TW201605857A

TW201605857A - Therapeutic inhibitors of CDK8 and uses thereof

Info

Publication number: TW201605857A
Application number: TW103134458A
Authority: TW
Inventors: 飛利浦伯格倫; 麥可克勒
Original assignee: 赫孚孟拉羅股份公司
Priority date: 2013-10-03
Filing date: 2014-10-02
Publication date: 2016-02-16
Also published as: AR097894A1; WO2015049325A1

Abstract

The present invention relates to compounds formula (I): and to salts thereof, wherein R1-R4 have any of he values defined in the specification, and compositions and uses thereof. The compounds are useful as inhibitors of CDK8. Also included are pharmaceutically acceptable compositions comprising the compounds of the present invention and methods of using said compositions in the treatment of various disorders.

Description

CDK8之醫療性抑制劑及其用途 Medical inhibitor of CDK8 and its use

本發明係關於適用作CDK8抑制劑之化合物。 This invention relates to compounds useful as CDK8 inhibitors.

CDK8為介體複合物的組分²。介體複合物藉由偶合序列特異性轉錄因子與轉錄機構在轉錄中起重要作用。CDK8與細胞週期素C、MED12及MED13一起形成該複合物的CDK8模組。其可將RNA聚合酶II之C末端結構域、組蛋白H3之絲胺酸10及Smad1³之絲胺酸206以及許多其他受質磷酸化。其調節轉錄路徑，包括β-索烴素、Notch、p53、血清反應因子及SMAD。其亦藉由使E2F1磷酸化且藉此逆轉其對β-索烴素活性之抑制而間接作用於β-索烴素^4,5。 CDK8 is component ² of the mediator complex. The mediator complex plays an important role in transcription by coupling sequence-specific transcription factors with transcriptional machinery. CDK8, together with cyclin C, MED12 and MED13, forms a CDK8 module of the complex. It phosphorylates the C-terminal domain of RNA polymerase II, the serine 10 of histone H3, and the serine acid 206 of Smadl ³ as well as many other receptors. It regulates the transcriptional pathway, including beta-soda, Notch, p53, serum response factors, and SMAD. It also acts indirectly on β- ^{sodamer 4,5} by phosphorylating E2F1 and thereby reversing its inhibition of β-sodacin activity.

CDK8為致癌基因^6,7。其在結腸癌中得以擴增且得以過度表現。另外，其能夠轉型NIH3T3細胞，如喪失接觸抑制、固著非依賴性生長及體內腫瘤生長所證明。值得注意的是，轉型在激酶死亡型CDK8的情況下不會發生，因此，其看似依賴於激酶活性。複本數增加之細胞株之CDK8阻斷基因表現將抑制細胞增殖。另外，在具有可誘導CDK8阻斷基因表現之鼠類異種移植模型中觀測到腫瘤生長抑制⁸。結腸癌中之CDK8介導之抑制的一種提議機制為下調CDK8含量較高之癌症中之β-索烴素路徑。然而，阻斷基因表現結果未使得能夠辨別CDK8之骨架及激酶功能之重要性。 CDK8 is an oncogene ^6,7 . It is amplified in colon cancer and is overexpressed. In addition, it is capable of transforming NIH3T3 cells as evidenced by loss of contact inhibition, fixation-independent growth, and tumor growth in vivo. It is worth noting that the transformation does not occur in the case of kinase-death CDK8 and, therefore, it appears to be dependent on kinase activity. The CDK8 blocking gene expression of a cell line with an increased number of copies will inhibit cell proliferation. Further, inhibition of tumor growth was observed in a murine xenograft model ⁸ having inducible expression of genes in block CDK8. One proposed mechanism for CDK8 mediated inhibition in colon cancer is to down-regulate the beta-sucrose pathway in cancers with higher CDK8 levels. However, blocking gene expression results in the ability to discern the backbone of CDK8 and the importance of kinase function.

CDK8及其搭配物細胞週期素C在人類癌症中失調⁹。對人類結腸腫瘤樣品之回顧性分析顯示，CDK8之表現與β-索烴素活化及不良預後有關^10,11。亦發現CDK8誘導富集於分化不良之結腸腫瘤中之胚胎幹細胞標籤且與不良預後有關⁸。其他細胞株、鼠類異種移植及人類腫瘤組織研究亦將CDK8與黑素瘤相關聯¹³。此研究所依據之治療性假設為CDK8之小分子抑制劑將抑制展現CDK8擴增及/或過度表現之腫瘤子集生長。可能之適應症包括結腸癌及黑素瘤。 CDK8 and its agonist cyclin C are dysregulated in human cancers ⁹ . Retrospective analysis of human colon tumor samples showed that CDK8 performance was associated with beta-sodium hydroxyl activation and poor prognosis ^10,11 . CDK8 also found to induce undesirable enrichment of the differentiated colon tumors of embryonic stem cells and is associated with poor prognosis tag ^8. Other cell lines, murine xenografts, and human tumor tissue studies have also linked CDK8 to melanoma ¹³ . The therapeutic hypothesis based on this study is that small molecule inhibitors of CDK8 will inhibit tumor subset growth that exhibits CDK8 expansion and/or overexpression. Possible indications include colon cancer and melanoma.

當前需要可抑制CDK8以便治療過度增殖性疾病的化合物。 There is a current need for compounds that inhibit CDK8 in the treatment of hyperproliferative diseases.

一個態樣包括式(I)化合物：或其鹽，其中：R¹係選自：且其中R¹係獨立地視情況經1、2或3個R^x基團取代；R²及R³獨立地為H、C_1-12烷基、C_2-12烯基、C_2-12炔基、碳環基、芳基、雜芳基、雜環基、鹵基、-OR^a、-SR^a、-N(R^a)₂、-CN、-NO₂、-C(O)R^a、-CO₂R^a、-C(O)N(R^a)₂、-C(O)SR^a、-C(O)C(O)R^a、-C(O)CH₂C(O)R^a、-C(S)N(R^a)₂、-C(S)OR^a、-S(O)R^a、-SO₂R^a、-SO₂N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)C(O)N(R^a)₂、-N(R^a)SO₂R^a、-N(R^a)SO₂N(R^a)₂、-N(R^a)N(R^a)₂、-N(R^a)C(=N(R^a))N(R^a)₂、-C(=N)N(R^a)₂、-C=NOR^a、-C(=N(R^a))N(R^a)₂、-OC(O)R^a或- OC(O)N(R^a)₂，其中R²及R³之各C_1-12烷基、C_2-12烯基、C_2-12炔基、碳環基、芳基、雜芳基及雜環基係各自獨立地視情況經一或多個基團R^x取代；或R¹及R²與其所連接之原子一起形成4、5、6、7或8員碳環基、雜環基、雜芳基或芳基，該碳環基、雜環基、雜芳基及芳基視情況經一或多個基團R^x取代；各R^a及R^b獨立地為H、C_1-6烷基、C_2-6烯基、C_2-6炔基、碳環基、芳基、雜芳基或雜環基，其中各C_1-6烷基、C_3-6烯基、C_3-6炔基、碳環基、芳基、雜芳基及雜環基係獨立地視情況經一或多個基團R^x取代；或R^a及R^b與其所連接之氮一起形成3-6員雜環，該雜環視情況經側氧基、鹵基或視情況經側氧基或鹵基取代之C_1-6烷基取代；各R^v獨立地為氫、C_1-6烷基、C_2-6烯基、C_2-6炔基、碳環基、芳基、雜芳基或雜環基，其中各C_1-6烷基、C_2-6烯基、C_2-6炔基、碳環基、芳基、雜芳基及雜環基視情況經一或多個基團取代，該一或多個基團係獨立地選自側氧基、鹵基、胺基、羥基及視情況經一或多個獨立地選自側氧基及鹵基之基團取代之C₁-C₆烷基；或兩個R^v與其所連接之氮一起形成3-6員雜環基，該雜環基視情況經一或多個基團取代，該一或多個基團係獨立地選自側氧基、鹵基及視情況經一或多個獨立地選自側氧基及鹵基之基團取代之C_1-3烷基；且各R^x獨立地為側氧基、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6鹵烷基、碳環基、芳基、雜芳基、雜環基、-F、-Cl、-Br、-I、-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-O-C(O)-N(R^v)₂、-N(R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^v、-N(R^v)-S(O)-N(R^v)₂或-N(R^v)-S(O)₂-N(R^v)₂，其中任何C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6鹵烷基、碳環基、芳基、雜芳基及雜環基係獨立地視情況經一或多個基團取代，該一或多個基團係選自側氧基、鹵基、-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^v及視情況經一或多個獨立地選自側氧基及鹵基之基團取代之C_1-6烷基；且其中當R²為F且R³為氫時，則R^x不為甲基、乙基、三氟甲基或2-氟苯基。 One aspect includes a compound of formula (I): Or a salt thereof, wherein: R ¹ is selected from the group consisting of: And wherein R ¹ is independently substituted by 1, 2 or 3 R ^x groups; R ² and R ^{3 are} independently H, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 Alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, halo, -OR ^a , -SR ^a , -N(R ^a ) ₂ , -CN, -NO ₂ , -C(O)R ^a , -CO ₂ R ^a , -C(O)N(R ^a ) ₂ , -C(O)SR ^a , -C(O)C(O)R ^a , -C(O)CH ₂ C(O R ^a , -C(S)N(R ^a ) ₂ , -C(S)OR ^a , -S(O)R ^a , -SO ₂ R ^a , -SO ₂ N(R ^a ) ₂ , -N (R ^a )C(O)R ^a , -N(R ^a )C(O)N(R ^a ) ₂ , -N(R ^a )SO ₂ R ^a , -N(R ^a )SO ₂ N(R ^a ) ₂ , -N(R ^a )N(R ^a ) ₂ , -N(R ^a )C(=N(R ^a ))N(R ^a ) ₂ , -C(=N)N(R ^a ) ₂ , -C=NOR ^a , -C(=N(R ^a ))N(R ^a ) ₂ , -OC(O)R ^a or - OC(O)N(R ^a ) ₂ , wherein R ² and R ³ of each of C _1-12 alkyl, C _2-12 alkenyl group, C _2-12 alkynyl, carbocyclyl, aryl, heteroaryl and heterocyclyl groups are each independently system optionally substituted with one or more groups a group R ^x substituted; or R ¹ and R ² together with the atom to which they are attached form a 4, 5, 6, 7 or 8 membered carbocyclyl, heterocyclyl, heteroaryl or aryl group, which is a heterocyclic or heterocyclic ring. group, aryl group and heteroaryl group optionally substituted with one or more radicals R ^x taken ; Each R ^a and R ^b are independently H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl, wherein each C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, carbocyclyl, aryl, heteroaryl and heterocyclic are independently substituted by one or more groups R ^x as appropriate ; or R ^a and R ^b form a 3-6 membered heterocyclic ring together with the nitrogen to which they are attached, which heteroaryl ring optionally substituted with oxo or halo by oxo, halo or C _1-6 alkyl optionally of Substituted; each R ^{v is} independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl, wherein each C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl, aryl, heteroaryl and heterocyclyl group optionally substituted with one or more groups, one or more of the group The group is independently selected from the group consisting of a pendant oxy group, a halogen group, an amine group, a hydroxyl group, and optionally a C ₁ -C ₆ alkyl group substituted with one or more groups independently selected from the pendant oxy group and a halogen group; or two forming a R ^v together with the nitrogen to which they are attached 3-6 membered heterocyclic group, the heterocyclic group optionally substituted by one or more groups, the one or more groups independently selected from side-based oxygen , Halo and optionally substituted with one or more of the substituents independently selected from halo and oxo group of the C _1-3 alkyl group; and each R ^x is independently oxo, C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, -F, -Cl, -Br, -I, -NO ₂ , -N(R ^v ) ₂ , -CN, -C(O)-N(R ^v ) ₂ , -S(O)-N(R ^v ) ₂ , -S(O) ₂ -N( R ^v ) ₂ , -OR ^v , -SR ^v , -OC(O)-R ^v , -OC(O)-OR ^v , -C(O)-R ^v , -C(O)-OR ^v ,- S(O)-R ^v , -S(O) ₂ -R ^v , -OC(O)-N(R ^v ) ₂ , -N(R ^v )-C(O)-OR ^v , -N(R ^v )-C(O)-N(R ^v ) ₂ , -S(O) ₂ -N(R ^v ) ₂ , -N(R ^v )-C(O)-R ^v , -N(R ^v ) -S(O)-R ^v , -N(R ^v )-S(O) ₂ -R ^v , -N(R ^v )-S(O)-N(R ^v ) ₂ or -N(R ^v ) -S(O) ₂ -N(R ^v ) ₂ , wherein any C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 haloalkyl group, carbocyclic group, aromatic The base, heteroaryl and heterocyclic groups are, independently, optionally substituted by one or more groups selected from the group consisting of pendant oxy, halo, -NO ₂ , -N(R ^v ) ₂ , -CN, -C(O)-N(R ^v ) ₂ , -S(O)-N(R ^v ) ₂ , -S(O) ₂ -N(R ^v ) ₂ , -OR ^v ,- SR ^v , -OC(O)-R ^v , -C(O)-R ^v , -C(O)-OR ^v , -S(O)-R ^v , -S(O) ₂ -R ^v , -C(O)-N(R ^v ) ₂ , -S(O) ₂ -N(R ^v ) ₂ , -N(R ^v )-C(O)-R ^v , -N(R ^v )-S(O)-R ^v , -N(R ^v And -S(O) ₂ -R ^v and, optionally, a C _1-6 alkyl group substituted with one or more groups independently selected from the group consisting of pendant and halogen; and wherein when R ² is F and R ³ In the case of hydrogen, R ^{x is} not methyl, ethyl, trifluoromethyl or 2-fluorophenyl.

另一態樣包括一種醫藥組合物，其包含式(I)化合物或其醫藥學上可接受之鹽及醫藥學上可接受之佐劑、載劑或媒劑。 Another aspect includes a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier or vehicle.

另一態樣包括一種治療與CDK8活性相關之疾病的方法，其包含向有需要之患者投與治療有效量之式(I)化合物或其醫藥學上可接受之鹽。 Another aspect includes a method of treating a condition associated with CDK8 activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

另一態樣包括式(I)化合物或其醫藥學上可接受之鹽之用途，其係用於治療。另一態樣包括式(I)化合物或其醫藥學上可接受之鹽之用途，其係用於治療過度增殖性病症(在一個實例中為癌症)。 Another aspect includes the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. Another aspect includes the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of a hyperproliferative disorder (in one example, cancer).

另一態樣包括式(I)化合物或其醫藥學上可接受之鹽的用途，其係用於製造可治療與CDK8活性相關之疾病的藥物。 Another aspect includes the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease associated with CDK8 activity.

另一態樣包括用於研究諸如CDK8之激酶、研究由該CDK8介導之細胞內信號轉導路徑及比較性評估CDK8調節劑之化合物。 Another aspect includes compounds for studying kinases such as CDK8, studying intracellular signal transduction pathways mediated by the CDK8, and comparatively evaluating CDK8 modulators.

另一態樣包括一種製備式I化合物或其鹽之方法。 Another aspect includes a method of preparing a compound of Formula I or a salt thereof.

化合物及定義Compounds and definitions

以下更詳細地描述定義及術語。根據Periodic Table of the Elements,CAS版本，Handbook of Chemistry and Physics，第75版鑑別化學元素。 Definitions and terms are described in more detail below. The chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics , 75th edition.

除非另外說明，否則式(I)化合物包括指定結構之對映異構、非對映異構及幾何(或構形)異構形式。舉例而言，包括針對各不對稱中心之R及S構形、Z及E雙鍵異構體、Z及E構形異構體、單一立體化學異構體以及對映異構、非對映異構及幾何(或構形)混合物。除非另外說明，否則包括本文中所描繪之結構的所有互變異構形式。另外，除非另外說明，否則本文所述之結構亦意欲包括僅在一或多個同位素富集原子之存在方面不同之化合物。舉例而言，包括式I化合物，其中進行以下獨立置換或富集中的一或多種：以氘或氚置換或富集氫、以¹³C或¹⁴C碳置換或富集碳、以¹⁵N氮置換或富集氮、以³³S、³⁴S或³⁶S硫置換或富集硫、或以¹⁷O或¹⁸O氧置換或富集氧。該等化合物適用作例如分析工具、生物檢定中之探針或治療劑。 Unless otherwise stated, a compound of formula (I) includes the enantiomeric, diastereomeric, and geometric (or conformational) isomeric forms of the specified structure. For example, including R and S configurations for each asymmetric center, Z and E double bond isomers, Z and E configuration isomers, single stereochemical isomers, and enantiomeric, diastereomeric Heterogeneous and geometric (or conformational) mixtures. All tautomeric forms of the structures depicted herein are included unless otherwise stated. Additionally, unless otherwise stated, structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. By way of example, include a compound of formula I wherein one or more of the following independent substitutions or enrichment are carried out: replacement or enrichment of hydrogen with hydrazine or hydrazine, replacement or enrichment of carbon with ¹³ C or ¹⁴ C carbon, replacement with ¹⁵ N nitrogen Or enrichment of nitrogen, displacement or enrichment of sulfur with ³³ S, ³⁴ S or ³⁶ S sulfur, or replacement or enrichment of oxygen with ¹⁷ O or ¹⁸ O oxygen. Such compounds are useful, for example, as analytical tools, probes in biological assays, or therapeutic agents.

在描述特定對映異構體之情況下，在某些實施方案中，可提供實質上不含相應對映異構體之對映異構體，且亦可稱為「經光學富集」。如本文中所使用之「經光學富集」意謂由顯著較大比例之一種對映異構體組成且可由對映異構過量(ee%)加以描述之對映異構體混合物。在某些實施例中，對映異構體混合物由至少約90重量%指定對映異構體組成(約90% ee)。在其他實施例中，對映異構體混合物由至少約95重量%、98重量%或99重量%指定對映異構體組成(約95%、98%或99% ee)。可藉由熟習此項技術者已知的任何方法自外消旋混合物中分離對映異構體及非對映異構體，包括自溶劑中再結晶(其中一種立體異構體之溶解度大於另一種)、對掌性高壓液相層析法(HPLC)、超臨界流體層析法(SFC)、形成對掌性鹽及使其結晶，隨後藉由上述方法中之任一種加以分離或藉由不對稱合成且視情況進一步富集來製備。參見例如Jacques等人，Enantiomers,Racemates and Resolutions(Wiley Interscience,New York,1981)；Wilen等人，Tetrahedron 33：2725(1977)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions第268頁(E.L.Eliel編，Univ.of Notre Dame Press,Notre Dame,IN 1972)。 Where a particular enantiomer is described, in certain embodiments, an enantiomer that is substantially free of the corresponding enantiomer may be provided and may also be referred to as "optically enriched." As used herein, "optically enriched" means a mixture of enantiomers consisting of a significantly larger proportion of one enantiomer and which may be described by enantiomeric excess (ee%). In certain embodiments, the enantiomeric mixture consists of at least about 90% by weight of the designated enantiomer (about 90% ee). In other embodiments, the enantiomeric mixture consists of at least about 95%, 98%, or 99% by weight of the designated enantiomer (about 95%, 98%, or 99% ee). The enantiomers and diastereomers can be separated from the racemic mixture by any method known to those skilled in the art, including recrystallization from a solvent (wherein one stereoisomer has a solubility greater than the other a method of high pressure liquid chromatography (HPLC), supercritical fluid chromatography (SFC), formation of a palmitic salt and crystallization thereof, followed by separation by or by any of the above methods Asymmetric synthesis and further enrichment as appropriate. See, for example, Jacques et al, Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al, Tetrahedron 33: 2725 (1977); Eliel, EL Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, SH Tables of Resolving Agents and Optical Resolutions, p. 268 (edited by ELEliel, Univ. of Notre Dame Press, Notre Dame, IN 1972).

術語「雜原子」意謂獨立地選自除碳或氫以外之原子的任何原子，例如氧、硫、氮、磷或矽中之一或多者(包括氮、硫、磷或矽之任何氧化形式；及任何氮之四級銨化形式)。 The term "heteroatom" means any atom independently selected from an atom other than carbon or hydrogen, such as one or more of oxygen, sulfur, nitrogen, phosphorus or antimony (including any oxidation of nitrogen, sulfur, phosphorus or antimony). Form; and any quaternary ammonium form of nitrogen).

如本文中所使用之術語「鹵基」及「鹵素」係指選自氟(氟基，-F)、氯(氯基，-Cl)、溴(溴基，-Br)及碘(碘基，-I)的原子。鹵基之特定實例為氟基及氯基。 The terms "halo" and "halogen" as used herein mean selected from fluoro (fluoro, -F), chloro (chloro, -Cl), bromo (bromo, -Br) and iodine (iodo). , the atom of -I). Specific examples of the halogen group are a fluorine group and a chlorine group.

如本文中所使用之術語「不飽和」意謂部分具有一個或多個不飽和單元。 The term "unsaturated" as used herein means that the moiety has one or more units of unsaturation.

單獨或作為更大部分之一部分使用之術語「碳環基」係指具有3至20個碳原子之飽和、部分不飽和或芳族環系統。在一個實施例中，碳環基包括3至12個碳原子(C₃-C₁₂)。在另一實施例中，碳環基包括C₃-C₈、C₃-C₁₀或C₅-C₁₀。在其他實施例中，呈單環形式之碳環基包括C₃-C₈、C₃-C₆或C₅-C₆。在另一實施例中，呈雙環形式之碳環基包括C₇-C₁₂。在另一實施例中，呈螺環系統形式之碳環基包括C₅-C₁₂。單環碳環基之實例包括環丙基、環丁基、環戊基、1-環戊-1-烯基、1-環戊-2-烯基、1-環戊-3-烯基、環己基、氘代環己基、1-環己-1-烯基、1-環己-2-烯基、1-環己-3-烯基、環己二烯基、環庚基、環辛基、環壬基、環癸基、環十一烷基、苯基及環十二烷基；具有7至12個環原子之雙環碳環基包括[4,3]、[4,4]、[4,5]、[5,5]、[5,6]或[6,6]環狀系統，例如雙環[2.2.1]庚烷、雙環[2.2.2]辛烷、萘及雙環[3.2.2]壬烷；且螺碳環基包括螺[2.2]戊烷、螺[2.3]己烷、螺[2.4]庚烷、螺[2.5]辛烷及螺[4.5]癸烷，各碳環基獨立地視情況經一或多個本文中所描述之基團取代。術語碳環基包括如本文中所定義之芳基環系統。 The term "carbocyclyl" used alone or as part of a larger moiety refers to a saturated, partially unsaturated or aromatic ring system having from 3 to 20 carbon atoms. In one embodiment, a carbocyclic group comprises from 3 to 12 carbon atoms (C ₃ -C _12). In another embodiment, the carbocyclic group comprises C ₃ -C ₈ , C ₃ -C ₁₀ or C ₅ -C ₁₀ . In other embodiments, as a form of monocyclic carbocyclic groups include _{_{_{C 3 -C 8, C 3 -C}}} 6 or C ₅ -C _6. In another embodiment, the carbocyclic group in the form of a bicyclic ring comprises C ₇ -C ₁₂ . In another embodiment, the form of the spiro ring system carbocyclic groups include C ₅ -C _12. Examples of the monocyclic carbocyclic group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a 1-cyclopent-1-enyl group, a 1-cyclopent-2-enyl group, a 1-cyclopent-3-enyl group, Cyclohexyl, deuterated cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl , cyclodecyl, cyclodecyl, cyclodecyl, phenyl and cyclododecyl; bicyclic carbocyclyl having 7 to 12 ring atoms including [4,3], [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems, such as bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, naphthalene and bicyclo [ 3.2.2] decane; and the spiro carbocyclic group includes spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane, each carbon The ring group is independently substituted with one or more of the groups described herein, as appropriate. The term carbocyclyl includes an aryl ring system as defined herein.

如本文中所使用之術語「烷基」係指飽和直鏈或分支鏈單價烴基。在一個實施例中，烷基為1至18個碳原子(C₁-C₁₈)。在其他實施例中，烷基為C₀-C₆、C₀-C₅、C₀-C₃、C₁-C₁₂、C₁-C_10、C₁-C₈、C₁-C₆、C₁-C₅、C₁-C₄或C₁-C₃。C₀烷基係指鍵。烷基之實例包括甲基(Me、-CH₃)、乙基(Et、-CH₂CH₃)、1-丙基(n-Pr、正-丙基、-CH₂CH₂CH₃)、2-丙基(i-Pr、異丙基、-CH(CH₃)₂)、1-丁基(n-Bu、正丁基、-CH₂CH₂CH₂CH₃)、2-甲基-1-丙基(i-Bu、異丁基、-CH₂CH(CH₃)₂)、2-丁基(s-Bu、s-丁基、-CH(CH₃)CH₂CH₃)、2-甲基-2-丙基(t-Bu、t-丁基、-C(CH₃)₃)、1-戊基(正戊基、-CH₂CH₂CH₂CH₂CH₃)、2-戊基(-CH(CH₃)CH₂CH₂CH₃)、3-戊基(-CH(CH₂CH₃)₂)、2-甲基-2-丁基(-C(CH₃)₂CH₂CH₃)、3-甲基-2-丁基(-CH(CH₃)CH(CH₃)₂)、3-甲基-1-丁基(-CH₂CH₂CH(CH₃)₂)、2-甲基-1-丁基(-CH₂CH(CH₃)CH₂CH₃)、1-己基(-CH₂CH₂CH₂CH₂CH₂CH₃)、2-己基(-CH(CH₃)CH₂CH₂CH₂CH₃)、3-己基(-CH(CH₂CH₃)(CH₂CH₂CH₃))、2-甲基-2-戊基(-C(CH₃)₂CH₂CH₂CH₃)、3-甲基-2-戊基(-CH(CH₃)CH(CH₃)CH₂CH₃)、4-甲基-2-戊基(-CH(CH₃)CH₂CH(CH₃)₂)、3-甲基-3-戊基(-C(CH₃)(CH₂CH₃)₂)、2-甲基-3-戊基(-CH(CH₂CH₃)CH(CH₃)₂)、2,3-二甲基-2-丁基(-C(CH₃)₂CH(CH₃)₂)、3,3-二甲基-2-丁基(-CH(CH₃)C(CH₃)₃)、庚基、辛基、壬基、癸基、十一烷基及十二烷基。C_1-12烷基之特定實例為C_1-6烷基。C_1-6烷基之特定實例為甲基及乙基。 The term "alkyl" as used herein refers to a saturated straight or branched chain monovalent hydrocarbon group. In one embodiment, an alkyl group of 1 to 18 carbon atoms (C ₁ -C _18). In other embodiments, the alkyl group is C ₀ -C ₆ , C ₀ -C ₅ , C ₀ -C ₃ , C ₁ -C ₁₂ , C ₁ -C _{10 ,} C ₁ -C ₈ , C ₁ -C ₆ , C ₁ -C ₅ , C ₁ -C ₄ or C ₁ -C ₃ . C ₀ alkyl means a bond. Examples of the alkyl group include a methyl group (Me, -CH ₃ ), an ethyl group (Et, -CH ₂ CH ₃ ), a 1-propyl group (n-Pr, n-propyl group, -CH ₂ CH ₂ CH ₃ ), 2-propyl (i-Pr, isopropyl, -CH(CH ₃ ) ₂ ), 1-butyl (n-Bu, n-butyl, -CH ₂ CH ₂ CH ₂ CH ₃ ), 2-methyl 1-propyl (i-Bu, isobutyl, -CH ₂ CH(CH ₃ ) ₂ ), 2-butyl (s-Bu, s-butyl, -CH(CH ₃ )CH ₂ CH ₃ ) , 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH ₃ ) ₃ ), 1-pentyl (n-pentyl, -CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ) , 2-pentyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₃ ), 3-pentyl (-CH(CH ₂ CH ₃ ) ₂ ), 2-methyl-2-butyl (-C(CH) ₃ ) ₂ CH ₂ CH ₃ ), 3-methyl-2-butyl (-CH(CH ₃ )CH(CH ₃ ) ₂ ), 3-methyl-1-butyl (-CH ₂ CH ₂ CH ( CH ₃ ) ₂ ), 2-methyl-1-butyl (-CH ₂ CH(CH ₃ )CH ₂ CH ₃ ), 1-hexyl (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₃ ), 2 -hexyl (-CH(CH ₃ )CH ₂ CH ₂ CH ₂ CH ₃ ), 3-hexyl (-CH(CH ₂ CH ₃ )(CH ₂ CH ₂ CH ₃ )), 2-methyl-2-pentyl (-C(CH ₃ ) ₂ CH ₂ CH ₂ CH ₃ ), 3-methyl-2-pentyl (-CH(CH ₃ )CH(CH ₃ )CH ₂ CH ₃ ), 4-methyl-2- Pentyl (-CH(CH ₃ )CH ₂ CH(CH ₃ ) ₂ ), 3-methyl-3-pentyl (-C(CH ₃ )(CH ₂ CH ₃ ) ₂ ), 2-methyl-3-pentyl (-CH(CH ₂ CH ₃ )CH(CH ₃ ) ₂ ), 2,3-dimethyl-2-butyl (-C(CH ₃ ) ₂ CH (CH ₃ ) ₂ ), 3,3-dimethyl-2-butyl (-CH(CH ₃ )C(CH ₃ ) ₃ ), heptyl, octyl, decyl, decyl, undecyl And dodecyl. A specific example of a C _1-12 alkyl group is a C _1-6 alkyl group. Specific examples of the C _1-6 alkyl group are a methyl group and an ethyl group.

如本文中所使用之術語「烯基」表示具有至少一個雙鍵之直鏈或分支鏈單價烴基。烯基包括具有「順式」及「反式」定向或者「E」及「Z」定向之基團。在一個實例中，烯基為2至18個碳原子(C₂-C₁₈)。在其他實例中，烯基為C₂-C₁₂、C₂-C₁₀、C₂-C₈、C₂-C₆或C₂- C₃。實例包括(但不限於)乙烯基(ethenyl或vinyl)(-CH=CH₂)、丙-1-烯基(-CH=CHCH₃)、丙-2-烯基(-CH₂CH=CH₂)、2-甲基丙-1-烯基、丁-1-烯基、丁-2-烯基、丁-3-烯基、丁-1,3-二烯基、2-甲基丁-1,3-二烯、己-1-烯基、己-2-烯基、己-3-烯基、己-4-烯基及己-1,3-二烯基。 The term "alkenyl" as used herein denotes a straight or branched chain monovalent hydrocarbon radical having at least one double bond. Alkenyl groups include groups having "cis" and "trans" orientations or "E" and "Z" orientations. In one example, the alkenyl group is 2 to 18 carbon atoms (C ₂ -C ₁₈ ). In other examples, the alkenyl group is C ₂ -C ₁₂ , C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ or C ₂ -C ₃ . Examples include, but are not limited to, ethenyl or vinyl (-CH=CH ₂ ), prop-1-enyl (-CH=CHCH ₃ ), prop-2-enyl (-CH ₂ CH=CH ₂ ), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, butane-1,3-dienyl, 2-methylbutyl- 1,3-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl and hexa-1,3-dienyl.

如本文中所使用之術語「炔基」係指具有至少一個碳-碳三鍵之直鏈或分支鏈單價烴基。在一個實例中，炔基為2至18個碳原子(C₂-C₁₈)。在其他實例中，炔基為C₂-C₁₂、C₂-C₁₀、C₂-C₈、C₂-C₆或C₂-C₃。實例包括(但不限於)乙炔基(-C≡CH)、丙-1-炔基(-C≡CCH₃)、丙-2-炔基(炔丙基，-CH₂C≡CH)、丁-1-炔基、丁-2-炔基及丁-3-炔基。 The term "alkynyl" as used herein refers to a straight or branched chain monovalent hydrocarbon radical having at least one carbon-carbon triple bond. In one example, the alkynyl group is 2 to 18 carbon atoms (C ₂ -C ₁₈ ). In other examples, the alkynyl group is C ₂ -C ₁₂ , C ₂ -C ₁₀ , C ₂ -C ₈ , C ₂ -C ₆ or C ₂ -C ₃ . Examples include, but are not limited to, ethynyl (-C≡CH), prop-1-ynyl (-C≡CCH ₃ ), prop-2-ynyl (propargyl, -CH ₂ C≡CH), 1-ynyl, but-2-ynyl and but-3-ynyl.

術語「烷氧基」係指由式-OR表示之直鏈或分支鏈單價基團，其中R為烷基、烯基、炔基或碳環基。烷氧基包括甲氧基、乙氧基、丙氧基、異丙氧基、單氟甲氧基、二氟甲氧基及三氟甲氧基及環丙氧基。烷氧基之特定實例為甲氧基。 The term "alkoxy" refers to a straight or branched chain monovalent group represented by the formula -OR wherein R is alkyl, alkenyl, alkynyl or carbocyclyl. Alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, monofluoromethoxy, difluoromethoxy, and trifluoromethoxy and cyclopropoxy. A specific example of an alkoxy group is a methoxy group.

如本文中所使用之術語「鹵烷基」係指經一或多(例如1、2、3或4)個鹵基取代之如本文中所定義之烷基。鹵烷基之特定實例為三氟甲基及二氟甲基。 The term "haloalkyl" as used herein, refers to an alkyl group, as defined herein, substituted by one or more (eg 1, 2, 3 or 4) halo groups. Specific examples of haloalkyl groups are trifluoromethyl and difluoromethyl.

單獨或作為更大部分(如「芳基烷基」、「芳基烷氧基」或「芳氧基烷基」中)之一部分使用之術語係指單環、雙環或三環碳環系統，其包括稠合環，其中該系統中至少一個環為芳族。術語「芳基」可與術語「芳基環」可互換使用。在一個實施例中，芳基包括具有6-18個碳原子之基團。在另一實施例中，芳基包括具有6-10個碳原子之基團。芳基之實例包括苯基、萘基、蒽基、聯苯、菲基、稠四苯基、1,2,3,4-四氫萘基、1H-茚基、2,3-二氫-1H-茚基及其類似基團，其可以經或獨立地經一或多個本文中所描述之取代基取代。一個特定芳基為苯基。在另一個實施例中，芳基包括與一或多個碳環稠合之芳基環，諸如茚滿基、鄰苯二甲醯亞胺基、萘醯亞胺基、啡啶基或四氫萘基及其類似基團，其中連接基團或點在芳環上。 The term "partially used alone or as part of a larger moiety (such as "arylalkyl", "arylalkoxy" or "aryloxyalkyl") refers to a monocyclic, bicyclic or tricyclic carbocyclic ring system, It includes a fused ring wherein at least one of the rings in the system is aromatic. The term "aryl" is used interchangeably with the term "aryl ring". In one embodiment, the aryl group includes a group having 6 to 18 carbon atoms. In another embodiment, the aryl group includes a group having 6-10 carbon atoms. Examples of the aryl group include phenyl, naphthyl, anthracenyl, biphenyl, phenanthryl, fused tetraphenyl, 1,2,3,4-tetrahydronaphthyl, 1H-fluorenyl, 2,3-dihydro- 1H-indenyl and the like, which may be substituted, independently or independently, with one or more substituents as described herein. One particular aryl group is a phenyl group. In another embodiment, the aryl group includes an aryl ring fused to one or more carbocyclic rings, such as indanyl, phthalimido, naphthoquinone, phenanthryl or tetrahydrogen. Naphthalene And a group thereof, wherein the linking group or point is on the aromatic ring.

單獨或作為更大部分(例如「雜芳基烷基」或「雜芳基烷氧基」)之一部分使用的術語「雜芳基」係指具有5至14個環原子之單環、雙環或三環系統，其中至少一個環為芳族且含有至少一個雜原子。在一個實施例中，雜芳基包括4-6員單環芳族基團，其中一或多個環原子為氮、硫或氧且獨立地視情況經取代。在另一實施例中，雜芳基包括5-6員單環芳族基團，其中一或多個環原子為獨立地視情況取代之氮、硫或氧。雜芳基之實例包括噻吩基、呋喃基、咪唑基、吡唑基、噻唑基、異噻唑基、噁唑基、異噁唑基、***基、噻二唑基、噁二唑基、四唑基、噻***基、噁***基、吡啶基、嘧啶基、吡嗪基、噠嗪基、三嗪基、四嗪基、四唑并[1,5-b]噠嗪基、咪唑[1,2-a]嘧啶基、嘌呤基、苯并噁唑基、苯并呋喃基、苯并噻唑基、苯并噻二唑基、苯并***基、苯并咪唑基、吲哚基、1,3-噻唑-2-基、1,3,4-***-5-基、1,3-噁唑-2-基、1,3,4-噁二唑-5-基、1,2,4-噁二唑-5-基、1,3,4-噻二唑-5-基、1H-四唑-5-基、1,2,3-***-5-基及吡啶-2-基N-氧化物。術語「雜芳基」亦包括雜芳基與一或多個芳基、碳環基或雜環基環稠合之基團，其中連接基團或點在雜芳基環上。非限制性實例包括吲哚基、異吲哚基、苯并噻吩基、苯并呋喃基、二苯并呋喃基、吲唑基、苯并咪唑基、苯并噻唑基、喹啉基、異喹啉基、啉基、酞嗪基、喹唑啉基、喹喏啉基、4H-喹嗪基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基、四氫喹啉基、四氫異喹啉基及吡啶并[2,3-b]-1,4-噁嗪-3(4H)-酮。雜芳基可為單環、雙環或三環。 The term "heteroaryl" used alone or as part of a larger moiety, such as "heteroarylalkyl" or "heteroarylalkoxy", refers to a monocyclic, bicyclic, or 5- to 14 ring atom. A tricyclic system wherein at least one ring is aromatic and contains at least one hetero atom. In one embodiment, the heteroaryl group comprises a 4-6 membered monocyclic aromatic group wherein one or more ring atoms are nitrogen, sulfur or oxygen and are independently substituted as appropriate. In another embodiment, the heteroaryl group comprises a 5-6 membered monocyclic aromatic group wherein one or more ring atoms are independently substituted nitrogen, sulfur or oxygen. Examples of heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetra Azyl, thiatriazole, oxatriazole, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[1,5-b]pyridazinyl, imidazole [1,2-a]pyrimidinyl, fluorenyl, benzoxazolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzimidazolyl, fluorenyl , 1,3-thiazol-2-yl, 1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 1 , 2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5-yl, 1H-tetrazol-5-yl, 1,2,3-triazol-5-yl and pyridine -2-yl N-oxide. The term "heteroaryl" also includes groups in which a heteroaryl group is fused to one or more aryl, carbocyclyl or heterocyclyl rings wherein the linking group or point is on the heteroaryl ring. Non-limiting examples include mercapto, isodecyl, benzothienyl, benzofuranyl, dibenzofuranyl, oxazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquine Olinyl group, Lolinyl, pyridazinyl, quinazolinyl, quinoxalinyl, 4 H -quinazinyl, oxazolyl, acridinyl, phenazinyl, phenothiazine, phenoxazinyl, tetrahydroquinoline Base, tetrahydroisoquinolyl and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group can be monocyclic, bicyclic or tricyclic.

如本文中所使用，術語「雜環基」係指如本文中所定義之「碳環基」，其中一或多(例如1、2、3或4)個碳原子已經雜原子(例如O、N或S)置換。雜環基可視情況經一或多個獨立地選自本文中所定義之取代基的取代基取代。 As used herein, the term "heterocyclyl" refers to a "carbocyclyl" group as defined herein, wherein one or more (eg 1, 2, 3 or 4) carbon atoms have been heteroatoms (eg O, N or S) replacement. The heterocyclic group may be optionally substituted with one or more substituents independently selected from the substituents defined herein.

在一個實例中，雜環基包括3-12個環原子且包括單環、雙環、三環及螺環系統，其中環原子為碳，且1至5個環原子為選自氮、硫或氧之雜原子，其獨立地視情況經一或多個基團取代。在一個實例中，雜環基包括1至4個雜原子。在另一實例中，雜環基包括具有一或多個選自氮、硫或氧之雜原子的3至7員單環。在另一實例中，雜環基包括具有一或多個選自氮、硫或氧之雜原子的4至6員單環。在另一實例中，雜環基包括3員單環。在另一實例中，雜環基包括4員單環。在另一實例中，雜環基包括5-6員單環。在一個實例中，雜環基包括0至3個雙鍵。任何氮或硫雜原子可視情況經氧化(例如NO、SO、SO₂)，且任何氮雜原子均可視情況經四級銨化(例如[NR₄]⁺Cl^-、[NR₄]⁺OH^-)。例示性雜環基包括環氧乙烷基、氮丙啶基、硫雜環丙烷基、氮雜環丁烷基、氧雜環丁烷基、硫雜環丁烷基、1,2-二硫雜環丁烷基、1,3-二硫雜環丁烷基、吡咯啶基、二氫-1H-吡咯基、二氫呋喃基、四氫呋喃基、二氫噻吩基、四氫噻吩基、咪唑啶基、哌啶基、哌嗪基、嗎啉基、硫代嗎啉基、1,1-二側氧基-硫代嗎啉基、二氫哌喃基、四氫哌喃基、六氫硫代哌喃基、六氫嘧啶基、氧氮雜環己烷基、硫氮雜環己烷基、硫氧雜環己基、高哌嗪基、高哌啶基、氮雜環庚烷基、氧雜環庚烷基、硫雜環庚烷基、噁氮呯基、氧氮雜環庚烷基、二氮雜環庚烷基、1,4-二氮雜環庚烷基、二氮呯基、噻氮呯基、硫氮雜環庚烷基、四氫硫代哌喃基、噁唑啶基、噻唑啶基、異噻唑啶基、1,1-二側氧基異噻唑啶酮基、噁唑啶酮基、咪唑啶酮基、4,5,6,7-四氫[2H]吲唑基、四氫苯并咪唑基、4,5,6,7-四氫苯并[d]咪唑基、1,6-二氫咪唑并[4,5-d]吡咯并[2,3-b]吡啶基、噻嗪基、噁嗪基、硫二氮雜環己烷基、氧二氮雜環己烷基、二噻嗪基、二噁嗪基、噁噻嗪基、噻三嗪基、噁三嗪基、二噻二嗪基、咪唑啉基、二氫嘧啶基、四氫嘧啶基、1-吡咯啉基、2-吡咯啉基、3-吡咯啉基、吲哚啉基、噻哌喃基、2H-哌喃基、4H-哌喃基、二噁烷基、1,3-二氧戊環基、吡唑啉基、吡唑啶基、二噻烷基、二硫雜環戊烷基、嘧啶酮基、嘧啶二酮基、嘧啶-2,4-二酮基、哌嗪酮基、哌嗪二酮基、吡唑啶基咪唑啉基、3-氮雜雙環[3.1.0]己基、3,6-二氮雜雙環[3.1.1]庚基、6-氮雜雙環[3.1.1]庚基、3-氮雜雙環[3.1.1]庚基、3-氮雜雙環[4.1.0]庚基、氮雜雙環[2.2.2]己基、2-氮雜雙環[3.2.1]辛基、8-氮雜雙環[3.2.1]辛基、2-氮雜雙環[2.2.2]辛基、8-氮雜雙環[2.2.2]辛基、7-氧雜雙環[2.2.1]庚烷、氮雜螺[3.5]壬基、氮雜螺[2.5]辛基、氮雜螺[4.5]癸基、1-氮雜螺[4.5]癸-2-酮基、氮雜螺[5.5]十一烷基、四氫吲哚基、八氫吲哚基、四氫異吲哚基、四氫吲唑基、1,1-二側氧基六氫硫代哌喃基。含有1個硫或氧原子及1至3個氮原子之5員雜環基之實例為噻唑基(包括噻唑-2-基及噻唑-2-基N-氧化物)、噻二唑基(包括1,3,4-噻二唑-5-基及1,2,4-噻二唑-5-基)、噁唑基(例如噁唑-2-基)及噁二唑基(諸如1,3,4-噁二唑-5-基及1,2,4-噁二唑-5-基)。含有2至4個氮原子之例示性5員環雜環基包括咪唑基，諸如咪唑-2-基；***基，諸如1,3,4-***-5-基；1,2,3-***-5-基、1,2,4-***-5-基；及四唑基，諸如1H-四唑-5-基。例示性苯并稠合5員雜環基為苯并噁唑-2-基、苯并噻唑-2-基及苯并咪唑-2-基。例示性6員雜環基含有1至3個氮原子及視情況存在之硫或氧原子，例如吡啶基，諸如吡啶-2-基、吡啶-3-基及吡啶-4-基；嘧啶基，諸如嘧啶-2-基及嘧啶-4-基；三嗪基，諸如1,3,4-三嗪-2-基及1,3,5-三嗪-4-基；噠嗪基，詳言之噠嗪-3-基；及吡嗪基。吡啶N-氧化物及噠嗪N-氧化物及吡啶基、嘧啶-2-基、嘧啶-4-基、噠嗪基及1,3,4-三嗪-2-基為其他例示性雜環基。雜環基之特定實例為氮雜環丁烷基、吡咯啶基、哌嗪基及嗎啉基，更特定言之為氮雜環丁烷-1-基、吡咯啶-1-基、哌嗪-1-基及嗎啉-4-基。 In one example, a heterocyclyl includes 3-12 ring atoms and includes monocyclic, bicyclic, tricyclic, and spiro ring systems wherein the ring atom is carbon and 1 to 5 ring atoms are selected from nitrogen, sulfur, or oxygen. A hetero atom, which is independently substituted with one or more groups, as appropriate. In one example, a heterocyclic group includes from 1 to 4 heteroatoms. In another example, a heterocyclic group includes a 3 to 7 membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, a heterocyclic group includes a 4 to 6 membered monocyclic ring having one or more heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, a heterocyclic group includes a 3-membered single ring. In another example, a heterocyclic group includes a 4-membered single ring. In another example, a heterocyclic group includes a 5-6 membered monocyclic ring. In one example, a heterocyclic group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may be oxidized (eg, NO, SO, SO ₂ ) as appropriate, and any nitrogen heteroatom may be ammonium quaternized as appropriate (eg, [NR ₄ ] ⁺ Cl ^- , [NR ₄ ] ⁺ OH ^- ). Exemplary heterocyclic groups include oxiranyl, aziridine, thietyl, azetidinyl, oxetanyl, thietane, 1,2-disulfide Heterocyclic butane, 1,3-dithiacycloalkyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothiophenyl, imidazolidinyl , piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-di-oxy-thiomorpholinyl, dihydropiperidyl, tetrahydropyranyl, hexahydrosulfur Piperacinyl, hexahydropyrimidinyl, oxazepine, thiazepine, thioxanthyl, homopiperazinyl, homopiperidinyl, azepanyl, oxygen Heterocyclic heptyl, thiaheptanyl, oxazinyl, oxazepine, diazepine, 1,4-diazepanyl, diazenium , thiazolidine, thiazepine, tetrahydrothiopiperidyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-di- oxyisothiazolidinone, Oxazolidinone, imidazolidinone, 4,5,6,7-tetrahydro[2H]carbazolyl, tetrahydrobenzimidazolyl, 4,5,6, 7-tetrahydrobenzo[d]imidazolyl, 1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl,oxazinyl, thiodiazepine Heterocyclohexane, oxadiazepine, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, Dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrroline, 2-pyrolinyl, 3-pyrroyl, porphyrin, thiopyranyl, 2H-pyranyl, 4H-pyranyl, Dioxoalkyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithiaalkyl, dithiolanyl, pyrimidinone, pyrimidindione, pyrimidine-2 , 4-dione, piperazinone, piperazinedione, pyrazolyl imidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.1 Heptyl, 6-azabicyclo[3.1.1]heptyl, 3-azabicyclo[3.1.1]heptyl, 3-azabicyclo[4.1.0]heptyl, azabicyclo[2.2.2 Hexyl, 2-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 8-azabicyclo[2.2. 2] Octyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]fluorenyl, aza Snail [2.5] octyl, azaspiro[4.5]decyl, 1-azaspiro[4.5]non-2-one, azaspiro[5.5]undecyl, tetrahydroindenyl, octahydro Indenyl, tetrahydroisodecyl, tetrahydrocarbazolyl, 1,1-di-oxy hexahydrothiopiperidyl. Examples of a 5-membered heterocyclic group containing 1 sulfur or oxygen atom and 1 to 3 nitrogen atoms are thiazolyl (including thiazol-2-yl and thiazol-2-yl N-oxide), thiadiazolyl (including 1,3,4-thiadiazol-5-yl and 1,2,4-thiadiazol-5-yl), oxazolyl (such as oxazol-2-yl) and oxadiazolyl (such as 1, 3,4-oxadiazol-5-yl and 1,2,4-oxadiazol-5-yl). Exemplary 5-membered ring heterocyclyl containing 2 to 4 nitrogen atoms includes imidazolyl, such as imidazol-2-yl; triazolyl, such as 1,3,4-triazol-5-yl; 1,2,3 a triazol-5-yl, 1,2,4-triazol-5-yl; and a tetrazolyl group such as a 1H-tetrazol-5-yl group. Exemplary benzo-fused 5-membered heterocyclic groups are benzoxazol-2-yl, benzothiazol-2-yl and benzimidazol-2-yl. Exemplary 6 membered heterocyclic groups contain 1 to 3 nitrogen atoms and optionally sulfur or oxygen atoms, such as pyridyl, such as pyridin-2-yl, pyridin-3-yl and pyridin-4-yl; pyrimidinyl, Such as pyrimidin-2-yl and pyrimidin-4-yl; triazinyl, such as 1,3,4-triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in detail Pyridazin-3-yl; and pyrazinyl. Pyridine N-oxides and pyridazine N-oxides and pyridyl, pyrimidin-2-yl, pyrimidin-4-yl, pyridazinyl and 1,3,4-triazin-2-yl are other exemplary heterocyclic rings base. Specific examples of heterocyclic groups are azetidinyl, pyrrolidinyl, piperazinyl and morpholinyl, more specifically azetidin-1-yl, pyrrolidin-1-yl, piperazine -1-yl and morpholin-4-yl.

如本文中所使用，術語「部分不飽和」係指在環原子之間包括至少一個雙鍵或三鍵且環部分不為芳族的環部分。 As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms and the ring moiety is not aromatic.

如本文中所使用，術語「抑制劑」係指結合且以可量測之生物化學親和力及活性抑制CDK8酶的化合物。在某些實施例中，抑制劑之生物化學IC₅₀及/或結合常數小於約50μM、小於約1μM、小於約500nM、小於約100nM或小於約10nM。 As used herein, the term "inhibitor" refers to a compound that binds to and inhibits the CDK8 enzyme with a measurable biochemical affinity and activity. In certain embodiments, an inhibitor of biochemical IC ₅₀ and / or the binding constant of less than about 50 M, less than about [mu] M, less than about 500 nM, less than about 100nM, or less than about 10nM.

「醫藥學上可接受之鹽」包括酸及鹼加成鹽。「醫藥學上可接受之酸加成鹽」係指保留游離鹼之生物有效性及性質且不會在生物學或其他方面不合需要之鹽，其係用諸如鹽酸、氫溴酸、硫酸、硝酸、碳酸、磷酸及其類似物之無機酸形成，且有機酸可選自脂族、環脂族、芳族、芳脂族、雜環、羧酸及磺酸類有機酸，諸如甲酸、乙酸、丙酸、羥基乙酸、葡萄糖酸、乳酸、丙酮酸、乙二酸、蘋果酸、馬來酸、丙二酸、丁二酸、富馬酸、酒石酸、檸檬酸、天冬胺酸、抗壞血酸、麩胺酸、鄰胺基苯甲酸、苯甲酸、肉桂酸、扁桃酸、恩波酸、苯乙酸、甲烷磺酸、乙烷磺酸、苯磺酸、對甲苯磺酸、水楊酸及其類似物。 "Pharmaceutically acceptable salts" include acid and base addition salts. "Pharmaceutically acceptable acid addition salt" means a salt which retains the biological effectiveness and properties of the free base and which is not biologically or otherwise undesirable, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid. The inorganic acid of carbonic acid, phosphoric acid and the like is formed, and the organic acid may be selected from the group consisting of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic acid and sulfonic acid organic acids, such as formic acid, acetic acid, and C. Acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamine Acid, o-aminobenzoic acid, benzoic acid, cinnamic acid, mandelic acid, en-poic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

「醫藥學上可接受之鹼加成鹽」包括衍生自無機鹼的鹽，諸如鈉鹽、鉀鹽、鋰鹽、銨鹽、鈣鹽、鎂鹽、鐵鹽、鋅鹽、銅鹽、錳鹽、鋁鹽及其類似物。特定言之，鹼加成鹽為銨鹽、鉀鹽、鈉鹽、鈣鹽及鎂鹽。衍生自醫藥學上可接受之有機無毒鹼之鹽包括以下各物之鹽：一級胺、二級胺及三級胺、經取代胺(包括天然存在之經取代胺)、環胺及鹼性離子交換樹脂，諸如異丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙基胺基乙醇、三羥甲基胺基甲烷、二環己胺、離胺酸、精胺酸、組胺酸、咖啡因(caffeine)、普魯卡因(procaine)、海卓胺(hydrabamine)、膽鹼、甜菜鹼、乙二胺、葡糖胺、甲基葡糖胺、可可豆鹼、嘌呤、哌嗪、哌啶、N-乙基哌啶、多元胺樹脂及其類似物。特定言之，有機無毒鹼為異丙胺、二乙胺、乙醇胺、三羥甲基胺基甲烷、二環己胺、膽鹼及咖啡因。 "Pharmaceutically acceptable base addition salts" include salts derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese salts. , aluminum salts and their analogues. Specifically, the base addition salts are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of the following: primary amines, secondary amines and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines and basic ions Exchange resin such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethylolaminomethane, dicyclohexylamine, lysine, fine Aminic acid, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, cocoa beans Base, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin and the like. Specifically, the organic non-toxic base is isopropylamine, diethylamine, ethanolamine, trimethylolaminomethane, dicyclohexylamine, choline and caffeine.

術語「互變異構體」或「互變異構形式」係指可經由低能量障壁相互轉化之具有不同能量之結構異構體。舉例而言，質子互變異構體(亦稱為質子轉移互變異構體)包括經由質子遷移而相互轉化，諸如酮-烯醇及亞胺-烯胺異構化。價鍵互變異構體包括藉由一些鍵結電子重組而相互轉化。 The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton transfer tautomers) include interconversion via proton transfer, such as keto-enol and imine-enamine isomerization. Valence bond tautomers include interconversions by some bond electron recombination.

「溶劑合物」係指一或多個溶劑分子與本發明化合物之締合或複合物。溶劑之實例包括水、異丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸及乙醇胺。術語「水合物」係指溶劑分子為水的複合物。 "Solvate" means an association or complex of one or more solvent molecules with a compound of the invention. Examples of the solvent include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

「治療有效量」係指(i)治療特定疾病、病狀或病症，(ii)減輕、改善或消除特定疾病、病狀或病症之一或多種症狀，或(iii)預防或延遲本文所述之特定疾病、病狀或病症之一或多種症狀之發作的本發明化合物之量。在癌症之情況下，治療有效量之藥物可減少癌細胞數目；減小腫瘤尺寸；抑制(亦即在一定程度上延緩，且較佳終止)癌細胞浸潤至周邊器官中；抑制(亦即在一定程度上延緩，且較佳終止)腫瘤轉移；在一定程度上抑制腫瘤生長；及/或在一定程度上緩解一或多種與癌症相關之症狀。對於癌症療法，可例如藉由評定疾病進展時間(TTP)及/或測定反應率(RR)來量測功效。在免疫病症之情況下，治療有效量為足以減少或減輕過敏性病症、自體免疫性及/或發炎性疾病之症狀或急性發炎性反應之症狀(例如哮喘)的量。在一些實施例中，治療有效量為本文中所描述之化學實體之足以顯著降低耐藥性癌細胞或耐藥性頑固癌細胞之活性或數目的量。 "Therapeutically effective amount" means (i) treating a particular disease, condition or condition, (ii) reducing, ameliorating or eliminating one or more symptoms of a particular disease, condition or condition, or (iii) preventing or delaying the treatment described herein. The amount of a compound of the invention that is one or more of the symptoms of a particular disease, condition or condition. In the case of cancer, a therapeutically effective amount of the drug reduces the number of cancer cells; reduces the size of the tumor; inhibits (ie, to some extent, and preferably terminates) the infiltration of the cancer cells into the surrounding organs; To some extent, and preferably terminates) tumor metastasis; inhibits tumor growth to some extent; and/or relieves one or more symptoms associated with cancer to some extent. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and/or determining the response rate (RR). In the case of an immune disorder, the therapeutically effective amount is an amount sufficient to reduce or alleviate the symptoms of an allergic condition, an autoimmune and/or inflammatory disease, or a symptom of an acute inflammatory response, such as asthma. In some embodiments, the therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly reduce the activity or number of drug resistant cancer cells or drug resistant refractory cancer cells.

「治療(Treatment)」(及變化形式，諸如「治療(treat)」或「治療(treating)」)係指試圖改變所治療之個體或細胞之天然過程且可出於預防目的或在臨床病理學過程中執行的臨床介入。治療之理想效應包括以下各項中之一或多者：預防疾病發生或復發、減輕症狀、減少疾病之任何直接或間接病理學後果、穩定(亦即，不惡化)疾病狀態、預防轉移、降低疾病進展速率、改善或緩和疾病狀態、與不接受治療時之預期存活時間相比延長存活時間及緩解或改良預後。在某些實施例中，使用式I化合物來延遲疾病或病症發展或減緩疾病或病症進展。需要治療之個體包括已具有病狀或病症之個體以及傾向於患有病狀或病症之個體(例如，藉由基因或蛋白質之基因突變或異常表現)或欲預防病狀或病症之個體。 "Treatment" (and variants such as "treat" or "treating") refers to the natural process of attempting to alter the individual or cell being treated and may be for preventive purposes or in clinical pathology. Clinical intervention performed during the process. The ideal effect of treatment includes one or more of the following: preventing the occurrence or recurrence of the disease, alleviating the symptoms, reducing any direct or indirect pathological consequences of the disease, stabilizing (ie, not worsening) the disease state, pre- Preventing metastasis, reducing the rate of disease progression, improving or mitigating the disease state, prolonging survival time and ameliorating or improving prognosis compared to the expected survival time when no treatment is received. In certain embodiments, a compound of Formula I is used to delay or slow the progression of a disease or condition. The individual in need of treatment includes an individual who has a condition or disorder as well as an individual who is prone to have a condition or disorder (e.g., by mutation or abnormal expression of a gene or protein) or an individual to be prevented from developing a condition or disorder.

例示性值Exemplary value

一個實施例包括式(I)化合物：或其鹽，其中：R¹係選自：且其中R¹係獨立地視情況經1、2或3個R^x基團取代；R²及R³獨立地為H、C_1-12烷基、C_2-12烯基、C_2-12炔基、碳環基、芳基、雜芳基、雜環基、鹵基、-OR^a、-SR^a、-N(R^a)₂、-CN、-NO₂、-C(O)R^a、-CO₂R^a、-C(O)N(R^a)₂、-C(O)SR^a、-C(O)C(O)R^a、-C(O)CH₂C(O)R^a、-C(S)N(R^a)₂、-C(S)OR^a、-S(O)R^a、-SO₂R^a、-SO₂N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)C(O)N(R^a)₂、-N(R^a)SO₂R^a、-N(R^a)SO₂N(R^a)₂、-N(R^a)N(R^a)₂、-N(R^a)C(=N(R^a))N(R^a)₂、-C(=N)N(R^a)₂、-C=NOR^a、-C(=N(R^a))N(R^a)₂、-OC(O)R^a或-OC(O)N(R^a)₂，其中R²及R³之各C_1-12烷基、C_2-12烯基、C_2-12炔基、碳環基、芳基、雜芳基及雜環基係各自獨立地視情況經一或多個基團R^x取代；或R¹及R²與其所連接之原子一起形成4、5、6、7或8員碳環基、雜環基、雜芳基或芳基，該碳環基、雜環基、雜芳基及芳基視情況經一或多個基團R^x取代；各R^a及R^b獨立地為H、C_1-6烷基、C_2-6烯基、C_2-6炔基、碳環基、芳基、雜芳基或雜環基，其中各C_1-6烷基、C_3-6烯基、C_3-6炔基、碳環基、芳基、雜芳基及雜環基係獨立地視情況經一或多個基團R^x取代；或R^a及R^b與其所連接之氮一起形成3-6員雜環，該雜環視情況經側氧基、鹵基或視情況經側氧基或鹵基取代之C_1-6烷基取代；各R^v獨立地為氫、C_1-6烷基、C_2-6烯基、C_2-6炔基、碳環基、芳基、雜芳基或雜環基，其中各C_1-6烷基、C_2-6烯基、C_2-6炔基、碳環基、芳基、雜芳基及雜環基視情況經一或多個基團取代，該一或多個基團係獨立地選自側氧基、鹵基、胺基、羥基及視情況經一或多個獨立地選自側氧基及鹵基之基團取代之C₁-C₆烷基；或兩個R^v與其所連接之氮一起形成3-6員雜環基，該雜環基視情況經一或多個基團取代，該一或多個基團係獨立地選自側氧基、鹵基及視情況經一或多個獨立地選自側氧基及鹵基之基團取代之C_1-3烷基；且各R^x獨立地為側氧基、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6鹵烷基、碳環基、芳基、雜芳基、雜環基、-F、-Cl、-Br、-I、-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-O-C(O)-N(R^v)₂、-N(R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^v、-N(R^v)-S(O)-N(R^v)₂或-N(R^v)-S(O)₂-N(R^v)₂，其中任何C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6鹵烷基、碳環基、芳基、雜芳基及雜環基係獨立地視情況經一或多個基團取代，該一或多個基團係選自側氧基、鹵基、-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^v及視情況經一或多個獨立地選自側氧基及鹵基之基團取代之C_1-6烷基；且其中當R²為F且R³為氫時，則R^x不為甲基、乙基、三氟甲基或2-氟苯基。 One embodiment includes a compound of formula (I): Or a salt thereof, wherein: R ¹ is selected from the group consisting of: And wherein R ¹ is independently substituted by 1, 2 or 3 R ^x groups; R ² and R ^{3 are} independently H, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 Alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, halo, -OR ^a , -SR ^a , -N(R ^a ) ₂ , -CN, -NO ₂ , -C(O)R ^a , -CO ₂ R ^a , -C(O)N(R ^a ) ₂ , -C(O)SR ^a , -C(O)C(O)R ^a , -C(O)CH ₂ C(O R ^a , -C(S)N(R ^a ) ₂ , -C(S)OR ^a , -S(O)R ^a , -SO ₂ R ^a , -SO ₂ N(R ^a ) ₂ , -N (R ^a )C(O)R ^a , -N(R ^a )C(O)N(R ^a ) ₂ , -N(R ^a )SO ₂ R ^a , -N(R ^a )SO ₂ N(R ^a ) ₂ , -N(R ^a )N(R ^a ) ₂ , -N(R ^a )C(=N(R ^a ))N(R ^a ) ₂ , -C(=N)N(R ^a ) ₂ , -C=NOR ^a , -C(=N(R ^a ))N(R ^a ) ₂ , -OC(O)R ^a or -OC(O)N(R ^a ) ₂ , wherein R ² and R ³ of each of C _1-12 alkyl, C _2-12 alkenyl group, C _2-12 alkynyl, carbocyclyl, aryl, heteroaryl and heterocyclyl groups are each independently system optionally substituted with one or more groups a group R ^x substituted; or R ¹ and R ² together with the atom to which they are attached form a 4, 5, 6, 7 or 8 membered carbocyclyl, heterocyclyl, heteroaryl or aryl group, which is a heterocyclic or heterocyclic ring. The base, heteroaryl and aryl are optionally substituted by one or more groups R ^x Each of R ^a and R ^{b is} independently H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclic, each of which C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, carbocyclyl, aryl, heteroaryl and heterocyclic are independently substituted by one or more groups R ^x as appropriate ; or R ^a and R ^b form a 3-6 membered heterocyclic ring together with the nitrogen to which they are attached, which heteroaryl ring optionally substituted with oxo or halo by oxo, halo or C _1-6 alkyl optionally of Substituted; each R ^{v is} independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl, wherein each C _{1 -6} alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl, aryl, heteroaryl and heterocyclyl group optionally substituted with one or more groups, one or more of the group The group is independently selected from the group consisting of a pendant oxy group, a halogen group, an amine group, a hydroxyl group, and optionally a C ₁ -C ₆ alkyl group substituted with one or more groups independently selected from the pendant oxy group and a halogen group; or two forming a R ^v together with the nitrogen to which they are attached 3-6 membered heterocyclic group, the heterocyclic group optionally substituted by one or more groups, the one or more groups independently selected from side-based oxygen , Halo and optionally substituted with one or more of the substituents independently selected from halo and oxo group of the C _1-3 alkyl group; and each R ^x is independently oxo, C _1-6 alkyl , C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 haloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, -F, -Cl, -Br, -I, -NO ₂ , -N(R ^v ) ₂ , -CN, -C(O)-N(R ^v ) ₂ , -S(O)-N(R ^v ) ₂ , -S(O) ₂ -N( R ^v ) ₂ , -OR ^v , -SR ^v , -OC(O)-R ^v , -OC(O)-OR ^v , -C(O)-R ^v , -C(O)-OR ^v ,- S(O)-R ^v , -S(O) ₂ -R ^v , -OC(O)-N(R ^v ) ₂ , -N(R ^v )-C(O)-OR ^v , -N(R ^v )-C(O)-N(R ^v ) ₂ , -S(O) ₂ -N(R ^v ) ₂ , -N(R ^v )-C(O)-R ^v , -N(R ^v ) -S(O)-R ^v , -N(R ^v )-S(O) ₂ -R ^v , -N(R ^v )-S(O)-N(R ^v ) ₂ or -N(R ^v ) -S(O) ₂ -N(R ^v ) ₂ , wherein any C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 haloalkyl group, carbocyclic group, aromatic The base, heteroaryl and heterocyclic groups are, independently, optionally substituted by one or more groups selected from the group consisting of pendant oxy, halo, -NO ₂ , -N(R ^v ) ₂ , -CN, -C(O)-N(R ^v ) ₂ , -S(O)-N(R ^v ) ₂ , -S(O) ₂ -N(R ^v ) ₂ , -OR ^v ,- ^{SR v, -OC (O) -R} v ^{-C (O) -R v, -C} (O) -OR v, -S (O) -R v, -S (O) 2 -R v, -C (O) -N (R v) 2, -S(O) ₂ -N(R ^v ) ₂ , -N(R ^v )-C(O)-R ^v , -N(R ^v )-S(O)-R ^v , -N(R ^v ) -S(O) ₂ -R ^v and, optionally, a C _1-6 alkyl group substituted with one or more groups independently selected from the group consisting of pendant and halogen; and wherein when R ² is F and R ³ is In the case of hydrogen, R ^{x is} not a methyl group, an ethyl group, a trifluoromethyl group or a 2-fluorophenyl group.

一個特定實施例係關於式(I)化合物或其鹽，其中：R¹係選自： R²及R³獨立地為H、C_1-12烷基、鹵基或-OR^a，其中R²及R³之各C_1-12烷基各自獨立地視情況經一或多個基團R^x取代；各R^a及R^b獨立地為H、C_1-6烷基，其中各C_1-6烷基獨立地視情況經一或多個基團R^x取代；各R^v獨立地為C_1-6烷基；且各R^x獨立地為雜環基、-F或-N(R^v)₂，其中任何雜環基均獨立地視情況經一或多個選自C_1-6烷基之基團取代；且其中當R²為F且R³為氫時，則R^x不為甲基、乙基、三氟甲基或2-氟苯基。 A particular embodiment relates to a compound of formula (I) or a salt thereof, wherein: R ¹ is selected from the group consisting of: R ² and R ^{3 are} independently H, C _1-12 alkyl, halo or -OR ^a , wherein each C _1-12 alkyl of R ² and R ³ is independently independently one or more groups, as appropriate R ^{x is} substituted; each R ^a and R ^{b is} independently H, C _1-6 alkyl, wherein each C _1-6 alkyl group is independently substituted with one or more groups R ^x as appropriate; each R ^v independently Is a C _1-6 alkyl group; and each R ^{x is} independently a heterocyclic group, -F or -N(R ^v ) ₂ , wherein any heterocyclic group is independently selected from one or more selected from C _{1- a} group of ₆ alkyl groups; and wherein when R ² is F and R ³ is hydrogen, then R ^{x is} not methyl, ethyl, trifluoromethyl or 2-fluorophenyl.

在某些實施例中，R²及R³獨立地為鹵基、三氟甲基、C_1-6烷基或C_1-6烷氧基，其中所述烷基及烷氧基獨立地視情況經-N(R^v)₂或雜環基取代，其中該雜環基視情況經側氧基、鹵基或視情況經鹵基或側氧基取代之C_1-6烷基取代。 In certain embodiments, R ² and R ^{3 are} independently halo, trifluoromethyl, C _1-6 alkyl or C _1-6 alkoxy, wherein the alkyl and alkoxy are independently considered The case is substituted by -N(R ^v ) ₂ or a heterocyclic group, wherein the heterocyclic group is optionally substituted by a pendant oxy group, a halogen group or a C _1-6 alkyl group optionally substituted by a halogen group or a pendant oxy group.

在某些實施例中，R²為氫、氯基、甲基、(4-甲基哌嗪-1-基)甲基、三氟甲氧基、二氟甲氧基、4-氮雜環丁烷-1-基甲基、嗎啉-4-基甲基、二甲基胺基甲基、吡咯啶-1-基甲基或4-乙基哌嗪-1-基甲基。 In certain embodiments, R ² is hydrogen, chloro, methyl, (4-methylpiperazin-1-yl)methyl, trifluoromethoxy, difluoromethoxy, 4-nitroheterocycle Butan-1-ylmethyl, morpholin-4-ylmethyl, dimethylaminomethyl, pyrrolidin-1-ylmethyl or 4-ethylpiperazin-1-ylmethyl.

在某些實施例中，R³為氫、三氟甲基、氟基或氯基。 In certain embodiments, R ³ is hydrogen, trifluoromethyl, fluoro or chloro.

在某些實施例中，各R^a及R^b獨立地為氫或C_1-6烷基。 In certain embodiments, each of R ^a and R ^{b is} independently hydrogen or C _1-6 alkyl.

在某些實施例中，R^a為氫。 In certain embodiments, R ^a is hydrogen.

在某些實施例中，R^b為甲基。 In certain embodiments, R ^b is methyl.

在某些實施例中，R^v為氫或C_1-6烷基。 In certain embodiments, R ^v is hydrogen or C _1-6 alkyl.

在某些實施例中，R^v為甲基。 In certain embodiments, R ^v is methyl.

在某些實施例中，R²為氫、氯基、甲基、(4-甲基哌嗪-1-基)甲基、三氟甲氧基、二氟甲氧基、4-氮雜環丁烷-1-基甲基、嗎啉-4-基甲基、二甲基胺基甲基、吡咯啶-1-基甲基或4-乙基哌嗪-1-基甲基；R³為氫、三氟甲基或氯基；R^a及R^b獨立地為氫或甲基。 In certain embodiments, R ² is hydrogen, chloro, methyl, (4-methylpiperazin-1-yl)methyl, trifluoromethoxy, difluoromethoxy, 4-nitroheterocycle Butan-1-ylmethyl, morpholin-4-ylmethyl, dimethylaminomethyl, pyrrolidin-1-ylmethyl or 4-ethylpiperazin-1-ylmethyl; R ³ Is hydrogen, trifluoromethyl or chloro; R ^a and R ^{b are} independently hydrogen or methyl.

另一實施例包括一種具有下式之化合物： Another embodiment includes a compound having the formula:

或其鹽，其中R¹、R²及R³如針對式I化合物之任何實施例所定義。 Or a salt thereof, wherein R ¹ , R ² and R ^{3 are} as defined for any embodiment of a compound of formula I.

另一實施例包括選自由以下組成之群的化合物：1-[(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]-3-[3-(三氟甲基)苯基]脲；1-[4-氯-3-(三氟甲基)苯基]-3-[(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]脲；1-(3-氯苯基)-3-[(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]脲； 1-[(3R)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]-3-[3-(三氟甲基)苯基]脲；1-[4-氯-3-(三氟甲基)苯基]-3-[(3R)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]脲；1-(3-氯苯基)-3-[(3R)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]脲；(S)-1-(1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基)-3-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)脲；1-[(3S)-1-(2-胺基嘧啶-4-基)吡咯啶-3-基]-3-(3-氯-4-甲基-苯基)脲；1-[(S)-1-(2-胺基-嘧啶-4-基)-吡咯啶-3-基]-3-(4-氯-3-三氟甲基-苯基)-脲；1-[4-氯-3-(三氟甲基)苯基]-3-[(3S)-1-[2-(甲基胺基)嘧啶-4-基]吡咯啶-3-基]脲；1-(3-氯-4-甲基-苯基)-3-[(3S)-1-[2-(甲基胺基)嘧啶-4-基]吡咯啶-3-基]脲；1-[(3S)-1-[2-(甲基胺基)嘧啶-4-基]吡咯啶-3-基]-3-[4-(三氟甲氧基)苯基]脲；1-[4-(二氟甲氧基)苯基]-3-[(3S)-1-[2-(甲基胺基)嘧啶-4-基]吡咯啶-3-基]脲；(S)-1-(4-(氮雜環丁烷-1-基甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(4-(氮雜環丁烷-1-基甲基)-3-氟苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(3-氯-4-((二甲基胺基)甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲； (S)-1-(4-(氮雜環丁烷-1-基甲基)-3-氯苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(3-氯-4-((4-乙基哌嗪-1-基)甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(3-氯-4-(N-嗎啉基甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(4-((二甲基胺基)甲基)-3-(三氟甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(4-(氮雜環丁烷-1-基甲基)-3-(三氟甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)-3-(4-(吡咯啶-1-基甲基)-3-(三氟甲基)苯基)脲；(S)-1-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)-3-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)脲；(S)-1-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)-3-(4-(N-嗎啉基甲基)-3-(三氟甲基)苯基)脲；1-(4-氮雜環丁烷-1-基甲基-3-三氟甲基-苯基)-3-[(S)-1-(2-甲基胺基-嘧啶-4-基)-吡咯啶-3-基]-脲；(S)-1-(1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基)-3-(3-氯-4-甲基苯基)脲；及其醫藥學上可接受之鹽。 Another embodiment comprises a compound selected from the group consisting of 1-[(3S)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidine 3-yl]-3-[3-(trifluoromethyl)phenyl]urea; 1-[4-chloro-3-(trifluoromethyl)phenyl]-3-[(3S)-1- ([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidin-3-yl]urea; 1-(3-chlorophenyl)-3-[(3S) 1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidin-3-yl]urea; 1-[(3R)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidin-3-yl]-3-[3-(trifluoro Methyl)phenyl]urea; 1-[4-chloro-3-(trifluoromethyl)phenyl]-3-[(3R)-1-([1,2,4]triazolo[4, 3-b]pyridazin-6-yl)pyrrolidin-3-yl]urea; 1-(3-chlorophenyl)-3-[(3R)-1-([1,2,4]triazolo [4,3-b]pyridazin-6-yl)pyrrolidin-3-yl]urea; (S)-1-(1-([1,2,4]triazolo[4,3-b] Pyridazin-6-yl)pyrrolidin-3-yl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea; 1-[(3S)-1-(2-Aminopyrimidin-4-yl)pyrrolidin-3-yl]-3-(3-chloro-4-methyl-phenyl)urea; 1-[(S --1-(2-amino-pyrimidin-4-yl)-pyrrolidin-3-yl]-3-(4-chloro-3-trifluoromethyl-phenyl)-urea; 1-[4- Chloro-3-(trifluoromethyl)phenyl]-3-[(3S)-1-[2-(methylamino)pyrimidin-4-yl]pyrrolidin-3-yl]urea; 1-( 3-chloro-4-methyl-phenyl)-3-[(3S)-1-[2-(methylamino)pyrimidin-4-yl]pyrrolidin-3-yl]urea; 1-[( 3S)-1-[2-(methylamino)pyrimidin-4-yl]pyrrolidin-3-yl]-3-[4-(trifluoromethoxy)phenyl]urea; 1-[4- (difluoromethoxy)phenyl]-3-[(3S)-1-[2-(methylamino)pyrimidin-4-yl]pyrrolidin-3-yl]urea; (S)-1- (4-(azetidin-1-ylmethyl)phenyl)-3-(1-(2- (methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea; (S)-1-(4-(azetidin-1-ylmethyl)-3-fluorophenyl) -3-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea; (S)-1-(3-chloro-4-((dimethylamino) Methyl)phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea; (S)-1-(4-(azetidin-1-ylmethyl)-3-chlorophenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl) Pyrrolidin-3-yl)urea; (S)-1-(3-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(1-(2- (Methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea; (S)-1-(3-chloro-4-((4-ethylpiperazin-1-yl)methyl) Phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea; (S)-1-(3-chloro-4-(N-? Polinylmethyl)phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea; (S)-1-(4-((2) Methylamino)methyl)-3-(trifluoromethyl)phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea; (S)-1-(4-(azetidin-1-ylmethyl)-3-(trifluoromethyl)phenyl)-3-(1-(2-(methylamino)pyrimidine) -4-yl)pyrrolidin-3-yl)urea; (S)-1-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)-3-(4 -(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)phenyl)urea; (S)-1-(1-(2-(methylamino)pyrimidin-4-yl)pyrrole Pyridin-3-yl)-3-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea; (S)-1-(4) -((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl) (r)-1-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)-3-(4-(N-? Lolinylmethyl)-3-(trifluoromethyl)phenyl)urea; 1-(4-azetidin-1-ylmethyl-3-trifluoromethyl-phenyl)-3-[ (S)-1-(2-methylamino-pyrimidin-4-yl)-pyrrolidin-3-yl]-urea; (S)-1-(1-([1,2,4]triazole And [4,3-b]pyridazin-6-yl)pyrrolidin-3-yl)-3-(3-chloro-4-methylphenyl)urea; and a pharmaceutically acceptable salt thereof.

另一實施例包括選自以下之化合物： Another embodiment includes a compound selected from the group consisting of:

及其鹽。 And its salt.

用途、調配及投藥Use, formulation and administration 醫藥學上可接受之組合物Pharmaceutically acceptable composition

另一態樣包括一種醫藥組合物，其包含式(I)化合物或其醫藥學上可接受之鹽。在一個實施例中，該組合物進一步包含醫藥學上可接受之載劑、佐劑或媒劑。在另一實施例中，該組合物進一步包含一定量的可有效地適度抑制CDK8之化合物。在某些實施例中，該組合物經調配以便投與有需要之患者。 Another aspect includes a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the composition further comprises a pharmaceutically acceptable carrier, adjuvant or vehicle. In another embodiment, the composition further comprises an amount of a compound that is effective to moderately inhibit CDK8. In certain embodiments, the composition is formulated for administration to a patient in need thereof.

如本文中所使用之術語「患者」或「個體」係指動物，諸如哺乳動物，諸如人類。在一個實施例中，患者或個體係指人類。 The term "patient" or "individual" as used herein refers to an animal, such as a mammal, such as a human. In one embodiment, the patient or system refers to a human.

術語「醫藥學上可接受之載劑、佐劑或媒劑」係指不會破壞用其調配之化合物之藥理學活性的無毒載劑、佐劑或媒劑。可用於本發明組合物之醫藥學上可接受之載劑、佐劑或媒劑包括(但不限於)離子交換劑；氧化鋁；硬脂酸鋁；卵磷脂；血清蛋白，諸如人血清白蛋白；緩衝物質，諸如磷酸鹽；甘胺酸；山梨酸；山梨酸鉀；飽和植物脂肪酸之偏甘油酯混合物；水；鹽或電解質，諸如硫酸魚精蛋白、磷酸氫二鈉、磷酸氫鉀、氯化鈉、鋅鹽；膠狀二氧化矽；三矽酸鎂；聚乙烯吡咯啶酮；纖維素基物質；聚乙二醇；羧甲基纖維素鈉；聚丙烯酸酯；蠟；聚乙烯-聚氧丙烯-嵌段聚合物；聚乙二醇及羊毛脂。 The term "pharmaceutically acceptable carrier, adjuvant or vehicle" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles which can be used in the compositions of the invention include, but are not limited to, ion exchangers; alumina; aluminum stearate; lecithin; serum proteins, such as human serum white eggs White; buffer substances such as phosphate; glycine; sorbic acid; potassium sorbate; a mixture of partial glycerides of saturated plant fatty acids; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium chloride, zinc salt; colloidal cerium oxide; magnesium tricaprate; polyvinylpyrrolidone; cellulose-based material; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylate; wax; Polyoxypropylene-block polymer; polyethylene glycol and lanolin.

包含式I化合物或其鹽之組合物可經口、非經腸、藉由吸入噴霧、經局部、經皮、經直腸、經鼻、經頰、經舌下、經***、經腹膜內、經肺內、經真皮內、經硬膜外或經由植入式貯器投與。本文所使用術語「非經腸」包括皮下、靜脈內、肌肉內、關節內、滑膜內、胸骨內、鞘內、肝內、局部和顱內注射或輸注技術。 A composition comprising a compound of formula I or a salt thereof, can be administered orally, parenterally, by inhalation spray, topically, transdermally, rectally, nasally, buccally, sublingually, transvaginally, intraperitoneally, via Intrapulmonary, intradermal, epidural or via an implantable reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, topical, and intracranial injection or infusion techniques.

在一個實施例中，包含式I化合物或其鹽之組合物係調配為用於經口投與之固體劑型。用於經口投與之固體劑型包括膠囊劑、錠劑、丸劑、散劑及顆粒劑。在某些實施例中，包含式(I)化合物或其鹽之固體經口劑型進一步包含以下各項中之一或多者：(i)醫藥學上可接受之惰性賦形劑或載劑，諸如檸檬酸鈉或磷酸二鈣；及(ii)填充劑或增量劑，諸如澱粉、乳糖、蔗糖、葡萄糖、甘露醇或矽酸；(iii)黏合劑，諸如羧甲基纖維素、海藻酸鹽、明膠、聚乙烯吡咯啶酮、蔗糖或***膠；(iv)濕潤劑，諸如甘油；(v)崩解劑，諸如瓊脂、碳酸鈣、馬鈴薯或木薯澱粉、海藻酸、某些矽酸鹽或碳酸鈉；(vi)溶液阻滯劑，諸如石蠟；(vii)吸收促進劑，諸如四級銨鹽；(viii)潤濕劑，諸如鯨蠟醇或單硬脂酸甘油酯；(ix)吸附劑，諸如高嶺土或膨潤土；及(x)潤滑劑，諸如滑石、硬脂酸鈣、硬脂酸鎂、聚乙二醇或月桂基硫酸鈉。在某些實施例中，將固體經口劑型調配為膠囊劑、錠劑或丸劑。在某些實施例中，固體經口劑型進一步包含緩衝劑。在某些實施例中，用於固體經口劑型之該等組合物可調配為包含一或多種賦形劑(諸如乳糖(lactose)或乳糖(milk sugar)、聚乙二醇及其類似物)之軟填充型明膠膠囊及硬填充型明膠膠囊中之填充物。 In one embodiment, a composition comprising a compound of Formula I or a salt thereof is formulated as a solid dosage form for oral administration. Solid dosage forms for oral administration include capsules, troches, pills, powders, and granules. In certain embodiments, a solid oral dosage form comprising a compound of Formula (I) or a salt thereof further comprises one or more of the following: (i) a pharmaceutically acceptable inert excipient or carrier, Such as sodium citrate or dicalcium phosphate; and (ii) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol or citric acid; (iii) binders such as carboxymethylcellulose, alginic acid Salt, gelatin, polyvinylpyrrolidone, sucrose or gum arabic; (iv) humectants such as glycerin; (v) disintegrants such as agar, calcium carbonate, potato or tapioca, alginic acid, certain citrate Or sodium carbonate; (vi) solution blocker, such as paraffin; (vii) absorption enhancer, such as a quaternary ammonium salt; (viii) a wetting agent, such as cetyl or glyceryl monostearate; (ix) An adsorbent such as kaolin or bentonite; and (x) a lubricant such as talc, calcium stearate, magnesium stearate, polyethylene glycol or sodium lauryl sulfate. In certain embodiments, a solid oral dosage form is formulated as a capsule, lozenge or pill. In certain embodiments, the solid oral dosage form further comprises a buffer. In certain embodiments, such compositions for solid oral dosage forms can be formulated to contain one or more excipients (such as lactose or milk sugar, polyethylene glycol, and the like). Soft filled gelatin Filler in pouches and hard-filled gelatin capsules.

在某些實施例中，包含式I化合物或其鹽之組合物之錠劑、糖衣藥丸、膠囊劑、丸劑及顆粒劑視情況包含塗層或殼體，諸如腸塗層。其可視情況包含遮光劑，且亦可為使其僅或優先在腸道之某一部分中視情況以延遲方式釋放活性成分的組合物。包埋組合物之實例包括聚合物及蠟，其亦可用作使用諸如乳糖或乳糖以及高分子量聚乙二醇及其類似物之賦形劑之軟填充型明膠膠囊及硬填充型明膠膠囊中之填充物。 In certain embodiments, lozenges, dragees, capsules, pills, and granules comprising a composition of a compound of Formula I or a salt thereof, optionally comprise a coating or shell, such as an enteric coating. It may optionally comprise an opacifying agent, and may also be a composition which will release the active ingredient in a delayed manner, as appropriate or preferentially, in a certain portion of the intestinal tract. Examples of the embedding composition include polymers and waxes, which can also be used as soft-filled gelatin capsules and hard-filled gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols and the like. Filler.

在另一實施例中，組合物包含微囊封之式(I)化合物或其鹽，且視情況進一步包含一或多種賦形劑。 In another embodiment, the composition comprises a microencapsulated compound of formula (I) or a salt thereof, and optionally further comprises one or more excipients.

在另一實施例中，組合物包含有包含式I化合物或其鹽之液體劑量調配物以便經口投與，且視情況進一步包含一或多種醫藥學上可接受之乳液、微乳液、溶液、懸浮液、糖漿及酏劑。在某些實施例中，液體劑型視情況進一步包含一或多種惰性稀釋劑，諸如水或其他溶劑、增溶劑及乳化劑，諸如乙醇、異丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苯甲酯、丙二醇、1,3-丁二醇、二甲基甲醯胺、油(詳言之，棉籽油、花生油、玉米油、胚芽油、橄欖油、蓖麻油及芝麻油)、甘油、四氫糠醇、聚乙二醇或脫水山梨糖醇脂肪酸酯及其混合物。在某些實施例中，液體經口組合物視情況進一步包含一或多種佐劑，諸如潤濕劑、懸浮劑、甜味劑、調味劑及香味劑。 In another embodiment, the composition comprises a liquid dosage formulation comprising a compound of Formula I or a salt thereof for oral administration, and optionally further comprising one or more pharmaceutically acceptable emulsions, microemulsions, solutions, Suspensions, syrups and tinctures. In certain embodiments, the liquid dosage form optionally further comprises one or more inert diluents such as water or other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, Benzoyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oil (in detail, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerin , tetrahydrofurfuryl alcohol, polyethylene glycol or sorbitan fatty acid esters and mixtures thereof. In certain embodiments, the liquid oral compositions further comprise one or more adjuvants such as wetting agents, suspending agents, sweetening agents, flavoring agents, and flavoring agents, as appropriate.

可根據已知技術，使用適合分散劑或潤濕劑及懸浮劑來調配可注射製劑，例如無菌可注射水性或油性懸浮液。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、懸浮液或乳液，例如呈1,3-丁二醇溶液形式。可採用之可接受媒劑及溶劑為水、林格氏溶液(Ringer's solution)、U.S.P.及等張氯化鈉溶液。另外，按慣例採用無菌固定油作為溶劑或懸浮介質。出於此目的，可採用任何無刺激固定油，包括合成甘油單酯或二甘油酯。另外，將諸如油酸之脂肪酸用於製備可注射劑。 Injectable preparations, for example, sterile injectable aqueous or oily suspensions, may be employed in accordance with known techniques using dispersible or wetting agents and suspending agents. The sterile injectable preparation may be in the form of a sterile injectable solution, suspension or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, in the form of a solution of 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, Use any non-irritating fixed oil, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

可注射調配物可例如藉由經細菌截留過濾器過濾或藉由併入可在使用前溶解或分散於無菌水或其他無菌可注射介質中呈無菌固體組合物形式之滅菌劑來滅菌。 Injectable formulations can be sterilized, for example, by filtration through a bacterial retention filter or by incorporating a sterilizing agent which can be dissolved or dissolved in sterile water or other sterile injectable medium before use in the form of a sterile solid composition.

為了延長式(I)化合物之效應，通常需要減緩來自於皮下或肌肉內注射之化合物的吸收。此可藉由使用具有不良水溶解度之結晶或非晶材料之液體懸浮液來實現。化合物之吸收速率則視其溶解速率而定，溶解率又可視晶體尺寸及結晶形式而定。或者，藉由將化合物溶解或懸浮於油媒劑中來延遲非經腸投與之化合物形式之吸收。可注射積貯(depot)形式係藉由在生物可降解聚合物(諸如聚丙交酯-聚乙交酯)中形成化合物之微膠囊基質來製備。視化合物與聚合物之比率及所採用之特定聚合物之性質而定，可控制化合物釋放速率。其他生物可降解聚合物之實例包括聚(原酸酯)及聚(酸酐)。亦藉由將化合物包埋於與身體組織相容之脂質體或微乳液中來製備積貯式可注射調配物。 In order to prolong the effect of the compound of formula (I), it is generally desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of a compound depends on its rate of dissolution, which in turn depends on crystal size and crystalline form. Alternatively, absorption of the parenterally administered compound form is delayed by dissolving or suspending the compound in an oil vehicle. The injectable depot form is prepared by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolide. The rate of release of the compound can be controlled depending on the ratio of compound to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). A bulk injectable formulation is also prepared by embedding the compound in a liposome or microemulsion that is compatible with body tissues.

在某些實施例中，將用於經直腸或***投與之組合物調配為栓劑，其可藉由混合式(I)化合物或其鹽與適合之非刺激性賦形劑或載劑來製備，該等賦形劑或載劑為諸如可可脂、聚乙二醇或栓劑蠟，例如在環境溫度為固體但在體溫為液體且因此在直腸或***腔中融化並且釋放式(I)化合物之賦形劑或載劑。 In certain embodiments, a composition for rectal or vaginal administration is formulated as a suppository, which may be prepared by mixing a compound of formula (I) or a salt thereof with a suitable non-irritating excipient or carrier. Such excipients or carriers are, for example, cocoa butter, polyethylene glycol or suppository wax, for example solid at ambient temperature but liquid at body temperature and thus thawed in the rectum or vaginal cavity and release the compound of formula (I) Excipient or carrier.

用於經局部或經皮投與式(I)化合物之例示性劑型包括軟膏、糊劑、乳膏劑、洗劑、凝膠劑、散劑、溶液、噴霧、吸入劑或貼片。在無菌條件下將式(I)化合物或其鹽與醫藥學上可接受之載劑及視情況選用之防腐劑或緩衝劑混合。其他調配物實例包括眼用調配物、耳滴劑、眼滴劑、經皮貼片。經皮劑型可藉由式(I)化合物或其鹽溶解或分散於介質(例如乙醇或二甲亞碸)中製造。亦可使用吸收增強劑來增加化合物越過皮膚之流量。可藉由提供速率控制膜或藉由化合物分散在聚合物基質或凝膠中來控制速率。 Exemplary dosage forms for topical or transdermal administration of a compound of formula (I) include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The compound of formula (I) or a salt thereof is admixed under sterile conditions with a pharmaceutically acceptable carrier and optionally a preservative or buffer. Examples of other formulations include ophthalmic formulations, ear drops, eye drops, transdermal patches. Transdermal dosage forms can be made by dissolving or dispersing a compound of formula (I) or a salt thereof in a medium such as ethanol or dimethylhydrazine. Can also use absorption enhancer to increase The flow of the compound across the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

式(I)化合物或其鹽之經鼻氣霧劑或吸入調配物可採用苯甲醇或其他適合防腐劑、用於提高生物可用性之吸收促進劑、氟碳化物及/或其他常規溶解或分散劑而製備為生理鹽水溶液。 Nasal aerosol or inhalation formulations of a compound of formula (I) or a salt thereof may employ benzyl alcohol or other suitable preservatives, absorption enhancers for improving bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents. It was prepared as a physiological saline solution.

在某些實施例中，可在有或無食物的情況下投與醫藥組合物。在某些實施例中，可在無食物的情況下投與醫藥學上可接受之組合物。在某些實施例中，可將本發明之醫藥學上可接受之組合物與食物一起投與。 In certain embodiments, the pharmaceutical composition can be administered with or without food. In certain embodiments, a pharmaceutically acceptable composition can be administered without food. In certain embodiments, the pharmaceutically acceptable compositions of the invention can be administered with food.

用於任何特定患者之特定劑量及治療方案將視多種因素而定，包括年齡、體重、一般健康狀況、性別、飲食、投藥時間、***速率、藥物組合、治療醫師之判斷及所治療之特定疾病之嚴重程度。組合物中之所提供之式I化合物或其鹽之量亦將視組合物中之特定化合物而定。 The specific dosage and treatment regimen for any particular patient will depend on a number of factors, including age, weight, general health, sex, diet, time of administration, rate of excretion, combination of drugs, judgment of the treating physician, and the particular condition being treated The severity. The amount of a compound of formula I or a salt thereof provided in the composition will also depend on the particular compound in the composition.

在一個實施例中，每劑量中非經腸投與之本發明化合物之治療有效量將在約0.01-100毫克/公斤範圍內，或者約0.1-20毫克/公斤患者體重/天，其中所使用之化合物之典型初始範圍為0.3-15毫克/公斤/天。在另一個實施例中，諸如錠劑及膠囊劑之經口單位劑型含有約5至約100mg本發明化合物。 In one embodiment, the therapeutically effective amount of a compound of the invention administered parenterally in each dose will range from about 0.01 to 100 mg/kg, or from about 0.1 to 20 mg/kg of patient body weight per day, wherein A typical initial range for the compound is 0.3-15 mg/kg/day. In another embodiment, oral unit dosage forms such as tablets and capsules contain from about 5 to about 100 mg of a compound of the invention.

例示性錠劑經口劑型包含約2mg、5mg、25mg、50mg、100mg、250mg或500mg式(I)化合物或其鹽，且進一步包含約95-30mg無水乳糖、約5-40mg交聯羧甲基纖維素鈉、約5-30mg聚乙烯吡咯烷酮(PVP)K30及約1-10mg硬脂酸鎂。調配錠劑之方法包含將粉末狀成分混合在一起及與PVP溶液進一步混合。可乾燥所得組合物、粒化、與硬脂酸鎂混合，且使用常規設備壓製成錠劑形式。可藉由將約2-500mg式I化合物或其鹽溶解於適合緩衝溶液(例如磷酸鹽緩衝液)中且在需要時添加調滲劑(例如鹽，諸如氯化鈉)來製備氣霧劑調配物之一個實例。可例如使用0.2微米過濾器對溶液進行過濾，以移除雜質及污染物。 An exemplary tablet dosage form comprises about 2 mg, 5 mg, 25 mg, 50 mg, 100 mg, 250 mg or 500 mg of a compound of formula (I) or a salt thereof, and further comprises about 95-30 mg of anhydrous lactose, about 5-40 mg of crosslinked carboxymethyl. Cellulose sodium, about 5-30 mg of polyvinylpyrrolidone (PVP) K30 and about 1-10 mg of magnesium stearate. A method of formulating a tablet comprises mixing the powdered ingredients together and further mixing with the PVP solution. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into a tablet form using conventional equipment. About 2-500 mg of a compound of formula I or a salt thereof can be dissolved in a suitable buffer solution (eg, phosphate buffer) and An example of an aerosol formulation is prepared by adding a osmotic agent, such as a salt, such as sodium chloride, as needed. The solution can be filtered, for example, using a 0.2 micron filter to remove impurities and contaminants.

化合物及醫藥學上可接受之組合物之用途Use of the compound and pharmaceutically acceptable composition

另一態樣包括式(I)化合物或其鹽之用途，其係用於抑制CDK8，從而治療疾病，諸如癌症。 Another aspect includes the use of a compound of formula (I) or a salt thereof for inhibiting CDK8, thereby treating a disease, such as cancer.

另一態樣包括一種治療或預防患者之能響應CDK8活性抑制之疾病的方法。該方法包括向有需要之患者投與治療有效量之式(I)化合物或其鹽。 Another aspect includes a method of treating or preventing a disease in a patient that is responsive to inhibition of CDK8 activity. The method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a salt thereof.

另一態樣包括式(I)化合物或其醫藥學上可接受之鹽之用途，其係用於治療。另一態樣包括一種包含式(I)化合物或其醫藥學上可接受之鹽的醫藥組合物之用途，其係用於治療。 Another aspect includes the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy. Another aspect includes the use of a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in therapy.

另一態樣包括一種式(I)化合物或其醫藥學上可接受之鹽的用途，其係用於治療與CDK8活性相關之疾病。 Another aspect includes the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the treatment of a disease associated with CDK8 activity.

另一態樣包括式(I)化合物或其醫藥學上可接受之鹽，其係用作治療活性物質。 Another aspect includes a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a therapeutically active substance.

另一態樣包括式(I)化合物或其醫藥學上可接受之鹽，其係用作治療活性物質以治療過度增殖性病症。 Another aspect includes a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance for the treatment of a hyperproliferative disorder.

在某些實施例中，該疾病或病狀為過度增殖性疾病、癌症、中風、糖尿病、肝腫大、心血管疾病、多發性硬化、阿茲海默氏病(Alzheimer's disease)、囊性纖維化、病毒病、自體免疫疾病、動脈粥樣硬化、再狹窄、牛皮癬、變形性關節炎、發炎性腸病、哮喘、過敏性病症、炎症、神經病症、激素相關之疾病、與器官移植相關之病狀、免疫缺乏病症、毀壞性骨骼病症、增殖性病症、傳染性疾病、與細胞死亡相關之病狀、凝血酶誘導之血小板凝集、肝病、涉及T細胞活化之病理性免疫病狀、CNS病症或脊髓增生性病症。 In certain embodiments, the disease or condition is hyperproliferative disease, cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, multiple sclerosis, Alzheimer's disease, cystic fiber , viral disease, autoimmune disease, atherosclerosis, restenosis, psoriasis, osteoarthritis, inflammatory bowel disease, asthma, allergic conditions, inflammation, neurological disorders, hormone-related diseases, associated with organ transplantation Symptoms, immunodeficiency disorders, destructive skeletal disorders, proliferative disorders, infectious diseases, and Pathogenesis-related conditions, thrombin-induced platelet aggregation, liver disease, pathological immunological conditions involving T cell activation, CNS disorders, or spinal proliferative disorders.

在某些實施例中，可在已罹患一或多種症狀之後投與治療。在其他實施例中，治療可在不存在症狀時投與。舉例而言，治療可在症狀發作之前投與易感個體(例如根據症狀病史及/或根據遺傳或其他易感性因素)。治療亦可在症狀已消退之後繼續進行，例如以預防或延遲其復發。 In certain embodiments, the treatment can be administered after one or more symptoms have been suffered. In other embodiments, the treatment can be administered in the absence of symptoms. For example, treatment can be administered to a susceptible individual prior to the onset of symptoms (eg, based on a history of symptoms and/or according to genetic or other susceptibility factors). Treatment can also continue after the symptoms have subsided, for example to prevent or delay their recurrence.

另一態樣包括一種用於治療、改善或預防癌症、抗藥性癌症或另一增殖性病症之方法，該方法係藉由向需要該治療之哺乳動物(例如人類)投與有效量之式(I)化合物或其鹽。在某些實施例中，欲治療之疾病為癌症或抗藥性癌症。 Another aspect includes a method for treating, ameliorating or preventing cancer, drug-resistant cancer, or another proliferative disorder by administering an effective amount to a mammal (eg, a human) in need of such treatment ( I) a compound or a salt thereof. In certain embodiments, the disease to be treated is a cancer or a drug resistant cancer.

可使用本文中所描述之化合物及方法治療之癌症的實例包括(但不限於)腎上腺癌、腺泡細胞癌、聽神經瘤、肢端雀斑樣黑素瘤、肢端汗腺瘤、急性嗜伊紅白血球性白血病、急性紅血球性白血病、急性淋巴母細胞性白血病、急性巨核母細胞白血病、急性單核細胞性白血病、急性前髓細胞白血病、腺癌、腺樣囊性癌、腺瘤、腺瘤樣牙原性腫瘤、腺鱗癌、脂肪組織贅瘤、腎上腺皮質癌、成人T細胞白血病/淋巴瘤、侵襲性NK細胞白血病、AIDS相關淋巴瘤、腺泡狀橫紋肌肉瘤、肺泡柔軟部分肉瘤、釉母細胞纖維瘤、退行性大細胞淋巴瘤、退行性甲狀腺癌、雄激素依賴性癌症、血管免疫胚細胞T細胞淋巴瘤、血管肌脂瘤、血管肉瘤、星形細胞瘤、非典型畸胎樣桿狀腫瘤、B細胞慢性淋巴細胞性白血病、B細胞淋巴瘤、基底細胞癌、膽道癌、膀胱癌、母細胞瘤、骨癌、布倫納腫瘤(Brenner tumor)、布朗腫瘤(Brown tumor)、伯基特淋巴瘤(Burkitt's lymphoma)、乳癌、腦癌、癌瘤、原位癌、癌肉瘤、軟骨腫瘤、牙骨質瘤、脊髓肉瘤、軟骨瘤、脊索瘤、絨毛膜癌、脈絡叢乳頭狀瘤、腎透明細胞肉瘤、顱咽管瘤、皮膚T細胞淋巴瘤、子宮頸癌、結腸直腸癌、德戈斯病(Degos disease)、促結締組織增生性小圓細胞腫瘤、擴散性大B細胞淋巴瘤、胚胎發育不良性神經上皮腫瘤、無性細胞瘤、胚胎癌、內分泌腺贅瘤、內胚層竇瘤、腸病相關T細胞淋巴瘤、食道癌、胎中胎、纖維瘤、纖維肉瘤、濾泡性淋巴瘤、濾泡性甲狀腺癌、神經節細胞瘤、胃腸癌、生殖細胞腫瘤、妊娠期絨毛膜癌、巨細胞纖維母細胞瘤、骨骼巨細胞腫瘤、神經膠質腫瘤、多形性膠質母細胞瘤、神經膠質瘤、大腦神經膠瘤病、升糖素瘤、性腺母細胞瘤、粒層細胞瘤、兩性胚細胞瘤、膽囊癌、胃癌、血管母細胞瘤、頭頸癌、血管外皮瘤、血液惡性病、肝母細胞瘤、肝脾T細胞淋巴瘤、霍奇金氏淋巴瘤(Hodgkin's lymphoma)、非霍奇金氏淋巴瘤(non-Hodgkin's lymphoma)、侵襲性小葉癌、腸癌、腎癌、喉癌、惡性小痣、白血病、萊氏細胞腫瘤(leydig cell tumor)、脂肉瘤、肺癌、***瘤、***肉瘤、淋巴上皮癌、淋巴瘤、急性淋巴細胞性白血病、急性粒細胞白血病、慢性淋巴細胞性白血病、肝癌、小細胞肺癌、非小細胞肺癌、MALT淋巴瘤、惡性纖維組織細胞瘤、惡性周圍神經鞘腫瘤、惡性蠑螈瘤、套細胞淋巴瘤、邊緣區B細胞淋巴瘤、肥大細胞白血病、縱隔生殖細胞腫瘤、***髓性癌、髓性甲狀腺癌、髓母細胞瘤、黑素瘤、腦膜瘤、梅克爾細胞癌(merkel cell cancer)、間皮瘤、轉移性尿道上皮癌、混合型苗勒氏腫瘤(mixed Mullerian tumor)、黏質腫瘤、多發性骨髓瘤、肌肉組織贅瘤、蕈樣真菌病、黏液樣脂肉瘤、黏液瘤、黏液肉瘤、鼻咽癌、神經鞘瘤、神經母細胞瘤、纖維神經瘤、神經瘤、小節黑素瘤、眼癌、少突星形細胞瘤、少突神經膠質瘤、嗜酸性腺瘤、視神經鞘腦膜瘤、視神經腫瘤、口腔癌、骨肉瘤、卵巢癌、潘科斯特腫瘤(Pancoast tumor)、乳頭狀甲狀腺癌、副神經節瘤、松果體母細胞瘤、松果體母細胞瘤、垂體細胞瘤、垂體腺瘤、垂體腫瘤、漿細胞瘤、多胚瘤、前驅T-淋巴母細胞淋巴瘤、原發性中樞神經系統淋巴瘤、原發性滲出性淋巴瘤、原發性腹膜癌、***癌、胰臟癌、咽癌、腹膜假性黏液瘤、腎細胞癌、腎髓性癌、視網膜母細胞瘤、橫紋肌瘤、橫紋肌肉瘤、李希特氏轉化(Richter's transformation)、直腸癌、肉瘤、神經鞘瘤(Schwannomatosis)、精原細胞瘤、塞特利氏細胞腫瘤、生殖索性腺基質細胞腫瘤、印戒細胞癌、皮膚癌、小藍圓細胞腫瘤、小細胞癌、軟組織肉瘤、生長抑素瘤、煤煙疣、脊髓腫瘤、脾邊緣區淋巴瘤、鱗狀細胞癌、滑膜肉瘤、塞紮里病(Sezary's disease)、小腸癌、胃癌、T細胞淋巴瘤、睾丸癌、泡膜細胞瘤、甲狀腺癌、移行細胞癌、咽癌、臍尿管癌、泌尿生殖器癌、尿道上皮癌、葡萄膜黑素瘤、子宮癌、疣狀癌、視通路膠質瘤、外陰腫瘤、***癌、瓦爾登斯特倫巨球蛋白血症(Waldenstrom's macroglobulinemia)、沃辛腫瘤(Warthin's tumor)及威爾姆斯腫瘤(Wilms' tumor)。 Examples of cancers that can be treated using the compounds and methods described herein include, but are not limited to, adrenal cancer, acinar cell carcinoma, acoustic neuroma, acral freckle-like melanoma, acromegaly, acute eosinophils Leukemia, acute erythrocytic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenoma-like teeth Primary tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T cell leukemia/lymphoma, invasive NK cell leukemia, AIDS-associated lymphoma, alveolar rhabdomyosarcoma, alveolar soft sarcoma, glazed cells Fibroids, degenerative large cell lymphoma, degenerative thyroid cancer, androgen-dependent cancer, vascular immune blast T cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rod Tumor, B cell chronic lymphocytic leukemia, B cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, cloth Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementum, spinal sarcoma, Chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, renal clear cell sarcoma, craniopharyngioma, skin T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, connective tissue proliferative small round cell tumor, diffuse large B-cell lymphoma, embryonic dysplastic neuroepithelial neoplasm, no Stromal cell, embryonic carcinoma, endocrine adenoma, endoderm sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetal mid-fetal, fibroid, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, Ganglion cell tumor, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of bone, glial tumor, glioblastoma multiforme, glioma, brain neuroglioma Disease, glioma, gonadal tumor, granulosa cell tumor, amphoteric blastoma, gallbladder cancer, gastric cancer, hemangioblastoma, head and neck cancer, vascular epithelioma, hematological malignancies, hepatoblastoma, liver and spleen T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, colon cancer, kidney cancer, laryngeal cancer, malignant sputum, leukemia Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphatic epithelial carcinoma, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, liver cancer, small Cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant neoplasm, mantle cell lymphoma, marginal zone B cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, Breast myeloid carcinoma, myeloid thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed mullerian tumor (mixed Mullerian tumor), mucinous tumor, multiple myeloma, muscle tissue tumor, mycosis fungoid, mucinous liposarcoma, myxoma, mucinous sarcoma, nasopharyngeal carcinoma, schwannomas, neuroblastoma, fibromas , neuroma, melanoma, eye cancer, oligodendroglioma, oligodendroglioma, eosinophilic adenoma, optic nerve sheath meningioma, optic nerve Tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid carcinoma, paraganglioma, pineal blastoma, pineal blastoma, pituitary cell tumor, pituitary gland Tumor, pituitary tumor, plasmacytoma, multi-embryo, pre- Drive T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary exudative lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, peritoneal pseudomyxoma, renal cells Cancer, renal myeloma, retinoblastoma, rhabdomyosarcoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, and Settle's cells Tumor, reproductive gonad stromal cell tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumor, small cell carcinoma, soft tissue sarcoma, somatostatin tumor, soot, spinal cord tumor, spleen marginal lymphoma, squamous cell Cancer, synovial sarcoma, Sezary's disease, small bowel cancer, gastric cancer, T-cell lymphoma, testicular cancer, vesicular cell tumor, thyroid cancer, transitional cell carcinoma, pharyngeal cancer, urachal cancer, genitourinary Cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar tumor, vaginal cancer, Waldenstrom's macroglobulinemia , Warthin's tumor and Wilms' tumor.

另一實施例包括一種用於治療良性增殖性病症之方法。良性增殖性病症之實例(但不限於)良性軟組織腫瘤、骨腫瘤、腦及脊髓腫瘤、眼瞼及眼眶腫瘤、肉芽瘤、脂瘤、腦膜瘤、多發性內分泌瘤、鼻息肉、垂體瘤、泌乳素瘤、假性腦瘤、皮脂溢性角化症、胃息肉、甲狀腺節結、胰臟膀胱贅瘤、血管瘤、聲帶節結、息肉及囊腫、卡斯特曼病(Castleman disease)、慢性藏毛病、皮膚纖維瘤、毛髮囊腫、膿性肉芽腫及青少年息肉症候群。 Another embodiment includes a method for treating a benign proliferative disorder. Examples of benign proliferative disorders (but not limited to) benign soft tissue tumors, bone tumors, brain and spinal cord tumors, orbital and orbital tumors, granuloma, lipoma, meningiomas, multiple endocrine neoplasms, nasal polyps, pituitary tumors, prolactin Tumor, pseudo-brain tumor, seborrheic keratosis, gastric polyps, thyroid nodules, pancreatic bladder tumor, hemangioma, vocal cord nodules, polyps and cysts, Castleman disease, chronic Problems, cutaneous fibroids, hair cysts, purulent granuloma and adolescent polyp syndrome.

另一實施例包括式I化合物或其鹽之用途，其係用於製造可用於治療及/或預防及/或改善如本文中所提及之疾病、病症、病情及/或病狀之醫藥組合物。 Another embodiment comprises the use of a compound of formula I or a salt thereof for the manufacture of a pharmaceutical combination useful for the treatment and/or prevention and/or amelioration of a disease, disorder, condition and/or condition as referred to herein. Things.

另一實施例包括式I化合物或其鹽之用途，其係用於製造可用於治療及/或預防對CDK8抑制有反應或敏感之疾病及/或病症，詳言之如上文所提及之疾病(諸如癌症)的醫藥組合物。 Another embodiment comprises the use of a compound of formula I or a salt thereof for the manufacture of a disease and/or condition useful for the treatment and/or prevention of response or inhibition of CDK8, in particular as described above. A pharmaceutical composition (such as cancer).

可使用能有效治療病症或減輕病症之嚴重程度的任何量及任何投藥途徑來投與式(I)化合物或其鹽。視患者之物種、年齡及一般病狀，例如病症嚴重程度、特定化合物、其投與模式及其類似物，所需精確量將因患者而異。指定患者使用式(I)化合物之總每日用量將由主治醫師在合理醫學判斷範疇內決定。用於任何特定患者之特定有效劑量水平將視多種因素而定，包括所治療之病症及病症之嚴重程度；所採用之特定化合物之活性；所採用之特定組合物；患者之年齡、體重、一般健康狀況、性別及飲食；所採用之特定化合物之投藥時間、投藥途徑及***速率；治療持續時間；與所採用之特定化合物組合使用或相符合的藥物；及醫學技術中熟知之類似因素。 The compound of formula (I) or a salt thereof can be administered in any amount and in any route of administration effective to treat or alleviate the severity of the condition. Depending on the patient's species, age, and general condition, such as the severity of the condition, the particular compound, its mode of administration, and its analogs, the exact amount required will vary from patient to patient. The total daily usage of the compound of formula (I) for a given patient will be determined by the attending physician within the scope of sound medical judgment. The particular effective dosage level for any particular patient will depend on a number of factors, including the severity of the condition or condition being treated; the activity of the particular compound employed; the particular composition employed; the age, weight, and general Health status, gender and diet; time of administration, route of administration and rate of excretion of the particular compound employed; duration of treatment; drugs used or compatible with the particular compound employed; and similar factors well known in the medical arts.

另一實施例包括一種抑制生物樣品中之CDK8活性之方法，其包含使該生物樣品與式I化合物或其鹽接觸。 Another embodiment includes a method of inhibiting CDK8 activity in a biological sample comprising contacting the biological sample with a compound of Formula I or a salt thereof.

如本文所使用之術語「生物樣本」包括(而不限於)細胞、細胞培養物或其萃取物；獲自哺乳動物之活組織檢查材料或其萃取物；及血液、唾液、尿液、糞便、***、淚液或其他體液或其萃取物。 The term "biological sample" as used herein includes, without limitation, cells, cell cultures or extracts thereof; biopsies obtained from mammals or extracts thereof; and blood, saliva, urine, feces, Semen, tears or other body fluids or their extracts.

共同投與化合物及其他藥劑Co-administering compounds and other pharmaceutical agents

式(I)化合物或其鹽可單獨或與其他治療藥劑組合使用。舉例而言，醫藥組合調配物或給藥方案之第二藥劑可與式(I)化合物具有互補活性，從而其不會對彼此造成不利影響。該等化合物可於整體醫藥組合物中一起或分開投與。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治療增殖性疾病及癌症。 The compound of formula (I) or a salt thereof can be used alone or in combination with other therapeutic agents. For example, a second agent of a pharmaceutical combination formulation or dosing regimen can have complementary activities with a compound of formula (I) such that it does not adversely affect each other. The compounds can be administered together or separately in the overall pharmaceutical composition. In one embodiment, the compound or pharmaceutically acceptable salt can be co-administered with a cytotoxic agent to treat a proliferative disease and cancer.

術語「共同投與」係指同時投與式(I)化合物或其鹽及其他活性醫藥成分(包括細胞毒性劑及輻射處理)或其任何按順序分開投與方式。若不同時投與，則化合物係在彼此密切接近之時間投與。此外，即使化合物於同一劑型中投與亦不重要，例如一種化合物可經局部投與，而另一種化合物可經口投與。 The term "co-administered" means the simultaneous administration of a compound of formula (I) or a salt thereof and other active pharmaceutical ingredients (including cytotoxic agents and radiation treatment) or any of their sequential administration. If not administered at the same time, the compounds are administered at a time close to each other. Furthermore, it is not important even if the compound is administered in the same dosage form, for example one compound may be administered topically and the other compound may be administered orally.

典型地，對所治療之疾病或病狀具有活性的任何藥劑均可共同投與。該等藥劑之實例可見於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。熟習此項技術者應能夠基於藥物之特定特徵及所涉及之疾病來辨別何種藥劑組合將適用。 Typically, 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 (ed.), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. Those skilled in the art should be able to discern which combination of agents will be applicable based on the particular characteristics of the drug and the disease involved.

在一個實施例中，該治療方法包括共同投與式(I)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」係指抑制或防胞功能及/或引起細胞死亡或破壞的物質。細胞毒性劑包括(但不限於)放射性同位素(例如At²¹¹、I¹³¹、I¹²⁵、Y⁹⁰、Re¹⁸⁶、Re¹⁸⁸、Sm¹⁵³、Bi²¹²、P³²、Pb²¹²及Lu之放射性同位素)；化學治療劑；生長抑制劑；酶及其片段，諸如核分解酶；及毒素，諸如細菌、真菌、植物或動物來源之小分子毒素或酶活性毒素，包括其片段及/或變異體。 In one embodiment, the method of treatment comprises co-administering a compound of formula (I), 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 cell function and/or causes cell death or destruction. Cytotoxic agents include, but are not limited to, radioisotopes (eg, radioactive isotopes of At ²¹¹ , I ¹³¹ , I ¹²⁵ , Y ⁹⁰ , Re ¹⁸⁶ , Re ¹⁸⁸ , Sm ¹⁵³ , Bi ²¹² , P ³² , Pb ^{212 ,} and Lu); Therapeutic agents; 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.

例示性細胞毒性劑可選自抗微管劑、鉑配位錯合物、烷基化劑、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抑制劑；脂肪酸生物合成抑制劑；細胞週期信號傳導抑制劑；HDAC抑制劑、蛋白酶體抑制劑；及癌症代謝抑制劑。 Exemplary cytotoxic agents can be selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and Hormone analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutics, pro-apoptotic agents, LDH-A inhibitors; fatty acid biosynthesis inhibitors; cell cycle signaling inhibitors HDAC inhibitors, proteasome inhibitors; and cancer metabolism inhibitors.

「化學治療劑」包括適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.)、二硫龍(disulfiram)、表沒食子兒茶素沒食子酸酯、沙林泊拉米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)、費那舒奈(finasunate)(VATALANIB^®，Novartis)、奧沙利鉑(oxaliplatin)(ELOXATIN^®，Sanofi)、5-FU(5-氟尿嘧啶)、甲醯四氫葉酸、雷帕黴素(Rapamycin)(西羅莫司(Sirolimus)，RAPAMUNE^®，Wyeth)、拉帕替尼(Lapatinib)(TYKERB^®，GSK572016，Glaxo Smith Kline)、羅那法米(Lonafamib)(SCH 66336)、索拉非尼(NEXAVAR^®，Bayer Labs)、吉非替尼(gefitinib)(IRESSA^®，AstraZeneca)、AG1478；烷基化劑，諸如噻替派(thiotepa)及CYTOXAN^®環磷醯胺；磺酸烷基酯，諸如白消安(busulfan)、英丙舒凡(improsulfan)及哌泊舒凡(piposulfan)；氮丙啶，諸如苯佐替派(benzodopa)、卡波醌(carboquone)、美妥替哌(meturedopa)及烏瑞替派(uredopa)；伸乙基亞胺及羥甲基三聚氰胺，包括六甲密胺(altretamine)、三伸乙基密胺、三伸乙基磷醯胺、三伸乙基硫代磷醯胺及三羥甲基三聚氰胺；番荔枝內酯(尤其是布拉它辛(bullatacin)及布拉它辛酮(bullatacinone))；喜樹鹼(包括拓朴替康(topotecan)及伊立替康(irinotecan))；苔蘚抑素(bryostatin)；卡利他汀(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(cryptophycins)(詳言之念珠藻素1及念珠藻素8)；腎上腺類固醇(包括潑尼松(prednisone)及潑尼龍(prednisolone))；醋酸賽普羅特博(cyproterone acetate)；5α-還原酶，包括非那雄安(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)；阿地白介素、滑石度卡黴素(包括合成類似物KW-2189及CB1-TM1)；艾榴塞洛素(eleutherobin)；水鬼蕉鹼(pancratistatin)；珊瑚素(sarcodictyin)；海綿素 (spongistatin)；氮芥類，諸如苯丁酸氮芥、萘氮芥(chlomaphazine)、氯環磷醯胺(chlorophosphamide)、雌氮芥、異環磷醯胺(ifosfamide)、甲氮芥、氧化甲氮芥鹽酸鹽、***酸氫芥、新恩比興(novembichin)、苯芥膽固醇(phenesterine)、潑尼氮芥(prednimustine)、曲洛磷胺(trofosfamide)、尿嘧啶氮芥；亞硝基脲，諸如卡莫司汀(carmustine)、氯脲菌素(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(例如卡奇黴素，尤其是卡奇黴素γ1I及卡奇黴素ω1I(Angew Chem.Intl.Ed.Engl.1994 33：183-186)；達內黴素(dynemicin)，包括達內黴素A；二膦酸鹽，諸如氯膦酸鹽；埃斯培拉黴素(esperamicin)；以及新制癌菌素發色團及相關色蛋白烯二炔抗生素發色團)、阿克拉黴素(aclacinomysins)、放線菌素(actinomycin)、安麯黴素(authramycin)、重氮絲胺酸(azaserine)、爭光黴素(bleomycins)、放線菌素C(cactinomycin)、卡柔比星(carabicin)、洋紅黴素(caminomycin)、嗜癌菌素(carzinophilin)、色黴素(chromomycinis)、放線菌素D(dactinomycin)、道諾黴素(daunorubicin)、阿黴素(detorubicin)、6-重氮-5-側氧基-L-正白胺酸、ADRIAMYCIN^®(阿黴素)、N-嗎啉基阿黴素、氰基(N-嗎啉基)阿黴素、2-吡咯啉基阿黴素及脫氧阿黴素)、表柔比星(epirubicin)、依索比星(esorubicin)、伊達比星(idarubicin)、麻西羅黴素(marcellomycin)、絲裂黴素(mitomycins)(諸如絲裂黴素C)、黴酚酸(mycophenolic acid)、諾加黴素(nogalamycin)、橄欖黴素(olivomycins)、培洛黴素(peplomycin)、泊非黴素(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)、淨司他丁(zinostatin)、佐柔比星(zorubicin)；抗代謝物，諸如胺甲蝶呤及5-氟尿嘧啶(5-FU)；葉酸類似物，諸如二甲葉酸、胺甲蝶呤、蝶羅呤(pteropterin)、曲美沙特(trimetrexate)；嘌呤類似物，諸如氟達拉濱(fludarabine)、6-巰基嘌呤、硫咪嘌呤(thiamiprine)、硫鳥嘌呤；嘧啶類似物，諸如環胞苷、阿紮胞苷、6-氮尿苷、卡莫氟(carmofur)、阿糖胞苷、二脫氧尿苷、去氧氟尿苷(doxifluridine)、依諾他濱(enocitabine)、氟尿苷；雄激素，諸如二***、丙酸屈他雄酮(dromostanolone propionate)、環硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾內酯；抗腎上腺，諸如胺魯米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane)；葉酸補充劑，諸如亞葉酸；醋葡內酯；醛磷醯胺糖苷；胺基乙醯丙酸；恩尿嘧啶(eniluracil)；安吖啶(amsacrine)；貝他布昔(bestrabucil)；比生群(bisantrene)；依達曲沙(edatraxate)；地磷醯胺(defofamine)；秋水仙胺(demecolcine)；地吖醌(diaziquone)；依洛尼塞(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；氯尼達明(lonidainine)；美登素，諸如美坦辛及安絲菌素(ansamitocins)；丙脒腙(mitoguazone)；米托蒽醌(mitoxantrone)；莫哌達醇(mopidamnol)；硝呋旦(nitraerine)；噴司他丁(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^®多糖複合物(JHS Natural Products,Eugene,Oreg.)；雷佐生(razoxane)；根瘤菌素(rhizoxin)；西索菲蘭(sizofuran)；鍺螺胺(spirogermanium)；細交鏈孢菌酮酸(tenuazonic acid)；三亞胺醌(triaziquone)；2,2',2"-三氯三乙胺；單端孢菌素(尤其是T-2毒素、黏液黴素A(verracurin A)、漆斑菌素A(roridin A)及蛇形菌素(anguidine))；尿烷(urethan)；長春地辛(vindesine)；達卡巴嗪 (dacarbazine)；甘露醇氮芥；二溴甘露醇；二溴衛矛醇(mitolactol)；哌泊溴烷(pipobroman)；加西托辛(gacytosine)；***糖苷(「Ara-C」)；環磷醯胺；噻替派；紫杉烷，例如TAXOL(紫杉醇；Bristol-Myers Squibb Oncology,Princeton，N.J.)、ABRAXANE^®(無氫化蓖麻油)、紫杉醇之白蛋白工程改造之奈米粒子調配物(American Pharmaceutical Partners，Schaumberg，Ill.)及TAXOTERE^®(多西他賽(docetaxel)、多烯紫杉醇(doxetaxel)；Sanofi-Aventis)；苯丁酸氮芥；GEMZAR^®(吉西他濱)；6-硫代鳥嘌呤；巰基嘌呤；胺甲蝶呤；鉑類似物，諸如順鉑(cisplatin)及卡鉑(carboplatin)；長春花鹼；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))；諾消靈(novantrone)；替尼泊苷(teniposide)；依達曲沙；道諾黴素；胺基蝶呤；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)；類視黃素，諸如視黃酸；及上述任一者之醫藥學上可接受之鹽、酸及衍生物。 "Chemotherapeutic agents" include compounds that are useful in the treatment of cancer. Examples of chemotherapeutic agents include erlotinib (TARCEVA ^® , Genentech/OSI Pharm.), bortezomib (VELCADE ^® , Millennium Pharm.), disulfiram, epidermis Catechin gallate, salinosporamide A, carfilzomib, 17-AAG (geldanamycin), radicicol , lactate dehydrogenase A (LDH-A), fulvestrant (FASLODEX ^® , AstraZeneca), sunitini (Sunitent ^® , Pfizer / Sugen), letrozole (FEMARA) ^® , Novartis), imatinib mesylate (GLEEVEC ^® , Novartis), finasunate (VATALANIB ^® , Novartis), oxaliplatin (ELOXATIN ^® , Sanofi), 5-FU (5-fluorouracil), formazan tetrahydrofolate, rapamycin (Sirolimus, RAPAMUNE ^® , Wyeth), Lapatinib (TYKERB ^® , GSK572016, Glaxo Smith Kline), Lonafamib (SCH 66336), Solafenib (NEXAVAR ^® , Bayer Labs), gefitinib (IRESSA ^{® )} , AstraZeneca), AG1478; alkylating agents, such as Thiotepa (Thiotepa) and CYTOXAN ^® cyclophosphamide; alkyl sulfonates such as busulfan (busulfan), where English C Shu (improsulfan) piperazine and poise Piposulfan; aziridine, such as benzodopa, carboquone, meturedopa and uredopa; ethyl imino and hydroxymethyl Melamine, including altretamine, tri-ethyl melamine, tri-ethylphosphoniumamine, tri-ethyl thiophosphonamide and trimethylol melamine; lychee lactone (especially cloth) Bullatacin (bullatacinone); camptothecin (including topotecan and irinotecan); bryostatin; calstatin ); CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); cryptophycins (detailed spirulina 1) And spirulina 8); adrenal steroids (including prednisone and prednisolone); cyproterone ac Etate); 5α-reductase, including finasteride and dutasteride; vorinostat, romidepsin, panobinostat, Valproic acid, mocetinostat, dolastatin, arsenic, talc, and synthetic analogues KW-2189 and CB1-TM1; eleutherobin ); pancratistatin; sarcodictyin; spongistatin; nitrogen mustard, such as chlorambucil, chlomaphazine, chlorophosphamide, female Nitrogen mustard, ifosfamide, methotrexate, nitrous oxide mustard hydrochloride, amphetamine hydrogenated mustard, neombibichin, phenesterine, prednimustine ), trofosfamide, uracil mustard; nitrosourea, such as carmustine, chlorozotocin, fotemustine, lomustine ( Lomustine), nimustine and ranimnustine; antibiotics, such as enediyne antibiotics ( The calicheamicin, especially calicheamicin γ1I and calicheamicin ω1I (Angew Chem.Intl.Ed.Engl 1994 33:. 183-186); of the neomycin (dynemicin), comprising of the ADM A; bisphosphonates, such as clodronate; esperamicin; and new carotenoid chromophores and related chromoprotein diacetylene antibiotic chromophores, aclacinomysins ), actinomycin, authramycin, azaserine, bleomycins, cactinomycin, caraceptin, magentia Caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5- oxo-L-normal leucine, ADRIAMYCIN ^® (doxorubicin), N-morpholinyl doxorubicin, cyano (N-morpholinyl) doxorubicin, 2-pyrroline-based doxorubicin and Deoxytetracycline), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins (such as Mitomycin) C), mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, three Quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, net Zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as dimethyl folate, methotrexate, pteridophyte (pteropterin), trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as cyclocytidine, Cytosine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, dexifluridine, enocitabine, fluorouridine; androgen , such as dimethyltestosterone, dromostanolone propionate, epitiostanol, metoprolol (mepitio) Stane), testosterone; anti-adrenal, such as aminoglutethimide, mitotane, trilostane; folic acid supplements, such as folinic acid; acenolactone; Aminoglycoside; alanine; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; Defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; epothilone; etoglucid; Gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansine, such as maytansin and ansamitocins; mitoguazone; mitoxantrone; Mopidamnol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic Acid); 2-ethyl hydrazine; procarbazine; PSK ^® polysaccharide complex (JHS Natural P Roducts, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; Triaziquone; 2,2',2"-trichlorotriethylamine; trichothecene (especially T-2 toxin, verracurin A, roridin A) And angudin; urethan; vindesine; dacarbazine; mannitol mustard; dibromomannitol; dipothalol (mitolactol); Pipobroman; gacytosine; arabinoside ("Ara-C");cyclophosphamide;thiotepa; taxane, such as TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE ^® (no hydrogenated castor oil), paclitaxel albumin engineered nanoparticle formulation (American Pharmaceutical Partners, Schaumberg, Ill.) and TAXOTERE ^® (docetaxel, docetaxel ( doxetaxel); Sanofi-Aventis); chlorambucil; GEMZAR ^® (gemcitabine); 6-thioguanine; mercaptopurine; carbamoyl butterfly Platinum analogues such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); methotrexate; mitoxantrone; vincristine ); NAVELBINE ^® (vinorelbine); Novantrone; teniposide; edacoxacin; daunorubicin; aminopterin; capecitabine (XELODA ^® ); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; Any of the pharmaceutically acceptable salts, acids and derivatives.

化學治療劑亦包括：(i)可用於調節或抑制對腫瘤之激素作用的抗激素劑，諸如抗***及選擇性***受體調節劑(SERM)，包括例如他莫西芬(包括NOLVADEX^®；檸檬酸他莫西芬)、雷洛昔芬(raloxifene)、屈洛昔芬(droloxifene)、依多昔芬(iodoxyfene)、4-羥基他莫西芬、曲沃昔芬(trioxifene)、雷洛西芬(keoxifene)、LY117018、奧那司酮(onapristone)及FARESTON^®(檸檬酸托瑞米芬(toremifine citrate))；(ii)抑制在腎上腺中調節***產生之芳香酶之芳香酶抑制劑，諸如4(5)-咪唑、胺魯米特、MEGASE^®(甲地孕酮)、AROMASIN^®(依西斯坦；Pfizer)、福美司坦(formestanie)、法屈唑(fadrozole)、RIVISOR^®(伏氯唑(vorozole))、FEMARA^®(來曲唑； Novartis)及ARIMIDEX^®(阿那曲唑；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)及歌舍瑞林(goserelin)；布舍瑞林(buserelin)、曲普瑞林(tripterelin)、醋酸甲羥孕酮、二乙基己烯雌酚、普雷馬林、氟***(fluoxymesterone)、全反式維甲酸、芬維A胺(fenretinide)，以及曲沙他濱(troxacitabine)(1,3-二氧戊環核苷胞嘧啶類似物)；(iv)蛋白激酶抑制劑；(v)脂質激酶抑制劑；(vi)反義寡核苷酸，詳言之抑制牽涉異常細胞增殖之信號傳導路徑中之基因表現的反義寡核苷酸，諸如PKC-α、Ralf及H-Ras；(vii)核糖酶，諸如VEGF表現抑制劑(例如ANGIOZYME^®)及HER2表現抑制劑；(viii)疫苗，諸如基因治療疫苗，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)上述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 that can be used to modulate or inhibit the hormonal effects on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX) ^® ; tamoxifen citrate), raloxifene, droloxifene, iodoxyfene, 4-hydroxytamoxifen, trioxifene, Keoxifene, LY117018, onapristone, and FARESTON ^® (toremifine citrate); (ii) aromatase that inhibits the regulation of estrogen-producing aromatase in the adrenal gland Inhibitors such as 4(5)-imidazole, amine ubmetazole, MEGASE ^® (Megestrol), AROMASIN ^® (Ethistein; Pfizer), formestanie, fadrozole, RIVISOR ^® (vorozole), FEMARA ^® (letrozole; Novartis) and ARIMIDEX ^® (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide Nilutamide), bicalutamide, leuprolide and goserelin; Buscheri (buserelin), tripterelin, medroxyprogesterone acetate, diethylstilbestrol, premarin, fluoxymesterone, all-trans retinoic acid, fenretinide, and Troxacitabine (1,3-dioxolan nucleoside cytosine analog); (iv) protein kinase inhibitor; (v) lipid kinase inhibitor; (vi) antisense oligonucleotide, In particular, antisense oligonucleotides that inhibit the expression of genes involved in the signaling pathway of abnormal cell proliferation, such as PKC-α, Ralf, and H-Ras; (vii) ribozymes, such as VEGF expression inhibitors (eg, ANGIOZYME ^® And (egiii) 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) pharmaceutically acceptable salts, acids and derivatives of any of the above.

化學治療劑亦包括抗體，諸如阿侖單抗(alemtuzumab)(Campath)、貝伐單抗(bevacizumab)(AVASTIN®，Genentech)；西妥昔單抗(cetuximab)(ERBITUX®，Imclone)；帕尼單抗(panitumumab)(VECTIBIX®，Amgen)、利妥昔單抗(rituximab)(RITUXAN®，Genentech/Biogen Idec)、帕妥珠單抗(pertuzumab)(OMNITARG®，2C4，Genentech)、曲妥珠單抗(trastuzumab)(HERCEPTIN®，Genentech)、托西莫單抗(tositumomab)(Bexxar，Corixia)及抗體藥物結合物吉妥珠單抗奧唑米星(gemtuzumab ozogamicin)(MYLOTARG®，Wyeth)。具有作為與本發明化合物組合之藥劑之治療潛力的其他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(bivatuzumab mertansine)、坎妥珠單抗 (cantuzumab mertansine)、西地珠單抗(cedelizumab)、賽妥珠單抗(certolizumab pegol)、西福珠單抗(cidfusituzumab)、西土珠單抗(cidtuzumab)、達克珠單抗(daclizumab)、依庫珠單抗(eculizumab)、依法珠單抗(efalizumab)、依哌佐單抗(epratuzumab)、厄利珠單抗(erlizumab)、泛維珠單抗(felvizumab)、芳妥珠單抗(fontolizumab)、吉妥珠單抗奧唑米星、伊珠單抗奧唑米星(inotuzumab ozogamicin)、伊匹珠單抗(ipilimumab)、拉貝珠單抗(labetuzumab)、林妥珠單抗(lintuzumab)、馬妥珠單抗(matuzumab)、美泊珠單抗(mepolizumab)、莫他珠單抗(motavizumab)、莫妥珠單抗(motovizumab)、那他珠單抗(natalizumab)、尼妥珠單抗(nimotuzumab)、諾羅珠單抗(nolovizumab)、努瑪珠單抗(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)、帕西珠單抗(pecfusituzumab)、培妥珠單抗(pectuzumab)、培克珠單抗(pexelizumab)、拉利珠單抗(ralivizumab)、蘭尼單抗(ranibizumab)、瑞利維珠單抗(reslivizumab)、瑞利珠單抗(reslizumab)、瑞維珠單抗(resyvizumab)、羅維珠單抗(rovelizumab)、蘆利珠單抗(ruplizumab)、西羅珠單抗(sibrotuzumab)、西利珠單抗(siplizumab)、索土珠單抗(sontuzumab)、替他珠單抗(tacatuzumab tetraxetan)、他度珠單抗(tadocizumab)、他利珠單抗(talizumab)、替非珠單抗(tefibazumab)、妥珠單抗(tocilizumab)、妥利珠單抗(toralizumab)、西莫白介素突西珠單抗(tucotuzumab celmoleukin)、突西珠單抗(tucusituzumab)、烏瑪珠單抗(umavizumab)、烏珠單抗(urtoxazumab)、優特克單抗(ustekinumab)、維西珠單抗(visilizumab)及抗白介素-12(ABT-874/J695，Wyeth Research and Abbott Laboratories)，其為重組獨佔性人類序列，即經基因修飾以識別白介素-12 p40蛋白之全長IgG₁λ抗體。 Chemotherapeutic agents also include antibodies such as alemtuzumab (Campath), bevacizumab (AVASTIN®, Genentech); cetuximab (ERBITUX®, Imclone); Pani Monoclonal antibody (panitumumab) (VECTIBIX®, Amgen), rituximab (RITUXAN®, Genentech/Biogen Idec), pertuzumab (OMNITARG®, 2C4, Genentech), trastuzumab Trastuzumab (HERCEPTIN®, Genentech), tositumomab (Bexxar, Corixia) and antibody drug conjugate gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Other humanized monoclonal antibodies having therapeutic potential as agents in combination with the compounds of the invention include: apolizumab, aselizumab, atlizumab, bapi Betabeuzumab, bivatuzumab mertansine, cantuzumab mertansine, cedelizumab, certolizumab pegol, cefozumab (cidfusituzumab), cidtuzumab, daclizumab, eculizumab, efalizumab, etrapuzumab, erlib Monoclonal antibody (erlizumab), felvizumab, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, irizhu Monoclonal antibody (ipilimumab), labetuzumab, lintuzumab, matuzumab, mepolizumab, motavizumab , motolizumab, natalizumab, nimotuzumab (nimotuzum) Ab), nolovizumab, numavizumab, ocrelizumab, omalizumab, palivizumab, Pacozhu Monoclonal antibody (pascolizumab), paxicilizumab, pectuzumab, pexelizumab, ralivizumab, ranibizumab, Reslivizumab, reslizumab, resviviumab, rovelizumab, ruplizumab, sirolizumab ( Sibrotuzumab), sicilizumab, sotuzumab, tacatuzumab tetraxetan, tadocizumab, talizumab, tifibrate Tufibazumab, tocilizumab, toralizumab, tucotuzumab celmoleukin, tucusituzumab, ummazhudan Anti-(umavizumab), utoxazumab, ustekinumab, visilizumab and Interleukin -12 (ABT-874 / J695, Wyeth Research and Abbott Laboratories), which is a recombinant exclusively human sequence, i.e., genetically modified to recognize the full-length interleukin -12 p40 protein of the IgG ₁ λ antibodies.

化學治療劑亦包括「EGFR抑制劑」，其係指結合或直接與EGFR相互作用且防止或降低其信號傳導活性之化合物，且替代地稱為「EGFR拮抗劑」。該等藥劑之實例包括結合EGFR之抗體及小分子。結合EGFR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)(參見美國專利號4,943,533,Mendelsohn等人)及其變異體，諸如嵌合225(C225或西妥昔單抗(Cetuximab)；ERBUTIX^®)及重構人類225(H225)(參見WO 96/40210，Imclone Systems Inc.)；IMC-11F8，即全長人類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號中所描述之結合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(Panitumumab)(參見WO98/50433，Abgenix/Amgen)；EMD 55900(Stragliotto等，Eur.J.Cancer 32A：636-640(1996))；EMD7200(馬妥珠單抗(matuzumab))，即與EGF及TGF-α競爭EGFR結合之針對EGFR之人類化EGFR抗體(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且描述於US 6,235,883中之全長人類抗體；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抗體可與細胞毒性劑結合，因而產生免疫結合物(參見例如EP659,439A2,Merck Patent GmbH)。EGFR拮抗劑包括小分子，諸如以下各案中所描述之化合物：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 1033，2-丙烯醯胺，N-[4-[(3-氯-4-氟苯基)胺基]-7-[3-(4-嗎啉基)丙氧基]-6-喹唑啉基]-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-苯乙基)胺基]-1H-吡咯并[2,3-d]嘧啶-6-基]-苯酚)；(R)-6-(4-羥苯基)-4-[(1-苯乙基)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)。 A chemotherapeutic agent also includes an "EGFR inhibitor", which refers to a compound that binds or directly interacts with EGFR and prevents or reduces its signaling activity, and is alternatively referred to as an "EGFR antagonist." 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 reconstituted human 225 (H225) (see WO 96/40210, Imclone Systems Inc.); IMC-11F8, ie Full-length human EGFR-targeting antibody (Imclone); an antibody that binds to type II mutant EGFR (U.S. Patent No. 5,212,290); humanized and chimeric antibodies that bind EGFR as described in U.S. Patent No. 5,891,996; Antibodies such as ABX-EGF or Panitumumab (see WO 98/50433, Abgenix/Amgen); EMD 55900 (Stragliotto et al, Eur . J. Cancer 32A: 636-640 (1996)); EMD 7200 (Mato Mauzumab (matuzumab), a humanized EGFR antibody (EMD/Merck) against EGFR that competes with EGF and TGF-α for EGFR binding; human EGFR antibody HuMax-EGFR (GenMab); known as E1.1, E2. 4. Full length human antibodies of E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and described in US 6,235,883; MDX-447 (Medarex Inc And mAb 806 or humanized mAb 806 (Johns et al, J. Biol. Chem. 279(29): 30375-30384 (2004)). The anti-EGFR antibody can bind to a cytotoxic agent, thus producing an immunoconjugate (see, for example, EP 659, 439 A2, Merck Patent GmbH). EGFR antagonists include small molecules, such as those described in U.S. Patent Nos. 5,616,582, 5,457,105, 5,475,001, 5,654,307, 5,679,683, 6,084,095, 6,265,410, 6,455,534. , Nos. 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, 6,344,455, 5,760,041, No. 6,002,008 and 5,747,498, and the following PCT publications: WO 98/14451, WO 98/50038, WO 99/09016, and WO 99/24037. Specific small molecule EGFR antagonists include OSI-774 (CP-358774, erlotinib, TARCEVA ^® (Genentech/OSI Pharmaceuticals); PD 183805 (CI 1033, 2-propenylamine, N-[4-[(3- Chloro-4-fluorophenyl)amino]-7-[3-(4-morpholino)propoxy]-6-quinazolinyl]-dihydrochloride, Pfizer Inc.); ZD1839, Kyrgyzstan IRESSA® 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-(N-morpholinyl)propoxy)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-phenethyl)amino]-7H-pyrrolo[2,3-d]pyrimidine); CL-387785(N-[4-[(3-bromophenyl)amino]-6- Quinazolinyl]-2-butynylamine); EKB-569(N-[4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxy- 6-quinolinyl]-4-(dimethylamino)-2-butenoxime) (Wyeth); AG1478 (Pfizer); AG1571 (SU 5271; Pfizer); double EGFR/HER2 tyrosine kinase inhibition Agent Such as lapatinib (TYKERB®, GSK572016 or N-[3-chloro-4-[(3-fluorophenyl)methoxy]phenyl]-6[5[[[2-methylsulfonyl)) Ethyl]amino]methyl]-2-furanyl]-4-quinazolinamine).

化學治療劑亦包括「酪胺酸激酶抑制劑」，其包括前一段中所指出之EGFR靶向藥物；小分子HER2酪胺酸激酶抑制劑，諸如可獲自Takeda之TAK165；ErbB2受體酪胺酸激酶之口服選擇性抑制劑CP-724,714(Pfizer及OSI)；雙HER抑制劑，諸如EKB-569(可獲自Wyeth)，其優先結合EGFR但抑制過度表現HER2與EGFR之細胞；拉帕替尼(GSK572016；可獲自Glaxo-SmithKline)，其為一種口服HER2及EGFR酪胺酸激酶抑制劑；PKI-166(可獲自Novartis)；pan-HER抑制劑，諸如卡奈替尼(canertinib)(CI-1033；Pharmacia)；Raf-1抑制劑，諸如抑制Raf-1信號傳導之反義藥劑ISIS-5132(可獲自ISIS Pharmaceuticals)；非HER靶向TK抑制劑，諸如甲磺酸伊馬替尼(GLEEVEC®，可獲自Glaxo SmithKline)；多靶向酪胺酸激酶抑制劑，諸如舒尼替尼(SUTENT®，可獲自Pfizer)；VEGF受體酪胺酸激酶抑制劑，諸如瓦他拉尼(vatalanib)(PTK787/ZK222584，可獲自Novartis/Schering AG)；MAPK細胞外調節激酶I抑制劑CI-1040(可獲自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(二阿魏醯甲烷、4,5-雙(4-氟苯胺基)酞醯亞胺)；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(例如結合HER編碼核酸之反義分子)；喹喏啉(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)；pan-HER抑制劑，諸如CI-1033(Pfizer)；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)；司馬西尼(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任一者所描述：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-targeted drugs indicated in the previous paragraph; small molecule HER2 tyrosine kinase inhibitors such as TAK165 available from Takeda; ErbB2 receptor tyramine Oral selective inhibitors of acid kinases CP-724, 714 (Pfizer and OSI); dual HER inhibitors, such as EKB-569 (available from Wyeth), which preferentially bind to EGFR but inhibit cells that overexpress HER2 and EGFR; Nie (GSK572016; available from Glaxo-SmithKline), an oral HER2 and EGFR tyrosine kinase inhibitor; PKI-166 (available from Novartis); pan-HER inhibitors such as carnitinib (CI-1033; Pharmacia); Raf-1 inhibition Agents, such as the antisense agent ISIS-5132 (available from ISIS Pharmaceuticals) that inhibits Raf-1 signaling; non-HER targeted 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 tyrosine kinase inhibitors, such as vatalanib (PTK787/ZK222584, available) From Novartis/Schering AG); MAPK extracellular regulated kinase I inhibitor CI-1040 (available from Pharmacia); quinazoline, such as PD 153035, 4-(3-chloroanilino)quinazoline; pyridopyrimidine; Pyrimidopyrimidine; pyrrolopyrimidines such as CGP 59326, CGP 60261 and CGP 62706; pyrazolopyrimidine, 4-(phenylamino)-7H-pyrrolo[2,3-d]pyrimidine; curcumin Wei 醯 methane, 4,5-bis(4-fluoroanilino) quinone imine); tyrosine phosphorylation inhibitor containing nitrothiophene moiety; PD-0183805 (Warner-Lamber); antisense molecule (eg An antisense molecule that binds to a HER-encoding nucleic acid; quinoxaline (U.S. Patent No. 5,804,396); tyrosine phosphorylation inhibitor (U.S. Patent No. 5,804,396); ZD6474 (Astr a 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); Semaxinib (Pfizer); ZD6474 (AstraZeneca); PTK-787 (Novartis/Schering AG); </ RTI> </ RTI> <RTIgt; 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); and WO 1996/33980 (Zeneca).

化學治療劑亦包括***(dexamethasone)、干擾素、秋水仙鹼、氯苯氨啶(metoprine)、環孢黴素(cyclosporine)、兩性黴素、甲硝噠唑(metronidazole)、阿侖單抗(alemtuzumab)、阿利維甲酸(alitretinoin)、別嘌呤醇(allopurinol)、阿米福汀(amifostine)、三氧化二砷、天冬醯胺酶、活BCG、貝伐珠單抗、蓓薩羅丁(bexarotene)、克拉屈濱(cladribine)、克羅拉濱(clofarabine)、阿法達貝泊汀(darbepoetin alfa)、地尼白介素(denileukin)、右雷佐生(dexrazoxane)、阿法依伯汀(epoetin alfa)、厄洛替尼(elotinib)、非格司亭(filgrastim)、醋酸組胺瑞林(histrelin acetate)、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)、美司鈉(mesna)、甲氧沙林(methoxsalen)、諾龍(nandrolone)、奈拉濱(nelarabine)、若莫單抗(nofetumomab)、奧普瑞白介素(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)、喹吖因(quinacrine)、拉布立酶(rasburicase)、沙格司亭(sargramostim)、替莫唑胺(temozolomide)、VM-26、6-TG、托瑞米芬、維甲酸、ATRA、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, colchicum Alkali, metoprine, cyclosporine, amphotericin, metronidazole, alemtuzumab, alitretinoin, allopurinol ), amifostine, arsenic trioxide, aspartate, live BCG, bevacizumab, bexarotene, cladribine, clofarabine, ar Darbepoetin alfa, denileukin, dexrazoxane, epoetin alfa, elotinib, filgrastim, Histrelin acetate, ibritumomab, interferon alpha-2a, interferon alpha-2b, lenalidomide, levamisole, mesna , methoxsaren, nandrolone, nelarabine, nofetumomab, oprelvekin, palifermin, pamidronate (pamidronate), pegademase, pegaspargase, pegfilgrastim Pemetrexed disodium, plicamycin, porfimer sodium, quinacrine, rasburicase, sargramostim , temozolomide, VM-26, 6-TG, toremifene, retinoic acid, ATRA, valrubicin, zoledronate and zoledronic acid and their pharmaceutically acceptable Salt.

化學治療劑亦包括氫皮質酮(hydrocortisone)、醋酸氫皮質酮、醋酸可體松(cortisone acetate)、特戊酸替可體松(tixocortol pivalate)、丙酮化曲安新龍(triamcinolone acetonide)、曲安新龍醇(triamcinolone alcohol)、莫米松(mometasone)、安西奈德(amcinonide)、布***(budesonide)、***(desonide)、氟欣諾能(fluocinonide)、丙酮化氟新龍(fluocinolone acetonide)、倍他米松(betamethasone)、倍他米松磷酸鈉、***(dexamethasone)、***磷酸鈉、氟可龍 (fluocortolone)、氫皮質酮-17-丁酸酯、氫皮質酮-17-戊酸酯、二丙酸別氯地米松(aclometasone dipropionate)、戊酸倍他米松、二丙酸倍他米松、潑尼卡酯(prednicarbate)、氯倍他松-17-丁酸酯(clobetasone-17-butyrate)、氯倍他索-17-丙酸酯(clobetasol-17-propionate)、己酸氟可龍、戊酸氟可龍及醋酸氟潑尼定(fluprednidene acetate)；免疫選擇性消炎肽(ImSAIDs)，諸如***酸-麩醯胺酸-甘胺酸(FEG)及其D-異構形式(feG)(IMULAN BioTherapeutics，LLC)；抗風濕藥，諸如硫唑嘌呤、環孢靈(環孢菌素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)(恩博(Enbrel))、英夫利昔單抗(infliximab)(Remicade)、阿達木單抗(adalimumab)(Humira)、賽妥珠單抗(certolizumab pegol)(Cimzia)、戈利木單抗(golimumab)(Simponi)；白介素1(IL-1)阻斷劑，諸如阿那白滯素(anakinra)(Kineret)；T細胞共同刺激阻斷劑，諸如阿巴西普(abatacept)(Orencia)；白介素6(IL-6)阻斷劑，諸如妥珠單抗(ACTEMERA®)；白介素13(IL-13)阻斷劑，諸如來金珠單抗(lebrikizumab)；干擾素α(IFN)阻斷劑，諸如隆塔珠單抗(Rontalizumab)；β7整合素阻斷劑，諸如rhuMAb β7；IgE路徑阻斷劑，諸如抗M1初打疫苗；分泌同源三聚LTa3；及膜結合異源三聚物LTa1/β2阻斷劑，諸如抗淋巴毒素α(LTa)；放射性同位素(例如At²¹¹、I¹³¹、I¹²⁵、Y⁹⁰、Re¹⁸⁶、Re¹⁸⁸、Sm¹⁵³、Bi²¹²、P³²、Pb²¹²及Lu之放射性同位素)；多種研究劑，諸如硫鉑(thioplatin)、PS-341、苯基丁酸鹽、ET-18-OCH₃或法尼基轉移酶抑制劑(L-739749、L-744832)；多酚類，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(theaflavins)、黃烷醇(flavanols)、原花青素 (procyanidins)、樺木酸及其衍生物；自噬抑制劑，諸如氯喹；δ-9-四氫***酚(屈***酚(dronabinol)、MARINOL®)；β-拉帕醌(beta-lapachone)；拉帕醇(lapachol)；秋水仙鹼；樺木酸；乙醯基喜樹鹼、東莨菪素(scopolectin)及9-胺基喜樹鹼)；鬼臼毒素(podophyllotoxin)；替加氟(tegafur)(UFTORAL®)；蓓薩羅丁(bexarotene)(TARGRETIN®)；二膦酸鹽，諸如氯膦酸鹽(例如BONEFOS®或OSTAC®)、伊替膦酸鹽(etidronate)(DIDROCAL®)、NE-58095、唑來膦酸/唑來膦酸鹽(ZOMETA®)、阿倫膦酸鹽(alendronate)(FOSAMAX®)、帕米膦酸鹽(pamidronate)(AREDIA®)、替魯膦酸鹽(tiludronate)(SKELID®)或利塞膦酸鹽(risedronate)(ACTONEL®)；及上皮生長因子受體(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))、蛋白酶體抑制劑(例如PS341)；CCI-779；替吡法尼(tipifarnib)(R11577)；奧拉非尼(orafenib)、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)；及上述任一者之醫藥學上可接受之鹽、酸及衍生物；以及上述兩種或兩種以上之組合，諸如CHOP，即環磷醯胺、阿黴素、長春新鹼及潑尼龍組合療法之縮寫；及FOLFOX，即利用奧沙利鉑(ELOXATIN^TM)與5-FU及甲醯四氫葉酸之組合的治療方案之縮寫。 Chemotherapeutic agents also include hydrocortisone, hydrocortisone acetate, cortisone acetate, tixocortol pivalate, triamcinolone acetonide, and koji Triamcinolone alcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide, acetone albino Fluocinolone acetonide), betamethasone, betamethasone sodium phosphate, dexamethasone, dexamethasone sodium phosphate, fluocortolone, hydrocorticosterone-17-butyrate, hydrocortinone -17-valerate, aclometasone dipropionate, betamethasone valerate, betamethasone dipropionate, prednicarbate, clobetasone-17-butyrate (clobetasone-17-butyrate), clobetasol-17-propionate, fluconazole hexanoate, fluconazole valerate and fluprednidene acetate; immune selection Anti-inflammatory peptides (ImSAIDs), such as phenylalanine-glutamic acid-gan Amino acid (FEG) and its D-isomeric form (feG) (IMULAN BioTherapeutics, LLC); antirheumatic drugs such as azathioprine, cyclosporine (cyclosporin A), D-penicillamine (D-penicillamine) ), gold salt, hydroxychloroquine, leflunomide, minocycline, sulfasalazine; tumor necrosis factor alpha (TNFα) blockers, such as etasoxi Eternercept (Enbrel), infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), Goley Golimumab (Simponi); interleukin 1 (IL-1) blocker, such as anakinra (Kineret); T cell co-stimulatory blocker, such as abatacept (abatacept) Orencia); interleukin 6 (IL-6) blocker, such as tocilizumab (ACTEMERA®); interleukin 13 (IL-13) blocker, such as leflunibumab (lebrikizumab); interferon alpha (IFN a blocking agent, such as Rontalizumab; a beta7 integrin blocker, such as rhuMAb β7; an IgE pathway blocker, such as an anti-M1 initial vaccine; secretes homotrimeric LTa3 And a heterologous membrane-bound trimer LTa1 / β2 blockers, such as an anti-lymphotoxin α (LTa); radioactive isotopes (e.g. ^{^{^{At 211, I 131, I 125}}} , Y 90, Re 186, Re 188, Sm 153, Bi ²¹² , P ³² , Pb ²¹² and Lu radioisotopes); various research agents, such as thioplatin, PS-341, phenylbutyrate, ET-18-OCH ₃ or farnesyltransferase inhibitors ( L-739749, L-744832); polyphenols, such as quercetin, resveratrol, piceatannol, epigallocatechin gallate, Theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; autophagy inhibitors such as chloroquine; delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicine; betulinic acid; acetyl-camptothecin, scopolectin and 9-aminocamptothecin ); podophyllotoxin; tegafur (UFTORAL®); bexarotene (TARGRETIN®); bisphosphonates such as clodronate (eg BONEFOS®) OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid/zoledronate (ZOMETA®), alendronate (FOSAMAX®), Pa Pamidronate (AREDIA®), tiludronate (SKELID®) or risedronate (ACTONEL®); and epidermal growth factor receptor (EGF-R); Vaccines, such as THERATOPE® vaccine; perifosine, COX-2 inhibitors (eg celecoxib or etoricoxib), proteasome inhibitors (eg PS341); CCI-779 Tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitors, such as oblimersen sodium (GENASENSE®); pixantrone; farnesyltransferase inhibitors, such as Los that farnesyl (lonafarnib) (SCH 6636, SARASAR TM); and any of the foregoing the acceptable pharmaceutically salts, acids and derivatives thereof; and said two or the combination of the above, such as of CHOP, an abbreviation of cyclophosphamide, doxorubicin, vincristine, and prednisolone combination therapy of; and FOLFOX, namely the use of oxaliplatin (ELOXATIN ^TM) Acronym regimen of 5-FU and leucovorin combination of A XI.

化學治療劑亦包括具有止痛、退熱及消炎效應之非類固醇消炎藥。NSAID包括酶環加氧酶之非選擇性抑制劑。NSAID之特定實例包括阿司匹靈(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)、奧沙普秦(oxaprozin)及萘普生(naproxen)；乙酸衍生物，諸如吲哚美辛 (indomethacin)、舒林酸(sulindac)、依託度酸(etodolac)、雙氯芬酸(diclofenac)；烯醇酸衍生物，諸如吡羅昔康、美洛昔康(meloxicam)、替諾昔康(tenoxicam)、屈噁昔康(droxicam)、氯諾昔康(lornoxicam)及伊索昔康(isoxicam)；滅酸(fenamic acid)衍生物，諸如甲滅酸(mefenamic acid)、甲氯滅酸(meclofenamic acid)、氟滅酸(flufenamic acid)、托滅酸(tolfenamic acid)；及COX-2抑制劑，諸如塞來昔布、依託考昔、氯美昔布(lumiracoxib)、帕瑞昔布(parecoxib)、羅非考昔(rofecoxib)、羅非考昔及伐地昔布(valdecoxib)。NSAID可指示用於諸如變形性關節炎、骨關節炎、發炎性關節病、強直性脊椎炎、牛皮癬關節炎、萊特爾氏綜合征(Reiter's syndrome)、急性痛風、痛經、轉移性骨痛、頭痛及偏頭痛、手術後疼痛、由於炎症及組織損傷所致之輕度至中度疼痛、發熱、腸梗阻及腎絞痛之症狀減輕。 Chemotherapeutic agents also include non-steroidal anti-inflammatory drugs with analgesic, antipyretic and anti-inflammatory effects. NSAIDs include non-selective inhibitors of enzyme cyclooxygenase. Specific examples of NSAIDs include aspirin; propionic acid derivatives such as ibuprofen, fenoprofen, ketoprofen, flurbiprofen, ol. Oxprozin and naproxen; acetic acid derivatives such as indomethacin (indomethacin), sulindac, etodolac, diclofenac; enolic acid derivatives such as piroxicam, meloxicam, tenoxicam , droxicam, lornoxicam and isoxicam; fenamic acid derivatives such as mefenamic acid, meclofenamic acid ), flufenamic acid, tolfenamic acid; and COX-2 inhibitors such as celecoxib, etoricoxib, lumiracoxib, parecoxib , rofecoxib, rofecoxib and valdecoxib. NSAID can be indicated for use in, for example, osteoarthritis, osteoarthritis, inflammatory joint disease, ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, acute gout, dysmenorrhea, metastatic bone pain, headache And migraine, post-operative pain, mild to moderate pain due to inflammation and tissue damage, fever, intestinal obstruction and renal colic symptoms are alleviated.

化學治療劑亦包括用於阿茲海默氏病之治療，諸如鹽酸多奈哌齊(donepezil hydrochloride)及酒石酸卡巴拉汀(rivastigmine)；用於帕金森氏病(Parkinson's Disease)之治療，諸如L-DOPA/卡比多巴(carbidopa)、恩他卡朋(entacapone)、羅匹尼羅(ropinrole)、普拉克索(pramipexole)、溴隱亭(bromocriptine)、培高利特(pergolide)、三己芬迪(trihexephendyl)及阿曼他丁(amantadine)；用於治療多發性硬化(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；用於哮喘之治療，諸如舒喘寧(albuterol)及孟魯司特鈉(montelukast sodium)；用於治療精神***症之藥劑，諸如金普薩(zyprexa)、理思必妥(risperdal)、思樂康(seroquel)及氟哌啶醇(haloperidol)；消炎劑，諸如皮質類固醇、TNF阻斷劑、IL-1 RA、咪唑硫嘌呤、環磷醯胺及柳氮磺胺吡啶；免疫調節劑及免疫抑制劑，諸如環孢靈、他克莫司、雷帕黴素、黴酚酸嗎啉乙酯(mycophenolate mofetil)、干擾素、皮質類固醇、環磷醯胺、咪唑硫嘌呤及柳氮磺胺吡啶；神經營養性因子，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)及抗帕金森病(anti-Parkinsonian)劑；用於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、鈣離子通道阻斷劑及斯達汀(statins)；用於治療肝病之藥劑，諸如皮質類固醇、消膽胺(cholestyramine)、干擾素及抗病毒劑；用於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；及用於治療免疫缺乏病症之藥劑，諸如γ球蛋白。 Chemotherapeutic agents also include treatments for Alzheimer's disease, such as donepezil hydrochloride and rivastigmine; for the treatment of Parkinson's Disease, such as L-DOPA/ Carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, triheximide Trihexephendyl) and amantadine; agents for the treatment of multiple sclerosis (MS), such as beta interferon (eg Avonex ^® and Rebif ^® ), glatiramer acetate and mitoxantrone; For the treatment of asthma, such as albuterol and montelukast sodium; agents for the treatment of schizophrenia, such as zyprexa, risperdal, and spleen Seroquel and haloperidol; anti-inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine; immunomodulators and immunosuppression Agents, such as cyclosporine, tacrolimus, Rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibition Agents, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole and anti-Parkinsonian agents; agents for the treatment of cardiovascular diseases, such as beta blockers Agents, ACE inhibitors, diuretics, nitrates, calcium channel blockers and statins; agents for the treatment of liver diseases, such as corticosteroids, cholestyramine, interferons and antiviral agents An agent for treating a blood disorder, such as a corticosteroid, an anti-leukemia agent, and a growth factor; and an agent for treating an immunodeficiency disorder, such as gamma globulin.

另外，化學治療劑包括本文中所描述之任何化學治療劑之醫藥學上可接受之鹽、酸或衍生物以及其中兩種或兩種以上之組合。 Additionally, the chemotherapeutic agent includes a pharmaceutically acceptable salt, acid or derivative of any of the chemotherapeutic agents described herein, and combinations of two or more thereof.

可與載劑物質組合以製造單一劑型之式(I)化合物或其鹽及附加藥劑(在包含如上文所描述之附加治療劑之組合物中)之量將視所治療之主體及特定投藥模式而變化。在某些實施例中，本發明之組合物經調配以便可投與在0.01-100毫克之間本發明化合物/公斤體重/天之劑量。 The amount of the compound of formula (I) or a salt thereof and the additional agent (in a composition comprising an additional therapeutic agent as described above) which may be combined with the carrier material in a single dosage form will depend on the subject being treated and the particular mode of administration. And change. In certain embodiments, the compositions of the present invention are formulated so as to be administered at a dose of between 0.01 and 100 mg of the compound of the invention per kg body weight per day.

附加治療劑及式(I)化合物可協同作用。因此，該等組合物中之附加治療劑之量可少於僅利用該治療劑之單一療法中所需之量，或如使用較低劑量，可能對患者有較小副作用。在某些實施例中，在該等組合物中，可投與在0.01-1,000微克附加治療劑/公斤體重/天之間的劑量。 The additional therapeutic agent and the compound of formula (I) can act synergistically. Thus, the amount of additional therapeutic agent in such compositions may be less than that required in a single therapy using only the therapeutic agent, or if a lower dose is used, there may be less side effects to the patient. In certain embodiments, a dose between 0.01 and 1,000 micrograms of additional therapeutic agent per kilogram of body weight per day may be administered in the compositions.

詳言之，本文中提供治療個體之癌症之方法，其包含向該個體投與(a)式(I)化合物或其醫藥學上可接受之鹽及(b)細胞毒性劑(例如靶向療法、化學療法及/或放射療法)。 In particular, a method of treating cancer in an individual comprising administering to the individual (a) a compound of formula (I) or a pharmaceutically acceptable salt thereof and (b) a cytotoxic agent (eg, targeted therapy) is provided herein. , chemotherapy and / or radiation therapy).

本文中提供治療個體之癌症之方法，其中癌症治療包含向該個體投與(a)有效量之式(I)化合物或其醫藥學上可接受之鹽及(b)有效量之細胞毒性劑，其中該癌症治療與包含投與有效量之細胞毒性劑而無 (不存在)式(I)化合物或其醫藥學上可接受之鹽的治療(例如標準護理治療)相比具有提高之效力。 Provided herein are methods of treating cancer in a subject, wherein the cancer treatment comprises administering to the individual (a) an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, and (b) an effective amount of a cytotoxic agent, Wherein the cancer treatment comprises administering an effective amount of a cytotoxic agent without (absence of) the efficacy of a compound of formula (I) or a pharmaceutically acceptable salt thereof (e.g., standard care treatment).

在任何方法之某些實施例中，細胞毒性劑為放射療法。 In certain embodiments of any of the methods, the cytotoxic agent is radiation therapy.

在任何方法之某些實施例中，式(I)化合物或其醫藥學上可接受之鹽係伴隨細胞毒性劑(例如靶向療法、化學療法及/或放射療法)投與。在某些實施例中，式(I)化合物或其醫藥學上可接受之鹽係在細胞毒性劑(例如靶向療法、化學療法及/或放射療法)之前及/或與其同時投與。 In certain embodiments of any of the methods, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered with a cytotoxic agent (eg, targeted therapy, chemotherapy, and/or radiation therapy). In certain embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered prior to and/or concurrently with a cytotoxic agent (eg, targeted therapy, chemotherapy, and/or radiation therapy).

例證illustration

如以下實例中所描繪，在某些例示性實施例中，根據以下一般程序製備化合物，其中R¹、R²、R³及R^a及R^b如針對式I及其替代實施例所定義。應瞭解，儘管一般方法描繪某些本發明化合物之合成，但以下一般方法及熟習此項技術者已知之其他方法可應用於如本文中所描述之所有化合物及此等化合物中每一者之子類及種類。 As depicted in the following examples, in certain exemplary embodiments, compounds are prepared according to the following general procedures, wherein R ¹ , R ² , R ³ and R ^a and R ^{b are} as defined for Formula I and its alternate embodiments. It will be appreciated that while the general methods depict the synthesis of certain compounds of the invention, the following general methods and other methods known to those skilled in the art are applicable to all of the compounds and subclasses of each of these compounds as described herein. And the type.

(a)2-碘代乙腈、K₂CO₃、乙腈，90℃。(b)1-第三丁氧基-N,N,N',N'-四甲基-甲二胺、DMF，90℃。(c)鹽酸苯胺、DMF，110℃。(d)R^a-胍、K₂CO₃、1-丁醇、DMF，120℃。(e)Fe、AcOH，40℃。(f)DIEA、CH₂Cl₂。 (a) 2-iodoacetonitrile, K ₂ CO ₃ , acetonitrile, 90 ° C. (b) 1-Tertioxy-N,N,N',N'-tetramethyl-methylenediamine, DMF, 90 °C. (c) Aniline hydrochloride, DMF, 110 ° C. (d) R ^a -胍, K ₂ CO ₃ , 1-butanol, DMF, 120 °C. (e) Fe, AcOH, 40 ° C. (f) DIEA, CH ₂ Cl ₂ .

藉由以下實例來說明實施例。 The embodiments are illustrated by the following examples.

實例Instance HPLC分離方法A：HPLC separation method A:

儀器：Gilson-281 Instrument: Gilson-281

管柱：Gemini 150×30mm，5μm粒徑 Column: Gemini 150×30mm, 5μm particle size

移動相：ACN 25%-55% H₂O(+0.05%NH₄OH) Mobile phase: ACN 25%-55% H ₂ O (+0.05% NH ₄ OH)

速率：25ml/min Rate: 25ml/min

監測波長：220nm/254nm Monitoring wavelength: 220nm/254nm

運行時長：12min/15min Running time: 12min/15min

管柱溫度：30℃ Column temperature: 30 ° C

HPLC分離方法B：HPLC separation method B:

儀器：BH Instrument: BH

管柱：Phenomenex Gemini C18 200×25mm×10μm Column: Phenomenex Gemini C18 200×25mm×10μm

移動相：MeCN：25%-55%；H₂O(+0.05% NH₄OH) Mobile phase: MeCN: 25%-55%; H ₂ O (+0.05% NH ₄ OH)

速率：25mL/min Rate: 25mL/min

監測波長：220nm/254nm Monitoring wavelength: 220nm/254nm

運行時長：12min Running time: 12min

HPLC分離方法C：HPLC separation method C:

儀器：Gilson GX281 Instrument: Gilson GX281

管柱：YMC-Actus Triart C18 150×30mm Column: YMC-Actus Triart C18 150×30mm

移動相：MeCN：37%-67%；H₂O(+0.05%氨溶液) Mobile phase: MeCN: 37%-67%; H ₂ O (+0.05% ammonia solution)

速率：25ml/min Rate: 25ml/min

監測波長：220nm/254nm Monitoring wavelength: 220nm/254nm

運行時長：10min/15min Running time: 10min/15min

實例1：Example 1: 1-[(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]-3-[3-(三氟甲基)苯基]脲1-[(3S)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidin-3-yl]-3-[3-(trifluoro Methyl)phenyl]urea

步驟1a)N-[(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]胺基甲酸第三丁酯Step 1a) N-[(3S)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

在70℃下將6-氯-[1,2,4]***并[4,3-b]噠嗪(200mg，1.2940mmol)、N-[(3S)-吡咯啶-3-基]胺基甲酸第三丁酯(265mg，1.4234 mmol)及N,N-二異丙基乙胺(0.29mL，1.6822mmol)於乙醇(6mL，98.6mmol)中之混合物攪拌6小時。接著冷卻並濃縮混合物。在水中濕磨殘餘物且藉由過濾收集所獲得之固體，並且用水洗滌。接著在真空下乾燥此物質，得到240mg呈白色固體狀之N-[(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]胺基甲酸第三丁酯。¹H NMR(400MHz,DMSO)δ 9.18(s,1H),8.03(d,J=10.0Hz,1H),7.26(d,J=6.6Hz,1H),7.03(d,J=10.1Hz,1H),4.14(dd,J=11.7,6.0Hz,1H),3.75-3.43(m,4H),2.14(dq,J=13.4,7.0Hz,1H),1.91(dt,J=12.5,6.5Hz,1H),1.39(s,9H)。 6-Chloro-[1,2,4]triazolo[4,3-b]pyridazine (200 mg, 1.2940 mmol), N-[(3S)-pyrrolidin-3-yl]amine at 70 °C A mixture of tert-butyl carboxylic acid (265 mg, 1.4234 mmol) and N,N-diisopropylethylamine (0.29 mL, 1.6822 mmol) in ethanol (6 mL, 98.6 mmol) was stirred for 6 hr. The mixture was then cooled and concentrated. The residue was wet-milled in water and the solid obtained was collected by filtration and washed with water. This material was dried under vacuum to give 240 mg of N-[(3S)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrole as a white solid. Tributyl butyl-3-yl]carbamic acid. ^{1 H NMR (400MHz, DMSO)} δ 9.18 (s, 1H), 8.03 (d, J = 10.0Hz, 1H), 7.26 (d, J = 6.6Hz, 1H), 7.03 (d, J = 10.1Hz, 1H ), 4.14 (dd, J =11.7, 6.0 Hz, 1H), 3.75-3.43 (m, 4H), 2.14 (dq, J = 13.4, 7.0 Hz, 1H), 1.91 (dt, J = 12.5, 6.5 Hz, 1H), 1.39 (s, 9H).

步驟1b)(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-胺鹽酸鹽Step 1b) (3S)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidine-3-amine hydrochloride

在室溫下，在氯化氫(4mol/L)之1,4-二噁烷(9.8mL，39.42mmol)溶液中將N-[(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]胺基甲酸第三丁酯(240mg，0.7884mmol)攪拌30分鐘。接著在真空下濃縮並乾燥該混合物，得到190mg呈黃色固體狀之(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-胺鹽酸鹽，其不經純化即用於下一步驟。 N-[(3S)-1-([1,2,4]triazole in a solution of hydrogen chloride (4 mol/L) in 1,4-dioxane (9.8 mL, 39.42 mmol) at room temperature [4,3-b]Pyridazin-6-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester (240 mg, 0.7884 mmol) was stirred for 30 min. Concentration and drying of the mixture in vacuo gave 190 mg of (3S)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidine as a yellow solid. 3-Amine hydrochloride, which was used in the next step without purification.

步驟1c)1-[(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]-3-[3-(三氟甲基)苯基]脲Step 1c) 1-[(3S)-1-([1,2,4]Triazolo[4,3-b]pyridazin-6-yl)pyrrolidin-3-yl]-3-[3- (trifluoromethyl)phenyl]urea

將1-異氰酸酯基-3-(三氟甲基)苯(28mg，0.150mmol)添加至(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-胺鹽酸鹽(30mg，0.124mmol)及N-乙基二異丙胺(0.065mL，0.372mmol)於二氯甲烷(1mL)中之溶液中。在室溫下將混合物攪拌1小時。接著濃縮混合物且藉由HPLC(條件)加以純化，得到21.6mg呈白色固體狀之1-[(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]-3-[3-(三氟甲基)苯基]脲。LCMS m/z=392.2[M+1]⁺。¹H NMR(400MHz,DMSO)δ 9.24-9.17(s,1H),8.83-8.69(s,1H),8.14-8.02(d,J=10.0Hz,1H),8.02-7.94(s,1H), 7.53-7.38(m,2H),7.29-7.18(d,J=7.0Hz,1H),7.15-7.05(d,J=10.0Hz,1H),6.80-6.67(d,J=6.6Hz,1H),4.42-4.26(q,J=5.7Hz,1H),3.82-3.68(dd,J=10.9,6.0Hz,1H),3.66.3.51(m,2H),3.48-3.37(dd,J=10.9,4.1Hz,1H),2.30-2.16(dq,J=13.6,7.0Hz,1H),2.05-1.90(dq,J=12.4,6.2Hz,1H)。 Addition of 1-isocyanate-3-(trifluoromethyl)benzene (28 mg, 0.150 mmol) to (3S)-1-([1,2,4]triazolo[4,3-b]pyridazine- A solution of 6-yl)pyrrolidine-3-amine hydrochloride (30 mg, 0.124 mmol) and N-ethyldiisopropylamine (0.065 mL, 0.372 mmol) in dichloromethane (1 mL). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated and then be by HPLC (conditions) to give 21.6mg as a white solid of 1 - [(3S) -1 - ([1,2,4] triazolo [4,3-b] pyridazine -6-yl)pyrrolidin-3-yl]-3-[3-(trifluoromethyl)phenyl]urea. LCMS m/z = 392.2 [M+1] ⁺ . ^{1 H NMR (400MHz, DMSO)} δ 9.24-9.17 (s, 1H), 8.83-8.69 (s, 1H), 8.14-8.02 (d, J = 10.0Hz, 1H), 8.02-7.94 (s, 1H), 7.53-7.38 (m, 2H), 7.29-7.18 (d, J = 7.0 Hz, 1H), 7.15-7.05 (d, J = 10.0 Hz, 1H), 6.80-6.67 (d, J = 6.6 Hz, 1H) , 4.42-4.26 (q, J = 5.7 Hz, 1H), 3.82-3.68 (dd, J = 10.9, 6.0 Hz, 1H), 3.66.3.51 (m, 2H), 3.48-3.37 (dd, J = 10.9, 4.1 Hz, 1H), 2.30-2.16 (dq, J = 13.6, 7.0 Hz, 1H), 2.05-1.90 (dq, J = 12.4, 6.2 Hz, 1H).

實例2：Example 2: 1-[4-氯-3-(三氟甲基)苯基]-3-[(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]脲1-[4-chloro-3-(trifluoromethyl)phenyl]-3-[(3S)-1-([1,2,4]triazolo[4,3-b]pyridazine-6 -yl)pyrrolidin-3-yl]urea

LCMS m/z=426.1[M+1]⁺。¹H NMR(400MHz,DMSO)δ 9.26-9.13(s,1H),8.93-8.79(s,1H),8.16-7.97(m,2H),7.65-7.45(s,2H),7.16-6.98(d,J=10.0Hz,1H),6.87-6.75(d,J=6.6Hz,1H),4.43-4.26(q,J=5.5Hz,1H),3.79-3.66(dd,J=11.0,6.1Hz,1H),3.66-3.50(q,J=7.1,6.2Hz,2H),3.47-3.37(m,1H),2.30-2.17(dd,J=13.2,6.5Hz,1H),2.08-1.90(dd,J=12.2,6.1Hz,1H)。 LCMS m/z = 426.1 [M + 1] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.26-9.13 (s, 1H), 8.93-8.79 (s, 1H), 8.16-7.97 (m, 2H), 7.65-7.45 (s, 2H), 7.16-6.98 (d , J=10.0Hz, 1H), 6.87-6.75 (d, J=6.6Hz, 1H), 4.43-4.26 (q, J=5.5Hz, 1H), 3.79-3.66 (dd, J=11.0, 6.1Hz, 1H), 3.66-3.50 (q, J = 7.1, 6.2 Hz, 2H), 3.47-3.37 (m, 1H), 2.30-2.17 (dd, J = 13.2, 6.5 Hz, 1H), 2.08-1.90 (dd, J=12.2, 6.1 Hz, 1H).

實例3：1-(3-氯苯基)-3-[(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]脲Example 3: 1-(3-Chlorophenyl)-3-[(3S)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidine- 3-based urea

LCMS m/z=358.2[M+1]⁺。¹H NMR(400MHz,DMSO)δ 9.23-9.12(s,1H),8.84.8.68(s,1H),8.11-7.99(d,J=10.0Hz,1H),7.71-7.62(d,J=2.2Hz,1H),7.30-7.14(m,2H),7.11-7.04(d,J=10.1Hz,1H),6.98-6.90(d,J=7.6Hz,1H),6.91-6.83(d,J=6.7Hz,1H),4.41-4.25(q,J=5.6Hz,1H),3.79-3.65(dd,J=10.9,6.0Hz,1H),3.65-3.50(q,J =6.6,5.9Hz,2H),3.46-3.37(dd,J=10.9,4.1Hz,1H),2.29-2.16(dq,J=13.6,7.2Hz,1H),2.07-1.88(dq,J=12.6,6.2Hz,1H)。 LCMS m/z = 358.2 [M+1] ⁺ . ^{1 H NMR (400MHz, DMSO)} δ 9.23-9.12 (s, 1H), 8.84.8.68 (s, 1H), 8.11-7.99 (d, J = 10.0Hz, 1H), 7.71-7.62 (d, J = 2.2 Hz, 1H), 7.30-7.14 (m, 2H), 7.11-7.04 (d, J = 10.1 Hz, 1H), 6.98-6.90 (d, J = 7.6 Hz, 1H), 6.91-6.83 (d, J = 6.7 Hz, 1H), 4.41-4.25 (q, J = 5.6 Hz, 1H), 3.79-3.65 (dd, J = 10.9, 6.0 Hz, 1H), 3.65-3.50 (q, J = 6.6, 5.9 Hz, 2H) ), 3.46-3.37 (dd, J = 10.9, 4.1 Hz, 1H), 2.29-2.16 (dq, J = 13.6, 7.2 Hz, 1H), 2.07-1.88 (dq, J = 12.6, 6.2 Hz, 1H).

實例4：Example 4: 1-[(3R)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]-3-[3-(三氟甲基)苯基]脲1-[(3R)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidin-3-yl]-3-[3-(trifluoro Methyl)phenyl]urea

LCMS m/z=392.2[M+1]⁺。¹H NMR(400MHz,DMSO)δ 9.26-9.18(s,1H),8.78-8.65(s,1H),8.12-8.02(d,J=10.0Hz,1H),8.03-7.93(s,1H),7.53-7.38(m,2H),7.31-7.19(d,J=7.0Hz,1H),7.14-7.01(d,J=10.0Hz,1H),6.80-6.65(d,J=6.8Hz,1H),4.45-4.27(q,J=5.7Hz,1H),3.80-3.68(dd,J=10.9,6.1Hz,1H),3.65-3.52(m,2H),3.49-3.37(dd,J=10.6,4.0Hz,1H),2.30-2.16(dd,J=12.9,6.5Hz,1H),2.05-1.92(dd,J=12.6,6.4Hz,1H)。 LCMS m/z = 392.2 [M+1] ⁺ . ^{1 H NMR (400MHz, DMSO)} δ 9.26-9.18 (s, 1H), 8.78-8.65 (s, 1H), 8.12-8.02 (d, J = 10.0Hz, 1H), 8.03-7.93 (s, 1H), 7.53-7.38 (m, 2H), 7.31-7.19 (d, J = 7.0 Hz, 1H), 7.14 - 7.01 (d, J = 10.0 Hz, 1H), 6.80-6.65 (d, J = 6.8 Hz, 1H) , 4.45-4.27 (q, J = 5.7 Hz, 1H), 3.80-3.68 (dd, J = 10.9, 6.1 Hz, 1H), 3.65-3.52 (m, 2H), 3.49-3.37 (dd, J = 10.6, 4.0 Hz, 1H), 2.30-2.16 (dd, J = 12.9, 6.5 Hz, 1H), 2.05-1.92 (dd, J = 12.6, 6.4 Hz, 1H).

實例5：Example 5: 1-[4-氯-3-(三氟甲基)苯基]-3-[(3R)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]脲1-[4-chloro-3-(trifluoromethyl)phenyl]-3-[(3R)-1-([1,2,4]triazolo[4,3-b]pyridazine-6 -yl)pyrrolidin-3-yl]urea

LCMS m/z=426.1[M+1]⁺。¹H NMR(400MHz,DMSO)δ 9.25-9.11(s,1H),8.94-8.82(s,2H),8.12-8.00(m,3H),7.61-7.49(s,3H),7.15-6.99(d,J=10.0Hz,2H),6.89-6.75(d,J=6.8Hz,2H),2.30-2.15(m,2H),4.41-4.25(q,J=5.6Hz,2H),3.78-3.68(m,2H),2.07-1.91(m,2H),3.64-3.51(q,J=6.9,6.1Hz,3H),3.48-3.37(d,J=4.1Hz,1H)。 LCMS m/z = 426.1 [M + 1] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 9.25-9.11 (s, 1H), 8.94-8.82 (s, 2H), 8.12-8.00 (m, 3H), 7.61-7.49 (s, 3H), 7.15-6.99 (d , J = 10.0 Hz, 2H), 6.89-6.75 (d, J = 6.8 Hz, 2H), 2.30-2.15 (m, 2H), 4.41-4.25 (q, J = 5.6 Hz, 2H), 3.78-3.68 ( m, 2H), 2.07-1.91 (m, 2H), 3.64-3.51 (q, J = 6.9, 6.1 Hz, 3H), 3.48-3.37 (d, J = 4.1 Hz, 1H).

實例6：Example 6: 1-(3-氯苯基)-3-[(3R)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]脲1-(3-Chlorophenyl)-3-[(3R)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidin-3-yl Urea

LCMS m/z=358.2[M+1]⁺。¹H NMR(400MHz,DMSO)δ 9.24-9.15(s,1H),8.75-8.61(s,1H),8.12-8.00(d,J=10.0Hz,1H),7.70-7.61(s,1H),7.29-7.14(m,2H),7.13-7.03(d,J=10.0Hz,1H),6.97-6.89(m,1H),6.84-6.73(d,J=6.6Hz,1H),4.41-4.23(q,J=5.5Hz,1H),3.79-3.65(dd,J=10.8,6.0Hz,1H),3.65-3.50(q,J=6.4,5.5Hz,2H),3.45-3.36(dd,J=10.4,3.8Hz,1H),2.30-2.14(dq,J=13.7,7.2Hz,1H),2.03-1.89(dt,J=12.4,6.3Hz,1H)。 LCMS m/z = 358.2 [M+1] ⁺ . ^{1 H NMR (400MHz, DMSO)} δ 9.24-9.15 (s, 1H), 8.75-8.61 (s, 1H), 8.12-8.00 (d, J = 10.0Hz, 1H), 7.70-7.61 (s, 1H), 7.29-7.14(m,2H),7.13-7.03(d,J=10.0Hz,1H), 6.97-6.89(m,1H),6.84-6.73(d,J=6.6Hz,1H),4.41-4.23( q, J = 5.5 Hz, 1H), 3.79 - 3.65 (dd, J = 10.8, 6.0 Hz, 1H), 3.65 - 3.50 (q, J = 6.4, 5.5 Hz, 2H), 3.45 - 3.36 (dd, J = 10.4, 3.8 Hz, 1H), 2.30-2.14 (dq, J = 13.7, 7.2 Hz, 1H), 2.03-1.89 (dt, J = 12.4, 6.3 Hz, 1H).

實例7：Example 7: (S)-1-(1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基)-3-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)脲(S)-1-(1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidin-3-yl)-3-(4-((4) -ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea

LCMS m/z=518.3[M+1]⁺。¹H NMR(400MHz,DMSO)δ 9.24-9.12(m,1H),8.72(s,1H),8.05(dd,J=10.0,0.9Hz,1H),7.92(d,J=2.2Hz,1H),7.60-7.52(m,1H),7.51-7.43(m,1H),7.08(d,J=10.0Hz,1H),6.72(d,J=6.6Hz,1H),4.34(d,J=5.6Hz,1H),3.73(dd,J=11.0,6.0Hz,1H),3.58(d,J=7.0Hz,2H),3.49(s,2H),3.41(dd,J=11.0,4.2Hz,1H),2.43-2.16(m,10H),1.98(t,J=6.1Hz,1H),0.97(t, J=7.1Hz,3H)。 LCMS m/z = 518.3 [M + 1] ⁺ . ^{1 H NMR (400MHz, DMSO)} δ 9.24-9.12 (m, 1H), 8.72 (s, 1H), 8.05 (dd, J = 10.0,0.9Hz, 1H), 7.92 (d, J = 2.2Hz, 1H) , 7.60-7.52 (m, 1H), 7.51-7.43 (m, 1H), 7.08 (d, J = 10.0 Hz, 1H), 6.72 (d, J = 6.6 Hz, 1H), 4.34 (d, J = 5.6 Hz, 1H), 3.73 (dd, J = 11.0, 6.0 Hz, 1H), 3.58 (d, J = 7.0 Hz, 2H), 3.49 (s, 2H), 3.41 (dd, J = 11.0, 4.2 Hz, 1H) ), 2.43-2.16 (m, 10H), 1.98 (t, J = 6.1 Hz, 1H), 0.97 (t, J = 7.1 Hz, 3H).

實例8：Example 8: 1-[(3S)-1-(2-胺基嘧啶-4-基)吡咯啶-3-基]-3-(3-氯-4-甲基-苯基)脲1-[(3S)-1-(2-Aminopyrimidin-4-yl)pyrrolidin-3-yl]-3-(3-chloro-4-methyl-phenyl)urea

步驟8a)N-[(3S)-1-(2-胺基嘧啶-4-基)吡咯啶-3-基]胺基甲酸第三丁酯Step 8a) N-[(3S)-1-(2-Aminopyrimidin-4-yl)pyrrolidin-3-yl]carbamic acid tert-butyl ester

在90℃下對N-[(3S)-吡咯啶-3-基]胺基甲酸第三丁酯(200mg，1.074mmol)、4-氯嘧啶-2-胺(167mg，1.29mmol)及N,N'-二異丙基乙胺(0.28mL，1.61mmol)於異丙醇(3mL)中之混合物進行攪拌。接著將混合物冷卻至室溫且添加水。藉由過濾收集沈澱之固體，用水洗滌且在真空下乾燥，得到300mg呈白色固體狀之N-[(3S)-1-(2-胺基嘧啶-4-基)吡咯啶-3-基]胺基甲酸第三丁酯。此產物不經純化即用於下一步驟。 N-[(3S)-pyrrolidin-3-yl]carbamic acid tert-butyl ester (200 mg, 1.074 mmol), 4-chloropyrimidin-2-amine (167 mg, 1.29 mmol) and N, at 90 °C. A mixture of N'-diisopropylethylamine (0.28 mL, 1.61 mmol) in isopropyl alcohol (3 mL) was stirred. The mixture was then cooled to room temperature and water was added. The solid which precipitated was collected by filtration, washed with water and dried in vacuo to give crystals of <RTIgt; </RTI> <RTIgt; </RTI> N-[(3S)-1-(2-aminopyrimidin-4-yl)pyrrolidin-3-yl] Tert-butyl carbamic acid. This product was used in the next step without purification.

步驟8b)4-[(3S)-3-胺基吡咯啶-1-基]嘧啶-2-胺Step 8b) 4-[(3S)-3-Aminopyrrolidin-1-yl]pyrimidin-2-amine

在室溫下，在氯化氫(4mol/l)之1,4-二噁烷(2.7mL，10.74mmol)溶液中將N-[(3S)-1-(2-胺基嘧啶-4-基)吡咯啶-3-基]胺基甲酸第三丁酯(300mg，1.074mmol)攪拌1小時。接著濃縮反應物且在真空下乾燥，得到170mg呈白色固體狀之4-[(3S)-3-胺基吡咯啶-1-基]嘧啶-2-胺。此產物不經純化即用於下一步驟。 N-[(3S)-1-(2-Aminopyrimidin-4-yl) in a solution of hydrogen chloride (4 mol/l) in 1,4-dioxane (2.7 mL, 10.74 mmol) at room temperature Pyrrolidin-3-yl]carbamic acid tert-butyl ester (300 mg, 1.074 mmol) was stirred for 1 hour. The reaction was then concentrated and dried <RTI ID=0.0> This product was used in the next step without purification.

步驟8c)1-[(3S)-1-(2-胺基嘧啶-4-基)吡咯啶-3-基]-3-(3-氯-4-甲基-苯基)脲Step 8c) 1-[(3S)-1-(2-Aminopyrimidin-4-yl)pyrrolidin-3-yl]-3-(3-chloro-4-methyl-phenyl)urea

將2-氯-4-異氰酸酯基-1-甲基-苯(56mg，0.278mmol)添加至4-[(3S)-3-胺基吡咯啶-1-基]嘧啶-2-胺鹽酸鹽(50mg，0.232mmol)及N-乙基二異丙胺(0.204mL，1.159mmol)於二氯甲烷(3mL)中之溶液中。在室溫下將混合物攪拌1小時。接著濃縮混合物且藉由HPLC(條件)加以純化，得到55.4mg呈白色固體狀之1-[(3S)-1-(2-胺基嘧啶-4-基)吡咯啶-3-基]-3-(3-氯-4-甲基-苯基)脲。LCMS m/z=347.2[M+1]⁺。¹H NMR(400MHz,DMSO)δ 8.83(s,1H),8.12-8.00(m,1H),7.73(d,J=5.8Hz,1H),7.54(d,J=1.4Hz,2H),6.72(d,J=6.6Hz,1H),5.90(s,2H),5.74(d,J=5.8Hz,1H),4.26(s,1H),3.58(t,J=8.1Hz,1H),3.42(s,2H),2.15(dt,J=13.8,6.9Hz,1H),1.91(dd,J=11.2,6.0Hz,1H)。 2-Chloro-4-isocyanate-1-methyl-benzene (56 mg, 0.278 mmol) was added to 4-[(3S)-3-aminopyrrolidin-1-yl]pyrimidin-2-amine hydrochloride (50 mg, 0.232 mmol) and a solution of N-ethyldiisopropylamine (0.204 mL, 1.459 mmol) in dichloromethane (3 mL). The mixture was stirred at room temperature for 1 hour. The mixture was then concentrated and be by HPLC (conditions) to give 55.4mg as a white solid of 1 - [(3S) -1- ( 2- amino-4-yl) pyrrolidin-3-yl] -3 -(3-Chloro-4-methyl-phenyl)urea. LCMS m/z = 347.2 [M + 1] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.12 - 8.00 (m, 1H), 7.73 (d, J = 5.8 Hz, 1H), 7.54 (d, J = 1.4 Hz, 2H), 6.72 (d, J = 6.6 Hz, 1H), 5.90 (s, 2H), 5.74 (d, J = 5.8 Hz, 1H), 4.26 (s, 1H), 3.58 (t, J = 8.1 Hz, 1H), 3.42 (s, 2H), 2.15 (dt, J = 13.8, 6.9 Hz, 1H), 1.91 (dd, J = 11.2, 6.0 Hz, 1H).

實例9：Example 9: 1-[(S)-1-(2-胺基-嘧啶-4-基)-吡咯啶-3-基]-3-(4-氯-3-三氟甲基-苯基)-脲1-[(S)-1-(2-amino-pyrimidin-4-yl)-pyrrolidin-3-yl]-3-(4-chloro-3-trifluoromethyl-phenyl)-urea

LCMS m/z=401.1[M+1]⁺。¹H NMR(400MHz,DMSO)δ 8.83(s,1H),8.12-8.00(m,1H),7.73(d,J=5.8Hz,1H),7.54(d,J=1.4Hz,2H),6.72(d,J=6.6Hz,1H),5.90(s,2H),5.74(d,J=5.8Hz,1H),4.26(s,1H),3.58(t,J=8.1Hz,1H),3.42(s,2H),2.15(dt,J=13.8,6.9Hz,1H),1.91(dd,J=11.2,6.0Hz,1H)。 LCMS m/z = 401.1 [M + 1] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.12 - 8.00 (m, 1H), 7.73 (d, J = 5.8 Hz, 1H), 7.54 (d, J = 1.4 Hz, 2H), 6.72 (d, J = 6.6 Hz, 1H), 5.90 (s, 2H), 5.74 (d, J = 5.8 Hz, 1H), 4.26 (s, 1H), 3.58 (t, J = 8.1 Hz, 1H), 3.42 (s, 2H), 2.15 (dt, J = 13.8, 6.9 Hz, 1H), 1.91 (dd, J = 11.2, 6.0 Hz, 1H).

實例10：Example 10: 1-[4-氯-3-(三氟甲基)苯基]-3-[(3S)-1-[2-(甲基胺基)嘧啶-4-基]吡咯啶-3-基]脲1-[4-Chloro-3-(trifluoromethyl)phenyl]-3-[(3S)-1-[2-(methylamino)pyrimidin-4-yl]pyrrolidin-3-yl] Urea

LCMS m/z=415.2[M+1]⁺。¹H NMR(400MHz,DMSO)δ 8.83(s,1H),8.06(s,1H),7.76(d,J=5.8Hz,1H),7.54(d,J=1.4Hz,2H),6.73(d,J=6.7Hz,1H),6.32(d,J=5.0Hz,1H),5.73(d,J=5.9Hz,1H),4.27(s,1H),3.52(d,J=64.8Hz,4H),2.73(d,J=4.8Hz,3H),2.16(dd,J=12.5,6.5Hz,1H),1.92(t,J=8.1Hz,1H)。 LCMS m/z = 415.2 [M+1] ⁺ . ¹ H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.06 (s, 1H), 7.76 (d, J = 5.8 Hz, 1H), 7.54 (d, J = 1.4 Hz, 2H), 6.73 (d) , J = 6.7 Hz, 1H), 6.32 (d, J = 5.0 Hz, 1H), 5.73 (d, J = 5.9 Hz, 1H), 4.27 (s, 1H), 3.52 (d, J = 64.8 Hz, 4H ), 2.73 (d, J = 4.8 Hz, 3H), 2.16 (dd, J = 12.5, 6.5 Hz, 1H), 1.92 (t, J = 8.1 Hz, 1H).

實例11：Example 11: 1-(3-氯-4-甲基-苯基)-3-[(3S)-1-[2-(甲基胺基)嘧啶-4-基]吡咯啶-3-基]脲1-(3-Chloro-4-methyl-phenyl)-3-[(3S)-1-[2-(methylamino)pyrimidin-4-yl]pyrrolidin-3-yl]urea

LCMS m/z=361.2[M+1]⁺。¹H NMR(400MHz,DMSO)δ 8.41(s,1H),7.76(d,J=5.8Hz,1H),7.63(d,J=2.1Hz,1H),7.22-7.12(m,1H),7.08(dd,J=8.3,2.2Hz,1H),6.54(d,J=6.8Hz,1H),6.32(q,J=4.8Hz,1H),5.73(d,J=5.8Hz,1H),4.25(s,1H),3.59(s,1H),3.43(s,3H),2.73(d,J=4.7Hz,3H),2.23(s,3H),2.14(dt,J=13.9,7.7Hz,1H),1.89(s,1H)。 LCMS m/z = 361.2 [M+1] ⁺ . ^{1 H NMR (400MHz, DMSO)} δ 8.41 (s, 1H), 7.76 (d, J = 5.8Hz, 1H), 7.63 (d, J = 2.1Hz, 1H), 7.22-7.12 (m, 1H), 7.08 (dd, J = 8.3, 2.2 Hz, 1H), 6.54 (d, J = 6.8 Hz, 1H), 6.32 (q, J = 4.8 Hz, 1H), 5.73 (d, J = 5.8 Hz, 1H), 4.25 (s, 1H), 3.59 (s, 1H), 3.43 (s, 3H), 2.73 (d, J = 4.7 Hz, 3H), 2.23 (s, 3H), 2.14 (dt, J = 13.9, 7.7 Hz, 1H), 1.89 (s, 1H).

實例12：Example 12: 1-[(3S)-1-[2-(甲基胺基)嘧啶-4-基]吡咯啶-3-基]-3-[4-(三氟甲氧基)苯基]脲1-[(3S)-1-[2-(methylamino)pyrimidin-4-yl]pyrrolidin-3-yl]-3-[4-(trifluoromethoxy)phenyl]urea

LCMS m/z=397.2[M+1]⁺。¹H NMR(400MHz,DMSO)δ 8.53(s,1H),7.76(d,J=5.8Hz,1H),7.54-7.39(m,2H),7.22(d,J=8.5Hz,2H),6.56(d,J=6.8Hz,1H),6.32(d,J=5.3Hz,1H),5.73(d,J=5.8Hz,1H),4.27(s,1H),3.59(s,1H),3.44(s,2H),2.73(d,J=4.7Hz,3H),2.16(dd,J=13.0,6.8Hz,1H),1.89(s,1H)。 LCMS m/z = 397.2 [M + 1] ⁺ . ^{1 H NMR (400MHz, DMSO)} δ 8.53 (s, 1H), 7.76 (d, J = 5.8Hz, 1H), 7.54-7.39 (m, 2H), 7.22 (d, J = 8.5Hz, 2H), 6.56 (d, J = 6.8 Hz, 1H), 6.32 (d, J = 5.3 Hz, 1H), 5.73 (d, J = 5.8 Hz, 1H), 4.27 (s, 1H), 3.59 (s, 1H), 3.44 (s, 2H), 2.73 (d, J = 4.7 Hz, 3H), 2.16 (dd, J = 13.0, 6.8 Hz, 1H), 1.89 (s, 1H).

實例13：Example 13: 1-[4-(二氟甲氧基)苯基]-3-[(3S)-1-[2-(甲基胺基)嘧啶-4-基]吡咯啶-3-基]脲1-[4-(Difluoromethoxy)phenyl]-3-[(3S)-1-[2-(methylamino)pyrimidin-4-yl]pyrrolidin-3-yl]urea

LCMS m/z=379.2[M+1]⁺。¹H NMR(400MHz,DMSO)δ 8.39(s,1H),7.76(d,J=5.8Hz,1H),7.47-7.33(m,2H),7.11-6.99(m,2H),6.50(d,J=6.8Hz,1H),6.32(d,J=5.3Hz,1H),5.73(d,J=5.8Hz,1H),4.26(s,1H),3.57(s,4H),2.73(d,J=4.7Hz,3H),2.23-2.05(m,1H),1.89(s,1H)。 LCMS m/z =379.2 [M+1] ⁺ . ^{1 H NMR (400MHz, DMSO)} δ 8.39 (s, 1H), 7.76 (d, J = 5.8Hz, 1H), 7.47-7.33 (m, 2H), 7.11-6.99 (m, 2H), 6.50 (d, J = 6.8 Hz, 1H), 6.32 (d, J = 5.3 Hz, 1H), 5.73 (d, J = 5.8 Hz, 1H), 4.26 (s, 1H), 3.57 (s, 4H), 2.73 (d, J = 4.7 Hz, 3H), 2.23 - 2.05 (m, 1H), 1.89 (s, 1H).

實例14：Example 14: (S)-1-(4-(氮雜環丁烷-1-基甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲(S)-1-(4-(azetidin-1-ylmethyl)phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidine-3 -based urea

步驟14a)1-(4-硝基苯甲基)氮雜環丁烷Step 14a) 1-(4-Nitrobenzyl)azetidine

經30分鐘向氮雜環丁烷鹽酸鹽(1.4g，15mmol)及DIPEA(1.9g，15mmol)於CH₃CN(30mL)中之溶液中逐滴添加1-(溴甲基)-4-硝基苯(1.07g，5mmol)。在室溫下在N₂氛圍下將反應混合物攪拌3小時，接著用DCM(80mL)稀釋。用水(3×80mL)洗滌有機層並且濃縮，得到粗標題化合物，其不經進一步純化即繼續使用(0.77g，產率：81%)。 Over 30 minutes azetidine hydrochloride (1.4g, 15mmol) and DIPEA (1.9g, 15mmol) in the in CH ₃ CN (30mL) was added dropwise a solution of 1- (bromomethyl) -4- Nitrobenzene (1.07 g, 5 mmol). The reaction mixture was stirred for 3 hours under a N ₂ atmosphere at room temperature, then diluted with DCM (80mL). The organic layer was washed with EtOAc EtOAc m.

步驟14b)4-(氮雜環丁烷-1-基甲基)苯胺Step 14b) 4-(Azetidin-1-ylmethyl)aniline

向1-(4-硝基苯甲基)氮雜環丁烷(0.77g，4mmol)於AcOH(10mL)中之溶液中添加Fe(2.24g，40mmol)，且在室溫下在N₂氛圍下將反應混合物攪拌3小時。當起始物質耗盡時，濃縮反應混合物並且鹼化至約pH 9，接著用DCM(3×30mL)萃取。濃縮所合併之有機物，獲得標題化合物，其不經進一步純化即繼續使用(453mg，產率：71%)。 Was added a solution of 1- (4-nitrobenzyl) azetidine (0.77g, 4mmol) in AcOH (10mL) in a solution of Fe (2.24g, 40mmol), and at room temperature in N ₂ atmosphere The reaction mixture was stirred for 3 hours. When the starting material was consumed, the reaction mixture was concentrated and basified to about pH 9 then extracted with DCM (3×30 mL). The combined organics were concentrated to give the title compound, m.

步驟14c)(S)-(1-(2-氯嘧啶-4-基)吡咯啶-3-基)胺基甲酸第三丁酯Step 14c) (S)-(1-(2-chloropyrimidin-4-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester

向(S)-(1-(2-氯嘧啶-4-基)吡咯啶-3-基)胺基甲酸第三丁酯(14g，94.6mmol)於丙-2-醇(50mL)中之溶液中添加DIPEA(14.64g，113.51mmol)，並且將混合物冷卻至0℃，接著向該溶液中逐份添加(S)-吡咯啶-3-基胺基甲酸第三丁酯(17.6g，94.6mmol)。在25℃下將反應溶液攪拌30分鐘。接著濃縮混合物，且在矽膠管柱上純化殘餘物(用10%乙酸乙酯/石油醚溶離)，得到呈固體狀之(S)-(1-(2-氯嘧啶-4-基)吡咯啶-3-基)胺基甲酸第三丁酯(22.5g，產率80%)及(S)-(1-(4-氯嘧啶-2-基)吡咯啶-3-基)胺基甲酸第三丁酯(3.0g，產率10%)。 A solution of (S)-(1-(2-chloropyrimidin-4-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (14 g, 94.6 mmol) in propan-2-ol (50 mL) DIPEA (14.64 g, 113.51 mmol) was added, and the mixture was cooled to 0 ° C, then (S)-pyrrolidin-3-ylaminocarbamic acid tert-butyl ester (17.6 g, 94.6 mmol) was added portionwise to the solution. ). The reaction solution was stirred at 25 ° C for 30 minutes. The mixture was then concentrated, and the residue was purified (jjjjjjjjjjjj 3-butyl) butyl methacrylate (22.5 g, yield 80%) and (S)-(1-(4-chloropyrimidin-2-yl)pyrrolidin-3-yl)carbamic acid Tributyl ester (3.0 g, yield 10%).

(S)-(1-(2-氯嘧啶-4-基)吡咯啶-3-基)胺基甲酸第三丁酯 (S)-(1-(2-chloropyrimidin-4-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester

¹H NMR(CDCl₃,400MHz)：δ 7.97(d,J=6.0,1H),6.15(d,J=6.0,1H),4.79(s,1H),4.31(s,1H),3.22-3.82(m,4H),2.25(s,1H),1.91-2.03(m,1H),1.42(s,9H)； MS(ESI)：m/z 298.9[M+1]⁺。 ^{_{1 H NMR (CDCl 3, 400MHz}} ): δ 7.97 (d, J = 6.0,1H), 6.15 (d, J = 6.0,1H), 4.79 (s, 1H), 4.31 (s, 1H), 3.22-3.82 (m, 4H), 2.25 (s, 1H), 1.91-2.03 (m, 1H), 1.42 (s, 9H); MS (ESI): m/z 298.9 [M+1] ⁺ .

(S)-(1-(4-氯嘧啶-2-基)吡咯啶-3-基)胺基甲酸第三丁酯 (S)-(1-(4-chloropyrimidin-2-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester

¹H NMR(CDCl₃,400MHz)：δ 8.09(d,J=5.2,1H),6.45(d,J=5.2,1H),4.60(s,1H),4.26(s,1H),3.74-3.79(m,1H),3.53-3.63(m,2H),3.36-3.40(m,1H),2.15-2.23(m,1H),1.85-1.93(m,1H),1.38(s,9H)； MS(ESI)：m/z 298.9[M+1]⁺。 ^{_{1 H NMR (CDCl 3, 400MHz}} ): δ 8.09 (d, J = 5.2,1H), 6.45 (d, J = 5.2,1H), 4.60 (s, 1H), 4.26 (s, 1H), 3.74-3.79 (m, 1H), 3.53-3.63 (m, 2H), 3.36-3.40 (m, 1H), 2.15-2.23 (m, 1H), 1.85-1.93 (m, 1H), 1.38 (s, 9H); MS (ESI): m/z 298.9 [M+1] ⁺ .

步驟14d)(S)-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)胺基甲酸第三丁酯Step 14d) (S)-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester

向(S)-(1-(2-氯嘧啶-4-基)吡咯啶-3-基)胺基甲酸第三丁酯(22g，74mmol)於甲胺/THF(2M，100ml)中之溶液中添加CuSO₄(1.18g，7.4mmol)。在80℃下在高壓釜中將反應溶液攪拌16小時。濃縮該混合物且將殘餘物溶解於乙酸乙酯(600ml)中，用NH₄OH溶液(3×20ml)洗滌。使有機層經硫酸鈉乾燥並濃縮。在矽膠管柱上純化殘餘物(用45%乙酸乙酯/石油醚溶離)，獲得(S)-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)胺基甲酸第三丁酯(21g，產率97%)。 A solution of (S)-(1-(2-chloropyrimidin-4-yl)pyrrolidin-3-yl)carbamic acid tert-butyl ester (22 g, 74 mmol) in methylamine / THF (2M, 100 mL) CuSO ₄ (1.18 g, 7.4 mmol) was added. The reaction solution was stirred in an autoclave at 80 ° C for 16 hours. The mixture was concentrated and the residue was dissolved in ethyl acetate (600ml), washed with NH ₄ OH solution (3 × 20ml). The organic layer was dried over sodium sulfate and concentrated. The residue was purified on a silica gel column (solvent with 45% ethyl acetate / petroleum ether) to give (S)-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl Tributyl methacrylate (21 g, yield 97%).

¹H NMR(DMSO-d₆,400MHz)：δ 7.73(d,J=5.6,1H),7.18(d,J=5.6,1H),6.33(d,J=4.4,1H),5.68(d,J=5.6,1H),4.02-4.05(m,1H),3.54(m,4H),2.72(d,J=4.8,3H),2.07-2.08(m,1H),1.78-1.84(m,1H),1.39(s,9H)； MS(ESI)：m/z 294.1[M+1]⁺。 ^{_{1 H NMR (DMSO-d 6}} , 400MHz): δ 7.73 (d, J = 5.6,1H), 7.18 (d, J = 5.6,1H), 6.33 (d, J = 4.4,1H), 5.68 (d, J = 5.6, 1H), 4.02-4.05 (m, 1H), 3.54 (m, 4H), 2.72 (d, J = 4.8, 3H), 2.07-2.08 (m, 1H), 1.78-1.84 (m, 1H) ), 1.39 (s, 9H) ; MS (ESI): m / z 294.1 [m + 1] +.

步驟14e)(S)-4-(3-胺基吡咯啶-1-基)-N-甲基嘧啶-2-胺Step 14e) (S)-4-(3-Aminopyrrolidin-1-yl)-N-methylpyrimidin-2-amine

在室溫下，在4N HCl/二噁烷(50mL)中將(S)-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)胺基甲酸第三丁酯(21g，71.5mmol)攪拌1小時。濃縮反應混合物，得到呈鹽酸鹽形式之(S)-4-(3-胺基吡咯啶-1-基)-N-甲基嘧啶-2-胺(18，產率超過100%)。 (S)-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)carbamic acid in 4N HCl/dioxane (50 mL) at rt Tributyl ester (21 g, 71.5 mmol) was stirred for 1 hour. The reaction mixture was concentrated to give (S)-4-(3-aminopyrrolidin-1-yl)-N-methylpyrimidin-2-amine (18, yield over 100%).

¹H NMR(DMSO-d₆,400MHz)：δ 7.74(d,J=5.6,1H),7.34(d,J=4.8,1H),5.68(d,J=5.2,1H),3.63-3.67(m,1H),3.34-3.57(m,4H),2.72(d,J=4.8,3H),2.07-2.09(m,1H),1.77-1.85(m,1H)。 ^{_{1 H NMR (DMSO-d 6}} , 400MHz): δ 7.74 (d, J = 5.6,1H), 7.34 (d, J = 4.8,1H), 5.68 (d, J = 5.2,1H), 3.63-3.67 ( m, 1H), 3.34 - 3.57 (m, 4H), 2.72 (d, J = 4.8, 3H), 2.07 - 2.09 (m, 1H), 1.77-1.85 (m, 1H).

步驟14f)(S)-1-(4-(氮雜環丁烷-1-基甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲Step 14f) (S)-1-(4-(azetidin-1-ylmethyl)phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl)pyrrole Pyridin-3-yl)urea

向4-(氮雜環丁烷-1-基甲基)苯胺(162mg，1mmol)於DMF(4mL)中之溶液中添加TEA(303mg，3mmol)及CDI(194mg，1.3mmol)。在室溫下將反應物攪拌30分鐘，接著添加(S)-4-(3-胺基吡咯啶-1-基)-N-甲基嘧啶-2-胺(332mg，1.0mmol)。將混合物再攪拌2小時。在起始物質耗盡之後，藉由製備型HPLC在條件A下純化粗產物，得到(S)-1-(4-(氮雜環丁烷-1-基甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲(99.2mg，25.9%)。 To a solution of 4-(azetidin-1-ylmethyl)aniline (162 mg, 1 mmol) in EtOAc (EtOAc) The reaction was stirred at room temperature for 30 min then (S)-4-(3-aminopyrrolidin-1-yl)-N-methylpyrimidin-2-amine (332 mg, 1.0 mmol). The mixture was stirred for a further 2 hours. After the starting material was consumed, the crude product was purified by preparative HPLC under Condition A to give (S)-1-(4-(azetidin-1-ylmethyl)phenyl)-3- (1-(2-(Methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea (99.2 mg, 25.9%).

¹H NMR(400MHz,DMSO-d6)δ 8.28(s,1 H),7.76(d,J=5.6Hz,1 H),7.29(d,J=8.4Hz,2 H),7.09(d,J=8.4Hz,2 H),6.49(d,J=6.8Hz,1 H),6.35(d,J=4.8Hz,1 H),5.74(d,J=6.0Hz,1 H),4.24(brs, 1 H),3.68-3.21(m,6 H),3.05(t,J=6.8Hz,4 H),2.81-2.65(m,3 H),2.12(m,1 H),1.97-1.82(m,3 H)。LCMS(ESI)：m/z 382.2[M+H⁺]。 ^{1 H NMR (400MHz, DMSO-} d6) δ 8.28 (s, 1 H), 7.76 (d, J = 5.6Hz, 1 H), 7.29 (d, J = 8.4Hz, 2 H), 7.09 (d, J = 8.4 Hz, 2 H), 6.49 (d, J = 6.8 Hz, 1 H), 6.35 (d, J = 4.8 Hz, 1 H), 5.74 (d, J = 6.0 Hz, 1 H), 4.24 (brs , 1 H), 3.68-3.21 (m, 6 H), 3.05 (t, J = 6.8 Hz, 4 H), 2.81-2.65 (m, 3 H), 2.12 (m, 1 H), 1.97-1.82 ( m, 3 H). LCMS (ESI): m / z 382.2 [M + H +].

實例15：Example 15: (S)-1-(4-(氮雜環丁烷-1-基甲基)-3-氟苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲(S)-1-(4-(azetidin-1-ylmethyl)-3-fluorophenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl) Pyrrolidin-3-yl)urea

步驟15a)N-(4-(氮雜環丁烷-1-基甲基)-3-氟苯基)-2,2,2-三氟乙醯胺Step 15a) N-(4-(azetidin-1-ylmethyl)-3-fluorophenyl)-2,2,2-trifluoroacetamide

經30分鐘向氮雜環丁烷鹽酸鹽(1.4g，15mmol)及DIPEA(1.9g，15mmol)於CH₃CN(30mL)中之溶液中逐滴添加N-(4-(溴甲基)-3-氟苯基)-2,2,2-三氟乙醯胺(1.5g，5mmol)。在室溫下，在N₂氛圍下將反應混合物攪拌3小時。在起始物質耗盡之後，用DCM(80mL)稀釋反應混合物，且用水(3×80mL)洗滌有機層，接著濃縮，得到標題化合物，其不經進一步純化即使用(1.1g，產率：81%)。 Over 30 minutes azetidine hydrochloride (1.4g, 15mmol) and DIPEA (1.9g, 15mmol) in the in CH ₃ CN (30mL) was added dropwise a solution of N- (4- (bromomethyl) 3-fluorophenyl)-2,2,2-trifluoroacetamide (1.5 g, 5 mmol). The reaction mixture was stirred at room temperature for 3 hours under N ₂ atmosphere. The reaction mixture was diluted with EtOAc EtOAc EtOAc. %).

步驟15b)4-(氮雜環丁烷-1-基甲基)-3-氟苯胺Step 15b) 4-(Azetidin-1-ylmethyl)-3-fluoroaniline

向N-(4-(氮雜環丁烷-1-基甲基)-3-氟苯基)-2,2,2-三氟乙醯胺(1.1g，3.9mmol)於CH₃OH(30ml)中之溶液中添加K₂CO₃(1.62g，11.7mmol)之水(10ml)溶液，且在75℃下在N₂氛圍下將反應混合物攪拌3小時。在起始物質耗盡之後，用DCM(80mL)稀釋反應混合物，且用水(3×80mL)洗滌有機層，接著濃縮，得到標題化合物，其不經進一步純化即使用(645mg，產率：91%)。 To N- (4- (azetidin-1-ylmethyl) -3-fluorophenyl) -2,2,2-trifluoro-acetyl amine (1.1g, 3.9mmol) in CH ₃ OH ( A solution of K ₂ CO ₃ (1.62 g, 11.7 mmol) in water (10 ml) was added to a solution in 30 ml), and the reaction mixture was stirred at 75 ° C for 3 hours under N ₂ atmosphere. The reaction mixture was diluted with EtOAc EtOAc EtOAc. ).

步驟15c)(S)-1-(4-(氮雜環丁烷-1-基甲基)-3-氟苯基)-3-(1-(2-(甲基胺Step 15c) (S)-1-(4-(azetidin-1-ylmethyl)-3-fluorophenyl)-3-(1-(2-(methylamine) 基)嘧啶-4-基)吡咯啶-3-基)脲Pyrimidin-4-yl)pyrrolidin-3-yl)urea

向4-(氮雜環丁烷-1-基甲基)-3-氟苯胺(180mg，1mmol)於DMF(4mL)中之溶液中添加TEA(303mg，3mmol)及CDI(194mg，1.3mmol)。在室溫下將反應物攪拌30分鐘。添加(S)-4-(3-胺基吡咯啶-1-基)-N-甲基嘧啶-2-胺(332mg，1.0mmol)，且將混合物再攪拌2小時。在起始物質耗盡之後，藉由製備型HPLC，使用條件A來純化粗產物，得到標題化合物(37.1mg，9.3%)。 Add TEA (303 mg, 3 mmol) and CDI (194 mg, 1.3 mmol) to a solution of 4-(azetidin-1-ylmethyl)-3-fluoroaniline (180 mg, 1 mmol) in DMF (4 mL) . The reaction was stirred at room temperature for 30 minutes. (S)-4-(3-Aminopyrrolidin-1-yl)-N-methylpyrimidin-2-amine (332 mg, 1.0 mmol) was added, and the mixture was further stirred for 2 hr. The crude product was purified using EtOAc (EtOAc)

¹H NMR(400MHz,DMSO-d₆)δ 8.54(s,1 H),7.81-7.65(m,1H),7.41-6.85(m,3 H),6.65-6.22(m,2 H),5.74(d,J=7.2Hz,1 H),4.26(brs,1 H),3.82-3.01(m,9 H),2.89-2.42(m,4 H),2.32-1.71(m,4 H)。LCMS(ESI)：m/z 400.2[M+H⁺]。 ^{1 H NMR (400MHz, DMSO-} d 6) δ 8.54 (s, 1 H), 7.81-7.65 (m, 1H), 7.41-6.85 (m, 3 H), 6.65-6.22 (m, 2 H), 5.74 (d, J = 7.2 Hz, 1 H), 4.26 (brs, 1 H), 3.82-3.01 (m, 9 H), 2.89-2.42 (m, 4 H), 2.32-1.71 (m, 4 H). LCMS (ESI): m / z 400.2 [M + H +].

實例16：Example 16: (S)-1-(3-氯-4-((二甲基胺基)甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲(S)-1-(3-chloro-4-((dimethylamino)methyl)phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidine -3-yl)urea

步驟16a)N-(3-氯-4-甲基苯基)-2,2,2-三氟乙醯胺Step 16a) N-(3-Chloro-4-methylphenyl)-2,2,2-trifluoroacetamide

向3-氯-4-甲基苯胺(14.2g，100mmol)溶解於DCM(250ml)中之溶液中添加吡啶(75ml，0.80mol)且在0℃下逐滴添加三氟乙酸酐(16.5ml，112.5mmol)。在室溫下將混合物攪拌1小時。用10% HCl水溶液，接著用水洗滌反應混合物。使有機相經Na₂SO₄乾燥並濃縮，得到標題化合物，其不經進一步純化即使用(22g，92.8%)。 Pyridine (75 ml, 0.80 mol) was added to a solution of 3-chloro-4-methylaniline (14.2 g, 100 mmol) in DCM (250 ml), and trifluoroacetic acid anhydride (16.5 ml) was added dropwise at 0 °C. 112.5 mmol). The mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with 10% aq. HCl then water. The organic phase was dried and concentrated over Na ₂ SO _4, to give the title compound, which was used without further purification (22g, 92.8%).

步驟16b)N-(4-(溴甲基)-3-氯苯基)-2,2,2-三氟乙醯胺Step 16b) N-(4-(bromomethyl)-3-chlorophenyl)-2,2,2-trifluoroacetamide

向N-(3-氯-4-甲基苯基)-2,2,2-三氟乙醯胺(22g，92.2mmol)於CCl₄(740ml)中之溶液中添加BPO(6.7g，27.7mmol)及NBS(19.7g，110.6mmol)。使混合物升溫至100℃，且以高壓燈照明1小時。在100℃下將反應混合物攪拌36小時。在冷卻降至0℃之後，過濾反應混合物且用鹽水洗滌濾液，接著濃縮。用石油醚洗滌粗產物並且過濾，得到標題化合物，其不經進一步純化即使用(14g，48.3%)。 Add BPO (6.7 g, 27.7) to a solution of N-(3-chloro-4-methylphenyl)-2,2,2-trifluoroacetamide (22 g, 92.2 mmol) in CCI ₄ (740 mL) Methyl) and NBS (19.7 g, 110.6 mmol). The mixture was allowed to warm to 100 ° C and was illuminated with a high pressure lamp for 1 hour. The reaction mixture was stirred at 100 ° C for 36 hours. After cooling to 0 ° C, the reaction mixture was filtered and washed with brine, then concentrated. The crude product was washed with EtOAc (EtOAc)EtOAc.

步驟16c)N-(3-氯-4-((二甲基胺基)甲基)苯基)-2,2,2-三氟乙醯胺Step 16c) N-(3-Chloro-4-((dimethylamino)methyl)phenyl)-2,2,2-trifluoroacetamide

在0℃下經1小時向二甲胺鹽酸鹽(4.6g，56.4mmol)於MeCN(150ml)中之溶液中逐滴添加溶解於MeCN(150ml)中之N-(4-(溴甲基)-3-氯苯基)-2,2,2-三氟乙醯胺(3.0g，9.4mmol)，且在0℃下攪拌30分鐘。隨後，添加100mL飽和NaHCO₃，且使混合物分配在DCM與水之間。用水(15mL)洗滌有機層，經Na₂SO₄乾燥，濃縮且藉由製備型TLC加以純化(石油醚：EtOAc=2：1)，得到標題化合物(2.2g，83%)。 N-(4-(bromomethyl) dissolved in MeCN (150 ml) was added dropwise to a solution of dimethylamine hydrochloride (4.6 g, 56.4 mmol) in MeCN (150 mL) at EtOAc. 3-chlorophenyl)-2,2,2-trifluoroacetamide (3.0 g, 9.4 mmol), and stirred at 0 ° C for 30 min. Subsequently, 100 mL of saturated NaHCO _{3 was} added and the mixture was partitioned between DCM and water. The organic layer was washed with water (15mL), dried over Na ₂ SO _4, and concentrated to be purified by preparative TLC (petroleum ether: EtOAc = 2: 1), to give the title compound (2.2g, 83%).

步驟16d)3-氯-4-((二甲基胺基)甲基)苯胺Step 16d) 3-Chloro-4-((dimethylamino)methyl)aniline

在室溫下向N-(3-氯-4-((二甲基胺基)甲基)苯基)-2,2,2-三氟乙醯胺(2.2g，粗製)於MeOH(30mL)及H₂O(30ml)中之溶液中添加K₂CO₃(3.25g，23.6mmol)。接著在80℃下將混合物攪拌1小時。濃縮反應混合物，得到標題化合物(1.3g，90.1%)。 To N-(3-chloro-4-((dimethylamino)methyl)phenyl)-2,2,2-trifluoroacetamide (2.2 g, crude) in MeOH (30 mL) K ₂ CO ₃ (3.25 g, 23.6 mmol) was added to the solution in H ₂ O (30 mL). The mixture was then stirred at 80 ° C for 1 hour. The reaction mixture was concentrated to give title crystall

¹H NMR(400MHz,CDCl₃)δ 7.48(d,J=8.0Hz,1H),δ 6.91(d, J=2.4Hz,1H),6.79-6.77(m,1H),δ 3.77(s,2H),δ 3.52(s,2H),δ 2.47(d,J=10.8Hz,7H),δ 2.28(s,3H)。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.48 (d, J = 8.0 Hz, 1H), δ 6.91 (d, J = 2.4 Hz, 1H), 6.79-6.77 (m, 1H), δ 3.77 (s, 2H) ), δ 3.52 (s, 2H), δ 2.47 (d, J = 10.8 Hz, 7H), δ 2.28 (s, 3H).

步驟16e)(S)-1-(3-氯-4-((二甲基胺基)甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲Step 16e) (S)-1-(3-Chloro-4-((dimethylamino)methyl)phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl) Pyrrolidin-3-yl)urea

在25℃下向3-氯-4-((二甲基胺基)甲基)苯胺(200mg，1.08mmol)於無水DMF(5ml)中之溶液中添加CDI(224mg，1.4mmol)及DIPEA(413.2mg，3.26mmol)。在25℃下將混合物攪拌2小時。接著添加(S)-4-(3-胺基吡咯啶-1-基)-N-甲基嘧啶-2-胺(208mg，1.08mmol)，且在25℃下將混合物攪拌16小時。藉由製備型HPLC(方法B)純化混合物，得到標題化合物(22.0mg，5.0%)。 Add CDI (224 mg, 1.4 mmol) and DIPEA to a solution of 3-chloro-4-((dimethylamino)methyl)aniline (200 mg, 1.08 mmol) in anhydrous DMF (5 mL) 413.2 mg, 3.26 mmol). The mixture was stirred at 25 ° C for 2 hours. Then (S)-4-(3-Aminopyrrolidin-1-yl)-N-methylpyrimidin-2-amine (208 mg, 1.08 mmol) was added, and the mixture was stirred at 25 ° C for 16 hours. The mixture was purified by preparative EtOAc (EtOAc)

¹H NMR(400MHz,DMSO-d ₆)δ 8.42(s,1H),δ 7.74(d,j=6.0Hz,1H),7.62(d,j=2.0Hz,1H),7.24(d,j=8.4Hz,1H),7.13-7.11(m,1H),6.55(d,j=6.8Hz,1H),6.33(d,j=4.4Hz,1H),5.71(d,j=5.6Hz,1H),4.23(s,1H),3.55(d,j=2.8Hz,2H),3.34(s,3H),2.71(d,j=4.8Hz,3H),2.12(s,8H),1.87(d,j=9.6Hz,1H)。 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.42 (s, 1H), δ 7.74 (d,j=6.0 Hz, 1H), 7.62 (d,j=2.0 Hz, 1H), 7.24 (d,j= 8.4 Hz, 1H), 7.13 - 7.11 (m, 1H), 6.55 (d, j = 6.8 Hz, 1H), 6.33 (d, j = 4.4 Hz, 1H), 5.71 (d, j = 5.6 Hz, 1H) , 4.23 (s, 1H), 3.55 (d, j = 2.8 Hz, 2H), 3.34 (s, 3H), 2.71 (d, j = 4.8 Hz, 3H), 2.12 (s, 8H), 1.87 (d, j = 9.6 Hz, 1H).

LCMS(ESI)：m/z 404.0[M+H⁺]。 LCMS (ESI): m / z 404.0 [M + H +].

實例17：Example 17: (S)-1-(4-(氮雜環丁烷-1-基甲基)-3-氯苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲(S)-1-(4-(azetidin-1-ylmethyl)-3-chlorophenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl) Pyrrolidin-3-yl)urea

¹H NMR(400MHz,CDCl₃)δ 8.09(brs,1 H),7.67(d,J=6.0Hz,1 H),7.49(s,1 H),7.31-7.17(m,2 H),6.67(brs,1 H),5.57(d,J=6.0Hz,1 H),4.78(brs,1 H),4.50(brs,1 H),3.62(s,1 H),3.62-2.85(m,9 H),2.35-2.11(m,4 H),1.27(s,2 H)。LCMS(ESI)：m/z 416.2[M+H⁺]。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ 8.09 (brs, 1 H), 7.67 (d, J = 6.0Hz, 1 H), 7.49 (s, 1 H), 7.31-7.17 (m, 2 H), 6.67 (brs, 1 H), 5.57 (d, J = 6.0 Hz, 1 H), 4.78 (brs, 1 H), 4.50 (brs, 1 H), 3.62 (s, 1 H), 3.62-2.85 (m, 9 H), 2.35-2.11 (m, 4 H), 1.27 (s, 2 H). LCMS (ESI): m / z 416.2 [M + H +].

實例18：Example 18: (S)-1-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲(S)-1-(3-chloro-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-(1-(2-(methylamino)pyrimidine-4 -based pyrrolidin-3-yl)urea

¹H NMR(400MHz,DMSO-d ₆)δ 8.48(s,1H),δ 7.74(d,j=5.6Hz,1H),7.62(d,j=2.4Hz,1H),7.25(d,j=8.4Hz,1H),7.13-7.10(m,1H),6.58(d,j=6.8Hz,1H),5.71(d,j=6.0Hz,1H),4.23(s,1H),3.561(d,j=3.6Hz,1H),3.42(s,3H),2.71(d,j=4.8Hz,3H),2.50(d,j=2.0Hz,2H),2.35-2.28(m,8H),2.14(s,1H),2.11(s,3H),1.89-1.84(m,1H)。 ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.48 (s, 1H), δ 7.74 (d, j = 5.6 Hz, 1H), 7.62 (d, j = 2.4 Hz, 1H), 7.25 (d, j = 8.4 Hz, 1H), 7.13-7.10 (m, 1H), 6.58 (d, j = 6.8 Hz, 1H), 5.71 (d, j = 6.0 Hz, 1H), 4.23 (s, 1H), 3.561 (d, j=3.6 Hz, 1H), 3.42 (s, 3H), 2.71 (d, j = 4.8 Hz, 3H), 2.50 (d, j = 2.0 Hz, 2H), 2.35-2.28 (m, 8H), 2.14 ( s, 1H), 2.11 (s, 3H), 1.89-1.84 (m, 1H).

LCMS(ESI)：m/z 459.0[M+H⁺]。 LCMS (ESI): m / z 459.0 [M + H +].

實例19：Example 19: (S)-1-(3-氯-4-((4-乙基哌嗪-1-基)甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲(S)-1-(3-chloro-4-((4-ethylpiperazin-1-yl)methyl)phenyl)-3-(1-(2-(methylamino)pyrimidine-4) -based pyrrolidin-3-yl)urea

步驟19a)N-(3-氯-4-((4-乙基哌嗪-1-基)甲基)苯基)-2,2,2-三氟乙醯胺Step 19a) N-(3-Chloro-4-((4-ethylpiperazin-1-yl)methyl)phenyl)-2,2,2-trifluoroacetamide

在0℃下經1小時向N-(4-(溴甲基)-3-氯苯基)-2,2,2-三氟乙醯胺(2.0g，6.35mmol)於MeCN(150ml)中之溶液中逐滴添加溶解於MeCN(150ml)中之1-乙基哌嗪(4.3g，38.1mmol)。在0℃下將混合物攪拌30分鐘。在添加100mL飽和NaHCO₃之後，使混合物分配在DCM與水之間。用水(15ml)洗滌有機層，經Na₂SO₄乾燥，濃縮且藉由製備型TLC 加以純化(PE：EA=2：1)，得到標題化合物，其不經進一步純化即用於下一步驟(1.8g，81.8%)。 To N-(4-(bromomethyl)-3-chlorophenyl)-2,2,2-trifluoroacetamide (2.0 g, 6.35 mmol) in MeCN (150 mL) To the solution was added dropwise 1-ethylpiperazine (4.3 g, 38.1 mmol) dissolved in MeCN (150 ml). The mixture was stirred at 0 ° C for 30 minutes. After the addition of 100mL of saturated NaHCO _3, the mixture was partitioned between DCM and water. The organic layer was washed with water (15ml), dried over Na ₂ SO _4, and concentrated to be purified by preparative TLC (PE: EA = 2: 1 ), to give the title compound, which was used without further purification in the next step ( 1.8g, 81.8%).

步驟19b)3-氯-4-((4-乙基哌嗪-1-基)甲基)苯胺Step 19b) 3-Chloro-4-((4-ethylpiperazin-1-yl)methyl)aniline

以類似於3-氯-4-((二甲基胺基)甲基)苯胺之方式，以1-乙基哌嗪替代二甲胺鹽酸鹽來製備3-氯-4-((4-乙基哌嗪-1-基)甲基)苯胺。 Prepare 3-chloro-4-(4-4- in a manner similar to 3-chloro-4-((dimethylamino)methyl)aniline with 1-ethylpiperazine instead of dimethylamine hydrochloride Ethyl piperazin-1-yl)methyl)aniline.

¹H NMR(400MHz,CDCl₃)δ 7.01(d,J=7.6Hz,1H),6.55(d,J=1.2Hz,1H),6.45(m,1H),5.23(s,2H),2.23-2.33(m,10 H),0.93(m,3H)。 ^{_{1 H NMR (400MHz, CDCl 3}} ) δ 7.01 (d, J = 7.6Hz, 1H), 6.55 (d, J = 1.2Hz, 1H), 6.45 (m, 1H), 5.23 (s, 2H), 2.23- 2.33 (m, 10 H), 0.93 (m, 3H).

步驟19c)(3-氯-4-((4-乙基哌嗪-1-基)甲基)苯基)胺基甲酸苯酯Step 19c) (phenyl 3-chloro-4-((4-ethylpiperazin-1-yl)methyl)phenyl)carbamate

在65℃下向3-氯-4-((4-乙基哌嗪-1-基)甲基)苯胺(300mg，1.18mmol)於無水THF(12ml)中之溶液中逐滴添加氯甲酸苯酯(185mg，1.18mmol)。在65℃下將混合物攪拌30分鐘。在冷卻至25℃之後，過濾混合物，得到標題化合物，其不經進一步純化即使用(290mg，66%)。 To a solution of 3-chloro-4-((4-ethylpiperazin-1-yl)methyl)phenylamine (300 mg, 1.18 mmol) in anhydrous THF (12 mL) Ester (185 mg, 1.18 mmol). The mixture was stirred at 65 ° C for 30 minutes. After cooling to 25 <0>C, <RTI ID=0.0>

步驟19d)(S)-1-(3-氯-4-((4-乙基哌嗪-1-基)甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲Step 19d) (S)-1-(3-Chloro-4-((4-ethylpiperazin-1-yl)methyl)phenyl)-3-(1-(2-(methylamino)) Pyrimidin-4-yl)pyrrolidin-3-yl)urea

在室溫下向(3-氯-4-((4-乙基哌嗪-1-基)甲基)苯基)胺基甲酸苯酯(290mg)於無水DMF(3ml)中之溶液中添加DIPEA(102.7mg，0.79mmol)。在室溫下將混合物攪拌0.5小時。添加(S)-4-(3-胺基吡咯啶-1-基)-N-甲基嘧啶-2-胺(150mg，0.40mmol)，且在室溫下將混合物攪拌16小時。藉由製備型HPLC(方法C)純化混合物，得到標題化合物 (18.0mg，3.2%)。 Add to a solution of (3-chloro-4-((4-ethylpiperazin-1-yl)methyl)phenyl)carbamic acid phenyl ester (290 mg) in anhydrous DMF (3 mL) DIPEA (102.7 mg, 0.79 mmol). The mixture was stirred at room temperature for 0.5 hours. (S)-4-(3-Aminopyrrolidin-1-yl)-N-methylpyrimidin-2-amine (150 mg, 0.40 mmol) was added, and the mixture was stirred at room temperature for 16 hr. The mixture was purified by preparative HPLC (Method C) to give the title compound (18.0 mg, 3.2%).

¹H NMR(400MHz,DMSO-d ₆)δ 8.45(s,1H),7.74(d,J=6.0Hz,1H),7.62(d,J=2.0Hz,1H),7.25(d,J=8.8Hz,1H),7.12-7.10(m,1H),6.55(d,J=6.8Hz,1H),6.33-6.30(m,1H),5.71(d,J=6.4Hz,1H),3.57-3.54(m,2H),3.41(s,3H),3.37-3.32(m,2H),3.27(s,1H),2.71(d,J=4.8Hz,3H),2.52(d,1H),2.42-2.23(m,10H),2.13-2.10(m,1H),1.87(d,J=7.2Hz,1H),0.94(t,J=7.2Hz,3H)。 ^{1 H NMR (400MHz, DMSO- d} 6) δ 8.45 (s, 1H), 7.74 (d, J = 6.0Hz, 1H), 7.62 (d, J = 2.0Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.12-7.10 (m, 1H), 6.55 (d, J = 6.8 Hz, 1H), 6.33-6.30 (m, 1H), 5.71 (d, J = 6.4 Hz, 1H), 3.57-3.54 (m, 2H), 3.41 (s, 3H), 3.37-3.32 (m, 2H), 3.27 (s, 1H), 2.71 (d, J = 4.8 Hz, 3H), 2.52 (d, 1H), 2.42- 2.23 (m, 10H), 2.13-2.10 (m, 1H), 1.87 (d, J = 7.2 Hz, 1H), 0.94 (t, J = 7.2 Hz, 3H).

LCMS(ESI)：m/z 473.0[M+H⁺]。 LCMS (ESI): m / z 473.0 [M + H +].

實例20：Example 20: (S)-1-(3-氯-4-(N-嗎啉基甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲(S)-1-(3-chloro-4-(N-morpholinylmethyl)phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidine-3 -based urea

根據用於製造(S)-1-(3-氯-4-((4-乙基哌嗪-1-基)甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲之一般程序(實例19)來製備此化合物。 According to the manufacture of (S)-1-(3-chloro-4-((4-ethylpiperazin-1-yl)methyl)phenyl)-3-(1-(2-(methylamino) This compound was prepared by the general procedure of pyrimid-4-yl)pyrrolidin-3-yl)urea (Example 19).

¹H NMR(400MHz,DMSO-d ₆)δ 7.65-7.62(m,2 H),7.36(d,J=8.4Hz,1 H),7.22(dd,J=2.4,8.4Hz,1 H),6.17(s,1 H),4.46-4.40(m,1 H),3.95-3.82(m,2 H),3.71-3.68(m,8 H),3.48-3.47(m,1 H),2.96(s,3 H),2.61-2.59(m,4 H),2.38-2.32(m,1 H),2.12-2.04(m,1 H)。 ^{1 H NMR (400MHz, DMSO- d} 6) δ 7.65-7.62 (m, 2 H), 7.36 (d, J = 8.4Hz, 1 H), 7.22 (dd, J = 2.4,8.4Hz, 1 H), 6.17 (s, 1 H), 4.46-4.40 (m, 1 H), 3.95-3.82 (m, 2 H), 3.71-3.68 (m, 8 H), 3.48-3.47 (m, 1 H), 2.96 ( s, 3 H), 2.61-2.59 (m, 4 H), 2.38-2.32 (m, 1 H), 2.12-2.04 (m, 1 H).

LCMS(ESI)：m/z 446.0[M+H⁺]。 LCMS (ESI): m / z 446.0 [M + H +].

實例21：Example 21: (S)-1-(4-((二甲基胺基)甲基)-3-(三氟甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲(S)-1-(4-((Dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-3-(1-(2-(methylamino)pyrimidine-4) -based pyrrolidin-3-yl)urea

根據用於製造(S)-1-(4-(氮雜環丁烷-1-基甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲之一般程序(實例14)來製備此化合物。 According to the manufacture of (S)-1-(4-(azetidin-1-ylmethyl)phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl) This compound was prepared by the general procedure of pyrrolidin-3-yl)urea (Example 14).

¹H NMR(400MHz,CDCl₃)δ 8.22(br s,1 H),7.72-7.51(m,4 H),7.59-7.45(m,2 H),6.83(br s,1 H),5.61-5.57(m,1 H),4.99(brs,1 H),4.53(brs,1 H),3.82-3.25(m,6 H),2.93(d,J=4.4Hz,3 H),2.36-2.05(m,8 H)。LCMS(ESI)：m/z 438.2[M+H⁺]。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (br s, 1 H), 7.72-7.51 (m, 4 H), 7.59-7.45 (m, 2 H), 6.83 (br s, 1 H), 5. 5.57 (m, 1 H), 4.99 (brs, 1 H), 4.53 (brs, 1 H), 3.82-3.25 (m, 6 H), 2.93 (d, J = 4.4 Hz, 3 H), 2.36-2.05 (m, 8 H). LCMS (ESI): m / z 438.2 [M + H +].

實例22：Example 22: (S)-1-(4-(氮雜環丁烷-1-基甲基)-3-(三氟甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲(S)-1-(4-(azetidin-1-ylmethyl)-3-(trifluoromethyl)phenyl)-3-(1-(2-(methylamino)pyrimidine) -4-yl)pyrrolidin-3-yl)urea

¹H NMR(400MHz,CDCl₃)δ 8.22(brs,1 H),7.73-7.61(m,2 H),7.59-7.45(m,2 H),6.82(brs,1 H),5.62-5.51(m,1 H),4.84(brs,1 H),4.51(brs,1 H),3.71(s,2 H),3.72-3.05(m,8 H),2.93(d,J=4.8Hz,3 H),2.32-2.05(m,4 H)。LCMS(ESI)：m/z 450.2[M+H⁺]。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (brs, 1 H), 7.73-7.61 (m, 2 H), 7.59-7.45 (m, 2 H), 6.82 (brs, 1 H), 5.62-5.51 ( m,1 H), 4.84 (brs, 1 H), 4.51 (brs, 1 H), 3.71 (s, 2 H), 3.72-3.05 (m, 8 H), 2.93 (d, J = 4.8 Hz, 3 H), 2.32 - 2.05 (m, 4 H). LCMS (ESI): m / z 450.2 [M + H +].

實例23：Example 23: (S)-1-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)-3-(4-(吡咯啶-1-基甲基)-3-(三氟甲基)苯基)脲(S)-1-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)-3-(4-(pyrrolidin-1-ylmethyl)-3- (trifluoromethyl)phenyl)urea

¹H NMR(400MHz,CDCl₃)δ 8.12(brs,1 H),7.72-7.52(m,4 H),7.59-7.45(m,2 H),6.89(brs,1 H),5.64-5.62(m,1 H),5.39(brs,1 H),4.59(brs,1 H),3.76(s,3 H),3.72-3.41(m,3 H),2.92(d,J=4.0Hz,3 H),2.58(s,4 H),2.36-1.85(m,6 H)。LCMS(ESI)：m/z 464.2[M+H⁺]。 ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.12 (brs, 1 H), 7.72-7.52 (m, 4 H), 7.59-7.45 (m, 2 H), 6.89 (brs, 1 H), 5.64 - 5.62 ( m,1 H), 5.39 (brs, 1 H), 4.59 (brs, 1 H), 3.76 (s, 3 H), 3.72-3.41 (m, 3 H), 2.92 (d, J = 4.0 Hz, 3 H), 2.58 (s, 4 H), 2.36-1.85 (m, 6 H). LCMS (ESI): m / z 464.2 [M + H +].

實例24：Example 24: (S)-1-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)-3-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)脲(S)-1-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)-3-(4-((4-methylpiperazin-1-yl)) Methyl)-3-(trifluoromethyl)phenyl)urea

¹H NMR(400MHz,DMSO-d ₆)δ 8.83(s,1 H),8.16(s,2 H),7.90(d,J=2.0Hz,1 H),7.74(d,J=6.0Hz,1 H),7.52(d,J=8.4Hz,1 H),7.46-7.44(m,1 H),6.79(d,J=7.2Hz,1 H),6.48(brs,1 H),5.73(d,J=6.0Hz,1 H),4.24(s,2 H),3.58-3.55(m,2 H),3.43(s,3 H),2.71(d,J=4.8Hz,3 H),2.48-2.37(m,8 H),2.20(s,3 H),2.15-2.13(m,1 H), 1.89-1.86(m,1 H)。 ^{1 H NMR (400MHz, DMSO- d} 6) δ 8.83 (s, 1 H), 8.16 (s, 2 H), 7.90 (d, J = 2.0Hz, 1 H), 7.74 (d, J = 6.0Hz, 1 H), 7.52 (d, J = 8.4 Hz, 1 H), 7.46-7.44 (m, 1 H), 6.79 (d, J = 7.2 Hz, 1 H), 6.48 (brs, 1 H), 5.73 ( d, J = 6.0 Hz, 1 H), 4.24 (s, 2 H), 3.58-3.55 (m, 2 H), 3.43 (s, 3 H), 2.71 (d, J = 4.8 Hz, 3 H), 2.48-2.37 (m, 8 H), 2.20 (s, 3 H), 2.15-2.13 (m, 1 H), 1.89-1.86 (m, 1 H).

LCMS(ESI)：m/z 493.1[M+H⁺]。 LCMS (ESI): m / z 493.1 [M + H +].

實例25：Example 25: (S)-1-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲(S)-1-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(1-(2-(methylamine) Pyrimidin-4-yl)pyrrolidin-3-yl)urea

¹H NMR(400MHz,Methanol-d ₄))δ 7.81(s,1 H),7.74(d,J=6.0Hz,1 H),7.65(d,J=8.8Hz,1 H),7.53(d,J=8.0Hz,1 H),5.84(d,J=6.4Hz,1 H),4.62-4.51(m,2 H),4.49-4.32(m,1 H),3.61-3.37(m,5 H),2.88(s,3 H),2.65-1.95(m,11 H),1.12(t,J=7.2Hz,3 H)。LCMS(ESI)：m/z 507.2[M+H⁺]。 ¹ H NMR (400 MHz, Methanol- d ₄ )) δ 7.81 (s, 1 H), 7.74 (d, J = 6.0 Hz, 1 H), 7.65 (d, J = 8.8 Hz, 1 H), 7.53 (d) , J = 8.0 Hz, 1 H), 5.84 (d, J = 6.4 Hz, 1 H), 4.62-4.51 (m, 2 H), 4.49-4.32 (m, 1 H), 3.61-3.37 (m, 5) H), 2.88 (s, 3 H), 2.65-1.95 (m, 11 H), 1.12 (t, J = 7.2 Hz, 3 H). LCMS (ESI): m / z 507.2 [M + H +].

實例26：Example 26: (S)-1-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)-3-(4-(N-嗎啉基甲基)-3-(三氟甲基)苯基)脲(S)-1-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)-3-(4-(N-morpholinylmethyl)-3-( Trifluoromethyl)phenyl)urea

¹H NMR(400MHz,DMSO-d ₆)δ 8.80(s,1 H),7.93(s,1 H),7.77(d,J=6.0Hz,1 H),7.58(d,J=8.4Hz,1 H),7.49-7.47(m,1 H),6.76(d,J=6.4Hz,1 H),5.81(d,J=6.0Hz,1 H),4.27(s,2 H),3.65-3.62(m,1 H),3.58-3.56(m,5 H),3.51(s,3 H),2.75(d,J=8.8Hz,3 H),2.35(d,J=4.4Hz,4 H),2.18-2.17(m,1 H),1.92-1.91(m,1 H)。 ^{1 H NMR (400MHz, DMSO- d} 6) δ 8.80 (s, 1 H), 7.93 (s, 1 H), 7.77 (d, J = 6.0Hz, 1 H), 7.58 (d, J = 8.4Hz, 1 H), 7.49-7.47 (m, 1 H), 6.76 (d, J = 6.4 Hz, 1 H), 5.81 (d, J = 6.0 Hz, 1 H), 4.27 (s, 2 H), 3.65- 3.62 (m, 1 H), 3.58-3.56 (m, 5 H), 3.51 (s, 3 H), 2.75 (d, J = 8.8 Hz, 3 H), 2.35 (d, J = 4.4 Hz, 4 H ), 2.18-2.17 (m, 1 H), 1.92-1.91 (m, 1 H).

LCMS(ESI)：m/z 480.2[M+H⁺]。 LCMS (ESI): m / z 480.2 [M + H +].

實例27：Example 27: 1-(4-氮雜環丁烷-1-基甲基-3-三氟甲基-苯基)-3-[(S)-1-(2-甲基胺基-嘧啶-4-基)-吡咯啶-3-基]-脲1-(4-Azetidin-1-ylmethyl-3-trifluoromethyl-phenyl)-3-[(S)-1-(2-methylamino-pyrimidin-4-yl) )-pyrrolidin-3-yl]-urea

評定測試化合物對CDK8活性之抑制效應Assessing the inhibitory effect of test compounds on CDK8 activity

在競爭性ATP位點結合分析中評估CDK8抑制¹。將全長重組人類His標記之CDK8與細胞週期素C之二聚物與銪標記之抗His(Life Technologies，Madison，WI)預混合，且添加至含有稀釋至一定濃度範圍之測試化合物及比較化合物之分析板中。添加Tracer 236，即Alexa 647標記之專屬激酶抑制劑(Life Technologies)，且再培育60分鐘。藉由時差式螢光共振能量轉移(TR-FRET)來偵測示蹤劑與CDK8之結合。以340nm之光激發銪，使得能量轉移至Alexa 647，隨後在藉由結合相互作用使兩個螢光團密切鄰近時發射665nm之螢光。在ViewLux多模式板讀數器(PerkinElmer，Waltham，MA)上讀取螢光強度(在340nm激發且在615及665nm發射)。藉由將665nm下之螢光強度除以615nm下之螢光強度來計算TR-FRET信號。 CDK8 inhibition ¹ was assessed in a competitive ATP site binding assay. The full-length recombinant human His-tagged CDK8 is pre-mixed with the cyclin C dimer and the europium-labeled anti-His (Life Technologies, Madison, WI), and added to the test compound and the comparative compound containing the diluted to a certain concentration range. In the analysis board. Tracer 236, the exclusive kinase inhibitor labeled with Alexa 647 (Life Technologies), was added and incubated for an additional 60 minutes. The combination of the tracer and CDK8 was detected by time-lapse fluorescence resonance energy transfer (TR-FRET). The enthalpy is excited by light at 340 nm, causing the energy to transfer to Alexa 647, and then emitting 665 nm of fluorescence when the two fluorophores are in close proximity by binding interaction. Fluorescence intensity (excitation at 340 nm and emission at 615 and 665 nm) was read on a ViewLux multimode plate reader (PerkinElmer, Waltham, MA). The TR-FRET signal was calculated by dividing the fluorescence intensity at 665 nm by the fluorescence intensity at 615 nm.

在1536孔黑色微板上以4微升/孔之體積進行分析。CDK8/細胞週期素C二聚物、抗His及Tracer 236之最終濃度分別為5、4及10nM。分析緩衝液為50mM HEPES pH 7.5、10mM MgCl₂、0.01% Brij35、1mM EGTA、0.1%牛γ球蛋白及2mM二硫蘇糖醇。 Analysis was performed on a 1536-well black microplate in a volume of 4 μl/well. The final concentrations of CDK8/cyclin C dimer, anti-His and Tracer 236 were 5, 4 and 10 nM, respectively. The assay buffer was 50 mM HEPES pH 7.5, 10 mM MgCl ₂ , 0.01% Brij 35, 1 mM EGTA, 0.1% bovine gamma globulin and 2 mM dithiothreitol.

在具有DMSO作為樣品之對照孔中獲得最大示蹤劑結合及因此產生之最大TR-FRET信號。由化合物所致之示蹤劑位移引起信號減小。在CDK8/細胞週期素C二聚物不足之對照孔中獲得極小信號。計算在化合物存在下對示蹤劑結合之抑制百分比且繪製隨化合物濃度變化之曲線圖。將所得數據與四參數希爾曲線(Hill curves)擬合，且使用Genedata Screener軟體(Genedata，Basel，Switzerland)測定效能(IC₅₀值)。 Maximum tracer binding and the resulting maximum TR-FRET signal were obtained in control wells with DMSO as the sample. The tracer displacement caused by the compound causes a decrease in signal. Very small signals were obtained in control wells lacking CDK8/cyclin C dimer. The percent inhibition of tracer binding in the presence of the compound was calculated and plotted as a function of compound concentration. The resulting data with a four parameter Hill curve (Hill curves) fitting, and determines the effectiveness (IC ₅₀ value) using Genedata Screener software (Genedata, Basel, Switzerland).

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儘管已描述許多實施例，但可改變此等實例以提供利用本文中所描述之化合物及方法的其他實施例。因此，本發明之範疇將由所附申請專利範圍而不是由以實例為代表之特定實施例來定義。 Although a number of embodiments have been described, such examples can be modified to provide other embodiments utilizing the compounds and methods described herein. Therefore, the scope of the invention is defined by the scope of the appended claims rather than the specific embodiments represented by the examples.

Claims

一種式(I)化合物，或其鹽，其中：R¹係選自：且其中R¹係獨立地視情況經1、2或3個R^x基團取代；R²及R³獨立地為H、C_1-12烷基、C_2-12烯基、C_2-12炔基、碳環基、芳基、雜芳基、雜環基、鹵基、-OR^a、-SR^a、-N(R^a)₂、-CN、-NO₂、-C(O)R^a、-CO₂R^a、-C(O)N(R^a)₂、-C(O)SR^a、-C(O)C(O)R^a、-C(O)CH₂C(O)R^a、-C(S)N(R^a)₂、-C(S)OR^a、-S(O)R^a、-SO₂R^a、-SO₂N(R^a)₂、-N(R^a)C(O)R^a、-N(R^a)C(O)N(R^a)₂、-N(R^a)SO₂R^a、-N(R^a)SO₂N(R^a)₂、-N(R^a)N(R^a)₂、-N(R^a)C(=N(R^a))N(R^a)₂、-C(=N)N(R^a)₂、-C=NOR^a、-C(=N(R^a))N(R^a)₂、-OC(O)R^a或-OC(O)N(R^a)₂，其中R²及R³之各C_1-12烷基、C_2-12烯基、C_2-12炔基、碳環基、芳基、雜芳基及雜環基係各獨立地視情況經一或多個基團R^x取代；或R¹及R²與其所連接之原子一起形成4、5、6、7或8員碳環基、雜環基、雜芳基或芳基，該碳環基、雜環基、雜芳基及芳基視情況經一或多個基團R^x取代；各R^a及R^b獨立地為H、C_1-6烷基、C_2-6烯基、C_2-6炔基、碳環基、芳基、雜芳基或雜環基，其中各C_1-6烷基、C_3-6烯基、C_3-6炔基、碳環基、芳基、雜芳基及雜環基係獨立地視情況經一或多個基團R^x取代；或R^a及R^b與其所連接之氮一起形成3-6員雜環，該雜環視情況經側氧基(oxo)、鹵基或視情況經側氧基或鹵基取代之C_1-6烷基取代；各R^v獨立地為氫、C_1-6烷基、C_2-6烯基、C_2-6炔基、碳環基、芳基、雜芳基或雜環基，其中各C_1-6烷基、C_2-6烯基、C_2-6炔基、碳環基、芳基、雜芳基及雜環基視情況經一或多個獨立地選自以下之基團取代：側氧基、鹵基、胺基、羥基及視情況經一或多個獨立地選自側氧基及鹵基之基團取代之C₁-C₆烷基；或兩個R^v與其所連接之氮一起形成3-6員雜環基，該雜環基視情況經一或多個獨立地選自以下之基團取代：側氧基、鹵基及視情況經一或多個獨立地選自側氧基及鹵基之基團取代之C_1-3烷基；及各R^x獨立地為側氧基、C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6鹵烷基、碳環基、芳基、雜芳基、雜環基、-F、-Cl、-Br、-I、-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-O-C(O)-O-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-O-C(O)-N(R^v)₂、-N(R^v)-C(O)-OR^v、-N(R^v)-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、-N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^v、-N(R^v)-S(O)-N(R^v)₂或-N(R^v)-S(O)₂-N(R^v)₂，其中任何C_1-6烷基、C_2-6烯基、C_2-6炔基、C_1-6鹵烷基、碳環基、芳基、雜芳基及雜環基係獨立地視情況經一或多個選自以下之基團取代：側氧基、鹵基、-NO₂、-N(R^v)₂、-CN、-C(O)-N(R^v)₂、-S(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-O-R^v、-S-R^v、-O-C(O)-R^v、-C(O)-R^v、-C(O)-O-R^v、-S(O)-R^v、-S(O)₂-R^v、-C(O)-N(R^v)₂、-S(O)₂-N(R^v)₂、-N(R^v)-C(O)-R^v、- N(R^v)-S(O)-R^v、-N(R^v)-S(O)₂-R^v及視情況經一或多個獨立地選自側氧基及鹵基之基團取代之C_1-6烷基；及其中當R²為F且R³為氫時，則R^x不為甲基、乙基、三氟甲基或2-氟苯基。 a compound of formula (I), Or a salt thereof, wherein: R ¹ is selected from the group consisting of: And wherein R ¹ is independently substituted by 1, 2 or 3 R ^x groups; R ² and R ^{3 are} independently H, C _1-12 alkyl, C _2-12 alkenyl, C _2-12 Alkynyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, halo, -OR ^a , -SR ^a , -N(R ^a ) ₂ , -CN, -NO ₂ , -C(O)R ^a , -CO ₂ R ^a , -C(O)N(R ^a ) ₂ , -C(O)SR ^a , -C(O)C(O)R ^a , -C(O)CH ₂ C(O R ^a , -C(S)N(R ^a ) ₂ , -C(S)OR ^a , -S(O)R ^a , -SO ₂ R ^a , -SO ₂ N(R ^a ) ₂ , -N (R ^a )C(O)R ^a , -N(R ^a )C(O)N(R ^a ) ₂ , -N(R ^a )SO ₂ R ^a , -N(R ^a )SO ₂ N(R ^a ) ₂ , -N(R ^a )N(R ^a ) ₂ , -N(R ^a )C(=N(R ^a ))N(R ^a ) ₂ , -C(=N)N(R ^a ) ₂ , -C=NOR ^a , -C(=N(R ^a ))N(R ^a ) ₂ , -OC(O)R ^a or -OC(O)N(R ^a ) ₂ , wherein R ² and R each of C ³ _1-12 alkyl, C _2-12 alkenyl group, C _2-12 alkynyl, carbocyclyl, aryl, heteroaryl and heterocyclyl each line is independently optionally substituted with one or more groups a group R ^x substituted; or R ¹ and R ² together with the atom to which they are attached form a 4, 5, 6, 7 or 8 membered carbocyclyl, heterocyclyl, heteroaryl or aryl group, which is a heterocyclic or heterocyclic ring. The base, heteroaryl and aryl are optionally substituted by one or more groups R ^x ; Each of R ^a and R ^{b is} independently H, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclic, wherein each C _1-6 alkyl, C _3-6 alkenyl, C _3-6 alkynyl, carbocyclyl, aryl, heteroaryl and heterocyclyl are, independently, optionally substituted with one or more groups R ^x ; or R ^a and R ^b form a 3-6 membered heterocyclic ring together with the nitrogen to which they are attached, which heteroaryl ring optionally with oxo (oxo), halo or optionally substituted with oxo or halo C _1-6 of Alkyl substituted; each R ^{v is} independently hydrogen, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl, aryl, heteroaryl or heterocyclyl, each of which C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, carbocyclyl, aryl, heteroaryl and heterocyclyl are optionally optionally selected from the group consisting of Substituting: a pendant oxy group, a halogen group, an amine group, a hydroxyl group, and optionally a C ₁ -C ₆ alkyl group substituted with one or more groups independently selected from the pendant oxy group and a halogen group; or two R ^v The attached nitrogens together form a 3-6 membered heterocyclic group which is optionally substituted with one or more groups independently selected from the group consisting of pendant oxy groups, halo groups, and optionally Or a plurality of C _1-3 alkyl groups independently substituted with a group selected from a pendant oxy group and a halogen group; and each R ^{x is} independently a pendant oxy group, a C _1-6 alkyl group, a C _2-6 alkenyl group, C _2-6 alkynyl, C _1-6 haloalkyl, carbocyclyl, aryl, heteroaryl, heterocyclyl, -F, -Cl, -Br, -I, -NO ₂ , -N(R ^v ) ₂ , -CN, -C(O)-N(R ^v ) ₂ , -S(O)-N(R ^v ) ₂ , -S(O) ₂ -N(R ^v ) ₂ , -OR ^v , -SR ^v , -OC(O)-R ^v , -OC(O)-OR ^v , -C(O)-R ^v , -C(O)-OR ^v , -S(O)-R ^v , -S(O) ₂ -R ^v , -OC(O)-N(R ^v ) ₂ , -N(R ^v )-C(O)-OR ^v , -N(R ^v )-C(O)- N(R ^v ) ₂ , -S(O) ₂ -N(R ^v ) ₂ , -N(R ^v )-C(O)-R ^v , -N(R ^v )-S(O)-R ^v , -N(R ^v )-S(O) ₂ -R ^v , -N(R ^v )-S(O)-N(R ^v ) ₂ or -N(R ^v )-S(O) ₂ -N (R ^v ) ₂ , wherein any C _1-6 alkyl group, C _2-6 alkenyl group, C _2-6 alkynyl group, C _1-6 haloalkyl group, carbocyclic group, aryl group, heteroaryl group and heterocyclic ring The substrate is independently substituted with one or more groups selected from the group consisting of pendant oxy, halo, -NO ₂ , -N(R ^v ) ₂ , -CN, -C(O)-N(R). ^v ) ₂ , -S(O)-N(R ^v ) ₂ , -S(O) ₂ -N(R ^v ) ₂ , -OR ^v , -SR ^v , -OC(O)-R ^v , -C (O)-R ^v , -C(O)-OR ^v , -S(O)-R ^v ,- S(O) ₂ -R ^v , -C(O)-N(R ^v ) ₂ , -S(O) ₂ -N(R ^v ) ₂ , -N(R ^v )-C(O)-R ^v And -N(R ^v )-S(O)-R ^v , -N(R ^v )-S(O) ₂ -R ^v and optionally one or more selected from the group consisting of pendant and halogen groups a group substituted with a C _1-6 alkyl group; and wherein when R ² is F and R ³ is hydrogen, then R ^{x is} not methyl, ethyl, trifluoromethyl or 2-fluorophenyl.

如請求項1之化合物或其鹽，其中R¹係選自： R²及R³獨立地為H、C_1-12烷基、鹵基或-OR^a，其中R²及R³之各C_1-12烷基各獨立地視情況經一或多個基團R^x取代；各R^a及R^b獨立地為H、C_1-6烷基，其中各C_1-6烷基獨立地視情況經一或多個基團R^x取代；各R^v獨立地為C_1-6烷基；及各R^x獨立地為雜環基、-F或-N(R^v)₂，其中任何雜環基獨立地視情況經一或多個選自C_1-6烷基之基團取代；及其中當R²為F且R³為氫時，則R^x不為甲基、乙基、三氟甲基或2-氟苯基。 The compound of claim 1 or a salt thereof, wherein R ¹ is selected from the group consisting of: R ² and R ^{3 are} independently H, C _1-12 alkyl, halo or -OR ^a , wherein each C _1-12 alkyl of R ² and R ³ is independently independently one or more groups, as appropriate R ^{x is} substituted; each R ^a and R ^{b is} independently H, C _1-6 alkyl, wherein each C _1-6 alkyl group is independently substituted with one or more groups R ^x as appropriate; each R ^v independently Is a C _1-6 alkyl group; and each R ^{x is} independently a heterocyclic group, -F or -N(R ^v ) ₂ , wherein any heterocyclic group is independently selected from C _1-6 by one or more a group substituted with an alkyl group; and wherein when R ² is F and R ³ is hydrogen, then R ^{x is} not methyl, ethyl, trifluoromethyl or 2-fluorophenyl.

如請求項1或2之化合物，其中R²及R³獨立地為鹵基、三氟甲基、C_1-6烷基或C_1-6烷氧基，其中該烷基及烷氧基獨立地視情況經-N(R^v)₂或雜環基取代；其中該雜環基視情況經側氧基、鹵基或視情況經鹵基或側氧基取代之C_1-6烷基取代。 The compound of claim 1 or 2, wherein R ² and R ^{3 are} independently halo, trifluoromethyl, C _1-6 alkyl or C _1-6 alkoxy, wherein the alkyl and alkoxy are independently Substituted by -N(R ^v ) ₂ or a heterocyclic group; wherein the heterocyclic group is optionally substituted by a pendant oxy group, a halogen group or, optionally, a C _1-6 alkyl group substituted by a halo group or a pendant oxy group .

如請求項1或2之化合物，其中R²為氫、氯基、甲基、(4-甲基哌嗪-1-基)甲基、三氟甲氧基、二氟甲氧基、4-氮雜環丁烷-1-基甲基、嗎啉-4-基甲基、二甲基胺基甲基、吡咯啶-1-基甲基或4-乙基哌嗪-1-基甲基。 The compound of claim 1 or 2, wherein R ² is hydrogen, chloro, methyl, (4-methylpiperazin-1-yl)methyl, trifluoromethoxy, difluoromethoxy, 4- Azetidin-1-ylmethyl, morpholin-4-ylmethyl, dimethylaminomethyl, pyrrolidin-1-ylmethyl or 4-ethylpiperazin-1-ylmethyl .

如請求項1或2之化合物，其中R³為氫、三氟甲基、氟基或氯基。 A compound according to claim 1 or 2, wherein R ³ is hydrogen, trifluoromethyl, fluoro or chloro.

如請求項1或2之化合物，其中R^a及R^b獨立地為氫或C_1-6烷基。 The compound of claim 1 or 2, wherein R ^a and R ^{b are} independently hydrogen or C _1-6 alkyl.

如請求項1或2之化合物，其中R^a為氫。 A compound of claim 1 or 2 wherein R ^a is hydrogen.

如請求項1或2之化合物，其中R^b為甲基。 The compound of claim 1 or 2, wherein R ^b is methyl.

如請求項1或2之化合物，其係選自由以下組成之群：1-[(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]-3-[3-(三氟甲基)苯基]脲；1-[4-氯-3-(三氟甲基)苯基]-3-[(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]脲；1-(3-氯苯基)-3-[(3S)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]脲；1-[(3R)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]-3-[3-(三氟甲基)苯基]脲；1-[4-氯-3-(三氟甲基)苯基]-3-[(3R)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]脲；1-(3-氯苯基)-3-[(3R)-1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基]脲；(S)-1-(1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基)-3-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)脲；1-[(3S)-1-(2-胺基嘧啶-4-基)吡咯啶-3-基]-3-(3-氯-4-甲基-苯基)脲；1-[(S)-1-(2-胺基-嘧啶-4-基)-吡咯啶-3-基]-3-(4-氯-3-三氟甲基-苯基)-脲；1-[4-氯-3-(三氟甲基)苯基]-3-[(3S)-1-[2-(甲基胺基)嘧啶-4-基]吡咯啶-3-基]脲；1-(3-氯-4-甲基-苯基)-3-[(3S)-1-[2-(甲基胺基)嘧啶-4-基]吡咯啶-3-基]脲；1-[(3S)-1-[2-(甲基胺基)嘧啶-4-基]吡咯啶-3-基]-3-[4-(三氟甲氧基)苯基]脲；1-[4-(二氟甲氧基)苯基]-3-[(3S)-1-[2-(甲基胺基)嘧啶-4-基]吡咯啶-3-基]脲；(S)-1-(4-(氮雜環丁烷-1-基甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(4-(氮雜環丁烷-1-基甲基)-3-氟苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(3-氯-4-((二甲基胺基)甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(4-(氮雜環丁烷-1-基甲基)-3-氯苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(3-氯-4-((4-甲基哌嗪-1-基)甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(3-氯-4-((4-乙基哌嗪-1-基)甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(3-氯-4-(N-嗎啉基甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(4-((二甲基胺基)甲基)-3-(三氟甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(4-(氮雜環丁烷-1-基甲基)-3-(三氟甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)-3-(4-(吡咯啶-1-基甲基)-3-(三氟甲基)苯基)脲；(S)-1-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)-3-(4-((4-甲基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)脲；(S)-1-(4-((4-乙基哌嗪-1-基)甲基)-3-(三氟甲基)苯基)-3-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)脲；(S)-1-(1-(2-(甲基胺基)嘧啶-4-基)吡咯啶-3-基)-3-(4-(N-嗎啉基(morpholino)甲基)-3-(三氟甲基)苯基)脲；1-(4-氮雜環丁烷-1-基甲基-3-三氟甲基-苯基)-3-[(S)-1-(2-甲基胺基-嘧啶-4-基)-吡咯啶-3-基]-脲；(S)-1-(1-([1,2,4]***并[4,3-b]噠嗪-6-基)吡咯啶-3-基)-3-(3-氯-4-甲基苯基)脲；及其醫藥學上可接受之鹽。 A compound according to claim 1 or 2 which is selected from the group consisting of 1-[(3S)-1-([1,2,4]triazolo[4,3-b]pyridazine-6- Pyrrolidin-3-yl]-3-[3-(trifluoromethyl)phenyl]urea; 1-[4-chloro-3-(trifluoromethyl)phenyl]-3-[(3S -1([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidin-3-yl]urea; 1-(3-chlorophenyl)-3- [(3S)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidin-3-yl]urea; 1-[(3R)-1- ([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidin-3-yl]-3-[3-(trifluoromethyl)phenyl]urea; -[4-chloro-3-(trifluoromethyl)phenyl]-3-[(3R)-1-([1,2,4]triazolo[4,3-b]pyridazine-6- Pyrrolidin-3-yl]urea; 1-(3-chlorophenyl)-3-[(3R)-1-([1,2,4]triazolo[4,3-b]pyridazine -6-yl)pyrrolidin-3-yl]urea; (S)-1-(1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrolidine 3-yl)-3-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)urea; 1-[(3S)-1- (2-aminopyrimidin-4-yl)pyrrolidin-3-yl]-3-(3-chloro-4-methyl-phenyl)urea; 1-[(S)-1-(2-amino) -pyrimidin-4-yl)-pyrrolidin-3-yl]-3-(4-chloro-3-trifluoromethyl-phenyl)-urea; 1-[4-chloro-3-(trifluoromethyl) Phenyl]-3-[(3S)-1-[2-(methylamino)pyrimidine-4- Pyrrolidin-3-yl]urea; 1-(3-chloro-4-methyl-phenyl)-3-[(3S)-1-[2-(methylamino)pyrimidin-4-yl] Pyrrole Pyridin-3-yl]urea; 1-[(3S)-1-[2-(methylamino)pyrimidin-4-yl]pyrrolidin-3-yl]-3-[4-(trifluoromethoxy) Phenyl]urea; 1-[4-(difluoromethoxy)phenyl]-3-[(3S)-1-[2-(methylamino)pyrimidin-4-yl]pyrrolidine- 3-yl]urea; (S)-1-(4-(azetidin-1-ylmethyl)phenyl)-3-(1-(2-(methylamino)pyrimidine-4- () pyrrolidin-3-yl)urea; (S)-1-(4-(azetidin-1-ylmethyl)-3-fluorophenyl)-3-(1-(2-( Methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea; (S)-1-(3-chloro-4-((dimethylamino)methyl)phenyl)-3- (1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea; (S)-1-(4-(azetidin-1-ylmethyl)- 3-chlorophenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea; (S)-1-(3-chloro-4-( (4-methylpiperazin-1-yl)methyl)phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea; (S )-1-(3-chloro-4-((4-ethylpiperazin-1-yl)methyl)phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl) Pyrrolidin-3-yl)urea; (S)-1-(3-chloro-4-(N-morpholinylmethyl)phenyl)-3-(1-(2-(methylamino)) (S)-1-(4-((dimethylamino)methyl)-3-(trifluoromethyl)benzene -(3-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea; (S)-1-(4-(azetidin-1-yl) Methyl)-3-(trifluoromethyl)phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea; (S)-1 -(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)-3-(4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl) Phenyl)urea; (S)-1-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)-3-(4-((4-methylperidine) (X)-1-(4-((4-ethylpiperazin-1-yl)methyl)-3) -(trifluoromethyl)phenyl)-3-(1-(2-(methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)urea; (S)-1-(1-( 2-(Methylamino)pyrimidin-4-yl)pyrrolidin-3-yl)-3-(4-(N-morpholinomethyl)-3-(trifluoromethyl)phenyl Urea; 1-(4-azetidin-1-ylmethyl-3-trifluoromethyl-phenyl)-3-[(S)-1-(2-methylamino-pyrimidine- 4-(yl)-pyrrolidin-3-yl]-urea; (S)-1-(1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)pyrrole Pyridin-3-yl)-3-(3-chloro-4-methylphenyl)urea; and pharmaceutically acceptable salts thereof.

如請求項1或2之化合物，其係選自：及其鹽。 A compound according to claim 1 or 2, which is selected from the group consisting of: And its salt.

一種醫藥組合物，其包含如請求項1至10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佐劑、載劑或媒劑。 A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, carrier or vehicle.

一種如請求項1至10中任一項之化合物之用途，其為用於治療之藥物。 Use of a compound according to any one of claims 1 to 10 for treatment drug.

一種如請求項1至10中任一項之化合物之用途，其係用於製造用於治療過度增殖性病症之藥物。 A use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment of a hyperproliferative disorder.

一種如請求項1至10中任一項之化合物之用途，其係用於製造用於治療與CDK8活性相關疾病的藥物。 A use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment of a disease associated with CDK8 activity.

如請求項1或2之化合物或其醫藥學上可接受之鹽，其係用作治療活性物質。 A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

如請求項1或2之化合物或其醫藥學上可接受之鹽，其係用作用於治療過度增殖性病症之治療活性物質。 A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance for the treatment of a hyperproliferative disorder.