TW202321261A - Selective kras inhibitors - Google Patents

Selective kras inhibitors Download PDF

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TW202321261A
TW202321261A TW111129927A TW111129927A TW202321261A TW 202321261 A TW202321261 A TW 202321261A TW 111129927 A TW111129927 A TW 111129927A TW 111129927 A TW111129927 A TW 111129927A TW 202321261 A TW202321261 A TW 202321261A
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carcinoma
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fluoro
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TW111129927A
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恒淼 程
尚米榭 凡尼爾
璞慧 李
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美商伊瑞斯卡公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The present embodiments provide compounds of Formula I, compositions of the compounds, and methods for treating diseases such as cancer.

Description

選擇性ＫＲＡＳ抑制劑Selective KRAS inhibitors

本文之實施例係關於用於治療RAS介導之疾病的化合物、組合物及方法。具體而言，本文之實施例係關於經由靶向K-RAS同功型之致癌突變體來治療諸如癌症之疾病的化合物及方法。The embodiments herein relate to compounds, compositions and methods for the treatment of RAS-mediated diseases. In particular, the embodiments herein relate to compounds and methods for treating diseases such as cancer by targeting oncogenic mutants of K-RAS isoforms.

Ras蛋白為小的鳥嘌呤核苷酸結合蛋白，藉由在活性GTP結合構形與非活性GDP結合構形之間循環來充當分子開關。Ras信號傳導經由鳥嘌呤核苷酸交換因子(GEF) (最常見為非七激酶子(son of sevenless，SOS))活化與GTP酶活化蛋白(GAP) (諸如神經纖維瘤蛋白或p120GAP)失活之間的平衡來調節。Ras蛋白在細胞增殖、分化及存活之調節中起重要作用。Ras信號傳導路徑之失調幾乎總與疾病相關。Ras中之過度活化體細胞突變係人類癌症中最常見之病變之一。大多數此等突變已被證明會降低Ras對GAP刺激之敏感性且降低其內在GTP酶活性，從而導致活性GTP結合群體增加。儘管三種Ras同功型(K-Ras、N-Ras或H-Ras)中任一者之突變已被證明會導致致癌轉型，但迄今為止，K-Ras突變在人類癌症中最為常見。例如，已知K-Ras突變通常與胰臟癌、結直腸癌及非小細胞肺癌有關。同樣，H-Ras突變在諸如甲狀腺乳頭狀癌、肺癌及皮膚癌之癌症中亦為常見的。最後，N-Ras突變常常在肝細胞癌中發生。Ras proteins are small guanine nucleotide binding proteins that act as molecular switches by cycling between an active GTP-bound and an inactive GDP-bound conformation. Ras signaling is activated via guanine nucleotide exchange factors (GEFs) (most commonly son of sevenless (SOS)) and inactivated by GTPase activating proteins (GAPs) such as neurofibromin or p120GAP to adjust the balance between them. Ras proteins play an important role in the regulation of cell proliferation, differentiation and survival. Dysregulation of the Ras signaling pathway is almost always associated with disease. Hyperactivating somatic mutations in Ras are one of the most common lesions in human cancers. Most of these mutations have been shown to reduce the sensitivity of Ras to GAP stimulation and reduce its intrinsic GTPase activity, resulting in an increase in the active GTP-bound population. Although mutations in any of the three Ras isoforms (K-Ras, N-Ras or H-Ras) have been shown to result in oncogenic transformation, K-Ras mutations are by far the most common in human cancers. For example, K-Ras mutations are known to be commonly associated with pancreatic cancer, colorectal cancer, and non-small cell lung cancer. Also, H-Ras mutations are common in cancers such as papillary thyroid, lung and skin cancers. Finally, N-Ras mutations frequently occur in HCC.

K-Ras為人類癌症中之最頻繁突變之致癌蛋白，且G12D突變為最普遍之突變之一。因此，需要開發KRAS G12D選擇性抑制劑。本發明之實施例滿足此需求及其他需求。K-Ras is the most frequently mutated oncoprotein in human cancers, and the G12D mutation is one of the most prevalent. Therefore, there is a need to develop selective inhibitors of KRAS G12D. Embodiments of the present invention meet this need and other needs.

在一個態樣中，本發明之實施例提供式(I)化合物：

Figure 02_image001
或其立體異構物、互變異構物、醫藥學上可接受之鹽，其中： 環A係選自
Figure 02_image003
、
Figure 02_image005
、
Figure 02_image007
、
Figure 02_image009
、
Figure 02_image011
、
Figure 02_image013
及
Figure 02_image015
； W為O、NR 3、S或不存在； X為CR 1或N； Y為CR 1或N； Z 1為O、N(C 1-C 4烷基)、NH或S； 各Z 2獨立地為CH或N； L為C 1-3烷基或不存在； 各R 1獨立地為H、鹵基、C 1-6烷基或C 3-6環烷基； R 2為4-10員雜環基、3-10員環烷基、6-10員芳基或5-10員雜芳基，其中該雜環基、環烷基、芳基及雜芳基視情況經OH、鹵基、CN、CF 3、C 1-4烷基、C 1-4烷氧基及C 1-3烷基-OH取代； R 3為H或C 1-4烷基； 各R 4獨立地選自-OH、鹵基、C 1-3烷基、C 2-C 4炔基、C 1-3鹵烷基、-CN、-NH 2；且 n為0、1、2、3或4。 In one aspect, embodiments of the invention provide compounds of formula (I):
Figure 02_image001
Or its stereoisomer, tautomer, pharmaceutically acceptable salt, wherein: Ring A is selected from
Figure 02_image003
,
Figure 02_image005
,
Figure 02_image007
,
Figure 02_image009
,
Figure 02_image011
,
Figure 02_image013
and
Figure 02_image015
; W is O, NR 3 , S or absent; X is CR 1 or N; Y is CR 1 or N; Z 1 is O, N(C 1 -C 4 alkyl), NH or S; each Z 2 is independently CH or N; L is C 1-3 alkyl or does not exist; each R 1 is independently H, halo, C 1-6 alkyl or C 3-6 cycloalkyl; R 2 is 4- 10-membered heterocyclic group, 3-10-membered cycloalkyl group, 6-10-membered aryl group or 5-10-membered heteroaryl group, wherein the heterocyclic group, cycloalkyl group, aryl group and heteroaryl group are optionally modified by OH, Halo, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy and C 1-3 alkyl-OH substitution; R 3 is H or C 1-4 alkyl; each R 4 is independently selected from -OH, halo, C 1-3 alkyl, C 2 -C 4 alkynyl, C 1-3 haloalkyl, -CN, -NH 2 ; and n is 0, 1, 2, 3 or 4 .

在一實施例中，當X為式(I)之N時，環A不為

Figure 02_image009
。 In one embodiment, when X is N of formula (I), ring A is not
Figure 02_image009
.

在一實施例中，本申請案提供式(Ia)化合物：

Figure 02_image017
或其立體異構物、互變異構物、醫藥學上可接受之鹽。 In one embodiment, the application provides a compound of formula (Ia):
Figure 02_image017
Or its stereoisomer, tautomer, pharmaceutically acceptable salt.

在一實施例中，本申請案提供式(Ib)化合物：

Figure 02_image019
或其立體異構物、互變異構物、醫藥學上可接受之鹽。 In one embodiment, the application provides a compound of formula (Ib):
Figure 02_image019
Or its stereoisomer, tautomer, pharmaceutically acceptable salt.

在一實施例中，本申請案提供式(Ic)化合物：

Figure 02_image021
或其立體異構物、互變異構物、醫藥學上可接受之鹽。 In one embodiment, the application provides a compound of formula (Ic):
Figure 02_image021
Or its stereoisomer, tautomer, pharmaceutically acceptable salt.

在一實施例中，本申請案提供式(Id)化合物：

Figure 02_image023
或其立體異構物、互變異構物、醫藥學上可接受之鹽。 In one embodiment, the application provides a compound of formula (Id):
Figure 02_image023
Or its stereoisomer, tautomer, pharmaceutically acceptable salt.

在一實施例中，本申請案提供式(Ie)化合物：

Figure 02_image025
或其立體異構物、互變異構物、醫藥學上可接受之鹽。 In one embodiment, the application provides a compound of formula (Ie):
Figure 02_image025
Or its stereoisomer, tautomer, pharmaceutically acceptable salt.

在一實施例中，本申請案提供式(If)化合物：

Figure 02_image027
或立體異構物、互變異構物或其醫藥學上可接受之鹽。 In one embodiment, the application provides a compound of formula (If):
Figure 02_image027
Or stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

在另一態樣中，本發明之實施例提供一種醫藥組合物，其包含醫藥學上有效量之本文揭示之化合物或其醫藥學上可接受之鹽，及醫藥學上可接受之賦形劑。In another aspect, the embodiments of the present invention provide a pharmaceutical composition comprising a pharmaceutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient .

在另一實施例中，本發明之實施例提供一種治療患有癌症之個體的方法，該癌症之特徵在於存在KRAS G12D突變，該方法包括向該個體投與治療有效量之本文揭示之化合物或其醫藥學上可接受之鹽，或如本文揭示之醫藥組合物。In another embodiment, embodiments of the present invention provide a method of treating an individual with cancer characterized by the presence of a KRAS G12D mutation comprising administering to the individual a therapeutically effective amount of a compound disclosed herein or A pharmaceutically acceptable salt thereof, or a pharmaceutical composition as disclosed herein.

在另一實施例中，本發明之實施例提供一種用於製造供治療患有癌症之個體用之藥物的方法，該癌症之特徵在於存在KRAS G12D突變，使用包含本文揭示之化合物或其醫藥學上可接受之鹽或如本文揭示之醫藥組合物的該藥物。In another embodiment, embodiments of the present invention provide a method for the manufacture of a medicament for the treatment of an individual having a cancer characterized by the presence of a KRAS G12D mutation using a compound comprising a compound disclosed herein or a pharmaceutical product thereof The above acceptable salt or the drug of the pharmaceutical composition as disclosed herein.

在另一實施例中，本發明之實施例提供本文揭示之化合物或其醫藥學上可接受之鹽或如本文揭示之醫藥組合物的用途，其用於製造供治療個體之癌症用之藥物，該癌症之特徵在於存在KRAS G12D突變。In another embodiment, embodiments of the present invention provide the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as disclosed herein, for the manufacture of a medicament for treating cancer in an individual, The cancer is characterized by the presence of the KRAS G12D mutation.

在另一實施例中，本發明之實施例提供本文揭示之化合物或其醫藥學上可接受之鹽或如本文揭示之醫藥組合物，其用於治療個體之癌症，該癌症之特徵在於KRAS G12D突變。In another embodiment, embodiments of the present invention provide a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as disclosed herein, for use in the treatment of a cancer in a subject characterized by KRAS G12D mutation.

I.I. 總則General

本發明之實施例提供展現相對於野生型KRAS之良好選擇性且可用於治療特徵在於KRAS G12D突變之癌症的KRAS G12D抑制劑。 II. 定義 Embodiments of the present invention provide KRAS G12D inhibitors that exhibit good selectivity over wild-type KRAS and are useful in the treatment of cancers characterized by KRAS G12D mutations. II. Definition

除非另外具體指示，否則本文中使用之所有技術及科學術語具有與熟習實施例所屬領域技術者通常理解之含義相同的含義。另外，與本文所述之方法或材料類似或等效之任何方法或材料可用於實踐本發明之實施例。出於本發明之實施例之目的，定義以下術語。Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the embodiments belong. In addition, any methods or materials similar or equivalent to those described herein can be used in the practice of embodiments of the invention. For the purposes of the embodiments of the present invention, the following terms are defined.

如本文所用之「一(個/種)(a/an)」或「該(the)」不僅包括具有一個成員之態樣，而且包括具有超過一個成員之態樣。例如，單數形式「一(個/種)(a/an)」及「該(the)」包括複數個指示物，除非上下文另有明確規定。因此，例如，提及「細胞」包括複數個此類細胞且提及「該試劑」包括提及熟習此項技術者已知之一或多種試劑，諸如此類。As used herein, "a/an" or "the" includes not only aspects having one member, but also aspects having more than one member. For example, the singular forms "a (a/an)" and "the" include plural referents unless the context clearly requires otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells and reference to "the agent" includes reference to one or more agents known to those skilled in the art, and so on.

「烷基」係指具有所指示碳原子數目之直鏈或支鏈、飽和、脂族基團。烷基可包括任何數目之碳，諸如C 1-2、C 1-3、C 1-4、C 1-5、C 1-6、C 1-7、C 1-8、C 1-9、C 1-10、C 2-3、C 2-4、C 2-5、C 2-6、C 3-4、C 3-5、C 3-6、C 4-5、C 4-6及 C 5-6。例如，C 1-6烷基包括但不限於甲基、乙基、丙基、異丙基、丁基、異丁基、第二丁基、第三丁基、戊基、異戊基、己基等。烷基亦可指具有多達20個碳原子之烷基，諸如但不限於庚基、辛基、壬基、癸基等。烷基可經取代或未經取代。 "Alkyl" means a straight or branched chain, saturated, aliphatic group having the indicated number of carbon atoms. Alkyl groups may include any number of carbons, such as C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 . For example, C 1-6 alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, second butyl, third butyl, pentyl, isopentyl, hexyl wait. Alkyl may also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, and the like. Alkyl groups can be substituted or unsubstituted.

「伸烷基」係指具有所指示碳原子數目且連接至少兩個其他基團之直鏈或支鏈、飽和、脂族基團，亦即，二價烴基。連接至伸烷基之兩個部分可連接至伸烷基之同一原子或不同原子。例如，直鏈伸烷基可為-(CH 2) n-之二價基團，其中n為1、2、3、4、5或6。代表性伸烷基包括但不限於亞甲基、伸乙基、伸丙基、伸異丙基、伸丁基、伸異丁基、伸第二丁基、伸戊基及伸己基。伸烷基可經取代或未經取代。 "Alkylene" refers to a straight or branched chain, saturated, aliphatic group having the indicated number of carbon atoms and linked to at least two other groups, ie, a divalent hydrocarbon group. The two moieties attached to the alkylene group may be attached to the same atom or different atoms of the alkylene group. For example, the linear alkylene group can be a divalent group of -(CH 2 ) n -, wherein n is 1, 2, 3, 4, 5 or 6. Representative alkylene groups include, but are not limited to, methylene, ethylidene, propylidene, isopropylidene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. Alkylene groups can be substituted or unsubstituted.

「烯基」係指具有至少2個碳原子及至少一個雙鍵之直鏈或支鏈烴。烯基可包括任何數目之碳，諸如C 2、C 2-3、C 2-4、C 2-5、C 2-6、C 2-7、C 2-8、C 2-9、C 2-10、C 3、C 3-4、C 3-5、C 3-6、C 4、C 4-5、C 4-6、C 5、C 5-6及C 6。烯基可具有任何合適數目之雙鍵，包括但不限於1個、2個、3個、4個、5個或更多個。烯基之實例包括但不限於乙烯基(乙烯基)、丙烯基、異丙烯基、1-丁烯基、2-丁烯基、異丁烯基、丁二烯基、1-戊烯基、2-戊烯基、異戊烯基、1,3-戊二烯基、1,4-戊二烯基、1-己烯基、2-己烯基、3-己烯基、1,3-己二烯基、1,4-己二烯基、1,5-己二烯基、2,4-己二烯基或1,3,5-己三烯基。烯基可經取代或未經取代。 "Alkenyl" means a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl can include any number of carbons, such as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2 -10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 and C 6 . An alkenyl group can have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-butenyl, Pentenyl, Prenyl, 1,3-Pentadienyl, 1,4-Pentadienyl, 1-Hexenyl, 2-Hexenyl, 3-Hexenyl, 1,3-Hexyl Dienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.

「伸烯基」係指連接至少兩個其他基團之如上文定義之烯基，亦即，二價烴基。連接至伸烯基之兩個部分可連接至伸烯基之同一原子或不同原子。伸烯基包括但不限於伸乙烯基、伸丙烯基、伸異丙烯基、伸丁烯基、伸異丁烯基、伸第二丁烯基、伸戊烯基及伸己烯基。伸烯基可經取代或未經取代。"Alkenylene" means an alkenyl group as defined above linked to at least two other groups, ie, a divalent hydrocarbon group. The two moieties attached to the alkenylene group can be attached to the same atom or different atoms of the alkenylene group. Alkenylene groups include, but are not limited to, ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, sec-butenyl, pentenyl, and hexenyl. Alkenylene groups can be substituted or unsubstituted.

「炔基」係指具有至少2個碳原子及至少一個參鍵之直鏈或支鏈烴。炔基可包括任何數目之碳，諸如C 2、C 2-3、C 2-4、C 2-5、C 2-6、C 2-7、C 2-8、C 2-9、C 2-10、C 3、C 3-4、C 3-5、C 3-6、C 4、C 4-5、C 4-6、C 5、C 5-6及C 6。炔基之實例包括但不限於乙炔基、丙炔基、1-丁炔基、2-丁炔基、丁二炔基、1-戊炔基、2-戊炔基、異戊炔基、1,3-戊二炔基、1,4-戊二炔基、1-己炔基、2-己炔基、3-己炔基、1,3-己二炔基、1,4-己二炔基、1,5-己二炔基、2,4-己二炔基或1,3,5-己三炔基。炔基可經取代或未經取代。 "Alkynyl" means a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one bond. Alkynyl groups may include any number of carbons, such as C 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2 -10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 and C 6 . Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1 ,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexanedi Alkynyl, 1,5-hexadiynyl, 2,4-hexadiynyl or 1,3,5-hexatriynyl. Alkynyl groups can be substituted or unsubstituted.

「伸炔基」係指連接至少兩個其他基團之如上文定義之炔基，亦即，二價烴基。連接至伸炔基之兩個部分可連接至伸炔基之同一原子或不同原子。伸炔基包括但不限於伸乙炔基、伸丙炔基、伸異丙炔基、伸丁炔基、伸第二丁炔基、伸戊炔基及伸己炔基。伸炔基可經取代或未經取代。"Alkynylene" means an alkynyl group as defined above linked to at least two other groups, ie, a divalent hydrocarbon group. The two moieties attached to the alkynylene group can be attached to the same atom or different atoms of the alkynylene group. Alkynyl groups include, but are not limited to, ethynyl, propynyl, isopropynyl, butynyl, second butynyl, pentynyl, and hexynyl. Alkynylene groups can be substituted or unsubstituted.

「烷氧基」係指具有將烷基連接至附接點之氧原子之烷基：烷基-O-。如同烷基，烷氧基可具有任何合適數目之碳原子，諸如C 1-6。烷氧基包括例如甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、2-丁氧基、異丁氧基、第二丁氧基、第三丁氧基、戊氧基、己氧基等。烷氧基可進一步經其中描述之各種取代基取代。烷氧基可經取代或未經取代。 "Alkoxy" means an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. Like alkyl, alkoxy may have any suitable number of carbon atoms, such as C 1-6 . Alkoxy includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, Oxygen, Hexyloxy, etc. The alkoxy group may be further substituted with various substituents described therein. Alkoxy groups can be substituted or unsubstituted.

「烷氧基烷基」係指具有烷基組分及烷氧基組分之基團，其中烷基組分將烷氧基組分連接至附接點。烷基組分如上文定義，只是該烷基組分為至少二價，為伸烷基，連接至烷氧基組分且連接至附接點。烷基組分可包括任何數目之碳，諸如C 0-6、C 1-2、C 1-3、C 1-4、C 1-5、C 1-6、C 2-3、C 2-4、C 2-5、C 2-6、C 3-4、C 3-5、C 3-6、C 4-5、C 4-6及C 5-6。烷氧基組分如上文定義。烷氧基烷基之實例包括但不限於2-乙氧基-乙基及甲氧基甲基。 "Alkoxyalkyl" means a group having an alkyl component and an alkoxy component, wherein the alkyl component links the alkoxy component to the point of attachment. The alkyl component is as defined above except that the alkyl component is at least divalent, is an alkylene group, is attached to the alkoxy component and is attached to the point of attachment. The alkyl component may include any number of carbons, such as C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2- 4. C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 . The alkoxy component is as defined above. Examples of alkoxyalkyl include, but are not limited to, 2-ethoxy-ethyl and methoxymethyl.

「烷基羥基」或「羥基烷基」係指如上文定義之烷基，其中氫原子中之至少一者經羥基置換。如同烷基，烷基羥基可具有任何合適數目之碳原子，諸如C 1-6。示例性烷基羥基包括但不限於羥基-甲基、羥基乙基(其中羥基在1-位置或2-位置)、羥基丙基(其中羥基在1-位置、2-位置或3-位置)、羥基丁基(其中羥基在1-位置、2-位置、3-位置或4-位置)、羥基戊基(其中羥基在1-位置、2-位置、3-位置、4-位置或5-位置)、羥基己基(其中羥基在1-位置、2-位置、3-位置、4-位置、5-位置或6-位置)、1,2-二羥基乙基及其類似基團。 "Alkylhydroxy" or "hydroxyalkyl" refers to an alkyl group as defined above wherein at least one of the hydrogen atoms is replaced by a hydroxy group. Like an alkyl group, an alkylhydroxy group can have any suitable number of carbon atoms, such as C 1-6 . Exemplary alkylhydroxyl groups include, but are not limited to, hydroxy-methyl, hydroxyethyl (wherein the hydroxyl is at the 1-position or 2-position), hydroxypropyl (wherein the hydroxyl is at the 1-position, 2-position, or 3-position), Hydroxybutyl (wherein the hydroxyl is at the 1-position, 2-position, 3-position or 4-position), hydroxypentyl (wherein the hydroxyl is at the 1-position, 2-position, 3-position, 4-position or 5-position ), hydroxyhexyl (wherein the hydroxyl group is at the 1-position, 2-position, 3-position, 4-position, 5-position or 6-position), 1,2-dihydroxyethyl and the like.

「鹵素」或「鹵基」係指氟、氯、溴及碘。"Halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.

「鹵烷基」係指如上文定義之烷基，其中一些或所有氫原子經鹵素原子置換。如同烷基，鹵烷基可具有任何合適數目之碳原子，諸如C 1-6。例如，鹵烷基包括三氟甲基、氟甲基等。在一些情況下，術語「全氟」可用於定義其中所有氫經氟置換之化合物或基團。例如，全氟甲基係指1,1,1-三氟甲基。 "Haloalkyl" means an alkyl group as defined above in which some or all of the hydrogen atoms are replaced by halogen atoms. Like alkyl groups, haloalkyl groups can have any suitable number of carbon atoms, such as C 1-6 . For example, haloalkyl includes trifluoromethyl, fluoromethyl, and the like. In some instances, the term "perfluoro" may be used to define a compound or group in which all hydrogens are replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

「鹵烷氧基」係指其中一些或所有氫原子經鹵素原子取代之烷氧基。如同烷基，鹵烷氧基可具有任何合適數目之碳原子，諸如C 1-6。烷氧基可經1個、2個、3個或更多個鹵素取代。當所有氫經例如氟之鹵素置換時，化合物經全取代，例如，全氟化。鹵烷氧基包括但不限於三氟甲氧基、2,2,2,-三氟乙氧基、全氟乙氧基等。 "Haloalkoxy" means an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. Like alkyl, haloalkoxy may have any suitable number of carbon atoms, such as C 1-6 . Alkoxy may be substituted with 1, 2, 3 or more halogens. A compound is fully substituted, eg, perfluorinated, when all hydrogens are replaced with a halogen such as fluorine. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, and the like.

「環烷基」係指飽和或部分不飽和、單環、稠合雙環或橋接多環組合，其含有3至12個環原子或所指示原子數目。環烷基可包括任何數目之碳，諸如C 3-6、 C 4-6、C 5-6、C 3-8、C 4-8、C 5-8、C 6-8、C 3-9、C 3-10、C 3-11及C 3-12。飽和單環環烷基環包括例如環丙基、環丁基、環戊基、環己基及環辛基。飽和雙環及多環環烷基環包括例如降莰烷、[2.2.2]雙環辛烷、十氫化萘及金剛烷。環烷基亦可部分不飽和，在環中具有一或多個雙鍵或參鍵。代表性部分不飽和環烷基包括但不限於環丁烯、環戊烯、環己烯、環己二烯(1,3-異構物及1,4-異構物)、環庚烯、環庚二烯、環辛烯、環辛二烯(1,3-異構物、1,4-異構物及1,5-異構物)、降莰烯及降莰二烯。當環烷基為飽和單環C 3-8環烷基時，示例性基團包括但不限於環丙基、環丁基、環戊基、環己基、環庚基及環辛基。當環烷基為飽和單環C 3-6環烷基時，示例性基團包括但不限於環丙基、環丁基、環戊基及環己基。環烷基可經取代或未經取代。 "Cycloalkyl" means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic combination containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 and C 3-12 . Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds in the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, Cycloheptadiene, cyclooctene, cyclooctadiene (1,3-isomer, 1,4-isomer and 1,5-isomer), norcamphene and norcamphene. When the cycloalkyl is a saturated monocyclic C 3-8 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When the cycloalkyl is a saturated monocyclic C 3-6 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.

「伸環烷基」係指具有所指示碳原子數目且連接至少兩個其他基團之環烷基，亦即，二價基團。連接至伸環烷基之兩個部分可連接至伸環烷基之同一原子或不同原子。伸環烷基環之實例尤其包括伸環丙基、伸環丁基、伸環戊基及伸環己基。伸環烷基可1,1、1,2、1,3或1,4連接。伸環己基環例如可採用許多構形，包括舟式及椅式構形。伸環己基之椅式構形可在軸向或赤道取向中具有取代基。伸環烷基之二價性質引起順式及反式結構，其中順式係指兩個取代基在伸環烷基環之同一側(頂部或底部)，且其中反式係指該等取代基在伸環烷基環之相對側。例如，順式-1,2-伸環己基及順式-1,4-伸環己基可在軸向取向中具有一個取代基且在赤道取向中具有另一個取代基，而反式-1,2-伸環己基及反式-1,4-伸環己基在軸向或赤道取向中具有兩個取代基。順式-1,3-伸環己基在軸向或赤道取向中具有兩個取代基，且反式-1,3-伸環己基可在軸向取向中具有一個取代基且在赤道取向中具有另一個取代基。伸環烷基可經取代或未經取代。"Cycloalkylene" refers to a cycloalkyl group having the indicated number of carbon atoms to which at least two other groups are attached, ie, a divalent group. The two moieties attached to the cycloalkylene can be attached to the same atom or different atoms of the cycloalkylene. Examples of cycloalkylene rings include, inter alia, cyclopropyl, cyclobutylene, cyclopentylene and cyclohexylene. Cycloalkylene groups can be linked 1,1, 1,2, 1,3 or 1,4. The cyclohexylene ring, for example, can adopt a number of configurations, including boat and chair configurations. The chair configuration of the cyclohexylene group may have substituents in the axial or equatorial orientation. The divalent nature of the cycloalkylene gives rise to cis and trans structures, where cis means the two substituents are on the same side (top or bottom) of the cycloalkylene ring, and where trans means the substituents are on opposite sides of the cycloalkylene ring. For example, cis-1,2-cyclohexylene and cis-1,4-cyclohexylene can have one substituent in the axial orientation and the other in the equatorial orientation, while trans-1, 2-cyclohexylene and trans-1,4-cyclohexylene have two substituents in the axial direction or equatorial orientation. cis-1,3-cyclohexylene has two substituents in axial or equatorial orientation, and trans-1,3-cyclohexylene can have one substituent in axial orientation and equatorial orientation Another substituent. Cycloalkylene groups can be substituted or unsubstituted.

「烷基-環烷基」係指具有烷基組分及環烷基組分之基團，其中烷基組分將環烷基組分連接至附接點。烷基組分如上文定義，只是該烷基組分為至少二價，為伸烷基，連接至環烷基組分且連接至附接點。在一些情況下，烷基組分可不存在。烷基組分可包括任何數目之碳，諸如C 1-6、C 1-2、C 1-3、C 1-4、C 1-5、C 2-3、C 2-4、C 2-5、C 2-6、C 3-4、C 3-5、C 3-6、C 4-5、C 4-6及C 5-6。環烷基組分如其中定義。示例性烷基-環烷基包括但不限於甲基-環丙基、甲基-環丁基、甲基-環戊基及甲基-環己基。 "Alkyl-cycloalkyl" means a group having an alkyl component and a cycloalkyl component, wherein the alkyl component links the cycloalkyl component to a point of attachment. The alkyl component is as defined above except that the alkyl component is at least divalent, is an alkylene, is attached to the cycloalkyl component and is attached to the point of attachment. In some cases, the alkyl component may be absent. The alkyl component may include any number of carbons, such as C 1-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-3 , C 2-4 , C 2- 5. C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 . The cycloalkyl component is as defined therein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

「雜環烷基」或「雜環基」係指具有3至12個環成員及1至4個N、O及S之雜原子之飽和環系統。額外雜原子亦可有用，包括但不限於B、Al、Si及P。雜原子亦可氧化，諸如但不限於-S(O)-及-S(O) 2-。雜環烷基可包括任何數目之環原子，諸如3至6個、4至6個、5至6個、3至8個、4至8個、5至8個、6至8個、3至9個、3至10個、3至11個或3至12個環成員。任何合適數目之雜原子可包括於雜環烷基中，諸如1、2、3或4個、或1至2個、1至3個、1至4個、2至3個、2至4個、或3至4個。雜環烷基可包括諸如氮雜環丙烷、氮雜環丁烷、吡咯啶、哌啶、氮呯、氮雜環辛烷、奎寧環、吡唑啶、咪唑啶、哌嗪(1,2-異構物、1,3-異構物及1,4-異構物)、環氧乙烷、氧雜環丁烷、四氫呋喃、噁烷(四氫哌喃)、環氧己烷、環硫乙烷、硫雜環丁烷、硫雜環戊烷(四氫噻吩)、噻烷(四氫噻喃)、噁唑啶、異噁唑啶、噻唑啶、異噻唑啶、二氧雜環戊烷、二硫雜環戊烷、嗎啉、硫嗎啉、二噁烷、二噻烷及六氫-1H-吡咯嗪之基團。雜環烷基亦可與芳族或非芳族環系統稠合以形成包括但不限於吲哚啉之成員。雜環烷基可未經取代或經取代。例如，雜環烷基可經C 1-6烷基或側氧基(=O)以及許多其他基團取代。 "Heterocycloalkyl" or "heterocyclyl" refers to a saturated ring system having 3 to 12 ring members and 1 to 4 N, O and S heteroatoms. Additional heteroatoms may also be useful, including but not limited to B, Al, Si, and P. Heteroatoms can also be oxidized, such as but not limited to -S(O)- and -S(O) 2- . The heterocycloalkyl group may comprise any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11 or 3 to 12 ring members. Any suitable number of heteroatoms may be included in the heterocycloalkyl, such as 1, 2, 3 or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4 , or 3 to 4. Heterocycloalkyl groups may include examples such as aziridine, azetidine, pyrrolidine, piperidine, nitrogen, azacyclooctane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2 -isomers, 1,3-isomers and 1,4-isomers), ethylene oxide, oxetane, tetrahydrofuran, oxane (tetrahydropyran), hexane oxide, cyclo Thiolane, Thietane, Thiolane (Tetrahydrothiophene), Thiane (Tetrahydrothiopyran), Oxazolidine, Isoxazolidine, Thiazolidine, Isothiazolidine, Dioxane Groups of pentane, dithiolane, morpholine, thiomorpholine, dioxane, dithiane and hexahydro-1H-pyrrolazine. Heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indolines. A heterocycloalkyl group can be unsubstituted or substituted. For example, a heterocycloalkyl group can be substituted with C 1-6 alkyl or pendant oxy (=O), among many others.

雜環烷基可經由環上之任何位置來連接。例如，氮雜環丙烷可為1-氮雜環丙烷或2-氮雜環丙烷，氮雜環丁烷可為1-氮雜環丁烷或2-氮雜環丁烷，吡咯啶可為1-吡咯啶、2-吡咯啶或3-吡咯啶，哌啶可為1-哌啶、2-哌啶、3-哌啶或4-哌啶，吡唑啶可為1-吡唑啶、2-吡唑啶、3-吡唑啶或4-吡唑啶，咪唑啶可為1-咪唑啶、2-咪唑啶、3-咪唑啶或4-咪唑啶，哌嗪可為1-哌嗪、2-哌嗪、3-哌嗪或4-哌嗪，四氫呋喃可為1-四氫呋喃或2-四氫呋喃，噁唑啶可為2-噁唑啶、3-噁唑啶、4-噁唑啶或5-噁唑啶，異噁唑啶可為2-異噁唑啶、3-異噁唑啶、4-異噁唑啶或5-異噁唑啶，噻唑啶可為2-噻唑啶、3-噻唑啶、4-噻唑啶或5-噻唑啶，異噻唑啶可為2-異噻唑啶、3-異噻唑啶、4-異噻唑啶或5-異噻唑啶，且嗎啉可為2-嗎啉、3-嗎啉或4-嗎啉。A heterocycloalkyl group can be attached via any position on the ring. For example, aziridine can be 1-aziridine or 2-azetidine, azetidine can be 1-azetidine or 2-azetidine, and pyrrolidine can be 1 -pyrrolidine, 2-pyrrolidine or 3-pyrrolidine, piperidine can be 1-piperidine, 2-piperidine, 3-piperidine or 4-piperidine, pyrazolidine can be 1-pyrazolidine, 2 -pyrazolidine, 3-pyrazolidine or 4-pyrazolidine, imidazolidine can be 1-imidazolidine, 2-imidazolidine, 3-imidazolidine or 4-imidazolidine, piperazine can be 1-piperazine, 2-piperazine, 3-piperazine or 4-piperazine, tetrahydrofuran can be 1-tetrahydrofuran or 2-tetrahydrofuran, oxazolidine can be 2-oxazolidine, 3-oxazolidine, 4-oxazolidine or 5 -oxazolidine, isoxazolidine can be 2-isoxazolidine, 3-isoxazolidine, 4-isoxazolidine or 5-isoxazolidine, thiazolidine can be 2-thiazolidine, 3- Thiazolidine, 4-thiazolidine or 5-thiazolidine, isothiazolidine can be 2-isothiazolidine, 3-isothiazolidine, 4-isothiazolidine or 5-isothiazolidine, and morpholine can be 2- morpholine, 3-morpholine or 4-morpholine.

當雜環烷基包括3至8個環成員及1至3個雜原子時，代表性成員包括但不限於吡咯啶、哌啶、四氫呋喃、噁烷、四氫噻吩、噻烷、吡唑啶、咪唑啶、哌嗪、噁唑啶、異噁唑啶、噻唑啶、異噻唑啶、嗎啉、硫嗎啉、二噁烷及二噻烷。雜環烷基亦可形成具有5至6個環成員及1至2個雜原子之環，代表性成員包括但不限於吡咯啶、哌啶、四氫呋喃、四氫噻吩、吡唑啶、咪唑啶、哌嗪、噁唑啶、異噁唑啶、噻唑啶、異噻唑啶、嗎啉及六氫-1H-吡咯嗪。When the heterocycloalkyl group includes 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazolidine, Imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane and dithiane. Heterocycloalkyl groups can also form rings having 5 to 6 ring members and 1 to 2 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperidine, tetrahydrofuran, tetrahydrothiophene, pyrazolidine, imidazolidine, Piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine and hexahydro-1H-pyrrolizine.

「伸雜環烷基」係指連接至少兩個其他基團之如上文定義之雜環烷基。連接至伸雜環烷基之兩個部分可連接至伸雜環烷基之同一原子或不同原子。伸雜環烷基可經取代或未經取代。"Heterocycloalkylene" means a heterocycloalkyl group as defined above linked to at least two other groups. The two moieties attached to the heterocycloalkylene can be attached to the same atom or different atoms of the heterocycloalkylene. A heterocycloalkylene group can be substituted or unsubstituted.

「烷基-雜環烷基」係指具有烷基組分及雜環烷基組分之基團，其中烷基組分將雜環烷基組分連接至附接點。烷基組分如上文定義，只是該烷基組分為至少二價，為伸烷基，連接至雜環烷基組分且連接至附接點。烷基組分可包括任何數目之碳，諸如C 0-6、C 1-2、C 1-3、C 1-4、C 1-5、C 1-6、C 2-3、C 2-4、C 2-5、C 2-6、C 3-4、C 3-5、C 3-6、C 4-5、C 4-6及C 5-6。在一些情況下，烷基組分可不存在。雜環烷基組分如上文定義。烷基-雜環烷基可經取代或未經取代。 "Alkyl-heterocycloalkyl" means a group having an alkyl component and a heterocycloalkyl component, wherein the alkyl component links the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above except that the alkyl component is at least divalent, is an alkylene, is attached to the heterocycloalkyl component and is attached to the point of attachment. The alkyl component may include any number of carbons, such as C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2- 4. C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 . In some cases, the alkyl component may be absent. The heterocycloalkyl component is as defined above. Alkyl-heterocycloalkyl groups can be substituted or unsubstituted.

「芳基」係指具有任何合適數目之環原子及任何合適數目之環之芳族環系統。芳基可包括任何合適數目之環原子，諸如6個、7個、8個、9個、10個、11個、12個、13個、14個、15個或16個環原子，以及6至10個、6至12個或6至14個環成員。芳基可為單環，稠合形成雙環或三環基團，或藉由鍵來連接以形成聯芳基團。代表性芳基包括苯基、萘基及聯苯基。其他芳基包括苯甲基，其具有亞甲基連接基團。一些芳基具有6至12個環成員，諸如苯基、萘基或聯苯基。其他芳基具有6至10個環成員，諸如苯基或萘基。一些其他芳基具有6個環成員，諸如苯基。芳基可經取代或未經取代。"Aryl" means an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. The aryl group may comprise any suitable number of ring atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, and 6 to 10, 6 to 12 or 6 to 14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl and biphenyl. Other aryl groups include benzyl, which has a methylene linking group. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. Aryl groups can be substituted or unsubstituted.

「烷基-芳基」係指具有烷基組分及芳基組分之基團，其中烷基組分將芳基組分連接至附接點。烷基組分如上文定義，只是該烷基組分為至少二價，為伸烷基，連接至芳基組分且連接至附接點。烷基組分可包括任何數目之碳，諸如C 0-6、C 1-2、C 1-3、C 1-4、C 1-5、C 1-6、C 2-3、C 2-4、C 2-5、C 2-6、C 3-4、C 3-5、C 3-6、C 4-5、C 4-6及C 5-6。在一些情況下，烷基組分可不存在。芳基組分如上文定義。烷基-芳基之實例包括但不限於苯甲基及乙基-苯。烷基-芳基可經取代或未經取代。 "Alkyl-aryl" means a group having an alkyl component and an aryl component, wherein the alkyl component links the aryl component to a point of attachment. The alkyl component is as defined above except that the alkyl component is at least divalent, is an alkylene, is attached to the aryl component and is attached to the point of attachment. The alkyl component may include any number of carbons, such as C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2- 4. C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 . In some cases, the alkyl component may be absent. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethyl-benzene. Alkyl-aryl groups can be substituted or unsubstituted.

「伸芳基」係指連接至少兩個其他基團之如上文定義之芳基。連接至芳基之兩個部分可連接至芳基之同一原子或不同原子。伸芳基可經取代或未經取代。"Arylenyl" means an aryl group as defined above linked to at least two other groups. The two moieties attached to the aryl group may be attached to the same atom or different atoms of the aryl group. Arylene groups can be substituted or unsubstituted.

「雜芳基」係指含有5至16個環原子之單環或稠合雙環或三環芳族環組合，其中環原子中之1至5個為雜原子，諸如N、O或S。額外雜原子亦可有用，包括但不限於B、Al、Si及P。雜原子亦可氧化，諸如但不限於   -S(O)-及-S(O) 2-。雜芳基可包括任何數目之環原子，諸如5至6個、5至8個、6至8個、5至9個、5至10個、5至11個或5至12個環成員。任何合適數目之雜原子可包括於雜芳基中，諸如1個、2個、3個、4個或5個，或1至2個、1至3個、1至4個、1至5個、2至3個、2至4個、2至5個、3至4個或3至5個。雜芳基可具有5至8個環成員及1至4個雜原子，或5至8個環成員及1至3個雜原子，或5至6個環成員及1至4個雜原子，或5至6個環成員及1至3個雜原子。雜芳基可包括諸如吡咯、吡啶、咪唑、吡唑、***、四唑、吡嗪、嘧啶、噠嗪、三嗪(1,2,3-異構物、1,2,4-異構物及1,3,5-異構物)、噻吩、呋喃、噻唑、異噻唑、噁唑及異噁唑之基團。雜芳基亦可與諸如苯環之芳環系統稠合以形成包括但不限於以下之之成員：苯并吡咯，諸如吲哚及異吲哚；苯并吡啶，諸如喹啉及異喹啉；苯并吡嗪(喹噁啉)；苯并嘧啶(喹唑啉)；苯并噠嗪，諸如酞嗪及㖕啉；苯并噻吩及苯并呋喃。其他雜芳基包括藉由鍵連接之雜芳環，諸如聯吡啶。雜芳基可經取代或未經取代。 "Heteroaryl" refers to monocyclic or fused bicyclic or tricyclic aromatic ring combinations containing 5 to 16 ring atoms, wherein 1 to 5 of the ring atoms are heteroatoms, such as N, O or S. Additional heteroatoms may also be useful, including but not limited to B, Al, Si, and P. Heteroatoms can also be oxidized, such as but not limited to -S(O)- and -S(O) 2- . A heteroaryl group may comprise any number of ring atoms, such as 5 to 6, 5 to 8, 6 to 8, 5 to 9, 5 to 10, 5 to 11 or 5 to 12 ring members. Any suitable number of heteroatoms may be included in the heteroaryl, such as 1, 2, 3, 4 or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5 , 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. The heteroaryl group can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups may include compounds such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1,2,4-isomer and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole and isoxazole groups. Heteroaryl groups can also be fused with aromatic ring systems such as benzene rings to form members including, but not limited to: benzopyrroles, such as indole and isoindole; benzopyridines, such as quinoline and isoquinoline; Benzopyrazines (quinoxalines); benzopyrimidines (quinazolines); benzopyridazines, such as phthalazines and phenolines; benzothiophenes and benzofurans. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridyl. Heteroaryl groups can be substituted or unsubstituted.

雜芳基可經由環上之任何位置來連接。例如，吡咯包括1-吡咯、2-吡咯及3-吡咯，吡啶包括2-吡啶、3-吡啶及4-吡啶，咪唑包括1-咪唑、2-咪唑、4-咪唑及5-咪唑，吡唑包括1-吡唑、3-吡唑、4-吡唑及5-吡唑，***包括1-***、4-***及5-***，四唑包括1-四唑及5-四唑，嘧啶包括2-嘧啶、4-嘧啶、5-嘧啶及6-嘧啶，噠嗪包括3-噠嗪及4-噠嗪，1,2,3-三嗪包括4-三嗪及5-三嗪，1,2,4-三嗪包括3-三嗪、5-三嗪及6-三嗪，1,3,5-三嗪包括2-三嗪，噻吩包括2-噻吩及3-噻吩，呋喃包括2-呋喃及3-呋喃，噻唑包括2-噻唑、4-噻唑及5-噻唑，異噻唑包括3-異噻唑、4-異噻唑及5-異噻唑，噁唑包括2-噁唑、4-噁唑及5-噁唑，異噁唑包括3-異噁唑、4-異噁唑及5-異噁唑，吲哚包括1-吲哚、2-吲哚及3-吲哚，異吲哚包括1-異吲哚及2-異吲哚，喹啉包括2-喹啉、3-喹啉及4-喹啉，異喹啉包括1-異喹啉、3-異喹啉及4-異喹啉，喹唑啉包括2-喹唑啉及4-喹唑啉，㖕啉包括3-㖕啉及4-㖕啉，苯并噻吩包括2-苯并噻吩及3-苯并噻吩，且苯并呋喃包括2-苯并呋喃及3-苯并呋喃。A heteroaryl group can be attached via any position on the ring. For example, pyrrole includes 1-pyrrole, 2-pyrrole and 3-pyrrole, pyridine includes 2-pyridine, 3-pyridine and 4-pyridine, imidazole includes 1-imidazole, 2-imidazole, 4-imidazole and 5-imidazole, pyrazole Including 1-pyrazole, 3-pyrazole, 4-pyrazole and 5-pyrazole, triazole includes 1-triazole, 4-triazole and 5-triazole, tetrazole includes 1-tetrazole and 5-tetrazole Azole, pyrimidine includes 2-pyrimidine, 4-pyrimidine, 5-pyrimidine and 6-pyrimidine, pyridazine includes 3-pyridazine and 4-pyridazine, 1,2,3-triazine includes 4-triazine and 5-triazine 1,2,4-triazine includes 3-triazine, 5-triazine and 6-triazine, 1,3,5-triazine includes 2-triazine, thiophene includes 2-thiophene and 3-thiophene, Furan includes 2-furan and 3-furan, thiazole includes 2-thiazole, 4-thiazole and 5-thiazole, isothiazole includes 3-isothiazole, 4-isothiazole and 5-isothiazole, and oxazole includes 2-oxazole, 4-oxazole and 5-oxazole, isoxazole includes 3-isoxazole, 4-isoxazole and 5-isoxazole, indole includes 1-indole, 2-indole and 3-indole, Isoindole includes 1-isoindole and 2-isoindole, quinoline includes 2-quinoline, 3-quinoline and 4-quinoline, isoquinoline includes 1-isoquinoline, 3-isoquinoline and 4-isoquinoline, quinazoline includes 2-quinazoline and 4-quinazoline, phenoline includes 3-phenoline and 4-phenoline, benzothiophene includes 2-benzothiophene and 3-benzothiophene , and benzofuran includes 2-benzofuran and 3-benzofuran.

一些雜芳基包括具有5至10個環成員及1至3個包括N、O或S之環原子之雜芳基，諸如吡咯、吡啶、咪唑、吡唑、***、吡嗪、嘧啶、噠嗪、三嗪(1,2,3-異構物、1,2,4-異構物及1,3,5-異構物)、噻吩、呋喃、噻唑、異噻唑、噁唑、異噁唑、吲哚、異吲哚、喹啉、異喹啉、喹噁啉、喹唑啉、酞嗪、㖕啉、苯并噻吩及苯并呋喃。其他雜芳基包括具有5至8個環成員及1至3個雜原子之雜芳基，諸如吡咯、吡啶、咪唑、吡唑、***、吡嗪、嘧啶、噠嗪、三嗪(1,2,3-異構物、1,2,4-異構物及1,3,5-異構物)、噻吩、呋喃、噻唑、異噻唑、噁唑及異噁唑。一些其他雜芳基包括具有9至12個環成員及1至3個雜原子之雜芳基，諸如吲哚、異吲哚、喹啉、異喹啉、喹噁啉、喹唑啉、酞嗪、㖕啉、苯并噻吩、苯并呋喃及聯吡啶。其他雜芳基包括具有5至6個環成員及1至2個包括N、O或S之環原子之雜芳基，諸如吡咯、吡啶、咪唑、吡唑、吡嗪、嘧啶、噠嗪、噻吩、呋喃、噻唑、異噻唑、噁唑及異噁唑。Some heteroaryl groups include heteroaryl groups having 5 to 10 ring members and 1 to 3 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridyl Azine, triazine (1,2,3-isomer, 1,2,4-isomer and 1,3,5-isomer), thiophene, furan, thiazole, isothiazole, oxazole, isoxa oxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, phenoline, benzothiophene and benzofuran. Other heteroaryl groups include those having 5 to 8 ring members and 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1, 2,3-isomers, 1,2,4-isomers and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole and isoxazole. Some other heteroaryl groups include heteroaryl groups having 9 to 12 ring members and 1 to 3 heteroatoms such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine , phenoline, benzothiophene, benzofuran and bipyridine. Other heteroaryl groups include heteroaryl groups having 5 to 6 ring members and 1 to 2 ring atoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene , furan, thiazole, isothiazole, oxazole and isoxazole.

一些雜芳基包括5至10個環成員及僅氮雜原子，諸如吡咯、吡啶、咪唑、吡唑、***、吡嗪、嘧啶、噠嗪、三嗪(1,2,3-異構物、1,2,4-異構物及1,3,5-異構物)、吲哚、異吲哚、喹啉、異喹啉、喹噁啉、喹唑啉、酞嗪及㖕啉。其他雜芳基包括5至10個環成員及僅氧雜原子，諸如呋喃及苯并呋喃。一些其他雜芳基包括5至10個環成員及僅硫雜原子，諸如噻吩及苯并噻吩。其他雜芳基包括5至10個環成員及至少兩個雜原子，諸如咪唑、吡唑、***、吡嗪、嘧啶、噠嗪、三嗪(1,2,3-異構物、1,2,4-異構物及1,3,5-異構物)、噻唑、異噻唑、噁唑、異噁唑、喹噁啉、喹唑啉、酞嗪及㖕啉。Some heteroaryl groups include 5 to 10 ring members and only nitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer , 1,2,4-isomers and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine and phenoline. Other heteroaryl groups include 5 to 10 ring members and only oxygen heteroatoms, such as furan and benzofuran. Some other heteroaryl groups include 5 to 10 ring members and only sulfur heteroatoms, such as thiophene and benzothiophene. Other heteroaryl groups include 5 to 10 ring members and at least two heteroatoms, such as imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-isomer, 1, 2,4-isomers and 1,3,5-isomers), thiazoles, isothiazoles, oxazoles, isoxazoles, quinoxalines, quinazolines, phthalazines and phenolines.

「伸雜芳基」係指連接至少兩個其他基團之如上文定義之雜芳基。連接至雜芳基之兩個部分連接至雜芳基之不同原子。伸雜芳基可經取代或未經取代。"Heteroaryl" means a heteroaryl group as defined above linked to at least two other groups. The two moieties attached to the heteroaryl are attached to different atoms of the heteroaryl. Heteroaryl groups can be substituted or unsubstituted.

「烷基-雜芳基」係指具有烷基組分及雜芳基組分之基團，其中烷基組分將雜芳基組分連接至附接點。烷基組分如上文定義，只是該烷基組分為至少二價，為伸烷基，連接至雜芳基組分且連接至附接點。烷基組分可包括任何數目之碳，諸如C 0-6、C 1-2、C 1-3、C 1-4、C 1-5、C 1-6、C 2-3、C 2-4、C 2-5、C 2-6、C 3-4、C 3-5、C 3-6、C 4-5、 C 4-6及C 5-6。在一些情況下，烷基組分可不存在。雜芳基組分如其中定義。烷基-雜芳基可經取代或未經取代。 "Alkyl-heteroaryl" means a group having an alkyl component and a heteroaryl component, wherein the alkyl component links the heteroaryl component to a point of attachment. The alkyl component is as defined above except that the alkyl component is at least divalent, is an alkylene group, is attached to the heteroaryl component and is attached to the point of attachment. The alkyl component may include any number of carbons, such as C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2- 4. C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 . In some cases, the alkyl component may be absent. The heteroaryl component is as defined therein. Alkyl-heteroaryl groups can be substituted or unsubstituted.

以上定義之基團可視情況經任何合適數目及類型之取代基取代。代表性取代基包括但不限於鹵素、鹵烷基、鹵烷氧基、-OR’、=O、-OC(O)R’、-(O)R’、-O 2R’、-ONR’R”、-OC(O)NR’R”、=NR’、=N-OR’、-NR’R”、 -NR”C(O)R’、-NR’-(O)NR”R”’、-NR”C(O)OR’、 -NH-(NH 2)=NH、-NR’C(NH 2)=NH、-NH-(NH 2)=NR’、-SR’、-S(O)R’、-S(O) 2R’、-S(O) 2NR’R”、-NR’S(O) 2R”、-N 3及-NO 2。R’、R”及R”’各自獨立地係指氫、未經取代之烷基，諸如未經取代之C 1-6烷基。或者，當連接至同一氮時，R’及R”、或R”及R”’與其附接之氮組合形成如上文定義之雜環烷基或雜芳基環。 The groups defined above may optionally be substituted with any suitable number and type of substituents. Representative substituents include, but are not limited to, halo, haloalkyl, haloalkoxy, -OR', =O, -OC(O)R', -(O)R', -O2R ', -ONR'R",-OC(O)NR'R",=NR',=N-OR',-NR'R",-NR"C(O)R',-NR'-(O)NR"R"',-NR”C(O)OR', -NH-(NH 2 )=NH, -NR'C(NH 2 )=NH, -NH-(NH 2 )=NR', -SR', -S (O)R', -S(O) 2 R', -S(O) 2 NR'R", -NR'S(O) 2 R", -N 3 and -NO 2 . R', R" and R "' each independently means hydrogen, unsubstituted alkyl, such as unsubstituted C 1-6 alkyl. Or, when attached to the same nitrogen, R' and R", or R" and R"' Combination with the nitrogen to which it is attached forms a heterocycloalkyl or heteroaryl ring as defined above.

「鹽」係指可用於本文揭示之方法中之化合物之酸式鹽或鹼式鹽。醫藥學上可接受之鹽之說明性實例為無機酸(鹽酸、氫溴酸、磷酸及其類似酸)鹽、有機酸(乙酸、丙酸、麩胺酸、檸檬酸及其類似酸)鹽、四級銨(甲基碘化物、乙基碘化物及其類似物)鹽。可理解，醫藥學上可接受之鹽為無毒的。關於合適醫藥學上可接受之鹽之額外資訊可見於Remington’s Pharmaceutical Sciences, 第17版, Mack Publishing Company, Easton, Pa., 1985中，其以引用方式併入本文。"Salt" refers to acid or base salts of compounds useful in the methods disclosed herein. Illustrative examples of pharmaceutically acceptable salts are salts of inorganic acids (hydrochloric, hydrobromic, phosphoric and the like), organic acids (acetic, propionic, glutamic, citric and the like), Quaternary ammonium (methyl iodide, ethyl iodide and the like) salts. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

本文揭示之酸性化合物之醫藥學上可接受之鹽為與鹼形成之鹽，亦即陽離子鹽，諸如鹼金屬及鹼土金屬鹽，諸如鈉、鋰、鉀、鈣、鎂，以及銨鹽，諸如銨、三甲基銨、二乙銨及參-(羥甲基)-甲基-銨鹽。The pharmaceutically acceptable salts of the acidic compounds disclosed herein are salts with bases, i.e., cationic salts, such as alkali metal and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, and ammonium salts, such as ammonium , trimethylammonium, diethylammonium and ginseng-(hydroxymethyl)-methyl-ammonium salt.

類似地，諸如無機酸、有機羧酸及有機磺酸，例如鹽酸、甲磺酸、順丁烯二酸之酸加成鹽亦為可能的，只要諸如吡啶基之鹼性基團構成結構之一部分。Similarly, acid addition salts such as inorganic acids, organic carboxylic and organic sulfonic acids, e.g. hydrochloric acid, methanesulfonic acid, maleic acid are also possible as long as a basic group such as pyridyl forms part of the structure .

中性形式之化合物可藉由使鹽與鹼或酸接觸且以習知方式來分離母體化合物而再生。母體形式之化合物在某些物理性質，諸如在極性溶劑中之溶解性方面不同於各種鹽形式，但是出於本發明之實施例之目的，在其他方面，該等鹽與母體形式之化合物等效。The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the embodiments of this invention are otherwise equivalent to the parent form of the compound .

本文揭示之某些化合物具有不對稱碳原子(光學中心)或雙鍵；外消旋物、非鏡像異構物、幾何異構物及個別異構物均意欲涵蓋於本發明之實施例之範疇內。Certain compounds disclosed herein possess asymmetric carbon atoms (optical centers) or double bonds; racemates, diastereomers, geometric isomers, and individual isomers are all intended to be encompassed within the scope of embodiments of the invention Inside.

「水合物」係指與至少一個水分子複合之化合物。本文揭示之化合物可與1至10個水分子複合。"Hydrate" means a compound complexed with at least one water molecule. The compounds disclosed herein can complex with 1 to 10 water molecules.

如本文所用之「組合物」意欲涵蓋包含指定量之指定成分之產物，以及由指定量之指定成分之組合直接或間接地產生的任何產物。「醫藥學上可接受」意謂載劑、稀釋劑或賦形劑必須與調配物之其他成分相容且對其接受者有害。A "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product resulting, directly or indirectly, from the combination of the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not harmful to the recipient thereof.

「醫藥學上可接受之賦形劑」係指有助於將活性劑投與個體且由個體吸收之物質。可用於本發明之實施例中之醫藥賦形劑包括但不限於黏合劑、填充劑、崩解劑、潤滑劑、塗料、甜味劑、調味劑及顏料。熟習此項技術者認識到其他醫藥賦形劑可用於本發明之實施例中。A "pharmaceutically acceptable excipient" refers to a substance that facilitates administration of an active agent to and absorption by a subject. Pharmaceutical excipients that can be used in embodiments of the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, and pigments. Those skilled in the art will recognize that other pharmaceutical excipients may be used in embodiments of the invention.

「治療(Treat/treating/treatment)」係指成功治療或改善損傷、病理、疾患或症狀(例如疼痛)之任何標誌，包括任何客觀或主觀參數，諸如減輕；緩解；減弱症狀或使患者更能耐受症狀、損傷、病理或疾患；減少症狀或疾患之頻率或持續時間；或者，在一些情況下，防止症狀發作。症狀之治療或改善可基於任何客觀或主觀參數；包括例如身體檢查之結果。"Treat/treating/treatment" means the successful treatment or amelioration of any indication of an injury, pathology, disorder or symptom (e.g. pain), including any objective or subjective parameter such as alleviation; palliation; Tolerating a symptom, injury, pathology, or disorder; reducing the frequency or duration of a symptom or disorder; or, in some cases, preventing the onset of symptoms. Treatment or amelioration of symptoms may be based on any objective or subjective parameter; including, for example, the results of a physical examination.

「投與」係指經口投與、以栓劑投與、局部接觸、非經腸、靜脈內、腹膜內、肌肉內、病灶內、鼻內或皮下投與、鞘內投與或將緩慢釋放裝置例如微型滲透泵浦植入個體。"Administration" means oral administration, administration by suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration or slow release Devices such as miniature osmotic pumps are implanted in the individual.

「治療有效量或劑量」或「治療足夠量或劑量」或「有效或足夠量或劑量」係指產生其投與所欲達成之治療效果之劑量。精確劑量視治療目的而定，且可由熟習此項技術者使用已知技術來確定(參見例如Lieberman, Pharmaceutical Dosage Forms(第1-3卷, 1992)；Lloyd, The Art, Science and Technology of Pharmaceutical Compounding(1999)；Pickar, Dosage Calculations(1999)；及 Remington: The Science and Practice of Pharmacy, 第20版, 2003, Gennaro編輯, Lippincott, Williams & Wilkins)。在敏化細胞中，治療有效劑量可通常低於未敏化細胞之習知治療有效劑量。 A "therapeutically effective amount or dose" or "therapeutically sufficient amount or dose" or "effective or sufficient amount or dose" refers to a dose that produces the therapeutic effect for which its administration is intended. The precise dosage will depend on the purpose of the treatment and can be determined by one skilled in the art using known techniques (see for example Lieberman, Pharmaceutical Dosage Forms (Volumes 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington : The Science and Practice of Pharmacy , 20th ed., 2003, edited by Gennaro, Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective dose may generally be lower than the conventional therapeutically effective dose for non-sensitized cells.

「個體」係指動物，諸如哺乳動物，包括但不限於靈長類動物(例如，人類)、牛、綿羊、山羊、馬、犬、貓、兔、大鼠、小鼠及其類似動物。在某些實施例中，個體為人類。 III. 化合物 "Individual" refers to an animal, such as a mammal, including but not limited to primates (eg, humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In certain embodiments, the individual is human. III. Compounds

本發明之實施例提供式(I)化合物，及其醫藥學上可接受之鹽：

Figure 02_image029
。 Embodiments of the present invention provide compounds of formula (I) and pharmaceutically acceptable salts thereof:
Figure 02_image029
.

在一些實施例中，化合物為式(I)之單一阻轉異構物：

Figure 02_image031
或
Figure 02_image033
。 In some embodiments, the compound is a single atropisomer of Formula (I):
Figure 02_image031
or
Figure 02_image033
.

在一些實施例中，化合物為：

Figure 02_image035
、
Figure 02_image037
、
Figure 02_image039
、
Figure 02_image041
、
Figure 02_image043
、
Figure 02_image045
、
Figure 02_image047
、
Figure 02_image049
、
Figure 02_image051
、
Figure 02_image053
、
Figure 02_image055
、
Figure 02_image057
、
Figure 02_image059
、
Figure 02_image061
、
Figure 02_image063
、
Figure 02_image065
、
Figure 02_image067
、
Figure 02_image069
、
Figure 02_image071
、
Figure 02_image073
、
Figure 02_image075
、
Figure 02_image077
、
Figure 02_image079
、
Figure 02_image081
、
Figure 02_image083
、
Figure 02_image085
、
Figure 02_image087
、
Figure 02_image089
、
Figure 02_image091
、
Figure 02_image093
、
Figure 02_image095
、
Figure 02_image097
、
Figure 02_image099
、
Figure 02_image101
、
Figure 02_image103
、
Figure 02_image105
、
Figure 02_image107
、
Figure 02_image109
、
Figure 02_image111
、
Figure 02_image113
、
Figure 02_image115
、
Figure 02_image117
、
Figure 02_image119
、
Figure 02_image121
、
Figure 02_image123
、
Figure 02_image125
、
Figure 02_image127
、
Figure 02_image129
、
Figure 02_image131
、
Figure 02_image133
、
Figure 02_image135
、
Figure 02_image137
、
Figure 02_image139
、
Figure 02_image141
、
Figure 02_image143
、
Figure 02_image145
、
Figure 02_image147
、
Figure 02_image149
、
Figure 02_image151
、
Figure 02_image153
、
Figure 02_image155
、
Figure 02_image157
、
Figure 02_image159
、
Figure 02_image161
、
Figure 02_image163
、
Figure 02_image165
、
Figure 02_image167
、
Figure 02_image169
、
Figure 02_image171
、
Figure 02_image173
、
Figure 02_image175
、
Figure 02_image177
、
Figure 02_image179
、
Figure 02_image181
、
Figure 02_image183
、
Figure 02_image185
、
Figure 02_image187
、
Figure 02_image189
、
Figure 02_image191
、
Figure 02_image193
、
Figure 02_image195
、
Figure 02_image197
、
Figure 02_image199
、
Figure 02_image201
、
Figure 02_image202
、
Figure 02_image204
、
Figure 02_image206
、
Figure 02_image208
、
Figure 02_image210
、
Figure 02_image212
、
Figure 02_image214
、
Figure 02_image216
、
Figure 02_image218
、
Figure 02_image220
、
Figure 02_image222
、
Figure 02_image224
、
Figure 02_image226
、
Figure 02_image228
、
Figure 02_image230
、
Figure 02_image232
或
Figure 02_image234
。 In some embodiments, the compound is:
Figure 02_image035
,
Figure 02_image037
,
Figure 02_image039
,
Figure 02_image041
,
Figure 02_image043
,
Figure 02_image045
,
Figure 02_image047
,
Figure 02_image049
,
Figure 02_image051
,
Figure 02_image053
,
Figure 02_image055
,
Figure 02_image057
,
Figure 02_image059
,
Figure 02_image061
,
Figure 02_image063
,
Figure 02_image065
,
Figure 02_image067
,
Figure 02_image069
,
Figure 02_image071
,
Figure 02_image073
,
Figure 02_image075
,
Figure 02_image077
,
Figure 02_image079
,
Figure 02_image081
,
Figure 02_image083
,
Figure 02_image085
,
Figure 02_image087
,
Figure 02_image089
,
Figure 02_image091
,
Figure 02_image093
,
Figure 02_image095
,
Figure 02_image097
,
Figure 02_image099
,
Figure 02_image101
,
Figure 02_image103
,
Figure 02_image105
,
Figure 02_image107
,
Figure 02_image109
,
Figure 02_image111
,
Figure 02_image113
,
Figure 02_image115
,
Figure 02_image117
,
Figure 02_image119
,
Figure 02_image121
,
Figure 02_image123
,
Figure 02_image125
,
Figure 02_image127
,
Figure 02_image129
,
Figure 02_image131
,
Figure 02_image133
,
Figure 02_image135
,
Figure 02_image137
,
Figure 02_image139
,
Figure 02_image141
,
Figure 02_image143
,
Figure 02_image145
,
Figure 02_image147
,
Figure 02_image149
,
Figure 02_image151
,
Figure 02_image153
,
Figure 02_image155
,
Figure 02_image157
,
Figure 02_image159
,
Figure 02_image161
,
Figure 02_image163
,
Figure 02_image165
,
Figure 02_image167
,
Figure 02_image169
,
Figure 02_image171
,
Figure 02_image173
,
Figure 02_image175
,
Figure 02_image177
,
Figure 02_image179
,
Figure 02_image181
,
Figure 02_image183
,
Figure 02_image185
,
Figure 02_image187
,
Figure 02_image189
,
Figure 02_image191
,
Figure 02_image193
,
Figure 02_image195
,
Figure 02_image197
,
Figure 02_image199
,
Figure 02_image201
,
Figure 02_image202
,
Figure 02_image204
,
Figure 02_image206
,
Figure 02_image208
,
Figure 02_image210
,
Figure 02_image212
,
Figure 02_image214
,
Figure 02_image216
,
Figure 02_image218
,
Figure 02_image220
,
Figure 02_image222
,
Figure 02_image224
,
Figure 02_image226
,
Figure 02_image228
,
Figure 02_image230
,
Figure 02_image232
or
Figure 02_image234
.

在一些實施例中，化合物為：

Figure 02_image236
、
Figure 02_image238
、
Figure 02_image240
、
Figure 02_image242
、
Figure 02_image244
、
Figure 02_image246
、
Figure 02_image248
、
Figure 02_image250
、
Figure 02_image252
、
Figure 02_image254
、
Figure 02_image256
或
Figure 02_image258
。 In some embodiments, the compound is:
Figure 02_image236
,
Figure 02_image238
,
Figure 02_image240
,
Figure 02_image242
,
Figure 02_image244
,
Figure 02_image246
,
Figure 02_image248
,
Figure 02_image250
,
Figure 02_image252
,
Figure 02_image254
,
Figure 02_image256
or
Figure 02_image258
.

本文揭示之化合物可呈鹽形式存在。本發明之實施例包括此類鹽，其可為醫藥學上可接受之鹽。適用之鹽形式之實例包括鹽酸鹽、氫溴酸鹽、硫酸鹽、甲磺酸鹽、硝酸鹽、順丁烯二酸鹽、乙酸鹽、檸檬酸鹽、反丁烯二酸鹽、酒石酸鹽(例如(+)-酒石酸鹽、(-)-酒石酸鹽或其混合物，包括外消旋混合物)、琥珀酸鹽、苯甲酸鹽及與諸如麩胺酸之胺基酸之鹽。此等鹽可藉由熟習此項技術者已知之方法製備。亦包括鹼加成鹽，諸如鈉鹽、鉀鹽、鈣鹽、銨鹽、有機胺基鹽或鎂鹽，或類似之鹽。當本文揭示之化合物含有相對鹼性官能基時，酸加成鹽可藉由使此類化合物之中性形式與足夠量之所需酸在無溶劑下或在合適惰性溶劑中接觸來獲得。可接受之酸加成鹽之實例包括衍生自無機酸如鹽酸、氫溴酸、硝酸、碳酸、碳酸氫鹽、磷酸、磷酸氫鹽、磷酸二氫鹽、硫酸、硫酸氫鹽、氫碘酸或亞磷酸及其類似酸之酸加成鹽，以及衍生自有機酸如乙酸、丙酸、異丁酸、順丁烯二酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、鄰苯二甲酸、苯磺酸、對甲苯磺酸、檸檬酸、酒石酸、甲磺酸及其類似酸之酸加成鹽。亦包括胺基酸之鹽，諸如精胺酸鹽及其類似酸，以及有機酸如葡萄糖醛酸或半乳糖醛酸及其類似酸之鹽。本文揭示之某些特定化合物含有允許將化合物轉化成鹼加成鹽或酸加成鹽之鹼性及酸性官能基。The compounds disclosed herein may exist in the form of salts. Embodiments of the present invention include such salts, which may be pharmaceutically acceptable salts. Examples of suitable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate (eg (+)-tartrate, (-)-tartrate or mixtures thereof, including racemic mixtures), succinate, benzoate and salts with amino acids such as glutamic acid. Such salts can be prepared by methods known to those skilled in the art. Also included are base addition salts, such as sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When compounds disclosed herein contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid or Acid addition salts of phosphorous acid and similar acids, and those derived from organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid Acid addition salts of diacids, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and similar acids. Also included are salts of amino acids, such as arginate and similar acids, and salts of organic acids such as glucuronic or galacturonic acid and similar acids. Certain specific compounds disclosed herein contain basic and acidic functional groups that allow conversion of the compounds into base or acid addition salts.

其他鹽包括用於本發明之實施例之方法中的化合物之酸式鹽或鹼式鹽。醫藥學上可接受之鹽之說明性實例為無機酸(鹽酸、氫溴酸、磷酸及其類似酸)鹽、有機酸(乙酸、丙酸、麩胺酸、檸檬酸及其類似酸)鹽及四級銨(甲基碘化物、乙基碘化物及其類似物)鹽。可理解，醫藥學上可接受之鹽為無毒的。關於合適醫藥學上可接受之鹽之額外資訊可見於Remington’s Pharmaceutical Sciences, 第17版, Mack Publishing Company, Easton, Pa., 1985中，其以引用方式併入本文。Other salts include acid or base salts of compounds used in the methods of the embodiments of the invention. Illustrative examples of pharmaceutically acceptable salts are salts of inorganic acids (hydrochloric acid, hydrobromic acid, phosphoric acid and the like), organic acids (acetic acid, propionic acid, glutamic acid, citric acid and the like) and Quaternary ammonium (methyl iodide, ethyl iodide and the like) salts. It is understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

醫藥學上可接受之鹽包括用相對無毒酸或鹼來製備之活性化合物之鹽，此舉視存在於本文描述之化合物上之特定取代基而定。當本文揭示之化合物含有相對酸性官能基時，鹼加成鹽可藉由使此類化合物之中性形式與足夠量之所需鹼在無溶劑下或在合適惰性溶劑中接觸來獲得。醫藥學上可接受之鹼加成鹽之實例包括鈉鹽、鉀鹽、鈣鹽、銨鹽、有機胺基鹽或鎂鹽，或類似之鹽。當本文揭示之化合物含有相對鹼性官能基時，酸加成鹽可藉由使此類化合物之中性形式與足夠量之所需酸在無溶劑下或在合適惰性溶劑中接觸來獲得。醫藥學上可接受之酸加成鹽之實例包括衍生自無機酸如鹽酸、氫溴酸、硝酸、碳酸、碳酸氫鹽、磷酸、磷酸氫鹽、磷酸二氫鹽、硫酸、硫酸氫鹽、氫碘酸或亞磷酸及其類似酸之酸加成鹽，以及衍生自相對無毒之有機酸如乙酸、丙酸、異丁酸、順丁烯二酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、鄰苯二甲酸、苯磺酸、對甲苯磺酸、檸檬酸、酒石酸、甲磺酸及其類似酸之鹽。亦包括胺基酸之鹽，諸如精胺酸鹽及其類似酸，以及有機酸如葡萄糖醛酸或半乳糖醛酸及其類似酸之鹽(參見例如Berge等人, 「Pharmaceutical Salts」, Journal of Pharmaceutical Science, 1977, 66, 1-19)。本文揭示之某些特定化合物含有允許將化合物轉化成鹼加成鹽或酸加成鹽之鹼性及酸性官能基。 Pharmaceutically acceptable salts include salts of the active compounds which are prepared with relatively non-toxic acids or bases, depending on the particular substituents present on the compounds described herein. When compounds disclosed herein contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts, or similar salts. When compounds disclosed herein contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, hydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydrogen Acid addition salts of iodic acid or phosphorous acid and similar acids, and organic acids derived from relatively non-toxic, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid Salts of diacid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and similar acids. Also included are salts of amino acids, such as arginate and similar acids, and salts of organic acids such as glucuronic acid or galacturonic acid and similar acids (see, e.g., Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science , 1977 , 66 , 1-19). Certain specific compounds disclosed herein contain basic and acidic functional groups that allow conversion of the compounds into base or acid addition salts.

中性形式之化合物較佳藉由使鹽與鹼或酸接觸且以習知方式來分離母體化合物而再生。母體形式之化合物在某些物理性質，諸如在極性溶劑中之溶解性方面不同於各種鹽形式。The neutral form of the compound is preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in a known manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

本文揭示之某些化合物可呈未溶劑化形式以及溶劑化形式，包括水合形式存在。通常，溶劑化形式與未溶劑化形式等效且涵蓋於本發明之實施例之範疇內。本文揭示之某些化合物可呈多種結晶或非晶形式存在。通常，對於本發明之實施例涵蓋之用途而言，所有物理形式均等效，且意欲在本發明之實施例之範疇內。Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the embodiments of this invention. Certain compounds disclosed herein can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the embodiments of the invention and are intended to be within the scope of the embodiments of the invention.

本文揭示之某些化合物具有不對稱碳原子(光學中心)或雙鍵；鏡像異構物、外消旋物、非鏡像異構物、互變異構物、幾何異構物、可針對胺基酸按照絕對立體化學來定義為(R)-或(S)-或(D)-或(L)-之立體異構形式、及個別異構物涵蓋於本發明之實施例之範疇內。本文揭示之化合物不包括在此項技術已知太不穩定以致於不能合成及/或分離之化合物。本發明之實施例旨在包括呈外消旋及光學純形式之化合物。光學活性(R)-及(S)-或(D)-及(L)-異構物可使用對掌性合成子或對掌性試劑製備，或使用習知技術製備。本文揭示之化合物可提供為阻轉異構物之混合物或可為純阻轉異構物。Certain compounds disclosed herein have asymmetric carbon atoms (optical centers) or double bonds; enantiomers, racemates, diastereomers, tautomers, geometric isomers, amino acid Stereoisomeric forms defined as (R)- or (S)- or (D)- or (L)- in terms of absolute stereochemistry, and individual isomers are encompassed within the scope of the embodiments of the invention. Compounds disclosed herein do not include compounds known in the art to be too unstable to be synthesized and/or isolated. Embodiments of the present invention are intended to include the compounds in racemic and optically pure form. Optically active (R)- and (S)- or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents, or using known techniques. Compounds disclosed herein may be provided as mixtures of atropisomers or may be pure atropisomers.

異構物包括具有相同數目及種類之原子，由此具有相同分子量，但是在原子之結構佈置或組態方面不同之化合物。Isomers include compounds that have the same number and kind of atoms, and thus the same molecular weight, but differ in the structural arrangement or configuration of the atoms.

除非另外說明，否則本文描述之結構亦旨在包括該結構之所有立體化學形式；亦即，各不對稱中心之R及S組態。因此，本發明化合物之單一立體化學異構物以及鏡像異構及非鏡像異構混合物在實施例之範疇內。Unless otherwise indicated, structures depicted herein are also intended to include all stereochemical forms of the structure; that is, the R and S configurations of each asymmetric center. Thus, single stereochemical isomers as well as enantiomerically and diastereomeric mixtures of the compounds of the present invention are within the scope of the embodiments.

除非另外說明，否則本文揭示之化合物亦可在構成此類化合物之原子中之一或多者處含有非天然比例之原子同位素。例如，本文揭示之化合物可用放射性或穩定同位素，諸如例如氘( 2H)、氘( 3H)、碘-125 ( 125I)、氟-18 ( 18F)、氮-15 ( 15N)、氧-17 ( 17O)、氧-18 ( 18O)、碳-13 ( 13C)或碳-14 ( 14C)來標記。本文揭示之化合物之所有同位素變化形式，不論是否具有放射性，均涵蓋於本發明之實施例之範疇內。 Unless otherwise indicated, the compounds disclosed herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds disclosed herein can be used with radioactive or stable isotopes such as, for example, deuterium ( 2 H), deuterium ( 3 H), iodine-125 ( 125 I), fluorine-18 ( 18 F), nitrogen-15 ( 15 N), Oxygen-17 ( 17 O), Oxygen-18 ( 18 O), Carbon-13 ( 13 C) or Carbon-14 ( 14 C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are encompassed within the scope of the embodiments of the present invention.

除鹽形式以外，本發明之實施例提供呈前藥形式之化合物。本文描述之化合物之前藥係在生理條件下容易經歷化學變化以提供本文揭示之化合物之彼等化合物。此外，前藥可以在離體環境中藉由化學或生化方法轉化為本文揭示之化合物。舉例而言，在與合適酶或化學試劑一起安置於經皮貼片儲器中時，前藥可緩慢轉化成本文揭示之化合物。In addition to salt forms, embodiments of the present invention provide compounds that are in prodrug form. Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds disclosed herein. In addition, prodrugs can be converted to the compounds disclosed herein by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to compounds disclosed herein when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

本文揭示之化合物可藉由在以下展示及描述之說明性合成反應流程中描繪之各種方法來製得。用於製備此等化合物之起始物質及試劑通常可自諸如Aldrich Chemical Co.之商業供應商獲得，或藉由熟習此項技術者已知之方法，遵循諸如以下之參考文獻中闡述之程序來製備：Fieser and Fieser’s Reagents for Organic Synthesis; Wiley & Sons: New York, 第1-21卷；R. C. LaRock, Comprehensive Organic Transformations, 第2版Wiley-VCH, New York 1999； Comprehensive Organic Synthesis, B. Trost及I. Fleming (編) 第1-9卷 Pergamon, Oxford, 1991； Comprehensive Heterocyclic Chemistry, A. R. Katritzky及C. W. Rees (編) Pergamon, Oxford 1984, 第1-9卷； Comprehensive Heterocyclic Chemistry II, A. R. Katritzky及C. W. Rees (編) Pergamon, Oxford 1996, 第1-11卷；及 Organic Reactions, Wiley & Sons: New York, 1991, 第1-40卷。以下合成反應流程僅僅說明可合成本文揭示之化合物之一些方法，且此等合成反應流程可進行各種修改且熟習此項技術者參考本文所含之揭示內容將想到此等修改。 The compounds disclosed herein can be prepared by various methods depicted in the illustrative synthetic reaction schemes shown and described below. Starting materials and reagents for the preparation of these compounds are generally available from commercial suppliers such as Aldrich Chemical Co., or can be prepared by methods known to those skilled in the art, following the procedures set forth in references such as the following : Fieser and Fieser's Reagents for Organic Synthesis ; Wiley & Sons: New York, Vol. 1-21; RC LaRock, Comprehensive Organic Transformations , 2nd Edition Wiley-VCH, New York 1999 ; Comprehensive Organic Synthesis , B. Trost and I. Fleming (ed.) Volumes 1-9 Pergamon, Oxford, 1991 ; Comprehensive Heterocyclic Chemistry , AR Katritzky and CW Rees (eds.) Pergamon, Oxford 1984 , volumes 1-9; Comprehensive Heterocyclic Chemistry II , AR Katritzky and CW Rees (eds. ) Pergamon, Oxford 1996 , vol. 1-11; and Organic Reactions , Wiley & Sons: New York, 1991 , vol. 1-40. The following synthetic reaction schemes illustrate only some of the ways in which the compounds disclosed herein may be synthesized, and such synthetic reaction schemes are susceptible to various modifications and would occur to those skilled in the art in view of the disclosure contained herein.

出於說明性目的，以下反應流程提供合成本文揭示之化合物以及關鍵中間物之途徑。對於個別反應步驟之更詳細描述，參見以下實例部分。熟習此項技術者將理解可使用其他合成途徑。儘管在流程中描繪一些特定起始物質及試劑且在下面討論，但其他起始物質及試劑可替代以提供多種衍生物或反應條件。另外，藉由以下描述之方法製備之許多化合物可鑒於本揭示案使用熟習此項技術者熟知之習知化學來進一步改質。For illustrative purposes, the following reaction schemes provide routes to the synthesis of compounds disclosed herein as well as key intermediates. For a more detailed description of individual reaction steps, see the Examples section below. Those skilled in the art will appreciate that other synthetic routes can be used. Although some specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be substituted to provide various derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

合成反應流程之起始物質及中間物若需要可使用習知技術，包括但不限於過濾、蒸餾、結晶、層析及其類似技術來分離及純化。此類物質可使用習知手段，包括物理常數及光譜資料來表徵。The starting materials and intermediates of the synthetic reaction schemes can be separated and purified if necessary using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography and the like. Such substances can be characterized using conventional means, including physical constants and spectral data.

除非相反地指定，否則本文所述之反應較佳在惰性氛圍下，在大氣壓力下，在約-78℃至約150℃，更佳約0℃至約125℃之反應溫度範圍下，且最佳及適宜在約房間(或周圍)溫度或約20℃下進行。Unless specified to the contrary, the reactions described herein are preferably performed under an inert atmosphere at atmospheric pressure, at a reaction temperature range of from about -78°C to about 150°C, more preferably from about 0°C to about 125°C, and most preferably Preferably and suitably at about room (or ambient) temperature or about 20°C.

以下方案中之一些化合物被描繪成具有通用取代基；然而，熟習此項技術者立即認識到取代基之性質可改變以便提供涵蓋於本發明之實施例中之各種化合物。另外，反應條件為示例性的且替代條件為熟知的。以下實例中之反應順序並不意味著限制如申請專利範圍中所闡述之實施例之範疇。 IV. 醫藥調配物 Some of the compounds in the following schemes are depicted as having common substituents; however, one skilled in the art immediately recognizes that the nature of the substituents can be varied in order to provide a variety of compounds encompassed within the examples of the invention. In addition, reaction conditions are exemplary and alternative conditions are well known. The reaction sequence in the following examples is not meant to limit the scope of the embodiments as set forth in the claims. IV. Pharmaceutical formulations

在一些實施例中，醫藥組合物包含本文揭示之化合物中任一者之化合物及醫藥學上可接受之賦形劑。In some embodiments, a pharmaceutical composition comprises a compound of any one of the compounds disclosed herein and a pharmaceutically acceptable excipient.

在一些實施例中，提供一種醫藥組合物，其包含醫藥學上有效量之式(I)之任一化合物，

Figure 02_image260
或其醫藥學上可接受之鹽，及醫藥學上可接受之賦形劑。 In some embodiments, there is provided a pharmaceutical composition comprising a pharmaceutically effective amount of any compound of formula (I),
Figure 02_image260
Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

在一些實施例中，醫藥組合物進一步包含另一治療劑。In some embodiments, the pharmaceutical composition further comprises another therapeutic agent.

在一些實施例中，另一治療劑為化學治療劑。在一些實施例中，化學治療劑為抗微管劑、鉑配位錯合物、烷化劑、抗生素劑、拓撲異構酶II抑制劑、抗代謝物、拓撲異構酶I抑制劑、激素或激素類似物、信號轉導路徑抑制劑、非受體酪胺酸激酶血管生成抑制劑、免疫治療劑、促凋亡劑、LDH-A之抑制劑、脂肪酸生物合成之抑制劑、細胞週期信號傳導抑制劑、HDAC抑制劑、蛋白酶體抑制劑或癌症代謝之抑制劑。在一些實施例中，化學治療劑為順鉑(cisplatin)、卡鉑(carboplatin)、多柔比星(doxorubicin)、電離輻射、多烯紫杉醇(docetaxel)或太平洋紫杉醇(paclitaxel)。In some embodiments, the other therapeutic agent is a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is an antimicrotubule agent, platinum coordination complex, alkylating agent, antibiotic agent, topoisomerase II inhibitor, antimetabolite, topoisomerase I inhibitor, hormone Or hormone analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutics, pro-apoptotic agents, inhibitors of LDH-A, inhibitors of fatty acid biosynthesis, cell cycle signals Conduction inhibitors, HDAC inhibitors, proteasome inhibitors or inhibitors of cancer metabolism. In some embodiments, the chemotherapeutic agent is cisplatin, carboplatin, doxorubicin, ionizing radiation, docetaxel, or paclitaxel.

本文揭示之化合物可呈多種經口、非經腸及局部劑型來製備及投與。經口製劑包括適合於由患者攝入之錠劑、丸劑、粉劑、糖衣藥丸、膠囊、液體、糖錠、凝膠、糖漿、漿液、懸浮液等。本文揭示之化合物亦可藉由注射投與，亦即，靜脈內、肌內、皮內、皮下、十二指腸內或腹膜內。此外，本文所述之化合物可藉由吸入投與，例如鼻內投與。此外，本文揭示之化合物可經皮給藥。本文揭示之化合物亦可藉由眼內、***內及直腸內途徑投與，包括栓劑、吹入劑、粉劑及氣溶膠調配物(例如類固醇吸入劑，參見Rohatagi, J. Clin. Pharmacol.35:1187-1193, 1995；Tjwa, Ann. Allergy Asthma Immunol.75:107-111, 1995)。因此，本發明之實施例亦提供醫藥組合物，其包括一或多種醫藥學上可接受之載劑及/或賦形劑及式I化合物或式I化合物之醫藥學上可接受之鹽。 The compounds disclosed herein can be prepared and administered in a variety of oral, parenteral, and topical dosage forms. Oral formulations include tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions and the like suitable for ingestion by the patient. The compounds disclosed herein can also be administered by injection, ie, intravenous, intramuscular, intradermal, subcutaneous, intraduodenal or intraperitoneal. In addition, the compounds described herein can be administered by inhalation, eg, intranasally. In addition, the compounds disclosed herein can be administered transdermally. The compounds disclosed herein can also be administered by intraocular, intravaginal, and intrarectal routes, including suppository, insufflation, powder, and aerosol formulations (eg, steroid inhalation, see Rohatagi, J. Clin. Pharmacol. 35: 1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Therefore, embodiments of the present invention also provide pharmaceutical compositions, which include one or more pharmaceutically acceptable carriers and/or excipients and the compound of formula I or a pharmaceutically acceptable salt of the compound of formula I.

為自本文揭示之化合物製備醫藥組合物，醫藥學上可接受之載劑可為固體或液體。固體形式製劑包括粉劑、錠劑、丸劑、膠囊、扁囊劑、栓劑及可分散顆粒。固體載劑可為亦可充當稀釋劑、調味劑、界面活性劑、黏合劑、防腐劑、錠劑崩解劑或囊封材料之一或多種物質。關於調配及投與技術之詳情在科學及專利文獻中很好地描述，參見例如最新版本之Remington’s Pharmaceutical Sciences, Maack Publishing Co, Easton PA (「Remington’s」)。For preparing pharmaceutical compositions from the compounds disclosed herein, pharmaceutically acceptable carriers can be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier can be one or more of diluents, flavoring agents, surfactants, binders, preservatives, tablet disintegrating agents or encapsulating materials. Details regarding formulation and administration techniques are well described in the scientific and patent literature, see, eg, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

在粉劑中，載劑為細粉狀固體，其與細粉狀活性組分混合。在錠劑中，活性組分與具有必要黏合性質之載劑及根據需要與合適比例之額外賦形劑混合且壓縮成所需形狀及大小。In powders, the carrier is a finely divided solid, which is in admixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties and, if necessary, additional excipients in suitable proportions and compacted in the shape and size desired.

粉劑、膠囊及錠劑較佳含有5%或10%至70%之活性化合物。合適載劑為碳酸鎂、硬脂酸鎂、滑石、糖、乳糖、果膠、糊精、澱粉、明膠、黃蓍膠、甲基纖維素、羧甲基纖維素鈉、低熔點蠟、可可脂及其類似物質。術語「製劑」意欲包括活性化合物與作為載劑之囊封材料之調配物，此提供一種膠囊，其中含有或不含有其他賦形劑之活性組分被載劑包圍，因此與其結合。類似地，包括扁囊劑及糖錠。錠劑、粉劑、膠囊、丸劑、扁囊劑及糖錠可用作適合於經口投與之固體劑型。Powders, capsules and lozenges preferably contain from 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and similar substances. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as carrier, which provides a capsule in which the active component, with or without other excipients, is surrounded by the carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

合適固體賦形劑為碳水化合物或蛋白填充劑，包括但不限於糖，包括乳糖、蔗糖、甘露糖醇或山梨糖醇；來自玉米、小麥、大米、馬鈴薯或其他植物之澱粉；纖維素，諸如甲基纖維素、羥丙基甲基纖維素或羧甲基纖維素鈉；及樹膠，包括***膠及黃蓍膠；以及蛋白質，諸如明膠及膠原。若需要，則可添加崩解劑或溶解劑，諸如交聯聚乙烯吡咯啶酮、瓊脂、褐藻酸或其鹽，諸如褐藻酸鈉。Suitable solid excipients are carbohydrate or protein fillers, including but not limited to sugars, including lactose, sucrose, mannitol or sorbitol; starches from corn, wheat, rice, potatoes or other plants; celluloses such as Methylcellulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose; and gums, including acacia and tragacanth; and proteins, such as gelatin and collagen. If necessary, a disintegrating or dissolving agent may be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.

糖衣藥丸核心具備合適包衣，諸如濃縮糖溶液，其亦可含有***膠、滑石、聚乙烯吡咯啶酮、卡波姆凝膠、聚乙二醇及/或二氧化鈦、清漆溶液及合適有機溶劑或溶劑混合物。染料或顏料可添加至錠劑或糖衣藥丸包衣以便產品識別或表徵活性化合物之數量(亦即，劑量)。醫藥製劑亦可經口使用，例如使用由明膠製成之推入式膠囊，以及由明膠及包衣如甘油或山梨糖醇製成之軟密封膠囊。推入式膠囊可含有與填充劑或黏合劑(諸如乳糖或澱粉)、潤滑劑(諸如滑石或硬脂酸鎂)以及視情況選用之穩定劑混合的本文揭示之化合物。在軟膠囊中，可在存在或不存在穩定劑之情況下，將本文揭示之化合物溶解或懸浮於合適液體，諸如脂肪油、液體石蠟或液體聚乙二醇中。Dragee cores are provided with suitable coatings, such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbomer gel, polyethylene glycol and/or titanium dioxide, varnish solutions and suitable organic solvents or solvent mixture. Dyestuffs or pigments can be added to tablets or dragee coatings for product identification or to characterize the amount (ie, dose) of active compound. The pharmaceutical preparations can also be used orally, using, for example, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating, eg glycerol or sorbitol. The push-fit capsules can contain the compounds disclosed herein in admixture with filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the compounds disclosed herein may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols, with or without stabilizers.

為製備栓劑，首先將低熔點蠟，諸如脂肪酸甘油酯或可可脂之混合物熔化且諸如藉由攪拌，將活性組分均勻地分散於其中。然後，將熔化之均勻混合物傾倒至便利大小之模具中，使其冷卻，且藉此凝固。To prepare suppositories, a low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active ingredient is dispersed uniformly therein, such as by stirring. The molten homogeneous mixture is then poured into conveniently sized molds, allowed to cool, and thereby solidified.

液體形式製劑包括溶液、懸浮液及乳液，例如，水或水/丙二醇溶液。對於非經腸注射，液體製劑可在溶液中在水性聚乙二醇溶液中調配。Liquid form preparations include solutions, suspensions and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

適合於經口使用之水溶液可藉由將活性組分溶解於水中且根據需要，添加合適著色劑、調味劑、穩定劑及增稠劑來製備。適合於經口使用之水性懸浮液可藉由將細粉狀活性組分與黏性材料及分散劑或潤濕劑一起分散於水中來製得，該黏性材料諸如天然或合成樹膠、樹脂、甲基纖維素、羧甲基纖維素鈉、羥丙基甲基纖維素、褐藻酸鈉、聚乙烯吡咯啶酮、黃蓍膠及***膠，該等分散劑或潤濕劑諸如天然存在之磷脂(例如，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)、環氧乙烷與長鏈脂肪醇之縮合產物(例如，十七乙烯氧十六醇)、環氧乙烷與衍生自脂肪酸及己糖醇之偏酯之縮合產物(例如，聚氧乙烯山梨糖醇單油酸酯)或環氧乙烷與衍生自脂肪酸及己糖醇酐之偏酯之縮合產物(例如，聚氧乙烯山梨醇酐單油酸酯)。水性懸浮液亦可含有一或多種防腐劑(諸如對羥基苯甲酸乙酯或對羥基苯甲酸正丙酯)、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、阿斯巴甜或糖精)。調配物可針對滲透性進行調整。Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilizing and thickening agents, as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active ingredient in water with a viscous material, such as natural or synthetic gums, resins, dispersants, or wetting agents, and a dispersing or wetting agent. Methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic, such as dispersing or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxide and fatty acid (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohol (e.g., heptadecanyloxycetyl alcohol) , Condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g. polyoxyethylene sorbitan monooleate) or partial esters of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides Condensation products (for example, polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents such as sucrose. , aspartame or saccharin). Formulations can be adjusted for osmolarity.

亦包括固體形式製劑，該等製劑意欲在使用之前不久轉化成用於經口投與之液體形式製劑。此等液體形式包括溶液、懸浮液及乳液。除活性組分以外，此等製劑可含有著色劑、調味劑、穩定劑、緩衝劑、人工及天然甜味劑、分散劑、增稠劑、助溶劑及其類似組分。Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions and emulsions. Such preparations may contain, in addition to the active ingredient, coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

油懸浮液可藉由將本文揭示之化合物懸浮於植物油(諸如花生油、橄欖油、芝麻油或椰子油)或礦物油(諸如液體石蠟)或此等物質之混合物中來調配。油懸浮液可含有增稠劑，諸如蜂蠟、固體石蠟或十六醇。可添加甜味劑以提供適口之口服製劑，諸如甘油、山梨糖醇或蔗糖。此等調配物可藉由添加抗氧化劑，諸如抗壞血酸來保存。作為可注射油媒劑之實例，參見Minto, J. Pharmacol. Exp. Ther.281:93-102, 1997。醫藥調配物亦可呈水包油乳液形式。油相可為上述植物油或礦物油，或此等油之混合物。合適之乳化劑包括天然存在之樹膠(諸如***膠及黃蓍膠)、天然存在之磷脂(例如大豆卵磷脂)、衍生自脂肪酸及己糖醇酐之酯或偏酯(諸如山梨醇酐單油酸酯)以及此等偏酯與環氧乙烷之縮合產物(諸如聚氧乙烯山梨醇酐單油酸酯)。如糖漿及酏劑之調配物中，乳液亦可含有甜味劑及調味劑。此類調配物亦可含有緩和劑、防腐劑或著色劑。 Oily suspensions can be formulated by suspending a compound disclosed herein in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or mineral oil such as liquid paraffin, or mixtures of these substances. The oily suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents may be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of antioxidants, such as ascorbic acid. For examples of injectable oil vehicles, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. Pharmaceutical formulations may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil or a mineral oil as described above, or a mixture of these oils. Suitable emulsifiers include naturally occurring gums such as acacia and tragacanth, naturally occurring phospholipids such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate acid esters) and condensation products of such partial esters with ethylene oxide (such as polyoxyethylene sorbitan monooleate). As in the preparation of syrups and elixirs, the emulsions may also contain sweetening and flavoring agents. Such formulations may also contain a demulcent, preservative or coloring agent.

本文揭示之化合物可藉由局部途徑，調配為敷藥棒、溶液、懸浮液、乳液、凝膠、乳膏、軟膏、糊劑、膠體、塗料、粉劑及氣溶膠來經皮遞送。The compounds disclosed herein can be delivered transdermally by topical routes, formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, colloids, paints, powders and aerosols.

本文揭示之化合物亦可作為微球來遞送以便在體內緩慢釋放。例如，微球可經由皮內注射含有藥物之微球來投與，該等微球皮下緩慢釋放(參見Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995；作為可生物降解及可注射之凝膠調配物(參見例如Gao Pharm. Res. 12:857-863, 1995)；或者，作為用於口服投與之微球(參見例如Eyles, J. Pharm. Pharmacol.49:669-674, 1997)。經皮及皮內途徑提供持續數週或數月之恆定遞送。 The compounds disclosed herein can also be delivered as microspheres for slow release in vivo. For example, microspheres can be administered via intradermal injection of drug-containing microspheres that are slowly released subcutaneously (see Rao, J. Biomater Sci. Polym. Ed . 7:623-645, 1995; as biodegradable and injectable gel formulations (see, for example, Gao Pharm. Res . 12:857-863, 1995); or, as microspheres for oral administration (see, for example, Eyles, J. Pharm. Pharmacol. 49:669 -674, 1997). Transdermal and intradermal routes provide constant delivery over weeks or months.

本文揭示之化合物之醫藥調配物可呈鹽形式提供且可用許多酸來形成，該等酸包括但不限於鹽酸、硫酸、乙酸、乳酸、酒石酸、蘋果酸、琥珀酸等。鹽傾向於在呈對應游離鹼形式之水性或其他質子溶劑中更可溶解。在其他情況下，製劑可為在4.5至5.5之pH範圍下之1 mM-50 mM組胺酸、0.1%-2%蔗糖、2%-7%甘露糖醇中的凍乾粉末，其在使用之前與緩衝液組合。Pharmaceutical formulations of the compounds disclosed herein may be provided as salts and may be formed with a number of acids including, but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, and the like. Salts tend to be more soluble in aqueous or other protic solvents as the corresponding free base form. In other cases, the formulation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5, which is used in Combined with buffer before.

本文揭示之化合物之醫藥調配物可呈鹽形式提供且可用鹼形成，亦即，陽離子鹽，諸如鹼金屬及鹼土金屬鹽，諸如鈉、鋰、鉀、鈣、鎂，以及銨鹽，諸如銨、三甲基銨、二乙銨及參-(羥甲基)-甲基-銨鹽。Pharmaceutical formulations of the compounds disclosed herein may be provided as salts and may be formed with bases, that is, cationic salts, such as alkali metal and alkaline earth metal salts, such as sodium, lithium, potassium, calcium, magnesium, and ammonium salts, such as ammonium, Trimethylammonium, diethylammonium and ginseng-(hydroxymethyl)-methyl-ammonium salts.

在一些實施例中，本文揭示之化合物之調配物可使用脂質體來遞送，該等脂質體與細胞膜融合或被內吞，亦即，藉由採用連接至脂質體或直接連接至寡核苷酸之配位體，該等配位體與細胞之表面膜蛋白受體結合，從而導致內吞。藉由使用脂質體，尤其當脂質體表面帶有對於標靶細胞具有特異性之配位體，或在其他方面優先被引導至特定器官時，可致力於在活體內將GR調節劑遞送至標靶細胞。(參見例如Al-Muhammed, J. Microencapsul.13:293-306, 1996；Chonn, Curr. Opin. Biotechnol.6:698-708, 1995；Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989)。 In some embodiments, formulations of the compounds disclosed herein can be delivered using liposomes that fuse with cell membranes or are endocytosed, i.e., by employing methods attached to liposomes or directly to oligonucleotides. Ligands that bind to cell surface membrane protein receptors, leading to endocytosis. By using liposomes, especially when the liposome surface bears a ligand specific for the target cell, or is otherwise preferentially directed to a particular organ, one can aim to deliver GR modulators to target organs in vivo. target cells. (See e.g. Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587 , 1989).

醫藥製劑較佳呈單位劑型。在此形式下，製劑被細分成含有合適數量之活性組分之單位劑量。單位劑型可為包裝之製劑，該包裝含有離散量之製劑，諸如包裝之錠劑、膠囊及小瓶或安瓿中之粉末。此外，單位劑型可為膠囊、錠劑、扁囊劑或糖錠本身，或其可為合適數目的呈包裝形式之此等物質中之任一者。Pharmaceutical formulations are preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

根據活性組分之特定應用及效力，單位劑量製劑中之活性組分之數量可自0.1 mg至10000 mg，更通常1.0 mg至1000 mg，最通常10 mg至500 mg變化或調整。若需要，組合物亦可含有其他相容治療劑。Depending on the particular application and potency of the active ingredient, the amount of active ingredient in a unit dosage formulation may be varied or adjusted from 0.1 mg to 10000 mg, more usually 1.0 mg to 1000 mg, most usually 10 mg to 500 mg. The composition, if desired, can also contain other compatible therapeutic agents.

給藥方案亦考慮到在此項技術中熟知之藥物動力學參數，亦即，吸收率、生體可用率、代謝、清除率及其類似參數(參見例如Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol.58:611-617；Groning (1996) Pharmazie51:337-341；Fotherby (1996) Contraception54:59-69；Johnson (1995) J. Pharm. Sci. 84:1144-1146；Rohatagi (1995) Pharmazie50:610-613；Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108；最新Remington’s, 同上)。當前最新技術允許臨床醫師確定各個別患者、GR及/或MR調節劑及所治療疾病或疾患之給藥方案。 Dosing regimens also take into account pharmacokinetic parameters well known in the art, that is, absorption rate, bioavailability, metabolism, clearance and the like (see, e.g., Hidalgo-Aragones (1996) J. Steroid Biochem . Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci . 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol . 24:103-108; latest Remington's, supra ). Current state-of-the-art technology allows clinicians to determine dosing regimens for each individual patient, GR and/or MR modulator, and disease or condition being treated.

本文揭示之化合物調配物之單次或多次投與可視患者需要及耐受之劑量及頻率而定來投與。調配物應提供足夠數量之活性劑以便有效地治療疾病狀態。因此，在一個實施例中，用於口服投與本文揭示之化合物之醫藥調配物的每日量介於每天每千克體重約0.5至約30 mg之間。在一個替代實施例中，使用之劑量為每名患者每天每公斤體重約1 mg至約20 mg。可使用較低劑量，特別是當藥物投與至解剖學上之隱蔽部位，例如腦脊髓液(CSF)空間，與口服投與相反，進入血流，進入體腔或進入器官內腔時。可在局部投與中使用顯著更高之劑量。製備包括本文揭示之化合物的用於非經腸投與之調配物的實際方法係熟習此項技術者而言已知或顯而易見的，且在諸如Remington’s, 同上之出版物中進行更詳細之描述。亦參見Nieman, 「Receptor Mediated Antisteroid Action」, Agarwal等人編, De Gruyter, New York (1987)。Single or multiple administrations of the compound formulations disclosed herein may be administered at dosages and frequencies as needed and tolerated by the patient. The formulation should provide a sufficient amount of active agent to effectively treat the disease state. Thus, in one embodiment, the daily amount of a pharmaceutical formulation for oral administration of a compound disclosed herein is between about 0.5 to about 30 mg per kilogram of body weight per day. In an alternative embodiment, the dosage used is from about 1 mg to about 20 mg per kilogram of body weight per patient per day. Lower doses may be used, especially when the drug is administered to an anatomically hidden site, such as the cerebrospinal fluid (CSF) space, into the bloodstream, into a body cavity, or into an organ lumen, as opposed to oral administration. Significantly higher dosages may be used in topical administration. Actual methods of preparing formulations for parenteral administration comprising the compounds disclosed herein are known or will be apparent to those skilled in the art and are described in more detail in publications such as Remington's, supra. See also Nieman, "Receptor Mediated Antisteroid Action", eds. Agarwal et al., De Gruyter, New York (1987).

本文描述之化合物可彼此、與已知可用於調節糖皮質激素受體之其他活性劑、或與可能單獨無效但可有助於活性劑之功效的輔助劑組合使用。The compounds described herein may be used in combination with each other, with other active agents known to be useful in modulating glucocorticoid receptors, or with adjuvants that may not be effective alone but may aid the efficacy of the active agents.

在一些實施例中，共同投與包括將一種活性劑在第二活性劑之0.5小時、1小時、2小時、4小時、6小時、8小時、10小時、12小時、16小時、20小時或24小時內投與。共同投與包括同時、大約同時(例如，彼此在約1分鐘、5分鐘、10分鐘、15分鐘、20分鐘或30分鐘內)或以任何次序依序投與兩種活性劑。在一些實施例中，共同投與可藉由共同調配來完成，亦即，製備包括兩種活性劑之單一醫藥組合物。在一些實施例中，活性劑可單獨調配。在一些實施例中，活性劑及/或輔助劑可彼此連接或結合。In some embodiments, co-administration comprises administering one active agent within 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, or Administer within 24 hours. Co-administration includes simultaneous, approximately simultaneous (eg, within about 1, 5, 10, 15, 20, or 30 minutes of each other) or sequential administration of the two active agents in any order. In some embodiments, co-administration can be accomplished by co-formulation, ie, preparation of a single pharmaceutical composition that includes both active agents. In some embodiments, the active agents can be formulated separately. In some embodiments, active agents and/or adjuvants may be linked or combined with each other.

在包括本文揭示之化合物之醫藥組合物在一或多種可接受之載劑中調配之後，其可安置於合適容器中且標記為用於治療所指示疾患。對於式I化合物之投與，此類標記包括例如關於投與之量、頻率及方法之說明。After a pharmaceutical composition including a compound disclosed herein has been formulated in one or more acceptable carriers, it can be placed in a suitable container and labeled for treatment of an indicated condition. For administration of a compound of formula I, such labeling includes, for example, instructions as to the amount, frequency and method of administration.

在一些實施例中，本文揭示之組合物可用於非經腸投與，諸如靜脈內(IV)投與或投與至體腔或器官內腔中。投與之調配物通常包含本文揭示之組合物溶解於一或多種醫藥學上可接受之載劑中的溶液。可採用之可接受之媒劑及溶劑為水及林格氏溶液(Ringer’s solution) (一種等滲氯化鈉)。此外，無菌不揮髮油通常可用作溶劑或懸浮介質。出於此目的，可採用任何溫和不揮髮油，包括合成甘油單酯或甘油二酯。此外，諸如油酸之脂肪酸同樣可用於製備註射劑。此等溶液為無菌的且通常不含不合需要之物質。此等調配物可藉由習知之熟知滅菌技術進行滅菌。調配物可含有如接近生理條件所需之醫藥學上可接受之輔助物質，諸如pH調整及緩衝劑、張力調整劑，例如乙酸鈉、氯化鈉、氯化鉀、氯化鈣、乳酸鈉及其類似物。此等調配物中組合物之濃度可廣泛變化，且將主要根據流體體積、黏度、體重及其類似因素，根據所選之特定投藥方式及患者之需要進行選擇。對於IV投與，調配物可為無菌可注射製劑，諸如無菌可注射水性或油性懸浮液。此懸浮液可根據已知技術使用彼等合適分散劑或潤濕劑及懸浮劑來調配。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，例如1,3-丁二醇之溶液形式。In some embodiments, the compositions disclosed herein are useful for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or lumen of an organ. Formulations for administration generally comprise a solution of a composition disclosed herein dissolved in one or more pharmaceutically acceptable carriers. Among the acceptable vehicles and solvents that may be employed are water and Ringer's solution (an isotonic sodium chloride). In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are likewise used in the preparation of injectables. Such solutions are sterile and generally free of undesirable matter. These formulations can be sterilized by conventional and well-known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as necessary to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like. analog. The concentrations of the compositions in such formulations can vary widely and will be selected primarily based on fluid volume, viscosity, body weight and the like, the particular mode of administration chosen and the needs of the patient. For IV administration, the formulation may be a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be in the form of a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example a solution in 1,3-butanediol.

在一些實施例中，本文揭示之化合物之調配物可使用脂質體來遞送，該等脂質體與細胞膜融合或被內吞，亦即，藉由採用連接至脂質體或直接連接至寡核苷酸之配位體，該等配位體與細胞之表面膜蛋白受體結合，從而導致內吞。藉由使用脂質體，尤其當脂質體表面帶有對於標靶細胞具有特異性之配位體，或在其他方面優先被引導至特定器官時，可致力於在活體內將本文揭示之組合物遞送至標靶細胞。(參見例如Al-Muhammed, J. Microencapsul.13:293-306, 1996；Chonn, Curr. Opin. Biotechnol.6:698-708, 1995；Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989)。 V. 方法 In some embodiments, formulations of the compounds disclosed herein can be delivered using liposomes that fuse with cell membranes or are endocytosed, i.e., by employing methods attached to liposomes or directly to oligonucleotides. Ligands that bind to cell surface membrane protein receptors, leading to endocytosis. By using liposomes, especially when the liposome surface bears a ligand specific for the target cell, or is otherwise preferentially directed to a particular organ, one can aim to deliver the compositions disclosed herein in vivo to target cells. (See e.g. Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587 , 1989). V. method

在一些實施例中，提供一種治療個體之病症或疾患的方法，該方法包括向人類投與治療有效量之本文揭示之化合物或其醫藥學上可接受之鹽，或如本文揭示之醫藥組合物。In some embodiments, there is provided a method of treating a disorder or disorder in a subject comprising administering to a human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as disclosed herein .

在一些實施例中，提供一種用於抑制細胞中之KRAS G12D活性的方法，其包括使需要抑制KRAS G12D活性之細胞與有效量之本文揭示之化合物或其醫藥學上可接受之鹽接觸。In some embodiments, there is provided a method for inhibiting KRAS G12D activity in a cell comprising contacting a cell in need of inhibition of KRAS G12D activity with an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

在一些實施例中，提供一種用於抑制細胞中之KRAS G12D活性的方法，其包括使需要抑制KRAS G12D活性之細胞與本文揭示之醫藥組合物接觸。In some embodiments, there is provided a method for inhibiting KRAS G12D activity in a cell comprising contacting a cell in need of inhibition of KRAS G12D activity with a pharmaceutical composition disclosed herein.

在一些實施例中，提供一種用於治療KRAS G12D相關癌症之方法，其包括向有需要之患者投與治療有效量之本文揭示之化合物或其醫藥學上可接受之鹽。In some embodiments, there is provided a method for treating KRAS G12D-associated cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof.

在一些實施例中，提供一種用於治療KRAS G12D相關癌症之方法，其包括向有需要之患者投與本文揭示之醫藥組合物。In some embodiments, there is provided a method for treating KRAS G12D-associated cancer comprising administering a pharmaceutical composition disclosed herein to a patient in need thereof.

在一些實施例中，提供一種治療患有癌症之個體的方法，該癌症之特徵在於存在KRAS G12D突變，該方法包括向人類投與治療有效量之式(I)中任一者之化合物或其醫藥學上可接受之鹽，或如本文揭示之醫藥組合物。In some embodiments, there is provided a method of treating an individual with cancer characterized by the presence of a KRAS G12D mutation, the method comprising administering to the human a therapeutically effective amount of a compound of any one of formula (I) or A pharmaceutically acceptable salt, or a pharmaceutical composition as disclosed herein.

在一些實施例中，提供一種用於製造供治療患有癌症之個體用之藥物的方法，該癌症之特徵在於存在KRAS G12D突變，該方法使用包含式(I)之化合物或其醫藥學上可接受之鹽，或醫藥組合物。In some embodiments, there is provided a method for the manufacture of a medicament for treating an individual with cancer characterized by the presence of a KRAS G12D mutation using a compound comprising formula (I) or a pharmaceutically acceptable Acceptable salts, or pharmaceutical compositions.

在一些實施例中，提供式(I)化合物或其醫藥學上可接受之鹽或如本文揭示之醫藥組合物的用途，其用於製造供治療患有癌症之人類用之藥物，該癌症之特徵在於存在KRAS G12D突變。In some embodiments, there is provided a use of a compound of formula (I) or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as disclosed herein for the manufacture of a medicament for treating a human suffering from cancer, the cancer Characterized by the presence of the KRAS G12D mutation.

在一些實施例中，提供式(I)化合物或其醫藥學上可接受之鹽，或如本文揭示之醫藥組合物，其用於治療患有癌症之個體，該癌症之特徵在於存在KRAS G12D突變。In some embodiments, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as disclosed herein, for use in the treatment of an individual with cancer characterized by the presence of a KRAS G12D mutation .

在一些實施例中，提供一種用於治療有需要之患者之癌症的方法，該方法包括(a)確定該癌症與KRAS G12D突變相關(例如，KRAS G12D相關癌症)；及(b)向該患者投與治療有效量之本文揭示之化合物。In some embodiments, there is provided a method for treating cancer in a patient in need thereof, comprising (a) determining that the cancer is associated with a KRAS G12D mutation (e.g., a KRAS G12D-associated cancer); and (b) administering to the patient A therapeutically effective amount of a compound disclosed herein is administered.

在一些實施例中，提供一種用於治療有需要之患者之癌症的方法，該方法包括(a)確定該癌症與KRas G12D突變相關(例如，KRAS G12D相關癌症)；及(b)向該患者投與本文揭示之醫藥組合物。In some embodiments, there is provided a method for treating cancer in a patient in need thereof, the method comprising (a) determining that the cancer is associated with a KRas G12D mutation (e.g., a KRAS G12D-associated cancer); and (b) administering to the patient A pharmaceutical composition disclosed herein is administered.

在一些實施例中，癌症為心臟：肉瘤(血管肉瘤、纖維肉瘤、橫紋肌肉瘤、脂肪肉瘤)、黏液瘤、橫紋肌瘤、纖維瘤、脂肪瘤及畸胎瘤；肺：支氣管癌(鱗狀細胞、未分化小細胞、未分化大細胞、腺癌)、肺泡(細支氣管)癌、支氣管腺瘤、肉瘤、淋巴瘤、軟骨瘤性錯構瘤、間皮瘤；胃腸道：食道(鱗狀細胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃(癌瘤、淋巴瘤、平滑肌肉瘤)、胰臟(導管腺癌、胰島素瘤、胰高血糖素瘤、胃泌素瘤、類癌瘤、vip瘤)、小腸(腺癌、淋巴瘤、類癌瘤、卡波西氏肉瘤(Kaposi’s sarcoma)、平滑肌瘤、血管瘤、脂肪瘤、神經纖維瘤、纖維瘤)、大腸(腺癌、管狀腺瘤、絨毛狀腺瘤、錯構瘤、平滑肌瘤)；泌尿生殖道：腎臟(腺癌、威爾姆氏瘤(Wilm’s tumor) (腎母細胞瘤)、淋巴瘤、白血病)、膀胱及尿道(鱗狀細胞癌、移行細胞癌、腺癌)、***(腺癌、肉瘤)、睪丸(精原細胞瘤、畸胎瘤、胚胎癌、畸胎癌、絨毛膜癌、肉瘤、間質細胞癌、纖維瘤、纖維腺瘤、腺瘤樣腫瘤、脂肪瘤)；肝臟：肝腫瘤(肝細胞癌)、膽管癌、肝母細胞瘤、血管肉瘤、肝細胞腺瘤、血管瘤；膽道：膽囊癌、壺腹癌、膽管癌；骨：骨原性肉瘤(骨肉瘤)、纖維肉瘤、惡性纖維組織細胞瘤、軟骨肉瘤、尤文氏肉瘤(Ewing’s sarcoma)、惡性淋巴瘤(網狀細胞肉瘤)、多發性骨髓瘤、惡性巨細胞瘤脊索瘤、骨軟骨瘤(骨軟骨性外生骨疣)、良性軟骨瘤、軟骨母細胞瘤、軟骨黏液纖維瘤、骨樣骨瘤及巨細胞瘤；神經系統：顱骨(骨瘤、血管瘤、肉芽腫、黃色瘤、變形性骨炎)、腦膜(腦膜瘤、腦膜肉瘤、神經膠瘤病)、腦(星形細胞瘤、髓母細胞瘤、神經膠質瘤、室管膜瘤、生殖細胞瘤(松果體瘤)、多形性神經膠質母細胞瘤、寡樹突神經膠質瘤、神經鞘瘤、視網膜母細胞瘤、先天性腫瘤)、脊髓神經纖維瘤、腦膜瘤、神經膠質瘤、肉瘤)；婦科：子宮(子宮內膜癌(漿液性囊腺癌、黏液性囊腺癌、未分類癌)、粒層細胞-卵囊泡膜細胞瘤、賽特利-萊迪細胞瘤(Sertoli-Leydig cell tumor)、無性細胞瘤、惡性畸胎瘤)、陰門(鱗狀細胞癌、上皮內癌、腺癌、纖維肉瘤、黑色素瘤)、***(透明細胞癌、鱗狀細胞癌、葡萄狀肉瘤(胚胎性橫紋肌肉瘤)、輸卵管(癌瘤)；血液學：血液(骨髓性白血病(急性及慢性)、急性淋巴母細胞性白血病、慢性淋巴球性白血病、骨髓增生性疾病、多發性骨髓瘤、骨髓化生不良症候群)、霍奇金氏病(Hodgkin’s disease)、非霍奇金氏淋巴瘤(惡性淋巴瘤)；皮膚：惡性黑色素瘤、基底細胞癌、鱗狀細胞癌、卡波西氏肉瘤、痣發育不良痣、脂肪瘤、血管瘤、皮膚纖維瘤、瘢痕疙瘩、牛皮癬；或腎上腺：神經母細胞瘤。In some embodiments, the cancer is heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma, and teratoma; lung: bronchial carcinoma (squamous cell, Undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous cell carcinoma , adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, VIP tumor ), small bowel (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma , villous adenoma, hamartoma, leiomyoma); urogenital tract: kidney (adenocarcinoma, Wilm's tumor (Wilms tumor), lymphoma, leukemia), bladder and urethra ( Squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma); liver: liver neoplasms (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder carcinoma , ampullary carcinoma, cholangiocarcinoma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocyte sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system: Skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, Ependymoma, germ cell tumor (pineeal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), neurofibroma of the spinal cord, meningioma, glioma, sarcoma); gynecology: uterine (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell-ootheca cell tumor, Sately - Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma , squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematology: blood (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, bone marrow proliferative disease, multiple myeloma, myelometaplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous Cystoid cell carcinoma, Kaposi's sarcoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; or adrenal gland: neuroblastoma.

在一些實施例中，癌症為非小細胞肺癌、小細胞肺癌、結直腸癌、直腸癌或胰臟癌。In some embodiments, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer, or pancreatic cancer.

在某些實施例中，治療可在已出現一或多種症狀之後投與。在其他實施例中，治療可在不存在症狀時投與。例如，可在症狀發作之前對易感個體進行治療(例如，根據症狀史及/或根據遺傳或其他易感因素)。治療亦可在症狀消退之後繼續，例如以便預防或延遲其復發。In certain embodiments, treatment may be administered after one or more symptoms have occurred. In other embodiments, treatment can be administered in the absence of symptoms. For example, susceptible individuals can be treated prior to onset of symptoms (eg, based on history of symptoms and/or based on genetic or other predisposing factors). Treatment can also be continued after symptoms have subsided, for example, to prevent or delay their recurrence.

式(I)化合物或其醫藥學上可接受之鹽可為KRAS G12D之抑制劑。例如，本文揭示之化合物之抑制常數(Ki)可小於約50 µM，或小於約40 µM、30 µM、20 µM、10 µM、9 µM、8 µM、7 µM、6 µM、5 µM、4 µM、3 µM、2 µM或小於約1 µM。本文揭示之化合物之抑制常數(Ki)可小於約1,000 nM，或小於約900 nM、800 nM、700 nM、600 nM、500 nM、400 nM、300 nM、200 nM、100 nM、90 nM、80 nM、70 nM、60 nM、50 nM、40 nM、30 nM、20 nM、10 nM、9 nM、8 nM、7 nM、6 nM、5 nM、4 nM、3 nM、2 nM或小於約1 nM。本文揭示之化合物之抑制常數(Ki)可小於約1 nM，或小於約0.9 nM、0.8 nM、0.7 nM、0.6 nM、0.5 nM、0.4 nM、0.3 nM、0.2 nM或小於約0.1 nM。The compound of formula (I) or a pharmaceutically acceptable salt thereof can be an inhibitor of KRAS G12D. For example, compounds disclosed herein may have an inhibition constant (Ki) of less than about 50 µM, or less than about 40 µM, 30 µM, 20 µM, 10 µM, 9 µM, 8 µM, 7 µM, 6 µM, 5 µM, 4 µM , 3 µM, 2 µM, or less than about 1 µM. Compounds disclosed herein may have an inhibition constant (Ki) of less than about 1,000 nM, or less than about 900 nM, 800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 90 nM, 80 nM, 70 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM or less than about 1 nM. Compounds disclosed herein may have an inhibition constant (Ki) of less than about 1 nM, or less than about 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, or less than about 0.1 nM.

式(I)化合物或其醫藥學上可接受之鹽可為KRAS G12D之選擇性抑制劑。例如，本文揭示之化合物之KRAS G12D抑制常數(IC50)可比KRAS野生型或NRAS或HRAS中之一或多者之抑制常數低至少2倍，或低至少3、4、5、6、7、8、9、10、20、30、40、50、60、70、80、90或100倍。本文揭示之化合物之KRAS g12D抑制常數(Ki)亦可比KRAS野生型或NRAS或HRAS中之一或多者之抑制常數低至少100倍，或低至少200、300、400、500、600、700、800、900、1000或10,000倍。 A. 癌症組合療法 The compound of formula (I) or a pharmaceutically acceptable salt thereof may be a selective inhibitor of KRAS G12D. For example, the KRAS G12D inhibition constant (IC50) of the compounds disclosed herein can be at least 2-fold lower, or at least 3, 4, 5, 6, 7, 8 lower than the inhibition constant of KRAS wild-type or one or more of NRAS or HRAS , 9, 10, 20, 30, 40, 50, 60, 70, 80, 90 or 100 times. The KRAS g12D inhibition constant (Ki) of the compounds disclosed herein may also be at least 100-fold lower than that of KRAS wild-type or one or more of NRAS or HRAS, or at least 200, 300, 400, 500, 600, 700, 800, 900, 1000 or 10,000 times. A. Combination Therapies for Cancer

本文揭示之化合物或其鹽可單獨或與其他用於治療之藥劑組合使用。例如，醫藥組合調配物或給藥方案之第二藥劑可具有與本文揭示之化合物互補之活性以使得其不會不利地彼此影響。該等化合物可在單一醫藥組合物中一起投與或分開投與。在一個實施例中，化合物或醫藥學上可接受之鹽可與細胞毒性劑共同投與以便治療增生性疾病及癌症。The compounds disclosed herein, or salts thereof, may be used alone or in combination with other therapeutic agents. For example, the second agent of the pharmaceutical combination formulation or dosing regimen may have complementary activities to the compounds disclosed herein such that they do not adversely affect each other. The compounds can be administered together or separately in a single pharmaceutical composition. In one embodiment, the compounds or pharmaceutically acceptable salts may be co-administered with cytotoxic agents for the treatment of proliferative diseases and cancer.

術語「共同投與」係指同時投與、或以任何方式分開依序投與本文揭示之化合物或其鹽與包括細胞毒性劑及輻射治療之一或多種其他活性醫藥成分。若不同時投與，則化合物在彼此緊密接近之時間內來投與。此外，化合物是否以相同劑型投與並不重要，例如，一種化合物可局部投與且另一種化合物可經口投與。The term "co-administration" refers to the simultaneous administration, or the separate sequential administration in any manner, of a compound disclosed herein, or a salt thereof, and one or more other active pharmaceutical ingredients including cytotoxic agents and radiation therapy. If not administered simultaneously, the compounds are administered within close proximity of each other. Furthermore, it does not matter whether the compounds are administered in the same dosage form, eg, one compound may be administered topically and the other may be administered orally.

作為多重給藥方案之一部分，彼等額外藥劑可與含有本發明化合物之組合物分開投與。或者，彼等藥劑可為單一劑型之一部分，與本文揭示之化合物一起混合於單一組合物中。若作為多重給藥方案之一部分來投與，則兩種活性劑可同時、依序或在彼此一段時間內通常在彼此五小時內提供。Such additional agents may be administered separately from the compositions containing the compounds of the invention as part of a multiple dosing regimen. Alternatively, these agents may be part of a single dosage form, mixed together with the compounds disclosed herein in a single composition. If administered as part of a multiple dosing regimen, the two active agents may be provided simultaneously, sequentially, or within a period of each other, typically within five hours of each other.

如本文所用，術語「組合(combination/ combined)」及相關術語係指根據本文中之實施例之治療劑的同時或依序投與。例如，本文揭示之化合物可與另一種治療劑在分開單位劑型中同時或依序投與或在單一單位劑型中一起投與。因此，本發明之實施例提供包含式(I)化合物、另一治療劑及醫藥學上可接受之載劑、佐劑或媒劑之單一單位劑型。As used herein, the term "combination/combined" and related terms refer to the simultaneous or sequential administration of the therapeutic agents according to the embodiments herein. For example, a compound disclosed herein can be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, embodiments of the present invention provide single unit dosage forms comprising a compound of formula (I), another therapeutic agent and a pharmaceutically acceptable carrier, adjuvant or vehicle.

可與載劑材料組合以便產生單一劑型之本發明化合物及另一治療劑(在包含如上所述另一治療劑之組合物中)之量視所治療宿主及特定投與模式而變化。在某些實施例中，調配本文揭示之組合物以使得可投與0.01-100 mg/kg體重/天之間的本發明之劑量。The amount of a compound of the invention and another therapeutic agent (in a composition comprising another therapeutic agent as described above) that can be combined with a carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. In certain embodiments, the compositions disclosed herein are formulated such that a dosage of between 0.01-100 mg/kg body weight/day of the invention can be administered.

通常，具有針對所治療疾病或疾患之活性之任何藥劑均可共同投與。此類藥劑之實例可見於Cancer Principles and Practice of Oncology , V.T. Devita及S. Hellman (編), 第6版(2001年2月15日), Lippincott Williams & Wilkins Publishers。一般熟習此項技術者能夠基於藥物之特定特征及所涉及疾病來辨別哪些藥劑組合將可用。In general, any agent that is active against the disease or condition being treated can be co-administered. Examples of such agents can be found in Cancer Principles and Practice of Oncology, V.T. Devita and S. Hellman (Eds.), 6th Edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. Those of ordinary skill in the art will be able to discern which combinations of agents will be useful based on the particular characteristics of the drugs and the disease involved.

在一個實施例中，治療方法包括共同投與本文揭示之化合物或其醫藥學上可接受之鹽及至少一種細胞毒性劑。如本文所用之術語「細胞毒性劑」係指抑制或阻止細胞功能及/或導致細胞死亡或破壞之物質。細胞毒性劑包括但不限於放射性同位素(例如，At 211、I 131、I 125、Y 90、Re 186、Re 188、Sm 153、Bi 212、P 32、Pb 212及Lu之放射性同位素)；化學治療劑；生長抑制劑；酶及其片段，諸如溶核酶；及毒素，諸如小分子毒素或細菌、真菌、植物或動物來源之酶活性毒素，包括其片段及/或變異體。 In one embodiment, the method of treatment comprises co-administering a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and at least one cytotoxic agent. The term "cytotoxic agent" as used herein refers to a substance that inhibits or prevents cellular function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioisotopes (e.g., radioisotopes of At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and Lu); chemotherapy growth inhibitors; enzymes and fragments thereof, such as nucleolytic enzymes; and toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.

示例性細胞毒性劑可選自抗微管劑、鉑配位錯合物、烷化劑、抗生素劑、拓撲異構酶II抑制劑、抗代謝物、拓撲異構酶I抑制劑、激素及激素類似物、信號轉導路徑抑制劑、非受體酪胺酸激酶血管生成抑制劑、免疫治療劑、促凋亡劑、LDH-A之抑制劑；脂肪酸生物合成之抑制劑；細胞週期信號傳導抑制劑；HDAC抑制劑、蛋白酶體抑制劑；及癌症代謝之抑制劑。Exemplary cytotoxic agents may be selected from antimicrotubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones, and hormones Analogs, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutics, pro-apoptotic agents, inhibitors of LDH-A; inhibitors of fatty acid biosynthesis; cell cycle signaling inhibition agents; HDAC inhibitors, proteasome inhibitors; and inhibitors of cancer metabolism.

「化學治療劑」包括可用於治療癌症之化合物。化學治療劑之實例包括埃羅替尼(erlotinib) (TARCEVA ®，Genentech/OSI Pharm.)、硼替佐米(bortezomib) (VELCADE ®，Millennium Pharm.)、雙硫侖(disulfiram)、表沒食子兒茶素沒食子酸酯、鹽孢菌素A (salinosporamide A)、卡非佐米(carfilzomib)、17-AAG (格爾德黴素(geldanamycin))、根赤殼菌素(radicicol)、乳酸脫氫酶A (LDH-A)、氟維司群(fulvestrant) (FASLODEX ®，AstraZeneca)、舒尼替尼(sunitib) (SUTENT ®，Pfizer/Sugen)、來曲唑(letrozole) (FEMARA ®，Novartis)、甲磺酸伊馬替尼(imatinib mesylate) (GLEEVEC ®，Novartis)、菲那舒那(finasunate) (VATALANIB ®，Novartis)、奧沙利鉑(oxaliplatin) (ELOXATIN ®，Sanofi)、5-氟尿嘧啶(5-fluorouracil，5-FU)、亞葉酸(leucovorin)、雷帕黴素(Rapamycin) (西羅莫司(Sirolimus)、RAPAMUNE ®，Wyeth)、拉帕替尼(Lapatinib) (TYKERB ®、GSK572016，Glaxo Smith Kline)、洛那法尼(Lonafamib) (SCH 66336)、索拉非尼(sorafenib) (NEXAVAR ®，Bayer Labs)、吉非替尼(gefitinib) (IRESSA ®，AstraZeneca)、AG1478、烷化劑(諸如噻替派(thiotepa)及CYTOXAN ®環磷醯胺)；烷基磺酸酯，諸如白消安(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan)；氮丙啶，諸如本并多巴(benzodopa)、卡巴醌(carboquone)、美妥替哌(meturedopa)及烏瑞替哌(uredopa)；伸乙基亞胺及甲基蜜胺，包括六甲蜜胺(altretamine)、三伸乙基蜜胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺及三羥甲基蜜胺；番荔枝內酯(acetogenin) (尤其布拉它辛(bullatacin)及布拉它辛酮(bullatacinone))；喜樹鹼(camptothecin) (包括拓撲替康(topotecan)及伊立替康(irinotecan))；苔蘚抑素(bryostatin)；凱利他汀(callystatin)；CC-1065 (包括其阿多來新(adozelesin)、卡折來新(carzelesin)及比折來新(bizelesin)合成類似物)；念珠藻素(cryptophycin) (尤其念珠藻素1及念珠藻素8)；腎上腺皮質類固醇(包括潑尼松(prednisone)及普賴蘇穠(prednisolone))；醋酸環丙孕酮(cyproterone acetate)；5α-還原酶，包括非那雄胺(finasteride)及度他雄胺(dutasteride))；伏立諾他(vorinostat)、羅米地辛(romidepsin)、帕比司他(panobinostat)、丙戊酸、莫西司他(mocetinostat)、多拉司他汀(dolastatin)；阿地介白素(aldesleukin)、滑石、倍癌黴素(duocarmycin) (包括合成類似物KW-2189及CB1-TM1)；艾榴塞洛素(eleutherobin)；潘卡他汀(pancratistatin)；匍枝珊瑚醇(sarcodictyin)；海綿抑制素(spongistatin)；氮芥，諸如苯丁酸氮芥(chlorambucil)、氯瑪法辛(chlomaphazine)、氯磷醯胺(chlorophosphamide)、雌氮芥(estramustine)、異環磷醯胺(ifosfamide)、二氯甲基二乙胺(mechlorethamine)、二氯甲基二乙胺氧化物鹽酸鹽、美法侖(melphalan)、新恩比興(novembichin)、膽固醇苯乙酸氮芥(phenesterine)、松龍苯芥(prednimustine)、氯乙環磷醯胺(trofosfamide)、尿嘧啶氮芥；亞硝基脲，諸如卡莫司汀(carmustine)、氯脲黴素(chlorozotocin)、福莫司汀(fotemustine)、洛莫司汀(lomustine)、尼莫司汀(nimustine)及雷莫司汀(ranimnustine)；抗生素，諸如烯二炔抗生素(例如卡里奇黴素(calicheamicin)、尤其卡里奇黴素γ1I及卡里奇黴素ω1I ( Angew Chem. Intl. Ed. Engl. 199433:183-186)；達內黴素(dynemicin)，包括達內黴素A；雙膦酸鹽，諸如氯膦酸鹽(clodronate)；埃斯培拉黴素(esperamicin)；以及新制癌菌素(neocarzinostatin)發色團及相關色蛋白烯二炔抗生素發色團)、阿克拉黴素(aclacinomysin)、放線菌素(actinomycin)、安麯黴素(authramycin)、重氮絲胺酸(azaserine)、博萊黴素(bleomycin)、放線菌素C (cactinomycin)、卡拉比星(carabicin)、洋紅黴素(caminomycin)、嗜癌菌素(carzinophilin)、色黴素(chromomycinis)、放線菌素D (dactinomycin)、柔紅黴素(daunorubicin)、地托比星(detorubicin)、6-重氮基-5-側氧基-L-正白胺酸、ADRIAMYCIN ®(多柔比星)、N-嗎啉基-多柔比星、氰基(N-嗎啉基)-多柔比星、2-(N-吡咯基)-多柔比星及去氧多柔比星)、泛艾黴素(epirubicin)、依索比星(esorubicin)、艾達黴素(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(mitomycin) (諸如絲裂黴素C)、黴酚酸、諾加黴素(nogalamycin)、橄欖黴素(olivomycin)、培洛黴素(peplomycin)、波弗黴素(porfiromycin)、嘌呤黴素(puromycin)、三鐵阿黴素(quelamycin)、羅多比星(rodorubicin)、鏈黑菌素(streptonigrin)、鏈脲黴素(streptozocin)、殺結核菌素(tubercidin)、烏苯美司(ubenimex)、淨司他汀(zinostatin)、佐柔比星(zorubicin)；抗代謝物，諸如甲胺喋呤(methotrexate)及5-氟尿嘧啶(5-FU)；葉酸類似物，諸如二甲葉酸(denopterin)、甲胺喋呤、喋羅呤(pteropterin)、三甲曲沙(trimetrexate)；嘌呤類似物，諸如氟達拉濱(fludarabine)、6-巰基嘌呤(6-mercaptopurine)、硫咪嘌呤(thiamiprine)、硫鳥嘌呤；嘧啶類似物，諸如環胞苷(ancitabine)、阿紮胞苷(azacitidine)、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二去氧尿苷、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷(floxuridine)；雄激素，諸如二甲睪酮(calusterone)、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睪內酯(testolactone)；抗腎上腺素，諸如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane)；葉酸補充劑，諸如弗羅林酸(frolinic acid)；乙醯葡醛酯(aceglatone)；醛磷醯胺糖苷(aldophosphamide glycoside)；胺基乙醯丙酸(aminolevulinic acid)；恩尿嘧啶(eniluracil)；安吖啶(amsacrine)；倍曲布西(bestrabucil)；比生群(bisantrene)；依達曲沙(edatraxate)；地佛法明(defofamine)；地美可辛(demecolcine)；地吖醌(diaziquone)；伊佛米新(elfomithine)；依利醋銨(elliptinium acetate)；埃博黴素(epothilone)；依託格魯(etoglucid)；硝酸鎵；羥基脲；香菇多糖(lentinan)；洛尼代寧(lonidainine)；類美登醇(maytansinoid)，諸如美登素(maytansine)及安絲菌素(ansamitocin)；米托胍腙(mitoguazone)；米托蒽醌(mitoxantrone)；莫匹達洛(mopidamnol)；二胺硝吖啶(nitraerine)；噴司他汀(pentostatin)；苯來美特(phenamet)；吡柔比星(pirarubicin)；洛索蒽醌(losoxantrone)；足葉草酸(podophyllinic acid)；2-乙基醯肼；丙卡巴肼(procarbazine)；PSK ®多醣複合物(JHS Natural Products, Eugene, Oreg.)；雷佐生(razoxane)；根黴素(rhizoxin)；西索菲蘭(sizofuran)；螺旋鍺(spirogermanium)；細交鏈孢菌酮酸(tenuazonic acid)；三亞胺醌(triaziquone)；2,2’,2”-三氯三乙胺；新月毒素(trichothecene) (尤其T-2毒素、維拉庫林A (verracurin A)、桿孢菌素A (roridin A)及蛇形菌素(anguidine))；烏拉坦(urethan)；長春地辛(vindesine)；達卡巴嗪(dacarbazine)；甘露醇氮芥(mannomustine)；二溴甘露醇(mitobronitol)；二溴衛矛醇(mitolactol)；哌泊溴烷(pipobroman)；格塞圖辛(gacytosine)；***糖苷(「Ara-C」)；環磷醯胺；噻替派；類紫杉醇(taxoid)，例如TAXOL (太平洋紫杉醇；Bristol-Myers Squibb Oncology, Princeton, N.J.)、ABRAXANE ®(不含聚氧乙烯氫化蓖麻油(Cremophor-free))、太平洋紫杉醇之白蛋白工程改造奈米粒子調配物(American Pharmaceutical Partners, Schaumberg, Ill.)及TAXOTERE ®(多西紫杉醇、多西他賽(doxetaxel)；Sanofi-Aventis)；苯丁酸氮芥(chloranmbucil)；GEMZAR ®(吉西他濱(gemcitabine))；6-硫鳥嘌呤；巰基嘌呤；甲胺喋呤；鉑類似物，諸如順鉑及卡鉑；長春花鹼(vinblastine)；依託泊苷(etoposide) (VP-16)；異環磷醯胺；米托蒽醌；長春新鹼(vincristine)；NAVELBINE ®(長春瑞濱(vinorelbine))；諾安托(novantrone)；替尼泊苷(teniposide)；依達曲沙(edatrexate)；道諾黴素(daunomycin)；胺基喋呤；卡培他濱(capecitabine) (XELODA ®)；伊班膦酸鹽(ibandronate)；CPT-11；拓撲異構酶抑制劑RFS 2000；二氟甲基鳥胺酸(DMFO)；類視色素(retinoid)，諸如視黃酸(retinoic acid)；及以上任一者之醫藥學上可接受之鹽、酸及衍生物。 "Chemotherapeutic agents" include compounds useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib ( TARCEVA® , Genentech/OSI Pharm.), bortezomib ( VELCADE® , Millennium Pharm.), disulfiram, epigalloc Catechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol, Lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX ® , AstraZeneca), sunitinib (SUTENT ® , Pfizer/Sugen), letrozole (FEMARA ® , Novartis), imatinib mesylate (GLEEVEC ® , Novartis), finasunate (VATALANIB ® , Novartis), oxaliplatin (ELOXATIN ® , Sanofi), 5 -Fluorouracil (5-fluorouracil, 5-FU), leucovorin, rapamycin (Sirolimus, RAPAMUNE ® , Wyeth), lapatinib (TYKERB ® , GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), sorafenib (NEXAVAR ® , Bayer Labs), gefitinib (IRESSA ® , AstraZeneca), AG1478 , alkylating agents (such as thiotepa and CYTOXAN® cyclophosphamide); alkyl sulfonates such as busulfan, improsulfan, and piposulfan aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylmelamines, including melamine altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenin (especially bratasine (bulatacin and bullatacinone); camptothecin (including topotecan and irinotecan); bryostatin; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycin (especially nodocin 1 and nodocin 8); adrenal corticosteroids (including prednisone and prednisolone); cyproterone acetate; 5α-reductase, including finasteride and duta androstamine (dutasteride); vorinostat, romidepsin, panobinostat, valproic acid, mocetinostat, dolastatin ; aldesleukin, talc, duocarmycin (including synthetic analogues KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyn; spongistatin; nitrogen mustards such as chlorambucil, chlormaphazine, chlorophosphamide, etramustine, Ifosfamide, mechlorethamine, dichloromethyldiethylamine oxide hydrochloride, melphalan, novembichin, cholesterylbenzene phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin ), fotemustine, lomustine, nimustine and ranimnustine; antibiotics such as enediyne antibiotics (e.g. calicheamicin ), especially calicheamicin γ1I and calicheamicin ω1I ( Angew Chem. Intl. Ed. Engl. 1994 33:183-186); dynemicin (dynemicin), including dynemicin A; double Phosphonates, such as clodronate; esperamicin; and the neocarzinostatin chromophore and related chromophores (endiyne antibiotic chromophore), aclaramycin aclacinomysin, actinomycin, athramycin, azaserine, bleomycin, cactinomycin, carabicin , caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-heavy Nitro-5-oxo-L-norleucine, ADRIAMYCIN ® (doxorubicin), N-morpholino-doxorubicin, cyano(N-morpholino)-doxorubicin , 2-(N-pyrrolyl)-doxorubicin and deoxydoxorubicin), pan-epirubicin, esorubicin, idarubicin, maxiluo marcellomycin, mitomycin (such as mitomycin C), mycophenolic acid, nogalamycin, olivomycin, peplomycin, wave Porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tuberculocidal tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); Folic acid analogues, such as dimethylfolate (denopterin), methotrexate, pteropterin (pteropterin), trimetrexate (trimetrexate); purine analogues, such as fludarabine (fludarabine), 6-mercaptopurine (6-mercaptopurine) -mercaptopurine), thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azuridine, carmofur, arabinose cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dropropionate Dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenergics such as aminoglutethimide, mitotane, koji Trilostane; folic acid supplements such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid ; Eniluracil (eniluracil); Amsacrine (amsacrine); Betrabucil (bestrabucil); Bisantrene (bisantrene); Edatraxate (edatraxate); demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan ( lentinan; lonidainine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone ; Mopidamnol; Nitraerine; Pentostatin; Phenamet; Pirarubicin; Podophyllinic acid; 2-ethylhydrazine; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichlorotriethylamine; crescent toxin (trichothecene) (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethan; vindesine ); dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; Arabinoside ("Ara-C");cyclophosphamide;thiotepa; taxoids such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE ® (polyoxyethylene-free Hydrogenated castor oil (Cremophor-free)), albumin-engineered nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.) and TAXOTERE ® (docetaxel, doxetaxel; Sanofi- Aventis); chlorambucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine ( vinblastine); etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE ® (vinorelbine); ; teniposide; edatrexate; daunomycin; aminopterin; capecitabine (XELODA ® ); ibandronate ; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoid (retinoid), such as retinoic acid (retinoic acid); Acceptable salts, acids and derivatives.

化學治療劑亦包括：(i)用於調節或抑制激素對腫瘤之作用之抗激素劑，諸如抗***及選擇性***受體調節劑(SERM)，其包括例如他莫昔芬(tamoxifen) (包括NOLVADEX ®；檸檬酸他莫昔芬)、雷諾昔芬(raloxifene)、屈洛昔芬(droloxifene)、依朵昔芬(iodoxyfene)、4-羥基他莫昔芬、曲沃昔芬(trioxifene)、可莫昔芬(keoxifene)、LY117018、奧那司酮(onapristone)及FARESTON ®(檸檬酸托瑞米芬(toremifine citrate))；(ii)抑制芳香酶之芳香酶抑制劑，其調節腎上腺中之***產生，諸如4(5)-咪唑、胺魯米特、MEGASE ®(醋酸甲地孕酮(megestrol acetate))、AROMASIN ®(依西美坦(exemestane)；Pfizer)、福美斯坦(formestanie)、法屈唑(fadrozole)、RIVISOR ®(伏氯唑(vorozole))、FEMARA ®(來曲唑；Novartis)及ARIMIDEX ®(阿那曲唑(anastrozole)；AstraZeneca)；(iii)抗雄激素，諸如氟他胺(flutamide)、尼魯米特(nilutamide)、比卡魯胺(bicalutamide)、亮丙瑞林(leuprolide)及戈舍瑞林(goserelin)；布舍瑞林(buserelin)、曲普瑞林(tripterelin)、醋酸甲羥孕酮、己烯雌酚、普雷馬林(premarin)、氟羥甲睪酮(fluoxymesterone)、全反式視黃酸、芬維A胺(fenretinide)以及曲沙他濱(troxacitabine) (1,3-二氧雜環戊烷核苷胞嘧啶類似物)；(iv)蛋白激酶抑制劑；(v)脂質激酶抑制劑；(vi)反義寡核苷酸，尤其抑制參與異常細胞增殖之信號傳導路徑中之基因(諸如PKC-α、Raf及H-Ras)表現者；(vii)核糖核酸酶，諸如VEGF表現抑制劑(例如ANGIOZYME ®)及HER2表現抑制劑；(viii)疫苗，諸如基因療法疫苗，例如ALLOVECTIN ®、LEUVECTIN ®及VAXID ®；PROLEUKIN ®；rIL-2；拓撲異構酶1抑制劑，諸如LURTOTECAN ®；ABARELIX ®rmRH；及(ix)以上任一者之醫藥學上可接受之鹽、酸及衍生物。 Chemotherapeutic agents also include: (i) antihormonal agents used to modulate or inhibit the effects of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), which include, for example, tamoxifen ) (including NOLVADEX ® ; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, travoxifen ( trioxifene), keoxifene, LY117018, onapristone, and FARESTON ® (toremifine citrate); (ii) aromatase inhibitors that inhibit aromatase, which regulate Estrogen production in the adrenal glands, such as 4(5)-imidazole, aminoglutethimide, MEGASE ® (megestrol acetate), AROMASIN ® (exemestane; Pfizer), formestane (formestanie), fadrozole, RIVISOR ® (vorozole), FEMARA ® (letrozole; Novartis), and ARIMIDEX ® (anastrozole; AstraZeneca); (iii) antiandrogenic Hormones such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; buserelin, Triptorelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retinoic acid, fenretinide, and troxastat (troxacitabine) (1,3-dioxolane nucleoside cytosine analog); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, especially Those who inhibit expression of genes involved in signal transduction pathways of abnormal cell proliferation (such as PKC-α, Raf and H-Ras); (vii) ribonucleases, such as VEGF expression inhibitors (eg ANGIOZYME ® ) and HER2 expression inhibitors; (viii) Vaccines, such as gene therapy vaccines, such as ALLOVECTIN® , LEUVECTIN® , and VAXID® ; PROLEUKIN® ; rIL-2; topoisomerase 1 inhibitors, such as LURTOTECAN® ; ABARELIX® rmRH; and (ix) any of the above Pharmaceutically acceptable salts, acids and derivatives thereof.

化學治療劑亦包括抗體，諸如阿侖單抗(alemtuzumab) (Campath)、貝伐單抗(AVASTIN®，Genentech)；西妥昔單抗(ERBITUX®，Imclone)；帕尼單抗(VECTIBIX®，Amgen)、利妥昔單抗(RITUXAN®，Genentech/Biogen Idec)、帕妥珠單抗(OMNITARG®、2C4，Genentech)、曲妥珠單抗(HERCEPTIN®，Genentech)、托西莫單抗(Bexxar，Corixia)及抗體藥物結合物，吉妥珠單抗奧佐米星(gemtuzumab ozogamicin) (MYLOTARG®，Wyeth)。具有作為與本文揭示之化合物組合之藥劑的治療潛力之額外人類化單株抗體包括：阿泊珠單抗(apolizumab)、阿塞珠單抗(aselizumab)、阿力珠單抗(atlizumab)、巴匹珠單抗(bapineuzumab)、比伐珠單抗-美登素(bivatuzumab mertansine)、坎妥珠單抗-美登素(cantuzumab mertansine)、西利珠單抗(cedelizumab)、賽妥珠單抗-聚乙二醇(certolizumab pegol)、次福珠單抗(cidfusituzumab)、次妥珠單抗(cidtuzumab)、達利珠單抗(daclizumab)、依庫珠單抗(eculizumab)、依法珠單抗(efalizumab)、艾波妥珠單抗(epratuzumab)、厄利珠單抗(erlizumab)、非維珠單抗(felvizumab)、芳妥珠單抗(fontolizumab)、吉妥珠單抗奧佐米星、奧英妥珠單抗奧佐米星(inotuzumab ozogamicin)、伊匹單抗(ipilimumab)、拉美珠單抗(labetuzumab)、林妥珠單抗(lintuzumab)、馬妥珠單抗(matuzumab)、美泊利單抗(mepolizumab)、莫維珠單抗(motavizumab)、莫托珠單抗(motovizumab)、那他珠單抗(natalizumab)、尼妥珠單抗(nimotuzumab)、諾維珠單抗(nolovizumab)、努馬珠單抗(numavizumab)、奧瑞珠單抗(ocrelizumab)、奧馬珠單抗(omalizumab)、帕利珠單抗(palivizumab)、帕考珠單抗(pascolizumab)、帕福珠單抗(pecfusituzumab)、帕妥珠單抗(pectuzumab)、派利珠單抗(pexelizumab)、拉利珠單抗(ralivizumab)、雷珠單抗(ranibizumab)、瑞利珠單抗(reslivizumab)、瑞斯珠單抗(reslizumab)、瑞維珠單抗(resyvizumab)、羅維珠單抗(rovelizumab)、盧利珠單抗(ruplizumab)、西羅珠單抗(sibrotuzumab)、西利珠單抗(siplizumab)、索妥珠單抗(sontuzumab)、他珠單抗-替崔斯坦(tacatuzumab tetraxetan)、他度珠單抗(tadocizumab)、他利珠單抗(talizumab)、特非珠單抗(tefibazumab)、托珠單抗(tocilizumab)、托利珠單抗(toralizumab)、妥可妥珠單抗-西莫白介素(tucotuzumab celmoleukin)、圖庫珠單抗(tucusituzumab)、烏瑪珠單抗(umavizumab)、烏珠單抗(urtoxazumab)、優特克單抗(ustekinumab)、維西珠單抗(visilizumab)以及抗介白素-12 (ABT-874/J695，Wyeth Research and Abbott Laboratories)，其為一種經基因修飾以識別介白素-12 p40蛋白之重組專性人類序列全長IgG 1λ抗體。 Chemotherapeutic agents also include antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); panitumumab (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab (HERCEPTIN®, Genentech), tositumomab ( Bexxar, Corixia) and an antibody-drug conjugate, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibodies that have therapeutic potential as agents in combination with the compounds disclosed herein include: apolizumab, aselizumab, atlizumab, Pilizumab, bivatuzumab-maytansine, cantuzumab-maytansine, cedelizumab, certolizumab- Polyethylene glycol (certolizumab pegol), cidfusituzumab, cidtuzumab, daclizumab, eculizumab, efalizumab ), epratuzumab, erlizumab, felvizumab, fontolizumab, gemtuzumab ozogamicin, ozogamicin Inotuzumab ozogamicin, ipilimumab, labetuzumab, lintuzumab, matuzumab, mepor Mepolizumab, motavizumab, motovizumab, natalizumab, nimotuzumab, nolovizumab ), numavizumab, ocrelizumab, omalizumab, palivizumab, pascolizumab, pafuzumab Pecfusituzumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, reslivizumab, Reslizumab, resyvizumab, rovelizumab, ruplizumab, sibrotuzumab, siplizumab, Soto Sontuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tefibazumab, tocilizumab Tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, umavizumab, umavizumab (urtoxazumab), ustekinumab, visilizumab, and anti-interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories), which are genetically modified to recognize Recombinant obligate human sequence full-length IgG 1 λ antibody to interleukin-12 p40 protein.

化學治療劑亦包括「EGFR抑制劑」，其係指與EGFR結合或以其他方式直接與EGFR相互作用且防止或減少其信號傳導活性之化合物，且替代地被稱為「EGFR拮抗劑」。此類藥劑之實例包括與EGFR結合之抗體及小分子。與EGFR結合之抗體之實例包括MAb 579 (ATCC CRL HB 8506)、MAb 455 (ATCC CRL HB8507)、MAb 225 (ATCC CRL 8508)、MAb 528 (ATCC CRL 8509) (參見美國專利第4,943, 533號，Mendelsohn等人)及其變異體，諸如嵌合225 (C225或西妥昔單抗；ERBUTIX ®)及再成形人類225 (H225) (參見WO 96/40210，Imclone Systems Inc.)；IMC-11F8，一種完全人類EGFR靶向抗體(Imclone)；結合II型突變EGFR之抗體(美國專利第5,212,290號)；如美國專利第5,891,996號中所述結合EGFR之人類化及嵌合抗體；及結合EGFR之人類抗體，諸如ABX-EGF或帕尼單抗(參見WO98/50433，Abgenix/ Amgen)；EMD 55900 (Stragliotto等人 , Eur. J. Cancer32A:636-640 (1996))；EMD7200 (馬妥珠單抗)，一種針對EGFR之人類化EGFR抗體，其與EGF及TGF-α兩者競爭結合EGFR (EMD/Merck)；人類EGFR抗體，HuMax-EGFR (GenMab)；稱為E1.1、E2.4、E2.5、E6.2、E6.4、E2.11、E6. 3及E7.6. 3且在US 6,235,883中描述之完全人類抗體；MDX-447 (Medarex Inc)；及mAb 806或人類化mAb 806 (Johns等人 , J. Biol. Chem. 279(29):30375-30384 (2004))。抗EGFR抗體可與細胞毒劑結合，從而產生免疫結合物(參見例如EP659,439A2，Merck Patent GmbH)。EGFR拮抗劑包括小分子，諸如在以下中描述之化合物：美國專利第5,616,582號、第5,457,105號、第5,475,001號、第5,654,307號、第5,679,683號、第6,084,095號、第6,265,410號、第6,455,534號、第6,521,620號、第6,596,726號、第6,713,484號、第5,770,599號、第6,140,332號、第5,866,572號、第6,399,602號、第6,344,459號、第6,602,863號、第6,391,874號、第6,344,455號、第5,760,041號、第6,002,008號及第5,747,498號，以及以下PCT公開案：WO98/14451、WO98/50038、WO99/09016及WO99/24037。特定小分子EGFR拮抗劑包括OSI-774 (CP-358774，埃羅替尼，TARCEVA ®Genentech/OSI Pharmaceuticals)；PD 183805 (CI 1033，N-[4-[(3-氯-4-氟苯基)胺基]-7-[3-(4-嗎啉基)丙氧基]-6-喹唑啉基]-2-丙烯醯胺二鹽酸鹽，Pfizer Inc.)；ZD1839，吉非替尼(IRESSA®) (4-(3’-氯-4’-氟苯胺基)-7-甲氧基-6-(3-N-嗎啉基丙氧基)喹唑啉，AstraZeneca)；ZM 105180 ((6-胺基-4-(3-甲基苯基-胺基)-喹唑啉，Zeneca)；BIBX-1382 (N8-(3-氯-4-氟-苯基)-N2-(1-甲基-哌啶-4-基)-嘧啶并[5,4-d]嘧啶-2,8-二胺，Boehringer Ingelheim)；PKI-166 ((R)-4-[4-[(1-苯基乙基)胺基]-1H-吡咯并[2,3-d]嘧啶-6-基]-苯酚)；(R)-6-(4-羥基苯基)-4-[(1-苯基乙基)胺基]-7H-吡咯并[2,3-d]嘧啶)；CL-387785 (N-[4-[(3-溴苯基)胺基]-6-喹唑啉基]-2-丁炔醯胺)；EKB-569 (N-[4-[(3-氯-4-氟苯基)胺基]-3-氰基-7-乙氧基-6-喹啉基]-4-(二甲基胺基)-2-丁烯醯胺) (Wyeth)；AG1478 (Pfizer)；AG1571 (SU 5271；Pfizer)；雙重EGFR/HER2酪胺酸激酶抑制劑，諸如拉帕替尼(TYKERB®、GSK572016或N-[3-氯-4-[(3-氟苯基)甲氧基]苯基]-6[5[[[2-甲基磺醯基)乙基]胺基]甲基]-2-呋喃基]-4-喹唑啉胺)。 Chemotherapeutic agents also include "EGFR inhibitors," which refer to compounds that bind to or otherwise directly interact with EGFR and prevent or reduce its signaling activity, and are alternatively referred to as "EGFR antagonists." Examples of such agents include antibodies and small molecules that bind to EGFR. Examples of antibodies that bind to EGFR include MAb 579 (ATCC CRL HB 8506), MAb 455 (ATCC CRL HB8507), MAb 225 (ATCC CRL 8508), MAb 528 (ATCC CRL 8509) (see U.S. Patent No. 4,943,533, Mendelsohn et al) and variants thereof such as chimeric 225 (C225 or cetuximab; ERBUTIX® ) and reshaped human 225 (H225) (see WO 96/40210, Imclone Systems Inc.); IMC-11F8, A fully human EGFR targeting antibody (Imclone); an antibody that binds type II mutant EGFR (US Patent No. 5,212,290); a humanized and chimeric antibody that binds EGFR as described in US Patent No. 5,891,996; and a human that binds EGFR Antibodies, such as ABX-EGF or panitumumab (see WO98/50433, Abgenix/Amgen); EMD 55900 (Stragliotto et al. , Eur. J. Cancer 32A:636-640 (1996)); EMD7200 (matuzumab anti), a humanized EGFR antibody against EGFR that competes with both EGF and TGF-α for binding to EGFR (EMD/Merck); human EGFR antibody, HuMax-EGFR (GenMab); designated E1.1, E2.4 , E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and the fully human antibody described in US 6,235,883; MDX-447 (Medarex Inc); and mAb 806 or human ChemAb 806 (Johns et al. , J. Biol. Chem . 279(29):30375-30384 (2004)). Anti-EGFR antibodies can be conjugated with cytotoxic agents to generate immunoconjugates (see eg EP659,439A2, Merck Patent GmbH). EGFR antagonists include small molecules, such as the compounds described in U.S. Pat. 6,521,620, 6,596,726, 6,713,484, 5,770,599, 6,140,332, 5,866,572, 6,399,602, 6,344,459, 6,602,863, 6,391,874, 6 , No. 344,455, No. 5,760,041, No. 6,002,008 and No. 5,747,498, and the following PCT publications: WO98/14451, WO98/50038, WO99/09016, and WO99/24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA ® Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, N-[4-[(3-chloro-4-fluorophenyl )amino]-7-[3-(4-morpholinyl)propoxy]-6-quinazolinyl]-2-acrylamide dihydrochloride, Pfizer Inc.); ZD1839, gefitinib IRESSA® (4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-N-morpholinopropoxy)quinazoline, AstraZeneca); ZM 105180 ((6-amino-4-(3-methylphenyl-amino)-quinazoline, Zeneca); BIBX-1382 (N8-(3-chloro-4-fluoro-phenyl)-N2- (1-methyl-piperidin-4-yl)-pyrimido[5,4-d]pyrimidine-2,8-diamine, Boehringer Ingelheim); PKI-166 ((R)-4-[4-[ (1-phenylethyl)amino]-1H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenol); (R)-6-(4-hydroxyphenyl)-4-[ (1-phenylethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785 (N-[4-[(3-bromophenyl)amino]-6-quinone Azolinyl]-2-butynamide); EKB-569 (N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy-6 -quinolyl]-4-(dimethylamino)-2-butenamide) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); dual EGFR/HER2 tyrosine kinase inhibitor , such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2-methylsulfonyl ) ethyl] amino] methyl] -2-furyl] -4-quinazolinamine).

化學治療劑亦包括「酪胺酸激酶抑制劑」，其包括前一段中提及之EGFR靶向藥物；小分子HER2酪胺酸激酶抑制劑，諸如可購自Takeda之TAK165；CP-724,714，一種ErbB2受體酪胺酸激酶之口服選擇性抑制劑(Pfizer及OSI)；雙重HER抑制劑，諸如EKB-569 (可購自Wyeth)，其優先結合EGFR但抑制過度表現HER2之細胞及過度表現EGFR之細胞兩者；拉帕替尼(GSK572016；可購自Glaxo-SmithKline)，一種口服HER2及EGFR酪胺酸激酶抑制劑；PKI-166 (可購自Novartis)；泛HER抑制劑，諸如卡奈替尼(canertinib) (CI-1033；Pharmacia)；Raf-1抑制劑，諸如可購自ISIS Pharmaceuticals之反義試劑ISIS-5132，其抑制Raf-1信號傳導；非HER靶向TK抑制劑，諸如甲磺酸伊馬替尼(GLEEVEC®，可購自Glaxo SmithKline)；多靶向酪胺酸激酶抑制劑，諸如舒尼替尼(sunitinib) (SUTENT®，可購自Pfizer)；VEGF受體酪胺酸激酶抑制劑，諸如瓦他拉尼(vatalanib) (PTK787/ ZK222584，可購自Novartis/Schering AG)；MAPK細胞外調節激酶I抑制劑CI-1040 (可購自Pharmacia)；喹唑啉，諸如PD 153035、4-(3-氯苯胺基)喹唑啉；吡啶并嘧啶；嘧啶并嘧啶；吡咯并嘧啶，諸如CGP 59326、CGP 60261及CGP 62706；吡唑并嘧啶、4-(苯基胺基)-7H-吡咯并[2,3-d]嘧啶；薑黃素(二阿魏醯基甲烷、4,5-雙(4-氟苯胺基)鄰苯二甲醯亞胺)；含有硝基噻吩部分之酪胺酸磷酸化抑制劑；PD-0183805 (Warner-Lamber)；反義分子(例如與HER編碼核酸結合之分子)；喹噁啉(美國專利第5,804,396號)；酪胺酸磷酸化抑制劑(美國專利第5,804,396號)；ZD6474 (Astra Zeneca)；PTK-787 (Novartis/Schering AG)；泛HER抑制劑，諸如CI-1033 (Pfizer)；艾菲尼塔(Affinitac) (ISIS 3521；Isis/Lilly)；甲磺酸伊馬替尼(GLEEVEC®)；PKI 166 (Novartis)；GW2016 (Glaxo SmithKline)；CI-1033 (Pfizer)；EKB-569 (Wyeth)；司馬沙尼(Semaxinib) (Pfizer)；ZD6474 (AstraZeneca)；PTK-787 (Novartis/ Schering AG)；INC-1C11 (Imclone)、雷帕黴素(西羅莫司，RAPAMUNE®)；或如以下專利公開案中之任一者中所述之酪胺酸激酶抑制劑：美國專利第5,804,396號；WO 1999/09016 (American Cyanamid)；WO 1998/43960 (American Cyanamid)；WO 1997/38983 (Warner Lambert)；WO 1999/06378 (Warner Lambert)；WO 1999/06396 (Warner Lambert)；WO 1996/30347 (Pfizer, Inc)；WO 1996/33978 (Zeneca)；WO 1996/3397 (Zeneca)及WO 1996/33980 (Zeneca)。Chemotherapeutic agents also include "tyrosine kinase inhibitors", which include the EGFR targeting drugs mentioned in the previous paragraph; small molecule HER2 tyrosine kinase inhibitors, such as TAK165 available from Takeda; CP-724,714, a Oral selective inhibitors of ErbB2 receptor tyrosine kinase (Pfizer and OSI); dual HER inhibitors, such as EKB-569 (commercially available from Wyeth), which bind preferentially to EGFR but inhibit cells overexpressing HER2 and overexpressing EGFR Both; lapatinib (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as Canel Canertinib (CI-1033; Pharmacia); Raf-1 inhibitors, such as the antisense reagent ISIS-5132 available from ISIS Pharmaceuticals, which inhibits Raf-1 signaling; non-HER-targeting TK inhibitors, such as Imatinib mesylate (GLEEVEC®, available from Glaxo SmithKline); multi-targeted tyrosine kinase inhibitors such as sunitinib (SUTENT®, available from Pfizer); VEGF receptor tyramine Acid kinase inhibitors, such as vatalanib (PTK787/ ZK222584, available from Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazolines, such as PD 153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidines; pyrimidopyrimidines; pyrrolopyrimidines such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidines, 4-(phenylamino )-7H-pyrrolo[2,3-d]pyrimidine; curcumin (diferuloylmethane, 4,5-bis(4-fluoroanilino)phthalimide); Tyrosine phosphorylation inhibitors; PD-0183805 (Warner-Lamber); antisense molecules (such as molecules that bind to HER-encoding nucleic acids); quinoxalines (U.S. Patent No. 5,804,396); tyrosine phosphorylation inhibitors ( U.S. Patent No. 5,804,396); ZD6474 (Astra Zeneca); PTK-787 (Novartis/Schering AG); pan-HER inhibitors such as CI-1033 (Pfizer); Affinitac (ISIS 3521; Isis/Lilly ); Imatinib mesylate (GLEEVEC®); PKI 166 (Novartis); GW2016 (Glaxo SmithKline); CI-1033 (Pfizer); EKB-569 (Wyeth); Sematinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); INC-1C11 (Imclone), rapamycin (sirolimus, RAPAMUNE®); or as described in any of the following patent publications Tyrosine Kinase Inhibitors: U.S. Patent No. 5,804,396; WO 1999/09016 (American Cyanamid); WO 1998/43960 (American Cyanamid); WO 1997/38983 (Warner Lambert); WO 1999/06378 (Warner Lambert); 1999/06396 (Warner Lambert); WO 1996/30347 (Pfizer, Inc); WO 1996/33978 (Zeneca); WO 1996/3397 (Zeneca) and WO 1996/33980 (Zeneca).

化學治療劑亦包括***(dexamethasone)、干擾素、秋水仙鹼(colchicine)、氯苯胺啶(metoprine)、環孢菌素(cyclosporine)、兩性黴素(amphotericin)、甲硝噠唑(metronidazole)、阿侖單抗、阿利維A酸(alitretinoin)、別嘌呤醇(allopurinol)、阿米福汀(amifostine)、三氧化二砷、天冬醯胺酶、BCG live、貝伐單抗(bevacuzimab)、貝沙羅汀(bexarotene)、克拉屈濱(cladribine)、氯法拉濱(clofarabine)、阿法達貝泊汀(darbepoetin alfa)、地尼介白素(denileukin)、右雷佐生(dexrazoxane)、阿法依伯汀(epoetin alfa)、埃羅替尼(elotinib)、非格司亭(filgrastim)、醋酸組胺瑞林(histrelin acetate)、替伊莫單抗(ibritumomab)、干擾素α-2a、干擾素α-2b、來那度胺(lenalidomide)、左旋咪唑(levamisole)、美司那(mesna)、甲氧沙林(methoxsalen)、諾龍(nandrolone)、奈拉濱(nelarabine)、諾莫單抗(nofetumomab)、奧普瑞介白素(oprelvekin)、帕利夫明(palifermin)、帕米膦酸鹽(pamidronate)、培加酶(pegademase)、培門冬酶(pegaspargase)、培非格司亭(pegfilgrastim)、培美曲塞二鈉(pemetrexed disodium)、普卡黴素(plicamycin)、卟吩姆鈉(porfimer sodium)、奎納克林(quinacrine)、拉布立酶(rasburicase)、沙格司亭(sargramostim)、替莫唑胺(temozolomide)、VM-26、6-TG、托瑞米芬(toremifene)、維A酸(tretinoin)、ATRA、戊柔比星(valrubicin)、唑來膦酸鹽(zoledronate)及唑來膦酸(zoledronic acid)及其醫藥學上可接受之鹽。Chemotherapeutic agents also include dexamethasone, interferon, colchicine, metoprine, cyclosporine, amphotericin, metronidazole ), alemtuzumab, alitretinoin, allopurinol, amifostine, arsenic trioxide, asparaginase, BCG live, bevacizimab, bevacizimab Bexarotene, cladribine, clofarabine, darbepoetin alfa, denileukin, dexrazoxane, alfa Epoetin alfa, erlotinib, filgrastim, histrelin acetate, ibritumomab, interferon alpha-2a, interferon Alpha-2b, lenalidomide, levamisole, mesna, methoxsalen, nandrolone, nelarabine, normomab (nofetumomab), oprelvekin, palifermin, pamidronate, pegademase, pegaspargase, pegfilgrastim (pegfilgrastim), pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sag Sargramostim, temozolomide, VM-26, 6-TG, toremifene, tretinoin, ATRA, valrubicin, zoledronate ( zoledronate), zoledronic acid and pharmaceutically acceptable salts thereof.

化學治療劑亦包括氫化可體松(hydrocortisone)、醋酸氫化可體松(hydrocortisone acetate)、醋酸可體松(cortisone acetate)、特戊酸替可的松(tixocortol pivalate)、曲安奈德(triamcinolone acetonide)、曲安西龍醇(triamcinolone alcohol)、莫米松(mometasone)、安西奈德(amcinonide)、布***(budesonide)、***(desonide)、氟洛奈皮質醇(fluocinonide)、氟西奈德(fluocinolone acetonide)、倍他米松(betamethasone)、倍他米松磷酸鈉(betamethasone sodium phosphate)、***、***磷酸鈉(dexamethasone sodium phosphate)、氟可龍(fluocortolone)、氫化可體松-17-丁酸鹽、氫化可體松-17-戊酸鹽、二丙酸阿氯米松(alclometasone dipropionate)、戊酸倍他米松(betamethasone valerate)、二丙酸倍他米松(betamethasone dipropionate)、潑尼卡酯(prednicarbate)、氯倍他松-17-丁酸鹽(clobetasone-17-butyrate)、氯倍他索-17-丙酸鹽(clobetasol-17-propionate)、己酸氟可龍(fluocortolone caproate)、特戊酸氟可龍(fluocortolone pivalate)及醋酸氟潑尼定(fluprednidene acetate)；免疫選擇性抗發炎肽(ImSAID)，諸如***酸-麩醯胺酸-甘胺酸(FEG)及其D-異構形式(feG) (IMULAN Bio Therapeutics，LLC)；抗風濕藥物，諸如硫唑嘌呤(azathioprine)、環孢素(ciclosporin) (環孢素A)、D-青黴胺(D-penicillamine)、金鹽、羥氯喹(hydroxychloroquine)、來氟米特(leflunomide)米諾環素(minocycline)、柳氮磺胺吡啶(sulfasalazine)、腫瘤壞死因子α (TNFα)阻斷劑(諸如依那西普(etanercept；Enbrel)、英利昔單抗(infliximab；Remicade)、阿達木單抗(adalimumab；Humira)、塞妥珠單抗-聚乙二醇(certolizumab pegol；Cimzia)、戈利木單抗(golimumab；Simponi)、介白素1(IL-1)阻斷劑(諸如阿那白滯素(anakinra；Kineret))、T細胞共刺激阻斷劑(諸如阿巴西普(abatacept；Orencia))、介白素6 (IL-6)阻斷劑(諸如托珠單抗(ACTEMERA®))；介白素13 (IL-13)阻斷劑，諸如金珠單抗(lebrikizumab)；干擾素α (IFN)阻斷劑，諸如羅利珠單抗(Rontalizumab)；β7整聯蛋白阻斷劑，諸如rhuMAb β7；IgE路徑阻斷劑，諸如抗-M1 prime；分泌之同三聚體LTa3及膜結合之異三聚體LTa1/β2阻斷劑，諸如抗淋巴毒素α (LTa)；放射性同位素(例如，At 211、I 131、I 125、Y 90、Re 186、Re 188、Sm 153、Bi 212、P 32、Pb 212及Lu之放射性同位素)；各種研究藥劑，諸如硫鉑、PS-341、苯基丁酸鹽、ET-18-OCH 3或法尼基轉移酶抑制劑(L-739749，L-744832)；多酚，諸如槲皮素(quercetin)、白藜蘆醇(resveratrol)、白皮杉醇(piceatannol)、表沒食子兒茶素沒食子酸酯、茶黃素(theaflavin)、黃烷醇(flavanol)、原花青素(procyanidin)、樺木酸及其衍生物；自噬抑制劑，諸如氯喹(chloroquine)；δ-9-四氫***酚(屈***酚(dronabinol)，MARINOL®)；β-拉帕醌(beta-lapachone)；拉帕醇(lapachol)；秋水仙鹼(colchicine)；樺木酸；乙醯基喜樹鹼(acetylcamptothecin)、莨菪素(scopolectin)及9-胺基喜樹鹼(9-aminocamptothecin)；鬼臼毒素(podophyllotoxin)；喃氟啶(tegafur，UFTORAL®)；蓓薩羅丁(TARGRETIN®)；雙膦酸鹽類藥物，諸如氯膦酸鹽(例如，BONEFOS®或OSTAC®)、依替膦酸鹽(etidronate，DIDROCAL®)、NE-58095、唑來膦酸/唑來膦酸(ZOMETA®)、阿侖膦酸鹽(alendronate，FOSAMAX®)、帕米膦酸鹽(AREDIA®)、替魯膦酸鹽(tiludronate，SKELID®)或利塞膦酸鹽(risedronate，ACTONEL®)；及表皮生長因子受體(EGF-R)；疫苗，諸如THERATOPE®疫苗；哌立福辛(perifosine)、COX-2抑制劑(例如，塞來昔布(celecoxib)或依託考昔(etoricoxib))、蛋白體抑制劑(例如PS341)；CCI-779；替吡法尼(tipifarnib，R11577)；索拉非尼(sorafenib)、ABT510；Bcl-2抑制劑，諸如奧利默森鈉(oblimersen sodium，GENASENSE®)；匹杉瓊(pixantrone)；法尼基轉移酶抑制劑，諸如洛那法尼(lonafarnib，SCH 6636，SARASAR TM)；及以上任一者之醫藥學上可接受之鹽、酸或衍生物；以及上述兩者或兩者以上之組合，諸如CHOP，其為環磷醯胺、多柔比星、長春新鹼及普賴蘇穠之組合療法之縮寫；及FOLFOX，其為利用與5-FU及亞葉酸組合之奧沙利鉑(ELOXATIN TM)之治療方案的縮寫。 Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide ), triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, fluocinonide (fluocinolone acetonide), betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocortisone- 17-butyrate, hydrocortisone-17-pentanoate, alclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednisone Prednicarbate, clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolone hexanoate caproate), fluocortolone pivalate, and fluprednidene acetate; immunoselective anti-inflammatory peptides (ImSAID), such as phenylalanine-glutamine-glycine (FEG) and Its D-isomer form (feG) (IMULAN Bio Therapeutics, LLC); antirheumatic drugs such as azathioprine (azathioprine), ciclosporin (ciclosporin) (cyclosporine A), D-penicillamine (D-penicillamine ), gold salts, hydroxychloroquine, leflunomide, minocycline, sulfasalazine, tumor necrosis factor alpha (TNFα) blockers (such as etanercept (etanercept; Enbrel), infliximab (Infliximab; Remicade), adalimumab (adalimumab; Humira), certolizumab pegol (Cimzia), golimumab (golimumab Simponi), interleukin 1 (IL-1) blockers (such as anakinra (Kineret)), T cell co-stimulation blockers (such as abatacept (Orencia)), mediator Interleukin 6 (IL-6) blockers such as tocilizumab (ACTEMERA®); interleukin 13 (IL-13) blockers such as lebrikizumab; interferon alpha (IFN ) blockers such as Rontalizumab; β7 integrin blockers such as rhuMAb β7; IgE pathway blockers such as anti-M1 prime; secreted homotrimeric LTa3 and membrane bound heterotrimeric Aggregate LTa1/β2 blockers , such as antilymphotoxin alpha (LTa); radioactive isotopes (e.g., At 211 , I 131 , I 125 , Y 90 , Re 186 , Re 188 , Sm 153 , Bi 212 , P 32 , radioisotopes of Pb 212 and Lu); various investigational agents such as thioplatinum, PS-341, phenylbutyrate, ET-18-OCH 3 or farnesyltransferase inhibitors (L-739749, L-744832) polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, theaflavin, flavans Alcohol (flavanol), procyanidin (procyanidin), betulinic acid and its derivatives; autophagy inhibitors, such as chloroquine (chloroquine); delta-9-tetrahydrocannabinol (dronabinol (dronabinol), MARINOL®); beta-lapachone; lapachol; colchicine; betulinic acid; acetylcamptothecin, scopolamine, and 9-aminocamptothecin ( 9-aminocamptothecin); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates such as clodronate (e.g., BONEFOS® or OSTAC ®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronic acid (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (tiludronate, SKELID®), or risedronate (risedronate, ACTONEL®); and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine; Perifosine, COX-2 inhibitors (eg, celecoxib or etoricoxib), proteosome inhibitors (eg, PS341); CCI-779; tipifarnib, R11577); sorafenib, ABT510; Bcl-2 inhibitors, such as oblimersen sodium (GENASENSE®); pixantrone; farnesyltransferase inhibitors, such as Nafarnib (lonafarnib, SCH 6636, SARASAR TM ); and a pharmaceutically acceptable salt, acid or derivative of any of the above; and a combination of two or more of the above, such as CHOP, which is cyclophosphine An abbreviation for Combination Therapy with Amide, Doxorubicin, Vincristine, and Presuvate; and FOLFOX, which is an abbreviation for a treatment regimen utilizing oxaliplatin (ELOXATIN ™ ) in combination with 5-FU and leucovorin .

化學治療劑亦包括具有鎮痛、解熱及消炎作用之非類固醇消炎藥。NSAID包括環加氧酶之非選擇性抑制劑。NSAID之具體實例包括阿司匹林(aspirin)、丙酸衍生物(諸如布洛芬(ibuprofen)、非諾洛芬(fenoprofen)、酮洛芬(ketoprofen)、氟比洛芬(flurbiprofen)、噁丙嗪(oxaprozin)及萘普生(naproxen))、乙酸衍生物(諸如吲哚美辛(indomethacin)、舒林酸(sulindac)、依托度酸(etodolac)、雙氯芬酸(diclofenac))、烯醇酸衍生物(諸如吡羅昔康(piroxicam)、美洛昔康(meloxicam)、替諾昔康(tenoxicam)、屈洛昔康(droxicam)、氯諾昔康(lornoxicam)及異昔康(isoxicam))、芬那酸衍生物(諸如甲芬那酸(mefenamic acid)、甲氯芬那酸(meclofenamic acid)、氟滅酸(flufenamic acid)、托芬那酸(tolfenamic acid))以及COX-2抑製劑(諸如塞來考昔(celecoxib)、依托考昔(etoricoxib)、魯米考昔(lumiracoxib)、帕瑞考昔(parecoxib)、羅非考昔(rofecoxib)、羅非考昔及伐地考昔(valdecoxib))。NSAID可為諸如以下之疾患之症狀減輕所需要：類風濕性關節炎、骨關節炎、發炎性關節病、強直性脊柱炎、牛皮癬性關節炎、賴特爾症候群(Reiter’s syndrome)、急性痛風、痛經、轉移性骨骼疼痛、頭痛及偏頭痛、手術後疼痛、由於發炎及組織損傷導致之輕度至中度疼痛、發熱、腸梗阻及腎絞痛。Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs that have analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of cyclooxygenases. Specific examples of NSAIDs include aspirin, propionic acid derivatives (such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, oxaprofen ( oxaprozin and naproxen), acetic acid derivatives (such as indomethacin, sulindac, etodolac, diclofenac), enolic acid derivatives ( such as piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam and isoxicam), fenox Derivatives of acid such as mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib, rofecoxib, rofecoxib, and valdecoxib). NSAIDs may be required for symptom relief in conditions such as: rheumatoid arthritis, osteoarthritis, inflammatory joint disease, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, Dysmenorrhea, metastatic bone pain, headache and migraine, postoperative pain, mild to moderate pain due to inflammation and tissue damage, fever, intestinal obstruction and renal colic.

在某些實施例中，化學治療劑尤其包括但不限於多柔比星、***、長春新鹼、環磷醯胺、氟尿嘧啶、拓撲替康、干擾素、鉑衍生物、紫杉烷(例如，太平洋紫杉醇、多烯紫杉醇)、長春花生物鹼(例如，長春花鹼)、蒽環類藥物(例如，多柔比星)、表鬼臼毒素(例如，依託泊苷)、順鉑、mTOR抑制劑(例如，雷帕黴素)、胺甲蝶呤、放線菌素D、多拉司他汀10、秋水仙素、三甲曲沙、氯苯胺啶、環孢素、柔紅黴素、替尼泊苷、兩性黴素、烷化劑(例如，苯丁酸氮芥)、5-氟尿嘧啶、喜樹鹼、順鉑、甲硝唑及甲磺酸伊馬替尼。在其他實施例中，本文揭示之化合物與諸如貝伐單抗或帕尼單抗之生物製劑組合投與。In certain embodiments, chemotherapeutic agents include, but are not limited to, doxorubicin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, interferon, platinum derivatives, taxanes ( For example, paclitaxel, docetaxel), vinca alkaloids (eg, vinblastine), anthracyclines (eg, doxorubicin), epipodophyllotoxins (eg, etoposide), cisplatin, mTOR inhibitors (eg, rapamycin), methotrexate, actinomycin D, dolastatin 10, colchicine, trimetrexate, chloraniline, cyclosporine, daunorubicin, Niposide, amphotericin, alkylating agents (eg, chlorambucil), 5-fluorouracil, camptothecin, cisplatin, metronidazole, and imatinib mesylate. In other embodiments, compounds disclosed herein are administered in combination with biologics such as bevacizumab or panitumumab.

在某些實施例中，本文揭示之化合物或其醫藥學上可接受之組合物與選自以下任一者或多者之抗增殖或化學治療劑組合投與：阿巴瑞克(abarelix)、阿地白介素、阿侖單抗、阿利維A酸、別嘌呤醇、六甲蜜胺、阿米福汀、阿那曲唑、三氧化二砷、天冬醯胺酶、阿紮胞苷、BCG live、貝伐單抗、氟尿嘧啶、貝沙羅汀、博萊黴素、硼替佐米、白消安、二甲睪酮、卡培他濱、喜樹鹼、卡鉑、卡莫司汀、西妥昔單抗、苯丁酸氮芥、克拉屈濱、氯法拉濱、環磷醯胺、阿糖胞苷、放線菌素D、阿法達貝泊汀、柔紅黴素、地尼白介素、右雷佐生、多烯紫杉醇、多柔比星(中性)、多柔比星鹽酸鹽、丙酸屈他雄酮、表柔比星、阿法依伯汀、埃羅替尼、雌氮芥、依託泊苷磷酸鹽、依託泊苷、依西美坦、非格司亭、氟尿苷、氟達拉濱、氟維司群、吉非替尼、吉西他賓、吉妥珠單抗、醋酸戈舍瑞林(goserelin acetate)、醋酸組胺瑞林、羥基脲、替伊莫單抗、伊達比星、異環磷醯胺、甲磺酸伊馬替尼、干擾素α-2a、干擾素α-2b、伊立替康、來那度胺、來曲唑、亞葉酸、醋酸亮丙瑞林、左旋咪唑、洛莫司汀、醋酸甲地孕酮、美法侖、巰基嘌呤、6-MP、美司那、胺甲蝶呤、甲氧沙林、絲裂黴素C、米托坦、米托蒽醌、諾龍、奈拉濱、諾莫單抗、奧普瑞介白素、奧沙利鉑、太平洋紫杉醇、帕利夫明、帕米膦酸鹽、培加酶、培門冬酶、培非格司亭、培美曲塞二鈉、噴司他丁、哌泊溴烷、普卡黴素、卟吩姆鈉、丙卡巴肼、奎納克林、拉布立酶、利妥昔單抗、沙格司亭、索拉非尼、鏈佐星、順丁烯二酸舒尼替尼、滑石、他莫西芬、替莫唑胺、替尼泊苷、VM-26、睪內酯、硫鳥嘌呤、6-TG、塞替派、拓撲替康、托瑞米芬、托西莫單抗、曲妥珠單抗、維A酸、ATRA、尿嘧啶氮芥、戊柔比星、長春鹼、長春新鹼、長春瑞賓、唑來膦酸鹽或唑來膦酸。In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable composition thereof, is administered in combination with an antiproliferative or chemotherapeutic agent selected from any one or more of: abarelix, Aldesleukin, alemtuzumab, alitretinoin, allopurinol, hexamethylmelamine, amifostine, anastrozole, arsenic trioxide, asparaginase, azacitidine, BCG live, bevacizumab Antibiotics, fluorouracil, bexarotene, bleomycin, bortezomib, busulfan, dimethyltestosterone, capecitabine, camptothecin, carboplatin, carmustine, cetuximab, phentermine Mechlorethamine, cladribine, clofarabine, cyclophosphamide, cytarabine, actinomycin D, darbepoetin alfa, daunorubicin, denileukin, dexrazoxane, docetaxel , doxorubicin (neutral), doxorubicin hydrochloride, drotandrosterone propionate, epirubicin, epoetin alfa, erlotinib, estramustine, etoposide phosphate , etoposide, exemestane, filgrastim, floxuridine, fludarabine, fulvestrant, gefitinib, gemcitabine, gemtuzumab, goserelin acetate (goserelin acetate), histrelin acetate, hydroxyurea, icomomab, idarubicin, ifosfamide, imatinib mesylate, interferon α-2a, interferon α-2b, i Rinotecan, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, megestrol acetate, melphalan, mercaptopurine, 6-MP, mesna, Methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone, nelarabine, nomotomab, oprel interleukin, oxaliplatin, Pacific Paclitaxel, palifermin, pamidronate, pegasin, pegaspargase, pefilgrastim, pemetrexed disodium, pentostatin, pipobromane, plicamycin, porphyrin Phenomer sodium, procarbazine, quinacrine, rasburicase, rituximab, sargragrastim, sorafenib, streptozocin, sunitinib maleate, talc, Tamoxifen, temozolomide, teniposide, VM-26, testolactone, thioguanine, 6-TG, thiotepa, topotecan, toremifene, tositumomab, trastuzumab Monoclonal antibody, tretinoin, ATRA, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, zoledronate, or zoledronic acid.

化學治療劑亦包括阿茲海默氏症(Alzheimer’s Disease)之治療劑，諸如多奈哌齊鹽酸鹽(donepezil hydrochloride)及利凡斯的明(rivastigmine)；帕金森氏症(Parkinson’s Disease)之治療劑，諸如L-DOPA/卡比多巴(carbidopa)、恩他卡朋(entacapone)、羅吡尼洛(ropinrole)、普拉克索(pramipexole)、溴隱亭(bromocriptine)、培高利特(pergolide)、三己芬迪及金剛胺(amantadine)；治療多發性硬化症(MS)之藥劑，諸如β干擾素(例如，Avonex ®及Rebif ®)、醋酸格拉替雷(glatiramer acetate)及米托蒽醌；哮喘之治療劑，諸如沙丁胺醇(albuterol)及孟魯司特鈉(montelukast sodium)；治療精神***症之藥劑，諸如賽普樂(zyprexa)、利培酮(risperdal)、思瑞康(seroquel)及氟哌啶醇(haloperidol)；消炎劑，諸如皮質類固醇、TNF阻斷劑、IL-1 RA、硫唑嘌呤、環磷醯胺及柳氮磺胺吡啶；免疫調節及免疫抑制劑，諸如環孢菌素、他克莫司、雷帕黴素、黴酚酸酯、干擾素、皮質類固醇、環磷醯胺、硫唑嘌呤及柳氮磺胺吡啶；神經滋養因子，諸如乙醯膽鹼酯酶抑制劑、MAO抑制劑、干擾素、抗驚厥劑、離子通道阻斷劑、利魯唑(riluzole)及抗帕金森氏病劑；治療心血管疾病之藥劑，諸如β-阻斷劑、ACE抑制劑、利尿劑、硝酸鹽、鈣通道阻斷劑及他汀類藥物(statins)；治療肝臟疾病之藥劑，諸如皮質類固醇、消膽胺、干擾素及抗病毒劑；治療血液病症之藥劑，諸如皮質類固醇、抗白血病劑及生長因子；及治療免疫缺陷病症之藥劑，諸如γ球蛋白。 Chemotherapeutic agents also include therapeutic agents for Alzheimer's Disease, such as donepezil hydrochloride and rivastigmine; therapeutic agents for Parkinson's Disease, Such as L-DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, Trihexafendi and amantadine; agents for the treatment of multiple sclerosis (MS), such as beta interferon (eg, Avonex ® and Rebif ® ), glatiramer acetate, and mitoxantrone; Drugs for treating asthma, such as albuterol and montelukast sodium; drugs for treating schizophrenia, such as zyprexa, risperdal, seroquel and Haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulators and immunosuppressants such as Cyclospora tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors , MAO inhibitors, interferon, anticonvulsants, ion channel blockers, riluzole (riluzole) and anti-Parkinson's disease agents; agents for the treatment of cardiovascular diseases, such as β-blockers, ACE inhibitors, Diuretics, nitrates, calcium channel blockers, and statins; agents for liver disease, such as corticosteroids, cholestyramine, interferon, and antiviral agents; agents for blood disorders, such as corticosteroids, Anti-leukemic agents and growth factors; and agents for the treatment of immunodeficiency disorders, such as gamma globulin.

另外，化學治療劑包括任何本文所述化學治療劑之醫藥學上可接受之鹽、酸或衍生物，以及其兩者或兩者以上之組合。 VI. 實例縮寫： ACN - 乙腈 AC 2O - 乙醯乙酸酯 BINAP - (+/-)-2,2’-雙(二苯基膦基)-l,r-聯萘 Boc 2O - 二碳酸二-第三丁酯 BOP - 六氟磷酸(苯并***-l-基氧基)參(二甲基胺基)鏻 DBU - l,8-二氮雜雙環[5.4.0]十一-7-烯 DCE- 1,2-二氯乙烷 DCM - 二氯甲烷 DIEA或DIPEA - Ν, Ν-二異丙基乙胺 DMA - N, N-二甲基乙醯胺 DMAc - N, N-二甲基乙醯胺 DMAP - 4-二甲基胺基吡啶 DMF - N, N-二甲基甲醯胺 DMSO - 二甲亞砜 EA - 乙酸乙酯 EtOAc - 乙酸乙酯 EtOH - 乙醇 HATU -六氟磷酸2-(7-氮雜苯并***-l -基)- N, N, N’, N’-四甲基脲 HFIP - 六氟異丙醇 HOAc - 乙酸 iPrOAc - 乙酸異丙酯 KF - 氟化鉀 KOAc – 乙酸鉀 LDA - 二異丙基胺基鋰 LiHMDS - 雙(三甲基甲矽烷基)胺基鋰 mCPBA -  3-氯過氧苯甲酸 MeCN - 乙腈 MeI - 碘甲烷 MeOH - 甲醇 MeONa - 甲氧化鈉或甲醇鈉 MTBE - 甲基第三丁基醚 MW - 微波 NaBH(OAc) 3- 三乙醯氧基硼氫化鈉 NIS - N-碘琥珀醯亞胺 P(Cy) 3或PCy 3- 三環己基膦 P(t-Bu) 3HBF 4- 四氟硼酸三第三丁基鏻 Pd/C - 鈀/碳 Pd 2(dba) 3- 參(二亞芐基丙酮)二鈀(0) Pd 2(dba) 3CHCl 3- 參(二亞芐基丙酮)二鈀(0)氯仿 Pd(dppf)Cl 2.CH 2Cl 2- [1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II)或二氯[1.1’-雙(二苯基膦基)二茂鐵]鈀(II)，與二氯甲烷錯合 Pd(PPh 3) 4- 肆(三苯基膦)鈀(0) Pd(PPh 3) 2Cl 2- 二氯化雙(三苯基膦)鈀(II) PE - 石油醚 PMBCl - 4-甲氧基芐基氯 pTsA - 對甲苯磺酸 r.t. - 室溫 Sn 2(n-Bu) 6- 六丁基二錫 TBSCl - 第三丁基二甲基矽烷基氯或第三丁基二甲基氯矽烷 [Rh(COD)Cl] 2- 氯(l,5-環辛二烯)銠(I)二聚體 TEA - 三乙胺 TFA- 三氟乙酸或2,2,2-三氟乙酸 THF - 四氫呋喃 THP - 四氫哌喃 TsOH - 對甲苯磺酸 A. 合成程序 通用程序 In addition, chemotherapeutic agents include pharmaceutically acceptable salts, acids, or derivatives of any of the chemotherapeutic agents described herein, as well as combinations of two or more thereof. VI. Example Abbreviations: ACN - Acetonitrile AC 2 O - Acetyl Acetate BINAP - (+/-)-2,2'-Bis(diphenylphosphino)-l,r-binaphthyl Boc 2 O - Di Di-tert-butyl carbonate BOP - (benzotriazol-l-yloxy)para(dimethylamino)phosphonium hexafluorophosphate DBU - 1,8-diazabicyclo[5.4.0]undeca -7-ene DCE- 1,2-dichloroethane DCM - dichloromethane DIEA or DIPEA - N , N - diisopropylethylamine DMA - N , N - dimethylacetamide DMAc - N , N - Dimethylacetamide DMAP - 4-Dimethylaminopyridine DMF - N , N - Dimethylformamide DMSO - Dimethylsulfoxide EA - Ethyl acetate EtOAc - Ethyl acetate EtOH - Ethanol HATU - Hexafluorophosphate 2-(7-azabenzotriazol-l-yl) -N , N , N' , N' -tetramethylurea HFIP - Hexafluoroisopropanol HOAc - Acetate iPrOAc - Isopropyl acetate KF - Potassium fluoride KOAc - Potassium acetate LDA - Lithium diisopropylamide LiHMDS - Lithium bis(trimethylsilyl)amide mCPBA - 3-chloroperbenzoic acid MeCN - Acetonitrile MeI - Methyl iodide MeOH - Methanol MeONa - sodium methoxide or sodium methoxide MTBE - methyl tertiary butyl ether MW - microwave NaBH(OAc) 3 - sodium triacetyloxyborohydride NIS - N -iodosuccinimide P(Cy) 3 or PCy 3 - Tricyclohexylphosphine P(t-Bu) 3 HBF 4 - Tritert-butylphosphonium tetrafluoroborate Pd/C - Palladium/Carbon Pd 2 (dba) 3 - Dibenzylideneacetone)dipalladium (0) Pd 2 (dba) 3 CHCl 3 - ginseng(dibenzylideneacetone)dipalladium(0)chloroform Pd(dppf)Cl 2 .CH 2 Cl 2 -[1,1'-bis(diphenylphosphine base) ferrocene]dichloropalladium(II) or dichloro[1.1'-bis(diphenylphosphino)ferrocene]palladium(II), complexed with dichloromethane Pd(PPh 3 ) 4 - tetra (Triphenylphosphine)palladium(0) Pd(PPh 3 ) 2 Cl 2 - bis(triphenylphosphine)palladium(II) PE dichloride - petroleum ether PMBCl - 4-methoxybenzyl chloride pTsA - para rt-toluenesulfonate - room temperature Sn 2 (n-Bu) 6 - hexabutylditin TBSCl - tertiary butyldimethylsilyl chloride or tertiary butyldimethylsilyl chloride [Rh(COD)Cl] 2 -Chloro(l,5-cyclooctadiene)rhodium(I) dimer TEA - Triethylamine TFA - Trifluoroacetic acid or 2,2,2-trifluoroacetic acid THF - Tetrahydrofuran THP - Tetrahydropyranan TsOH - General procedure for the synthetic procedure of p-toluenesulfonic acid A.

式I、Ia、Ib、Ic、Id及Ie之化合物可使用本文中之合成方法及反應流程自市售試劑來製備，或使用熟習此項技術者熟知之其他試劑及習知方法來製備。例如，本發明之化合物可根據通用反應流程I來製備：

Figure 02_image262
Figure 02_image264
流程I Compounds of Formula I, Ia, Ib, Ic, Id and Ie can be prepared from commercially available reagents using the synthetic methods and reaction schemes herein, or using other reagents and conventional methods well known to those skilled in the art. For example, compounds of the invention can be prepared according to the general reaction scheme I:
Figure 02_image262
Figure 02_image264
Process I

可根據流程I製備除了不存在之Y之外，所有取代基均如式I所定義之式(I)化合物。在步驟A中，化合物(1)與經單Boc保護之二氮雜雙環[3,3,1]辛烷在諸如二氯甲烷之溶劑中及在諸如三乙胺之鹼存在下進行S NAr反應，得到化合物(2)。在步驟B中，化合物(2)在諸如 N, N-二甲基乙醯胺之溶劑中用KF處理，生成化合物(3)。在步驟C中，化合物(3)在鈴木反應條件(Suzuki reaction condition)下用硼酸處理，得到化合物(3)。在步驟D中，在諸如乙腈之溶劑中，在諸如二異丙基乙胺之鹼存在下，藉由用具有式H-W-L-R 1之親核劑取代氟化物來引入取代基-W-L-R 1，提供化合物(5)。在步驟E中，使用此項技術中已知之條件，例如用三氟乙酸來移除化合物(5)之Boc基團，提供式(I)化合物。當存在阻轉異構物時，可藉由習知方法，諸如對掌性HPLC進行分離。 合成(1R,5S)-3-(7-溴-2,8-二氟-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯 ( 中間物 1)

Figure 02_image266
流程II 步驟 1 ：2-胺基-4-溴-3-氟-5-碘苯甲酸
Figure 02_image268
Compounds of formula (I) having all substituents as defined for formula I except for the absence of Y can be prepared according to Scheme I. In Step A, compound (1) and mono-Boc-protected diazabicyclo[3,3,1]octane are subjected to S N Ar in a solvent such as dichloromethane in the presence of a base such as triethylamine reaction to obtain compound (2). In step B, compound (2) is treated with KF in a solvent such as N , N -dimethylacetamide to give compound (3). In Step C, compound (3) is treated with boronic acid under Suzuki reaction conditions to give compound (3). In step D, the substituent -WLR 1 is introduced by displacing the fluoride with a nucleophile of formula HWLR 1 in the presence of a base such as diisopropylethylamine in a solvent such as acetonitrile, providing the compound ( 5). In step E, removal of the Boc group of compound (5) using conditions known in the art, such as trifluoroacetic acid, provides compounds of formula (I). Atropisomers, when present, can be separated by conventional methods, such as chiral HPLC. Synthesis of (1R,5S)-3-(7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1 ] tert-butyl octane-8-carboxylate ( intermediate 1)
Figure 02_image266
Scheme II Step 1 : 2-Amino-4-bromo-3-fluoro-5-iodobenzoic acid
Figure 02_image268

向2-胺基-4-溴-3-氟-苯甲酸(32 g，136.74 mmol)於DMF (300 mL)中之溶液中在室溫下添加1-碘吡咯啶-2,5-二酮(36.92 g，164.09 mmol)。將混合物在80℃下攪拌2小時。將混合物用水(500 ml)稀釋，將沈澱過濾，用水洗滌且乾燥，得到呈棕色固體狀之所需產物(47 g，130.59 mmol，95.50%產率)。ESI-MS: 359.9, 361.9 [M+H] +。 1H NMR (400 MHz, DMSO-d 6) δ 7.98 (s, 1H), 6.88 (s, 2H)。 步驟 2 ：2-胺基-4-溴-3-氟-5-碘苯甲酸甲酯

Figure 02_image270
To a solution of 2-amino-4-bromo-3-fluoro-benzoic acid (32 g, 136.74 mmol) in DMF (300 mL) was added 1-iodopyrrolidine-2,5-dione at room temperature (36.92 g, 164.09 mmol). The mixture was stirred at 80°C for 2 hours. The mixture was diluted with water (500 ml), the precipitate was filtered, washed with water and dried to give the desired product (47 g, 130.59 mmol, 95.50% yield) as a brown solid. ESI-MS: 359.9, 361.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.98 (s, 1H), 6.88 (s, 2H). Step 2 : Methyl 2-amino-4-bromo-3-fluoro-5-iodobenzoate
Figure 02_image270

在室溫下向2-胺基-4-溴-3-氟-5-碘-苯甲酸(13 g，36.12 mmol)於DCM/MeOH (120 mL)中之溶液中逐滴添加TMSCHN 2(36.12 mmol)。將混合物在室溫下攪拌15分鐘。將混合物真空移除且將所得粗殘餘物用EtOAc (200 ml)稀釋，用鹽水洗滌且經硫酸鈉乾燥且過濾。將濾液濃縮且藉由矽膠管柱層析法(溶析液：PE/EtOAc=20/1)來純化，得到呈灰白色固體狀之標題化合物(11 g，29.42 mmol，81.44%產率)。 1H NMR (400 MHz, DMSO-d 6) δ 7.98 (d, J= 1.8 Hz, 1H), 6.85 (s, 2H), 3.82 (s, 3H)。 步驟 3 ：2-乙醯胺基-4-溴-3-氟-5-碘苯甲酸甲酯

Figure 02_image272
To a solution of 2-amino-4-bromo-3-fluoro-5-iodo-benzoic acid (13 g, 36.12 mmol) in DCM/MeOH (120 mL) was added TMSCHN 2 (36.12 mmol). The mixture was stirred at room temperature for 15 minutes. The mixture was removed in vacuo and the resulting crude residue was diluted with EtOAc (200 ml), washed with brine and dried over sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography (eluent: PE/EtOAc=20/1) to obtain the title compound (11 g, 29.42 mmol, 81.44% yield) as an off-white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.98 (d, J = 1.8 Hz, 1H), 6.85 (s, 2H), 3.82 (s, 3H). Step 3 : Methyl 2-acetamido-4-bromo-3-fluoro-5-iodobenzoate
Figure 02_image272

將2-胺基-4-溴-3-氟-5-碘-苯甲酸甲酯(47 g，125.69 mmol)於Ac 2O (90 mL)及AcOH (150 mL)中之溶液在90℃下攪拌隔夜。將混合物真空濃縮。將殘餘物藉由矽膠管柱層析法(溶析液：PE/EtOAc = 4/1)來純化，得到呈灰白色固體狀之標題產物(42.6 g，102.41 mmol，81.48%產率)。ESI-MS計算值: 415.9, 417.9 [M+H] +。 1H NMR (400 MHz, DMSO-d 6) δ 10.00 (s, 1H), 8.03 (d, J= 1.7 Hz, 1H), 3.77 (s, 3H), 2.04 (s, 3H)。 步驟 4 ：2-乙醯胺基-4-溴-3-氟-5-(三氟甲基)苯甲酸甲酯

Figure 02_image274
A solution of 2-amino-4-bromo-3-fluoro-5-iodo-benzoic acid methyl ester (47 g, 125.69 mmol) in Ac 2 O (90 mL) and AcOH (150 mL) was heated at 90 °C Stir overnight. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (eluent: PE/EtOAc = 4/1) to give the title product (42.6 g, 102.41 mmol, 81.48% yield) as an off-white solid. ESI-MS calculated: 415.9, 417.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.00 (s, 1H), 8.03 (d, J = 1.7 Hz, 1H), 3.77 (s, 3H), 2.04 (s, 3H). Step 4 : Methyl 2-acetamido-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate
Figure 02_image274

向2-乙醯胺基-4-溴-3-氟-5-碘-苯甲酸甲酯(19 g，45.68 mmol)於NMP (150 mL)中之混合物中添加CuI (2.61 g，13.70 mmol)及2,2-二氟-2-氟磺醯基-乙酸甲酯(17.55 g，91.35 mmol)。將混合物在90℃下攪拌隔夜。將混合物用水(200 mL)稀釋且用EtOAc (500 mL)萃取。將有機相用鹽水洗滌，經硫酸鈉乾燥。過濾及濃縮後，殘餘物藉由矽膠管柱層析法(溶析液：PE/EtOAc = 5/2)來純化，得到呈米黃色固體狀之所需產物(13.5 g，37.70 mmol，82.54%產率)。ESI-MS: 358.0, 360.0 [M+H] +。 1H NMR (400 MHz, DMSO-d 6) δ 10.36 (s, 1H), 7.89 (s, 1H), 3.80 (s, 3H), 2.10 (s, 3H)。 步驟 5：2-胺基-4-溴-3-氟-5-(三氟甲基)苯甲酸甲酯

Figure 02_image276
To a mixture of methyl 2-acetamido-4-bromo-3-fluoro-5-iodo-benzoate (19 g, 45.68 mmol) in NMP (150 mL) was added CuI (2.61 g, 13.70 mmol) and 2,2-difluoro-2-fluorosulfonyl-acetic acid methyl ester (17.55 g, 91.35 mmol). The mixture was stirred overnight at 90 °C. The mixture was diluted with water (200 mL) and extracted with EtOAc (500 mL). The organic phase was washed with brine and dried over sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (eluent: PE/EtOAc=5/2) to obtain the desired product (13.5 g, 37.70 mmol, 82.54% Yield). ESI-MS: 358.0, 360.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.36 (s, 1H), 7.89 (s, 1H), 3.80 (s, 3H), 2.10 (s, 3H). Step 5 : Methyl 2-amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate
Figure 02_image276

將2-乙醯胺基-4-溴-3-氟-5-(三氟甲基)苯甲酸甲酯(13.5 g，37.81 mmol)於HCl之MeOH溶液(3M，100 mL)中之溶液在80℃下攪拌3小時。將混合物真空濃縮且將所得粗殘餘物用MTBE (100 mL)濕磨，得到呈白色固體狀之所需產物(10.3 g，32.70 mmol，86.4%產率)。ESI-MS: 316.0, 318.0[M+H] +。 1H NMR (400 MHz, DMSO-d 6) δ 7.86 (s, 1H), 7.40 (s, 2H), 3.85 (s, 3H)。 步驟 6：4-溴-3-氟-2-(3-(2,2,2-三氯乙醯基)脲基)-5-(三氟甲基)苯甲酸甲酯

Figure 02_image278
A solution of methyl 2-acetamido-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate (13.5 g, 37.81 mmol) in HCl in MeOH (3M, 100 mL) was dissolved in Stir at 80°C for 3 hours. The mixture was concentrated in vacuo and the resulting crude residue was triturated with MTBE (100 mL) to afford the desired product (10.3 g, 32.70 mmol, 86.4% yield) as a white solid. ESI-MS: 316.0, 318.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.86 (s, 1H), 7.40 (s, 2H), 3.85 (s, 3H). Step 6 : Methyl 4-bromo-3-fluoro-2-(3-(2,2,2-trichloroacetyl)ureido)-5-(trifluoromethyl)benzoate
Figure 02_image278

在室溫下向2-胺基-4-溴-3-氟-5-(三氟甲基)苯甲酸甲酯(10 g，31.75 mmol)於THF (80 mL)中之溶液中添加2,2,2-三氯乙醯基異氰酸酯(11.87 g，63.49 mmol)。將反應混合物在室溫下攪拌0.5小時。將混合物真空濃縮且將所得粗殘餘物用MTBE (100 mL)濕磨，得到呈白色固體狀之所需產物(13 g，25.90 mmol，81.59%產率)。ESI-MS: 502.9, 504.9[M+H] +。 1H NMR (400 MHz, DMSO-d 6) δ 11.90 (s, 1H), 10.33 (s, 1H), 8.02 (s, 1H), 3.86 (s, 3H)。 步驟 7：7-溴-8-氟-6-(三氟甲基)喹唑啉-2,4-二醇

Figure 02_image280
To a solution of methyl 2-amino-4-bromo-3-fluoro-5-(trifluoromethyl)benzoate (10 g, 31.75 mmol) in THF (80 mL) was added 2, 2,2-Trichloroacetylisocyanate (11.87 g, 63.49 mmol). The reaction mixture was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuo and the resulting crude residue was triturated with MTBE (100 mL) to afford the desired product (13 g, 25.90 mmol, 81.59% yield) as a white solid. ESI-MS: 502.9, 504.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.90 (s, 1H), 10.33 (s, 1H), 8.02 (s, 1H), 3.86 (s, 3H). Step 7 : 7-Bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4-diol
Figure 02_image280

在室溫下向4-溴-3-氟-2-(3-(2,2,2-三氯乙醯基)脲基)-5-(三氟甲基)苯甲酸甲酯(13 g，25.90 mmol)於MeOH (200 mL)中之溶液中添加NH 3 . MeOH (40 mL)。將混合物在室溫下攪拌1小時。將混合物真空濃縮且將所得粗殘餘物用MTBE (150 mL)濕磨，得到呈白色固體狀之所需產物(7.55 g，23.16 mmol，90.0%產率)。ESI-MS: 324.9, 326.9[M-H] +。 1H NMR (400 MHz, DMSO-d 6) δ 8.82 (s, 2H), 7.90 (s, 1H)。 步驟 8 ：7-溴-2,4-二氯-8-氟-6-(三氟甲基)喹唑啉

Figure 02_image282
Methyl 4-bromo-3-fluoro-2-(3-(2,2,2-trichloroacetyl)ureido)-5-(trifluoromethyl)benzoate (13 g , 25.90 mmol) in MeOH (200 mL) was added NH 3 .MeOH (40 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the resulting crude residue was triturated with MTBE (150 mL) to afford the desired product (7.55 g, 23.16 mmol, 90.0% yield) as a white solid. ESI-MS: 324.9, 326.9[MH] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.82 (s, 2H), 7.90 (s, 1H). Step 8 : 7-Bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline
Figure 02_image282

在室溫下向7-溴-8-氟-6-(三氟甲基)喹唑啉-2,4-二醇(7.55 g，23.16 mmol)於甲苯(60 mL)中之混合物中添加0℃下N-乙基-N-異丙基-丙-2-胺(8.98 g，69.48 mmol)及POCl 3(10.65 g，69.48 mmol)。將混合物在氮氣下在110℃下攪拌3小時。將混合物真空移除且將所得粗殘餘物用EtOAc (50 mL)稀釋。將有機相用鹽水洗滌且乾燥且濃縮。將殘餘物藉由矽膠管柱層析法(溶析液： PE/EtOAc = 4/1)來純化，得到呈白色固體狀之標題產物(7 g，22.11 mmol，59.61%產率)。 1H NMR (400 MHz, DMSO-d 6) δ 8.15 (s, 1H)。 步驟 9：(1R,5S)-3-(7-溴-2-氯-8-氟-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image284
To a mixture of 7-bromo-8-fluoro-6-(trifluoromethyl)quinazoline-2,4-diol (7.55 g, 23.16 mmol) in toluene (60 mL) was added 0 at room temperature. N-Ethyl-N-isopropyl-propan-2-amine (8.98 g, 69.48 mmol) and POCl3 (10.65 g, 69.48 mmol) at °C. The mixture was stirred at 110° C. for 3 hours under nitrogen. The mixture was removed in vacuo and the resulting crude residue was diluted with EtOAc (50 mL). The organic phase was washed with brine and dried and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EtOAc = 4/1) to obtain the title product (7 g, 22.11 mmol, 59.61% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.15 (s, 1H). Step 9 : (1R,5S)-3-(7-Bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[ 3.2.1] tert-butyl octane-8-carboxylate
Figure 02_image284

在室溫下向7-溴-2,4-二氯-8-氟-6-(三氟甲基)喹唑啉(7 g，22.11 mmol)於DCM (50 mL)中之溶液中添加N,N-二乙基乙胺(6.70 g，66.33 mmol，6.30 mL)。接著在-40℃下添加(1S,5R)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(3.75 g，17.69 mmol)。將混合物在-40℃下攪拌0.5小時。將混合物用鹽水(100 mL)稀釋且用DCM (80 mL×3)萃取。有機相經Na 2SO 4乾燥且過濾且濃縮。將殘餘物藉由矽膠管柱層析法(溶析液：PE/EtOAc = 8/1)來純化，得到呈黃色固體狀之標題產物(7.24 g，13.45 mmol，60.86%產率)。ESI-MS: 539.0, 541.0 [M+H] +。 步驟 10：(1R,5S)-3-(7-溴-2,8-二氟-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯( 中間物 1)

Figure 02_image286
To a solution of 7-bromo-2,4-dichloro-8-fluoro-6-(trifluoromethyl)quinazoline (7 g, 22.11 mmol) in DCM (50 mL) at room temperature was added N , N-diethylethylamine (6.70 g, 66.33 mmol, 6.30 mL). Then tert-butyl (1S,5R)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (3.75 g, 17.69 mmol) was added at -40°C. The mixture was stirred at -40°C for 0.5 hours. The mixture was diluted with brine (100 mL) and extracted with DCM (80 mL×3). The organic phase was dried over Na 2 SO 4 and filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: PE/EtOAc = 8/1) to obtain the title product (7.24 g, 13.45 mmol, 60.86% yield) as a yellow solid. ESI-MS: 539.0, 541.0 [M+H] + . Step 10 : (1R,5S)-3-(7-Bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2 .1] tert-butyl octane-8-carboxylate ( intermediate 1 )
Figure 02_image286

在室溫下向(1R,5S)-3-[7-溴-2-氯-8-氟-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(8.6 g，15.93 mmol)於DMA (80 mL)中之溶液中添加CsF (46.29 g，796.67 mmol)。將混合物在120℃下攪拌隔夜。將混合物真空濃縮且殘餘物藉由矽膠管柱層析法(溶析液：PE/EtOAc = 20/1)來純化，得到呈白色固體狀之所需產物(2 g，3.82 mmol，23.99%產率)。ESI-MS: 523.2，525.2[M+H] +。 1H NMR (400 MHz, DMSO-d 6) δ 8.23 (s, 1H), 4.43 (d, J= 12.2 Hz, 2H), 4.26 (s, 2H), 3.69 (d, J= 11.6 Hz, 2H), 1.77 (s, 2H), 1.61 (d, J= 7.4 Hz, 2H), 1.46 (s, 9H)。 合成[2-[雙(第三丁氧羰基)胺基]噻吩并[3,2-d]嘧啶-7-基]硼酸 ( 中間物 2)

Figure 02_image288
流程III 步驟 1：7-溴-2-氯-3,4-二氫噻吩并[3,2-d]嘧啶
Figure 02_image290
To (1R,5S)-3-[7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl]-3,8-diazepine at room temperature To a solution of tert-butyl bicyclo[3.2.1]octane-8-carboxylate (8.6 g, 15.93 mmol) in DMA (80 mL) was added CsF (46.29 g, 796.67 mmol). The mixture was stirred overnight at 120 °C. The mixture was concentrated in vacuo and the residue was purified by silica gel column chromatography (eluent: PE/EtOAc = 20/1) to give the desired product (2 g, 3.82 mmol, 23.99% yield) as a white solid Rate). ESI-MS: 523.2, 525.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.23 (s, 1H), 4.43 (d, J = 12.2 Hz, 2H), 4.26 (s, 2H), 3.69 (d, J = 11.6 Hz, 2H) , 1.77 (s, 2H), 1.61 (d, J = 7.4 Hz, 2H), 1.46 (s, 9H). Synthesis of [2-[bis(tert-butoxycarbonyl)amino]thieno[3,2-d]pyrimidin-7-yl]boronic acid ( Intermediate 2)
Figure 02_image288
Process III step 1 : 7-bromo-2-chloro-3,4-dihydrothieno[3,2-d]pyrimidine
Figure 02_image290

向7-溴-2,4-二氯-噻吩并[3,2-d]嘧啶(2 g，7.04 mmol，1當量)於乙醇(30 mL)及四氫呋喃(30 mL)中之溶液中添加硼氫化鈉(1.74 g，45.99 mmol，6.53當量)。將混合物在25℃下攪拌1小時。LCMS顯示反應完成。將反應用水(50 mL)稀釋且用乙酸乙酯(50 mL×3)萃取。將合併之有機層用鹽水(20 mL×2)洗滌。有機層經無水硫酸鈉乾燥，過濾且真空濃縮，得到呈黃色固體狀之粗產物(1.6 g，6.36 mmol，90%產率)，其未經進一步純化即用於下一步。LCMS (ESI, m/z): 252.8 [M+1] +。 步驟2：7-溴-2-氯-噻吩并[3,2-d]嘧啶

Figure 02_image292
To a solution of 7-bromo-2,4-dichloro-thieno[3,2-d]pyrimidine (2 g, 7.04 mmol, 1 equiv) in ethanol (30 mL) and tetrahydrofuran (30 mL) was added boron Sodium hydride (1.74 g, 45.99 mmol, 6.53 equiv). The mixture was stirred at 25°C for 1 hour. LCMS showed the reaction was complete. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (20 mL×2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude product (1.6 g, 6.36 mmol, 90% yield) as a yellow solid, which was used in the next step without further purification. LCMS (ESI, m/z): 252.8 [M+1] + . Step 2: 7-Bromo-2-chloro-thieno[3,2-d]pyrimidine
Figure 02_image292

向7-溴-2-氯-3,4-二氫噻吩并[3,2-d]嘧啶(1.6 g，6.36 mmol，1當量)於甲苯(60 mL)中之溶液中添加氯醌(1.56 g，6.36 mmol，1當量)。將混合物在110℃下攪拌12小時。LCMS顯示反應完成。將反應混合物用 甲苯 (60mL)稀釋，接著用0.5 N氫氧化鈉溶液( 60mL)及水(60 mL)洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮，得到殘餘物，將其藉由矽膠層析法(石油醚/乙酸乙酯= 20/1至10/1)來純化，得到呈白色固體狀之所需產物(600 mg，2.40 mmol，38%產率)。LCMS: (ESI, m/z): 250.8 [M+1] +。 步驟 3：7-溴噻吩并[3,2-d]嘧啶-2-胺

Figure 02_image294
To a solution of 7-bromo-2-chloro-3,4-dihydrothieno[3,2-d]pyrimidine (1.6 g, 6.36 mmol, 1 equiv) in toluene (60 mL) was added chloranil (1.56 g, 6.36 mmol, 1 equiv). The mixture was stirred at 110°C for 12 hours. LCMS showed the reaction was complete. The reaction mixture was diluted with toluene (60 mL), then washed with 0.5 N sodium hydroxide solution ( 60 mL) and water (60 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue, which was It was purified by silica gel chromatography (petroleum ether/ethyl acetate = 20/1 to 10/1) to give the desired product (600 mg, 2.40 mmol, 38% yield) as a white solid. LCMS: (ESI, m/z): 250.8 [M+1] + . Step 3 : 7-Bromothieno[3,2-d]pyrimidin-2-amine
Figure 02_image294

向7-溴-2-氯-噻吩并[3,2-d]嘧啶(1.8 g，7.21 mmol，1當量)於異丙醇(2 mL)中之溶液中添加氨(3.5 M異丙醇溶液，27 mL，13.10當量)。接著將混合物在100℃下攪拌12小時。LCMS顯示反應完成。將反應混合物在減壓下濃縮，得到殘餘物，將其藉由製備型HPLC (管柱：Phenomenex Luna C8 250×50 mm×10 um；移動相：[水(FA)-ACN]；B%：5%-35%，20分鐘)來純化，得到呈黃色固體狀之所需產物(540 mg，2.35 mmol，33%產率)。 步驟 4：N-(7-溴噻吩并[3,2-d]嘧啶-2-基)-N-第三丁氧羰基-胺基甲酸第三丁酯

Figure 02_image296
To a solution of 7-bromo-2-chloro-thieno[3,2-d]pyrimidine (1.8 g, 7.21 mmol, 1 eq) in isopropanol (2 mL) was added ammonia (3.5 M in isopropanol , 27 mL, 13.10 equivalents). The mixture was then stirred at 100°C for 12 hours. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was analyzed by preparative HPLC (column: Phenomenex Luna C8 250×50 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 5%-35%, 20 min) to give the desired product (540 mg, 2.35 mmol, 33% yield) as a yellow solid. Step 4 : N-(7-bromothieno[3,2-d]pyrimidin-2-yl)-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester
Figure 02_image296

向7-溴噻吩并[3,2-d]嘧啶-2-胺(880 mg，3.82 mmol，1當量)於二氯甲烷(30 mL)中之溶液中添加二甲胺基吡啶(47 mg，0.38 mmol，0.1當量)、三乙胺(774 mg，7.65 mmol，1.1 mL，2當量)及二碳酸二-第三丁酯(2.0 g，9.18 mmol，2.1 mL，2.4當量)。將混合物在25℃下攪拌12小時。LCMS顯示反應完成。向溶液添加水(40 mL)，用乙酸乙酯(80 mL×3)萃取。將合併之有機層用鹽水(150 mL×3)洗滌。有機層經無水硫酸鈉乾燥，過濾且真空濃縮，獲得殘餘物，將其藉由矽膠層析法(石油醚/乙酸乙酯= 100/1至1/1)來純化，產生呈白色固體狀之所需產物(1.1 g，2.56 mmol，67%產率)。LCMS: (ESI, m/z): 429.8 [M+1] +。 1H NMR: (400 MHz, DMSO-d 6) δ: 9.63 (s, 1H), 8.80 (s, 1H), 1.41 (s, 18H)。 步驟 5：[2-[雙(第三丁氧羰基)胺基]噻吩并[3,2-d]嘧啶-7-基]硼酸

Figure 02_image298
To a solution of 7-bromothieno[3,2-d]pyrimidin-2-amine (880 mg, 3.82 mmol, 1 equiv) in dichloromethane (30 mL) was added dimethylaminopyridine (47 mg, 0.38 mmol, 0.1 equiv), triethylamine (774 mg, 7.65 mmol, 1.1 mL, 2 equiv), and di-tert-butyl dicarbonate (2.0 g, 9.18 mmol, 2.1 mL, 2.4 equiv). The mixture was stirred at 25°C for 12 hours. LCMS showed the reaction was complete. Water (40 mL) was added to the solution, extracted with ethyl acetate (80 mL×3). The combined organic layers were washed with brine (150 mL×3). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a residue, which was purified by silica gel chromatography (petroleum ether/ethyl acetate = 100/1 to 1/1) to yield β-R as a white solid. Desired product (1.1 g, 2.56 mmol, 67% yield). LCMS: (ESI, m/z): 429.8 [M+1] + . 1 H NMR: (400 MHz, DMSO-d 6 ) δ : 9.63 (s, 1H), 8.80 (s, 1H), 1.41 (s, 18H). Step 5 : [2-[bis(tert-butoxycarbonyl)amino]thieno[3,2-d]pyrimidin-7-yl]boronic acid
Figure 02_image298

使 N-(7-溴噻吩并[3,2-d]嘧啶-2-基)-N-第三丁氧羰基-胺基甲酸第三丁酯(300 mg，0.73 mmol，1當量)、乙酸鉀(138 mg，1,1 mmol，2當量)、[1,1’-雙(二苯基膦基)二茂鐵]二氯鈀(II) (50 mg，0.075 mmol，0.1當量)及雙(頻哪醇基)二硼(265 mg，1.05 mmol，1.5當量)於四氫呋喃(5 mL)中之混合物脫氣且用氮氣吹掃3次，且接著將混合物在氮氣下在70℃下攪拌5小時。LCMS顯示反應完成。將反應混合物過濾，且向濾液添加水(10 mL)，然後用乙酸乙酯(10 mL×3)萃取。將合併之有機層用鹽水(20 mL×3)洗滌，經無水硫酸鈉乾燥，過濾且真空濃縮，獲得殘餘物，將其藉由製備型TLC (石油醚中50%乙酸乙酯)來純化，得到獲得呈無色油狀之所需產物(127 mg，0.32 mmol，46%產率)。LCMS: (ESI, m/z): 396.1 [M+1] +。 合成3-(7-溴-6-氯-2,8-二氟-喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯 ( 中間物 3)

Figure 02_image300
流程IV 步驟 1 ：2-胺基-4-溴-5-氯-3-氟-苯甲酸
Figure 02_image302
Make N- (7-bromothieno[3,2-d]pyrimidin-2-yl)-N-tert-butoxycarbonyl-carbamic acid tert-butyl ester (300 mg, 0.73 mmol, 1 equivalent), acetic acid Potassium (138 mg, 1,1 mmol, 2 equiv), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (50 mg, 0.075 mmol, 0.1 equiv) and bis A mixture of (pinacoyl)diboron (265 mg, 1.05 mmol, 1.5 eq) in THF (5 mL) was degassed and purged 3 times with nitrogen, and then the mixture was stirred at 70 °C under nitrogen for 5 Hour. LCMS showed the reaction was complete. The reaction mixture was filtered, and water (10 mL) was added to the filtrate, followed by extraction with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (20 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain a residue, which was purified by preparative TLC (50% ethyl acetate in petroleum ether), The desired product was obtained as a colorless oil (127 mg, 0.32 mmol, 46% yield). LCMS: (ESI, m/z): 396.1 [M+1] + . Synthesis of tert-butyl 3-(7-bromo-6-chloro-2,8-difluoro-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Esters ( Intermediate 3)
Figure 02_image300
Scheme IV Step 1 : 2-Amino-4-bromo-5-chloro-3-fluoro-benzoic acid
Figure 02_image302

向2-胺基-4-溴-3-氟-苯甲酸(25 g，106.83 mmol，1當量)於 N, N-二甲基甲醯胺(400 mL)中之溶液中添加 N-氯琥珀醯亞胺(15.69 g，117.51 mmol，1.1當量)。將混合物在70℃下攪拌12小時。使混合物冷卻至25℃，且接著傾倒至水(2000 mL)中。將所得混合物過濾且收集濾餅，在減壓下乾燥，獲得呈黃色固體狀之粗產物(28 g，104.30 mmol，97%產率)，其直接用於下一步。 1H NMR: (400 MHz, DMSO- d 6) δ: 13.48 (s,1H), 7.68 (s, 1H), 6.90 (s, 2H)。 步驟 2：7-溴-6-氯-8-氟-1H-喹唑啉-2,4-二酮

Figure 02_image304
To a solution of 2-amino-4-bromo-3-fluoro-benzoic acid (25 g, 106.83 mmol, 1 equiv) in N , N -dimethylformamide (400 mL) was added N -chlorosuccinate Amide (15.69 g, 117.51 mmol, 1.1 equiv). The mixture was stirred at 70°C for 12 hours. The mixture was cooled to 25 °C, and then poured into water (2000 mL). The resulting mixture was filtered and the filter cake was collected, dried under reduced pressure to obtain the crude product (28 g, 104.30 mmol, 97% yield) as a yellow solid, which was used directly in the next step. 1 H NMR: (400 MHz, DMSO- d 6 ) δ : 13.48 (s, 1H), 7.68 (s, 1H), 6.90 (s, 2H). Step 2 : 7-Bromo-6-chloro-8-fluoro-1H-quinazoline-2,4-dione
Figure 02_image304

將2-胺基-4-溴-5-氯-3-氟-苯甲酸(29 g，108.0 mmol，1當量)於尿素(64.87 g，1.08 mol，10當量)中之混合物在200℃下攪拌1小時。LCMS顯示偵測到所需質量。使混合物冷卻至25℃，用水(800 mL)稀釋且在25℃下攪拌1小時。將混合物過濾且將固體真空乾燥，得到呈棕色固體狀之粗產物(31 g，105.63 mmol，97%產率)，其直接用於下一步。LCMS (ESI, m/z): 293.9 [M+1] +。 1H NMR (400 MHz, DMSO- d 6) δ: 7.24 (s, 1H)。 步驟 3：7-溴-2,4,6-三氯-8-氟-喹唑啉

Figure 02_image306
A mixture of 2-amino-4-bromo-5-chloro-3-fluoro-benzoic acid (29 g, 108.0 mmol, 1 equiv) in urea (64.87 g, 1.08 mol, 10 equiv) was stirred at 200 °C 1 hour. LCMS showed the desired mass was detected. The mixture was cooled to 25 °C, diluted with water (800 mL) and stirred at 25 °C for 1 h. The mixture was filtered and the solid was dried in vacuo to give the crude product (31 g, 105.63 mmol, 97% yield) as a brown solid, which was used directly in the next step. LCMS (ESI, m/z): 293.9 [M+1] + . 1 H NMR (400 MHz, DMSO- d 6 ) δ : 7.24 (s, 1H). Step 3 : 7-Bromo-2,4,6-trichloro-8-fluoro-quinazoline
Figure 02_image306

向7-溴-6-氯-8-氟-1H-喹唑啉-2,4-二酮(31 g，105.6 mmol，1當量)於氯化磷醯(360 mL)中之溶液中添加 N, N-二異丙基乙胺(310.0 mmol，54 mL，2.94當量)，將混合物在110℃下攪拌16小時。LCMS顯示反應物完全消耗掉。將混合物在減壓下濃縮，得到粗產物。將粗產物藉由矽膠管柱層析法，用石油醚/四氫呋喃= 40/1溶析來純化，得到呈黃色固體狀之產物(24 g，72.65 mmol，68%產率)。 1H NMR: (400 MHz, DMSO- d 6) δ: 8.03 (s, 1H)。 步驟 4 ：3-(7-溴-2,6-二氯-8-氟-喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image308
To a solution of 7-bromo-6-chloro-8-fluoro-1H-quinazoline-2,4-dione (31 g, 105.6 mmol, 1 equiv) in phosphoryl chloride (360 mL) was added N , N -diisopropylethylamine (310.0 mmol, 54 mL, 2.94 equiv), and the mixture was stirred at 110° C. for 16 hours. LCMS showed complete consumption of reactant. The mixture was concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography with petroleum ether/THF=40/1 to obtain the product (24 g, 72.65 mmol, 68% yield) as a yellow solid. 1 H NMR: (400 MHz, DMSO- d 6 ) δ : 8.03 (s, 1H). Step 4 : 3-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester
Figure 02_image308

向3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(1.93 g，9.08 mmol，1當量)於二氯甲烷(40 mL)中之溶液中添加三乙胺(2.76 g，27.24 mmol，3.8 mL，3當量)及7-溴-2,4,6-三氯-8-氟-喹唑啉(3 g，9.08 mmol，1當量)。將混合物在20℃下攪拌2小時。LCMS顯示起始物質完全消耗掉且偵測到具有所需質量之一個主要峰。添加水(50 mL)，接著將混合物用二氯甲烷(30 mL×3)萃取。將合併之有機層用鹽水(30 mL×3 )洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮，得到殘餘物。將殘餘物藉由管柱層析法(二氧化矽，石油醚/乙酸乙酯 =30/1至10/1)來純化，得到呈白色固體狀之產物(3.6 g，7.11 mmol，78 %產率)。LCMS (ESI, m/z): 507.2 [M+1] +。 1H NMR: (400 MHz, CHLOROFORM-d) δ: 7.75 (d, J= 2.0 Hz, 1H), 4.40 (s, 4H), 3.80 - 3.52 (m, 2H), 2.02 - 1.92 (m, 2H), 1.80 - 1.68 (m, 2H), 1.53 (s, 9H)。 步驟 5 ：3-(7-溴-6-氯-2,8-二氟-喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image310
To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.93 g, 9.08 mmol, 1 equiv) in dichloromethane (40 mL) was added triethylamine (2.76 g, 27.24 mmol, 3.8 mL, 3 equiv) and 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (3 g, 9.08 mmol, 1 equiv). The mixture was stirred at 20°C for 2 hours. LCMS showed complete consumption of the starting material and one major peak with the desired mass was detected. Water (50 mL) was added, and the mixture was extracted with dichloromethane (30 mL×3). The combined organic layers were washed with brine (30 mL×3 ) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 30/1 to 10/1) to give the product as a white solid (3.6 g, 7.11 mmol, 78% yield Rate). LCMS (ESI, m/z): 507.2 [M+1] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ : 7.75 (d, J = 2.0 Hz, 1H), 4.40 (s, 4H), 3.80 - 3.52 (m, 2H), 2.02 - 1.92 (m, 2H) , 1.80 - 1.68 (m, 2H), 1.53 (s, 9H). Step 5 : 3-(7-bromo-6-chloro-2,8-difluoro-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl ester
Figure 02_image310

向3-(7-溴-2,6-二氯-8-氟-喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(3.5 g，6.91 mmol，1當量)於 N, N-二甲基乙醯胺(50 mL)中之溶液中添加氟化鉀(12.05 g，207.43 mmol，4.9 mL，30當量)。將混合物在120℃下攪拌36小時。LCMS顯示起始物質完全消耗掉且偵測到具有所需質量之一個主要峰。添加水(500 mL)，接著混合物用乙酸乙酯(250 mL×3)萃取。將合併之有機層用鹽水(500 mL×2)洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮，得到殘餘物。將殘餘物藉由管柱層析法(二氧化矽，石油醚/乙酸乙酯= 1/0至5/1)來純化，得到呈白色固體狀之產物(1.9 g，3.88 mmol，56%產率)。LCMS (ESI, m/z): 491.2 [M+1] + 。 1H NMR: (400 MHz, CHLOROFORM-d) δ: 7.80 (d, J= 0.8 Hz, 1H), 4.52 - 4.29 (m, 4H), 3.85 - 3.53 (m, 2H), 2.02 - 1.86 (m, 2H), 1.81 - 1.67 (m, 2H), 1.53 (s, 9H)。 合成7-[4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-7-基]噻吩并[3,2-d]嘧啶-2-胺 ( 實例 1)

Figure 02_image312
流程V 步驟 1：(1R,5S)-3-(7-溴-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯
Figure 02_image314
To 3-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl To a solution of the ester (3.5 g, 6.91 mmol, 1 equiv) in N , N -dimethylacetamide (50 mL) was added potassium fluoride (12.05 g, 207.43 mmol, 4.9 mL, 30 equiv). The mixture was stirred at 120°C for 36 hours. LCMS showed complete consumption of the starting material and one major peak with the desired mass was detected. Water (500 mL) was added, and the mixture was extracted with ethyl acetate (250 mL×3). The combined organic layers were washed with brine (500 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate = 1/0 to 5/1) to give the product (1.9 g, 3.88 mmol, 56% yield) as a white solid Rate). LCMS (ESI, m/z): 491.2 [M+1] + . 1 H NMR: (400 MHz, CHLOROFORM-d) δ : 7.80 (d, J = 0.8 Hz, 1H), 4.52 - 4.29 (m, 4H), 3.85 - 3.53 (m, 2H), 2.02 - 1.86 (m, 2H), 1.81 - 1.67 (m, 2H), 1.53 (s, 9H). Synthesis of 7-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2, 3,5,6,7-Hexahydropyrrolidin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]thieno[3,2-d]pyrimidine-2 - amine ( example 1)
Figure 02_image312
Scheme V Step 1 : (1R,5S)-3-(7-bromo-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl) Methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure 02_image314

在室溫下將[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲醇(162.22 mg，1.02 mmol)、K 3PO 4(393.28 mg，1.85 mmol)及CuI (35.28 mg，185.27 µmol)添加至3-[7-溴-2-氯-8-氟-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(500 mg，926.36 µmol)於DMF (20 mL)中之溶液中，接著將混合物在氮氣氛圍下在110℃下攪拌16小時。將混合物用EtOAc (150 mL)稀釋。將有機相用水(50 mL×3)洗滌，經Na 2SO 4乾燥。過濾後，將濾液在減壓下濃縮且殘餘物藉由矽膠管柱層析法，用PE/EtOAc= 1/1溶析來純化，得到呈白色固體狀之所需產物(200 mg，粗)。ESI-MS: 662.3 [M+H] +。 1H NMR (400 MHz, DMSO) δ 6.87 (s, 1H), 5.29 (d, J= 53.9 Hz, 1H), 4.38 (d, J= 12.2 Hz, 2H), 4.14 (d, J= 9.8 Hz, 1H), 4.05 (d, J= 10.3 Hz, 1H), 3.59 (d, J= 12.3 Hz, 2H), 3.11 (s, 2H), 3.03 (br s, 1H), 2.85 (br s, 1H), 2.18 (br s, 1H), 2.13 (br s, 1H), 2.06 (br s, 1H), 2.01 - 1.87 (m, 2H), 1.78 (s, 4H), 1.62 (d, J= 7.4 Hz, 2H), 1.46 (s, 9H)。 步驟 2：3-[7-[2-[雙(第三丁氧羰基)胺基]噻吩并[3,2-d]嘧啶-7-基]-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image316
[(2R,8S)-2-Fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (162.22 mg, 1.02 mmol), K 3 PO 4 (393.28 mg, 1.85 mmol) and CuI (35.28 mg, 185.27 µmol) were added to 3-[7-bromo-2-chloro-8-fluoro-6-(trifluoromethyl)quinazolin-4-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (500 mg, 926.36 μmol) in a solution in DMF (20 mL), then the mixture was heated at 110 Stir at °C for 16 hours. The mixture was diluted with EtOAc (150 mL). The organic phase was washed with water (50 mL×3), dried over Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography with PE/EtOAc=1/1 to give the desired product (200 mg, crude) as a white solid . ESI-MS: 662.3 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 6.87 (s, 1H), 5.29 (d, J = 53.9 Hz, 1H), 4.38 (d, J = 12.2 Hz, 2H), 4.14 (d, J = 9.8 Hz, 1H), 4.05 (d, J = 10.3 Hz, 1H), 3.59 (d, J = 12.3 Hz, 2H), 3.11 (s, 2H), 3.03 (br s, 1H), 2.85 (br s, 1H), 2.18 (br s, 1H), 2.13 (br s, 1H), 2.06 (br s, 1H), 2.01 - 1.87 (m, 2H), 1.78 (s, 4H), 1.62 (d, J = 7.4 Hz, 2H ), 1.46 (s, 9H). Step 2 : 3-[7-[2-[bis(tertiary butoxycarbonyl)amino]thieno[3,2-d]pyrimidin-7-yl]-8-fluoro-2-[[(2R, 8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-4-yl]- 3,8-Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure 02_image316

使[2-[雙(第三丁氧羰基)胺基]噻吩并[3,2-d]嘧啶-7-基]硼酸(14 mg，0.03 mmol，1.2當量)、3-[7-溴-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(20 mg，0.03 mmol，1當量)、甲烷磺酸(2-二環己基膦基-2,6-二異丙氧基-1,1-聯苯)(2-甲基胺基-1,1-聯苯-2-基)鈀(ii) (8 mg，0.01 mmol，0.3當量)、磷酸鉀(1.5 M，0.06 mL，3當量)於二噁烷(1 mL)中之混合物脫氣且用氮氣吹掃3次，且接著將混合物在氮氣下在80℃下攪拌15分鐘。LCMS顯示反應完成。將反應混合物用水(10 mL)稀釋，用二氯甲烷(5 mL×3)萃取。將合併之有機層用鹽水(10 mL×2)洗滌，經無水硫酸鈉乾燥，過濾且真空濃縮。將殘餘物藉由製備型TLC (二氯甲烷中9%甲醇)來純化，得到呈白色固體狀之所需產物(10 mg，0.004 mmol，35%產率)。LCMS: (ESI, m/z): 932.9 [M] +。 步驟 3：7-[4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-7-基]噻吩并[3,2-d]嘧啶-2-胺

Figure 02_image318
Make [2-[bis(tertiary butoxycarbonyl)amino]thieno[3,2-d]pyrimidin-7-yl]boronic acid (14 mg, 0.03 mmol, 1.2 equivalents), 3-[7-bromo- 8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-6-(trifluoromethyl Base) quinazoline-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (20 mg, 0.03 mmol, 1 equivalent), methanesulfonic acid (2 -Dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-methylamino-1,1-biphenyl-2-yl)palladium(ii) (8 mg , 0.01 mmol, 0.3 equiv), a mixture of potassium phosphate (1.5 M, 0.06 mL, 3 equiv) in dioxane (1 mL) was degassed and purged 3 times with nitrogen, and then the mixture was heated under nitrogen at 80 Stir for 15 minutes at °C. LCMS showed the reaction was complete. The reaction mixture was diluted with water (10 mL), extracted with dichloromethane (5 mL×3). The combined organic layers were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative TLC (9% methanol in dichloromethane) to give the desired product (10 mg, 0.004 mmol, 35% yield) as a white solid. LCMS: (ESI, m/z): 932.9 [M] + . Step 3 : 7-[4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1, 2,3,5,6,7-Hexahydropyrrolidin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]thieno[3,2-d]pyrimidine -2-amine
Figure 02_image318

向3-[7-[2-[雙(第三丁氧羰基)胺基]噻吩并[3,2-d]嘧啶-7-基]-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(31 mg，0.03 mmol，1當量)於二氯甲烷(1 mL)中之溶液中添加三氟乙酸。將混合物在25℃下攪拌5分鐘。LCMS顯示反應完成。將反應混合物在減壓下濃縮，得到殘餘物，將其藉由製備型HPLC (管柱：Unisil 3-100 C18 Ultra 150×50 mm×3 µm；移動相：[水(FA)-ACN]；B%：1%-20%，10分鐘)來純化，得到呈白色固體狀之所需產物(13.51 mg，0.02 mmol，57%產率，96%純度，甲酸鹽)。LCMS: (ESI, m/z): 633.2 [M+1] +。 1H NMR: (400 MHz, DMSO -d 6) δ: 9.02 (s, 1H), 8.28 (s, 1H), 8.24 - 8.20 (m, 1H), 8.10 (s, 1H), 6.63 (s, 2H), 5.38 - 5.18 (m, 1H), 4.40 - 4.22 (m, 2H), 4.14 - 4.00 (m, 2H), 3.63 - 3.52 (m, 3H), 3.07 (br d, J= 1.6 Hz, 1H), 3.03 - 2.98 (m, 1H), 2.86 - 2.78 (m, 1H), 2.13 (br d, J= 3.6 Hz, 1H), 2.06 - 1.99 (m, 2H), 1.88 - 1.73 (m, 4H), 1.69 - 1.56 (m, 6H)。 合成2-胺基-4-[6-氯-4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]喹唑啉-7-基]-7-氟-苯并噻吩-3-甲腈( 實例 2)

Figure 02_image320
流程VI 步驟 1：3-[7-溴-6-氯-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯
Figure 02_image322
To 3-[7-[2-[bis(tertiary butoxycarbonyl)amino]thieno[3,2-d]pyrimidin-7-yl]-8-fluoro-2-[[(2R,8S) -2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-4-yl]-3, To a solution of tert-butyl 8-diazabicyclo[3.2.1]octane-8-carboxylate (31 mg, 0.03 mmol, 1 equiv) in dichloromethane (1 mL) was added trifluoroacetic acid. The mixture was stirred at 25°C for 5 minutes. LCMS showed the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was analyzed by preparative HPLC (column: Unisil 3-100 C18 Ultra 150×50 mm×3 μm; mobile phase: [water (FA)-ACN]; B%: 1%-20%, 10 min) to give the desired product (13.51 mg, 0.02 mmol, 57% yield, 96% purity, formate salt) as a white solid. LCMS: (ESI, m/z): 633.2 [M+1] + . 1 H NMR: (400 MHz, DMSO -d 6 ) δ : 9.02 (s, 1H), 8.28 (s, 1H), 8.24 - 8.20 (m, 1H), 8.10 (s, 1H), 6.63 (s, 2H ), 5.38 - 5.18 (m, 1H), 4.40 - 4.22 (m, 2H), 4.14 - 4.00 (m, 2H), 3.63 - 3.52 (m, 3H), 3.07 (br d, J = 1.6 Hz, 1H) , 3.03 - 2.98 (m, 1H), 2.86 - 2.78 (m, 1H), 2.13 (br d, J = 3.6 Hz, 1H), 2.06 - 1.99 (m, 2H), 1.88 - 1.73 (m, 4H), 1.69 - 1.56 (m, 6H). Synthesis of 2-amino-4-[6-chloro-4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-[[(2R,8S) -2-Fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-methyl Nitrile ( Example 2 )
Figure 02_image320
Scheme VI step 1 : 3-[7-bromo-6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazine -8-yl]methoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure 02_image322

向3-(7-溴-6-氯-2,8-二氟-喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(500 mg，1.02 mmol，1當量)及[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲醇(179 mg，1.12 mmol，1.1當量)於乙腈(5 mL)中之混合物中添加碳酸銫(665 mg，2.04 mmol，2當量)及1,4-二氮雜雙環[2.2.2]辛烷(11 mg，0.1 mmol， 0.1當量)。使混合物脫氣且用氮氣吹掃3次，且接著將混合物在50℃下攪拌4小時。將混合物過濾且濃縮，得到殘餘物，將其藉由製備型TLC (二氧化矽，二氯甲烷/甲醇= 10/1)來純化，得到呈白色固體狀之所需產物(500 mg，0.79 mmol，78%產率)。LCMS: (ESI, m/z): 630.1[M+1] +。 1H NMR: (400MHz, CHLOROFORM-d) δ: 7.69 (d, J= 2.0 Hz, 1H), 5.37 - 5.19 (m, 1H), 4.38 - 4.28 (m, 3H), 4.26 - 4.20 (m, 1H), 4.16 - 4.09 (m, 1H), 3.71 - 3.39 (m, 2H), 3.27 - 3.15 (m, 2H), 3.04 - 2.93 (m, 1H), 2.29 - 2.21 (m, 1H), 2.19 - 2.12 (m, 1H), 1.99 - 1.87 (m, 4H), 1.76 (d, J= 7.6 Hz, 2H), 1.52 (s, 9H), 1.26 (s, 3H), 0.94 - 0.79 (m, 2H)。 步驟 2：3-[7-[2-(第三丁氧羰基胺基)-3-氰基-7-氟-苯并噻吩-4-基]-6-氯-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image324
To 3-(7-bromo-6-chloro-2,8-difluoro-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl Esters (500 mg, 1.02 mmol, 1 equivalent) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (179 mg, 1.12 To a mixture of mmol, 1.1 eq) in acetonitrile (5 mL) was added cesium carbonate (665 mg, 2.04 mmol, 2 eq) and 1,4-diazabicyclo[2.2.2]octane (11 mg, 0.1 mmol , 0.1 equivalent). The mixture was degassed and purged 3 times with nitrogen, and then the mixture was stirred at 50 °C for 4 hours. The mixture was filtered and concentrated to give a residue which was purified by preparative TLC (silica, dichloromethane/methanol = 10/1) to give the desired product as a white solid (500 mg, 0.79 mmol , 78% yield). LCMS: (ESI, m/z): 630.1[M+1] + . 1 H NMR: (400MHz, CHLOROFORM-d) δ : 7.69 (d, J = 2.0 Hz, 1H), 5.37 - 5.19 (m, 1H), 4.38 - 4.28 (m, 3H), 4.26 - 4.20 (m, 1H ), 4.16 - 4.09 (m, 1H), 3.71 - 3.39 (m, 2H), 3.27 - 3.15 (m, 2H), 3.04 - 2.93 (m, 1H), 2.29 - 2.21 (m, 1H), 2.19 - 2.12 (m, 1H), 1.99 - 1.87 (m, 4H), 1.76 (d, J = 7.6 Hz, 2H), 1.52 (s, 9H), 1.26 (s, 3H), 0.94 - 0.79 (m, 2H). Step 2 : 3-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-[ [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-3,8-di tert-butyl azabicyclo[3.2.1]octane-8-carboxylate
Figure 02_image324

向3-[7-溴-6-氯-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(180 mg，0.29 mmol，1當量)及 N-[3-氰基-7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯并噻吩-2-基]胺基甲酸第三丁酯(239 mg，0.57 mmol，2當量)於二噁烷(5 mL)中之溶液中添加碳酸鈉(91 mg，0.86 mmol，3當量)。將混合物用氮氣吹掃3次且將二-第三丁基(環戊基)磷烷;二氯鈀;鐵(19 mg，0.03 mmol，0.1當量)添加至混合物中，將混合物在90℃下攪拌6小時。將混合物過濾且接著濃縮，獲得殘餘物，將其藉由製備型TLC (二氧化矽，石油醚/乙酸乙酯/三乙胺= 1/1/0.01)來純化，得到呈黃色油狀之所需產物(40 mg，0.048 mmol，17%產率)。LCMS: (ESI, m/z): 839.7[M] +。 步驟 3：2-胺基-4-[6-氯-4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]喹唑啉-7-基]-7-氟-苯并噻吩-3-甲腈

Figure 02_image326
實例 2 To 3-[7-bromo-6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl ]methoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (180 mg, 0.29 mmol, 1 equivalent) and N- [3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl] To a solution of tert-butyl carbamate (239 mg, 0.57 mmol, 2 equiv) in dioxane (5 mL) was added sodium carbonate (91 mg, 0.86 mmol, 3 equiv). The mixture was purged 3 times with nitrogen and di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (19 mg, 0.03 mmol, 0.1 equiv) was added to the mixture, and the mixture was heated at 90° C. Stir for 6 hours. The mixture was filtered and then concentrated to obtain a residue which was purified by preparative TLC (silica, petroleum ether/ethyl acetate/triethylamine = 1/1/0.01) to give the compound as a yellow oil. The desired product (40 mg, 0.048 mmol, 17% yield). LCMS: (ESI, m/z): 839.7[M] + . Step 3 : 2-Amino-4-[6-chloro-4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-[[(2R, 8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3 -Formonitrile
Figure 02_image326
Example 2

向3-[7-[2-(第三丁氧羰基胺基)-3-氰基-7-氟-苯并噻吩-4-基]-6-氯-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(30 mg，0.036 mmol，1當量)於二氯甲烷(1 mL)中之溶液中添加三氟乙酸(0.3 mL)。接著將混合物在20℃下攪拌0.5小時。將混合物在減壓下濃縮，獲得殘餘物，將其藉由製備型HPLC (管柱：Phenomenex Synergi C18 150×25 mm×10 um；移動相：[水(FA)-ACN]；B%：5%-29%，12分鐘)來純化，得到呈黃色固體狀之所需產物(11.31 mg，0.016 mmol，48%產率，95%純度，甲酸鹽[1])。LCMS: (ESI, m/z): 640.0 [M] +。 1H NMR: (400MHz, DMSO- d 6 ) δ: 8.25 (s, 1H), 8.10 (s, 2H), 7.84 (s, 1H), 7.30 - 7.21 (m, 1H), 7.20 - 7.09 (m, 1H), 5.37 - 5.18 (m, 1H), 4.32 - 4.22 (m, 2H), 4.10 - 4.06 (m, 1H), 4.01 - 3.97 (m, 1H), 3.56 (m, 4H), 3.13 - 2.98 (m, 4H), 2.85 - 2.78 (m, 1H), 2.18 - 2.10 (m, 1H), 2.08 - 1.97 (m, 2H), 1.86 - 1.73 (m, 3H), 1.69 - 1.56 (m, 4H)。 合成 2- 胺基 -(S)-4-[4-(3,8- 二氮雜雙環 [3.2.1] 辛烷 -3- 基 )-8- 氟 -2-[[(2R,8S)-2- 氟 -1,2,3,5,6,7- 六氫吡咯嗪 -8- 基 ] 甲氧基 ]-6-( 三氟甲基 ) 喹唑啉 -7- 基 ]-7- 氟 - 苯并噻吩 -3- 甲腈 ( 實例 3)

Figure 02_image328
步驟 1：3-[7-溴-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯
Figure 02_image330
To 3-[7-[2-(tertiary butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-[[( 2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-3,8-diazepine To a solution of tert-butyl bicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.036 mmol, 1 eq) in dichloromethane (1 mL) was added trifluoroacetic acid (0.3 mL). The mixture was then stirred at 20°C for 0.5 hours. The mixture was concentrated under reduced pressure to obtain a residue, which was analyzed by preparative HPLC (column: Phenomenex Synergi C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 5 %-29%, 12 min) to give the desired product (11.31 mg, 0.016 mmol, 48% yield, 95% purity, formate salt [1]) as a yellow solid. LCMS: (ESI, m/z): 640.0 [M] + . 1 H NMR: (400MHz, DMSO- d 6 ) δ : 8.25 (s, 1H), 8.10 (s, 2H), 7.84 (s, 1H), 7.30 - 7.21 (m, 1H), 7.20 - 7.09 (m, 1H), 5.37 - 5.18 (m, 1H), 4.32 - 4.22 (m, 2H), 4.10 - 4.06 (m, 1H), 4.01 - 3.97 (m, 1H), 3.56 (m, 4H), 3.13 - 2.98 ( m, 4H), 2.85 - 2.78 (m, 1H), 2.18 - 2.10 (m, 1H), 2.08 - 1.97 (m, 2H), 1.86 - 1.73 (m, 3H), 1.69 - 1.56 (m, 4H). Synthesis of 2- amino- (S)-4-[4-(3,8- diazabicyclo [3.2.1] octane -3- yl )-8- fluoro -2-[[(2R,8S) -2- fluoro -1,2,3,5,6,7- hexahydropyrrolidin -8- yl ] methoxy ]-6-( trifluoromethyl ) quinazolin- 7- yl ]-7- Fluoro - benzothiophene -3- carbonitrile ( Example 3)
Figure 02_image328
Step 1 : 3-[7-Bromo-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol Oxy]-6-(trifluoromethyl)quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure 02_image330

在50℃下向[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲醇(365 mg，2.29 mmol，2.00當量)於乙腈(10 mL)中之溶液中添加3-[7-溴-2,8-二氟-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(600 mg，1.15 mmol，1.00當量)、碳酸銫(747 mg，2.29 mmol，2.00當量)及1,4-二氮雜雙環[2.2.2]辛烷(25.72 mg，0.23 mmol，0.1 mL，0.20當量)。將混合物在50℃下攪拌5小時。薄層層析法(二氯甲烷：甲醇= 10:1)顯示反應完成。將混合物過濾且接著在減壓下濃縮，得到殘餘物，將其藉由矽膠上管柱層析法(石油醚:乙酸乙酯= 5:1至1:1)來純化，得到呈淡黃色固體狀之所需產物(1.50 g，2.26 mmol，66%產率)。 1H NMR: (400 MHz, CDCl 3) δ: 7.83 (s, 1H), 5.35 - 5.05 (m, 1H), 4.28 (s, 4H), 4.20 - 4.12 (m, 1H), 4.10 - 4.03 (m, 1H), 3.69 - 3.40 (m, 2H), 3.26 - 3.02 (m, 3H), 2.95 - 2.84 (m, 1H), 2.25 - 2.03 (m, 3H), 1.89 - 1.77 (m, 5H), 1.71 - 1.60 (m, 2H), 1.45 (s, 9H)。 步驟 2：3-[7-[2-(第三丁氧羰基胺基)-7-氟-苯并噻吩-4-基]-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image332
[(2R,8S)-2-Fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methanol (365 mg, 2.29 mmol, 2.00 equiv) in acetonitrile at 50°C (10 mL) was added 3-[7-bromo-2,8-difluoro-6-(trifluoromethyl)quinazolin-4-yl]-3,8-diazabicyclo[3.2 .1] tert-butyl octane-8-carboxylate (600 mg, 1.15 mmol, 1.00 equiv), cesium carbonate (747 mg, 2.29 mmol, 2.00 equiv) and 1,4-diazabicyclo[2.2.2] Octane (25.72 mg, 0.23 mmol, 0.1 mL, 0.20 equiv). The mixture was stirred at 50°C for 5 hours. Thin layer chromatography (dichloromethane: methanol = 10:1) showed the reaction was complete. The mixture was filtered and then concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 5:1 to 1:1) to give a light yellow solid The desired product (1.50 g, 2.26 mmol, 66% yield). 1 H NMR: (400 MHz, CDCl 3 ) δ : 7.83 (s, 1H), 5.35 - 5.05 (m, 1H), 4.28 (s, 4H), 4.20 - 4.12 (m, 1H), 4.10 - 4.03 (m , 1H), 3.69 - 3.40 (m, 2H), 3.26 - 3.02 (m, 3H), 2.95 - 2.84 (m, 1H), 2.25 - 2.03 (m, 3H), 1.89 - 1.77 (m, 5H), 1.71 - 1.60 (m, 2H), 1.45 (s, 9H). Step 2 : 3-[7-[2-(tert-butoxycarbonylamino)-7-fluoro-benzothiophen-4-yl]-8-fluoro-2-[[(2R,8S)-2- Fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-4-yl]-3,8-di tert-butyl azabicyclo[3.2.1]octane-8-carboxylate
Figure 02_image332

在氮氣下在80℃下向3-[7-溴-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(500 mg，0.75 mmol，1.00當量)於二噁烷(12 mL)及水(3 mL)中之溶液中添加RuPhos Pd G4 (189 mg，0.23 mmol，0.30當量)及N-[7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯并噻吩-2-基]胺基甲酸第三丁酯(445 mg，1.13 mmol，1.50當量)、磷酸鉀(481 mg，2.26 mmol，3.00當量)且將混合物在80℃下攪拌20分鐘。LCMS顯示反應完成。將混合物用水(150 mL)稀釋且用乙酸乙酯(100 mL)萃取。將有機層用水(100 mL)、鹽水(80 mL)洗滌，經硫酸鈉乾燥且接著在減壓下濃縮，得到殘餘物，將其藉由矽膠上管柱層析法(石油醚:乙酸乙酯= 10:1至1:1)來純化，得到黃色固體，將其藉由製備型高效液相層析法(管柱：Phenomenex luna C18 (250×70 mm，10 um)；移動相：[水(FA)-ACN]；B%：45%-65%，15分鐘)進一步純化，得到呈淡黃色固體狀之所需產物(2.00 g，2.36 mmol，69%產率)。LCMS (ESI, m/z): 849.2[M+1] +。 1H NMR: (400 MHz, DMSO-d 6) δ: 11.15 - 10.53 (m, 1H), 8.25 (s, 1H), 7.31 - 7.23 (m, 1H), 7.22 - 7.15 (m, 1H), 6.33 (d, J= 3.2 Hz, 1H), 5.80 - 5.40 (m, 1H), 4.66 - 4.53 (m, 3H), 4.49 - 4.26 (m, 3H), 3.85 - 3.57 (m, 5H), 3.41 - 3.20 (m, 2H), 2.65 - 2.56 (m, 1H), 2.37 - 2.27 (m, 1H), 2.23 - 2.01 (m, 3H), 1.89 - 1.62 (m, 4H), 1.47 (d, J= 4.0 Hz, 18H)。 步驟 3：3-[7-[2-(第三丁氧羰基胺基)-7-氟-3-碘-苯并噻吩-4-基]-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image334
3-[7-Bromo-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazine- 8-yl] methoxy] -6- (trifluoromethyl) quinazoline -4- base] -3,8- diazabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl ester ( To a solution of 500 mg, 0.75 mmol, 1.00 equiv) in dioxane (12 mL) and water (3 mL) was added RuPhos Pd G4 (189 mg, 0.23 mmol, 0.30 equiv) and N-[7-fluoro-4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate (445 mg, 1.13 mmol, 1.50 equiv), potassium phosphate (481 mg, 2.26 mmol, 3.00 equiv), and the mixture was stirred at 80°C for 20 minutes. LCMS showed the reaction was complete. The mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL), brine (80 mL), dried over sodium sulfate and then concentrated under reduced pressure to obtain a residue, which was subjected to column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain a yellow solid, which was subjected to preparative high-performance liquid chromatography (column: Phenomenex luna C18 (250×70 mm, 10 um); mobile phase: [water (FA)-ACN]; B%: 45%-65%, 15 min) was further purified to give the desired product (2.00 g, 2.36 mmol, 69% yield) as a light yellow solid. LCMS (ESI, m/z): 849.2[M+1] + . 1 H NMR: (400 MHz, DMSO-d 6 ) δ : 11.15 - 10.53 (m, 1H), 8.25 (s, 1H), 7.31 - 7.23 (m, 1H), 7.22 - 7.15 (m, 1H), 6.33 (d, J = 3.2 Hz, 1H), 5.80 - 5.40 (m, 1H), 4.66 - 4.53 (m, 3H), 4.49 - 4.26 (m, 3H), 3.85 - 3.57 (m, 5H), 3.41 - 3.20 (m, 2H), 2.65 - 2.56 (m, 1H), 2.37 - 2.27 (m, 1H), 2.23 - 2.01 (m, 3H), 1.89 - 1.62 (m, 4H), 1.47 (d, J = 4.0 Hz , 18H). Step 3 : 3-[7-[2-(tertiary butoxycarbonylamino)-7-fluoro-3-iodo-benzothiophen-4-yl]-8-fluoro-2-[[(2R,8S )-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-4-yl]-3 ,8-Diazabicyclo[3.2.1]octane-8-carboxylate tertiary butyl ester
Figure 02_image334

在氮氣下在20℃下向3-[7-[2-(第三丁氧羰基胺基)-7-氟-苯并噻吩-4-基]-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(1.00 g，1.18 mmol，1.00當量)於二甲基甲醯胺(15 mL)中之溶液中添加 N-碘琥珀醯亞胺(530 mg，2.36 mmol，2.00當量)且將混合物在20℃下攪拌6小時。LCMS及HPLC顯示反應完成。將反應混合物用水(100 mL)稀釋且用乙酸乙酯(60 mL)萃取。將有機層用水(80 mL)、鹽水(40 mL)洗滌，經硫酸鈉乾燥且接著在減壓下濃縮，得到殘餘物，將其藉由製備型高效液相層析法(管柱：Phenomenex Synergi Max-RP 250×50 mm×10 um；移動相：[水(FA)-ACN]；B%：50%-80%，21分鐘)來純化，得到呈黃色固體狀之所需產物(1.30 g，1.33 mmol，57%產率)。LCMS (ESI, m/z): 975.0[M+1] + 步驟 4 ：3-[7-(2-胺基-3-氰基-7-氟-苯并噻吩-4-基)-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image336
To 3-[7-[2-(tert-butoxycarbonylamino)-7-fluoro-benzothiophen-4-yl]-8-fluoro-2-[[(2R, 8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-4-yl]- N - Iodosuccinimide (530 mg, 2.36 mmol, 2.00 equiv) and the mixture was stirred at 20°C for 6 hours. LCMS and HPLC showed the reaction was complete. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (60 mL). The organic layer was washed with water (80 mL), brine (40 mL), dried over sodium sulfate and then concentrated under reduced pressure to obtain a residue, which was analyzed by preparative high performance liquid chromatography (column: Phenomenex Synergi Max-RP 250×50 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 21 minutes) to obtain the desired product as a yellow solid (1.30 g , 1.33 mmol, 57% yield). LCMS (ESI, m/z): 975.0[M+1] + step 4 : 3-[7-(2-Amino-3-cyano-7-fluoro-benzothiophen-4-yl)-8- Fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6-(trifluoromethyl) Quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure 02_image336

在氮氣下在100℃下向3-[7-[2-(第三丁氧羰基胺基)-7-氟-3-碘-苯并噻吩-4-基]-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(700 mg，0.72 mmol，1.00當量)於二甲基甲醯胺(10 mL)中之溶液中添加氰化鋅(354 mg，3.01 mmol，0.2 mL，4.20當量)、四三苯基膦鈀(250 mg，0.22 mmol，0.3當量)且將混合物在100℃下攪拌6小時。LCMS顯示反應完成。將混合物用水(40 mL)稀釋且用乙酸乙酯(40 mL)萃取。將有機層用水(40 mL)、鹽水(40 mL)洗滌，經硫酸鈉乾燥且接著在減壓下濃縮，得到殘餘物。向水相添加氫氧化鈉以調整pH=14且藉由次氯酸鈉溶液(50 mL)淬滅且丟棄。將混合物藉由製備型高效液相層析法(管柱：Phenomenex luna C18 150×25 mm×10 um；移動相：[水(FA)-ACN]；B%：28%-58%，10分鐘)來純化，得到呈白色固體狀之3-[7-(2-胺基-3-氰基-7-氟-苯并噻吩-4-基)-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(50 mg，0.06 mmol，9%產率)。LCMS (ESI, m/z): 774.2[M+1] +。 步驟 5：3-[7-((S)-2-胺基-3-氰基-7-氟-苯并噻吩-4-基)-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image338
3-[7-[2-(tert-butoxycarbonylamino)-7-fluoro-3-iodo-benzothiophen-4-yl]-8-fluoro-2-[ [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6-(trifluoromethyl)quinazoline-4 -yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (700 mg, 0.72 mmol, 1.00 equiv) in dimethylformamide (10 mL) To the solution were added zinc cyanide (354 mg, 3.01 mmol, 0.2 mL, 4.20 equiv), tetrakistriphenylphosphine palladium (250 mg, 0.22 mmol, 0.3 equiv) and the mixture was stirred at 100°C for 6 hours. LCMS showed the reaction was complete. The mixture was diluted with water (40 mL) and extracted with ethyl acetate (40 mL). The organic layer was washed with water (40 mL), brine (40 mL), dried over sodium sulfate and then concentrated under reduced pressure to give a residue. Sodium hydroxide was added to the aqueous phase to adjust pH = 14 and quenched by sodium hypochlorite solution (50 mL) and discarded. The mixture was subjected to preparative high-performance liquid chromatography (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 28%-58%, 10 minutes ) to give 3-[7-(2-amino-3-cyano-7-fluoro-benzothiophen-4-yl)-8-fluoro-2-[[(2R, 8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-4-yl]- tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.06 mmol, 9% yield). LCMS (ESI, m/z): 774.2[M+1] + . Step 5 : 3-[7-((S)-2-Amino-3-cyano-7-fluoro-benzothiophen-4-yl)-8-fluoro-2-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-4-yl]-3,8 - Tertiary butyl diazabicyclo[3.2.1]octane-8-carboxylate
Figure 02_image338

將阻轉異構物之混合物(3-[7-((S)-2-胺基-3-氰基-7-氟-苯并噻吩-4-基)-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯及3-[7-((R)-2-胺基-3-氰基-7-氟-苯并噻吩-4-基)-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯) (150 mg，0.19 mmol，1.00當量)藉由SFC (管柱：DAICEL CHIRALPAK IC(250 mm×30 mm，10 um)；移動相：[0.1%NH 3H 2O ETOH]；B%：50%-50%，5.3分鐘)分離，且第一溶析液經鑑定為所需阻轉異構物3-[7-((S)-2-胺基-3-氰基-7-氟-苯并噻吩-4-基)-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(60 mg，0.08 mmol，40%產率)，呈白色固體狀。LCMS (ESI, m/z): 774.1[M+1] +。 步驟 6：2-胺基-(S)-4-[4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-7-基]-7-氟-苯并噻吩-3-甲腈(實例3)

Figure 02_image340
實例 3 The mixture of atropisomers (3-[7-((S)-2-amino-3-cyano-7-fluoro-benzothiophen-4-yl)-8-fluoro-2-[[ (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6-(trifluoromethyl)quinazoline-4- Base]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 3-[7-((R)-2-amino-3-cyano-7-fluoro -Benzothiophen-4-yl)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol Oxy]-6-(trifluoromethyl)quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester) (150 mg, 0.19 mmol, 1.00 equivalent) by SFC (column: DAICEL CHIRALPAK IC (250 mm × 30 mm, 10 um); mobile phase: [0.1%NH 3 H 2 O ETOH]; B%: 50%-50%, 5.3 minutes) and the first eluate was identified as the desired atropisomer 3-[7-((S)-2-amino-3-cyano-7-fluoro-benzothiophene-4- Base)-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-6-( Trifluoromethyl)quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (60 mg, 0.08 mmol, 40% yield), Appears as white solid. LCMS (ESI, m/z): 774.1[M+1] + . Step 6 : 2-amino-(S)-4-[4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-[[(2R, 8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-7-yl]- 7-Fluoro-benzothiophene-3-carbonitrile (Example 3)
Figure 02_image340
Example 3

在20℃下向3-[7-((S)-2-胺基-3-氰基-7-氟-苯并噻吩-4-基)-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(60.00 mg，0.08 mmol，1.00當量)於二氯甲烷(5 mL)中之溶液中添加三氟乙酸(1.54 g，13.51 mmol，1.0 mL，174.18當量)且將混合物在20℃下攪拌0.5小時。LCMS顯示反應完成。將混合物在減壓下濃縮，得到殘餘物，將其藉由製備型高層層析法(管柱：Phenomenex luna C18 150×25 mm×10um；移動相：[水(FA)-ACN]；B%：5%-35%，10分鐘)來純化，得到呈灰白色固體狀之所需產物(37.22 mg，0.05 mmol，67%產率，100%純度，甲酸鹽[1])。LCMS (ESI, m/z): 674.2[M+1] +。 1H NMR: (400 MHz, DMSO-d 6) δ: 8.17 (s, 1H), 8.12 - 8.02 (m, 3H), 7.29 - 7.21 (m, 1H), 7.18 - 7.09 (m, 1H), 5.39 - 5.17 (m, 1H), 4.41 - 4.30 (m, 2H), 4.16 - 4.10 (m, 1H), 4.06 - 4.00 (m, 1H), 3.78 - 3.70 (m, 4H), 3.09 (d, J= 6.0 Hz, 2H), 3.02 (s, 1H), 2.87 - 2.79 (m, 1H), 2.16 - 1.99 (m, 3H), 1.87 - 1.63 (m, 7H)。 合成N-[3-氰基-7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯并噻吩-2-基]胺基甲酸第三丁酯 ( 中間物 4)

Figure 02_image342
步驟1：(6-溴-2,3-二氟-苯基)甲醇
Figure 02_image344
3-[7-((S)-2-amino-3-cyano-7-fluoro-benzothiophen-4-yl)-8-fluoro-2-[[(2R,8S )-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6-(trifluoromethyl)quinazolin-4-yl]-3 , To a solution of tert-butyl 8-diazabicyclo[3.2.1]octane-8-carboxylate (60.00 mg, 0.08 mmol, 1.00 eq) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol, 1.0 mL, 174.18 eq) and the mixture was stirred at 20 °C for 0.5 h. LCMS showed the reaction was complete. The mixture was concentrated under reduced pressure to obtain a residue, which was subjected to preparative high-layer chromatography (column: Phenomenex luna C18 150×25 mm×10um; mobile phase: [water (FA)-ACN]; B% : 5%-35%, 10 min) to give the desired product (37.22 mg, 0.05 mmol, 67% yield, 100% purity, formate salt [1]) as an off-white solid. LCMS (ESI, m/z): 674.2[M+1] + . 1 H NMR: (400 MHz, DMSO-d 6 ) δ : 8.17 (s, 1H), 8.12 - 8.02 (m, 3H), 7.29 - 7.21 (m, 1H), 7.18 - 7.09 (m, 1H), 5.39 - 5.17 (m, 1H), 4.41 - 4.30 (m, 2H), 4.16 - 4.10 (m, 1H), 4.06 - 4.00 (m, 1H), 3.78 - 3.70 (m, 4H), 3.09 (d, J = 6.0 Hz, 2H), 3.02 (s, 1H), 2.87 - 2.79 (m, 1H), 2.16 - 1.99 (m, 3H), 1.87 - 1.63 (m, 7H). Synthesis of N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophene-2 -yl] tertiary butyl carbamate ( intermediate 4)
Figure 02_image342
Step 1: (6-Bromo-2,3-difluoro-phenyl)methanol
Figure 02_image344

在0℃下向6-溴-2,3-二氟-苯甲醛(50 g，226.25 mmol，1當量)於甲醇(500 mL)中之溶液中添加硼氫化鈉(17.12 g，452.49 mmol，2當量)。接著將混合物在20℃下攪拌0.5小時。TLC (石油醚/乙酸乙酯= 5/1)顯示6-溴-2,3-二氟-苯甲醛完全消耗掉。在0℃下將混合物傾倒至飽和氯化銨水溶液(500 mL)，用乙酸乙酯(500 mL×2)萃取。將有機層用鹽水(300 mL)洗滌，經硫酸鈉乾燥，過濾且接著在減壓下濃縮，得到呈白色固體狀之所需粗產物(50 g，44.84 mmol，99%產率)，其直接用於下一步。 1H NMR (400 MHz, CDCl 3) δ 7.41 - 7.31 (m, 1H), 7.14 - 6.98 (m, 1H), 4.94 - 4.82 (m, 2H), 2.21 (t, J= 6.8 Hz, 1H)。 步驟 2：1-溴-2-(溴甲基)-3,4-二氟-苯

Figure 02_image346
To a solution of 6-bromo-2,3-difluoro-benzaldehyde (50 g, 226.25 mmol, 1 equiv) in methanol (500 mL) was added sodium borohydride (17.12 g, 452.49 mmol, 2 equivalent). The mixture was then stirred at 20°C for 0.5 hours. TLC (petroleum ether/ethyl acetate=5/1) showed complete consumption of 6-bromo-2,3-difluoro-benzaldehyde. The mixture was poured into saturated aqueous ammonium chloride (500 mL) at 0°C, extracted with ethyl acetate (500 mL×2). The organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and then concentrated under reduced pressure to give the desired crude product (50 g, 44.84 mmol, 99% yield) as a white solid, which was directly for the next step. 1 H NMR (400 MHz, CDCl 3 ) δ 7.41 - 7.31 (m, 1H), 7.14 - 6.98 (m, 1H), 4.94 - 4.82 (m, 2H), 2.21 (t, J = 6.8 Hz, 1H). Step 2 : 1-Bromo-2-(bromomethyl)-3,4-difluoro-benzene
Figure 02_image346

在0℃下向(6-溴-2,3-二氟-苯基)甲醇(50 g，224.20 mmol，1當量)於二氯甲烷(500 mL)中之溶液中添加三溴化磷(24.28 g，89.68 mmol，0.4當量)。接著將混合物在20℃下攪拌0.5小時。TLC (石油醚/乙酸乙酯= 10/1)顯示(6-溴-2,3-二氟-苯基)甲醇完全消耗掉。將混合物用飽和碳酸氫鈉水溶液(500 mL)淬滅，用乙酸乙酯(500 mL×2)萃取。將有機層用鹽水(300 mL)洗滌，經硫酸鈉乾燥，過濾且接著在減壓下濃縮，得到呈黃色油狀之所需產物(52 g，4.55 mmol，82%產率)。 1H NMR (400 MHz, CDCl 3) δ 7.41 - 7.33 (m, 1H), 7.13 - 7.03 (m, 1H), 4.86 (s, 2H)。 步驟 3：2-(6-溴-2,3-二氟-苯基)乙腈

Figure 02_image348
To a solution of (6-bromo-2,3-difluoro-phenyl)methanol (50 g, 224.20 mmol, 1 equiv) in dichloromethane (500 mL) was added phosphorus tribromide (24.28 g, 89.68 mmol, 0.4 equiv). The mixture was then stirred at 20°C for 0.5 hours. TLC (petroleum ether/ethyl acetate=10/1) showed complete consumption of (6-bromo-2,3-difluoro-phenyl)methanol. The mixture was quenched with saturated aqueous sodium bicarbonate (500 mL), extracted with ethyl acetate (500 mL×2). The organic layer was washed with brine (300 mL), dried over sodium sulfate, filtered and then concentrated under reduced pressure to give the desired product (52 g, 4.55 mmol, 82% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.41 - 7.33 (m, 1H), 7.13 - 7.03 (m, 1H), 4.86 (s, 2H). Step 3 : 2-(6-Bromo-2,3-difluoro-phenyl)acetonitrile
Figure 02_image348

在0℃下向1-溴-2-(溴甲基)-3,4-二氟-苯(45 g，157.39 mmol，1當量)及三甲基氯矽烷(17.18 g，173.13 mmol，1.1當量)於乙腈(300 mL)中之溶液中添加氟化四丁基銨(1 M，173.13 mL，1.1當量)。接著將混合物在80℃下攪拌0.5小時。TLC (石油醚/乙酸乙酯= 5/1)顯示1-溴-2-(溴甲基)-3,4-二氟-苯完全消耗掉。將混合物在減壓下濃縮，獲得殘餘物。將殘餘物藉由管柱層析法(二氧化矽，石油醚/乙酸乙酯= 30/1至5/1)來純化，得到呈白色固體狀之所需產物(35 g，150.85 mmol，96%產率)。 1H NMR (400 MHz, CDCl 3) δ 7.41 - 7.33 (m, 1H), 7.13 - 7.03 (m, 1H), 4.86 (s, 2H)。 步驟 4：N-(4-溴-3-氰基-7-氟-苯并噻吩-2-基)胺基甲酸乙酯

Figure 02_image350
1-bromo-2-(bromomethyl)-3,4-difluoro-benzene (45 g, 157.39 mmol, 1 eq) and trimethylchlorosilane (17.18 g, 173.13 mmol, 1.1 eq ) in acetonitrile (300 mL) was added tetrabutylammonium fluoride (1 M, 173.13 mL, 1.1 equiv). The mixture was then stirred at 80°C for 0.5 hours. TLC (petroleum ether/ethyl acetate = 5/1) showed complete consumption of 1-bromo-2-(bromomethyl)-3,4-difluoro-benzene. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=30/1 to 5/1) to obtain the desired product (35 g, 150.85 mmol, 96 %Yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.41 - 7.33 (m, 1H), 7.13 - 7.03 (m, 1H), 4.86 (s, 2H). Step 4 : Ethyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate
Figure 02_image350

在0℃下向2-(6-溴-2,3-二氟-苯基)乙腈(35 g，150.85 mmol，1當量)於 N, N-二甲基甲醯胺(300 mL)中之溶液中添加第三丁醇鉀(20.31 g，181.02 mmol，1.2當量)。將混合物在0℃下攪拌10分鐘。將N-(硫酮基亞甲基)胺基甲酸乙酯(21.76 g，165.93 mmol，1.1當量)添加至混合物中且在25℃下攪拌50分鐘。將混合物在100℃下攪拌0.5小時。TLC (石油醚/乙酸乙酯= 3/1)顯示2-(6-溴-2,3-二氟-苯基)乙腈完全消耗掉。將混合物傾倒至冰水(1500 mL)中，過濾，得到呈黃色固體狀之產物(75 g，粗)。 1H NMR (400 MHz, DMSO) δ 12.11 (d, J= 1.2 Hz, 1H), 7.68 (m, J= 4.8, 8.6 Hz, 1H), 7.21 (t, J= 8.8 Hz, 1H), 4.29 (m, J= 7.2 Hz, 2H), 1.31 (t, J= 7.2 Hz, 3H)。 步驟 5：2-胺基-4-溴-7-氟-苯并噻吩-3-甲腈

Figure 02_image352
Dissolve 2-(6-bromo-2,3-difluoro-phenyl)acetonitrile (35 g, 150.85 mmol, 1 equivalent) in N , N -dimethylformamide (300 mL) at 0°C Potassium tert-butoxide (20.31 g, 181.02 mmol, 1.2 equiv) was added to the solution. The mixture was stirred at 0°C for 10 minutes. Ethyl N-(thioketomethylene)urethane (21.76 g, 165.93 mmol, 1.1 equiv) was added to the mixture and stirred at 25°C for 50 minutes. The mixture was stirred at 100°C for 0.5 hours. TLC (petroleum ether/ethyl acetate=3/1) showed complete consumption of 2-(6-bromo-2,3-difluoro-phenyl)acetonitrile. The mixture was poured into ice water (1500 mL) and filtered to give the product (75 g, crude) as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 12.11 (d, J = 1.2 Hz, 1H), 7.68 (m, J = 4.8, 8.6 Hz, 1H), 7.21 (t, J = 8.8 Hz, 1H), 4.29 ( m, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H). Step 5 : 2-Amino-4-bromo-7-fluoro-benzothiophene-3-carbonitrile
Figure 02_image352

向N-(4-溴-3-氰基-7-氟-苯并噻吩-2-基)胺基甲酸乙酯(40 g，116.56 mmol，1當量)於二甲亞砜(200 mL)中之溶液中添加氫氧化鈉(5 M，180 mL，7.72當量)。接著將混合物在125℃下攪拌12小時。TLC (二氯甲烷/石油醚 = 2/1)顯示N-(4-溴-3-氰基-7-氟-苯并噻吩-2-基)胺基甲酸乙酯完全消耗掉且偵測到新斑點。使混合物冷卻至20℃，傾倒至冰水(500 mL)中，過濾，得到呈黃色固體狀之所需產物(28 g，103.28 mmol，89%產率)，其直接用於下一步。 1H NMR (400 MHz, DMSO) δ 7.53 - 7.41 (m, 1H), 6.94 (t, J= 8.8 Hz, 1H)。 步驟 6：N-(4-溴-3-氰基-7-氟-苯并噻吩-2-基)胺基甲酸第三丁酯

Figure 02_image354
Ethyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate (40 g, 116.56 mmol, 1 equiv) in dimethyl sulfoxide (200 mL) Sodium hydroxide (5 M, 180 mL, 7.72 equiv) was added to the solution. The mixture was then stirred at 125°C for 12 hours. TLC (dichloromethane/petroleum ether=2/1) showed complete consumption of ethyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate and detected new spot. The mixture was cooled to 20 °C, poured into ice water (500 mL), and filtered to afford the desired product (28 g, 103.28 mmol, 89% yield) as a yellow solid, which was used directly in the next step. 1 H NMR (400 MHz, DMSO) δ 7.53 - 7.41 (m, 1H), 6.94 (t, J = 8.8 Hz, 1H). Step 6 : Tertiary butyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate
Figure 02_image354

向2-胺基-4-溴-7-氟-苯并噻吩-3-甲腈(50 g，184.43 mmol，1當量)及二碳酸二-第三丁酯(44.28 g，202.87 mmol，1.1當量)於四氫呋喃(500 mL)中之溶液中添加 N, N-二異丙基乙胺(47.67 g，368.86 mmol，2當量)及二甲胺基吡啶(2.25 g，18.44 mmol，0.1當量)。將混合物在20℃下攪拌12小時。TLC (二氯甲烷/石油醚=2/1)顯示2-胺基-4-溴-7-氟-苯并噻吩-3-甲腈完全消耗掉且偵測到新斑點。將混合物用乙酸乙酯(300 mL)及水(200 mL)稀釋，用乙酸乙酯(300 mL×2)萃取。將有機層用鹽水(200 mL)洗滌，經硫酸鈉乾燥，過濾且接著在減壓下濃縮，獲得殘餘物。將殘餘物藉由管柱層析法(二氧化矽，二氯甲烷/ 石油醚 = 1/0)來純化，得到呈黃色固體狀之所需產物(52 g，140.08 mmol，76%產率)。 1H NMR (400 MHz, DMSO) δ 11.81 (s, 1H), 7.69 (m, J= 4.8, 8.8 Hz, 1H), 7.21 (t, J= 9.2 Hz, 1H), 1.54 (s, 9H)。 步驟 7：N-[3-氰基-7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯并噻吩-2-基]胺基甲酸第三丁酯

Figure 02_image356
To 2-amino-4-bromo-7-fluoro-benzothiophene-3-carbonitrile (50 g, 184.43 mmol, 1 equivalent) and di-tert-butyl dicarbonate (44.28 g, 202.87 mmol, 1.1 equivalent ) in tetrahydrofuran (500 mL) were added N , N -diisopropylethylamine (47.67 g, 368.86 mmol, 2 eq) and dimethylaminopyridine (2.25 g, 18.44 mmol, 0.1 eq). The mixture was stirred at 20°C for 12 hours. TLC (dichloromethane/petroleum ether=2/1) showed complete consumption of 2-amino-4-bromo-7-fluoro-benzothiophene-3-carbonitrile and detection of new spots. The mixture was diluted with ethyl acetate (300 mL) and water (200 mL), extracted with ethyl acetate (300 mL×2). The organic layer was washed with brine (200 mL), dried over sodium sulfate, filtered and then concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, dichloromethane/petroleum ether=1/0) to give the desired product (52 g, 140.08 mmol, 76% yield) as a yellow solid . 1 H NMR (400 MHz, DMSO) δ 11.81 (s, 1H), 7.69 (m, J = 4.8, 8.8 Hz, 1H), 7.21 (t, J = 9.2 Hz, 1H), 1.54 (s, 9H). Step 7 : N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophene -2-yl] tertiary butyl carbamate
Figure 02_image356

向N-(4-溴-3-氰基-7-氟-苯并噻吩-2-基)胺基甲酸第三丁酯(12 g，32.32 mmol，1當量)及雙(頻哪醇基)二硼(9.86 g，38.80 mmol，1.2當量)於二噁烷(300 mL)中之溶液中添加乙酸鉀(9.52 g，96.9 mmol，3當量)。接著將混合物用氮氣吹掃3次。將[1,1’-雙(二苯基膦基)二茂鐵]-二氯鈀(ii) (2.36 g，3.24 mmol，0.1當量)添加至混合物中且在80℃下攪拌12小時。TLC (石油醚/乙酸乙酯= 3/1)顯示N-(4-溴-3-氰基-7-氟-苯并噻吩-2-基)胺基甲酸第三丁酯完全消耗掉且偵測到若干新斑點。將混合物過濾且接著在減壓下濃縮，獲得殘餘物。將殘餘物藉由管柱層析法(二氧化矽，石油醚/乙酸乙酯= 50/1至3/1)來純化，得到呈黃色固體狀之所需產物(9.6 g，22.95 mmol，71%產率)。 1H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.77 - 7.70 (m, 1H), 6.96 - 6.90 (m, 1H), 1.51 (s, 9H), 1.37 - 1.35 (m, 12H)。 合成N-[7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯并噻吩-2-基]胺基甲酸第三丁酯 ( 中間物 5)

Figure 02_image358
步驟 1：4-溴-7-氟-苯并噻吩-2-甲酸甲酯
Figure 02_image360
To tert-butyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate (12 g, 32.32 mmol, 1 equivalent) and bis(pinacolyl) To a solution of diboron (9.86 g, 38.80 mmol, 1.2 equiv) in dioxane (300 mL) was added potassium acetate (9.52 g, 96.9 mmol, 3 equiv). The mixture was then purged 3 times with nitrogen. [1,1′-Bis(diphenylphosphino)ferrocene]-dichloropalladium(ii) (2.36 g, 3.24 mmol, 0.1 equiv) was added to the mixture and stirred at 80° C. for 12 hours. TLC (petroleum ether/ethyl acetate=3/1) showed complete consumption of tert-butyl N-(4-bromo-3-cyano-7-fluoro-benzothiophen-2-yl)carbamate and Several new spots were detected. The mixture was filtered and then concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (silica, petroleum ether/ethyl acetate=50/1 to 3/1) to give the desired product as a yellow solid (9.6 g, 22.95 mmol, 71 %Yield). 1 H NMR (400 MHz, DMSO) δ 7.89 (s, 1H), 7.77 - 7.70 (m, 1H), 6.96 - 6.90 (m, 1H), 1.51 (s, 9H), 1.37 - 1.35 (m, 12H) . Synthesis of N-[7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]amino group Tertiary butyl formate ( intermediate 5)
Figure 02_image358
Step 1 : 4-Bromo-7-fluoro-benzothiophene-2-carboxylic acid methyl ester
Figure 02_image360

在氮氣氛圍下向6-溴-2,3-二氟-苯甲醛(50.00 g，226.25 mmol，1.00當量)於二甲基甲醯胺(500 mL)中之溶液中添加碳酸鉀(62.54 g，452.49 mmol，2.00當量)。接著將2-硫烷基乙酸甲酯(26.74 g，251.92 mmol，22.8 mL，1.11當量)添加至混合物中。將混合物在60℃下攪拌3小時。將反應混合物用水(1000 mL)稀釋且用乙酸乙酯(400 mL×3)萃取。將合併之有機層用鹽水(500 mL×3)洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮，得到殘餘物。將殘餘物用石油醚與乙酸乙酯之混合溶劑(v/v = 10:1，300 mL)濕磨，獲得呈白色固體狀之所需產物(55.00 g，182.62 mmol，81%產率)。 1H NMR (400 MHz, CDCl 3) δ 8.16 (d, J= 3.2 Hz, 1H), 7.61 - 7.46 (m, 1H), 7.05 (t, J= 8.8 Hz, 1H), 3.99 (s, 3H)。 步驟 2：4-溴-7-氟-苯并噻吩-2-甲酸

Figure 02_image362
To a solution of 6-bromo-2,3-difluoro-benzaldehyde (50.00 g, 226.25 mmol, 1.00 equiv) in dimethylformamide (500 mL) was added potassium carbonate (62.54 g, 452.49 mmol, 2.00 equiv). Then methyl 2-sulfanylacetate (26.74 g, 251.92 mmol, 22.8 mL, 1.11 equiv) was added to the mixture. The mixture was stirred at 60°C for 3 hours. The reaction mixture was diluted with water (1000 mL) and extracted with ethyl acetate (400 mL×3). The combined organic layers were washed with brine (500 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with a mixed solvent of petroleum ether and ethyl acetate (v/v = 10:1, 300 mL) to obtain the desired product (55.00 g, 182.62 mmol, 81% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.16 (d, J = 3.2 Hz, 1H), 7.61 - 7.46 (m, 1H), 7.05 (t, J = 8.8 Hz, 1H), 3.99 (s, 3H) . Step 2 : 4-Bromo-7-fluoro-benzothiophene-2-carboxylic acid
Figure 02_image362

使4-溴-7-氟-苯并噻吩-2-甲酸甲酯(50.00 g，172.94 mmol，1.00當量)及氫氧化鋰單水合物(25.00 g，595.81 mmol，3.45當量)於四氫呋喃(200 mL)、甲醇(200 mL)及水(100 mL)中之混合物脫氣且用氮氣吹掃3次，且接著將混合物在氮氣氛圍下在20℃下攪拌1小時。將混合物用水(1000 mL)稀釋且將pH值用4M鹽酸調至3且用乙酸乙酯(500 mL×2)萃取。將合併之有機層用鹽水(1000 ml)洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮，得到呈白色固體狀之所需產物(45.00 g，163.58 mmol，95%產率)。 1H NMR (400 MHz, DMSO-d 6) δ 7.88 (d, J= 3.2 Hz, 1H), 7.74 - 7.56 (m, 1H), 7.32 (t, J= 9.2 Hz, 1H)。 步驟 3：N-(4-溴-7-氟-苯并噻吩-2-基)胺基甲酸第三丁酯

Figure 02_image364
Make 4-bromo-7-fluoro-benzothiophene-2-carboxylic acid methyl ester (50.00 g, 172.94 mmol, 1.00 equivalent) and lithium hydroxide monohydrate (25.00 g, 595.81 mmol, 3.45 equivalent) in tetrahydrofuran (200 mL ), methanol (200 mL) and water (100 mL) was degassed and purged 3 times with nitrogen, and then the mixture was stirred at 20 °C for 1 h under nitrogen atmosphere. The mixture was diluted with water (1000 mL) and the pH was adjusted to 3 with 4M hydrochloric acid and extracted with ethyl acetate (500 mL×2). The combined organic layers were washed with brine (1000 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the desired product (45.00 g, 163.58 mmol, 95% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.88 (d, J = 3.2 Hz, 1H), 7.74 - 7.56 (m, 1H), 7.32 (t, J = 9.2 Hz, 1H). Step 3 : Tertiary butyl N-(4-bromo-7-fluoro-benzothiophen-2-yl)carbamate
Figure 02_image364

向4-溴-7-氟-苯并噻吩-2-甲酸(15.00 g，54.53 mmol，1.00當量)於第三丁醇(200 mL)中之溶液中添加二苯基磷醯基疊氮化物(19.51 g，70.88 mmol，15.4 mL，1.30當量)及二異丙基乙胺(14.09 g，109.05 mmol，19.0 mL，2.00當量)。將混合物在85℃下攪拌12小時。將混合物用水(500 mL)稀釋且用乙酸乙酯(250 mL×2)萃取。將合併之有機層用鹽水(500 ml)洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮，獲得殘餘物。將殘餘物藉由矽膠上管柱層析法(石油醚:乙酸乙酯= 1:0至20:1)來純化，獲得呈黃色固體狀之N-(4-溴-7-氟-苯并噻吩-2-基)胺基甲酸第三丁酯(15.00 g，43.33 mmol，79%產率)。 1H NMR (400 MHz, DMSO-d 6) δ 11.16 (s, 1H), 7.56 - 7.41 (m, 1H), 6.99 (t, J= 9.2 Hz, 1H), 6.80 (d, J= 3.6 Hz, 1H), 1.50 (s, 9H)。 步驟 4：N-[7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯并噻吩-2-基]胺基甲酸第三丁酯

Figure 02_image366
To a solution of 4-bromo-7-fluoro-benzothiophene-2-carboxylic acid (15.00 g, 54.53 mmol, 1.00 equiv) in tert-butanol (200 mL) was added diphenylphosphoryl azide ( 19.51 g, 70.88 mmol, 15.4 mL, 1.30 equiv) and diisopropylethylamine (14.09 g, 109.05 mmol, 19.0 mL, 2.00 equiv). The mixture was stirred at 85°C for 12 hours. The mixture was diluted with water (500 mL) and extracted with ethyl acetate (250 mL×2). The combined organic layers were washed with brine (500 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:0 to 20:1) to obtain N-(4-bromo-7-fluoro-benzo Thiophen-2-yl) tert-butyl carbamate (15.00 g, 43.33 mmol, 79% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.16 (s, 1H), 7.56 - 7.41 (m, 1H), 6.99 (t, J = 9.2 Hz, 1H), 6.80 (d, J = 3.6 Hz, 1H), 1.50 (s, 9H). Step 4 : N-[7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl] tertiary butyl carbamate
Figure 02_image366

使N-(4-溴-7-氟-苯并噻吩-2-基)胺基甲酸第三丁酯(25.00 g，72.21 mmol，1.00當量)、雙(頻哪醇基)二硼(26.04 g，102.54 mmol，1.40當量)、[1,1-雙(二苯基膦基)二茂鐵]二氯鈀(II) (10.57 g，14.44 mmol，0.20當量)及乙酸鉀(21.26 g，216.63 mmol，3.00當量)於二噁烷(300 mL)中之混合物脫氣且用氮氣吹掃3次，且接著將混合物在氮氣氛圍下在100℃下攪拌10小時。將混合物過濾且將濾液在減壓下濃縮，得到殘餘物。將殘餘物藉由矽膠上管柱層析法(石油醚:乙酸乙酯= 20:1至10:1)來純化，獲得呈白色固體狀之所需產物(20.00 g，50.85 mmol，70%產率)。 1H NMR (400 MHz, DMSO-d 6) δ 10.97 (s, 1H), 7.67 (dd, J= 6.0, 8.0 Hz, 1H), 7.39 (d, J= 4.0 Hz, 1H), 7.01 (dd, J= 8.0, 10.4 Hz, 1H), 1.50 (s, 9H), 1.33 (s, 12H)。 合成(R)-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈 ( 實例 4)

Figure 02_image368
步驟 1 ：(1R,5S)-3-(7-(2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯
Figure 02_image370
Make tert-butyl N-(4-bromo-7-fluoro-benzothiophen-2-yl)carbamate (25.00 g, 72.21 mmol, 1.00 equivalents), bis(pinacolyl)diboron (26.04 g , 102.54 mmol, 1.40 equivalents), [1,1-bis(diphenylphosphino) ferrocene] dichloropalladium (II) (10.57 g, 14.44 mmol, 0.20 equivalents) and potassium acetate (21.26 g, 216.63 mmol , 3.00 equiv) in dioxane (300 mL) was degassed and purged 3 times with nitrogen, and then the mixture was stirred at 100° C. for 10 h under nitrogen atmosphere. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether:ethyl acetate=20:1 to 10:1) to obtain the desired product as a white solid (20.00 g, 50.85 mmol, 70% yield Rate). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.97 (s, 1H), 7.67 (dd, J = 6.0, 8.0 Hz, 1H), 7.39 (d, J = 4.0 Hz, 1H), 7.01 (dd, J = 8.0, 10.4 Hz, 1H), 1.50 (s, 9H), 1.33 (s, 12H). Synthesis of (R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-8-fluoro-2-(( (2R,7aS)-2-Fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b] Thiophene-3-carbonitrile ( Example 4)
Figure 02_image368
Step 1 : (1R,5S)-3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6 -Chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3, tertiary butyl 8-diazabicyclo[3.2.1]octane-8-carboxylate
Figure 02_image370

向 N-[3-氰基-7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯并噻吩-2-基]胺基甲酸第三丁酯(6.4 g，15.28 mmol，1.2當量)及3-[7-溴-6-氯-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(8 g，12.72 mmol，1當量)於2-甲基四氫呋喃(80 mL)及水(20 mL)中之溶液中添加二-第三丁基(環戊基)磷烷;二氯鈀;鐵(829 mg，1.27 mmol，0.1當量)。將混合物用吹掃氮氣3次，且接著將 N,N-二異丙基乙胺(4.92 g，38.16 mmol，3當量)添加至混合物中。將混合物在70℃下攪拌2小時。將混合物過濾且接著濃縮，獲得殘餘物。將殘餘物藉由製備型HPLC (管柱：Phenomenex luna C18 (250×70 mm，10 um)；移動相：[水(FA)-ACN]；B%：50%-70%，15分鐘)來純化。獲得呈黃色油狀之3-[7-[2-(第三丁氧羰基胺基)- 3-氰基-7-氟-苯并噻吩-4-基]-6-氯-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(4.6 g，5.42 mmol，50%產率，99%純度)。LCMS (ESI, m/z): 840.1[M] +。 步驟 2 ：(1R,5S)-3-(7-((R)-2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image372
To N- [3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophene-2 -yl] tert-butyl carbamate (6.4 g, 15.28 mmol, 1.2 equivalents) and 3-[7-bromo-6-chloro-8-fluoro-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-Hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane- To a solution of tert-butyl 8-carboxylate (8 g, 12.72 mmol, 1 eq) in 2-methyltetrahydrofuran (80 mL) and water (20 mL) was added di-tert-butyl(cyclopentyl)phosphine alkane; dichloropalladium; iron (829 mg, 1.27 mmol, 0.1 equiv). The mixture was purged with nitrogen 3 times, and then N,N -diisopropylethylamine (4.92 g, 38.16 mmol, 3 equiv) was added to the mixture. The mixture was stirred at 70°C for 2 hours. The mixture was filtered and then concentrated to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250×70 mm, 10 um); mobile phase: [water (FA)-ACN]; B%: 50%-70%, 15 minutes) purification. 3-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro- 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-3, Tert-butyl 8-diazabicyclo[3.2.1]octane-8-carboxylate (4.6 g, 5.42 mmol, 50% yield, 99% purity). LCMS (ESI, m/z): 840.1[M] + . Step 2 : (1R,5S)-3-(7-((R)-2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophene-4- Base) -6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl )-3,8-diazabicyclo[3.2.1]octane-8-carboxylate tertiary butyl ester
Figure 02_image372

將(1R,5S)-3-(7-(2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩- 4-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(4.6 g，5.47 mmol，1.0當量)藉由SFC (Rt = 0.898分鐘、1.172分鐘；管柱：DAICEL CHIRALPAK IC (250 mm×30 mm，10 um)；移動相：[0.1%NH 3H 2O ETOH]；B%：45%-45%，4，140分鐘)來純化，獲得產物。獲得呈黃色油狀之化合物(1R,5S)-3-(7-((R)-2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(2.1 g，2.50 mmol，46%產率)。 步驟 3 ：(R)-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈

Figure 02_image374
(1R,5S)-3-(7-(2-((tertiary butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro -8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8- Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (4.6 g, 5.47 mmol, 1.0 equivalent) by SFC (Rt = 0.898 minutes, 1.172 minutes; column: DAICEL CHIRALPAK IC (250 mm ×30 mm, 10 um); mobile phase: [0.1%NH 3 H 2 O ETOH]; B%: 45%-45%, 4, 140 minutes) to obtain the product. The compound (1R,5S)-3-(7-((R)-2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b] was obtained as a yellow oil Thiophen-4-yl)-6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline -tert-butyl-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.1 g, 2.50 mmol, 46% yield). Step 3 : (R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-8-fluoro-2- (((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[ b] Thiophene-3-carbonitrile
Figure 02_image374

向(1R,5S)-3-(7-((R)-2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(2.0 g，2.40 mmol，1當量)於二氯甲烷(20 mL)中之溶液中添加三氟乙酸(5 mL)。接著將混合物在20℃下攪拌0.5小時。LCMS顯示偵測到所需質量。將混合物在減壓下濃縮，獲得殘餘物。將殘餘物藉由製備型HPLC (管柱：Phenomenex luna C18 (250×70 mm，10 um)；移動相：[水(FA)-ACN]；B%：10%-40%，20分鐘)來純化。獲得呈黃色固體狀之(R)-4-(4-((1R,5S)-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-6-氯-8-氟-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈(1.4 g，2.00 mmol，84%產率，98%純度，甲酸鹽[1])。LCMS (ESI, m/z): 640.3 [M] +。 1H NMR: (400MHz, DMSO- d 6 ) δ: 8.15 (s, 1H), 8.13 (s, 2H), 7.91 (s, 1H), 7.28 - 7.20 (m, 1H), 7.20 - 7.12 (m, 1H), 5.44 - 5.21 (m, 1H), 4.52 (d, J= 13.2 Hz, 1H), 4.36 (d, J= 13.2 Hz, 1H), 4.24 - 4.05 (m, 4H), 3.85 (d, J= 13.2 Hz, 1H), 3.68 (d, J= 13.6 Hz, 1H), 3.23 - 3.12 (m, 3H), 2.95 - 2.85 (m, 1H), 2.28 - 2.01 (m, 3H), 1.96 - 1.77 (m, 7H)。 合成2-胺基-4-[6-氯-4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-2-[[(2S)-1,2-二甲基吡咯啶-2-基]甲氧基]-8-氟-喹唑啉-7-基]-7-氟-苯并噻吩-3-甲腈 ( 實例 5)

Figure 02_image376
步驟 1：[(2S)-1,2-二甲基吡咯啶-2-基]甲醇
Figure 02_image378
To (1R,5S)-3-(7-((R)-2-((tertiary butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl) -6-chloro-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)- To a solution of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.0 g, 2.40 mmol, 1 equiv) in dichloromethane (20 mL) was added trifluoroacetic acid ( 5 mL). The mixture was then stirred at 20°C for 0.5 hours. LCMS showed the desired mass was detected. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 (250×70 mm, 10 um); mobile phase: [water (FA)-ACN]; B%: 10%-40%, 20 minutes) purification. (R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro was obtained as a yellow solid -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluoro Benzo[b]thiophene-3-carbonitrile (1.4 g, 2.00 mmol, 84% yield, 98% purity, formate salt [1]). LCMS (ESI, m/z): 640.3 [M] + . 1 H NMR: (400MHz, DMSO- d 6 ) δ : 8.15 (s, 1H), 8.13 (s, 2H), 7.91 (s, 1H), 7.28 - 7.20 (m, 1H), 7.20 - 7.12 (m, 1H), 5.44 - 5.21 (m, 1H), 4.52 (d, J = 13.2 Hz, 1H), 4.36 (d, J = 13.2 Hz, 1H), 4.24 - 4.05 (m, 4H), 3.85 (d, J = 13.2 Hz, 1H), 3.68 (d, J = 13.6 Hz, 1H), 3.23 - 3.12 (m, 3H), 2.95 - 2.85 (m, 1H), 2.28 - 2.01 (m, 3H), 1.96 - 1.77 ( m, 7H). Synthesis of 2-amino-4-[6-chloro-4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-2-[[(2S)-1,2-di Methylpyrrolidin-2-yl]methoxy]-8-fluoro-quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile ( Example 5)
Figure 02_image376
Step 1 : [(2S)-1,2-Dimethylpyrrolidin-2-yl]methanol
Figure 02_image378

在0℃下向鋁氫化锂(2.64 g，69.67 mmol)於四氫呋喃(25 mL)中之溶液中添加(2S)-2-(羥基甲基)-2-甲基-吡咯啶-1-甲酸第三丁酯(5 g，23.22 mmol)於四氫呋喃(25 mL)中之溶液。接著將混合物在60℃下攪拌1小時。薄層層析法(二氯甲烷:甲醇= 10:1)顯示反應完成。將混合物用水(8 mL)淬滅且經無水硫酸鈉乾燥，過濾且將濾液在減壓下濃縮，獲得呈無色油狀之[(2S)-1,2-二甲基吡咯啶-2-基]甲醇(2.50 g，19.35 mmol，83%產率)。 1H NMR (400 MHz, CDCl 3-d) δ3.37 - 3.20 (m, 2H), 3.03 (td, J= 5.2, 9.2 Hz, 1H), 2.55 (q, J= 8.8 Hz, 1H), 2.19 (s, 3H), 2.10 - 2.01 (m, 1H), 1.76 - 1.65 (m, 2H), 1.57 - 1.40 (m, 2H), 0.85 (s, 3H)。 步驟 2：3-[7-溴-6-氯-2-[[(2S)-1,2-二甲基吡咯啶-2-基]甲氧基]-8-氟-喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image380
To a solution of lithium aluminum hydride (2.64 g, 69.67 mmol) in tetrahydrofuran (25 mL) at 0 °C was added (2S)-2-(hydroxymethyl)-2-methyl-pyrrolidine-1-carboxylic acid A solution of tributyl ester (5 g, 23.22 mmol) in tetrahydrofuran (25 mL). The mixture was then stirred at 60°C for 1 hour. Thin layer chromatography (dichloromethane:methanol=10:1) showed that the reaction was complete. The mixture was quenched with water (8 mL) and dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain [(2S)-1,2-dimethylpyrrolidin-2-yl as a colorless oil ] methanol (2.50 g, 19.35 mmol, 83% yield). 1 H NMR (400 MHz, CDCl 3 -d) δ 3.37 - 3.20 (m, 2H), 3.03 (td, J = 5.2, 9.2 Hz, 1H), 2.55 (q, J = 8.8 Hz, 1H), 2.19 ( s, 3H), 2.10 - 2.01 (m, 1H), 1.76 - 1.65 (m, 2H), 1.57 - 1.40 (m, 2H), 0.85 (s, 3H). Step 2 : 3-[7-Bromo-6-chloro-2-[[(2S)-1,2-dimethylpyrrolidin-2-yl]methoxy]-8-fluoro-quinazoline-4 -yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure 02_image380

向3-(7-溴-6-氯-2,8-二氟-喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(1.5 g，3.06 mmol)及[(2S)-1,2-二甲基吡咯啶-2-基]甲醇(791 mg，6.13 mmol)於乙腈(30 mL)中之溶液中添加碳酸銫(2 g，6.13 mmol)及1,4-二氮雜雙環[2.2.2]辛烷(34 mg，0.3 mmol)。將混合物在50℃下攪拌12小時。LCMS顯示反應完成。將混合物過濾且將濾液在減壓下濃縮，獲得殘餘物。將殘餘物藉由矽膠上管柱層析法(溶析液：二氯甲烷/甲醇= 10/1)來純化，獲得殘餘物。將殘餘物藉由製備型高效液相層析法(管柱：Phenomenex luna C18 150×40 mm×15 um；移動相：[水(FA)-ACN]；B%：23%-53%，10分鐘)來純化，獲得呈黃色固體狀之所需產物(220 mg，0.36 mmol，12%產率)。LCMS (ESI, m/z): 598.2, 600.2 [M+H] +。 步驟 3：3-[7-[2-(第三丁氧羰基胺基)-3-氰基-7-氟-苯并噻吩-4-基]-6-氯-2-[[(2S)-1,2-二甲基吡咯啶-2-基]甲氧基]-8-氟-喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image382
To 3-(7-bromo-6-chloro-2,8-difluoro-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl To a solution of the ester (1.5 g, 3.06 mmol) and [(2S)-1,2-dimethylpyrrolidin-2-yl]methanol (791 mg, 6.13 mmol) in acetonitrile (30 mL) was added cesium carbonate ( 2 g, 6.13 mmol) and 1,4-diazabicyclo[2.2.2]octane (34 mg, 0.3 mmol). The mixture was stirred at 50°C for 12 hours. LCMS showed the reaction was complete. The mixture was filtered and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to obtain a residue. The residue was subjected to preparative high-performance liquid chromatography (column: Phenomenex luna C18 150×40 mm×15 um; mobile phase: [water (FA)-ACN]; B%: 23%-53%, 10 min) to obtain the desired product (220 mg, 0.36 mmol, 12% yield) as a yellow solid. LCMS (ESI, m/z): 598.2, 600.2 [M+H] + . Step 3 : 3-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-2-[[(2S) -1,2-Dimethylpyrrolidin-2-yl]methoxy]-8-fluoro-quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8 - Tertiary butyl formate
Figure 02_image382

使3-[7-溴-6-氯-2-[[(2S)-1,2-二甲基吡咯啶-2-基]甲氧基]-8-氟-喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(0.18 g，0.30 mmol)、N-[3-氰基-7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯并噻吩-2-基]胺基甲酸第三丁酯(251 mg，0.60 mmol)、二-第三丁基(環戊基)磷烷;二氯鈀;鐵(19 mg，0.03 mmol)、碳酸鈉(95 mg，0.90 mmol)於二噁烷(3 mL)及水(0.6 mL)中之混合物脫氣且用氮氣吹掃3次，接著將混合物在氮氣氛圍下在80℃下攪拌30分鐘。LCMS顯示反應完成。將反應混合物用水(10 mL)稀釋且用二氯甲烷(20 mL×3)萃取。將合併之有機層用鹽水(50 mL)洗滌，經無水硫酸鈉乾燥，過濾且將濾液在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型高效液相層析法(管柱：Phenomenex Synergi Polar-RP 100×25 mm×4 um；移動相：[水(TFA)-ACN]；B%：58%-78%，7分鐘)來純化，得到呈白色固體狀之所需產物(30 mg，0.03 mmol，12%產率)。LCMS (ESI, m/z): 810.1 [M+H] +。 步驟 4：2-胺基-4-[6-氯-4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-2-[[(2S)-1,2-二甲基吡咯啶-2-基]甲氧基]-8-氟-喹唑啉-7-基]-7-氟-苯并噻吩-3-甲腈。

Figure 02_image384
實例 5 Make 3-[7-bromo-6-chloro-2-[[(2S)-1,2-dimethylpyrrolidin-2-yl]methoxy]-8-fluoro-quinazolin-4-yl ]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.18 g, 0.30 mmol), N-[3-cyano-7-fluoro-4-(4, tert-butyl 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate (251 mg, 0.60 mmol), Di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (19 mg, 0.03 mmol), sodium carbonate (95 mg, 0.90 mmol) in dioxane (3 mL) and water (0.6 mL) The mixture in was degassed and purged 3 times with nitrogen, then the mixture was stirred at 80 °C for 30 min under nitrogen atmosphere. LCMS showed the reaction was complete. The reaction mixture was diluted with water (10 mL) and extracted with dichloromethane (20 mL×3). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was subjected to preparative high-performance liquid chromatography (column: Phenomenex Synergi Polar-RP 100×25 mm×4 um; mobile phase: [water (TFA)-ACN]; B%: 58%-78% , 7 min) to give the desired product (30 mg, 0.03 mmol, 12% yield) as a white solid. LCMS (ESI, m/z): 810.1 [M+H] + . Step 4 : 2-Amino-4-[6-chloro-4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-2-[[(2S)-1,2 -Dimethylpyrrolidin-2-yl]methoxy]-8-fluoro-quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile.
Figure 02_image384
Example 5

向3-[7-[2-(第三丁氧羰基胺基)-3-氰基-7-氟-苯并噻吩-4-基]-6-氯-2-[[(2S)-1,2-二甲基吡咯啶-2-基]甲氧基]-8-氟-喹唑啉-4-基]-3,8–二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(25 mg，0.03 mmol)於二氯甲烷(2 mL)中之溶液中添加三氟乙酸(3.08 g，27.01 mmol，2 mL)。將混合物在25℃下攪拌10分鐘。薄層層析法(二氯甲烷:甲醇= 10:1)顯示反應完成。將反應混合物真空濃縮，得到殘餘物。將殘餘物藉由製備型高效液相層析法(管柱：Phenomenex C18 75×30 mm×3 um；移動相：[水(FA)-ACN]；B%：8%-38%，7分鐘)來純化，得到呈黃色固體狀之產物(4 mg，0.01 mmol，19%產率，甲酸鹽[2])。LCMS (ESI, m/z): 610.2[M+H] +。 1H NMR (400 MHz, DMSO) δ 8.28 (s, 2H), 8.13 (s, 2H), 7.86 (s, 1H), 7.26 (dd, J= 5.2, 8.4 Hz, 1H), 7.20 - 7.11 (m, 1H), 4.42 - 4.24 (m, 2H), 4.22 - 4.15 (m, 2H), 3.56 - 3.27 (m, 5H), 2.95 - 2.81 (m, 1H), 2.62 (q, J= 8.4 Hz, 1H), 2.30 (s, 3H), 1.93 (td, J= 7.2, 12.4 Hz, 1H), 1.79 - 1.56 (m, 7H), 1.11 - 1.02 (m, 3H)。 合成2-胺基-4-[6-氯-4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-8-氟-2-[[(2R)-2-(羥基甲基)-1-甲基-吡咯啶-2-基]甲氧基]喹唑啉-7-基]-7-氟-苯并噻吩-3-甲腈 ( 實例 6)

Figure 02_image386
步驟 1：(3R,7aR)-7a-(苯甲氧基甲基)-3-(三氯甲基)-3,5,6,7-四氫吡咯并[1,2-c]噁唑-1-酮
Figure 02_image388
To 3-[7-[2-(tertiary butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-2-[[(2S)-1 ,2-Dimethylpyrrolidin-2-yl]methoxy]-8-fluoro-quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid To a solution of tert-butyl ester (25 mg, 0.03 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (3.08 g, 27.01 mmol, 2 mL). The mixture was stirred at 25°C for 10 minutes. Thin layer chromatography (dichloromethane:methanol=10:1) showed that the reaction was complete. The reaction mixture was concentrated in vacuo to give a residue. The residue was subjected to preparative high-performance liquid chromatography (column: Phenomenex C18 75×30 mm×3 um; mobile phase: [water (FA)-ACN]; B%: 8%-38%, 7 minutes ) to give the product (4 mg, 0.01 mmol, 19% yield, formate salt [2]) as a yellow solid. LCMS (ESI, m/z): 610.2 [M+H] + . 1 H NMR (400 MHz, DMSO) δ 8.28 (s, 2H), 8.13 (s, 2H), 7.86 (s, 1H), 7.26 (dd, J = 5.2, 8.4 Hz, 1H), 7.20 - 7.11 (m , 1H), 4.42 - 4.24 (m, 2H), 4.22 - 4.15 (m, 2H), 3.56 - 3.27 (m, 5H), 2.95 - 2.81 (m, 1H), 2.62 (q, J = 8.4 Hz, 1H ), 2.30 (s, 3H), 1.93 (td, J = 7.2, 12.4 Hz, 1H), 1.79 - 1.56 (m, 7H), 1.11 - 1.02 (m, 3H). Synthesis of 2-amino-4-[6-chloro-4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-[[(2R)-2 -(Hydroxymethyl)-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile ( example 6)
Figure 02_image386
Step 1 : (3R,7aR)-7a-(Benzyloxymethyl)-3-(trichloromethyl)-3,5,6,7-tetrahydropyrrolo[1,2-c]oxazole -1-one
Figure 02_image388

使(3R,7aS)-3-(三氯甲基)-5,6,7,7a-四氫-3H-吡咯并[1,2-c]噁唑-1-酮(30.00 g，122.70 mmol)、氯甲氧基甲基苯(38.43 g，245.40 mmol)、二(丙烷-2-基)氨合鋰(2 M，92 mL)於四氫呋喃(300 mL)中之混合物脫氣且在-78℃下用氮氣吹掃3次，且接著將混合物在氮氣氛圍下在-40℃下攪拌4小時。將反應混合物藉由緩慢添加水(300 mL)來淬滅，且接著將混合物用乙酸乙酯(300 mL×3)萃取。將合併之有機層用鹽水(500 mL)洗滌，經硫酸鈉乾燥，過濾且將濾液在減壓下濃縮，得到殘餘物。將殘餘物藉由矽膠管柱層析法(溶析液：PE/EtOAc = 5/1)來純化，得到呈黃色油狀之(3R,7aR)-7a-(苯甲氧基甲基)-3-(三氯甲基)-3,5,6,7-四氫吡咯并[1,2-c]噁唑-1-酮(21 g，58.14 mmol，47%產率)。 1H NMR (400 MHz, CDCl 3) δ 7.27 - 7.17 (m, 5H), 4.92 (s, 1H), 4.55 (d, J = 1.6 Hz, 2H), 3.66 (s, 2H), 3.30 - 3.22 (m, 1H), 3.21 - 3.14 (m, 1H), 2.24 (ddd, J = 7.2, 9.6, 13.2 Hz, 1H), 2.09 - 2.01 (m, 1H), 1.95 - 1.87 (m, 1H), 1.65 - 1.60 (m, 1H)。 步驟 2：(2R)-2-(苯甲氧基甲基)吡咯啶-2-甲酸甲酯

Figure 02_image390
Make (3R,7aS)-3-(trichloromethyl)-5,6,7,7a-tetrahydro-3H-pyrrolo[1,2-c]oxazol-1-one (30.00 g, 122.70 mmol ), a mixture of chloromethoxymethylbenzene (38.43 g, 245.40 mmol), bis(propan-2-yl) lithium amide (2 M, 92 mL) in tetrahydrofuran (300 mL) was degassed and heated at -78 °C was purged with nitrogen 3 times, and then the mixture was stirred at -40 °C for 4 h under nitrogen atmosphere. The reaction mixture was quenched by adding water (300 mL) slowly, and then the mixture was extracted with ethyl acetate (300 mL×3). The combined organic layers were washed with brine (500 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (eluent: PE/EtOAc = 5/1) to obtain (3R,7aR)-7a-(benzyloxymethyl)- 3-(Trichloromethyl)-3,5,6,7-tetrahydropyrrolo[1,2-c]oxazol-1-one (21 g, 58.14 mmol, 47% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 - 7.17 (m, 5H), 4.92 (s, 1H), 4.55 (d, J = 1.6 Hz, 2H), 3.66 (s, 2H), 3.30 - 3.22 ( m, 1H), 3.21 - 3.14 (m, 1H), 2.24 (ddd, J = 7.2, 9.6, 13.2 Hz, 1H), 2.09 - 2.01 (m, 1H), 1.95 - 1.87 (m, 1H), 1.65 - 1.60 (m, 1H). Step 2 : (2R)-2-(Benzyloxymethyl)pyrrolidine-2-carboxylic acid methyl ester
Figure 02_image390

向(3R,7aR)-7a-(苯甲氧基甲基)-3-(三氯甲基)-3,5,6,7-四氫吡咯并[1,2-c]噁唑-1-酮(5 g，13.71 mmol)於甲醇(100 mL)中之溶液中添加甲醇鈉(518 mg，9.60 mmol)。將混合物在室溫下攪拌12小時。接著在0℃下添加乙醯氯(22 g，280.26 mmo)。將混合物在65℃下攪拌1小時。將混合物真空濃縮。向殘餘物添加飽和碳酸鈉溶液(100 ml)，用乙酸乙酯(100 mL×3)萃取。將合併之有機層用鹽水洗滌，經硫酸鈉乾燥，過濾且將濾液在減壓下濃縮，得到呈黃色油狀之(2R)-2-(苯甲氧基甲基)吡咯啶-2-甲酸甲酯(2.2 g，8.82 mmol，64%產率)，其未經進一步純化即用於下一步。LCMS (ESI, m/z): 250.0 [M+H] +. 1H NMR (400 MHz, CDCl3) δ 7.36 - 7.28 (m, 5H), 4.64 - 4.59 (m, 1H), 4.52 - 4.47 (m, 1H), 3.76 (d, J= 8.8 Hz, 1H), 3.73 (s, 3H), 3.45 (d, J= 8.8 Hz, 1H), 3.10 - 2.96 (m, 2H), 2.67 (s, 1H), 2.10 - 2.01 (m, 1H), 1.83 - 1.67 (m, 3H)。 步驟 3：(2R)-2-(苯甲氧基甲基)-1-甲基-吡咯啶-2-甲酸甲酯

Figure 02_image392
To (3R,7aR)-7a-(benzyloxymethyl)-3-(trichloromethyl)-3,5,6,7-tetrahydropyrrolo[1,2-c]oxazole-1 - To a solution of the ketone (5 g, 13.71 mmol) in methanol (100 mL) was added sodium methoxide (518 mg, 9.60 mmol). The mixture was stirred at room temperature for 12 hours. Acetyl chloride (22 g, 280.26 mmol) was then added at 0 °C. The mixture was stirred at 65°C for 1 hour. The mixture was concentrated in vacuo. A saturated sodium carbonate solution (100 ml) was added to the residue, extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give (2R)-2-(benzyloxymethyl)pyrrolidine-2-carboxylic acid as a yellow oil Methyl ester (2.2 g, 8.82 mmol, 64% yield), which was used in the next step without further purification. LCMS (ESI, m/z): 250.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.36 - 7.28 (m, 5H), 4.64 - 4.59 (m, 1H), 4.52 - 4.47 (m , 1H), 3.76 (d, J = 8.8 Hz, 1H), 3.73 (s, 3H), 3.45 (d, J = 8.8 Hz, 1H), 3.10 - 2.96 (m, 2H), 2.67 (s, 1H) , 2.10 - 2.01 (m, 1H), 1.83 - 1.67 (m, 3H). Step 3 : (2R)-2-(Benzyloxymethyl)-1-methyl-pyrrolidine-2-carboxylic acid methyl ester
Figure 02_image392

使(2R)-2-(苯甲氧基甲基)吡咯啶-2-甲酸甲酯(2.2 g，8.82 mmol，1.00當量)、甲醛(2.86 g，35.30 mmol，37%純度)於二氯甲烷(100 mL)中之混合物脫氣且用氮氣吹掃3次，且接著將混合物在氮氣氛圍下在室溫下攪拌0.5小時。接著將三乙醯氧基硼氫化鈉(3.74 g，17.65 mmol)添加至混合物，將混合物在25℃下攪拌12小時。LCMS顯示反應完成。反應混合物藉由添加飽和碳酸氫鈉水溶液(100 mL)而淬滅，用二氯甲烷(100 mL×2)萃取。將合併之有機層用鹽水(200 mL)洗滌，經硫酸鈉乾燥，過濾且將濾液在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型高效液相層析法(管柱：Phenomenex luna C18 250×50 mm×10 um；移動相：[水(FA)-ACN]；B%：1%-30%，20分鐘)來純化，得到呈無色油狀之所需產物(1.30 g，4.94 mmol，56%產率)。LCMS (ESI, m/z): 264.3 [M+H] +。 步驟 4：[(2S)-2-(苯甲氧基甲基)-1-甲基-吡咯啶-2-基]甲醇

Figure 02_image394
Make (2R)-2-(benzyloxymethyl)pyrrolidine-2-carboxylic acid methyl ester (2.2 g, 8.82 mmol, 1.00 equiv), formaldehyde (2.86 g, 35.30 mmol, 37% purity) in dichloromethane (100 mL) was degassed and purged 3 times with nitrogen, and then the mixture was stirred at room temperature under nitrogen atmosphere for 0.5 h. Sodium triacetyloxyborohydride (3.74 g, 17.65 mmol) was then added to the mixture, and the mixture was stirred at 25°C for 12 hours. LCMS showed the reaction was complete. The reaction mixture was quenched by adding saturated aqueous sodium bicarbonate (100 mL), extracted with dichloromethane (100 mL×2). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was subjected to preparative high-performance liquid chromatography (column: Phenomenex luna C18 250×50 mm×10 um; mobile phase: [water (FA)-ACN]; B%: 1%-30%, 20 min) to afford the desired product (1.30 g, 4.94 mmol, 56% yield) as a colorless oil. LCMS (ESI, m/z): 264.3 [M+H] + . Step 4 : [(2S)-2-(Benzyloxymethyl)-1-methyl-pyrrolidin-2-yl]methanol
Figure 02_image394

使(2R)-2-(苯甲氧基甲基)-1-甲基-吡咯啶-2-甲酸甲酯(1.30 g，4.94 mmol)於四氫呋喃(30 mL)中之混合物脫氣且用氮氣吹掃3次，且接著在0℃下將鋁氫化锂(562 mg，14.81 mmol)添加至反應混合物，將混合物在氮氣氛圍下在室溫下攪拌2小時。其藉由在25℃下添加水(1 mL)、氫氧化鈉水溶液(15%，2 ml)、水(3 ml)而淬滅，且接著過濾以移除不溶性部分。將濾液在減壓下濃縮以移除溶劑，得到殘餘物。將殘餘物藉由製備型高效液相層析法(管柱：Phenomenex luna C18 150×40 mm×15 um；移動相：[水(FA)-ACN]；B%：2%-32%，10分鐘)來純化，得到呈無色油狀之產物。LCMS (ESI, m/z): 236.5 [M+H] +。 步驟 5：3-[2-[[(2R)-2-(苯甲氧基甲基)-1-甲基-吡咯啶-2-基]甲氧基]-7-溴-6-氯-8-氟-喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image396
A mixture of (2R)-2-(benzyloxymethyl)-1-methyl-pyrrolidine-2-carboxylate (1.30 g, 4.94 mmol) in THF (30 mL) was degassed and flushed with nitrogen. It was purged 3 times, and then lithium aluminum hydride (562 mg, 14.81 mmol) was added to the reaction mixture at 0°C, and the mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. It was quenched by addition of water (1 mL), aqueous sodium hydroxide (15%, 2 ml), water (3 ml) at 25 °C, and then filtered to remove the insoluble fraction. The filtrate was concentrated under reduced pressure to remove solvent to give a residue. The residue was subjected to preparative high-performance liquid chromatography (column: Phenomenex luna C18 150×40 mm×15 um; mobile phase: [water (FA)-ACN]; B%: 2%-32%, 10 min) to give the product as a colorless oil. LCMS (ESI, m/z): 236.5 [M+H] + . Step 5 : 3-[2-[[(2R)-2-(Benzyloxymethyl)-1-methyl-pyrrolidin-2-yl]methoxy]-7-bromo-6-chloro- 8-Fluoro-quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure 02_image396

向[(2S)-2-(苯甲氧基甲基)-1-甲基-吡咯啶-2-基]甲醇(216 mg，0.9 mmol)、3-(7-溴-6-氯-2,8-二氟-喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(300 mg，0.6 mmol)於乙腈(10 mL)中之溶液中添加1,4-二氮雜雙環[2.2.2]辛烷(7 mg，0.06 mmol)及碳酸銫(599 mg，1.84 mmol)。將混合物在50℃下攪拌2小時。將反應混合物過濾以移除不溶性副產物。將濾液在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC (二氯甲烷中9%甲醇)來純化，得到呈黃色固體狀之所需產物(200 mg，0.28 mmol，46%產率)。LCMS (ESI, m/z): 704.1, 706.0[M+H] +。 步驟 6：[(2R)-2-[[7-溴-6-氯-4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-8-氟-喹唑啉-2-基]氧基甲基]-1-甲基-吡咯啶-2-基]甲醇

Figure 02_image398
[(2S)-2-(Benzyloxymethyl)-1-methyl-pyrrolidin-2-yl]methanol (216 mg, 0.9 mmol), 3-(7-bromo-6-chloro-2 ,8-difluoro-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (300 mg, 0.6 mmol) in acetonitrile (10 mL ) were added 1,4-diazabicyclo[2.2.2]octane (7 mg, 0.06 mmol) and cesium carbonate (599 mg, 1.84 mmol). The mixture was stirred at 50°C for 2 hours. The reaction mixture was filtered to remove insoluble by-products. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (9% methanol in dichloromethane) to give the desired product (200 mg, 0.28 mmol, 46% yield) as a yellow solid. LCMS (ESI, m/z): 704.1, 706.0 [M+H] + . Step 6 : [(2R)-2-[[7-Bromo-6-chloro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-quinazole Lin-2-yl]oxymethyl]-1-methyl-pyrrolidin-2-yl]methanol
Figure 02_image398

向3-[2-[[(2R)-2-(苯甲氧基甲基)-1-甲基-吡咯啶-2-基]甲氧基]-7-溴-6-氯-8-氟-喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(200 mg，0.28 mmol)於二氯甲烷(2 mL)中之溶液中添加三氟乙酸(3.66 g，32.08 mmol)及三氟甲烷磺酸(212 mg，1.42 mmol)。將混合物在室溫下攪拌0.5小時。將反應混合物在減壓下濃縮以移除溶劑，得到呈黃色油狀之產物(140 mg，0.27 mmol，96%產率)，其未經進一步純化即用於下一步。LCMS (ESI, m/z): 514.2, 516.1[M+H] +。 步驟 7：3-[7-溴-6-氯-8-氟-2-[[(2R)-2-(羥基甲基)-1-甲基-吡咯啶-2-基]甲氧基]喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image400
To 3-[2-[[(2R)-2-(benzyloxymethyl)-1-methyl-pyrrolidin-2-yl]methoxy]-7-bromo-6-chloro-8- Fluoro-quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (200 mg, 0.28 mmol) in dichloromethane (2 mL) Trifluoroacetic acid (3.66 g, 32.08 mmol) and trifluoromethanesulfonic acid (212 mg, 1.42 mmol) were added to the solution of the solution. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent to give the product as a yellow oil (140 mg, 0.27 mmol, 96% yield), which was used in the next step without further purification. LCMS (ESI, m/z): 514.2, 516.1 [M+H] + . Step 7 : 3-[7-Bromo-6-chloro-8-fluoro-2-[[(2R)-2-(hydroxymethyl)-1-methyl-pyrrolidin-2-yl]methoxy] Quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure 02_image400

向[(2R)-2-[[7-溴-6-氯-4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-8-氟-喹唑啉-2-基]氧基甲基]-1-甲基-吡咯啶-2-基]甲醇(140 mg，0.27 mmol)於二氯甲烷(8 mL)中之溶液中添加二碳酸二-第三丁酯(178 mg，0.82 mmol)及三乙胺(82 mg，0.82 mmol)。將混合物在室溫下攪拌1小時。在25℃下反應混合物用水(10 mL)淬滅，且接著用乙酸乙酯(30 mL×3)萃取。將合併之有機層用鹽水(50 mL)洗滌，經硫酸鈉乾燥，過濾且將濾液在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC (二氯甲烷中9%甲醇)來純化，得到呈白色固體狀之所需產物(105 mg，0.17 mmol，62%產率)。LCMS (ESI, m/z): 613.9, 615.8[M+H] + 步驟 8：3-[7-[2-(第三丁氧羰基胺基)-3-氰基-7-氟-苯并噻吩-4-基]-6-氯-8-氟-2-[[(2R)-2-(羥基甲基)-1-甲基-吡咯啶-2-基]甲氧基]喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image402
To [(2R)-2-[[7-bromo-6-chloro-4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-quinazoline- 2-yl]oxymethyl]-1-methyl-pyrrolidin-2-yl]methanol (140 mg, 0.27 mmol) in dichloromethane (8 mL) was added di-tert-butyl dicarbonate Esters (178 mg, 0.82 mmol) and triethylamine (82 mg, 0.82 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with water (10 mL) at 25°C, and then extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (50 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (9% methanol in dichloromethane) to give the desired product (105 mg, 0.17 mmol, 62% yield) as a white solid. LCMS (ESI, m/z): 613.9, 615.8[M+H] + step 8 : 3-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzo Thiophen-4-yl]-6-chloro-8-fluoro-2-[[(2R)-2-(hydroxymethyl)-1-methyl-pyrrolidin-2-yl]methoxy]quinazoline -4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure 02_image402

使3-[7-溴-6-氯-8-氟-2-[[(2R)-2-(羥基甲基)-1-甲基-吡咯啶-2-基]甲氧基]喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(105 mg，0.17 mmol，1.00當量)、N-[3-氰基-7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯并噻吩-2-基]胺基甲酸第三丁酯(93 mg，0.22 mmol)、二-第三丁基(環戊基)磷烷;二氯鈀;鐵(11 mg，0.02 mmol)、二異丙基乙胺(66 mg，0.51 mmol)於2-甲基四氫呋喃(2 mL)、水(0.2 mL)中之混合物脫氣且用氮氣吹掃3次，且接著將混合物在氮氣氛圍下在80℃下攪拌3小時。在25℃下反應混合物用水(10 mL)淬滅，用乙酸乙酯(10 mL×3)萃取。將合併之有機層用鹽水(30 mL)洗滌，經硫酸鈉乾燥，過濾且將濾液在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型高層層析法(管柱：Phenomenex Synergi Polar-RP 100×25 mm×4 um；移動相：[水(TFA)-ACN]；B%：67%-87%，7分鐘)來純化，得到呈黃色固體狀之所需產物(18 mg，0.02 mmol，13%產率)。LCMS (ESI, m/z): 826.0 [M] +。 步驟 9：2-胺基-4-[6-氯-4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-8-氟-2-[[(2R)-2-(羥基甲基)-1-甲基-吡咯啶-2-基]甲氧基]喹唑啉-7-基]-7-氟-苯并噻吩-3-甲腈

Figure 02_image404
Make 3-[7-bromo-6-chloro-8-fluoro-2-[[(2R)-2-(hydroxymethyl)-1-methyl-pyrrolidin-2-yl]methoxy]quinazole Phenyl-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (105 mg, 0.17 mmol, 1.00 equiv), N-[3-cyano-7 -Tertiary butyl fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate (93 mg, 0.22 mmol), di-tert-butyl (cyclopentyl) phosphine; dichloropalladium; iron (11 mg, 0.02 mmol), diisopropylethylamine (66 mg, 0.51 mmol) in 2 - A mixture in methyltetrahydrofuran (2 mL), water (0.2 mL) was degassed and purged 3 times with nitrogen, and then the mixture was stirred at 80°C under nitrogen atmosphere for 3 hours. The reaction mixture was quenched with water (10 mL) at 25 °C, extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was subjected to preparative high-layer chromatography (column: Phenomenex Synergi Polar-RP 100×25 mm×4 um; mobile phase: [water (TFA)-ACN]; B%: 67%-87%, 7 min) to afford the desired product (18 mg, 0.02 mmol, 13% yield) as a yellow solid. LCMS (ESI, m/z): 826.0 [M] + . Step 9 : 2-Amino-4-[6-chloro-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-8-fluoro-2-[[(2R) -2-(Hydroxymethyl)-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzothiophene-3-carbonitrile
Figure 02_image404

向3-[7-[2-(第三丁氧羰基胺基)-3-氰基-7-氟-苯并噻吩-4-基]-6-氯-8-氟-2-[[(2R)-2-(羥基甲基)-1-甲基-吡咯啶-2-基]甲氧基]喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(18 mg，0.02 mmol)於二氯甲烷(0.5 mL)中之溶液中添加三氟乙酸(1.54 g，13.51 mmol)。將混合物在25℃下攪拌0.5小時。將反應混合物在減壓下濃縮以移除溶劑，得到殘餘物。將殘餘物藉由製備型高層層析法(管柱：Unisil 3-100 C18 Ultra 150×50 mm×3 um；移動相：[水(FA)-ACN]；B%：3%-33%，10分鐘)來純化，得到呈白色固體狀之所需產物(6.05 mg，0.01 mmol，41%產率，100%純度，甲酸鹽[1])。LCMS (ESI, m/z): 626.2 [M] +. 1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.10 (s, 2H), 7.85 (s, 1H), 7.27 (dd, J= 5.2, 8.4 Hz, 1H), 7.18 - 7.13 (m, 1H), 4.33 - 4.24 (m, 4H), 3.64 (d, J= 5.6 Hz, 5H), 2.83 - 2.76 (m, 3H), 2.42 (s, 3H), 2.03 - 1.97 (m, 1H), 1.81 (dd, J= 2.8, 8.0 Hz, 1H), 1.71 - 1.66 (m, 4H), 1.26 - 1.23 (m, 4H)。 合成4-((R)-4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈 ( 實例 7)

Figure 02_image406
步驟 1：3-[7-溴-6-氯-8-氟-2-[[(2S)-1-甲基吡咯啶-2-基]甲氧基]喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯
Figure 02_image408
To 3-[7-[2-(tertiary butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-[[( 2R)-2-(Hydroxymethyl)-1-methyl-pyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane To a solution of tert-butyl alkane-8-carboxylate (18 mg, 0.02 mmol) in dichloromethane (0.5 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol). The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to remove solvent to obtain a residue. The residue was subjected to preparative high-layer chromatography (column: Unisil 3-100 C18 Ultra 150×50 mm×3 um; mobile phase: [water (FA)-ACN]; B%: 3%-33%, 10 min) to afford the desired product (6.05 mg, 0.01 mmol, 41% yield, 100% purity, formate salt [1]) as a white solid. LCMS (ESI, m/z): 626.2 [M] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 8.10 (s, 2H), 7.85 (s, 1H), 7.27 ( dd, J = 5.2, 8.4 Hz, 1H), 7.18 - 7.13 (m, 1H), 4.33 - 4.24 (m, 4H), 3.64 (d, J = 5.6 Hz, 5H), 2.83 - 2.76 (m, 3H) , 2.42 (s, 3H), 2.03 - 1.97 (m, 1H), 1.81 (dd, J = 2.8, 8.0 Hz, 1H), 1.71 - 1.66 (m, 4H), 1.26 - 1.23 (m, 4H). Synthesis of 4-((R)-4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((S)-1- Methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile ( Example 7)
Figure 02_image406
Step 1 : 3-[7-Bromo-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]- 3,8-Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure 02_image408

向3-(7-溴-6-氯-2,8-二氟-喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(100 mg，0.2 mmol，1當量)及[(2S)-1-甲基吡咯啶-2-基]甲醇(23 mg，0.2 mmol，1當量)於乙腈(5 mL)中之溶液中添加 N, N-二異丙基乙胺(79 mg，0.6 mmol，3當量)。將混合物在70℃下攪拌12小時。薄層層析法(二氯甲烷:甲醇= 10:1)顯示起始物質完全消耗掉。添加水(10 mL)，接著將混合物用乙酸乙酯萃取。將合併之有機層用鹽水洗滌，經無水硫酸鈉乾燥且過濾。將濾液濃縮且藉由製備型TLC (二氯甲烷中9%甲醇)來純化，得到呈白色固體狀之標題化合物(51 mg，0.05 mmol，26%產率)。LCMS (ESI, m/z): 584.1, 586.1[M+1] +. 1H NMR (400 MHz, DMSO) δ = 7.97 (s, 1H), 4.33 (d, J= 11.6 Hz, 2H), 4.21 (s, 2H), 4.10 (d, J= 4.4 Hz, 2H), 3.62 - 3.49 (m, 2H), 3.17 (d, J= 3.6 Hz, 6H), 2.27 - 2.15 (m, 1H), 2.00 - 1.89 (m, 1H), 1.77 (s, 2H), 1.70 - 1.61 (m, 4H), 1.45 (s, 9H)。 步驟 2：3-[7-[2-(第三丁氧羰基胺基)-3-氰基-7-氟-苯并噻吩-4-基]-6-氯-8-氟-2-[[(2S)-1-甲基吡咯啶-2-基]甲氧基]喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image410
To 3-(7-bromo-6-chloro-2,8-difluoro-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl To a solution of ester (100 mg, 0.2 mmol, 1 equiv) and [(2S)-1-methylpyrrolidin-2-yl]methanol (23 mg, 0.2 mmol, 1 equiv) in acetonitrile (5 mL) was added N , N -Diisopropylethylamine (79 mg, 0.6 mmol, 3 equiv). The mixture was stirred at 70°C for 12 hours. Thin layer chromatography (dichloromethane:methanol = 10:1) showed complete consumption of the starting material. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by prep-TLC (9% methanol in dichloromethane) to afford the title compound (51 mg, 0.05 mmol, 26% yield) as a white solid. LCMS (ESI, m/z): 584.1, 586.1[M+1] + . 1 H NMR (400 MHz, DMSO) δ = 7.97 (s, 1H), 4.33 (d, J = 11.6 Hz, 2H), 4.21 (s, 2H), 4.10 (d, J = 4.4 Hz, 2H), 3.62 - 3.49 (m, 2H), 3.17 (d, J = 3.6 Hz, 6H), 2.27 - 2.15 (m, 1H), 2.00 - 1.89 (m, 1H), 1.77 (s, 2H), 1.70 - 1.61 (m, 4H), 1.45 (s, 9H). Step 2 : 3-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-[ [(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid third Butyl ester
Figure 02_image410

使3-[7-溴-6-氯-8-氟-2-[[(2S)-1-甲基吡咯啶-2-基]甲氧基]喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(50 mg，0.08 mmol，1當量)、N-[3-氰基-7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯并噻吩-2-基]胺基甲酸第三丁酯(50 mg，0.1 mmol，1.4當量)、二-第三丁基(環戊基)磷烷;二氯鈀;鐵(6 mg，0.01 mmol，0.1當量)、 N, N-二異丙基乙胺(33 mg，0.26 mmol，3當量)於四氫呋喃(4 mL)及水(1 mL)中之混合物脫氣且用氮氣吹掃3次，且接著將混合物在氮氣氛圍下在70℃下攪拌2小時。薄層層析法(二氯甲烷:甲醇= 10:1)及LCMS顯示起始物質完全消耗掉。將反應混合物用水(10 mL)稀釋且用乙酸乙酯(30 mL)萃取。將合併之有機層用鹽水洗滌，經無水硫酸鈉乾燥且過濾。將濾液濃縮且藉由製備型TLC (二氯甲烷中9%甲醇)來純化，得到呈黃色固體狀之所需產物(30 mg，0.03 mmol，38%產率)。LCMS (ESI, m/z): 438.4 [M+1] +。 步驟 3：(3-((R)-7-(2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image412
Make 3-[7-bromo-6-chloro-8-fluoro-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-yl]-3, 8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (50 mg, 0.08 mmol, 1 equivalent), N-[3-cyano-7-fluoro-4-(4,4 ,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamic acid tert-butyl ester (50 mg, 0.1 mmol, 1.4 equiv. ), two-tert-butyl (cyclopentyl) phosphine; dichloropalladium; iron (6 mg, 0.01 mmol, 0.1 equivalent), N , N -diisopropylethylamine (33 mg, 0.26 mmol, 3 eq.) in tetrahydrofuran (4 mL) and water (1 mL) was degassed and flushed with nitrogen 3 times, and then the mixture was stirred at 70 °C for 2 h under nitrogen atmosphere. TLC (dichloromethane:methanol = 10:1) and LCMS showed complete consumption of the starting material. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by prep-TLC (9% methanol in dichloromethane) to give the desired product (30 mg, 0.03 mmol, 38% yield) as a yellow solid. LCMS (ESI, m/z): 438.4 [M+1] + . Step 3 : (3-((R)-7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6- Chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1 ]Tert-Butyl Octane-8-carboxylate
Figure 02_image412

阻轉異構物(3-((R)-7-(2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯與(3-((S)-7-(2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯之混合物(177 mg，0.22 mmol，1當量)藉由SFC (管柱：DAICEL CHIRALPAK AD (250 mm×30 mm，10 um)；移動相：[0.1%氫氧化銨乙醇]；B%：30%-30%，5.9分鐘)分離，且第一溶析液經鑑定為所需阻轉異構物(3-((R)-7-(2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(61 mg，0.7 mmol，34%產率)，呈白色固體狀。 步驟 4：4-((R)-4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈

Figure 02_image414
合成4-((S)-4-((3,8-二氮雜雙環[3.2.1]辛烷-3-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈 ( 實例 8)
Figure 02_image416
步驟 1：(3-((S)-7-(2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯
Figure 02_image418
Atropisomer (3-((R)-7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)- 6-Chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2 .1] tert-butyl octane-8-carboxylate and (3-((S)-7-(2-((tertiary butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[ b] thiophen-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3 , The mixture of 8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (177 mg, 0.22 mmol, 1 equivalent) was passed through SFC (column: DAICEL CHIRALPAK AD (250 mm×30 mm , 10 um); mobile phase: [0.1% ammonium hydroxide ethanol]; B%: 30%-30%, 5.9 minutes) separated, and the first eluate was identified as the desired atropisomer (3- ((R)-7-(2-((tertiary butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro- 2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- Tert-butyl formate (61 mg, 0.7 mmol, 34% yield) as a white solid. Step 4 : 4-((R)-4-(3,8-Diazabicyclo[3.2.1]octane Alkyl-3-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-2-amine yl-7-fluorobenzo[b]thiophene-3-carbonitrile
Figure 02_image414
Synthesis of 4-((S)-4-((3,8-diazabicyclo[3.2.1]octan-3-yl)-6-chloro-8-fluoro-2-(((S)-1 -methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile ( Example 8)
Figure 02_image416
Step 1 : (3-((S)-7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6- Chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1 ]Tert-Butyl Octane-8-carboxylate
Figure 02_image418

阻轉異構物(3-((R)-7-(2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯與(3-((S)-7-(2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯之混合物(177 mg，0.22 mmol，1當量)藉由SFC (管柱：DAICEL CHIRALPAK AD (250 mm×30 mm，10 um)；移動相：[0.1%氫氧化銨乙醇]；B%：30%-30%，5.9分鐘)分離，且第二溶析液經鑑定為所需阻轉異構物(3-((S)-7-(2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(67 mg，0.08 mmol，38%產率)，呈白色固體狀。 步驟 2：4-((S)-4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈

Figure 02_image420
Atropisomer (3-((R)-7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)- 6-Chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2 .1] tert-butyl octane-8-carboxylate and (3-((S)-7-(2-((tertiary butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[ b] thiophen-4-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3 , The mixture of 8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (177 mg, 0.22 mmol, 1 equivalent) was passed through SFC (column: DAICEL CHIRALPAK AD (250 mm×30 mm , 10 um); mobile phase: [0.1% ammonium hydroxide ethanol]; B%: 30%-30%, 5.9 minutes) separated, and the second eluate was identified as the desired atropisomer (3- ((S)-7-(2-((tertiary butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-8-fluoro- 2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8- Tert-butyl formate (67 mg, 0.08 mmol, 38% yield) as a white solid. Step 2 : 4-((S)-4-(3,8-Diazabicyclo[3.2.1]octane Alkyl-3-yl)-6-chloro-8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-7-yl)-2-amine yl-7-fluorobenzo[b]thiophene-3-carbonitrile
Figure 02_image420

向(3-((S)-7-(2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-8-氟-2-(((S)-1-甲基吡咯啶-2-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(67 mg，0.08 mmol，1當量)於二氯甲烷(2 mL)中之溶液中添加三氟乙酸(719. mg，6 mmol，75當量)。將混合物在20℃下攪拌0.5小時。HPLC顯示起始物質完全消耗掉。用氮氣使反應混合物鼓泡以移除二氯甲烷。將殘餘物藉由製備型高層層析法(管柱：Phenomenex Synergi C18 150×25 mm×10um；移動相：[水(甲酸)-乙腈]；B%：3%-33%，10分鐘)來純化，得到呈白色固體狀之所需產物(36 mg，0.06 mmol，72%產率)。LCMS (ESI, m/z): 596.2 [M] +。 1H NMR (400 MHz, DMSO) δ = 8.15 (d, J= 2.4 Hz, 1H), 8.11 (s, 2H), 7.88 (s, 1H), 7.25 (dd, J= 3.2, 8.0 Hz, 1H), 7.19 - 7.11 (m, 1H), 4.40 (d, J= 11.6 Hz, 2H), 4.33 - 4.29 (m, 1H), 4.25 - 4.22 (m, 1H), 3.83 (d, J= 3.6 Hz, 2H), 3.71 - 3.68 (m, 3H), 3.05 - 3.01 (m, 2H), 2.73 (s, 2H), 2.32 (dd, J= 2.0, 5.6 Hz, 1H), 1.98 (s, 1H), 1.80 - 1.69 (m, 7H) 合成R-4-(4-(-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-2-(((2R, 7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈 ( 實例 9)

Figure 02_image422
Figure 02_image424
步驟 1：5-氯-2-碘-4-(三氟甲基)苯胺
Figure 02_image426
To (3-((S)-7-(2-((tertiary butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro- 8-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane To a solution of tert-butyl alkane-8-carboxylate (67 mg, 0.08 mmol, 1 equiv) in dichloromethane (2 mL) was added trifluoroacetic acid (719. mg, 6 mmol, 75 equiv). The mixture was Stirred at 20° C. for 0.5 h. HPLC showed that the starting material was completely consumed. The reaction mixture was bubbled with nitrogen to remove dichloromethane. The residue was subjected to preparative high-layer chromatography (column: Phenomenex Synergi C18 150× 25 mm×10um; mobile phase: [water (formic acid)-acetonitrile]; B%: 3%-33%, 10 minutes) to purify, obtain the desired product (36 mg, 0.06 mmol, 72% yield). LCMS (ESI, m/z): 596.2 [M] + .1 H NMR (400 MHz, DMSO) δ = 8.15 (d, J = 2.4 Hz, 1H), 8.11 (s, 2H), 7.88 (s, 1H), 7.25 (dd, J = 3.2, 8.0 Hz, 1H), 7.19 - 7.11 (m, 1H), 4.40 (d, J = 11.6 Hz, 2H), 4.33 - 4.29 (m, 1H), 4.25 - 4.22 (m, 1H), 3.83 (d, J = 3.6 Hz, 2H), 3.71 - 3.68 (m, 3H), 3.05 - 3.01 (m, 2H), 2.73 (s, 2H), 2.32 (dd, J = 2.0, 5.6 Hz, 1H), 1.98 (s, 1H), 1.80 - 1.69 (m, 7H) Synthesis of R-4-(4-(-3,8-diazabicyclo[3.2.1]octane -3-yl)-2-(((2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazoline -7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile ( Example 9)
Figure 02_image422
Figure 02_image424
Step 1 : 5-Chloro-2-iodo-4-(trifluoromethyl)aniline
Figure 02_image426

向3-氯-4-(三氟甲基)苯胺(20 g，102.27 mmol，1當量)、過碘酸鈉(21.87 g，102.27 mmol，1當量)、氯化鈉(11.95 g，204.53 mmol，2當量)於乙酸酯(360 mL)中之溶液中緩慢添加含碘化鉀(16.98 g，102.27 mmol，1當量)之水(40 mL)。將混合物在50℃下攪拌12小時。將混合物傾倒至冰水(1000 mL)中，且接著用乙酸乙酯(1000 mL)稀釋且用飽和硫代硫酸鈉水溶液(500 mL×5)洗滌。有機層經無水硫酸鈉乾燥，過濾且在減壓下濃縮，得到殘餘物。將殘餘物藉由矽膠上管柱層析法(石油醚:乙酸乙酯= 1:0至20:1)來純化，得到呈棕色固體狀之所需產物(32 g，89.59 mmol，87%產率，90%純度)。LCMS (ESI, m/z): 322.0[M+1] +. 1H NMR: (400 MHz, DMSO-d 6) δ: 7.83 (s, 1H), 6.88 (s, 1H), 6.21 (s, 2H) 步驟 2：2-胺基-4-氯-5-(三氟甲基)苯甲腈

Figure 02_image428
To 3-chloro-4-(trifluoromethyl)aniline (20 g, 102.27 mmol, 1 equivalent), sodium periodate (21.87 g, 102.27 mmol, 1 equivalent), sodium chloride (11.95 g, 204.53 mmol, 2 equiv) in acetate (360 mL) was slowly added potassium iodide (16.98 g, 102.27 mmol, 1 equiv) in water (40 mL). The mixture was stirred at 50°C for 12 hours. The mixture was poured into ice water (1000 mL), and then diluted with ethyl acetate (1000 mL) and washed with saturated aqueous sodium thiosulfate (500 mL×5). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:0 to 20:1) to obtain the desired product (32 g, 89.59 mmol, 87% yield) as a brown solid rate, 90% purity). LCMS (ESI, m/z): 322.0[M+1] + . 1 H NMR: (400 MHz, DMSO-d 6 ) δ : 7.83 (s, 1H), 6.88 (s, 1H), 6.21 (s, 2H) Step 2 : 2-Amino-4-chloro-5-(trifluoromethyl)benzonitrile
Figure 02_image428

向5-氯-2-碘-4-(三氟甲基)苯胺(8 g，24.89 mmol，1當量)於 N,N-二甲基甲醯胺(80 mL)中之溶液中添加氰化亞酮(4.46 g，49.77 mmol，2當量)。將混合物在110℃下攪拌12小時。薄層層析法(石油醚:乙酸乙酯= 3:1)指示起始物質完全消耗掉。將反應混合物用乙酸乙酯(1000 mL)稀釋且過濾。將濾液用鹽水(400 mL)洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮，得到殘餘物。將殘餘物藉由矽膠上管柱層析法(石油醚:乙酸乙酯= 30:1至10:1)來純化，得到呈棕色固體狀之所需產物(9.22 g，粗)。 1H NMR: (400 MHz, DMSO-d 6) δ: 7.92 (s, 1H), 7.07 (s, 2H), 7.00 (s, 1H)。 步驟 3：7-氯-6-(三氟甲基)-1H-喹唑啉-2,4-二酮

Figure 02_image430
To a solution of 5-chloro-2-iodo-4-(trifluoromethyl)aniline (8 g, 24.89 mmol, 1 eq) in N,N -dimethylformamide (80 mL) was added cyanide Ketone (4.46 g, 49.77 mmol, 2 equiv). The mixture was stirred at 110°C for 12 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 3:1) indicated complete consumption of the starting material. The reaction mixture was diluted with ethyl acetate (1000 mL) and filtered. The filtrate was washed with brine (400 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 30:1 to 10:1) to give the desired product (9.22 g, crude) as a brown solid. 1 H NMR: (400 MHz, DMSO-d 6 ) δ : 7.92 (s, 1H), 7.07 (s, 2H), 7.00 (s, 1H). Step 3 : 7-Chloro-6-(trifluoromethyl)-1H-quinazoline-2,4-dione
Figure 02_image430

在二氧化碳下向2-胺基-4-氯-5-(三氟甲基)苯甲腈(9.3 g，42.16 mmol，1當量)於 N, N-二甲基甲醯胺(100 mL)中之溶液中添加1,8-二氮雜雙環[5.4.0]十一-7-烯(51.35 g，337.29 mmol，8當量)。將混合物在二氧化碳下在20℃下攪拌12小時。薄層層析法(石油醚:乙酸乙酯= 1:1)指示剩餘20%起始物質，且偵測到一個大的新斑點。將反應混合物用水(20 mL)稀釋且藉由添加鹽酸水溶液(1 M，15 mL)來淬滅。將混合物過濾且濾餅用水(15 ml×3)洗滌，且在減壓下濃縮，獲得粗產物。在25℃下將粗產物用石油醚與乙酸乙酯之混合溶劑(v/v = 1/1，40 mL)濕磨10分鐘。接著將溶液過濾且濾餅收集，得到呈黃色固體狀之所需產物(6.2 g，23.43 mmol，55%產率)。 1H NMR: (400 MHz, DMSO-d 6) δ: 11.74 - 11.55 (m, 2H), 8.15 (s, 1H), 7.36 (s, 1H) 步驟 4：2,4,7-三氯-6-(三氟甲基)喹唑啉

Figure 02_image432
2-Amino-4-chloro-5-(trifluoromethyl)benzonitrile (9.3 g, 42.16 mmol, 1 eq) in N , N -dimethylformamide (100 mL) under carbon dioxide 1,8-Diazabicyclo[5.4.0]undec-7-ene (51.35 g, 337.29 mmol, 8 eq.) was added to the solution of the solution. The mixture was stirred at 20°C under carbon dioxide for 12 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 1:1) indicated 20% starting material remained and a large new spot was detected. The reaction mixture was diluted with water (20 mL) and quenched by the addition of aqueous hydrochloric acid (1 M, 15 mL). The mixture was filtered and the filter cake was washed with water (15 ml x 3), and concentrated under reduced pressure to obtain crude product. The crude product was wet triturated with a mixed solvent of petroleum ether and ethyl acetate (v/v = 1/1, 40 mL) at 25°C for 10 minutes. The solution was then filtered and the filter cake was collected to give the desired product (6.2 g, 23.43 mmol, 55% yield) as a yellow solid. 1 H NMR: (400 MHz, DMSO-d 6 ) δ : 11.74 - 11.55 (m, 2H), 8.15 (s, 1H), 7.36 (s, 1H) Step 4 : 2,4,7-Trichloro-6 -(trifluoromethyl)quinazoline
Figure 02_image432

在25℃下向7-氯-6-(三氟甲基)-1H-喹唑啉-2,4-二酮(2.00 g，7.56 mmol，1當量)於***(25 mL)中之溶液中緩慢添加 N, N-二異丙基乙胺(2.93 g，22.68 mmol，3當量)。將混合物在110℃下攪拌12小時。薄層層析法(石油醚:乙酸乙酯= 3:1)指示起始物質完全消耗掉。將反應混合物在減壓下濃縮，得到殘餘物。將殘餘物藉由矽膠上管柱層析法(石油醚:乙酸乙酯= 1:0至20:1)來純化，得到呈白色固體狀之所需產物(1.66 g，5.51 mmol，72%產率)。 1H NMR: (400 MHz, DMSO-d 6) δ: 8.34 (s, 1H), 7.97 (s, 1H) 步驟 5：3-(2,7-二氯-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image434
Add 7-chloro-6-(trifluoromethyl)-1H-quinazoline-2,4-dione (2.00 g, 7.56 mmol, 1 equivalent) in phosphorus oxychloride (25 mL) at 25°C N , N -diisopropylethylamine (2.93 g, 22.68 mmol, 3 equiv) was added slowly to the solution of the solution. The mixture was stirred at 110°C for 12 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 3:1) indicated complete consumption of the starting material. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:0 to 20:1) to obtain the desired product (1.66 g, 5.51 mmol, 72% yield) as a white solid Rate). 1 H NMR: (400 MHz, DMSO-d 6 ) δ : 8.34 (s, 1H), 7.97 (s, 1H) Step 5 : 3-(2,7-Dichloro-6-(trifluoromethyl)quinone tert-butyl oxazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
Figure 02_image434

向2,4,7-三氯-6-(三氟甲基)喹唑啉(1.66 g，5.51 mmol，1當量)於二氯甲烷(25 mL)中之溶液中添加 N, N-二異丙基乙胺(2.13 g，16.52 mmol，3當量)及3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(1.17 g，5.51 mmol，1當量)。將混合物在0℃下攪拌30分鐘。薄層層析法(石油醚:乙酸乙酯= 3:1)指示起始物質完全消耗掉。反應混合物分配於二氯甲烷(20 mL)與水(20 mL)之間。將有機相分離，用鹽水(20 mL×3)洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮，得到殘餘物。在25℃下將粗產物用石油醚與乙酸乙酯之混合溶劑(v/v = 3/1，40 mL)濕磨30分鐘，得到呈黃色固體狀之所需產物(2.38 g，4.99 mmol，90%產率)。 1H NMR: (400 MHz, CDCl 3-d) δ: 8.17 (s, 1H), 7.90 (s, 1H), 4.57 - 4.26 (m, 4H), 3.87 - 3.49 (m, 2H), 2.03 - 1.88 (m, 2H), 1.80 - 1.65 (m, 2H), 1.53 (s, 9H) 步驟 6：3-(7-氯-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image436
To a solution of 2,4,7-trichloro-6-(trifluoromethyl)quinazoline (1.66 g, 5.51 mmol, 1 equiv) in dichloromethane (25 mL) was added N , N -diiso Propylethylamine (2.13 g, 16.52 mmol, 3 equiv) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (1.17 g, 5.51 mmol, 1 equiv). The mixture was stirred at 0°C for 30 minutes. Thin layer chromatography (petroleum ether: ethyl acetate = 3:1) indicated complete consumption of the starting material. The reaction mixture was partitioned between dichloromethane (20 mL) and water (20 mL). The organic phase was separated, washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The crude product was wet triturated with a mixed solvent of petroleum ether and ethyl acetate (v/v = 3/1, 40 mL) at 25°C for 30 minutes to obtain the desired product (2.38 g, 4.99 mmol, 90% yield). 1 H NMR: (400 MHz, CDCl 3 -d) δ : 8.17 (s, 1H), 7.90 (s, 1H), 4.57 - 4.26 (m, 4H), 3.87 - 3.49 (m, 2H), 2.03 - 1.88 (m, 2H), 1.80 - 1.65 (m, 2H), 1.53 (s, 9H) Step 6 : 3-(7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrole Oxyzin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tertiary butyl ester
Figure 02_image436

向3-(2,7-二氯-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(500 mg，1.05 mmol，1當量)及[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲醇(250 mg，1.58 mmol，1.5當量)於乙腈(8 mL)中之溶液中添加1,4-二氮雜雙環[2.2.2]辛烷(12 mg，0.10 mmol，0.1當量)及碳酸銫(684 mg，2.10 mmol，2當量)。將混合物在50℃下攪拌3小時。LCMS顯示起始物質完全消耗掉且偵測到具有所需質量之一個主要峰。反應混合物分配於水(20 mL)與乙酸乙酯(20 mL)之間。將有機相分離，用鹽水(15 mL×2)洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型TLC (二氧化矽，二氯甲烷:甲醇= 10:1)來純化，得到呈白色固體狀之所需產物(200 mg，0.33 mmol，31%產率)。 1H NMR: (400 MHz, CDCl 3) δ: 8.26 (s, 1H), 7.78 (s, 1H), 5.40 - 5.18 (m, 1H), 4.32 - 4.17 (m, 2H), 4.36 (d, J= 12.4 Hz, 2H), 4.14 - 4.08 (m, 1H), 4.06 - 3.99 (m, 1H), 3.57 (d, J= 12.8 Hz, 2H), 3.13 - 2.99 (m, 2H), 2.88 - 2.78 (m, 1H), 2.17 - 1.92 (m, 3H), 1.89 - 1.72 (m, 5H), 1.62 (d, J= 7.6 Hz, 2H), 1.45 (s, 9H) 步驟 7 ：3-(7-(2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image438
To 3-(2,7-dichloro-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl Esters (500 mg, 1.05 mmol, 1 equivalent) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (250 mg, 1.58 To a solution of mmol, 1.5 equiv) in acetonitrile (8 mL) was added 1,4-diazabicyclo[2.2.2]octane (12 mg, 0.10 mmol, 0.1 equiv) and cesium carbonate (684 mg, 2.10 mmol , 2 equivalents). The mixture was stirred at 50°C for 3 hours. LCMS showed complete consumption of the starting material and one major peak with the desired mass was detected. The reaction mixture was partitioned between water (20 mL) and ethyl acetate (20 mL). The organic phase was separated, washed with brine (15 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (silica, dichloromethane:methanol = 10:1) to give the desired product (200 mg, 0.33 mmol, 31% yield) as a white solid. 1 H NMR: (400 MHz, CDCl 3 ) δ : 8.26 (s, 1H), 7.78 (s, 1H), 5.40 - 5.18 (m, 1H), 4.32 - 4.17 (m, 2H), 4.36 (d, J = 12.4 Hz, 2H), 4.14 - 4.08 (m, 1H), 4.06 - 3.99 (m, 1H), 3.57 (d, J = 12.8 Hz, 2H), 3.13 - 2.99 (m, 2H), 2.88 - 2.78 ( m, 1H), 2.17 - 1.92 (m, 3H), 1.89 - 1.72 (m, 5H), 1.62 (d, J = 7.6 Hz, 2H), 1.45 (s, 9H) Step 7 : 3-(7-( 2-((tertiary butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro- 1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane- 8-Tertiary butyl carboxylate
Figure 02_image438

使3-(7-氯-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(91 mg，0.21 mmol，1.3當量)、 N, N-二異丙基乙胺(64 mg，0.49 mmol，3當量)、二-第三丁基(環戊基)磷烷;二氯鈀;鐵(11 mg，0.016 mmol，0.1當量)於四氫呋喃(4 mL)及水(1 mL)中之混合物脫氣且用氮氣吹掃3次，且接著將混合物在氮氣氛圍下在70℃下攪拌2小時。LCMS顯示起始物質完全消耗掉。反應混合物分配於乙酸乙酯(20 mL)與水(20 mL)之間。將有機相分離，用鹽水(20 mL×2)洗滌，經無水硫酸鈉乾燥，過濾且在減壓下濃縮，得到殘餘物。將殘餘物藉由製備型高效液相層析法(管柱：Phenomenex Synergi C18 150×25 mm×10um；移動相：[水(FA)-ACN]；B%：34%-64%，10分鐘)來純化，得到呈白色固體狀之所需產物(35 mg，0.040 mmol，24 %產率，99%純度)。 1H NMR: (400 MHz, DMSO-d 6) δ: 8.28 (s, 1H), 7.46 (s, 1H), 7.31 - 7.09 (m, 2H), 5.50 - 5.28 (m, 1H), 4.39 (d, J= 12.4 Hz, 2H), 4.33 - 4.14 (m, 4H), 3.73 - 3.56 (m, 2H), 3.34 - 3.29 (m, 4H), 3.07 - 2.90 (m, 1H), 2.31 - 2.08 (m, 3H), 2.03 - 1.76 (m, 5H), 1.71 - 1.57 (m, 2H), 1.46 (d, J= 2.0 Hz, 18H)。 步驟 8：3-(7-((R)-2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image440
Make 3-(7-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinone Azolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (91 mg, 0.21 mmol, 1.3 equivalents), N , N -diisopropyl Ethylamine (64 mg, 0.49 mmol, 3 equiv), di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (11 mg, 0.016 mmol, 0.1 equiv) in tetrahydrofuran (4 mL) and water (1 mL) was degassed and purged with nitrogen 3 times, and then the mixture was stirred at 70 °C for 2 h under nitrogen atmosphere. LCMS showed complete consumption of starting material. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic phase was separated, washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was subjected to preparative high-performance liquid chromatography (column: Phenomenex Synergi C18 150×25 mm×10um; mobile phase: [water (FA)-ACN]; B%: 34%-64%, 10 minutes ) to give the desired product (35 mg, 0.040 mmol, 24% yield, 99% purity) as a white solid. 1 H NMR: (400 MHz, DMSO-d 6 ) δ : 8.28 (s, 1H), 7.46 (s, 1H), 7.31 - 7.09 (m, 2H), 5.50 - 5.28 (m, 1H), 4.39 (d , J = 12.4 Hz, 2H), 4.33 - 4.14 (m, 4H), 3.73 - 3.56 (m, 2H), 3.34 - 3.29 (m, 4H), 3.07 - 2.90 (m, 1H), 2.31 - 2.08 (m , 3H), 2.03 - 1.76 (m, 5H), 1.71 - 1.57 (m, 2H), 1.46 (d, J = 2.0 Hz, 18H). Step 8 : 3-(7-((R)-2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8 - Tertiary butyl diazabicyclo[3.2.1]octane-8-carboxylate
Figure 02_image440

阻轉異構物3-(7-((R)-2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯與3-(7-((S)-2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯之混合物(45 mg，0.052 mmol，1當量)藉由SFC (管柱：DAICEL CHIRALPAK IE (250 mm×30 mm，10 um)；移動相：[ACN/IPA(0.1%NH 3H 2O)]；B%：70%-70%，10.9分鐘)分離，且第一溶析液經鑑定為所需阻轉異構物3-(7-((R)-2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(20 mg，0.023 mmol，44%產率，99%純度)，呈無色油狀。 步驟 9：R-4-(4-(-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈

Figure 02_image442
Atropisomer 3-(7-((R)-2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2 -(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3 , 8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 3-(7-((S)-2-((tertiary butoxycarbonyl)amino)-3-cyano Base-7-fluorobenzo[b]thiophen-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)- A mixture of tert-butyl 6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45 mg, 0.052 mmol, 1 equivalent) by SFC (column: DAICEL CHIRALPAK IE (250 mm×30 mm, 10 um); mobile phase: [ACN/IPA (0.1%NH 3 H 2 O)]; B%: 70%-70%, 10.9 minutes) separated and the first eluate was identified as the desired atropisomer 3-(7-((R)-2-((tertiary butoxycarbonyl)amino)-3-cyano- 7-fluorobenzo[b]thiophen-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6- (Trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (20 mg, 0.023 mmol, 44% yield, 99% purity), in the form of a colorless oil. Step 9 : R-4-(4-(-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H -pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3- Formaldehyde
Figure 02_image442

向3-(7-((R)-2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(20 mg，0.023 mmol，1當量)於二氯甲烷(5 mL)中之溶液中添加三氟乙酸(1.54 g，13.51 mmol，578.00當量)。將混合物在20℃下攪拌0.5小時。LCMS顯示起始物質完全消耗掉。在20℃下用氮氣使反應混合物鼓泡以移除二氯甲烷。將殘餘物用 N,N-二甲基甲醯胺(2 mL)稀釋，藉由製備型高層層析法(管柱：Phenomenex Synergi C18 150×25 mm×10 um；移動相：[水(FA)-ACN]；B%：7%-37%，10分鐘)來純化，得到呈白色固體狀之所需產物(7.91 mg，0.012 mmol，51%產率，100%純度，甲酸鹽[1])。LCMS: MS (ESI) m/z：656.3 [M+1] +。 1H NMR: (400 MHz, DMSO-d 6) δ: 8.20 (s, 2H), 7.98 (s, 2H), 7.40 (s, 1H), 7.20 (m, J= 5.2, 8.0 Hz, 1H), 7.12 - 7.04 (m, 1H), 5.37 - 5.19 (m, 1H), 4.41 - 4.32 (m, 1H), 4.25 (d, J= 12.4 Hz, 1H), 4.11 - 3.98 (m, 2H), 3.64 - 3.56 (m, 4H), 3.11 - 3.05 (m, 2H), 3.01 (s, 1H), 2.86 - 2.79 (m, 2H), 2.17 - 1.97 (m, 4H), 1.85 - 1.73 (m, 3H), 1.67 (s, 3H), 1.56 (d, J= 2.0 Hz, 1H) 合成S-4-(4-(-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈 ( 實例 10)

Figure 02_image444
步驟 1：3-(7-((S)-2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯
Figure 02_image446
To 3-(7-((R)-2-((tertiary butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-di To a solution of tert-butyl azabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.023 mmol, 1 equiv) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol , 578.00 equivalent). The mixture was stirred at 20°C for 0.5 hours. LCMS showed complete consumption of starting material. The reaction mixture was bubbled with nitrogen at 20 °C to remove dichloromethane. The residue was diluted with N,N -dimethylformamide (2 mL), and was subjected to preparative high-layer chromatography (column: Phenomenex Synergi C18 150×25 mm×10 um; mobile phase: [water (FA )-ACN]; B%: 7%-37%, 10 min) to obtain the desired product (7.91 mg, 0.012 mmol, 51% yield, 100% purity, formate salt [1 ]). LCMS: MS (ESI) m/z : 656.3 [M+1] + . 1 H NMR: (400 MHz, DMSO-d 6 ) δ : 8.20 (s, 2H), 7.98 (s, 2H), 7.40 (s, 1H), 7.20 (m, J = 5.2, 8.0 Hz, 1H), 7.12 - 7.04 (m, 1H), 5.37 - 5.19 (m, 1H), 4.41 - 4.32 (m, 1H), 4.25 (d, J = 12.4 Hz, 1H), 4.11 - 3.98 (m, 2H), 3.64 - 3.56 (m, 4H), 3.11 - 3.05 (m, 2H), 3.01 (s, 1H), 2.86 - 2.79 (m, 2H), 2.17 - 1.97 (m, 4H), 1.85 - 1.73 (m, 3H), 1.67 (s, 3H), 1.56 (d, J = 2.0 Hz, 1H) Synthesis of S-4-(4-(-3,8-diazabicyclo[3.2.1]octan-3-yl)-2 -(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2 -Amino-7-fluorobenzo[b]thiophene-3-carbonitrile ( Example 10)
Figure 02_image444
Step 1 : 3-(7-((S)-2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8 - Tertiary butyl diazabicyclo[3.2.1]octane-8-carboxylate
Figure 02_image446

阻轉異構物3-(7-((R)-2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯與3-(7-((S)-2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯之混合物(45 mg，0.052 mmol，1當量)藉由SFC (管柱：DAICEL CHIRALPAK IE(250 mm×30 mm，10 um)；移動相：[ACN/IPA(0.1%NH3H2O)]；B%：70%-70%，10.9分鐘)分離，且第二溶析液經鑑定為所需阻轉異構物3-(7-((S)-2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(20 mg，0.023 mmol，44%產率，99%純度)，呈無色油狀。 步驟 2：S-4-(4-(-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈

Figure 02_image448
Atropisomer 3-(7-((R)-2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2 -(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3 , 8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester and 3-(7-((S)-2-((tertiary butoxycarbonyl)amino)-3-cyano Base-7-fluorobenzo[b]thiophen-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)- A mixture of tert-butyl 6-(trifluoromethyl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (45 mg, 0.052 mmol, 1 equivalent) by SFC (column: DAICEL CHIRALPAK IE (250 mm × 30 mm, 10 um); mobile phase: [ACN/IPA (0.1%NH3H2O)]; B%: 70%-70%, 10.9 minutes) separation , and the second eluate was identified as the desired atropisomer 3-(7-((S)-2-((tertiary butoxycarbonyl)amino)-3-cyano-7-fluorobenzene And[b]thiophen-4-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethane yl)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (20 mg, 0.023 mmol, 44% yield, 99% purity) , in the form of colorless oil. Step 2 : S-4-(4-(-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H -pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3- Formaldehyde
Figure 02_image448

向3-(7-((S)-2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)-6-(三氟甲基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(20 mg，0.023 mmol，1當量)於二氯甲烷(5 mL)中之溶液中添加三氟乙酸(1.54 g，13.51 mmol，578.00當量)。將混合物在20℃下攪拌0.5小時。LCMS顯示起始物質完全消耗掉。在20℃下用氮氣使反應混合物鼓泡以移除二氯甲烷。將殘餘物用 N,N-二甲基甲醯胺(2 mL)稀釋。將殘餘物藉由製備型高層層析法(管柱：Phenomenex Synergi C18 150×25 mm×10um；移動相：[水(FA)-ACN]；B%：6%-36%，10分鐘)來純化，得到呈白色固體狀之所需產物(6.82 mg，0.010 mmol，44%產率，100%純度)。LCMS: MS (ESI) m/z：656.3 [M+1] +.. 1H NMR: (400 MHz, DMSO-d 6) δ: 8.21 (s, 2H), 7.98 (s, 2H), 7.41 (s, 1H), 7.24 - 7.16 (m, 1H), 7.12 - 7.04 (m, 1H), 5.37 - 5.17 (m, 1H), 4.40 - 4.24 (m, 2H), 4.11 - 3.98 (m, 2H), 3.66 - 3.58 (m, 4H), 3.14 - 3.06 (m, 2H), 3.03 - 2.98 (m, 1H), 2.86 - 2.78 (m, 1H), 2.16 - 1.93 (m, 4H), 1.86 - 1.73 (m, 3H), 1.68 (s, 3H), 1.62 - 1.53 (m, 1H) 合成4-(4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-6-氯-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈 ( 實例 11)

Figure 02_image450
步驟 1：3-(7-溴-2,6-二氯-喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯
Figure 02_image452
To 3-(7-((S)-2-((tertiary butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)-6-(trifluoromethyl)quinazolin-4-yl)-3,8-di To a solution of tert-butyl azabicyclo[3.2.1]octane-8-carboxylate (20 mg, 0.023 mmol, 1 equiv) in dichloromethane (5 mL) was added trifluoroacetic acid (1.54 g, 13.51 mmol , 578.00 equivalent). The mixture was stirred at 20°C for 0.5 hours. LCMS showed complete consumption of starting material. The reaction mixture was bubbled with nitrogen at 20 °C to remove dichloromethane. The residue was diluted with N,N -dimethylformamide (2 mL). The residue was purified by preparative high-layer chromatography (column: Phenomenex Synergi C18 150×25 mm×10um; mobile phase: [water (FA)-ACN]; B%: 6%-36%, 10 minutes) Purification afforded the desired product (6.82 mg, 0.010 mmol, 44% yield, 100% purity) as a white solid. LCMS: MS (ESI) m/z : 656.3 [M+1] + .. 1 H NMR: (400 MHz, DMSO-d 6 ) δ : 8.21 (s, 2H), 7.98 (s, 2H), 7.41 ( s, 1H), 7.24 - 7.16 (m, 1H), 7.12 - 7.04 (m, 1H), 5.37 - 5.17 (m, 1H), 4.40 - 4.24 (m, 2H), 4.11 - 3.98 (m, 2H), 3.66 - 3.58 (m, 4H), 3.14 - 3.06 (m, 2H), 3.03 - 2.98 (m, 1H), 2.86 - 2.78 (m, 1H), 2.16 - 1.93 (m, 4H), 1.86 - 1.73 (m , 3H), 1.68 (s, 3H), 1.62 - 1.53 (m, 1H) Synthesis of 4-(4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro -2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluoro Benzo[b]thiophene-3-carbonitrile ( Example 11)
Figure 02_image450
Step 1 : tert-butyl 3-(7-bromo-2,6-dichloro-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate
Figure 02_image452

向7-溴-2,4,6-三氯-喹唑啉(500 mg，1.60 mmol，1當量)及3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(340 mg，1.60 mmol，1當量)於二氯甲烷(3 mL)中之溶液中添加 N,N-二異丙基乙胺(621 mg，4.80 mmol，3當量)。將混合物在0℃下攪拌10分鐘。LCMS顯示起始物質完全消耗掉。將反應混合物用水(10 mL)稀釋且用乙酸乙酯(30 mL)萃取。將合併之有機層用鹽水(10 mL)洗滌，經無水硫酸鈉乾燥且過濾。將濾液濃縮且藉由矽膠上管柱層析法(石油醚:乙酸乙酯= 10:1至3:1)來純化，得到呈白色固體狀之所需化合物(704 mg，1.30 mmol，81 %產率)。LCMS (ESI, m/z): 487.2, 489.1 [M+1] +. 1H NMR (400 MHz, DMSO) δ = 8.22 (s, 1H), 8.11 (s, 1H), 4.37 (d, J= 11.2 Hz, 2H), 4.23 (s, 2H), 3.62 (d, J= 12.0 Hz, 2H), 1.77 (d, J= 4.4 Hz, 2H), 1.60 (d, J= 8.0 Hz, 2H), 1.46 (s, 9H)。 步驟 2：3-(7-溴-6-氯-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image454
To 7-bromo-2,4,6-trichloro-quinazoline (500 mg, 1.60 mmol, 1 equivalent) and 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tributyl To a solution of the ester (340 mg, 1.60 mmol, 1 equiv) in dichloromethane (3 mL) was added N,N -diisopropylethylamine (621 mg, 4.80 mmol, 3 equiv). The mixture was stirred at 0°C for 10 minutes. LCMS showed complete consumption of starting material. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10:1 to 3:1) to give the desired compound (704 mg, 1.30 mmol, 81% Yield). LCMS (ESI, m/z): 487.2, 489.1 [M+1] + . 1 H NMR (400 MHz, DMSO) δ = 8.22 (s, 1H), 8.11 (s, 1H), 4.37 (d, J = 11.2 Hz, 2H), 4.23 (s, 2H), 3.62 (d, J = 12.0 Hz, 2H), 1.77 (d, J = 4.4 Hz, 2H), 1.60 (d, J = 8.0 Hz, 2H), 1.46 (s, 9H). Step 2 : 3-(7-Bromo-6-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline- 4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure 02_image454

向3-(7-溴-2,6-二氯-喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(400 mg，0.8 mmol，1當量)及[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲醇(261 mg，1.64 mmol，2當量)於乙腈(5 mL)中之溶液中添加碳酸銫(534 mg，1.64 mmol，2當量)及1,4-二氮雜雙環[2.2.2]辛烷(9.2 mg，0.09 mmol，0.1當量)。將混合物在50℃下攪拌5小時。LCMS顯示起始物質完全消耗掉。將反應混合物用水(10 mL)稀釋且用乙酸乙酯(30 mL)萃取。將合併之有機層用鹽水(10 mL)洗滌，經無水鈉乾燥且過濾。將濾液濃縮且藉由製備型TLC (二氯甲烷中9%甲醇)來純化，得到呈白色固體狀之所需產物(336 mg，0.48 mmol，59%產率)。LCMS (ESI, m/z): 610.2, 612.2[M+1] +。 1H NMR (400 MHz, DMSO) δ = 8.07 (s, 1H), 7.92 - 7.90 (m, 1H), 5.38 - 5.17 (m, 1H), 4.31 (d, J= 11.6 Hz, 2H), 4.22 (s, 2H), 4.08 (d, J= 10.4 Hz, 1H), 4.03 - 3.95 (m, 1H), 3.52 (d, J= 12.4 Hz, 2H), 3.16 (s, 2H), 3.11 (d, J= 5.2 Hz, 2H), 3.03 (s, 1H), 2.90 - 2.80 (m, 1H), 2.15 - 2.10 (m, 1H), 2.05 (s, 1H), 1.84 - 1.75 (m, 4H), 1.63 (d, J= 8.0 Hz, 2H), 1.45 (s, 9H)。 步驟 3：3-(7-(2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image456
To tert-butyl 3-(7-bromo-2,6-dichloro-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (400 mg , 0.8 mmol, 1 equivalent) and [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (261 mg, 1.64 mmol, 2 equivalents ) in acetonitrile (5 mL) was added cesium carbonate (534 mg, 1.64 mmol, 2 equiv) and 1,4-diazabicyclo[2.2.2]octane (9.2 mg, 0.09 mmol, 0.1 equiv) . The mixture was stirred at 50°C for 5 hours. LCMS showed complete consumption of starting material. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium and filtered. The filtrate was concentrated and purified by prep-TLC (9% methanol in dichloromethane) to give the desired product (336 mg, 0.48 mmol, 59% yield) as a white solid. LCMS (ESI, m/z): 610.2, 612.2[M+1] + . 1 H NMR (400 MHz, DMSO) δ = 8.07 (s, 1H), 7.92 - 7.90 (m, 1H), 5.38 - 5.17 (m, 1H), 4.31 (d, J = 11.6 Hz, 2H), 4.22 ( s, 2H), 4.08 (d, J = 10.4 Hz, 1H), 4.03 - 3.95 (m, 1H), 3.52 (d, J = 12.4 Hz, 2H), 3.16 (s, 2H), 3.11 (d, J = 5.2 Hz, 2H), 3.03 (s, 1H), 2.90 - 2.80 (m, 1H), 2.15 - 2.10 (m, 1H), 2.05 (s, 1H), 1.84 - 1.75 (m, 4H), 1.63 ( d, J = 8.0 Hz, 2H), 1.45 (s, 9H). Step 3 : 3-(7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-2-( ((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1 ]Tert-Butyl Octane-8-carboxylate
Figure 02_image456

使3-(7-溴-6-氯-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(236 mg，0.39 mmol，1當量)、N-[3-氰基-7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯并噻吩-2-基]胺基甲酸第三丁酯(242.37 mg，579.43 umol，1.5當量)、 N, N-二異丙基乙胺(150 mg，1.16 mmol，3當量)、二-第三丁基(環戊基)-磷烷;二氯鈀;鐵(25 mg，0.04 mmol，0.1當量)於四氫呋喃(2 mL)及水(0.5 mL)中之混合物脫氣且用氮氣吹掃3次，且接著將混合物在氮氣氛圍下在70℃下攪拌2小時。將反應混合物用水(10 mL)稀釋且用乙酸乙酯(30 mL×3)萃取。將合併之有機層用鹽水(10 mL)洗滌，經無水鈉乾燥且過濾。將濾液濃縮且藉由製備型高效液相層析法(管柱：Phenomenex luna C18 150×25 mm×10 um；移動相：[水(甲酸)-乙腈]；B%：37%-67%，2分鐘)來純化，得到呈白色固體狀之所需產物(272 mg，0.3 mmol，86%)。LCMS (ESI, m/z): 822.0[M] +。 1H NMR (400 MHz, DMSO) δ = 8.14 (s, 1H), 8.05 (s, 1H), 7.53 (s, 1H), 7.24 (s, 2H), 5.49 - 5.28 (m, 1H), 4.49 - 4.36 (m, 1H), 4.35 - 4.12 (m, 5H), 3.72 - 3.62 (m, 1H), 3.58 - 3.48 (m, 1H), 3.30 (s, 4H), 3.06 - 2.94 (m, 1H), 2.24 - 2.17 (m, 1H), 2.16 - 2.08 (m, 1H), 2.02 - 1.77 (m, 5H), 1.72 - 1.63 (m, 2H), 1.47 (s, 18H)。 步驟 4：4-(4-(3,8-二氮雜雙環[3.2.1]辛烷-3-基)-6-氯-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-7-基)-2-胺基-7-氟苯并[b]噻吩-3-甲腈

Figure 02_image458
Make 3-(7-bromo-6-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolazin-7a(5H)-yl)methoxy)quinazoline-4- Base)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (236 mg, 0.39 mmol, 1 equivalent), N-[3-cyano-7-fluoro-4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate (242.37 mg, 579.43 umol, 1.5 equivalents), N , N -diisopropylethylamine (150 mg, 1.16 mmol, 3 equivalents), two-tertiary butyl (cyclopentyl)-phosphine; dichloropalladium; iron (25 mg, 0.04 mmol, 0.1 equiv) in tetrahydrofuran (2 mL) and water (0.5 mL) was degassed and flushed with nitrogen 3 times, and then the mixture was stirred at 70 °C under nitrogen atmosphere for 2 h. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous sodium and filtered. The filtrate was concentrated and separated by preparative high-performance liquid chromatography (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 37%-67%, 2 min) to afford the desired product (272 mg, 0.3 mmol, 86%) as a white solid. LCMS (ESI, m/z): 822.0[M] + . 1 H NMR (400 MHz, DMSO) δ = 8.14 (s, 1H), 8.05 (s, 1H), 7.53 (s, 1H), 7.24 (s, 2H), 5.49 - 5.28 (m, 1H), 4.49 - 4.36 (m, 1H), 4.35 - 4.12 (m, 5H), 3.72 - 3.62 (m, 1H), 3.58 - 3.48 (m, 1H), 3.30 (s, 4H), 3.06 - 2.94 (m, 1H), 2.24 - 2.17 (m, 1H), 2.16 - 2.08 (m, 1H), 2.02 - 1.77 (m, 5H), 1.72 - 1.63 (m, 2H), 1.47 (s, 18H). Step 4 : 4-(4-(3,8-diazabicyclo[3.2.1]octane-3-yl)-6-chloro-2-(((2R,7aS)-2-fluorotetrahydro- 1H-Pyrrolazin-7a(5H)-yl)methoxy)quinazolin-7-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile
Figure 02_image458

向3-(7-(2-((第三丁氧羰基)胺基)-3-氰基-7-氟苯并[b]噻吩-4-基)-6-氯-2-(((2R,7aS)-2-氟四氫-1H-吡咯嗪-7a(5H)-基)甲氧基)喹唑啉-4-基)-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(116 mg，0.14 mmol，1當量)於二氯甲烷(3 mL)中之溶液中添加三氟乙酸(1.21 g，11 mmol，75當量)。將混合物在25℃下攪拌1小時。LCMS顯示起始物質完全消耗掉。將反應混合物在減壓下濃縮以移除溶劑。將殘餘物藉由製備型高效液相層析法(管柱：Phenomenex luna C18 150×25 mm×10 um；移動相：[水(甲酸)-乙腈]；B%：0%-30%，2分鐘)來純化，得到呈白色固體狀之所需產物(44 mg，0.07 mmol，49%產率)。LCMS (ESI, m/z): 622.3[M] +。 1H NMR (400 MHz, DMSO) δ =8.23 - 8.18 (m, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.47 (s, 1H), 7.20 (dd, J= 5.6, 8.0 Hz, 1H), 7.14 - 7.06 (m, 1H), 5.37 - 5.16 (m, 1H), 4.27 (d, J= 13.2 Hz, 2H), 4.06 (d, J= 10.4 Hz, 1H), 3.97 (dd, J= 2.8, 10.4 Hz, 1H), 3.63 - 3.54 (m, 6H), 3.11 - 3.06 (m, 2H), 3.01 (s, 1H), 2.82 (dd, J= 8.4, 14.8 Hz, 2H), 2.15 - 2.09 (m, 1H), 2.05 (s, 1H), 1.99 (s, 1H), 1.78 (dd, J= 7.6, 12.4 Hz, 2H), 1.66 (s, 3H)。 合成2-胺基-4-[6-氯-8-氟-4-(6-氟-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-2-[[(2 R,8 S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]喹唑啉-7-基]-7-氟-苯并噻吩-3-甲腈 ( 實例 12)

Figure 02_image460
步驟 1：3-[7-溴-8-氟-2-[[(2R,8S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]-6-(三氟甲基)喹唑啉-4-基]-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯
Figure 02_image462
To 3-(7-(2-((tertiary butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-2-((( 2R,7aS)-2-fluorotetrahydro-1H-pyrrolidin-7a(5H)-yl)methoxy)quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane To a solution of tert-butyl alkane-8-carboxylate (116 mg, 0.14 mmol, 1 equiv) in dichloromethane (3 mL) was added trifluoroacetic acid (1.21 g, 11 mmol, 75 equiv). The mixture was stirred at 25°C for 1 hour. LCMS showed complete consumption of starting material. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was subjected to preparative high-performance liquid chromatography (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (formic acid)-acetonitrile]; B%: 0%-30%, 2 min) to afford the desired product (44 mg, 0.07 mmol, 49% yield) as a white solid. LCMS (ESI, m/z): 622.3[M] + . 1 H NMR (400 MHz, DMSO) δ =8.23 - 8.18 (m, 1H), 8.02 (s, 1H), 7.95 (s, 1H), 7.47 (s, 1H), 7.20 (dd, J = 5.6, 8.0 Hz, 1H), 7.14 - 7.06 (m, 1H), 5.37 - 5.16 (m, 1H), 4.27 (d, J = 13.2 Hz, 2H), 4.06 (d, J = 10.4 Hz, 1H), 3.97 (dd , J = 2.8, 10.4 Hz, 1H), 3.63 - 3.54 (m, 6H), 3.11 - 3.06 (m, 2H), 3.01 (s, 1H), 2.82 (dd, J = 8.4, 14.8 Hz, 2H), 2.15 - 2.09 (m, 1H), 2.05 (s, 1H), 1.99 (s, 1H), 1.78 (dd, J = 7.6, 12.4 Hz, 2H), 1.66 (s, 3H). Synthesis of 2-amino-4-[6-chloro-8-fluoro-4-(6-fluoro-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-[[( 2 R ,8 S )-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro-benzene Thiophene-3-carbonitrile ( Example 12)
Figure 02_image460
Step 1 : 3-[7-Bromo-8-fluoro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol Oxy]-6-(trifluoromethyl)quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure 02_image462

向7-溴-2,4,6-三氯-8-氟-喹唑啉(732.26 mg，2.216 mmol，1.10當量)及6-羥基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(460 mg，2.015 mmol，1.00當量)於乙腈(10 mL)中之溶液中添加 N, N-二異丙基乙胺(1.06 mL，6.045 mmol，3.00當量)。將所得溶液在室溫下攪拌1小時，然後在減壓下濃縮。將所得殘餘物藉由矽膠管柱層析法，用二氯甲烷:乙酸乙酯溶析來純化，得到所需產物(720 mg，1.3788 mmol，68.43%產率)。LCMS (ESI, m/z): 523.0 [M+1] +。 步驟 2：3-(7-溴-2,6-二氯-8-氟-喹唑啉-4-基)-6-氟-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image464
To 7-bromo-2,4,6-trichloro-8-fluoro-quinazoline (732.26 mg, 2.216 mmol, 1.10 equivalents) and 6-hydroxy-3,8-diazabicyclo[3.2.1]octane To a solution of tert-butyl alkane-8-carboxylate (460 mg, 2.015 mmol, 1.00 equiv) in acetonitrile (10 mL) was added N , N -diisopropylethylamine (1.06 mL, 6.045 mmol, 3.00 equiv) . The resulting solution was stirred at room temperature for 1 hour, then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with dichloromethane:ethyl acetate to obtain the desired product (720 mg, 1.3788 mmol, 68.43% yield). LCMS (ESI, m/z): 523.0 [M+1] + . Step 2 : 3-(7-Bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)-6-fluoro-3,8-diazabicyclo[3.2.1]octane- 8-Tertiary butyl carboxylate
Figure 02_image464

向3-(7-溴-2,6-二氯-8-氟-喹唑啉-4-基)-6-羥基-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(400 mg，0.766 mmol，1.00當量)於二氯甲烷(5 mL)中之溶液中添加二乙基胺基三氟化硫(740.82 mg，4.5959 mmol，6.00當量)。將所得溶液在室溫下攪拌30分鐘，然後在減壓下濃縮。將所得殘餘物藉由矽膠管柱層析法，用己烷:乙酸乙酯溶析來純化，得到所需產物(210 mg，0.401 mmol，52.31%產率)。LCMS (ESI, m/z): 525.1[M+1] +。 步驟 3：3-[7-溴-6-氯-8-氟-2-[[rac-(2 R,8 S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]喹唑啉-4-基]-6-氟-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image466
To 3-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)-6-hydroxy-3,8-diazabicyclo[3.2.1]octane-8- To a solution of tert-butyl formate (400 mg, 0.766 mmol, 1.00 equiv) in dichloromethane (5 mL) was added diethylaminosulfur trifluoride (740.82 mg, 4.5959 mmol, 6.00 equiv). The resulting solution was stirred at room temperature for 30 minutes, then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography and eluted with hexane:ethyl acetate to obtain the desired product (210 mg, 0.401 mmol, 52.31% yield). LCMS (ESI, m/z): 525.1[M+1] + . Step 3 : 3-[7-Bromo-6-chloro-8-fluoro-2-[[rac-( 2R , 8S )-2-fluoro-1,2,3,5,6,7-hexahydro Pyrrolizin-8-yl]methoxy]quinazolin-4-yl]-6-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure 02_image466

將3-(7-溴-2,6-二氯-8-氟-喹唑啉-4-基)-6-氟-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(210 mg，0.400 mmol，1.00當量)、[(2 R,8 S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲醇(191.34 mg，1.202 mmol，3.00當量)、碳酸銫(391.59 mg，1.2019 mmol，3.00當量)及1,4-二氮雜雙環[2.2.2]辛烷(134.81 mg，1.2019 mmol，3.00當量)之混合物在80℃下攪拌1小時。冷卻後，將混合物在減壓下濃縮，得到粗產物。將粗產物藉由矽膠管柱層析法，用二氯甲烷:甲醇溶析來純化，得到不純產物，將其藉由製備型HPLC (乙腈/水/1% 甲酸)進一步純化，得到呈淡黃色固體狀之所需產物(75 mg，0.1159 mmol，28.94%產率)。LCMS (ESI, m/z): 646.1 [M+1] +。 步驟 4 ：3-[7-[2-(第三丁氧羰基胺基)-3-氰基-7-氟-苯并噻吩-4-基]-6-氯-8-氟-2-[[(2 R,8 S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]喹唑啉-4-基]-6-氟-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯

Figure 02_image468
3-(7-bromo-2,6-dichloro-8-fluoro-quinazolin-4-yl)-6-fluoro-3,8-diazabicyclo[3.2.1]octane-8- tert-butyl formate (210 mg, 0.400 mmol, 1.00 equiv), [(2 R ,8 S )-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl] Methanol (191.34 mg, 1.202 mmol, 3.00 equiv), cesium carbonate (391.59 mg, 1.2019 mmol, 3.00 equiv) and 1,4-diazabicyclo[2.2.2]octane (134.81 mg, 1.2019 mmol, 3.00 equiv) The mixture was stirred at 80°C for 1 hour. After cooling, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography and eluted with dichloromethane:methanol to obtain an impure product, which was further purified by preparative HPLC (acetonitrile/water/1% formic acid) to obtain a light yellow Desired product as solid (75 mg, 0.1159 mmol, 28.94% yield). LCMS (ESI, m/z): 646.1 [M+1] + . Step 4 : 3-[7-[2-(tert-butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2-[ [(2 R ,8 S )-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-6-fluoro -3,8-Diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
Figure 02_image468

在氮氣氛圍下將3-[7-溴-6-氯-8-氟-2-[[(2 R,8 S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]喹唑啉-4-基]-6-氟-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(45 mg，0.070 mmol，1.00當量)、N-[3-氰基-7-氟-4-(4,4,5,5-四甲基-1,3,2-二氧雜硼戊環-2-基)苯并噻吩-2-基]胺基甲酸第三丁酯(58.2 mg，0.139 mmol，2.00當量)、[1,1’-雙(二-第三丁基膦基)二茂鐵]二氯鈀(II) (10 mg，0.0139 mmol，0.20當量)於2-甲基四氫呋喃(4 mL)及水(1 mL)中之混合物添加 N, N-二異丙基乙胺(0.06 mL，0.347 mmol，5.00當量)。將所得混合物在100℃下攪拌30分鐘。冷卻後，將混合物在減壓下濃縮，得到殘餘物，將其藉由製備型HPLC (乙腈/水/1% 甲酸)來純化，得到呈淡黃色固體狀之所需產物(15.03 mg， 0.0175 mmol，25.17%產率)。LCMS (ESI, m/z): 858.3 [M+1] +。 步驟 5：2-胺基-4-[6-氯-8-氟-4-(6-氟-3,8-二氮雜雙環[3.2.1]辛烷-3-基)-2-[[(2 R,8 S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]喹唑啉-7-基]-7-氟-苯并噻吩-3-甲腈

Figure 02_image470
3-[7-Bromo-6-chloro-8-fluoro-2-[[(2 R ,8 S )-2-fluoro-1,2,3,5,6,7-hexahydro Pyrrolizin-8-yl]methoxy]quinazolin-4-yl]-6-fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (45 mg , 0.070 mmol, 1.00 equivalents), N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2- yl) benzothiophen-2-yl] tert-butyl carbamate (58.2 mg, 0.139 mmol, 2.00 equiv), [1,1'-bis(di-tert-butylphosphino)ferrocene] di To a mixture of palladium(II) chloride (10 mg, 0.0139 mmol, 0.20 equiv) in 2-methyltetrahydrofuran (4 mL) and water (1 mL) was added N , N -diisopropylethylamine (0.06 mL, 0.347 mmol, 5.00 equiv). The resulting mixture was stirred at 100°C for 30 minutes. After cooling, the mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (acetonitrile/water/1% formic acid) to give the desired product as a light yellow solid (15.03 mg, 0.0175 mmol , 25.17% yield). LCMS (ESI, m/z): 858.3 [M+1] + . Step 5 : 2-Amino-4-[6-chloro-8-fluoro-4-(6-fluoro-3,8-diazabicyclo[3.2.1]octane-3-yl)-2-[ [(2 R ,8 S )-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-7-yl]-7-fluoro -Benzothiophene-3-carbonitrile
Figure 02_image470

在室溫下向3-[7-[2-(第三丁氧羰基胺基)-3-氰基-7-氟-苯并噻吩-4-基]-6-氯-8-氟-2-[[(2 R,8 S)-2-氟-1,2,3,5,6,7-六氫吡咯嗪-8-基]甲氧基]喹唑啉-4-基]-6-氟-3,8-二氮雜雙環[3.2.1]辛烷-8-甲酸第三丁酯(12.03 mg，0.014 mmol，1.00當量)之溶液中緩慢添加三氟乙酸(1.0 mL)。將混合物攪拌30分鐘，然後在減壓下濃縮，得到殘餘物，將其藉由製備型HPLC (乙腈/水/1%甲酸)來純化，得到呈淡黃色固體狀之所需產物(4.80 mg，0.0073 mmol，52.17%產率)。LCMS (ESI, m/z): 658.2 [M+1] +。 1H NMR: (400 MHz, CD 3OD) δ 8.00 (d, 1H), 7.13 (m, 1H), 6.96 (t, 1H), 5.52-5.43 (m, 2H), 4.58-4.18 (m, 5 H), 3.92-3.80 (m, 5H), 3.40-3.35 (m, 1H), 2.62-222 (m, 8H), 1.25-1.18 (m, 1H)。 B. 分析及活性資料KRAS G12D及野生型KRAS酶分析如下進行： KRAS G12D 及野生型 KRAS- 活體外 RAS-RAF 結合分析 (RRB) To 3-[7-[2-(tertiary butoxycarbonylamino)-3-cyano-7-fluoro-benzothiophen-4-yl]-6-chloro-8-fluoro-2 at room temperature -[[(2 R ,8 S )-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-6 - To a solution of tert-butyl fluoro-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (12.03 mg, 0.014 mmol, 1.00 eq) was slowly added trifluoroacetic acid (1.0 mL). The mixture was stirred for 30 minutes, then concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (acetonitrile/water/1% formic acid) to give the desired product as a light yellow solid (4.80 mg, 0.0073 mmol, 52.17% yield). LCMS (ESI, m/z): 658.2 [M+1] + . 1 H NMR: (400 MHz, CD 3 OD) δ 8.00 (d, 1H), 7.13 (m, 1H), 6.96 (t, 1H), 5.52-5.43 (m, 2H), 4.58-4.18 (m, 5 H), 3.92-3.80 (m, 5H), 3.40-3.35 (m, 1H), 2.62-222 (m, 8H), 1.25-1.18 (m, 1H). B. Assays and Activity Data KRAS G12D and wild-type KRAS enzyme assays were performed as follows: KRAS G12D and wild-type KRAS- in vitro RAS-RAF binding assay (RRB)

在分析緩衝液(50 mM HEPES pH 7.5、100 mM NaCl、1 mM MgCl 2、1 mM DTT)中，用卵白素-鋱(鑭系元素穴狀化合物供體螢光團)標記生物素化之KRAS蛋白胺基酸1-169 (在 Erasca生產)，最終濃度為30 nM。在單獨之反應混合物中，將30nM cRAF (RBD) (Abcam, Cambridge MA)用抗GST d2 (受體螢光團)標記。標記反應在室溫下培育一小時。 Biotinylated KRAS was labeled with avidin-cerium (lanthanide cryptate donor fluorophore) in assay buffer (50 mM HEPES pH 7.5, 100 mM NaCl, 1 mM MgCl 2 , 1 mM DTT) Protein amino acids 1-169 (manufactured at Erasca) at a final concentration of 30 nM. In a separate reaction mixture, 30 nM cRAF (RBD) (Abcam, Cambridge MA) was labeled with anti-GST d2 (acceptor fluorophore). Labeling reactions were incubated for one hour at room temperature.

在黑色半面積微量滴定盤中將所關注化合物與標記之KRAS在室溫下培育60分鐘，最終DMSO濃度為5% (50 µL最終反應體積)。培育化合物後，將SOS1催化結構域(在Erasca生產)及GTPgS添加至反應中以啟動核苷酸交換(60分鐘交換反應)。一旦進入GTP狀態，KRAS將結合於cRAF。若KRAS保持在GDP狀態，則不會發生結合。化合物可能會阻斷核苷酸交換或可能藉由與RAS效應位點結合而對cRAF-KRAS相互作用造成空間阻礙。Compounds of interest were incubated with labeled KRAS in black half-area microtiter plates at room temperature for 60 minutes at a final DMSO concentration of 5% (50 µL final reaction volume). After incubation of compounds, SOS1 catalytic domain (manufactured in Erasca) and GTPgS were added to the reaction to initiate nucleotide exchange (60 min exchange reaction). Once in the GTP state, KRAS binds to cRAF. If KRAS remains in the GDP state, no binding will occur. Compounds may block nucleotide exchange or may sterically hinder the cRAF-KRAS interaction by binding to the RAS effector site.

交換反應後，將標記之KRAS及cRAF以等體積(各30 µL)混合，且在室溫下培育30-60分鐘。將此混合物之一部分轉移至白色384孔盤(每孔20 µL，一式兩份)且在HTRF兼容讀盤器(ClarioSTAR)上讀取。在平衡時量測螢光共振能量轉移(FRET)。若發生KRAS-cRAF結合，FRET信號將很高。若KRAS-cRAF結合被測試化合物抑制，則FRET信號將很低。示例性化合物之結果如下 表 1所示。 表1

Figure 02_image472
Figure 02_image474
Figure 02_image476
After the exchange reaction, labeled KRAS and cRAF were mixed in equal volumes (30 µL each) and incubated at room temperature for 30-60 minutes. An aliquot of this mixture was transferred to a white 384-well plate (20 µL per well in duplicate) and read on a HTRF compatible plate reader (ClarioSTAR). Fluorescence resonance energy transfer (FRET) was measured at equilibrium. If KRAS-cRAF binding occurs, the FRET signal will be high. If KRAS-cRAF binding is inhibited by the test compound, the FRET signal will be low. Results for exemplary compounds are shown in Table 1 below. Table 1
Figure 02_image472
Figure 02_image474
Figure 02_image476

雖然出於清楚理解目的，前述實施例已藉助說明及實例相當詳細地描述，但是熟習此項技術者認識到可在隨附申請專利範圍之範疇內實施某些變化及修改。另外，本文提供之各參考文獻以全文引用之方式併入，其引用程度如同各參考文獻個別地以引用之方式併入。當在本申請案與本文提供之參考文獻之間存在衝突時，應以本申請案為準。While the foregoing embodiments have been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will recognize that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. In the event of a conflict between the present application and the references provided herein, the present application shall control.

Figure 111129927-A0101-11-0002-1
Figure 111129927-A0101-11-0002-1

Claims (23)

一種式(I)化合物，
Figure 03_image001
或其立體異構物、互變異構物、醫藥學上可接受之鹽，其中： 環A係選自
Figure 03_image003
、
Figure 03_image005
、
Figure 03_image007
、
Figure 03_image009
、
Figure 03_image011
、
Figure 03_image013
及
Figure 03_image015
； W為O、NR 3、S或不存在； X為CR 1或N； Y為CR 1或N； Z 1為O、N(C 1-C 4烷基)、NH或S； 各Z 2獨立地為CH或N； L為C 1-3烷基或不存在； 各R 1獨立地為H、鹵基、C 1-6烷基或C 3-6環烷基； R 2為4-10員雜環基、3-10員環烷基、6-10員芳基或5-10員雜芳基，其中該雜環基、環烷基、芳基及雜芳基視情況經OH、鹵基、CN、CF 3、C 1-4烷基、C 1-4烷氧基及C 1-3烷基-OH取代； R 3為H或C 1-4烷基； 各R 4獨立地選自-OH、鹵基、C 1-3烷基、C 2-C 4炔基、C 1-3鹵烷基、-CN、-NH 2；且 n為0、1、2、3或4。 A compound of formula (I),
Figure 03_image001
Or its stereoisomer, tautomer, pharmaceutically acceptable salt, wherein: Ring A is selected from
Figure 03_image003
,
Figure 03_image005
,
Figure 03_image007
,
Figure 03_image009
,
Figure 03_image011
,
Figure 03_image013
and
Figure 03_image015
; W is O, NR 3 , S or absent; X is CR 1 or N; Y is CR 1 or N; Z 1 is O, N(C 1 -C 4 alkyl), NH or S; each Z 2 is independently CH or N; L is C 1-3 alkyl or does not exist; each R 1 is independently H, halo, C 1-6 alkyl or C 3-6 cycloalkyl; R 2 is 4- 10-membered heterocyclic group, 3-10-membered cycloalkyl group, 6-10-membered aryl group or 5-10-membered heteroaryl group, wherein the heterocyclic group, cycloalkyl group, aryl group and heteroaryl group are optionally modified by OH, Halo, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy and C 1-3 alkyl-OH substitution; R 3 is H or C 1-4 alkyl; each R 4 is independently selected from -OH, halo, C 1-3 alkyl, C 2 -C 4 alkynyl, C 1-3 haloalkyl, -CN, -NH 2 ; and n is 0, 1, 2, 3 or 4 . 如請求項1之化合物，其中當X為N時，環A不為
Figure 03_image009
。 The compound as claimed in item 1, wherein when X is N, ring A is not
Figure 03_image009
. 如請求項1之化合物，其具有式(Ia)：
Figure 03_image017
或其立體異構物、互變異構物、醫藥學上可接受之鹽，其中： W為O、NR 3、S或不存在； X為CR 1或N； Y為CR 1或N； Z 1為O、N(C 1-C 4烷基)、NH或S； Z 2為CH或N； L為C 1-3烷基或不存在； 各R 1獨立地為H、鹵基、C 1-6烷基或C 3-6環烷基； R 2為4-10員雜環基、3-10員環烷基、6-10員芳基或5-10員雜芳基，其中該雜環基、環烷基、芳基及雜芳基視情況經OH、鹵基、CN、CF 3、C 1-4烷基、C 1-4烷氧基及C 1-3烷基-OH取代； R 3為H或C 1-4烷基； 各R 4獨立地選自-OH、鹵基、C 1-3烷基、C 2-C 4炔基、C 1-3鹵烷基、-CN、-NH 2；且 n為0、1、2、3或4。 As the compound of claim 1, it has formula (Ia):
Figure 03_image017
Or its stereoisomer, tautomer, pharmaceutically acceptable salt, wherein: W is O, NR 3 , S or absent; X is CR 1 or N; Y is CR 1 or N; Z 1 is O, N(C 1 -C 4 alkyl), NH or S; Z 2 is CH or N; L is C 1-3 alkyl or absent; each R 1 is independently H, halo, C 1 -6 alkyl or C 3-6 cycloalkyl; R 2 is 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the hetero Cyclic, cycloalkyl, aryl and heteroaryl are optionally substituted by OH, halo, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy and C 1-3 alkyl-OH ; R 3 is H or C 1-4 alkyl; Each R 4 is independently selected from -OH, halo, C 1-3 alkyl, C 2 -C 4 alkynyl, C 1-3 haloalkyl, - CN, —NH 2 ; and n is 0, 1, 2, 3 or 4. 如請求項1之化合物，其具有式(Ib)：
Figure 03_image019
或其立體異構物、互變異構物、醫藥學上可接受之鹽，其中： W為O、NR 3、S或不存在； X為CR 1或N； Y為CR 1或N； Z 1為O、N(C 1-C 4烷基)、NH或S； L為C 1-3烷基或不存在； 各R 1獨立地為H、鹵基、C 1-6烷基或C 3-6環烷基； R 2為4-10員雜環基、3-10員環烷基、6-10員芳基或5-10員雜芳基，其中該雜環基、環烷基、芳基及雜芳基視情況經OH、鹵基、CN、CF 3、C 1-4烷基、C 1-4烷氧基及C 1-3烷基-OH取代； R 3為H或C 1-4烷基； 各R 4獨立地選自-OH、鹵基、C 1-3烷基、C 2-C 4炔基、C 1-3鹵烷基、-CN、-NH 2；且 n為0、1、2、3或4。 As the compound of claim 1, it has formula (Ib):
Figure 03_image019
Or its stereoisomer, tautomer, pharmaceutically acceptable salt, wherein: W is O, NR 3 , S or absent; X is CR 1 or N; Y is CR 1 or N; Z 1 is O, N(C 1 -C 4 alkyl), NH or S; L is C 1-3 alkyl or absent; each R 1 is independently H, halo, C 1-6 alkyl or C 3 -6 cycloalkyl; R 2 is 4-10 membered heterocyclic group, 3-10 membered cycloalkyl group, 6-10 membered aryl group or 5-10 membered heteroaryl group, wherein the heterocyclic group, cycloalkyl group, Aryl and heteroaryl are optionally substituted by OH, halo, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy and C 1-3 alkyl-OH; R 3 is H or C 1-4 alkyl; each R 4 is independently selected from -OH, halo, C 1-3 alkyl, C 2 -C 4 alkynyl, C 1-3 haloalkyl, -CN, -NH 2 ; and n is 0, 1, 2, 3 or 4. 如請求項1之化合物，其具有式(Ic)：
Figure 03_image021
或其立體異構物、互變異構物、醫藥學上可接受之鹽，其中： W為O、NR 3、S或不存在； X為CR 1； Y為CR 1或N； L為C 1-3烷基或不存在； 各R 1獨立地為H、鹵基、C 1-6烷基或C 3-6環烷基； R 2為4-10員雜環基、3-10員環烷基、6-10員芳基或5-10員雜芳基，其中該雜環基、環烷基、芳基及雜芳基視情況經OH、鹵基、CN、CF 3、C 1-4烷基、C 1-4烷氧基及C 1-3烷基-OH取代； R 3為H或C 1-4烷基； 各R 4獨立地選自-OH、鹵基、C 1-3烷基、C 2-C 4炔基、C 1-3鹵烷基、-CN、-NH 2；且 n為0、1、2、3或4。 As the compound of claim 1, it has formula (Ic):
Figure 03_image021
Or its stereoisomer, tautomer, pharmaceutically acceptable salt, wherein: W is O, NR 3 , S or does not exist; X is CR 1 ; Y is CR 1 or N; L is C 1 -3 alkyl or not present; each R 1 is independently H, halo, C 1-6 alkyl or C 3-6 cycloalkyl; R 2 is 4-10 membered heterocyclyl, 3-10 membered ring Alkyl, 6-10 membered aryl or 5-10 membered heteroaryl, wherein the heterocyclyl, cycloalkyl, aryl and heteroaryl are optionally modified by OH, halo, CN, CF 3 , C 1- 4 alkyl, C 1-4 alkoxy and C 1-3 alkyl-OH substitution; R 3 is H or C 1-4 alkyl; each R 4 is independently selected from -OH, halo, C 1- 3 alkyl, C 2 -C 4 alkynyl, C 1-3 haloalkyl, -CN, -NH 2 ; and n is 0, 1, 2, 3 or 4. 如請求項1之化合物，其具有式(Id)：
Figure 03_image023
或其立體異構物、互變異構物、醫藥學上可接受之鹽，其中： W為O、NR 3、S或不存在； X為CR 1或N； Y為CR 1或N； Z 1為O、N(C 1-C 4烷基)、NH或S； L為C 1-3烷基或不存在； 各R 1獨立地為H、鹵基、C 1-6烷基或C 3-6環烷基； R 2為4-10員雜環基、3-10員環烷基、6-10員芳基或5-10員雜芳基，其中該雜環基、環烷基、芳基及雜芳基視情況經OH、鹵基、CN、CF 3、C 1-4烷基、C 1-4烷氧基及C 1-3烷基-OH取代； R 3為H或C 1-4烷基； 各R 4獨立地選自-OH、鹵基、C 1-3烷基、C 2-C 4炔基、C 1-3鹵烷基、-CN、-NH 2；且 n為0、1、2、3或4。 As the compound of claim 1, it has formula (Id):
Figure 03_image023
Or its stereoisomer, tautomer, pharmaceutically acceptable salt, wherein: W is O, NR 3 , S or absent; X is CR 1 or N; Y is CR 1 or N; Z 1 is O, N(C 1 -C 4 alkyl), NH or S; L is C 1-3 alkyl or absent; each R 1 is independently H, halo, C 1-6 alkyl or C 3 -6 cycloalkyl; R 2 is 4-10 membered heterocyclic group, 3-10 membered cycloalkyl group, 6-10 membered aryl group or 5-10 membered heteroaryl group, wherein the heterocyclic group, cycloalkyl group, Aryl and heteroaryl are optionally substituted by OH, halo, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy and C 1-3 alkyl-OH; R 3 is H or C 1-4 alkyl; each R 4 is independently selected from -OH, halo, C 1-3 alkyl, C 2 -C 4 alkynyl, C 1-3 haloalkyl, -CN, -NH 2 ; and n is 0, 1, 2, 3 or 4. 如請求項1之化合物，其具有式(Ie)：
Figure 03_image025
或其立體異構物、互變異構物、醫藥學上可接受之鹽，其中： W為O、NR 3、S或不存在； X為CR 1或N； Y為CR 1或N； Z 1為O、N(C 1-C 4烷基)、NH或S； L為C 1-3烷基或不存在； 各R 1獨立地為H、鹵基、C 1-6烷基或C 3-6環烷基； R 2為4-10員雜環基、3-10員環烷基、6-10員芳基或5-10員雜芳基，其中該雜環基、環烷基、芳基及雜芳基視情況經OH、鹵基、CN、CF 3、C 1-4烷基、C 1-4烷氧基及C 1-3烷基-OH取代； 各R 4獨立地選自-OH、鹵基、C 1-3烷基、C 2-C 4炔基、C 1-3鹵烷基、-CN、-NH 2；且 n為0、1、2、3或4。 As the compound of claim 1, it has formula (Ie):
Figure 03_image025
Or its stereoisomer, tautomer, pharmaceutically acceptable salt, wherein: W is O, NR 3 , S or absent; X is CR 1 or N; Y is CR 1 or N; Z 1 is O, N(C 1 -C 4 alkyl), NH or S; L is C 1-3 alkyl or absent; each R 1 is independently H, halo, C 1-6 alkyl or C 3 -6 cycloalkyl; R 2 is 4-10 membered heterocyclic group, 3-10 membered cycloalkyl group, 6-10 membered aryl group or 5-10 membered heteroaryl group, wherein the heterocyclic group, cycloalkyl group, Aryl and heteroaryl are optionally substituted by OH, halo, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy and C 1-3 alkyl-OH; each R 4 is independently selected from from -OH, halo, C 1-3 alkyl, C 2 -C 4 alkynyl, C 1-3 haloalkyl, -CN, -NH 2 ; and n is 0, 1, 2, 3 or 4. 如請求項1之化合物，其具有式(If)：
Figure 03_image027
或其立體異構物、互變異構物、醫藥學上可接受之鹽，其中： W為O、NR 3、S或不存在； X為CR 1或N； Y為CR 1或N； Z 1為O、N(C 1-C 4烷基)、NH或S； 各Z 2獨立地為CH或N； L為C 1-3烷基或不存在； 各R 1獨立地為H、鹵基、C 1-6烷基或C 3-6環烷基； R 2為4-10員雜環基、3-10員環烷基、6-10員芳基或5-10員雜芳基，其中該雜環基、環烷基、芳基及雜芳基視情況經OH、鹵基、CN、CF 3、C 1-4烷基、C 1-4烷氧基及C 1-3烷基-OH取代； R 3為H或C 1-4烷基； 各R 4獨立地選自-OH、鹵基、C 1-3烷基、C 2-C 4炔基、C 1-3鹵烷基、-CN、-NH 2；且 n為0、1、2、3或4。 As the compound of claim 1, it has formula (If):
Figure 03_image027
Or its stereoisomer, tautomer, pharmaceutically acceptable salt, wherein: W is O, NR 3 , S or absent; X is CR 1 or N; Y is CR 1 or N; Z 1 is O, N(C 1 -C 4 alkyl), NH or S; each Z 2 is independently CH or N; L is C 1-3 alkyl or absent; each R 1 is independently H, halo , C 1-6 alkyl or C 3-6 cycloalkyl; R 2 is 4-10 membered heterocyclyl, 3-10 membered cycloalkyl, 6-10 membered aryl or 5-10 membered heteroaryl, Wherein the heterocyclyl, cycloalkyl, aryl and heteroaryl are optionally modified by OH, halo, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy and C 1-3 alkyl -OH is substituted; R 3 is H or C 1-4 alkyl; each R 4 is independently selected from -OH, halo, C 1-3 alkyl, C 2 -C 4 alkynyl, C 1-3 haloalkane group, -CN, -NH 2 ; and n is 0, 1, 2, 3 or 4. 如請求項1之化合物，其中環A係選自：
Figure 03_image029
、
Figure 03_image031
、
Figure 03_image033
、
Figure 03_image035
、
Figure 03_image037
、
Figure 03_image039
、
Figure 03_image041
、
Figure 03_image043
、
Figure 03_image045
及
Figure 03_image047
。 As the compound of claim 1, wherein ring A is selected from:
Figure 03_image029
,
Figure 03_image031
,
Figure 03_image033
,
Figure 03_image035
,
Figure 03_image037
,
Figure 03_image039
,
Figure 03_image041
,
Figure 03_image043
,
Figure 03_image045
and
Figure 03_image047
. 如請求項1之化合物，其中n為1、2、3或4且環A係選自：
Figure 03_image049
、
Figure 03_image051
、
Figure 03_image053
、
Figure 03_image055
、
Figure 03_image057
、
Figure 03_image059
、
Figure 03_image061
、
Figure 03_image063
、
Figure 03_image065
、
Figure 03_image067
、
Figure 03_image069
、
Figure 03_image071
、
Figure 03_image073
、
Figure 03_image075
、
Figure 03_image077
、
Figure 03_image079
、
Figure 03_image081
、
Figure 03_image083
及
Figure 03_image085
。 As the compound of claim 1, wherein n is 1, 2, 3 or 4 and ring A is selected from:
Figure 03_image049
,
Figure 03_image051
,
Figure 03_image053
,
Figure 03_image055
,
Figure 03_image057
,
Figure 03_image059
,
Figure 03_image061
,
Figure 03_image063
,
Figure 03_image065
,
Figure 03_image067
,
Figure 03_image069
,
Figure 03_image071
,
Figure 03_image073
,
Figure 03_image075
,
Figure 03_image077
,
Figure 03_image079
,
Figure 03_image081
,
Figure 03_image083
and
Figure 03_image085
. 如請求項1之化合物，其中R 2係選自：
Figure 03_image087
、
Figure 03_image089
、
Figure 03_image091
及
Figure 03_image093
， 其中各自視情況經OH、鹵基、CN、CF 3、C 1-4烷基、C 1-4烷氧基及C 1-3烷基-OH取代。 As the compound of claim 1, wherein R is selected from:
Figure 03_image087
,
Figure 03_image089
,
Figure 03_image091
and
Figure 03_image093
, wherein each is optionally substituted by OH, halo, CN, CF 3 , C 1-4 alkyl, C 1-4 alkoxy and C 1-3 alkyl-OH. 如請求項1之化合物，其中R 2係選自：
Figure 03_image095
、
Figure 03_image097
、
Figure 03_image099
、
Figure 03_image101
、
Figure 03_image103
及
Figure 03_image105
。 As the compound of claim 1, wherein R is selected from:
Figure 03_image095
,
Figure 03_image097
,
Figure 03_image099
,
Figure 03_image101
,
Figure 03_image103
and
Figure 03_image105
. 一種化合物，其選自：
Figure 03_image107
、
Figure 03_image109
、
Figure 03_image111
、
Figure 03_image113
、
Figure 03_image115
、
Figure 03_image117
、
Figure 03_image119
、
Figure 03_image121
、
Figure 03_image123
、
Figure 03_image125
、
Figure 03_image127
、
Figure 03_image129
、
Figure 03_image131
、
Figure 03_image133
、
Figure 03_image135
、
Figure 03_image137
、
Figure 03_image139
、
Figure 03_image141
、
Figure 03_image143
、
Figure 03_image145
、
Figure 03_image147
、
Figure 03_image149
、
Figure 03_image151
、
Figure 03_image153
、
Figure 03_image155
、
Figure 03_image157
、
Figure 03_image159
、
Figure 03_image161
、
Figure 03_image163
、
Figure 03_image165
、
Figure 03_image167
、
Figure 03_image169
、
Figure 03_image171
、
Figure 03_image173
、
Figure 03_image175
、
Figure 03_image177
、
Figure 03_image179
、
Figure 03_image181
、
Figure 03_image183
、
Figure 03_image185
、
Figure 03_image187
、
Figure 03_image189
、
Figure 03_image191
、
Figure 03_image193
、
Figure 03_image195
、
Figure 03_image197
、
Figure 03_image199
、
Figure 03_image201
、
Figure 03_image203
、
Figure 03_image205
、
Figure 03_image207
、
Figure 03_image209
、
Figure 03_image211
、
Figure 03_image213
、
Figure 03_image215
、
Figure 03_image217
、
Figure 03_image219
、
Figure 03_image221
、
Figure 03_image223
、
Figure 03_image225
、
Figure 03_image227
、
Figure 03_image229
、
Figure 03_image231
、
Figure 03_image233
、
Figure 03_image235
、
Figure 03_image237
、
Figure 03_image239
、
Figure 03_image241
、
Figure 03_image243
、
Figure 03_image245
、
Figure 03_image247
、
Figure 03_image249
、
Figure 03_image251
、
Figure 03_image253
、
Figure 03_image255
、
Figure 03_image257
、
Figure 03_image259
、
Figure 03_image261
、
Figure 03_image263
、
Figure 03_image265
、
Figure 03_image267
、
Figure 03_image269
、
Figure 03_image271
、
Figure 03_image273
、
Figure 03_image275
、
Figure 03_image277
、
Figure 03_image279
、
Figure 03_image280
、
Figure 03_image282
、
Figure 03_image284
、
Figure 03_image286
、
Figure 03_image288
、
Figure 03_image290
、
Figure 03_image292
、
Figure 03_image294
、
Figure 03_image296
、
Figure 03_image298
、
Figure 03_image300
、
Figure 03_image302
、
Figure 03_image304
及
Figure 03_image306
； 或其立體異構物、互變異構物、醫藥學上可接受之鹽。 A compound selected from the group consisting of:
Figure 03_image107
,
Figure 03_image109
,
Figure 03_image111
,
Figure 03_image113
,
Figure 03_image115
,
Figure 03_image117
,
Figure 03_image119
,
Figure 03_image121
,
Figure 03_image123
,
Figure 03_image125
,
Figure 03_image127
,
Figure 03_image129
,
Figure 03_image131
,
Figure 03_image133
,
Figure 03_image135
,
Figure 03_image137
,
Figure 03_image139
,
Figure 03_image141
,
Figure 03_image143
,
Figure 03_image145
,
Figure 03_image147
,
Figure 03_image149
,
Figure 03_image151
,
Figure 03_image153
,
Figure 03_image155
,
Figure 03_image157
,
Figure 03_image159
,
Figure 03_image161
,
Figure 03_image163
,
Figure 03_image165
,
Figure 03_image167
,
Figure 03_image169
,
Figure 03_image171
,
Figure 03_image173
,
Figure 03_image175
,
Figure 03_image177
,
Figure 03_image179
,
Figure 03_image181
,
Figure 03_image183
,
Figure 03_image185
,
Figure 03_image187
,
Figure 03_image189
,
Figure 03_image191
,
Figure 03_image193
,
Figure 03_image195
,
Figure 03_image197
,
Figure 03_image199
,
Figure 03_image201
,
Figure 03_image203
,
Figure 03_image205
,
Figure 03_image207
,
Figure 03_image209
,
Figure 03_image211
,
Figure 03_image213
,
Figure 03_image215
,
Figure 03_image217
,
Figure 03_image219
,
Figure 03_image221
,
Figure 03_image223
,
Figure 03_image225
,
Figure 03_image227
,
Figure 03_image229
,
Figure 03_image231
,
Figure 03_image233
,
Figure 03_image235
,
Figure 03_image237
,
Figure 03_image239
,
Figure 03_image241
,
Figure 03_image243
,
Figure 03_image245
,
Figure 03_image247
,
Figure 03_image249
,
Figure 03_image251
,
Figure 03_image253
,
Figure 03_image255
,
Figure 03_image257
,
Figure 03_image259
,
Figure 03_image261
,
Figure 03_image263
,
Figure 03_image265
,
Figure 03_image267
,
Figure 03_image269
,
Figure 03_image271
,
Figure 03_image273
,
Figure 03_image275
,
Figure 03_image277
,
Figure 03_image279
,
Figure 03_image280
,
Figure 03_image282
,
Figure 03_image284
,
Figure 03_image286
,
Figure 03_image288
,
Figure 03_image290
,
Figure 03_image292
,
Figure 03_image294
,
Figure 03_image296
,
Figure 03_image298
,
Figure 03_image300
,
Figure 03_image302
,
Figure 03_image304
and
Figure 03_image306
; or its stereoisomers, tautomers, pharmaceutically acceptable salts. 一種化合物，其選自：
Figure 03_image308
、
Figure 03_image310
、
Figure 03_image312
、
Figure 03_image314
、
Figure 03_image316
、
Figure 03_image318
、
Figure 03_image320
、
Figure 03_image322
、
Figure 03_image324
、
Figure 03_image326
、
Figure 03_image328
及
Figure 03_image330
； 或其立體異構物、互變異構物、醫藥學上可接受之鹽。 A compound selected from the group consisting of:
Figure 03_image308
,
Figure 03_image310
,
Figure 03_image312
,
Figure 03_image314
,
Figure 03_image316
,
Figure 03_image318
,
Figure 03_image320
,
Figure 03_image322
,
Figure 03_image324
,
Figure 03_image326
,
Figure 03_image328
and
Figure 03_image330
; or its stereoisomers, tautomers, pharmaceutically acceptable salts. 一種化合物，其具有以下結構：
Figure 03_image310
，或其立體異構物、互變異構物、醫藥學上可接受之鹽。 A compound having the following structure:
Figure 03_image310
, or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof. 一種醫藥組合物，其包含醫藥學上有效量之如請求項1至15中任一項之化合物或其醫藥學上可接受之鹽，及醫藥學上可接受之賦形劑。A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 如請求項16之醫藥組合物，其進一步包含另一治療劑。The pharmaceutical composition according to claim 16, further comprising another therapeutic agent. 一種治療患有癌症之個體的方法，該癌症之特徵在於存在KRAS G12D突變，該方法包括向該個體投與治療有效量之如請求項1至15中任一項之化合物或其醫藥學上可接受之鹽或其醫藥組合物。A method of treating an individual with cancer characterized by the presence of a KRAS G12D mutation, the method comprising administering to the individual a therapeutically effective amount of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable Acceptable salts or pharmaceutical compositions thereof. 如請求項18之方法，其中該癌症為心臟：肉瘤(血管肉瘤、纖維肉瘤、橫紋肌肉瘤、脂肪肉瘤)、黏液瘤、橫紋肌瘤、纖維瘤、脂肪瘤及畸胎瘤；肺：支氣管癌(鱗狀細胞、未分化小細胞、未分化大細胞、腺癌)、肺泡(細支氣管)癌、支氣管腺瘤、肉瘤、淋巴瘤、軟骨瘤性錯構瘤、間皮瘤；胃腸道：食道(鱗狀細胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃(癌瘤、淋巴瘤、平滑肌肉瘤)、胰臟(導管腺癌、胰島素瘤、胰高血糖素瘤、胃泌素瘤、類癌瘤、vip瘤)、小腸(腺癌、淋巴瘤、類癌瘤、卡波西氏肉瘤(Kaposi's sarcoma)、平滑肌瘤、血管瘤、脂肪瘤、神經纖維瘤、纖維瘤)、大腸(腺癌、管狀腺瘤、絨毛狀腺瘤、錯構瘤、平滑肌瘤)；泌尿生殖道：腎臟(腺癌、威爾姆氏瘤(Wilm's tumor) (腎母細胞瘤)、淋巴瘤、白血病)、膀胱及尿道(鱗狀細胞癌、移行細胞癌、腺癌)、***(腺癌、肉瘤)、睪丸(精原細胞瘤、畸胎瘤、胚胎癌、畸胎癌、絨毛膜癌、肉瘤、間質細胞癌、纖維瘤、纖維腺瘤、腺瘤樣腫瘤、脂肪瘤)；肝臟：肝腫瘤(肝細胞癌)、膽管癌、肝母細胞瘤、血管肉瘤、肝細胞腺瘤、血管瘤；膽道：膽囊癌、壺腹癌、膽管癌；骨：骨原性肉瘤(骨肉瘤)、纖維肉瘤、惡性纖維組織細胞瘤、軟骨肉瘤、尤文氏肉瘤、惡性淋巴瘤(網狀細胞肉瘤)、多發性骨髓瘤、惡性巨細胞瘤脊索瘤、骨軟骨瘤(骨軟骨性外生骨疣)、良性軟骨瘤、軟骨母細胞瘤、軟骨黏液纖維瘤、骨樣骨瘤及巨細胞瘤；神經系統：顱骨(骨瘤、血管瘤、肉芽腫、黃色瘤、變形性骨炎)、腦膜(腦膜瘤、腦膜肉瘤、神經膠瘤病)、腦(星形細胞瘤、髓母細胞瘤、神經膠質瘤、室管膜瘤、生殖細胞瘤(松果體瘤)、多形性神經膠質母細胞瘤、寡樹突神經膠質瘤、神經鞘瘤、視網膜母細胞瘤、先天性腫瘤)、脊髓神經纖維瘤、腦膜瘤、神經膠質瘤、肉瘤)；婦科：子宮(子宮內膜癌(漿液性囊腺癌、黏液性囊腺癌、未分類癌)、粒層細胞-卵囊泡膜細胞瘤、賽特利-萊迪細胞瘤(Sertoli-Leydig cell tumor)、無性細胞瘤、惡性畸胎瘤)、陰門(鱗狀細胞癌、上皮內癌、腺癌、纖維肉瘤、黑色素瘤)、***(透明細胞癌、鱗狀細胞癌、葡萄狀肉瘤(胚胎性橫紋肌肉瘤)、輸卵管(癌瘤)；血液學：血液(骨髓性白血病(急性及慢性)、急性淋巴母細胞性白血病、慢性淋巴球性白血病、骨髓增生性疾病、多發性骨髓瘤、骨髓化生不良症候群)、霍奇金氏病(Hodgkin's disease)、非霍奇金氏淋巴瘤(惡性淋巴瘤)；皮膚：惡性黑色素瘤、基底細胞癌、鱗狀細胞癌、卡波西氏肉瘤、痣發育不良痣、脂肪瘤、血管瘤、皮膚纖維瘤、瘢痕疙瘩、牛皮癬；或腎上腺：神經母細胞瘤。The method of claim 18, wherein the cancer is heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung: bronchial carcinoma (squamous undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor , VIP tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma (Kaposi's sarcoma), leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, Tubular adenoma, villous adenoma, hamartoma, leiomyoma); urogenital tract: kidney (adenocarcinoma, Wilm's tumor (Wilms tumor), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroid, fibroadenoma, adenomatous tumor, lipoma); liver: liver neoplasms (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract Gallbladder carcinoma, ampullary carcinoma, bile duct carcinoma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocyte sarcoma), multiple Myeloma, malignant giant cell tumor chordoma, osteochondroma (osteochondral exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ventricular Angioma, germ cell tumor (pineeal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), neurofibroma of the spinal cord, meninges tumor, glioma, sarcoma); gynecology: uterine (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell-ootheca cell tumor, Sately- Sertoli-Leydig cell tumor, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, Squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tube (carcinoma); hematology: blood (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloid hyperplasia disease, multiple myeloma, myelometaplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous Cell carcinoma, Kaposi's sarcoma, nevus dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis; or adrenal: neuroblastoma. 如請求項18之方法，其中該癌症為非小細胞肺癌、小細胞肺癌、結直腸癌、直腸癌或胰臟癌。The method according to claim 18, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. 一種如請求項1至15中任一項之化合物或其醫藥學上可接受之鹽或其醫藥組合物的用途，其用於製造供治療個體之癌症用之藥物，該癌症之特徵在於存在KRAS G12D突變。Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for treating a cancer in an individual characterized by the presence of KRAS G12D mutation. 如請求項21之用途，其中該癌症為心臟：肉瘤(血管肉瘤、纖維肉瘤、橫紋肌肉瘤、脂肪肉瘤)、黏液瘤、橫紋肌瘤、纖維瘤、脂肪瘤及畸胎瘤；肺：支氣管癌(鱗狀細胞、未分化小細胞、未分化大細胞、腺癌)、肺泡(細支氣管)癌、支氣管腺瘤、肉瘤、淋巴瘤、軟骨瘤性錯構瘤、間皮瘤；胃腸道：食道(鱗狀細胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃(癌瘤、淋巴瘤、平滑肌肉瘤)、胰臟(導管腺癌、胰島素瘤、胰高血糖素瘤、胃泌素瘤、類癌瘤、vip瘤)、小腸(腺癌、淋巴瘤、類癌瘤、卡波西氏肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神經纖維瘤、纖維瘤)、大腸(腺癌、管狀腺瘤、絨毛狀腺瘤、錯構瘤、平滑肌瘤)；泌尿生殖道：腎臟(腺癌、威爾姆氏瘤(腎母細胞瘤)、淋巴瘤、白血病)、膀胱及尿道(鱗狀細胞癌、移行細胞癌、腺癌)、***(腺癌、肉瘤)、睪丸(精原細胞瘤、畸胎瘤、胚胎癌、畸胎癌、絨毛膜癌、肉瘤、間質細胞癌、纖維瘤、纖維腺瘤、腺瘤樣腫瘤、脂肪瘤)；肝臟：肝腫瘤(肝細胞癌)、膽管癌、肝母細胞瘤、血管肉瘤、肝細胞腺瘤、血管瘤；膽道：膽囊癌、壺腹癌、膽管癌；骨：骨原性肉瘤(骨肉瘤)、纖維肉瘤、惡性纖維組織細胞瘤、軟骨肉瘤、尤文氏肉瘤、惡性淋巴瘤(網狀細胞肉瘤)、多發性骨髓瘤、惡性巨細胞瘤脊索瘤、骨軟骨瘤(骨軟骨性外生骨疣)、良性軟骨瘤、軟骨母細胞瘤、軟骨黏液纖維瘤、骨樣骨瘤及巨細胞瘤；神經系統：顱骨(骨瘤、血管瘤、肉芽腫、黃色瘤、變形性骨炎)、腦膜(腦膜瘤、腦膜肉瘤、神經膠瘤病)、腦(星形細胞瘤、髓母細胞瘤、神經膠質瘤、室管膜瘤、生殖細胞瘤(松果體瘤)、多形性神經膠質母細胞瘤、寡樹突神經膠質瘤、神經鞘瘤、視網膜母細胞瘤、先天性腫瘤)、脊髓神經纖維瘤、腦膜瘤、神經膠質瘤、肉瘤)；婦科：子宮(子宮內膜癌(漿液性囊腺癌、黏液性囊腺癌、未分類癌)、粒層細胞-卵囊泡膜細胞瘤、賽特利-萊迪細胞瘤、無性細胞瘤、惡性畸胎瘤)、陰門(鱗狀細胞癌、上皮內癌、腺癌、纖維肉瘤、黑色素瘤)、***(透明細胞癌、鱗狀細胞癌、葡萄狀肉瘤(胚胎性橫紋肌肉瘤)、輸卵管(癌瘤)；血液學：血液(骨髓性白血病(急性及慢性)、急性淋巴母細胞性白血病、慢性淋巴球性白血病、骨髓增生性疾病、多發性骨髓瘤、骨髓化生不良症候群)、霍奇金氏病、非霍奇金氏淋巴瘤(惡性淋巴瘤)；皮膚：惡性黑色素瘤、基底細胞癌、鱗狀細胞癌、卡波西氏肉瘤、痣發育不良痣、脂肪瘤、血管瘤、皮膚纖維瘤、瘢痕疙瘩、牛皮癬；或腎上腺：神經母細胞瘤。Such as the purposes of claim 21, wherein the cancer is heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyosarcoma, fibroma, lipoma and teratoma; lung: bronchial carcinoma (squamous undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiole) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; gastrointestinal tract: esophagus (squamous carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor , VIP tumor), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large intestine (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (Wilms tumor), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, Transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroma tumor, adenomatous tumor, lipoma); liver: liver tumor (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; biliary tract: gallbladder carcinoma, ampullary carcinoma, Cholangiocarcinoma; bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulocyte sarcoma), multiple myeloma, malignant giant cell tumor notochord tumor, osteochondroma (osteochondral exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, and giant cell tumor; nervous system: skull (osteoma, hemangioma, granulation tumor, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor ( pineal tumor), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumor), neurofibroma of the spinal cord, meningioma, glioma, sarcoma) ; Gynecology: Uterine (endometrial carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa cell-ootheca cell tumor, Sately-Leddy cell tumor, asexual cell tumor malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonic rhabdomyosarcoma), fallopian tube (carcinoma); hematology: blood (myelogenous leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelometaplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, nevus dysplastic nevus, lipoma, hemangioma , dermatofibroma, keloid, psoriasis; or adrenal: neuroblastoma. 如請求項21之方法，其中該癌症為非小細胞肺癌、小細胞肺癌、結直腸癌、直腸癌或胰臟癌。The method according to claim 21, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.
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