,-(CO)NR7
R8
, -(SO2
)R9
, -(SO)R9
, -SR9
, -(SO2
)NR7
R8
, -NR7
(SO2
)R9
,-((SO)=NR11
)R10
, -N=(SO)R9
R10
, -SiR10
R11
R12
,-(PO)(OR7
)2
,-(PO)(OR7
)R10
Or -(PO)(R10
)2
, where each C1
-C6
-alkyl, C1
-C6
- alkoxy, 3 to 10 membered heterocycloalkoxy, C2
-C6
-alkenyl, C3
-C6
- cycloalkyl, 3 to 10 membered heterocycloalkyl, phenyl or heteroaryl, as the case may be, independently of one another, substituted one or more times by halogen, OH, -NR7
R8
Substituting one or more Cs with hydroxyl or phenyl groups as appropriate1
-C6
-alkyl, C1
-C6
-haloalkyl, C1
-C6
-alkoxy, C3
-C6
-cycloalkyl, 3- to 6-membered heterocycloalkyl, phenyl, -(CO)OR7
,-(CO)NR7
R8
, -NR7
(CO)R10
, -NR8
(CO)OR7
, -NR8
(CO)NR7
R8
, -(SO2
)R9
, -(SO)R9
, -SR9
, -(SO2
)R7
R8
, -NR7
(SO2
)R9
,-((SO)=NR11
)R10
, -N=(SO)R9
R10
,-(PO)(OR7
)2
,-(PO)(OR7
)R10
, -(PO)(R10
)2
Or as appropriate1
-C4
- an alkyl group substituted with one or more heteroaryl groups; wherein each 4 to 10 membered heterocycloalkenyl groups are independently of each other via C1
-C4
- alkyl substituted one or more times; R3
, R4
Representing hydrogen or methyl independently of each other; R7
, R8
Representing hydrogen, C independently of each other1
-C6
-alkyl, C3
-C6
a cycloalkyl or phenyl group which is optionally substituted by halogen one or more times; or R7
And R8
Representing 4, 5, 6 or 7 membered cyclic amine groups together, optionally independently of each other, selected from C1
-C6
-alkyl, C1
-C6
Substituting a substituent of a haloalkyl group one or more times, the 4 member, 5 member, 6 member or 7 membered cyclic amine group optionally containing another hetero atom selected from the group consisting of O, N and S;9
Express C1
-C4
- alkyl or phenyl, each C1
-C4
- an alkyl group or a phenyl group, depending on the case, independently of R13
Replace one or more times; R10
Express C1
-C4
-alkyl; or at -N=(SO)R9
R10
In the case of a group R9
And R10
Representing 5 to 8 heterocycloalkyl groups together; R11
Represents hydrogen, C1
-C4
-alkyl, -(CO)OR7
,-(CO)NR7
R8
Or CN; R12
Represents hydrogen or C1
-C4
-alkyl; R13
Indicates halogen, OH, -NR7
R8
, CN, NO2
, C1
-C6
-alkyl, C1
-C6
-haloalkyl, C1
-C6
-alkoxy, C1
-C6
-haloalkoxy, C2
-C6
-alkenyl, C3
-C6
-cycloalkyl, -(CO)OR7
Or -(CO)NR7
R8
Or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof. In the context of the present invention, the term "VX-803" means 2-amino-6-fluoro-N-[5-fluoro-4-(4-{[4-(oxetan-3-yl)) Piperazin-1-yl]carbonyl}piperidin-1-yl)pyridin-3-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide. It has the following structure:. In the context of the present invention, the term "VX-970" means 3-(3-{4-[(methylamino)methyl]phenyl}-1,2-oxazol-5-yl)-5- [4-(Prov-2-ylsulfonyl)phenyl]pyrazin-2-amine. It has the following structure:. In the context of the present invention, the term "AZD-6738" means 4-{4-[(3R)-3-methylmorpholin-4-yl]-6-[1-(S-methanesulfonimide) Cyclo)pyrimidin-2-yl}-1H-pyrrolo[2,3-b]pyridine. It has the following structure:. In another embodiment of the combination of the invention, the component A is selected from the group consisting of VX-803, VX-970, AZD-6738, and a compound of the formula (Ib), where R1
, R2
, R4
, R7
, R8
, R9
, R10
, R11
, R12
And R13
As defined above for the compounds of formula (I). In another embodiment of the invention, the component A is a compound of the formula (Ib), where R1
Indicates:, where * indicates the point at which the group is attached to the rest of the molecule; R2
Represents hydrogen, fluorine, chlorine, CN, methyl, C1
-C4
-alkoxy, C2
-C3
- alkenyl, cyclopropyl, 3- to 6-membered heterocycloalkyl, 4- to 6-membered heterocycloalkenyl, phenyl, pyridyl, thiazolyl, -(SO2
)R9
, -SR9
,-((SO)=NR11
)R10
, -N=(SO)R9
R10
, each of which is methyl, C1
-C4
-alkoxy, C2
-C3
Alkenyl, cyclopropyl, 3 to 6 membered heterocycloalkyl, phenyl, pyridyl or thiazolyl are optionally substituted one or more times independently of one another: fluorine, chlorine, OH, -NR7
R8
, methyl, 5-membered heterocycloalkyl, -NR8
(CO)OR7
, -(SO2
)R9
,-((SO)=NR11
)R10
,-(PO)(OR7
)2
Or a group selected from the following:Where * indicates the point at which the group is attached to the rest of the molecule; wherein each 4 to 6 membered heterocycloalkenyl group is optionally substituted with one or more methyl groups;4
Represents hydrogen or methyl; R7
, R8
Representing hydrogen or C independently of each other1
-C4
-alkyl; R9
Express C1
-C4
-alkyl; R10
Express C1
-C4
-alkyl; or at -N=(SO)R9
R10
In the case of a group R9
And R10
Together, 6-membered heterocycloalkyl; R11
Represents hydrogen, methyl, -(CO)OR7
Or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof. In another embodiment, the component A is a compound selected from the group consisting of 4-[(2-(morpholin-4-yl)-8-[2H-pyrazol-3-yl]-[ 1,7] acridine-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulfinimide 4-[(2-(morpholin-4-yl)-8-(2H-pyridyl) Zyrid-3-yl)-[1,7]acridin-4-yl]phenyl-S-methylsulfinimide 4-[6-(methylsulfonyl)pyridin-3-yl]-2 -(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(3,6-dihydro-2H-pyran-4-yl)-2 -(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]acridine 4-[4-(N,S-dimethylsulfonimido)phenyl ]-2-[morpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-[4-methyl-6-(methylsulfonyl)pyridine- 3-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(4-methanesulfonylphenyl)-2- (morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]-acridine 4-(2-methanesulfonylphenyl)-2-(morpholine-4 -yl)-8-(1H-pyrazol-3-yl)-[1,7]acridine hydrochloride {4-[2-(morpholin-4-yl)-8-(1H-pyrazole- 5-yl)-1,7-acridin-4-yl]phenyl}phosphonic acid dimethyl 4-isopropenyl-2-(morpholin-4-yl)-8-(1H-pyrazole-3 -yl)-[1,7]acridine 2-(morpholin-4-yl)-4-phenyl-8-(1H-pyrazol-3-yl)-[1,7]acridine 4-[ 4-(S-ethyl sulfonate Imino)phenyl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 3-[(2-(morpholin-4-) -8-[2H-pyrazol-3-yl]-[1,7]acridin-4-yl]phenyl-N-ethoxycarbonyl-S-methylsulfinimide 4-(1 -methyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-oxime 4-(3-Methanesulfonylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]acridine 4-[5- Methyl-6-(methylsulfonyl)pyridin-3-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1,7-acridine 4- Cyclopropyl-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]acridine 3-[(2-(morpholin-4-yl)- 8-(2H-pyrazol-3-yl)-[1,7]acridin-4-yl]phenyl-S-methylsulfinimide 4-methyl-2-(morpholin-4- -8-(1H-pyrazol-3-yl)-[1,7]acridine hydrochloride 4-[2-(methylsulfonyl)-1,3-thiazol-4-yl]-2 -(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-[2-(morpholin-4-yl)-8-(1H-pyrazole -5-yl)-1,7-acridin-4-yl]pyridine-2(1H)-one 5-[2-(morpholin-4-yl)-8-(1H-pyrazole-5-yl) -1,7-Acridine-4-yl]pyridine-2(1H)-one 4-[2-fluoro-4-(methylsulfonyl)phenyl]-2-(morpholine) 4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl)-4-{4-[S-(propyl-2-yl) Sulfonimido]phenyl}-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(4-methanesulfonylphenyl)-2-((R)- 3-methylmorpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]acridine 2-((R)-3-methylmorpholin-4-yl) 4-phenyl-8-(2H-pyrazol-3-yl)-[1,7]acridine 4-(3-methanesulfonylphenyl)-2-((R)-3-methyl Morpholin-4-yl)-8-(2H-pyrazol-3-yl)-[1,7]acridine 4-cyclopropyl-2-((R)-3-methylmorpholine-4- -8-(1H-pyrazol-3-yl)-[1,7]-acridine 4-[2-((R)-3-methylmorpholin-4-yl)-8-(2H -pyrazol-3-yl)-[1,7]acridin-4-yl]phenyl-S-methylsulfinimide 3-[2-((R)-3-methylmorpholine- 4-yl)-8-(2H-pyrazol-3-yl)-[1,7]acridin-4-yl]phenyl-S-methylsulfinimide 4-methanesulfonyl-2 -(morpholin-4-yl)-8-[2-(tetrahydropyran-2-yl)-2H-pyrazol-3-yl]-[1,7]acridine 2-[(3R)- 3-methylmorpholin-4-yl]-4-(methylsulfonyl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl) 8-(1H-pyrazol-3-yl)-[1,7]acridine-4-carbonitrile 2-((R)-3-methylmorpholin-4-yl)-8-(2H- Pyrazol-3-yl)-[1,7]acridine-4-carbonitrile 2-morpholin-4-yl-8-(1H-pyrazol-3-yl)-[1,7]acridine- 4- Indoleamine 4-methanesulfonylmethyl-2-morpholin-4-yl-8-(2H-pyrazol-3-yl)-[1,7]acridine [2-(morpholin-4-yl) 8-(2H-pyrazol-3-yl)-[1,7]acridin-4-yl]methanol 4-(1-methanesulfonylcyclopropyl)-2-(morpholin-4- 8-(2H-pyrazol-3-yl)-[1,7]acridine 4-isopropoxy-2-(morpholin-4-yl)-8-(1H-pyrazole-3 -yl)-[1,7]acridine 2-(morpholin-4-yl)-4-(propan-2-yloxy)-8-(1H-pyrrol-2-yl)-1,7- Acridine 4-[3-(S-methanesulfonimido)propoxy]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- Acridine 4-ethoxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]acridine 4-methoxy-2-(morpholine) 4-yl)-8-(1H-pyrazol-3-yl)-[1,7]acridine 2-methyl-1-{[2-(morpholin-4-yl)-8-(1H -pyrazol-5-yl)-1,7-acridin-4-yl]oxy}propan-2-ol 2-(morpholin-4-yl)-8-(1H-pyrazole-5-yl )-4-(tetrahydrofuran-2-ylmethoxy)-1,7-acridine 3-{[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1 ,7-Acridine-4-yl]oxy}dihydrofuran-2(3H)-one 4-[(3-methyl-1,2-oxazol-5-yl)methoxy]-2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-[(5-methyl-1,2-oxazol-3-yl)methoxy 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-benzene Oxy-2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]acridine 4-isopropoxy-2-((R)-3- Methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]acridine [4-({2-[(3R)-3-methylmorpholine-4) -yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}oxy)butyl]carbamic acid tert-butyl ester 4-methoxy-2-( (R)-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]acridine [3-({2-[(3R)-3-) Methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}oxy)propyl]carbamic acid tert-butyl ester 2-( {2-[(3R)-3-Methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}oxy)ethylamine [ 2-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}oxy) Ethyl]aminocarboxylic acid tert-butyl ester 4-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- Acridine-4-yl}oxy)butan-1-amine 2-[(3R,5S)-3,5-dimethylmorpholin-4-yl]-4-isopropoxy-8-(1H -pyrazol-5-yl)-1,7-acridine 2-[(3R,5R)-3,5-dimethylmorpholin-4-yl]-4-isopropoxy-8-(1H -pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyranose- 4-yl)-1,7-acridine 2-(morpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]㖠Pyridine hydrochloride 4-chloro-2-morpholin-4-yl-8-(1H-pyrazol-3-yl)-[1,7]acridine 2-[(3R)-3-methylmorpholine 4-yl]-4-(sulfanyl)-8-(1H-pyrazol-5-yl)-1,7-acridine N-{2-[(3R)-3-A Pyrazoline-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}-1,4λ4
- oxopurine-4-imine 4-oxide 4-{[dimethyl(a pendant)-λ6
- thio]amino}-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 2-[(3R)-3-methyl Morpholin-4-yl]-4-(piperazin-1-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-isopropoxy-2-((S )-3-methylmorpholin-4-yl)-8-(1H-pyrazol-3-yl)-[1,7]acridine 2-(morpholin-4-yl)-4-(propyl- 2-yloxy)-8-(1H-pyrrol-3-yl)-1,7-acridine 4-(1-ethyl-1H-pyrazol-5-yl)-2-[(3R)- 3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(1-methyl-1H-imidazol-5-yl)-2- [(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-{2-[(3R)-3-methyl Morpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]aniline 4-(2,3-difluorophenyl)-2-[( 3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-[2-methyl-6-(methylsulfonyl) Pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-[2- Fluoro-4-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- Acridine 4-fluoro-2-[2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4- Aniline 4-(1-benzyl-1H-imidazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazole-5- Base)-1,7-acridine 4-(2-Fluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2- [(3R)-3-methylmorpholin-4-yl]-4-(2-methyl-1,3-thiazol-5-yl)-8-(1H-pyrazol-5-yl)-1 , 7-Acridine 4-[4-methyl-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-( 1H-pyrazol-5-yl)-1,7-acridine 4-(1-cyclopropyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholine-4 -yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-[2-fluoro-4-(piperazin-1-yl)phenyl]-2-[(3R) 3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl] -4-[4-(methylsulfonyl)piperazin-1-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine N-(2,2-dimethylpropane -N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididine-4-amine (1-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}piperidine- 4-yl)methanol N-cyclopropyl-N-methyl-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1, 7-Acridine-4-amine 4-(5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)-2-[(3R)-3-methylmorpholine 4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine N-(4-fluorophenyl)-N-methyl-2-[(3R)-3-A Picomorpholin-4-yl]-8-(1H -pyrazol-5-yl)-1,7-acrididine-4-amine 2-[(3R)-3-methylmorpholin-4-yl]-4-(6-methylpyridin-3-yl) )-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(2-fluoropyridin-3-yl)-2-[(3R)-3-methylmorpholine-4- -8-(1H-pyrazol-5-yl)-1,7-acridine 4-(2-fluoro-4-methylpyridin-3-yl)-2-[(3R)-3-A Mymorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-( 1-methyl-1H-pyrrol-2-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(6-fluoro-5-methylpyridin-3-yl) -2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(2-fluoro-6-methyl Pyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(6- Fluoridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(6 -methoxypyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4 -(6-methoxy-5-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl) -1,7-acridine 4-(6-fluoro-2-methylpyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyridyl Zyrid-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-[1-methyl-3-(trifluoromethyl)-1H -pyrazole-5- -8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methyl-2 -thienyl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(5-methyl -2-Thienyl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(4- Methyl-3-thienyl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(3-chloro-2-thienyl)-2-[(3R)-3- Methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4- (2-methyl-3-thienyl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]- 8-(1H-pyrazol-5-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,7-acridine 4-(3,5-dimethyl -1,2-oxazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-oxime 4-(3-Chloro-2-methoxypyridin-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazole-5-yl) -1,7-Acridine 2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-pyran 4-yl)-1,7-acridine 4-(3,6-dihydro-2H-thiopiperazin-4-yl)-2-[(3R)-3-methylmorpholin-4-yl ]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(4-methylpiperidine- 1-yl)-8-(1H-pyridyl -5-yl)-1,7-acridine 4-(1-tert-butyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl] 8-(1-H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyridyl Zyrid-5-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(3- Methyl-1,2-oxazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(1-ethyl-3-methyl-1H-pyridyl Zyrid-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(1, 4-Dimethyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1, 7-Acridine 4-[2-methyl-6-(methylthio)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H -pyrazol-5-yl)-1,7-acridine 4-[2-methyl-6-(S-methylsulfonimido)pyridin-3-yl]-2-[(3R)-3 -methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4 -(1-propyl-1H-pyrazol-5-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(6,7-dihydro-5H-pyrrole [1,2-a]imidazol-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- Acridine 4-[1-ethyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8- (1H-pyrazole-5-yl)-1 ,7-Acridine 5-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl }-1H-pyrrole-2-carboxylic acid methyl ester 2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(1,2- Thiazol-5-yl)-1,7-acridine N,N-dimethyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazole -5-yl)-1,7-acridin-4-yl}aniline 4-(2,4-difluorophenyl)-2-[(3R)-3-methylmorpholin-4-yl]- 8-(1H-pyrazol-5-yl)-1,7-acridine 4-(1-isopropyl-1H-pyrazol-5-yl)-2-[(3R)-3-methyl?啉-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridinylmethyl{2-[(3R)-3-methylmorpholin-4-yl]-8- (1H-pyrazol-5-yl)-1,7-acridin-4-yl}phosphinate ethyl ester 4-{[diethyl(oxyloxy)-λ6
- thio]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididine {2- [(3R)-3-Methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}phosphinic acid isobutyl ester methyl ester 2 -{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}propan-2-ol 3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}pent-3- Alcohol 4-(5-chloropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- Acridine 5-fluoro-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4- Aniline 4-[2-fluoro-3-(methylsulfonyl)phenyl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazole-5 -yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-[1-(oxetan-3-yl)-1H-pyrazole- 5-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-[2-fluoro-4-(pyrrolidin-1-yl)phenyl]-2-[(3R )-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-[3-(methoxymethyl)-5-methyl -1,2-oxazol-4-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-oxime Pyridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(5-methyl-1,3,4-oxadiazol-2-yl)-8-(1H-pyrazole -5-yl)-1,7-acridine N-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}tetrahydro-1H -1λ4
-thiophene-1-imine 1-oxide 4-{[(4-fluorophenyl)(methyl) pendant oxy-λ6
- thio]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine, 2 Mixture of diastereomers 4-{[(2-fluorophenyl)(methyl) pendant oxy-λ6
- thio]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine, 2 Mixture of diastereomers 4-{[(R)(2-fluorophenyl)(methyl) pendant oxy-λ6
- thio]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine, non-pair 4'{[(S)(2-fluorophenyl)(methyl) pendantoxy-λ6
- thio]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine, non-pair 4-(Dimethylphosphonyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7 - acridine 4-(diethylphosphonyl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- Acridine isobutyl {2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl} Ethyl phosphonate 2-[(3R)-3-methylmorpholin-4-yl]-4-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7 - acridine 4-(1-isobutyl-1H-pyrazol-5-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazole-5 -yl)-1,7-acridine 4-[5-fluoro-6-(methylsulfonyl)pyridin-3-yl]-2-[(3R)-3-methylmorpholin-4-yl] 8-(1-H-pyrazol-5-yl)-1,7-acridine 4-[(3R)-3-methylmorpholin-4-yl]-2-(morpholin-4-yl)- 8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(4-methyl-1H-pyrazole -5-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-[2-fluoro-5-(methylsulfonyl)phenyl]-2-[(3R) 3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-[4-(isopropylsulfonyl)phenyl]-2 -[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(6-fluoropyridyl Pyridin-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(1- Ethyl-1H-imidazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 1-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl} amidoxime 3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}pyridine-2- Amine 2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-[1-(2,2,2-trifluoroethyl) -1H-pyrazol-5-yl]-1,7-acridine 1-methyl-4-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyridyl Zyrid-5-yl)-1,7-acridin-4-yl}piperazin-2-one 4-[1-(2-fluoroethyl)-1H-pyrazol-3-yl]-2-[ (3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-[1-(2-fluoroethyl)-1H- Pyrazol-5-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(3 -{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}-1H-pyrazole -1-yl)ethanol 2-methyl-1-(3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1 ,7-Acridine-4-yl}-1H-pyrazol-1-yl)propan-2-ol 4-[(2R)-2-methylmorpholin-4-yl]-2-(morpholine- 4-yl)-8-(1H-pyrazol-5-yl)-1,7-oxime 4-(5-fluoropyridin-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-oxime Pyridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(6-methylpyridin-2-yl)-8-(1H-pyrazol-5-yl)-1,7 -Acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methylpyridin-2-yl)-8-(1H-pyrazol-5-yl)-1 , 7-Acridine N-(2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine- 4-yl}phenyl)acetamide 3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-oxime 4-(3-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1 ,7-Acridine-4-yl}phenyl)propan-2-ol 4-(5,6-dihydroimidazo[1,2-a]pyrazine-7(8H)-yl)-2-( Morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-[(2S)-2-methylmorpholin-4-yl]-2-( Physo-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-[(trans)-2-methylcyclopropyl]-2-[(3R)- 3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(difluoromethoxy)-2-[(3R)-3- Methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[2-(morpholin-4-yl)-8-(1H-pyrazole -5-yl)-1,7-acridin-4-yl]propan-2-ol 2-(morpholin-4-yl)-4-(3-oxa-8-azabicyclo[3.2.1 ]辛-8-yl)-8-(1H- Pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(pyrrole Pyridin-1-yl)-1,7-acridine 4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl Piperazine-2-one 4-(dimethylphosphonium)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 4- [(trans)-2,5-dimethylpiperazin-1-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-oxime 4-[(cis)-3,5-dimethylpiperazin-1-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1, 7-Acridine 1-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]-3-(trifluoromethyl Azetidin-3-ol methyl hydrogen {4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl Phenyl}phosphonate 4-(4-methylpiperazin-1-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- Acridine 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-[(3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrole -5(3H)-yl]-1,7-acridine 4-(3-methoxy-3-methylazetidin-1-yl)-2-(morpholin-4-yl)-8 -(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl)-4-[(1S,4S)-2-oxo-5-azabicyclo[2.2. 1]hept-5-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-[ ( Thio)methyl]-8-(1H-pyrazol-5-yl)-1,7-acridine N,N-dimethyl-5-[2-(morpholin-4-yl)-8 -(1H-pyrazol-5-yl)-1,7-acridin-4-yl]pyridin-2-amine 4-(2-methylpyridin-4-yl)-2-(morpholin-4- -8-(1H-pyrazol-5-yl)-1,7-acridine 1-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyridyl Zyrid-5-yl)-1,7-acridin-4-yl}cyclohexanol 2-fluoro-6-{2-[(3R)-3-methylmorpholin-4-yl]-8-( 1H-pyrazol-5-yl)-1,7-acridin-4-yl}aniline (methyl{4-[2-(morpholin-4-yl)-8-(1H-pyrazole-5-) -1,7-acridin-4-yl]phenyl} sideoxy-λ6
- sulfinyl) cyanamide 1-ethyl-3-(methyl{4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-oxime Pyridin-4-yl]phenyl} sideoxy-λ6
- thiol)urea 3-({2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine-4 -yl}oxy)propan-1-amine 4-(4-cyclopropyl-1H-1,2,3-triazol-5-yl)-2-[(3R)-3-methylmorpholine- 4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-ethylsulfinyl-2-(morpholin-4-yl)-8-(1H-pyridyl Zyrid-5-yl)-1,7-acridine 2-(morpholin-4-yl)-4-[propan-2-ylsulfinyl]-8-(1H-pyrazol-5-yl) -1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-[3-(methylsulfonyl)propoxy]-8-(1H-pyrazole- 5-yl)-1,7-acridine 2-(morpholin-4-yl)-4-(phenylsulfonyl)-8-(1H-pyrazol-5-yl)-1,7-oxime 2-(morpholin-4-yl)-4-(propan-2-ylsulfonyl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(ethyl sulfonate Mercapto)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl)-4-(phenyl Sulfosyl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(methylsulfinyl)-2-(morpholin-4-yl)-8-( 1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-[1-lateral oxytetrahydro-2H-thiophene喃-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(1,1-di-sideoxytetrahydro-2H-thiopiperazin-4-yl) -2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R )-3-methylmorpholin-4-yl]-4,8-di(1H-pyrazol-5-yl)-1,7-acridine N,N-dimethyl-2-(morpholine- 4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine-4-amine 2-(morpholin-4-yl)-4-(phenylthio)-8- (1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl)-N-(propan-2-yl)-8-(1H-pyrazol-5-yl) -1,7-acrididine-4-amine 4-(ethylthio)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl)-4-(propan-2-ylthio)-8-(1H-pyrazol-5-yl)-1,7-acrididine 2-(morpholin-4- -8-(1H-pyrazol-5-yl)-4-(1H-pyrrol-2-yl)-1,7-acridine 2-(morpholin-4-yl)-8-(1H- Pyrazol-5-yl)-4-(1H-pyrrol-3-yl)-1,7-acridine 4-[(4-methoxyphenyl)thio]-2-(morpholin-4- -8-(1H-pyrazol-5-yl)-1,7-acridine 4-(5-methyl-1H-pyrazol-3-yl)-2-(morpholin-4-yl) 8-(1-H-pyrazol-5-yl)-1,7-acridine 1-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7 -Acridine-4-yl]pyrrolidin-2-one 4-(1,1-di-oxy-1,2-thiazolidin-2-yl)-2-(morpholin-4-yl)-8 -(1H-pyrazol-5-yl)-1,7-acridine 1-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-oxime Pyridin-4-yl]piperidin-2-one 2-[(3R)-3-methylmorpholin-4-yl]-4-(2-methylpyridin-3-yl)-8-(1H- Pyrazol-5-yl)-1,7-oxime 2-[(3R)-3-methylmorpholin-4-yl]-4-[2-(propan-2-yloxy)pyridin-3-yl]-8-(1H-pyrazole-5- -1,7-acridine 4-(2-methoxypyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazole -5-yl)-1,7-acridine 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(pyridin-4-yl)-1,7- Acridine 4-[(4-methoxyphenyl)thio]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)- 1,7-acridine 4-[3-fluoro-2-(morpholin-4-yl)pyridin-4-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8 -(1H-pyrazol-5-yl)-1,7-acridine 4-(6-fluoro-5-methylpyridin-3-yl)-2-(morpholin-4-yl)-8-( 1H-pyrazol-5-yl)-1,7-acridine 3-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine- 4-yl]-1,3-oxazacyclohexan-2-one 3-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-oxime Pyridin-4-yl]-1,3-oxazolidin-2-one 4-(3-methoxypyridin-4-yl)-2-[(3R)-3-methylmorpholin-4-yl ]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(2,6-difluoropyridin-3-yl)-2-[(3R)-3-methylmorpholine 4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(5-chloro-2-fluoropyridin-3-yl)-2-[(3R)-3 -methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(3-fluoropyridin-4-yl)-2-[(3R)- 3-methylmorpholine-4- ]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(2-chloro-6-methylpyridin-3-yl)-2-[(3R)-3-methyl Morpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(5,6-dimethylpyridin-3-yl)-2-[(3R) 3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(5-fluoro-6-methylpyridin-3-yl)- 2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methyl?啉-4-yl]-4-(5-methylthiophen-3-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(3-methoxythiophene- 2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(2-chlorothiophene -3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(isoquinoline 4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(5-chloro Thiophen-2-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R -3-methylmorpholin-4-yl]-4-(4-methylthien-2-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-( 2,5-Dimethylthiophen-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7- Acridine 2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(tetrahydro-2H-thiopiperazin-4-yl) -1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-8-(1H-pyridyl Zyrid-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1,2,3,6-tetrahydro Pyridin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-[1- Methylpiperidin-3-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-8- (1H-pyrazol-5-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)-1,7-acridine 2-[(3R)-3-methylmorpholine 4-yl]-8-(1H-pyrazol-5-yl)-4-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-3-yl]-1, 7-Acridine 4-(4,6-difluoropyridin-3-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazole-5-yl -1,7-Acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-4-yl)-8-(1H- Pyrazol-5-yl)-1,7-acridine 4-(1,3-dimethyl-1H-pyrazol-4-yl)-2-[(3R)-3-methylmorpholine-4 -yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(1,5-dimethyl-1H-pyrazol-4-yl)-2-[(3R) 3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl] 4-(piperidin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]- 8-(1H-pyrazol-5-yl)-4-[3-(trifluoromethyl) -1H-pyrazol-4-yl]-1,7-acridine 4-(1-cyclobutyl-1H-pyrazol-4-yl)-2-[(3R)-3-methylmorpholine 4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(1-cyclopropyl-1H-pyrazol-4-yl)-2-[(3R) 3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl] -4-[1-(propan-2-yl)-1H-pyrazol-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-[1-(two Fluoromethyl)-1H-pyrazol-4-yl]-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7 - acridine 4-(1-tert-butyl-1H-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazole- 5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(1,3, 5-trimethyl-1H-pyrazol-4-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-[1-methyl-3 -(trifluoromethyl)-1H-pyrazol-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(4-{2-[(3R)- 3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}-1H-pyrazol-1-yl)ethanol 4-( 1-ethyl-1H-pyrazol-4-yl)-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7 -Acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrrol-3-yl)-8-(1H-pyrazole-5-yl )-1,7-Acridine 2-[(3R)-3-A Pyrazoline-4-yl]-4-[1-(propan-2-yl)-1H-pyrazol-3-yl]-8-(1H-pyrazol-5-yl)-1,7-oxime Pyridine 2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-4-(1,2,5-trimethyl-1H-pyrrole- 3-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-phenyl-1H-pyrazol-4-yl)-8- (1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(3-methyl-1H-pyrazole-4 -yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazole- 5-yl)-1,7-acrididine-4-amine 2-[(3R)-3-methylmorpholin-4-yl]-4-[1-(2-methylpropyl)-1H- Pyrazol-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-(1H -pyrazol-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-[(3R)-3-methylmorpholin-4-yl]-4-( 1,3-oxazol-2-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(1,3-dimethyl-1H-pyrazol-4-yl )-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(1,5-dimethyl-1H-pyrazole-4- 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl)-8-(1H-pyridyl Zyrid-5-yl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,7-acrididine 4-{[(2-methoxyethyl)( Methyl) sideoxy-λ6
- thio]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-{ [(4-bromophenyl)(o-oxy)propan-2-yl-λ6
- thio]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-( Methyl-N-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}sulfonate醯imino)phenol 4-{[(4-bromophenyl)(methyl) pendant oxy-λ6
- thio]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-{ [Third butyl (methyl) pendant oxy-λ6
- thio]amino}-2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acrididinecarboxylic acid, N -[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]-1,4λ4
- oxopurine-4-imine 4-oxide (1:1) N-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-oxime Pyridin-4-yl]hexahydro-1λ4
-thiopentan-1-imine 1-oxide 3-methyl-2-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazole-5- -1,7-acridin-4-yl}butan-2-ol 1-{2-[(3R)-3-methylmorpholin-4-yl]-8-(1H-pyrazole-5 -yl)-1,7-acridin-4-yl}-1-(tetrahydro-2H-piperazin-4-yl)ethanol 3,3-dimethyl-2-{2-[(3R)- 3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}butan-2-ol 2-{2-[(3R) 3-methylmorpholin-4-yl]-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl}hexan-2-ol 2-[(3R)-3 -methylmorpholin-4-yl]-8-(1H-pyrazol-3-yl)-1,7-acrididine-4-carboxamide 2-[(3R)-3-methylmorpholine- 4-yl]-4-[1-(methylsulfonyl)cyclopropyl]-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl) 8-(1-H-pyrazol-5-yl)-4-(tetrahydro-2H-piperidin-4-ylmethoxy)-1,7-acridine N,N-dimethyl-3-[ 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]benzimidamide {4-[2-(morpholine-4) -yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]phenyl}(piperidin-1-yl)methanone N,N-dimethyl-2 -[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]benzimidamide N-cyclopropyl-4-[ 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]benzamide-5(4-methylpyridine- 3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(1H-indol-6-yl)-2- (morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(1H-indol-4-yl)-2-(morpholin-4-yl) -8-(1H-pyrazol-5-yl)-1,7-acrididine 3-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1, 7-Acridine-4-yl]benzamide-5-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl Benzylguanamine N-methyl-3-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]benzamide Indole 4-(3-fluorophenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(5-chlorothiophene- 2-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(2-methoxyphenyl)-2-( Morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl) -4-[2-(Trifluoromethyl)phenyl]-1,7-acridine 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-[4 -(trifluoromethyl)phenyl]-1,7-acridine 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-[3-(trifluoromethyl) Phenyl]-1,7-acridine 4-(3-chlorophenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- Acridine N-{3-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]phenyl}acetamidamine 4 -(3-methoxyphenyl )-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(3,5-dimethoxyphenyl)-2-( Morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(3-methylphenyl)-2-(morpholin-4-yl)-8 -(1H-pyrazol-5-yl)-1,7-acridine 4-(4-methoxyphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazole-5 -yl)-1,7-acridine 4-(furan-2-ylmethyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- Acridine 2,6-dimethyl-4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]phenol 4 -(2,3-dimethylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine {3-[2-( Morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]phenyl}methanol 4-(4-fluorophenyl)-2-( Physo-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(4-methylphenyl)-2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7-acridine 4-(4-chlorophenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl) -1,7-acridine 4-(2-fluoro-3-methoxyphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazole-5-yl)-1,7 - acridine 4-(2-methylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(2,3 -dimethoxyphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine N,N-dimethyl-3-[ 2-(morpholin-4-yl -8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]aniline N,N-dimethyl-2-[2-(morpholin-4-yl)-8 -(1H-pyrazol-5-yl)-1,7-acridin-4-yl]phenylamine N-{2-[2-(morpholin-4-yl)-8-(1H-pyrazole-5 -yl)-1,7-acridin-4-yl]phenyl}methanesulfonamide N-{4-[2-(morpholin-4-yl)-8-(1H-pyrazole-5-yl) -1,7-acridin-4-yl]phenyl}methanesulfonamide N,N-dimethyl-4-[2-(morpholin-4-yl)-8-(1H-pyrazole- 5-yl)-1,7-acridin-4-yl]benzamide 2-(morpholin-4-yl)-4-[(1E)-prop-1-en-1-yl]-8 -(1H-pyrazol-5-yl)-1,7-acridine 4-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-oxime 4-(2-fluorophenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine {3- [2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]phenyl}(piperidin-1-yl)methanone 2 -(morpholin-4-yl)-4-[4-(propan-2-yl)phenyl]-8-(1H-pyrazol-5-yl)-1,7-acridine N-cyclopropyl -3-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]benzamide-5-(biphenyl-4 -yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(2,4-dimethoxyphenyl)-2 -(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(2-chlorophenyl)-2-(morpholin-4-yl)- 8-(1H-pyrazole-5-yl) -1,7-Acridine 4-(2,5-dimethylphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- Acridine 3-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]aniline 2-(morpholin-4-yl )-8-(1H-pyrazol-5-yl)-4-[3-(1H-pyrazol-1-yl)phenyl]-1,7-acrididine 3-[2-(morpholine-4) -yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]phenol 4-(2-fluoro-5-methoxyphenyl)-2-(morpholine) 4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(5-fluoro-2-methoxyphenyl)-2-(morpholin-4-yl) )-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(2,4-difluorophenyl)-2-(morpholin-4-yl)-8-(1H- Pyrazol-5-yl)-1,7-acridine 4-(2,3-difluorophenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl) -1,7-acridine 4-(2,6-dimethoxyphenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- Acridine 2-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]aniline 4-(3,5-dichloro Phenyl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(biphenyl-2-yl)-2-(morpholine) 4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(2-chloropyridin-4-yl)-2-(morpholin-4-yl)-8 -(1H-pyrazol-5-yl)-1,7-acridine 4-(1-benzothiophen-2-yl)-2-(morpholin-4-yl)-8-(1H-pyrazole -5-yl)-1,7-acridine 4-( 1-methyl-1H-pyrazol-5-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 2-(morpholine) 4-yl)-8-(1H-pyrazol-5-yl)-4-(quinolin-5-yl)-1,7-acridine 2-(morpholin-4-yl)-8-( 1H-pyrazol-5-yl)-4-(pyridin-3-yl)-1,7-acridine 4-(2-methoxypyridin-4-yl)-2-(morpholin-4-yl) )-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(5-methylpyridin-3-yl)-2-(morpholin-4-yl)-8-(1H -pyrazol-5-yl)-1,7-acridine 4-(5-methoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazole-5 -yl)-1,7-acridine 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(quinolin-3-yl)-1,7-oxime 2-(morpholin-4-yl)-4-[1-(phenylsulfonyl)-1H-indol-2-yl]-8-(1H-pyrazol-5-yl)-1, 7-Acridine 4-(2-chloropyridin-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-( 6-chloropyridin-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine {5-[2-(morpholine- 4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]thiophen-2-yl}methanol 4-(2-fluoropyridin-3-yl)-2 -(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(6-fluoropyridin-3-yl)-2-(morpholin-4- 8-(1-H-pyrazol-5-yl)-1,7-acridine 4-(2-chloro-6-methylpyridin-3-yl)-2-(morpholin-4-yl) -8-(1H-pyrazole -5-yl)-1,7-acridine 4-(2-methoxypyridin-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl) -1,7-acridine 4-(isoquinolin-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4 -(3-chloropyridin-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(3-fluoropyridine- 4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(2,6-difluoropyridin-3-yl) -2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(1-methyl-1H-pyrazol-4-yl)-2 -(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 5-methoxy-2-[2-(morpholin-4-yl)-8 -(1H-pyrazol-5-yl)-1,7-acridin-4-yl]-1H-indole-1-carboxylic acid tert-butyl ester 2-(morpholin-4-yl)-4-[ 6-(morpholin-4-yl)pyridin-3-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(4-methylthiophen-3-yl)- 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl)-8-(1H-pyrazole-5 -yl)-4-(thiophen-2-yl)-1,7-acridine 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(thiophene-3 -yl)-1,7-acridine 4-(3-methylthiophen-2-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1, 7-Acridine 4-(2-chloro-5-methylpyridin-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- Acridine 4-(4-A Oxypyridin-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(5-chloro-2-methoxy Pyridin-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 5-methyl-2-[2-( Benzyl-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]-1H-indole-1-carboxylic acid tert-butyl ester 4-(5-chloro 2-fluoropyridin-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(3,5-dimethyl 1,2-oxazol-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholine- 4-yl)-8-(1H-pyrazol-5-yl)-4-(quinolin-8-yl)-1,7-acridine 4-(5-methylthiophen-2-yl)-2 -(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(6-ethoxypyridin-3-yl)-2-(morpholine- 4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(2-ethoxypyridin-3-yl)-2-(morpholin-4-yl)- 8-(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4-(quinoline-6 -yl)-1,7-acridine 4-(2-chlorothiophen-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazole-5-yl)-1,7 -Acridine 5-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]pyridin-2-amine 2-(? Physo-4-yl)-4-(1H-pyrazol-3-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(6-methylpyridine-3- Base)-2-( Physo-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(1-methyl-1H-pyrrol-2-yl)-2-(morpholine-4 -yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 5-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)- 1,7-acridin-4-yl]pyridin-2-ol 4-(5-chloropyridin-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazole-5- -1,7-acridine 4-(3-chloro-2-methoxypyridin-4-yl)-2-(morpholin-4-yl)-8-(1H-pyrazole-5-yl -1,7-acridine 4-(3-chlorothien-2-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-oxime 4-(5-fluoropyridin-3-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-[2-( Methylthio)pyrimidin-5-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine N-cyclopropyl-5- [2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]pyrimidin-2-amine 4-(isoquinoline-5- 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine N-methyl-5-[2-(morpholin-4-yl) )-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]pyridine-2-carboxamide N-tert-butyl-5-[2-(morpholine-4) -yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]pyridine-3-carboxamide 4-[5-(methylthio)pyridine-3- 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl)-8-(1H-pyridyl Azole 5-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1,7-acrididine 3-[2-(morpholin-4-yl)-8-(1H -pyrazol-5-yl)-1,7-acridin-4-yl]pyridin-2-amine 4-[2-(morpholin-4-yl)-8-(1H-pyrazole-5-yl) -1,7-Acridine-4-yl]thiophene-2-carboxylic acid methyl ester 4-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-2-(morpholine- 4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl)-4-[2-(propan-2-yloxy)pyridine 3-yl]-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(5-chloro-6-ethoxypyridin-3-yl)-2-(morpholine- 4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(1-tert-butyl-1H-pyrazol-4-yl)-2-(morpholine- 4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl)-4-(piperidin-1-yl)-8-(1H -pyrazol-5-yl)-1,7-acridine 1-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine-4 -yl]piperidin-4-ol N-methyl-2-(morpholin-4-yl)-N-phenyl-8-(1H-pyrazol-5-yl)-1,7-acridine- 4-amine {1-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]pyrrolidin-2-yl}methanol N-methyl-2-(morpholin-4-yl)-N-propyl-8-(1H-pyrazol-5-yl)-1,7-acrididine-4-amine 4-(oxo-heterocycle Heptan-1-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(3-methylpiperidin-1- -2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(4-methylpiperidin-1-yl)-2-( Morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 1-[2-(morpholin-4-yl)-8-(1H-pyrazole-5 -yl)-1,7-acridin-4-yl]piperidine-3-carboxamide 4-(2,5-dihydro-1H-pyrrol-1-yl)-2-(morpholin-4- -8-(1H-pyrazol-5-yl)-1,7-acridine 4-(3,4-dihydroquinolin-1(2H)-yl)-2-(morpholin-4- -8-(1H-pyrazol-5-yl)-1,7-acridine 4-(3,4-dihydroisoquinolin-2(1H)-yl)-2-(morpholine-4 -yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 4-(1,3-dihydro-2H-isoindol-2-yl)-2-(morpholine- 4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine 2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-4- [1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl]-1,7-acridine 1-[2-(morpholin-4-yl)-8- (1H-pyrazol-5-yl)-1,7-acridin-4-yl]-proline acid tert-butyl ester N-methyl-N-(2-methylpropyl)-2-( Phenyl-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-amine N-(3-fluorophenyl)-N-methyl-2-(morpholine) 4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine-4-amine 4-(1,1-di-oxy-1-thia(thia)-6 -azaspiro[3.3]hept-6-yl)-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acrididine 4-(3-fluoro Piperidin-1-yl)-2-( Phenyl-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine N-(2-fluorophenyl)-N-methyl-2-(morpholin-4-yl -8-(1H-pyrazol-5-yl)-1,7-acrididine-4-amine 1-[2-(morpholin-4-yl)-8-(1H-pyrazole-5-yl) -1,7-acridin-4-yl]-nonylamine decylamine {1-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7- 4-(4-methoxypiperidin-1-yl)-2-(morpholin-4-yl)-8-(1H-pyrazole- 5-yl)-1,7-acridine N-(4-fluorophenyl)-N-methyl-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)- 1,7-Acridine-4-amine N-methyl-1-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine-4 -yl]-amidamine 4-[4-(ethylsulfonyl)piperazin-1-yl]-2-(morpholin-4-yl)-8-(1H-pyrazole-5-yl -1,7-acridine 4-[4-(methylsulfonyl)piperazin-1-yl]-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl) -1,7-acridine N-cyclopropyl-N-methyl-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridine-4 -amine N-(2,2-dimethylpropyl)-N-methyl-2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-oxime Pyridyl-4-amine {1-[2-(morpholin-4-yl)-8-(1H-pyrazol-5-yl)-1,7-acridin-4-yl]piperidin-3-yl }Methanol or its stereoisomers, tautomers, N-oxides, hydrates, solvates or pharmaceuticals A salt that is acceptable for learning. The synthesis of the compound of the formula (I) or (Ib) of the component A listed above is described in International Patent Publication No. WO2016020320 (A1). In a preferred embodiment, component A is 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazol-5-yl)- 8-(1H-pyrazol-5-yl)-1,7-acridine ("Compound A"), its tautomers, N-oxides, hydrates, solvates or pharmaceutically acceptable salt. In a preferred embodiment, the component A is a compound A having the following structure. The synthesis of Compound A is described in Example 111 of WO2016020320 (A1). The term "pharmaceutically acceptable salt" of component A, especially compound A, refers to a relatively non-toxic, inorganic or organic acid addition salt of a compound of the invention. See, for example, S. M. Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. The pharmaceutically acceptable salts include those obtained by reacting a main compound serving as a base with an inorganic or organic acid to form a salt, such as a hydrochloride, a sulfate, a phosphate, a methanesulfonate, a camphorsulfonate. Acid salts, oxalates, maleates, succinates and citrates. Pharmaceutically acceptable salts also include those in which the primary compound acts as an acid and reacts with a suitable base to form, for example, the sodium, potassium, calcium, magnesium, ammonium and chloride salts. It will be further appreciated by those skilled in the art that the acid addition salts of the claimed compounds can be prepared by reacting the compound with a suitable inorganic or organic acid via any of a variety of known methods. Alternatively, the alkali metal salts and alkaline earth metal salts of the acidic compounds of the present invention are prepared by reacting a compound of the present invention with a suitable base via various known methods. Representative salts of component A of the present invention include the conventional non-toxic salts and quaternary ammonium salts formed, for example, from inorganic or organic acids or bases by means well known in the art. For example, such acid addition salts include: acetates, adipates, alginates, ascorbates, aspartates, benzoates, besylate, hydrogen sulfate, butyrate , citrate, camphorate, camphor sulfonate, cinnamate, cyclopentane propionate, digluconate, lauryl sulfate, ethanesulfonate, fumarate, Glucose heptanoate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, itaconate, lactate, cisplatin Oleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinic acid salt, nitrate, oxalate, pamoate, pectate, peroxysulfate, 3 Phenylpropionate, picrate, pivalate, propionate, succinate, sulfonate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. The alkali salt includes alkali metal salts such as potassium salts and sodium salts; alkaline earth metal salts such as calcium salts and magnesium salts; and ammonium salts formed with organic bases such as dicyclohexylamine and N-methyl-D-glucosamine . Alternatively, the basic nitrogen-containing group can be quaternized by a reagent such as a lower alkyl halide such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; Alkyl esters such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate or diamyl sulfate; long chain halides such as sulfhydryl, lauryl, myristyl and stearyl chloride, bromide and iodine An aralkyl halide such as benzyl and phenethyl bromide; and others. This component A can be in the form of a pharmaceutical formulation which is ready for simultaneous, parallel, separate or sequential administration with component B and optionally component C, as further described below. Components A and B and optionally component C can be administered independently of one another by the oral, intravenous, topical, topical, intraperitoneal or nasal routes. The specific compound of the list as disclosed above is preferably component A in the combination, and is preferably used as "Compound A" in the experimental part. It will be understood that the invention is also in any combination with respect to the embodiments of component A described above.Components in the combination B
Component B is a pharmaceutically acceptable salt of the alkaline earth radioactive seed radium-223. The pharmaceutically acceptable salt of radium-223 may be, for example, an acid addition salt formed with an acid such as a mineral acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, heavy sulfuric acid, phosphoric acid or nitric acid; Or organic acids such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4) -Hydroxybenzhydryl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanoic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectic acid, persulfate, 3 -Phenylpropionic acid, bitter acid, pivalic acid, 2-hydroxyethanesulfonate, itaconic acid, aminesulfonic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene Sulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, fatty acid, alginic acid , maleic acid, fumaric acid, D gluconic acid, mandelic acid, ascorbic acid, glucose heptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalic acid, hemisulfuric acid or thiocyanate . The preferred pharmaceutically acceptable salt of radium-223 is dichloride (223
RaCl2
). Processes for the preparation of a pharmaceutically acceptable solution comprising radium-223 are disclosed, for example, in WO 2000/40275 (A2), WO 2011/134671 (A1) and WO 2011/134672 (A1). A pharmaceutically acceptable solution comprising radium-223 is used as a unique mechanism for targeting radiopharmaceuticals. These solutions represent a new generation of therapeutic drugs based on the natural osteogenic nuclear species radium-223. Preferably, radium chloride-223 (intravenous injection, sterile and free of bacterial endotoxin) is used (223
RaCl2
An aqueous solution. Preferably, the solution is isotonic and contains sodium citrate buffered saline to physiological pH. A preferred dosing regimen of radium chloride-223 injection is to give 50 kBq/kg body weight at intervals of 4 weeks in a course of treatment consisting of 6 injections. A single dose of radium-223 up to 250 kBq/kg body weight was assessed in Phase I clinical trials. The adverse reactions observed at this dose were diarrhea and reversible myelosuppression (including a grade 3 neutropenia (1/5)). As an example, an aqueous solution of radium dichloride-223 can be provided in a single dose 10 ml vial containing 6 ml of fill. This product has a radium-223 radioactivity concentration of 1,000 kBq/mL (0.03 mCi/mL), corresponding to 0.53 ng/mL radium on the reference date. The active part is alpha particle radionuclear radium-223 (half-life of 11.4 days), which is expressed as divalent cations (223
Ra2 +
). The energy fraction emitted from radium-223 and its daughters as alpha particles was 95.3%, the fraction of emission as beta particles was 3.6%, and the fraction of emission as gamma radiation was 1.1%. The combined energy from radiation emitted by the complete decay of radium-223 and its daughter nucleus is 28.2 MeV. Radium-223 will be administered intravenously by a professional in the form of a slow bolus injection. An intravenous access line should be used for administration of radium-223. The line must be flushed with isotonic saline before and after the injection of radium-223. Radium-223 selectively targets an increased bone turnover region, such as in bone metastases, and concentrates by forming a complex with hydroxyapatite. The alpha emission contributes approximately 93% of the total radiation absorbed dose. High linear energy alpha particle radiation induces double-stranded DNA breaks, producing a potent and localized cytotoxic effect in the target region containing metastatic cancer cells. The short path length of the alpha particles (less than 100 microns) minimizes the effects on adjacent healthy tissue, such as bone marrow.combination
According to another aspect, the invention provides a combination of at least two components, preferably two components, comprising component A and component B, component A being an ATR kinase inhibitor, in particular compound A, or Stereoisomers, tautomers, N-oxides, hydrates, solvates or pharmaceutically acceptable salts, and component B is a pharmaceutically acceptable salt of the alkaline earth radioactive seed radium-223. According to another aspect, the invention encompasses a combination of any of the components A referred to herein and any of the components B mentioned herein, optionally with any of the components C mentioned herein. According to another aspect, the invention relates to a combination of at least two components A and B, preferably two components, comprising an ATR kinase inhibitor, in particular component A of compound A and an alkaline earth radioactive seed radium- Component B of a pharmaceutically acceptable salt of 223. According to another aspect, the invention provides a combination of at least two components A and B, preferably two components, comprising a group of ATR kinase inhibitors, particularly Compound A or a pharmaceutically acceptable salt thereof Component A is component B of a pharmaceutically acceptable inorganic salt of the alkaline earth radioactive seed radium-223. According to another aspect, the invention provides a combination of at least two components, preferably two components, comprising component A as described above and component B as described above, component A being ATR kinase An inhibitor, in particular Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and Component B is an alkaline earth radioactive seed radium- A pharmaceutically acceptable salt of 223. A combination comprising at least two components A and B, preferably two components, as described and defined herein, is also referred to as "the combination of the invention." The synergistic behavior of the combinations of the invention and one of the ATR kinase inhibitors ("Compound A") specifically disclosed in the Examples section is demonstrated herein. Further, a pharmaceutically acceptable salt comprising the compound A and radium-223 as mentioned above, in particular223
RaCl2
The combination of the invention is a preferred aspect of the invention. In another aspect, the combination of the invention comprises Compound A or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable salt of an alkaline earth radioactive seed radium-223, preferably a radium-223 dichloride salt. In a preferred embodiment, the combination of the invention comprises Compound A or a pharmaceutically acceptable salt thereof and a di-chloride salt of radium-223. Additionally, the invention encompasses a kit comprising: Component A: one or more, preferably an ATR kinase inhibitor as described above, in particular Compound A, or a stereoisomer, tautomer thereof, N-oxide, hydrate, solvate or pharmaceutically acceptable salt; component B: a pharmaceutically acceptable salt of the alkaline earth radioactive seed radium-223 as described above or a solvate thereof or hydrated Things. In the kit, either or both of the component A and the component B are in the form of a pharmaceutical composition, as appropriate, for simultaneous, concurrent, separate or sequential administration. versus. Components A and B can be administered independently of one another by the oral, intravenous, topical, topical device, intraperitoneal or nasal route. Preferably, component A is administered by the oral route and component B is administered by the intravenous route. Additionally, the invention encompasses a kit comprising: Component A: one or more, preferably an ATR kinase inhibitor as described above, in particular Compound A, or a stereoisomer, tautomer thereof, N-oxide, hydrate, solvate or pharmaceutically acceptable salt; component B: a pharmaceutically acceptable salt of the alkaline earth radioactive seed radium-223 as described above or a solvate thereof or hydrated And, as the case may be, component C: one or more, preferably one, other pharmaceutical agent, wherein, as the case may be, any one of the above combinations, the component A, the component B, and the component C They are all in the form of a pharmaceutical composition which is intended for simultaneous, concurrent, separate or sequential administration. Components A and B, optionally C, can be administered independently of one another by the oral, intravenous, topical, topical, intraperitoneal or nasal route. The term "component C" of at least one pharmaceutical agent includes the active compound itself, and pharmaceutically acceptable salts, solvates, hydrates or stereoisomers thereof, and the active compound or pharmaceutically acceptable salt thereof. A pharmaceutical composition of a solvate, hydrate or stereoisomer. A list of pharmaceutical agents of component C is further provided below. Combinations of Component A and Component B of the present invention may be administered in the form of a single pharmaceutical agent or in combination with one or more other pharmaceutical agents C, wherein the combination of components A, B and C does not cause unacceptable adverse effects. For example, a combination of components A and B of the present invention may be combined with component C, that is, one or more other pharmaceutical agents, such as known anti-angiogenic agents, anti-hyperproliferative agents, anti-inflammatory agents, Analgesics, immunomodulators, diuretics, antiarrhythmic agents, anti-hypercholesterolemia agents, anti-hyperlipidemic agents, anti-diabetic or anti-viral agents, and the like, as well as admixtures and combinations thereof. An optional pharmaceutical agent that can be added as component C to the combination of components A and B can be one or more pharmaceutical agents such as 131I-chTNT, abarelix, abiraterone, Aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, Alectinib, alemtuzumab, alendronic acid, alitretinoin, hexamethylene melamine, amifostine, amine Aminoglutethimide, hexylamine hexylamine, amrubicin, amsacrine, anastrozole, anstim, aniseed brain, two Thioflavinone, attenumab ravtansine, angiotensin II, antithrombin III, aprepitant, acilimumab, Arglabin, arsenic trioxide, aspartate, axitinib, azacitidine, basiliximab (basiliximab), belopotecan (benotecan), bendamustine, besilesomab, belinostat, bevacizumab, beserzine ( Bexarotene), bicalutamide, bisantrene, bleomycin, blinatumomab, bortezomib, buserelin, Bosutinib, brentuximab vedotin, busulfan, cabazitaxel, cabozantinib, calcitonine, Calcium leucovorin, calcium leucovorin, capecitabine, capromab, carboplatin, carboquone, carfilzomib, carmofur ( Carmofur), carmustine, catummaxomab, celecoxib, celmoleukin, ceritinib, cetuximab (cetuximab), chlorambucil, chlormadinone, chlormethine, cidofovi r), cinacalcet, cisplatin, cladribine, clodronate, clofarabine, cobimetinib, copanlisib , cristantaspase, crizotinib, cyclophosphamide, cyproterone, cytarabine, dacarbazine, actinomycin , daratumumab, darbepoetin alfa, dabrafenib, dasatinib, daunorubicin, decitabine (decitabine) ), degarelix, denileukin diftitox, denosumab, depreotide, deslorelin, wolkonol (dianhydrogalactitol), dexrazoxane, dibrospidium chloride, diclofenac, dinutuximab, docetaxel, dolasetron , dexifluridine, doxorubicin, doxorubicin + estrone, Dronabinol, eculizumab, edrecolomab, elliptinium acetate, elotuzumab, eltrombopag, Endostatin, enocitabine, enzalutamide, epirubicin, cyclostretidine, epoetin alfa, betacitabine ( Epoetin beta), epotetin zeta, eptaplatin, eribulin, erlotinib, esomeprazole, estradiol, female Estramustine, ethinyl estradiol, etoposide, everolimus, exemestane, fadrozole, fentanyl, non-gem Filing (filgrastim), fluoromethylol testosterone, floxuridine, fludarabine, fluorouracil, flutamide, aldosteric acid, formestane, valsartan (fosaprepitant), fotemustine, fulvestrant, gadobutrol, gadoteridol, citric acid Gadoteric acid meglumine, gadoversetamide, gadoxetic acid, gallium nitrate, ganirelix, gefitinib, gemcitabine ), gemtuzumab, glutathione, glutathione, GM-CSF, goserelin, granisetron, granulocyte community Stimulating factor, histamine dihydrochloride, histrine, hydroxyurea, I-125 seed, lansoprazole, ibandronic acid, titan Ibritumomab tiuxetan, ibrutinib, idarubicin, ifosfamide, imatinib, imiquimod, acetaminophen Improsulfan, indisetron, incadronic acid, ingenol mebutate, interferon alpha, interferon beta, interferon gamma, iodine ratio Alcohol (iobitridol), iobenguane (123I), iomeprol (iomeprol), iprilumab (ipilim) Ubab), irinotecan, itraconazole, ixabepilone, ixazomib, lanreotide, lapatinib, AI Isoocholine, lenalidomide, lenvatinib, lenograstim, mushroom polysaccharide, letrozole, leuprorelin, Levamisole, levonorgestrel, levothyroxine sodium, lisuride, lobaplatin, lomustine, lonidamine, horse Masoprocol, medroxyprogesterone, megestrol acetate, melarsoprol, melphalan, mepitiostane, mercaptopurine, mesna , methadone, methotrexate, methoxsalen, methyl acetaminophen, methylprednisolone, methyltestosterone, formazanic acid, mitomycin ( Mifamurtide), miltefosine, miribatin, mitobronitol, mitoxantrone (mitoguazone), mitolactol, mitomycin, mitotane, mitoxantrone, mogamulizumab, molrasostim , mopidamol, morphine hydrochloride, morphine sulfate, nabilone, nabiximols, nafarelin, naloxone + naloxone + pentazocine, naltrexone, nartograstim, necitumumab, nedaplatin, nerarabine, neridronic acid ( Neridronic acid), neptidine/palonosetron, nivolumabpentetreotide, nilotinib, nilutamide, nimozolium Nimorazole), nimotuzumab, nimustine, nintedanib, nitracrine, nivolumab, orbital Anti (obinutuzumab), octreotide, atumlamab (ofatumumab), olaparib, oma Omecetaxine mepesuccinate, omeprazole, ondansetron, oprelvekin, orgonetin, orriolidemod Orilotimod), osimertinib, oxaliplatin, oxycodone, oxymetholone, ozogamicine, p53 gene therapy, paclitaxel Paclitaxel), palbociclib, palifermin, palladium-103 seed crystal, palonosetron, pamidronic acid, panitumumab, Panobinostat, pantoprazole, pazopanib, pegaspargase, PEG-beta epoxide (methoxy PEG-beta epoxide) ), pembrolizumab, pegfilgrastim, pegylated interferon alpha-2b, pemetrexed, tebuconazole, pentostatin, Peplomycin, perfluoro-n-butane, perfosfamide, pertuzumab, picibani l), pilocarpine, pirarubicin, pixantrone, plerixafor, plicamycin, polyglucan, polyphosphate Glycol, polyvinylpyrrolidone + sodium hyaluronate, polysaccharide-K, pomalidomide, ponatinib, porfimer sodium, pralatrexate, splash Prednimustine, prednisone, procarbazine, procodazole, propranolol, quinagolide, rabeprazole Rabeprazole), racotumomab, rarotinib, raloxifene, raltitrexed, ramosetron, ramerizumab (ramucirumab) ), ramimustine, rasburicase, razoxane, refametiniib, regorafenib, risedronic acid, Ethenium-186 etidronate, rituximab, rolapitant, romidepsin (romideps) In), romiposttim, romurtide, roniciclib, 153Sm (samarium (153Sm) lexidronam), saglastin ), satumomab, trypsin, siltuximab, sipuleucel-T, sizofiran, sobuzuxane , sodium glycididazole, sonydigib, sorafenib, stanozolol, streptozocin, sunitinib ), talaporfin, talimogene laherparepvec, tamibarotene, tamoxifen, tapentadol , his tasonermin, teceleukin, metoptanol (99mTc) (technetium (99mTc) nofetumomab merpentan), 99mTc-HYNIC-[Tyr3]-octreotide, fluoro Tegas (furafur), flupiridine + gimeracil + oteracil, temoporfin, temozolomide, temsirolimo (temsirolimus), teniposide, fluorenone, tetrofosmin, thalidomide, thiotepa, thymalfasin, thyrotropin alpha, sulphur bird Tioguanine, tocilizumab, topotecan, toremifene, tositumomab, trobectedin, trimetinib (trametinib), tramadol, trastuzumab, trastuzumab emtansine, treosulfan, retinoic acid, trifluridine + Tipiracil, trilostane, triptorelin, trofosfamide, thrombopoietin, tryptophan, ubenimex, varatinib (valatinib), valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine, vincristine, vinca Vindesine, vinflunine, vinorelbine, vismodegib Vorinostat, vorozole, 钇-90 glass microspheres, zostatin, zinostatin stimalamer, zoledronic acid ), zorubicin or a combination thereof. A preferred alternative pharmaceutical agent that can be added as component C to the combination of components A and B is one selected from the group consisting of enzalutamide, bicalutamide, flutamide, nirudamide, and/or abiraterone or A variety of medicines. In general, a combination of component C and a combination of components A and B of the present invention, a cytotoxin and/or a cytostatic agent, can be used for: (1) reducing tumor growth compared to administration of either agent alone And/or transfer or even eliminate the tumor and/or metastasis for better efficacy, (2) provide a reduced amount of administered chemotherapeutic agent, (3) provide good tolerance in patients, compared Chemotherapy for the treatment of fewer harmful pharmacological complications using single agent chemotherapy and some other combination therapies, (4) treatment of a wide range of different cancer types in mammals, especially humans, (5) Higher response rates are achieved in treated patients, (6) longer survival time in treated patients compared to standard chemotherapy, (7) longer tumor progression, and/or (8) compared to other cancer agents The known situation of combining antagonism produces a therapeutic and tolerable result that is at least as good as the agent alone. Additionally, the invention encompasses a pharmaceutical composition comprising a combination of the invention as described above and one or more pharmaceutically acceptable excipients. Further, the present invention encompasses a pharmaceutical composition comprising at least two components, a combination of component A and component B, component A being an ATR kinase inhibitor, in particular compound A, or a stereoisomer thereof, Isomers, N-oxides, hydrates, solvates or pharmaceutically acceptable salts, and component B is a pharmaceutically acceptable salt of an alkaline earth radioactive seed radium-223, and one or more pharmaceuticals Acceptable excipients. Further, the present invention encompasses a pharmaceutical composition comprising at least two components, Component A and Component B, optionally in combination with any of the components C mentioned herein, Component A is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and Component B is an alkaline earth radioactive seed radium-223 A pharmaceutically acceptable salt, and one or more pharmaceutically acceptable excipients. In another embodiment, components A and B and optionally component C are present in separate formulations. In another embodiment, components A and B and optionally component C are present in the combined formulation. Pharmaceutically acceptable excipients are non-toxic, preferably they are non-toxic and inert. Pharmaceutically acceptable excipients include, inter alia, fillers and excipients (for example cellulose, microcrystalline cellulose such as Avicel®, lactose, mannitol, starch, calcium phosphate, such as Di-Cafos®), Ointment base (eg petroleum jelly, paraffin, triglyceride, wax, plush wax, plush wax, wool wax, hydrophilic ointment, polyethylene glycol), · suppository base (eg polyethylene glycol, cocoa butter) , hard fat), · Solvents (eg water, ethanol, isopropanol, glycerol, propylene glycol, medium chain long triglyceride fatty oil, liquid polyethylene glycol, paraffin), · surfactants, emulsifiers, dispersion Agent or wetting agent (eg sodium lauryl sulfate, lecithin, phospholipids, fatty alcohols (such as Lanette®), sorbitan fatty acid esters (such as Span®), polyoxyethylene sorbitan fatty acid esters (such as Tween®), polyoxyethylene fatty acid glycerides (such as Cremophor®), polyoxyethylene fatty acid esters, polyoxyethylene fatty alcohol ethers, glycerol fatty acid esters, poloxamers (such as Pluronic®), · Buffers as well as acids and bases (eg phosphates, carbonates, lemons) Citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, tromethamine, triethanolamine), isotonic agents (such as glucose, sodium chloride), · adsorbents (such as highly dispersed cerium oxide), Tackifiers, gel formers, thickeners and/or binders (eg polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose) , starch, carbomer, polyacrylic acid (such as Carbopol®), alginate, gelatin), disintegrants (eg modified starch, sodium carboxymethylcellulose, sodium starch glycolate (such as Explotab®) ), cross-linked polyvinylpyrrolidone, croscarmellose sodium (such as AcDiSol®), · flow regulators, lubricants, slip agents and mold release agents (such as magnesium stearate, stearic acid, talc) Highly dispersed cerium oxide (such as Aerosil®), · coating materials (such as sugar, shellac) and film-forming agents for membranes or diffusion membranes that dissolve rapidly or in a regulated manner (eg polyvinylpyrrolidine) Ketones (such as Kollidon®), polyvinyl alcohol, hydroxypropyl methylcellulose, hydroxypropyl fibers , ethyl cellulose, hydroxypropyl methyl cellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylate, polymethacrylate (such as Eudragit®), · capsule material ( For example, gelatin, hydroxypropyl methylcellulose), synthetic polymers (such as polylactide, polyglycolide, polyacrylate, polymethacrylate (such as Eudragit®), polyvinylpyrrolidone (such as Kollidon®), polyvinyl alcohol, polyvinyl acetate, polyoxyethylene, polyethylene glycol and copolymers thereof and block copolymers), plasticizers (eg polyethylene glycol, propylene glycol, glycerol, triacetic acid) Glycerides, triethyl decyl citrate, dibutyl phthalate), · Penetration enhancers, · Stabilizers (eg antioxidants such as ascorbic acid, ascorbyl palmitate, sodium ascorbate, butyl hydroxyanisole) , butyl hydroxytoluene, propyl gallate), preservatives (eg, parabens, sorbic acid, thimerosal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate), · colorants (eg inorganic pigments such as iron oxide, dioxane Titanium), - flavoring agents, sweetening agents, taste and / or odor masking agent. Other excipients and procedures are described in the following references, each of which is incorporated herein by reference: Powell, M. F. Et al., "Compendium of Excipients for Parenteral Formulations" PDA Journal of Pharmaceutical Science & Technology 1998, 52(5), 238-311; Strickley, R. G "Parenteral Formulations of Small Molecule Therapeutics Marketed in the United States (1999)-Part-1" PDA Journal of Pharmaceutical Science & Technology 1999, 53(6), 324-349; and Nema, S. Et al, "Excipients and Their Use in Injectable Products" PDA Journal of Pharmaceutical Science & Technology 1997, 51(4), 166-171. Components A, B and C can be administered independently of one another by the oral, intravenous, topical, topical, intraperitoneal or nasal route. Component A is administered intravenously or intraperitoneally, preferably by oral administration. Component B is preferably administered by the intravenous route. Component C is administered intravenously or intraperitoneally, preferably by oral administration. Pharmaceutical compositions (formulations) vary depending on the route of administration. The components of the present invention may be combined with conventional lozenge matrices (such as lactose, sucrose, and corn starch) to form lozenges: binders such as acacia, corn starch or gelatin; a disintegrant which aids in the decomposition and dissolution of the tablet, such as potato starch, alginic acid, corn starch and guar gum, tragacanth, gum arabic; aims to improve the flow of the tablet particles and prevent the tablet A lubricant that adheres to the surface of the tablet and the surface of the punch, such as talc, stearic acid or magnesium stearate, calcium stearate or zinc stearate; it is intended to enhance the aesthetic quality of the tablet and make it easier Dyes, colorants, and flavorings received by the patient, such as peppermint, wintergreen, or cherry flavoring. Excipients suitable for oral liquid dosage forms include dicalcium phosphate; and diluents such as water and alcohols such as ethanol, benzyl alcohol and polyvinyl alcohol with or without the addition of pharmaceutically acceptable surfactants, suspending agents Or an emulsifier. Various other materials may be present in the form of a coating or otherwise alter the physical form of the dosage unit. For example, lozenges, pills or capsules may be coated with shellac, sugar or both. Dispersible powders and granules are suitable for the preparation of aqueous suspensions. It provides the active ingredient in admixture with dispersing or wetting agents, suspending agents and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by the reagents already mentioned above. Additional excipients, such as the sweeteners, flavoring agents, and coloring agents described above, may also be present. The components of the invention may also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil (such as liquid paraffin) or a mixture of vegetable oils. Suitable emulsifiers can be (1) naturally occurring gums such as acacia and tragacanth; (2) naturally occurring phospholipids such as soy and lecithin; (3) esters derived from fatty acids and hexitol anhydrides. Or a partial ester such as sorbitan monooleate; (4) a condensation product of the partial ester with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The lotion may also contain sweeteners and flavoring agents. An oily suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The suspension may also contain one or more preservatives, for example ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate; one or more coloring agents; one or more flavoring agents; and one or more sweeteners such as sucrose or saccharin. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent and preservative (such as methylparaben and propylparaben) and flavoring agents as well as coloring agents. The components of the present invention may also be administered parenterally (i.e., subcutaneously, intravenously, intraocularly, intrasynovally, intramuscularly or intraperitoneally) as a compound in a preferably pharmaceutically acceptable diluent and pharmaceutical carrier. Injectable dosage form of the agent, which may be added with or without the addition of a pharmaceutically acceptable surfactant (such as a soap or detergent), a suspending agent (such as gelatin, carbomer, methyl fiber). a sterile liquid or liquid mixture of emulsifiers, hydroxypropyl methylcellulose or carboxymethylcellulose) or an emulsifier and other pharmaceutical adjuvants, such as water, saline, aqueous dextrose and related sugar solutions; alcohols such as ethanol, Isopropanol or cetyl alcohol; a diol such as propylene glycol or polyethylene glycol; a glycerol ketal such as 2,2-dimethyl-1,1-dioxolane-4-methanol; Such as poly(ethylene glycol) 400; oil, fatty acid, fatty acid ester or fatty acid glyceride or acetylated fatty acid glyceride. Illustrative oils useful in parenteral formulations of the invention are oils of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, sesame oil, cottonseed oil, corn oil, olive oil, paraffin oil and mineral oil. Suitable fatty acids include oleic acid, stearic acid, isostearic acid and myristic acid. Suitable fatty acid esters are, for example, ethyl oleate and isopropyl myristate. Suitable soaps include alkali metal, ammonium and triethanolamine salts of fatty acids; and suitable detergents include: cationic detergents such as dimethyldialkylammonium halides, alkylpyridyl halides and alkylamines Acetate; anionic detergents such as alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates and sulfosuccinates; nonionic detergents such as fatty amine oxidation , fatty acid alkanolamines and poly(oxyethylene-oxypropylene), or ethylene oxide or propylene oxide copolymers; and amphoteric detergents, such as alkyl-β-aminopropionates and 2-alkylimidazolines Grade ammonium salts; and mixtures. The parenteral composition of the invention will typically contain about 0. 5% by weight to about 25% by weight of active ingredient. Preservatives and buffers should also be used. In order to minimize or eliminate irritation at the injection site, such compositions may contain a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of preferably from about 12 to about 17. The amount of surfactant in such formulations is preferably in the range of from about 5% by weight to about 15% by weight. The surfactant may be a single component having the above HLB or may be a mixture of two or more components having the desired HLB. Illustrative surfactants for use in parenteral formulations are polyethylene sorbitan fatty acid esters (such as sorbitan monooleate) and the hydrophobicity of ethylene oxide with condensation of propylene oxide with propylene glycol. A high molecular weight adduct of a sexual matrix. The pharmaceutical compositions of this invention may be in the form of a sterile injectable aqueous suspension. Such suspensions may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, Polyvinylpyrrolidone, tragacanth and acacia; dispersing or wetting agent, which may be a naturally occurring phospholipid such as lecithin; a condensation product of an alkylene oxide with a fatty acid, such as polyoxyethylene stearate; a condensation product of oxyethane with a long chain aliphatic alcohol, such as heptadecyl ethoxy hexadecanol; a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyoxyethylene sorbitol a monooleate; or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride, such as a polyoxyethylene sorbitan monooleate. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent. Diluents and solvents which can be used are, for example, water, Ringer's solution, isotonic sodium chloride solution and isotonic glucose solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspension medium. For this purpose any bland fixed oil comprising synthetic mono- or diglycerides may be employed. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The components of the invention may also be administered in the form of a suppository for rectal administration of a drug. These components can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and thus will melt in the rectum to release the drug. Such materials are, for example, cocoa butter and polyethylene glycol. Another formulation used in the methods of the invention uses a transdermal delivery device ("patch"). Such transdermal patches can be used to provide continuous or discontinuous infusion of a compound of the invention in a controlled amount. The construction and use of a transdermal patch for the delivery of a pharmaceutical agent is well known in the art (see, for example, U.S. Patent No. 5,023,252, issued Jun. Such patches can be constructed for continuous, pulsed or on-demand delivery of a pharmaceutical agent. Controlled release formulations for parenteral administration include liposomes, polymeric microspheres, and polymeric gel formulations known in the art. It may be necessary or necessary to introduce a patient of the present invention into a patient via a mechanical delivery device. The construction and use of mechanical delivery devices for the delivery of pharmaceutical agents are well known in the art. Direct techniques for direct techniques such as direct administration of drugs to the brain typically involve placing a drug delivery catheter into the ventricular system of the patient to bypass the blood brain barrier. One such implantable delivery system for delivering a medicament to a particular anatomical region of the body is described in U.S. Patent No. 5,011,472, issued Apr. 30, 1991. According to another aspect, the invention relates to the use of a combination of the invention as described herein for the treatment or prevention of a disease, preferably a hyperproliferative disease and/or metastasis thereof as described below, preferably bone metastasis. According to another aspect, the invention relates to a kit as described herein for use in the treatment or prevention of a disease, preferably a hyperproliferative disease and/or metastasis thereof as described below, preferably bone metastasis. According to another aspect, the present invention relates to a pharmaceutical composition as described above for use in the treatment or prevention of a disease, preferably a hyperproliferative disease and/or metastasis thereof as described below, preferably bone metastasis. According to another aspect, the invention encompasses the use of such a combination as described above for the preparation of a hyperproliferative disorder and/or its metastasis, preferably for the treatment or prevention of a disease, preferably as described below. The agent for bone metastasis. According to another aspect, the invention encompasses the use of such a kit as described above for the preparation of a hyperproliferative disorder and/or its metastasis for the treatment or prevention of a disease, preferably as described below Good bone transfer agent. According to another aspect, the invention encompasses the use of such a pharmaceutical composition as described above for the preparation of a hyperproliferative disorder and/or metastasis thereof, for the treatment or prevention of a disease, preferably as described below, An agent for better bone metastasis. According to another aspect, the invention relates to a method of treating and/or preventing a disease, preferably a hyperproliferative disease and/or metastasis thereof, preferably bone metastasis, as described below, using an effective amount of a combination as described above. According to another aspect, the invention relates to the use of an effective amount of a kit or pharmaceutical composition as described above for the treatment and/or prophylaxis of a disease, preferably a hyperproliferative disease and/or metastasis thereof as described below, preferably The method of bone transfer. According to another aspect, the present invention relates to a method of treating a disease in a patient, preferably a hyperproliferative disease and/or metastasis thereof, as described below, preferably a method of bone metastasis comprising a) administering component A, Is an ATR kinase inhibitor, particularly Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) a component thereof B, which is a pharmaceutically acceptable salt of an alkaline earth radioactive seed radium-223. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive nuclear species radium-223. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive nuclear radium-223 wherein components A and B are administered simultaneously, in parallel, separately or sequentially. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive seed radium-223 wherein components A and B are administered in parallel. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive seed radium-223 wherein component B is administered prior to component A. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive seed radium-223 wherein component B is administered from 2 hours to 96 hours prior to component A. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive seed radium-223 wherein component B is administered from 6 hours to 84 hours prior to component A. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive seed radium-223 wherein component B is administered from 12 hours to 72 hours prior to component A. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive seed radium-223 wherein component B is administered from 24 hours to 48 hours prior to component A. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive seed radium-223 wherein component B is administered 18 hours to 30 hours prior to component A. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive seed radium-223 wherein component B is administered from 20 hours to 28 hours prior to component A. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive seed radium-223 wherein component B is administered 22 hours to 26 hours prior to component A. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive seed radium-223 wherein component B is administered from 42 hours to 54 hours prior to component A. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive seed radium-223 wherein component B is administered from 44 hours to 52 hours prior to component A. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive seed radium-223 wherein component B is administered 46 hours to 50 hours prior to component A. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive seed radium-223 wherein component B is administered 24 hours prior to component A. According to another aspect, the present invention relates to a method of treating prostate cancer, particularly castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, comprising a) administering component A, which is an ATR kinase inhibitor , in particular, Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) component B, which is an alkaline earth A pharmaceutically acceptable salt of radioactive seed radium-223 wherein component B is administered 48 hours prior to component A. According to another aspect, the present invention relates to a method of treating a disease in a patient, preferably a hyperproliferative disease and/or metastasis thereof, as described below, preferably a method of bone metastasis comprising a) administering component A, Is an ATR kinase inhibitor, particularly Compound A, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or pharmaceutically acceptable salt thereof, and b) a component thereof B, which is a pharmaceutically acceptable salt of the alkaline earth radioactive seed radium-223, and optionally, component C, which is a pharmaceutical agent as described below. Thus, the combinations, kits or pharmaceutical compositions of the present invention are useful for treating or preventing hyperproliferative diseases, including diseases in which uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses; Diseases that have uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, particularly where uncontrolled cell growth, proliferation and/or survival, inappropriate cellular immune responses, or inappropriate cellular inflammatory responses, such as hematological tumors And/or its metastases, solid tumors and/or its metastases (eg leukemia, multiple myeloma and myelodysplastic syndromes), malignant lymphomas (including breast tumors and bone metastases), chest tumors (including non-small cells and Small cell lung tumors and their bone metastases), gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors and their bone metastases, urinary tumors (including kidney, bladder and prostate tumors), skin tumors and sarcomas, and/or their metastases. As used herein, the term "inappropriate" is used in the context of the present invention, particularly in the context of "inappropriate cellular immune response or inappropriate cellular inflammatory response", and is preferably understood to mean that the response is below or above normal and associated. Cause or cause disease of the disease. In particular, the present invention encompasses the treatment of lung cancer (especially small cell lung cancer), colorectal cancer, bladder cancer, lymphoma (especially diffuse large B-cell lymphoma (DLBC) and mantle cell lymphoma (MCL)), prostate cancer ( Especially castration resistant prostate cancer), glioma and ovarian cancer. In one embodiment, the invention encompasses a combination, kit or pharmaceutical composition as described above, comprising component A or a medicament thereof for the treatment of a cancer indication, in particular a cancer type that forms a bone metastasis An acceptable salt and component B, which is a pharmaceutically acceptable salt of the alkaline earth radioactive seed radium-223. Such cancer types are, for example, breast cancer, prostate cancer, lung cancer, multiple myeloma, kidney cancer or thyroid cancer. Another aspect of the invention relates to a combination, kit or pharmaceutical composition according to the invention for use in the treatment or prevention of a hyperproliferative disease and/or its metastasis. According to another aspect, the invention relates to a combination, kit or pharmaceutical composition according to the invention for use in the treatment or prevention of prostate cancer, in particular castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, wherein Components A and B are administered simultaneously, in parallel, separately or sequentially. According to another aspect, the invention relates to a combination, kit or pharmaceutical composition according to the invention for use in the treatment or prevention of prostate cancer, in particular castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, wherein Components A and B were administered in parallel. According to another aspect, the invention relates to a combination, kit or pharmaceutical composition according to the invention for use in the treatment or prevention of prostate cancer, in particular castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, wherein Component B is administered prior to component A. According to another aspect, the invention relates to a combination, kit or pharmaceutical composition according to the invention for use in the treatment or prevention of prostate cancer, in particular castration resistant prostate cancer and/or metastasis thereof, preferably bone metastasis, wherein Component B is 2 hours to 96 hours, or 6 hours to 84 hours, or 12 hours to 72 hours, or 24 hours to 48 hours, or 18 hours to 30 hours, or 20 hours to 28 hours before component A, Or 22 hours to 26 hours, or 42 hours to 54 hours, or 44 hours to 52 hours, or 46 hours to 50 hours, or 24 hours, or 48 hours. Another embodiment encompasses the use of a combination, kit or pharmaceutical composition according to the invention for the preparation or treatment of breast cancer, prostate cancer, multiple myeloma, non-small cell lung cancer and/or metastasis thereof, In particular, the transfer is an agent for bone metastasis. In one embodiment, the invention encompasses a method of treating or preventing cancer in a subject, particularly breast cancer, prostate cancer, multiple myeloma, hepatocellular carcinoma, lung cancer (especially non-small cell lung cancer), colorectal cancer, melanoma or A method of pancreatic cancer comprising administering to the individual a therapeutically effective amount of a combination according to the invention. In another embodiment, the invention encompasses a method of treating or preventing cancer in a subject, particularly breast cancer, prostate cancer, multiple myeloma, hepatocellular carcinoma, lung cancer (especially non-small cell lung cancer), colorectal cancer, melanoma Or a method of pancreatic cancer comprising administering to the individual a therapeutically effective amount of a combination according to the invention. In another embodiment, the invention encompasses a method of treating or preventing cancer in a subject, particularly breast cancer, prostate cancer, multiple myeloma, hepatocellular carcinoma, lung cancer (especially non-small cell lung cancer), colorectal cancer, melanoma Or a method of pancreatic cancer and/or metastasis thereof, comprising administering to the individual a therapeutically effective amount of a combination according to the invention. A preferred use of the combination of the invention is in the treatment of prostate cancer. The term "prostate cancer" as used herein means any type of prostate cancer of the histological type including, but not limited to, acinar adenocarcinoma, ductal adenocarcinoma, transitional cell (or urethral epithelial) cancer, squamous cell carcinoma, carcinoid, Small cell carcinoma, sarcoma and sarcomatoid carcinoma, especially acinar adenocarcinoma, M0 grade castration resistant prostate cancer (M0 CRPC) or M1 castration resistant prostate cancer (M1 CRPC), preferably M1 castration resistant prostate cancer ( M1 CRPC). The terms "M0" and "M1" (including M1a, M1b, M1c), such as "TNM CLASSIFICATION OF MALIGNANT TUMORS", are used according to the "TNM Grading System" developed by the American Joint Committee on Cancer for prostate cancer. , 7th edition, James D. Brierley, Mary K. Gospodarowicz, edited by Christian Wittekind, published by UICC, 2011. According to the TNM classification, the term "M0" means that there is no long-distance transfer and the cancer has not spread to other parts of the body. "M1" means that there is a long-distance transfer and the cancer has spread to distant parts of the body. A preferred use of the combination of the invention is in the treatment of castration resistant prostate cancer (CRPC), particularly M1 grade CRPC, preferably M1b grade castration resistant prostate cancer (M1b CRPC) or M1c grade castration resistant prostate cancer (M1c CRPC). The term "M1b CRPC" as used herein means that castration-resistant prostate cancer has spread to the bone. The term "M1c CRPC" as used herein means that castration-resistant prostate cancer has spread to other organs, such as the lungs, liver or brain (in the case of diffusion or non-diffusion to bone). A preferred use of the combination of the invention is in the treatment of prostate cancer, especially castration resistant prostate cancer (CRPC), preferably CRPC with symptomatic bone metastases and no known visceral metastatic disease. A preferred embodiment is the use of a combination, kit or pharmaceutical composition of the invention for the treatment of prostate cancer, especially castration-resistant prostate cancer (CRPC with symptomatic bone metastases and no known visceral metastatic disease) ). In another embodiment, the use of a combination, kit or pharmaceutical composition of the invention relates to treating castration resistant prostate cancer (M0 CRPC) or M1 castration resistant prostate cancer (M1 CRPC) in an individual, wherein the individual has not Chemotherapy treatment. The term "non-chemotherapeutic treatment" as used herein means that an individual has not received chemotherapy prior to treatment with a combination, kit or pharmaceutical composition of the invention. In another embodiment, the use of a combination, kit or pharmaceutical composition of the invention relates to treating castration resistant prostate cancer (M0 CRPC) or M1 castration resistant prostate cancer (M1 CRPC) in an individual, wherein the individual is in use The combination, kit or pharmaceutical composition of the invention has been subjected to chemotherapy prior to treatment. The term "chemotherapy" as used herein, refers to a category of cancer treatment that uses one or more chemotherapeutic agents as part of a standardized chemotherapy regimen. The chemotherapeutic agent is actually a non-specific agent such as an alkylating agent, an anthracycline, a taxane, an epothilone, a histone deacetylase inhibitor, a topoisomerase I ( Topoisomerase I) Inhibitors, topoisomerase II inhibitors, nucleotide analogs, platinum agents, vinca alkaloids, and the like. Another embodiment of the invention relates to the use of a combination according to the invention for the treatment of breast cancer, in particular breast cancer with bone metastases (Amol Takalkar et al., Exp Hematol Oncol. 2014; 3: 23. "Radium-223 dichloride bone-targeted alpha particle therapy for hormone-refractory breast cancer metastatic to bone"; Suominen et al, J Natl Cancer Inst. 2013 Jun 19;105(12):908-16. "Survival benefit with radium-223 dichloride in a mouse model of breast cancer bone metastasis"). In another embodiment, the invention relates to the use of a combination of the invention for the treatment of multiple myeloma. Combinations, kits or pharmaceutical compositions of the invention can be used to inhibit, block, reduce, reduce cell proliferation and/or cell division, etc., and/or produce apoptosis. The invention includes a method comprising administering to a mammal in need thereof, including a human, an amount of a component A of the invention and a quantity of a component B of the invention, or a pharmaceutically acceptable salt, isomer thereof , polymorphs, metabolites, hydrates, solvates or esters which are effective in the treatment of diseases. Hyperproliferative diseases include, but are not limited to, psoriasis, keloids, and other proliferation affecting the skin, benign prostatic hyperplasia (BPH), and malignant neoplasms. Examples of malignant neoplasms that can be treated with a compound according to the invention include solid tumors and hematological tumors. Solid tumors can be exemplified as breast tumors, bladder tumors, osteoma, brain tumors, central and peripheral neuroma tumors, colon tumors, anal tumors, endocrine glands (such as thyroid and adrenal cortex), esophage, endometrioma, reproduction Cell tumor, head and neck tumor, renal tumor, hepatoma, tumor, laryngeal and hypopharyngeal tumor, mesothelioma, ovarian tumor, pancreatic tumor, prostate tumor, rectal tumor, renal tumor, small intestine tumor, soft tissue tumor, sputum tumor, Gastric tumors, skin tumors, ureter tumors, vagina and vulvar tumors. Malignant neoplasms include hereditary cancers such as retinoblastoma and Wilms tumor. In addition, malignant neoplasms include primary tumors of these organs and corresponding secondary tumors of distant organs ("tumor metastasis"). Hematological tumors can be exemplified as invasive and inert forms of leukemia and lymphoma, namely non-Hodgkins disease, chronic myelogenous leukemia and acute myeloid leukemia (CML/AML), acute lymphoblastoid cells. Leukemia (ALL), Hodgkin's disease, multiple myeloma, and T-cell lymphoma. Also included are myelodysplastic syndromes, plasmacytoma formation, paraneoplastic syndromes, and cancers of unknown primary sites, as well as AIDS-related malignancies. Examples of breast cancer include, but are not limited to, invasive breast ductal carcinoma, invasive lobular carcinoma, in situ breast ductal carcinoma, and lobular carcinoma in situ, particularly such breast cancers with bone metastases. Examples of respiratory cancer include, but are not limited to, small cell lung cancer and non-small cell lung cancer, as well as bronchial adenomas and pleural pulmonary blastomas. Examples of brain cancer include, but are not limited to, brain stem and hypothalamic glioma, cerebellum and cerebral astrocytoma, glioblastoma, chorioblastoma, ependymoma, and neuroectodermal and pineal tumors. . Male reproductive organ tumors include, but are not limited to, prostate and testicular cancer. Tumors of the female reproductive organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer and vulvar cancer, and uterine sarcoma. Gastrointestinal tumors include, but are not limited to, anal cancer, colon cancer, colorectal cancer, esophageal cancer, gallbladder cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer, and salivary gland cancer. Urinary tract tumors include, but are not limited to, bladder cancer, penile cancer, kidney cancer, renal pelvic cancer, ureteral cancer, urethral cancer, and human papillary renal cancer. Eye cancer includes, but is not limited to, intraocular melanoma and retinoblastoma. Examples of liver cancer include, but are not limited to, hepatocellular carcinoma (hepatocellular carcinoma with or without fibrolamellar variation), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocyte cholangiocarcinoma. Skin cancers include, but are not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, and non-melanoma skin cancer. Head and neck cancers include, but are not limited to, laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, labial and oral cancer, and squamous cell carcinoma. Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system. Sarcomas include, but are not limited to, soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma. Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia. These diseases have been well characterized in humans and are also present in similar pathogens in other mammals and can be treated by administration of the pharmaceutical compositions of the present invention. Combinations of the invention may also be used to treat diseases associated with excessive and/or abnormal angiogenesis. Improper angiogenesis and ectopic performance may be harmful to the organism. A variety of pathological conditions are associated with extra blood vessel growth. Such conditions include, for example, diabetic retinopathy, ischemic retinal vein occlusion, and retinopathy of prematurity [Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer et al. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD; see Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855], neovascular glaucoma, psoriasis, post-lens fibrous tissue hyperplasia, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, increased blood supply associated with cancerous and neoplastic tissue promotes growth, leading to rapid tumor growth and metastasis. In addition, the growth of new blood vessels and lymphatic vessels in tumors provides escape pathways to rebel cells, thereby promoting cancer metastasis and subsequent cancer spread. Thus, the combination of the invention may be used to treat and/or prevent any of the aforementioned angiogenic diseases, for example by inhibiting and/or reducing angiogenesis; by inhibiting, blocking, reducing, reducing endothelial cell proliferation or involving angiogenesis Other types, etc., as well as promoting cell death or apoptosis in such cell types.Dosage and administration Component A
Based on standard laboratory techniques known to assess compounds suitable for the treatment of hyperproliferative and angiogenic diseases, by standard toxicity testing and by standard pharmacological analysis for the treatment of conditions identified in mammals as identified above And by comparing the results to the results of known agents for treating such conditions, the effective dosage of the compounds of the invention for the treatment of various desired indications can be readily determined. The amount of active ingredient administered to treat one of these conditions can vary greatly depending on factors such as the specific components and dosage units employed, the mode of administration, the duration of treatment, the age and sex of the patient being treated And the nature and extent of the condition being treated. The total amount of active ingredient administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 50 mg/kg body weight per day. The time course of administration of a compound that is clinically applicable will range from one to three times a day to once every four weeks. In addition, the "drug holiday" (not giving the patient's medication for a certain period of time) may be beneficial to the overall balance between pharmacological effects and tolerance. A unit dose can contain from about 0.5 mg to about 1500 mg of the active ingredient and can be administered one or more times a day or less than once a day. The average daily dose administered by injection (including intravenous, intramuscular, subcutaneous and parenteral injection) and by infusion techniques is preferably from 0.01 to 200 mg per kg of total body weight. The average daily rectal administration regimen is preferably from 0.01 to 200 mg per kg of total body weight. The average daily vaginal dosing regimen is preferably from 0.01 to 200 mg per kg of total body weight. The average daily topical dosage regimen is preferably from 0.1 to 200 mg and the number of administrations per day is between one and four times. The transdermal concentration is preferably a concentration necessary to maintain a daily dose of 0.01 to 200 mg/kg. The average daily inhalation dosing regimen is preferably from 0.01 to 100 mg per kg of total body weight.Component B
A preferred dosing regimen for radium-223 injection is to give 50 kBq/kg body weight at intervals of 4 weeks in a course of treatment consisting of 6 injections. A single dose of radium-223 up to 250 kBq/kg body weight was assessed in Phase I clinical trials. The adverse reactions observed at this dose were diarrhea and reversible myelosuppression (including a grade 3 neutropenia (1/5)). As an example, an aqueous solution of radium dichloride-223 can be provided in a single dose 10 ml vial containing 6 ml of fill. This product has a radium-223 radioactivity concentration of 1,000 kBq/mL (0.03 mCi/mL), corresponding to 0.53 ng/mL radium on the reference date. Radium-223 will be administered intravenously by a professional in the form of a slow bolus injection. Radium-223 should be administered using an intravenous access line. The line must be flushed with isotonic saline before and after the injection of radium-223. Of course, the specific initial and continuous dosing regimen for each patient will be based on the nature and severity of the condition as determined by the attending physician, the activity of the particular compound employed, the age and general condition of the patient, the time of administration, the route of administration, the drug The rate of excretion, drug combinations, and the like vary. The desired mode of treatment and the number of doses of a compound of the invention or a pharmaceutically acceptable salt or ester or composition thereof can be determined by those skilled in the art using conventional therapeutic tests.Experimental part Instance 1 Compound A Radium dichloride - 223 Synergistic effect Component A :
In the experimental part and the drawings, the term "compound A" is an example of component A. Compound A is described in Example 111 of International Patent Application WO2016020320 (A1). As shown herein, Compound A is 2-[(3R)-3-methylmorpholin-4-yl]-4-(1-methyl-1H-pyrazole-5-yl)-8 having the following structure -(1H-pyrazol-5-yl)-1,7-acridine: Compound A Component B :
In this experimental section and the drawings, component B is radium dichloride-223, the synthesis of which is disclosed in WO 2000/040275, the disclosure of which is incorporated herein by reference in its entirety.Test system / In vivo model ( Applied to experiment 1 , 2 and 3 in ) :
Therapeutic effect of compound A with radium dichloride-223 (Ra-223) in osteoblasts of male NOD/Scid mice and mixed prostate cancer bone metastasis model LNCaP-luc (Minhong Zou et al., ONCOLOGY REPORTS 30) : 615-622, 2013; Multiple metastases in a novel LNCaP model of human prostate cancer). LNCaP is a DNA damage or mismatch repair gene (APCR2714C, ARID1Afs, ATG5fs, ATMA1119V/K1572N, ATRXEE2264-2265E, BRCA2fs, CHEK2T430N, ERCC3A740T; R391W, ERCC5L1023I, FANCAE369D, Q652*, HDAC2A62V, MLH3I541V, MSH3PPA66-68-; Fs, POLBfs, POLHD631G, PRKDCfs, PTENfs, RAD50fs, RAD54LL532M, RB1splice_acceptor, SLX4S605N, TDP2T308S, TP53BP1R639Q; Q111*, TRRAPR2665W; P3554L, WDR48G107*, XRCC3P87L, XRCC4L70M) and in genes or oncogenes that induce replication stress (ATRK1379N, ERBB3K177N, MYCN45S, TOP2Afs, TOP2BG323*/V889A) Androgen receptor (AR) positive CRPC cell line with several mutations/deletions (fs: frame shift; del: deletion; *: stop codon; amp: gene amplification). LNCaP cells secrete prostate specific antigen (PSA) and are known to form osteoblasts and mixed lesions upon inoculation into the medullary cavity. Therefore, this model can be effectively used to test the effect of candidate cancer drugs on the growth of prostate cancer cells in bone. In this experiment, luciferase-transfected LNCaP cell line (LNCaP-luc) has been used to allow for additional tumor growth monitoring by bioluminescence imaging (BLI) (Ruxana T. Sadikot and Timothy S. Blackwell; Proc Am Thorac Soc Vol 2. pp 537-540, 2005; Bioluminescence Imaging). Mice were 5-8 weeks old at the start of the study. On day 0, the mouse tibia was inoculated with LNCaP-luc human prostate cancer cells. The progression of osteoblastic lesions was monitored by X-ray imaging before starting the dosing and after 3 week intervals. The lesion area of the hind limb was determined from the image by the MetaMorph image analysis software (Molecular Devices LLC, Sunnyvale, CA, USA) by plotting the radiopaque area and the contour of the radiolucent area. Tumor burden was quantified by imaging bioluminescence emitted by LNCaP-luc cells. The data obtained were analyzed using Living Image® software (PerkinElmer, Waltham, MA, USA) version 4.2. The average radiance (p/s/cm2/sr) was determined from the inoculation of the tibia. Blood samples were taken every two weeks from the fourth week and radiographed every three weeks. At the fifth week, the animals were classified into treatment groups (n=10-20) according to BLI signal, PSA and radiography and administration was started. Body weight was measured twice a week. Body weight changes are a measure of treatment-related toxicity (>10%=critical, discontinuation of treatment until recovery, >20%=toxicity, termination). Animals were sacrificed six or seven weeks after the start of dosing. PSA and type I N-terminal procollagen (PINP), which are markers of tumor growth and bone formation, were measured in plasma. Human PSA ELISA analysis (R&D Systems) was used to measure PSA (Hsing AW, Chokkalingam AP. Prostate cancer epidemiology. Front Biosci. 2006; 11:1388-413; Schröder FH, Wildhagen MF. Rotterdam Study Group of the 『 European Randomised Study Of Screening for Prostate Cancer (ERSPC) Screening for prostate cancer: Evidence and perspectives. BJU Int. 2001; 88:811-7), using VICTOR2 Multilabel Counter (PerkinElmer, Waltham, MA, USA) to determine the content of PINP (N. Koopmans et al, THE JOURNAL OF UROLOGY, Vol. 178, 849-853, September 2007. Serum Bone Turnover Markers (PINP and ICTP) for the Early Detection of Bone Metastases in Patients With Prostate Cancer: A Longitudinal Approach; Windy Dean -Colomb et al; Breast Cancer Res Treat. January 2013; 137(2). Elevated serum P1NP predicts development of bone metastasis and survival in early-stage breast cancer). Statistics were achieved by using single-factor ANOVA and by means of a pairwise comparison analysis (Dunnett's test) or a student's t-test. Learning analysis.experiment 1 :
The following experimental groups were analyzed: 1) Vehicle for Ra-223: 28 mmol/L sodium citrate, 5 ml/kg, iv (= intravenous), every 4 weeks (q4w) 2) Ra-223: 300 kBq /kg, 5 ml/kg, iv, q4w 3) Compound A dose 1:20 mg/kg, 2 days administration/5 days withdrawal, po (= oral), once daily (qd) + Ra-223 Vehicle, 28 mmol/L sodium citrate, 5 mL/kg, iv, q4w 4) Compound A dose 2: 50 mg/kg, 2 days administration/5 days withdrawal, po qd+ for Ra-223 Agent, 28 mmol/L sodium citrate, 5 ml/kg, iv, q4w 5) Combination Ra-223+ Compound A Dosage 1: Ra-223 (300 kBq/kg, 5 ml/kg, iv, q4W) + compound A (20 mg/kg, 2 days administration/5 days withdrawal, po qd, starting at 4 weeks after tumor cell inoculation) 6) Combination Ra-223+ Compound A dose 2: Ra-223 (300 kBq/kg , 5 ml/kg, iv, q4W, starting at week 4 after tumor cell inoculation) + Compound A (50 mg/kg, 2 days administration/5 days withdrawal, po qd, 4 weeks after tumor cell inoculation) Start)experiment 1 Result :
Tumor growth in the vehicle-treated control group resulted in an increase in plasma PSA content, an increase in BLI signal in the bone, and an enlarged bone lesion area. However, BLI analysis revealed high bias in the vehicle-treated control group, and this parameter has been excluded from the final study analysis. The Ra-223 single agent reduced the amount of PINP in the plasma compared to the vehicle treated control. Treatment with Compound A alone did not have a significant effect on tumor burden, as analyzed by PSA or PINP. Combination therapy was significantly more effective in reducing plasma PSA (see Figure 1A) and PINP (see Figure 1B) than vehicle, Ra-223 alone, or individually tested doses of Compound A (P < 0.05). The treatment was well tolerated with no critical weight loss >10% recorded (see Figure 2). In summary, our data indicate the synergistic effect of ATR inhibitor Compound A and radium-223 in inhibiting tumor growth of the prostate cancer bone metastasis model LNCaP-luc, indicating its potential as a future treatment for CRPC patients with bone metastases. Potential. In order to evaluate the synergy between the combination of Compound A and radium dichloride-223, the expected additiveity was calculated according to the Bliss model (C=A+BA*B; where C is Drug A and Drug B (if The expected T/C of the combination of which acts in an additive manner, A is T/C of drug A, and B is T/C of drug B). It is assumed that >10% beyond the expected additive effect indicates a synergistic effect of the two drugs, assuming that the additive effect is less than 10% indicating antagonism (Bliss, CI, The toxicity of poisons applied jointly. Ann. Appl. Biol. 26, 585 -615, 1939) (See Table 1):table 1 :
Antitumor activity of Compound A and Ra-223 in LNCaP-luc human prostate cancer bone metastasis xenograft model in NOD/Scid mice
* P < 0.05 compared to vehicle control group#
P < 0.05 a) T/C = ratio of PSA content in the treated and control groups at the end of the study compared to Ra-223. b) T/C = ratio of PINP content of the treatment group to the control group at the end of the study.experiment 2 :
To evaluate the different dosing schedules of Compound A in the Ra-223 combination therapy, the following experimental groups were analyzed in Experiment 2: 1) Vehicle for Ra-223: 28 mmol/L sodium citrate, 5 ml/kg , iv (= intravenous), every 4 weeks (q4w) 2) Ra-223: 150 kBq/kg, 5 ml/kg, iv, q4w 3) Compound A: 20 mg/kg, 2 days administration/5 days Discontinuation, po (= oral), once a day (qd) 4) Combination Ra-223 (150 kBq/kg, 5 ml/kg, iv, q4w) + Compound A (20 mg/kg, 2 days administration / 5 days withdrawal, po, qd, starting with Ra-223) 5) Combination Ra-223 (150 kBq/kg, 5 ml/kg, iv, q4w) + Compound A (20 mg/kg, 2 days administration /5 days withdrawal, po, qd, starting 24 hours after Ra-223) 6) Combination Ra-223 (150 kBq/kg, 5 ml/kg, iv, q4w) + Compound A (20 mg/kg, 2 Dosing for 5 days, po, qd, starting 48 hours after Ra-223) 7) Combination Ra-223 (150 kBq/kg, 5 ml/kg, iv, q4w) + Compound A (20 mg/ Kg, 2 days administration / 26 days withdrawal, po, qd, starting 24 hours after Ra-223)experiment 2 Result :
Tumor growth in the vehicle-treated control group resulted in an increase in plasma PSA content, an increase in BLI signal in the bone, and an enlarged bone lesion area. The Ra-223 or Compound A single-agent treatment did not have a significant effect on tumor burden compared to the vehicle-treated control group, as analyzed by PSA content in plasma, BLI signal, and total bone lesion area. In the weekly cycle of Compound A for 2 days of dosing and 5 days of discontinuation, combined with Ra-223 or at the beginning of 24 h or 48 h after Ra-223, combination therapy reduced PSA content in plasma It was more effective (P < 0.05) than the vehicle control group (see Figure 3A). In the weekly cycle of Compound A for 2 days of dosing and 5 days of discontinuation, starting with Ra-223 or at 24 h after Ra-223, the total bone lesion area in combination therapy was compared to vehicle The control group was significantly reduced (see Figure 3B). The tumor burden as determined by the BLI signal in the bone was significantly reduced by the BLI signal in the bone compared to the vehicle control group (see Figure 3C). Overall, the treatment is well tolerated. No treatment-related critical weight loss (>10%) or toxicity/death record (data not shown). In summary, our data indicate that based on tumor burden (PSA, BLI) and bone lesions, Compound A begins at 24 h after the first dose of Ra-223 and is applied to the continuous weekly cycle of Compound A treatment in prostate cancer. Optimal anti-tumor activity was achieved in the Ra-223 combination therapy in the bone metastasis model LNCaP-luc. However, starting in parallel or starting at 48 h after the first dose of Ra-223 and applied to the continuous weekly cycle of Compound A treatment and Ra-223 starting 24 h after each dose, applied to the 4-week cycle Compound A treatment also showed an inhibitory effect on LNCaP-luc bone tumor growth in combination with Ra-223.table 2 :
Anti-tumor activity of different administration schedules of combination therapy of compound A and Ra-223 in LNCaP-luc human prostate cancer bone metastasis xenograft model of NOD/Scid mice
* P < 0.05 b) compared to the vehicle control group T/C = ratio of PSA content in the treated and control groups at the end of the study. b) T/C = ratio of total bone lesion area between the treatment group and the control group at the end of the study. c) T/C = ratio of BLI signal between the treatment group and the control group at the end of the study.experiment 3 :
To evaluate the different doses of Compound A in the Ra-223 combination therapy, the following experimental groups were analyzed in Experiment 3: 1) Vehicle for Ra-223: 28 mmol/L sodium citrate, 5 ml/kg, iv ( = intravenous), every 4 weeks (q4w) 2) Ra-223: 150 kBq/kg, 5 ml/kg, iv, q4w 3) Compound A: 20 mg/kg, 2 days administration, 5 days withdrawal, Po (= oral), once a day (qd) 4) Combination Ra-223 (150 kBq/kg, 5 ml/kg, iv, q4w) + Compound A (5 mg/kg, 2 days administration/5 days stop Drug, po, qd, starting 24 hours after Ra-223) 5) Combination Ra-223 (150 kBq/kg, 5 ml/kg, iv, q4w) + Compound A (10 mg/kg, 2 days administration / 5 days withdrawal, po, qd, starting 24 hours after Ra-223) 6) Combination Ra-223 (150 kBq/kg, 5 ml/kg, iv, q4w) + Compound A (20 mg/kg, 2 days) Administration 5 days off, po, qd, starting 24 hours after Ra-223) 7) Combination Ra-223 (150 kBq/kg, 5 ml/kg, iv, q4w) + Compound A (40 mg/kg) , 1 day administration / 6 days withdrawal, po, qd, starting 24 hours after Ra-223)experiment 3 Result :
Tumor growth in the vehicle-treated control group resulted in an increase in plasma PSA content, an increase in BLI signal in the bone, and an enlarged bone lesion area. Ra-223 or Compound A single-agent treatment did not have a significant effect on tumor burden compared with vehicle-treated controls, such as bone growth in plasma by analysis of PSA content in plasma, BLI signal, and total bone lesion area. The evaluation of the marker PINP revealed a decrease in the Ra-223 alone compared to the vehicle-treated control. The dose of all tested Compound A evaluated in combination with Ra-223 was significantly (P < 0.05) decreased compared to the vehicle control group for serum PSA or PINP levels, BLI signal and bone lesion area (see Table 3, Figure 4A). Figure 4D), except that Ra-223 + Compound A 5 mg/kg did not reach significance for PSA (see Figure 4A). Overall, the treatment is well tolerated. No treatment-related critical weight loss (>10%) or toxicity/death record (data not shown). In summary, our data indicate that on the basis of tumor burden (PSA, BLI), bone growth (PINP) and bone lesions, once daily, 2 days of administration and 5 days of withdrawal, the first dose in Ra-223 A dose of Compound A at a high dose of 5 mg/kg, administered after 24 h and in a continuous weekly cycle, demonstrates the antitumor activity of combination therapy in the prostate cancer bone metastasis model LNCaP-luc and improves the efficacy of individual monotherapy . Overall, the best anti-tumor activity under good tolerance was started at 24 h after the first dose of Ra-223, once daily at 20 mg/kg, 2 days for administration and 5 days for withdrawal or once daily. 40 mg/kg, 1 day dosing and 6 days discontinuation and dose of Compound A administered in a continuous weekly cycle was achieved.table 3 :
Different doses of antitumor activity of combination of Compound A and Ra-223 in LNCaP-luc human prostate cancer bone metastasis xenograft model of NOD/Scid mice
*P < 0.05 compared to vehicle control group#
P < 0.05 a) T/C = ratio of PSA content in the treated and control groups at the end of the study compared to Ra-223. b) T/C = ratio of PINP content of the treatment group to the control group at the end of the study. c) T/C = ratio of total bone lesion area between the treatment group and the control group at the end of the study. d) T/C = ratio of BLI signal between treatment group and control group at the end of the study.