TW202126636A - Piperidine compounds as menin inhibitors - Google Patents
Piperidine compounds as menin inhibitors Download PDFInfo
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract
Description
本發明提供作為menin抑制劑之化合物及治療其中抑制menin提供益處之病狀及疾病的治療方法。The present invention provides compounds that are menin inhibitors and methods of treating conditions and diseases in which the inhibition of menin provides benefits.
混合系白血病(MLL)為一種最初發現於人類白血病中之染色體易位位點處的原癌基因。歸因於染色體易位，MLL與超過40種不同伴侶蛋白質融合以產生嵌合融合蛋白之相異集合。MLL蛋白為一種對染色體進行共價修飾且在急性白血病之某些子集中突變之組織蛋白甲基轉移酶。許多融合伴侶組成性激活MLL之新穎轉錄效應子特性，該等特性通常與其在急性白血病之動物模型中的致癌可能性相關。MLL通常與一組高度保守之輔因子結合以形成包括menin之大分子複合物，該大分子複合物為MEN1腫瘤抑制基因之產物。MEN1基因在遺傳性及偶發性內分泌腫瘤中突變。Mixed lineage leukemia (MLL) is a proto-oncogene originally found at the chromosomal translocation site in human leukemia. Due to chromosomal translocations, MLL is fused with more than 40 different chaperone proteins to create a distinct collection of chimeric fusion proteins. MLL protein is a tissue protein methyltransferase that covalently modifies chromosomes and mutates in certain subsets of acute leukemia. Many fusion partners constitutively activate the novel transcriptional effector properties of MLL, which are usually related to their carcinogenic potential in animal models of acute leukemia. MLL usually combines with a group of highly conserved cofactors to form a macromolecular complex including menin, which is the product of the MEN1 tumor suppressor gene. MEN1 gene is mutated in hereditary and occasional endocrine tumors.
Menin涉及相異蛋白質-蛋白質相互作用網絡。Cierpicki及Grembecka,Future Med. Chem. 6 :447-462 (2014)。menin之過度表現產生對經Ras轉化細胞之抑制。Menin與轉錄因子JunD及NF-κB相互作用且抑制其基因轉錄之活化。關於此等相互作用蛋白質之研究表明，menin主要經由對轉錄之抑制作用而發揮其作用。但一替代可能性為menin經由靶基因之轉錄激活而介導其作用。另外，menin與RPA2相互作用，該RPA2為涉及DNA修復及複製之單股DNA結合蛋白質之組分。Menin亦與FANCD2相互作用，該FANCD2為在維持具有乳癌1基因(Brea1)產物之基因組穩定性方面扮演重要角色之核蛋白質。Menin involves dissimilar protein-protein interaction networks. Cierpicki and Grembecka, Future Med. Chem. 6 :447-462 (2014). Overexpression of menin resulted in inhibition of Ras transformed cells. Menin interacts with the transcription factors JunD and NF-κB and inhibits the activation of its gene transcription. Studies on these interacting proteins have shown that menin exerts its effects mainly through the inhibition of transcription. But an alternative possibility is that menin mediates its effects via transcriptional activation of target genes. In addition, menin interacts with RPA2, which is a component of single-stranded DNA binding proteins involved in DNA repair and replication. Menin also interacts with FANCD2, which is a nuclear protein that plays an important role in maintaining the genomic stability of the Brea1 gene (Brea1) product.
與其他蛋白質不具有顯著同源性之menin藉以充當腫瘤抑制因子的機制不完全已知。Menin在調節細胞增殖方面起作用，此係因為Men1基因剔除小鼠顯示在神經內分泌組織中增殖增加，上皮細胞中menin之下調增加增殖，且如藉由氚化胸苷併入所分析，Men1基因剔除纖維母細胞比野生型細胞更快速增殖。MEN1細胞亦對DNA損傷劑具有增加的敏感性。Menin與HOX基因之啟動子相互作用。The mechanism by which menin, which does not have significant homology with other proteins, acts as a tumor suppressor is not fully known. Menin plays a role in regulating cell proliferation. This is because Men1 knockout mice show increased proliferation in neuroendocrine tissues, and downregulation of menin in epithelial cells increases proliferation, and as analyzed by tritiated thymidine incorporation, Men1 knockout Fibroblasts proliferate faster than wild-type cells. MEN1 cells also have increased sensitivity to DNA damaging agents. Menin interacts with the promoter of the HOX gene.
某些致癌MLL融合蛋白經由起始經MLL介導之白血病生成所需的高親和力相互作用而穩定地與menin結合。Menin為維持MLL相關聯但無其他癌基因誘導之骨髓轉化所必需的。menin之急性基因消融將由ML-menin啟動子相關聯之複合物介導之HOX基因表現逆轉，且特定言之消除MLL轉化白血病母細胞之分化遏止及致癌特性。Certain oncogenic MLL fusion proteins stably bind to menin via high-affinity interactions required to initiate MLL-mediated leukemia. Menin is necessary to maintain bone marrow transformation associated with MLL but not induced by other oncogenes. Acute gene ablation of menin reverses the HOX gene expression mediated by the complex associated with the ML-menin promoter, and specifically eliminates the differentiation inhibition and carcinogenic properties of MLL transformed leukemic blasts.
MLL融合蛋白質(獲得性基因畸變之結果)經由兩種替代機制藉由構成性轉錄效應子活性或誘導強制性MLL二聚化及寡聚化而轉化造血細胞。兩種機制導致HOX基因之子集(特定而言HOXA9)的不當表現，其一致表現為人類MLL白血病之典型特徵。The MLL fusion protein (the result of acquired gene aberration) transforms hematopoietic cells by constitutive transcription effector activity or inducing forced MLL dimerization and oligomerization via two alternative mechanisms. The two mechanisms lead to the improper performance of a subset of HOX genes (specifically HOXA9), which consistently appear as typical features of human MLL leukemia.
HOX 基因之異常表現亦見於NPM1 中具有突變之AML患者中。NPM1主要位於細胞核中且在不同細胞過程，包括核糖體組裝、核小體組裝及細胞增殖中起作用。NPM1突變產生異常細胞質定位且構成AML中第二最頻繁突變之一，在所有AML患者中佔幾乎30%。近來已證實menin有助於調變HOX基因及活體外及活體內NPM1突變型AML細胞中之細胞增殖，但該機制仍大部分未知。 Abnormal expression of HOX gene is also seen in AML patients with mutations in NPM1. NPM1 is mainly located in the nucleus and plays a role in different cellular processes, including ribosome assembly, nucleosome assembly and cell proliferation. NPM1 mutation produces abnormal cytoplasmic localization and constitutes one of the second most frequent mutations in AML, accounting for almost 30% of all AML patients. It has recently been confirmed that menin can help modulate the HOX gene and cell proliferation in NPM1 mutant AML cells in vitro and in vivo, but the mechanism is still largely unknown.
Menin與以下各者相互作用：轉錄活化子，例如sc-Myb、MLL1、SMAD 1,3,5、Pem、Runx2、Hlbx9、ER、PPARγ、維生素D受體；轉錄抑制子，例如JunD、Sin3A、HDAC、EZH2、PRMT5、NFκB、Sirt1、CHES1；細胞信令蛋白質，例如AKT、SOS1/GEF、β-索烴素、SMAD 1,3,5、NFκB；及其他蛋白質例如細胞循環：RPA2、ASK；DNA修復：FANCD2；細胞結構：GFAP、vimenten、NMMHCIIA、IQGAP1；其他：涉及調節基因轉錄及細胞信令之HSP70、CHIP (「menin相互作用蛋白質」)。Matkar,Trends in Biochemical Sciences 38 : 394-402 (2013)。靶向menin與小分子之相互作用，例如menin-MLL相互作用呈有吸引力的研發新抗癌劑之策略。參見例如Cierpicki及Grembecka,Future Med. Chem. 6 :447-462 (2014); He等人,J. Med. Chem. 57 :1543-1556 (2014);及Borkin等人,Cancer Cell 27 :589-602 (2015); Krivtsov等人Cancer Cell 36 : 660-673 (2019); Klossowski等人J. Clin. Invest. 130 :981-997 (2020); Uckelmann等人Science 367 :586-590 (2020)。Menin interacts with the following: transcriptional activators, such as sc-Myb, MLL1, SMAD 1,3,5, Pem, Runx2, Hlbx9, ER, PPARγ, vitamin D receptor; transcription repressors, such as JunD, Sin3A, HDAC, EZH2, PRMT5, NFκB, Sirt1, CHES1; cell signaling proteins, such as AKT, SOS1/GEF, β-candline, SMAD 1,3,5, NFκB; and other proteins such as cell cycle: RPA2, ASK; DNA repair: FANCD2; cell structure: GFAP, vimenten, NMHCIIA, IQGAP1; others: HSP70, CHIP ("menin interacting protein") involved in regulating gene transcription and cell signaling. Matkar, Trends in Biochemical Sciences 38 : 394-402 (2013). Targeting the interaction between menin and small molecules, such as the menin-MLL interaction, presents an attractive strategy for the development of new anticancer agents. See, for example, Cierpicki and Grembecka, Future Med.Chem. 6 :447-462 (2014); He et al., J. Med. Chem. 57 :1543-1556 (2014); and Borkin et al., Cancer Cell 27 :589- 602 (2015); Krivtsov et al. Cancer Cell 36 : 660-673 (2019); Klossowski et al . J. Clin. Invest. 130 : 981-997 (2020); Uckelmann et al. Science 367 : 586-590 (2020).
破壞MLL與menin之相互作用之小分子揭示於以下中：美國專利第9,212,180號及第9,216,993號；及美國專利申請公開案第2011/0065690號、第2014/0275070號、第2016/0045504號、第2016/0046647號及第2019/0152947號；以及第WO 2018/183857號、第WO 2019/191526號及第WO 2020/072391號。破壞MLL與menin之相互作用的肽揭示於美國專利申請公開案第2009/0298772號中。Small molecules that disrupt the interaction between MLL and menin are disclosed in the following: U.S. Patent Nos. 9,212,180 and 9,216,993; and U.S. Patent Application Publication Nos. 2011/0065690, 2014/0275070, 2016/0045504, and 2016/0046647 and 2019/0152947; and WO 2018/183857, WO 2019/191526 and WO 2020/072391. Peptides that disrupt the interaction between MLL and menin are disclosed in U.S. Patent Application Publication No. 2009/0298772.
持續需要新的試劑，例如小分子以用於治療癌症及對menin抑制有反應之其他疾病。There is a continuing need for new agents, such as small molecules for the treatment of cancer and other diseases that respond to menin inhibition.
在一個態樣中，本發明提供六氫吡啶及由以下式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示之相關類似物，以及其醫藥學上可接受之鹽，以上各者在本文中統稱為「本發明化合物」。「本發明化合物」為menin之抑制劑且因而適用於治療其中對menin之抑制向患者提供治療益處之疾病或病狀。In one aspect, the present invention provides hexahydropyridine and related analogues represented by any one or more of the following formulas I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc, and its pharmaceutically acceptable Accepted salts, all of the above are collectively referred to herein as "compounds of the present invention". The "compounds of the present invention" are inhibitors of menin and are therefore suitable for the treatment of diseases or conditions in which the inhibition of menin provides a therapeutic benefit to the patient.
在另一態樣中，本發明提供一種不可逆地抑制患者體內之menin之方法，該方法包含向患者投與有效量之本發明化合物。In another aspect, the present invention provides a method for irreversibly inhibiting menin in a patient, the method comprising administering to the patient an effective amount of a compound of the present invention.
在另一態樣中，本發明提供藉由向有需要之患者，例如人類投與治療有效量之本發明化合物來治療病狀或疾病的方法。疾病或病狀可藉由抑制menin來治療，例如癌症(例如白血病)、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒性感染。亦提供預防非所需增殖性細胞，諸如癌症在個體體內增殖之方法，其包含向處於發展特徵在於非所需增殖性細胞之病狀之風險下的個體投與治療有效量之本發明化合物。在一些實施例中，本發明化合物藉由在彼等細胞中誘導細胞死亡及/或分化來減少非所需細胞之增殖。In another aspect, the present invention provides a method of treating a condition or disease by administering a therapeutically effective amount of the compound of the present invention to a patient in need, such as a human. Diseases or conditions can be treated by inhibiting menin, such as cancer (e.g. leukemia), chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis, or viral infections. A method for preventing the proliferation of undesired proliferative cells, such as cancer, in an individual is also provided, which comprises administering a therapeutically effective amount of a compound of the present invention to an individual at risk of developing a condition characterized by undesired proliferative cells. In some embodiments, the compounds of the present invention reduce undesired cell proliferation by inducing cell death and/or differentiation in these cells.
在另一態樣中，本發明提供一種抑制個體體內之menin之方法，該方法包含向個體投與有效量之至少一種本發明化合物。In another aspect, the present invention provides a method of inhibiting menin in an individual, the method comprising administering to the individual an effective amount of at least one compound of the present invention.
在另一態樣中，本發明提供一種醫藥組合物，其包含本發明之化合物及賦形劑及/或藥學上可接受之載劑。In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and excipients and/or pharmaceutically acceptable carriers.
在另一態樣中，本發明提供一種組合物，其包含本發明之化合物及賦形劑及/或醫藥學上可接受之載劑，以用於治療其中對menin之抑制提供益處之疾病或病狀，例如癌症。In another aspect, the present invention provides a composition comprising the compound of the present invention and excipients and/or pharmaceutically acceptable carriers for the treatment of diseases or diseases in which the inhibition of menin provides benefits Symptoms, such as cancer.
在另一態樣中，本發明提供一種組合物，其包含：(a)本發明化合物；(b)第二治療活性劑；及(c)視情況選用之賦形劑及/或醫藥學上可接受之載劑。In another aspect, the present invention provides a composition comprising: (a) a compound of the present invention; (b) a second therapeutically active agent; and (c) optional excipients and/or pharmaceuticals Acceptable carrier.
在另一態樣中，本發明提供一種用於治療所關注疾病或病狀，例如癌症之本發明化合物。In another aspect, the invention provides a compound of the invention for use in the treatment of a disease or condition of interest, such as cancer.
在另一態樣中，本發明提供一種本發明之化合物之用途，其用於製造用於治療所關注疾病或病狀，例如癌症的藥劑。In another aspect, the present invention provides a use of the compound of the present invention for the manufacture of a medicament for the treatment of a disease or condition of interest, such as cancer.
在另一態樣中，本發明提供一種套組，其包含本發明化合物，及視情況選用之包含適用於治療所關注疾病或病狀之第二治療劑的經封裝組合物，以及含有用於治療疾病或病狀，例如癌症之說明的藥品說明書。In another aspect, the present invention provides a kit comprising a compound of the present invention, and optionally an encapsulated composition containing a second therapeutic agent suitable for treating the disease or condition of interest, and containing a compound for Instructions for treatment of diseases or conditions, such as cancer.
在另一態樣中，本發明提供製備本發明化合物之方法。In another aspect, the invention provides methods of preparing the compounds of the invention.
應理解，前述發明內容與以下實施方式僅為例示性及解釋性的，且不限制如所主張之本發明。It should be understood that the foregoing content of the invention and the following embodiments are only illustrative and explanatory, and do not limit the claimed invention.
相關申請Related application
本申請案主張2019年9月30日提交之美國臨時申請案第62/908,462號及2020年4月8日提交之美國臨時申請案第63/007,037號的權益，其各者之揭示內容以全文引用之方式併入。 美國政府許可權This application claims the rights and interests of U.S. Provisional Application No. 62/908,462 filed on September 30, 2019 and U.S. Provisional Application No. 63/007,037 filed on April 8, 2020. The disclosure of each is in full text Incorporated by reference. U.S. government license
本發明係在美國政府支持下，在由美國國家衛生研究院(National Institutes of Health)授予的批准號CA208267下進行。美國政府享有本發明的某些權利。The present invention was carried out under the approval number CA208267 granted by the National Institutes of Health with the support of the U.S. government. The U.S. government has certain rights in this invention.
本發明之化合物為menin抑制劑。在一些實施例中，本發明化合物與menin共價結合且抑制menin之功能。The compounds of the present invention are menin inhibitors. In some embodiments, the compounds of the present invention covalently bind to menin and inhibit the function of menin.
在一個實施例中，本發明化合物為由式I
表示之化合物：
及其醫藥學上可接受之鹽，其中：And its pharmaceutically acceptable salts, of which:
R1a 、R1b 及R1c 各自獨立地選自由氫及鹵基組成之群；R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen and halogen;
G為-SO2 -X-Z2 ；G is -SO 2 -XZ 2 ;
R2
係選自由以下組成之群：
R3
係選自由以下組成之群：
L為
R10a 係選自由以下組成之群：氫、鹵基、氰基、C1 - 4 烷基、C1 - 4 烷氧基及羥基；R 10a selected from the group consisting of the group consisting of: hydrogen, halo, cyano, C 1 - 4 alkyl, C 1 - 4 alkoxy and hydroxy;
X係選自由以下組成之群：
其中Y連接至Z2 ；Where Y is connected to Z 2 ;
Y為-C(=O)-；Y is -C(=O)-;
o及p各自獨立地為0、1、2或3；o and p are each independently 0, 1, 2 or 3;
Z2 係選自由以下組成之群：-C(R13a )=C(R13b )(R13c )、-C≡CR13d 及Ra4 ，其中當X為X-10時，Z2 不存在；Z 2 selected from the group consisting of the group consisting of: -C (R 13a) = C (R 13b) (R 13c), - when C≡CR 13d and R a4, wherein when X is X-10, Z 2 is absent;
R8a 及R8b 獨立地選自由以下組成之群：氫及鹵基；R 8a and R 8b are independently selected from the group consisting of hydrogen and halo;
R13a 、R13b 、R13c 及R13d 各自獨立地選自由以下組成之群：氫、甲基及二甲基胺基甲基；R 13a , R 13b , R 13c and R 13d are each independently selected from the group consisting of hydrogen, methyl, and dimethylaminomethyl;
Ra3 係選自由以下組成之群：烷氧基羰基及烷基磺醯基；R a3 is selected from the group consisting of alkoxycarbonyl and alkylsulfonyl;
Ra4 為-N(H)CH2 CH=CH-Ra5 ；且R a4 is -N(H)CH 2 CH=CH-R a5 ; and
Ra5 係選自由以下組成之群：烷氧基羰基及烷基磺醯基；R a5 is selected from the group consisting of: alkoxycarbonyl and alkylsulfonyl;
其限制條件為：The restrictions are:
當X為X-1，o及p各自為0，且Z2 為C(R13a )=C(R13b )(R13c )時，則R13a 、R13b 及R13c 中無一者為二甲基胺基甲基；When X is X-1, o and p are each 0, and Z 2 is C(R 13a )=C(R 13b )(R 13c ), then none of R 13a , R 13b and R 13c is two Methylaminomethyl;
當X為X-1，R10a
為氫、F、OH、甲基或甲氧基，Z2
為-C≡CR13d
，且R2
為
當X為X-1，Z2
為CH=CH2
，且R2
為
當X為X-9且Z2 為CH=CH2 時，則R10a 不為氫、F或甲基；且When X is X-9 and Z 2 is CH=CH 2 , then R 10a is not hydrogen, F or methyl; and
式(I)化合物不為
在一個實施例中，本發明化合物為由式Ia
表示之化合物：
L-M-G為
R1a 、R1b 及R1c 各自獨立地選自由氫及鹵基組成之群；R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen and halogen;
G為-SO2 -X-Z2 或-CH2 -X-Z2 ；G is -SO 2 -XZ 2 or -CH 2 -XZ 2 ;
R2
係選自由以下組成之群：
R3
係選自由以下組成之群：
L為
X係選自由以下組成之群：
其中Y連接至Z2 ；Where Y is connected to Z 2 ;
Y為-C(=O)-；Y is -C(=O)-;
o及p各自獨立地為0、1、2或3；o and p are each independently 0, 1, 2 or 3;
Z2 係選自由以下組成之群：-C(R13a )=C(R13b )(R13c )、-C≡CR13d 及Ra4 ，Z 2 selected from the group consisting of the group consisting of: -C (R 13a) = C (R 13b) (R 13c), - C≡CR 13d and R a4,
當X為X-10時或當X為X-45時，Z2 不存在；When X is X-10 or when X is X-45, Z 2 does not exist;
R8a 及R8b 獨立地選自由以下組成之群：氫、-SO2 -C1 -C6 烷基及鹵基；R 8a and R 8b are independently selected from the group consisting of hydrogen, -SO 2 -C 1 -C 6 alkyl and halo;
R13a 、R13b 、R13c 及R13d 各自獨立地選自由以下組成之群：氫、C1 -C6 烷基及二-C1 -C6 烷基胺基C1 -C4 烷基。R 13a , R 13b , R 13c and R 13d are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and di-C 1 -C 6 alkylamino C 1 -C 4 alkyl.
Ra3 係選自由以下組成之群：C1 -C6 烷氧基羰基-、雜環基-羰基-、經鹵基取代之雜環基-羰基-、C1 -C6 烷基醯胺及C1 -C6 烷基磺醯基；R a3 is selected from the group consisting of: C 1 -C 6 alkoxycarbonyl-, heterocyclyl-carbonyl-, heterocyclyl substituted by halo-carbonyl-, C 1 -C 6 alkyl amide and C 1 -C 6 alkylsulfonyl;
Ra4 為-N(H)CH2 CH=CH-Ra5 ；且R a4 is -N(H)CH 2 CH=CH-R a5 ; and
Ra5 係選自由以下組成之群：C1 -C6 烷氧基羰基-、雜環基-羰基-、經鹵基取代之雜環基-羰基-、C1 -C6 烷基醯胺及C1 -C6 烷基磺醯基；R a5 is selected from the group consisting of: C 1 -C 6 alkoxycarbonyl-, heterocyclic group-carbonyl-, heterocyclic group substituted by halo-carbonyl-, C 1 -C 6 alkyl amide and C 1 -C 6 alkylsulfonyl;
其限制條件為：The restrictions are:
當X為X-1，o及p各自為0，且Z2 為C(R13a )=C(R13b )(R13c )時，則R13a 、R13b 及R13c 中無一者為二甲基胺基甲基；When X is X-1, o and p are each 0, and Z 2 is C(R 13a )=C(R 13b )(R 13c ), then none of R 13a , R 13b and R 13c is two Methylaminomethyl;
當X為X-1或X-20，R10a
為氫、F、OH、甲基或甲氧基，Z2
為-C≡CR13
，且R2
為
當X為X-1或X-20，Z2
為CH=CH2
，且R2
為
且and
式(I)化合物不為
在另一實施例中，本發明化合物為由式I 或式Ia 表示之化合物及其醫藥學上可接受之鹽，其中：R10a 為氫、氟、氰基、甲基、甲氧基、乙氧基或羥基。In another embodiment, the compound of the present invention is a compound represented by formula I or formula Ia and a pharmaceutically acceptable salt thereof, wherein: R 10a is hydrogen, fluorine, cyano, methyl, methoxy, ethyl Oxy or hydroxy.
在另一實施例中，本發明化合物為由式I 或式Ia 表示之化合物，及其醫藥學上可接受之鹽，其中：In another embodiment, the compound of the present invention is a compound represented by Formula I or Formula Ia , and a pharmaceutically acceptable salt thereof, wherein:
R2
為
R3
為
X為X-1；X is X-1;
Z2 係選自由以下組成之群：-C(R13a )=C(R13b )(R13c )及-C≡CR13d ；Z 2 is selected from the group consisting of: -C(R 13a )=C(R 13b )(R 13c ) and -C≡CR 13d ;
R8a 及R8b 獨立地選自由以下組成之群：氫及氟；且R 8a and R 8b are independently selected from the group consisting of hydrogen and fluorine; and
R13a 、R13b 、R13c 及R13d 各自獨立地選自由以下組成之群：氫及二甲基胺基甲基。R 13a , R 13b , R 13c and R 13d are each independently selected from the group consisting of hydrogen and dimethylaminomethyl.
在另一實施例中，本發明化合物為由以下中之任何一或多者表示之化合物：式Ib - Ie ： 
或式Ic
：
或式Id
：
或式Ie
：
或其醫藥學上可接受之鹽，其中R1a 、R1b 、R1c 、R2 、R3 、R8a 、R8b 、R10a 、L、G及其餘變數如上文根據式I 或式Ia 所定義。Or a pharmaceutically acceptable salt thereof, wherein R 1a , R 1b , R 1c , R 2 , R 3 , R 8a , R 8b , R 10a , L, G and other variables are as described above according to Formula I or Formula Ia definition.
在另一實施例中，本發明化合物為由以下中之任何一或多者表示之化合物：式Ig
-Ij ： 
或式Ih
：
或式Ii
：
或式Ij
：
或其醫藥學上可接受之鹽，其中R1a 、R1b 、R1c 、R2 、R3 、R8a 、R8b 、L、X、Z2 及其餘變數如上文根據式I 或式Ia 所定義。Or a pharmaceutically acceptable salt thereof, wherein R 1a , R 1b , R 1c , R 2 , R 3 , R 8a , R 8b , L, X, Z 2 and other variables are as described above according to formula I or formula Ia definition.
在另一實施例中，本發明化合物為由以下中之任何一或多者表示之化合物：式XI - XIc
：
或式XIa
：
或式XIb
：
或式XIc
：
或其醫藥學上可接受之鹽，其中R1a 、R1b 、R2 、R3 、R8a 、R8b 、R10a 、X、Z2 及其餘變數如上文根據式I 或式Ia 所定義。Or a pharmaceutically acceptable salt thereof, wherein R 1a , R 1b , R 2 , R 3 , R 8a , R 8b , R 10a , X, Z 2 and other variables are as defined above according to Formula I or Formula Ia.
在另一實施例中，本發明化合物為由以下中之任何一或多者表示之化合物：式XII - XIIc ： 
或式XIIa
：
或式XIIb
：
或式XIIc
：
或其醫藥學上可接受之鹽，其中R10a 、X、Z2 及其餘變數如上文根據式I 或式Ia 所定義。Or a pharmaceutically acceptable salt thereof, wherein R 10a , X, Z 2 and other variables are as defined above according to Formula I or Formula Ia.
在另一實施例中，本發明化合物為由式II-IX
中之任何一或多者表示之化合物：
及其醫藥學上可接受之鹽，其中R1a 、R1b 、R1c 、R2 、R3 、R8a 、R8b 、L、X及Z2 如關於式I 或式Ia 所定義。And a pharmaceutically acceptable salt thereof, wherein R 1a , R 1b , R 1c , R 2 , R 3 , R 8a , R 8b , L, X and Z 2 are as defined in relation to formula I or formula Ia.
在另一實施例中，本發明化合物為由式X
表示之化合物：
及其醫藥學上可接受之鹽，其中R1a 、R2 、R8a 、L、X及Z2 如關於式I 或式Ia 所定義。在另一實施例中，本發明化合物為由具有式X之化合物表示的化合物及其醫藥學上可接受之鹽，其中R1a 及R8a 獨立地為氟，且R2 、L、X及Z2 如關於式I 或式Ia 所定義。And a pharmaceutically acceptable salt thereof, wherein R 1a , R 2 , R 8a , L, X, and Z 2 are as defined for formula I or formula Ia. In another embodiment, the compound of the present invention is a compound represented by a compound of formula X and a pharmaceutically acceptable salt thereof, wherein R 1a and R 8a are independently fluorine, and R 2 , L, X, and Z 2 As defined for Formula I or Formula Ia.
在另一實施例中，本發明化合物為由式I - X
中之任何一或多者表示之化合物，及其醫藥學上可接受之鹽。在另一實施例中，本發明化合物為由具有式XI '
之化合物表示的化合物：
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示之化合物及其醫藥學上可接受之鹽，其中R1a 為氫。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 1a is hydrogen.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R1b 為氫。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 1b is hydrogen.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R1c 為氫。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 1c is hydrogen.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R1a 為鹵素。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 1a is halogen.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R1a 為氟。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 1a is fluorine.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R1b 為鹵素。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 1b is halogen.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R1b 為氟。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 1b is fluorine.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R1c 為鹵素。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 1c is halogen.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R1c 為氟。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 1c is fluorine.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R1a 、R1b 及R1c 中之至少一者為鹵素。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R At least one of 1a , R 1b, and R 1c is halogen.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R1a 、R1b 及R1c 中之至少一者為氟。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R At least one of 1a , R 1b, and R 1c is fluorine.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Ra3 為烷氧基羰基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R a3 is an alkoxycarbonyl group.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Ra3 為烷基磺醯基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R a3 is an alkylsulfonyl group.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Ra3 為甲氧基羰基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R a3 is methoxycarbonyl.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Ra3 為乙氧基羰基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R a3 is ethoxycarbonyl.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Ra3 為甲磺醯基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R a3 is methanesulfonyl.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Ra3 為經鹵基取代之雜環基-羰基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R a3 is a heterocyclic group-carbonyl substituted by a halogen group.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Z2 為Ra4 。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein Z 2 is Ra4 .
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Ra5 為烷氧基羰基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R a5 is an alkoxycarbonyl group.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Ra5 為甲氧基羰基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R a5 is methoxycarbonyl.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Ra5 為乙氧基羰基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R a5 is ethoxycarbonyl.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Ra5 為烷基磺醯基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R a5 is an alkylsulfonyl group.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Ra5 為甲磺醯基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R a5 is methanesulfonyl.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Ra5 為雜環基-羰基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R a5 is heterocyclyl-carbonyl.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Ra5 為經鹵基取代之雜環基-羰基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R a5 is a heterocyclic group-carbonyl substituted by a halogen group.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Ra5 為經氟取代之雜環基-羰基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R a5 is a heterocyclic group-carbonyl substituted by fluorine.
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R2
為
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R2
為
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R2
為
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R2
為
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R2
為
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R2
為
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R2
為
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R2
為
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R2
為
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R3
為
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R3
為
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R3
為
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R3
為
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R3
為
本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R3
為
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R8a 及R8b 為氫。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 8a and R 8b are hydrogen.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R8a 及R8b 中之至少一者為氟。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R At least one of 8a and R 8b is fluorine.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R8a 及R8b 皆為氟。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R Both 8a and R 8b are fluorine.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中：R10a 為氫、氟、氰基、甲基、甲氧基、乙氧基或羥基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein: R 10a is hydrogen, fluorine, cyano, methyl, methoxy, ethoxy or hydroxyl.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R10a 為氫。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 10a is hydrogen.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R10a 為氟。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 10a is fluorine.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R10a 為氰基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 10a is cyano.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R10a 為甲基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 10a is methyl.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R10a 為甲氧基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 10a is methoxy.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R10a 為乙氧基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 10a is ethoxy.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R10a 為羥基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 10a is a hydroxyl group.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc
中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中X為X-1。在另一實施例中，o及p為0。在另一實施例中，X-1係選自由以下組成之群：
在另一實施例中，X-1係選自由以下組成之群：
在另一實施例中，X-1係選自由以下組成之群：
在另一實施例中，X-1係選自由以下組成之群：
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中X為X-9。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein X For X-9.
在另一實施例中，X-9係選自由以下組成之群：
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中X為X-10。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein X For X-10.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中X為X-12。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein X For X-12.
在另一實施例中，本發明化合物為彼等化合物，其中X為X-21、X-22、X-23、X-24、X-25、X-26、X-27、X-28、X-29、X-30、X-31、X-32、X-33、X-34、X-35、X-36、X-37、X-38、X-39、X-40、X-41、X-42、X-43、X-44或X-46。In another embodiment, the compounds of the present invention are those compounds, wherein X is X-21, X-22, X-23, X-24, X-25, X-26, X-27, X-28, X-29, X-30, X-31, X-32, X-33, X-34, X-35, X-36, X-37, X-38, X-39, X-40, X- 41, X-42, X-43, X-44 or X-46.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中X為X-45。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein X For X-45.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中X係選自由以下組成之群：X-21、X-22、X-23、X-24、X-25、X-26、X-27、X-28、X-29、X-30、X-31、X-32、X-33、X-34、X-35、X-36、X-37、X-38、X-39、X-40、X-41、X-42、X-43、X-44及X-46。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein X Department is selected from the group consisting of: X-21, X-22, X-23, X-24, X-25, X-26, X-27, X-28, X-29, X-30, X- 31, X-32, X-33, X-34, X-35, X-36, X-37, X-38, X-39, X-40, X-41, X-42, X-43, X-44 and X-46.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Z2 為-C(R13a )=C(R13b )(R13c )。在另一實施例中，R13a 、R13b 及R13c 各自為氫。在另一實施例中，R13a 為二甲基胺基甲基，且R13b 及R13c 獨立地選自由以下組成之群：氫及甲基。在另一實施例中，R13a 為氫，且R13b 及R13c 獨立地選自由以下組成之群：氫、甲基及二甲基胺基甲基。在另一實施例中，R13a 及R13b 為氫，且R13c 為二甲基胺基甲基或甲基。在另一實施例中，R13a 及R13b 為氫，且R13c 為二甲基胺基甲基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein Z 2 is -C(R 13a )=C(R 13b )(R 13c ). In another embodiment, R 13a , R 13b and R 13c are each hydrogen. In another embodiment, R 13a is dimethylaminomethyl, and R 13b and R 13c are independently selected from the group consisting of hydrogen and methyl. In another embodiment, R 13a is hydrogen, and R 13b and R 13c are independently selected from the group consisting of hydrogen, methyl, and dimethylaminomethyl. In another embodiment, R 13a and R 13b are hydrogen, and R 13c is dimethylaminomethyl or methyl. In another embodiment, R 13a and R 13b are hydrogen, and R 13c is dimethylaminomethyl.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R13a 、R13b 、R13c 及R13d 各自為氫。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 13a , R 13b , R 13c and R 13d are each hydrogen.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R13a 、R13b 、R13c 及R13d 各自獨立地選自由以下組成之群：氫及二甲基胺基甲基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 13a , R 13b , R 13c, and R 13d are each independently selected from the group consisting of hydrogen and dimethylaminomethyl.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R13a 、R13b 、R13c 及R13d 各自獨立地選自由以下組成之群：氫及甲基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R 13a , R 13b , R 13c, and R 13d are each independently selected from the group consisting of hydrogen and methyl.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R13a 、R13b 、R13c 及R13d 中之兩者各自獨立地選自由以下組成之群：甲基及二甲基胺基甲基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R Two of 13a , R 13b , R 13c, and R 13d are each independently selected from the group consisting of methyl and dimethylaminomethyl.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R13a 、R13b 、R13c 及R13d 中之不超過一者與氫不同。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R No more than one of 13a , R 13b , R 13c, and R 13d is different from hydrogen.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中R13a 、R13b 、R13c 及R13d 中之一或兩者不為氫。In another embodiment, the compound of the present invention is a compound represented by any one or more of formula I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc and a pharmaceutically acceptable salt thereof, wherein R One or both of 13a , R 13b , R 13c, and R 13d are not hydrogen.
在另一實施例中，本發明化合物為由式I - XII 、 Ia - Ij 、 XIa - XIc 、 XIIa - XIIc 中之任何一或多者表示的化合物及其醫藥學上可接受之鹽，其中Z2 為-C≡CR13d 。在另一實施例中，R13d 為氫。在另一實施例中，R13d 為甲基。In another embodiment, the compound of the present invention is a compound represented by any one or more of formulas I - XII , Ia - Ij , XIa - XIc , XIIa - XIIc , and a pharmaceutically acceptable salt thereof, wherein Z 2 is -C≡CR 13d . In another embodiment, R 13d is hydrogen. In another embodiment, R 13d is methyl.
在另一實施例中，本發明化合物為由選自表1及表1A之化合物中之任何一或多者的式I 或Ia 表示之化合物。表1及1A進一步提供由Chemdraw® Professional版本16.0產生之表1及1A之化合物的化學名稱。若在其化學結構與化學名稱之間具有任何不明確性，本發明之化合物由其化學結構限定。In another embodiment, the compound of the present invention is a compound represented by formula I or Ia selected from any one or more of the compounds in Table 1 and Table 1A. Tables 1 and 1A further provide the chemical names of the compounds in Tables 1 and 1A generated by Chemdraw ® Professional version 16.0. If there is any ambiguity between its chemical structure and chemical name, the compound of the present invention is defined by its chemical structure.
表1
表1A
本發明化合物抑制menin且適用於治療多種疾病及病狀。特定言之，本發明之化合物適用於治療其中抑制menin提供益處之疾病或病狀，例如癌症及增殖性疾病之方法中。本發明之方法包含向有需要之個體投與治療有效量之本發明化合物。除本發明化合物以外，本發明方法亦涵蓋向個體投與之第二治療劑。第二治療劑選自已知為適用於治療折磨有需要之個體的疾病或病狀之藥物，例如已知為適用於治療特定癌症之化學治療劑及/或輻射。The compound of the present invention inhibits menin and is suitable for the treatment of various diseases and conditions. In particular, the compounds of the present invention are suitable for treatment of diseases or conditions in which the inhibition of menin provides benefits, such as cancer and proliferative diseases. The method of the present invention comprises administering a therapeutically effective amount of a compound of the present invention to an individual in need. In addition to the compounds of the invention, the methods of the invention also encompass the administration of a second therapeutic agent to the individual. The second therapeutic agent is selected from drugs known to be suitable for treating diseases or conditions that afflict individuals in need, such as chemotherapeutic agents and/or radiation known to be suitable for treating specific cancers.
本發明化合物之鹽亦可用於本文所揭示之方法中。本發明進一步包括本發明化合物之所有可能立體異構體及幾何異構體，從而包括外消旋化合物及光學活性異構體兩者。當需要本發明化合物作為單一對映異構體時，其可藉由離析最終產物或藉由自任一異構性純淨起始物質進行立體特異性合成或使用對掌性輔助反應劑而獲得，例如見Z. Ma等人，Tetrahedron:Asymmetry, 8(6) , 第883-888頁(1997)。最終產物、中間產物或起始物質之離析可藉由此項技術中已知的任何合適之方法來達成。另外，在其中本發明化合物之互變異構體為可能的情形中，本發明意欲包括化合物之所有互變異構形式。The salts of the compounds of the invention can also be used in the methods disclosed herein. The present invention further includes all possible stereoisomers and geometric isomers of the compounds of the present invention, thereby including both racemic compounds and optically active isomers. When the compound of the present invention is required to be a single enantiomer, it can be obtained by isolating the final product or by stereospecific synthesis from any isomeric pure starting material or by using a counterpart auxiliary reactant, for example See Z. Ma et al., Tetrahedron: Asymmetry, 8(6) , pages 883-888 (1997). The isolation of the final product, intermediate product or starting material can be achieved by any suitable method known in the art. In addition, in situations where tautomers of the compounds of the present invention are possible, the present invention is intended to include all tautomeric forms of the compounds.
在一個實施例中，本發明化合物係經對映異構性富集的，例如藉由對掌性HPLC所量測，該化合物的對映異構體係過量的或該化合物之「ee」為約5%或更多。在另一實施例中，ee為約10%。在另一實施例中，ee為約20%。在另一實施例中，ee為約30%。在另一實施例中，ee為約40%。在另一實施例中，ee為約50%。在另一實施例中，ee為約60%。在另一實施例中，ee為約70%。在另一實施例中，ee為約80%。在另一實施例中，ee為約85%。在另一實施例中，ee為約90%。在另一實施例中，ee為約91%。在另一實施例中，ee為約92%。在另一實施例中，ee為約93%。在另一實施例中，ee為約94%。在另一實施例中，ee為約95%。在另一實施例中，ee為約96%。在另一實施例中，ee為約97%。在另一實施例中，ee為約98%。在另一實施例中，ee為約99%。In one embodiment, the compound of the present invention is enantiomerically enriched. For example, the enantiomeric system of the compound is in excess or the "ee" of the compound is approximately 5% or more. In another embodiment, ee is about 10%. In another embodiment, ee is about 20%. In another embodiment, ee is about 30%. In another embodiment, ee is about 40%. In another embodiment, ee is about 50%. In another embodiment, ee is about 60%. In another embodiment, ee is about 70%. In another embodiment, ee is about 80%. In another embodiment, ee is about 85%. In another embodiment, ee is about 90%. In another embodiment, ee is about 91%. In another embodiment, ee is about 92%. In another embodiment, ee is about 93%. In another embodiment, ee is about 94%. In another embodiment, ee is about 95%. In another embodiment, ee is about 96%. In another embodiment, ee is about 97%. In another embodiment, ee is about 98%. In another embodiment, ee is about 99%.
本發明涵蓋本發明化合物之鹽的製備及用途。如本文所用，藥物「醫藥學上可接受之鹽」係指本發明之化合物之鹽或兩性離子形式。本發明化合物之鹽可在化合物之最終分離及純化期間製備，或單獨藉由使化合物與具有適當陽離子之酸反應來製備。本發明化合物之醫藥學上可接受之鹽可為藉由醫藥學上可接受之酸形成的酸加成鹽。可用以形成醫藥學上可接受之鹽之酸的實例包括無機酸，諸如硝酸、硼酸、氫氯酸、氫溴酸、硫酸及磷酸；及有機酸，諸如草酸、馬來酸、丁二酸及檸檬酸。本發明化合物之鹽的非限制性實例包括但不限於氫氯酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、硫酸氫鹽、2-羥基乙烷磺酸鹽、磷酸鹽、磷酸氫鹽、乙酸鹽、己二酸鹽、褐藻酸鹽、天冬胺酸鹽、苯甲酸鹽、硫酸氫鹽、丁酸鹽、樟腦酸鹽、樟腦磺酸鹽、二葡糖酸鹽、甘油磷酸鹽、半硫酸鹽、庚酸鹽、己酸鹽、甲酸鹽、丁二酸鹽、反丁烯二酸鹽、順丁烯二酸鹽、抗壞血酸鹽、羥乙磺酸鹽、水楊酸鹽、甲磺酸鹽、均三甲苯磺酸鹽、萘磺酸鹽、菸鹼酸鹽、2-萘磺酸鹽、草酸鹽、雙羥萘酸鹽、果膠酸鹽、過硫酸鹽、3-苯基丙酸鹽、苦味酸鹽、特戊酸鹽、丙酸鹽、三氯乙酸鹽、三氟乙酸鹽、磷酸鹽、麩胺酸鹽、碳酸氫鹽、對甲苯磺酸鹽、十一烷酸鹽、乳酸鹽、檸檬酸鹽、酒石酸鹽、葡糖酸鹽、甲磺酸鹽、乙烷二磺酸鹽、苯磺酸鹽及對甲苯磺酸鹽。另外，存在於本發明化合物中之可用胺基可經以下各者四級銨化：甲基、乙基、丙基及丁基氯化物、溴化物及碘化物；二甲基、二乙基、二丁基及二戊基硫酸鹽；癸基、十二烷基、十四烷基及固醇氯化物、溴化物及碘化物；以及苄基及苯乙基溴化物。鑒於前述內容，本文中所出現之本發明的任何參考化合物意欲包括本發明化合物之化合物以及其醫藥學上可接受之鹽。The present invention covers the preparation and use of the salts of the compounds of the present invention. As used herein, a drug "pharmaceutically acceptable salt" refers to the salt or zwitterionic form of the compound of the present invention. The salt of the compound of the present invention may be prepared during the final isolation and purification of the compound, or may be prepared solely by reacting the compound with an acid having an appropriate cation. The pharmaceutically acceptable salt of the compound of the present invention may be an acid addition salt formed by a pharmaceutically acceptable acid. Examples of acids that can be used to form pharmaceutically acceptable salts include inorganic acids such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; and organic acids such as oxalic acid, maleic acid, succinic acid, and Citric acid. Non-limiting examples of salts of the compounds of the present invention include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethane sulfonate, phosphate, hydrogen phosphate Salt, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate Salt, hemisulfate, heptanoate, caproate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate , Methanesulfonate, mesitylenesulfonate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3 -Phenylpropionate, picrate, pivalate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate Alkanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate and p-toluenesulfonate. In addition, the available amine groups in the compounds of the present invention can be quaternary ammonium by each of the following: methyl, ethyl, propyl and butyl chloride, bromide and iodide; dimethyl, diethyl, Dibutyl and dipentyl sulfates; decyl, dodecyl, tetradecyl and sterol chlorides, bromides and iodides; and benzyl and phenethyl bromides. In view of the foregoing, any reference compound of the present invention appearing herein is intended to include the compound of the compound of the present invention and the pharmaceutically acceptable salts thereof.
本發明提供作為menin抑制劑之本發明化合物，其用於治療其中抑制menin具有有益效果之疾病及病狀。本發明化合物通常具有小於100 μM，例如小於50 μM、小於25 μM及小於5 μM、小於約1 µM、小於約0.5 µM、小於約0.1 µM、小於約0.05 µM或小於約0.01 µM之與menin的結合親和力(IC50 )。在一個實施例中，本發明係關於一種治療罹患其中抑制menin提供益處之疾病或病狀之個體的方法，該方法包含向有需要之個體投與治療有效量之本發明之化合物。The present invention provides compounds of the present invention as menin inhibitors for the treatment of diseases and conditions in which the inhibition of menin has a beneficial effect. The compound of the present invention generally has a compound of less than 100 μM, such as less than 50 μM, less than 25 μM, and less than 5 μM, less than about 1 μM, less than about 0.5 μM, less than about 0.1 μM, less than about 0.05 μM, or less than about 0.01 μM. binding affinity (IC 50). In one embodiment, the present invention relates to a method of treating an individual suffering from a disease or condition in which inhibition of menin provides benefit, the method comprising administering to the individual in need a therapeutically effective amount of a compound of the invention.
可藉由投與本發明化合物來治療由menin介導之疾病及病狀，此係因為此等化合物為menin之抑制劑。本發明因而大體上針對一種用於治療在罹患病狀或病症或處於罹患該病狀或病症之風險下的動物，例如人類體內對menin之抑制有反應之病狀或病症的方法，該方法包含向動物投與有效量之一或多種本發明化合物。The compounds of the present invention can be administered to treat diseases and conditions mediated by menin because these compounds are inhibitors of menin. The present invention is therefore generally directed to a method for treating an animal suffering from a condition or condition or at risk of suffering from the condition or condition, such as a condition or condition in humans that is responsive to the inhibition of menin, the method comprising An effective amount of one or more compounds of the invention is administered to the animal.
本發明進一步針對一種在有需要之動物體內抑制menin之方法，該方法包含向動物投與有效量之至少一種本發明化合物。The present invention is further directed to a method for inhibiting menin in an animal in need thereof, the method comprising administering to the animal an effective amount of at least one compound of the present invention.
本發明之方法可藉由以純化合物或以醫藥組合物形式投與本發明之化合物來實現。本發明化合物之醫藥組合物或純化合物之投與可在所關注疾病或病狀發病期間或之後執行。通常，醫藥組合物為無菌的，且不含有會在投與時引起不良反應之有毒、致癌或誘變化合物。進一步提供套組，其包含經單獨或一起封裝之本發明之化合物及視情況選用之第二治療劑，以及具有使用此等活性劑之指示的說明書。The method of the present invention can be achieved by administering the compound of the present invention as a pure compound or in the form of a pharmaceutical composition. The administration of the pharmaceutical composition or pure compound of the compound of the present invention can be performed during or after the onset of the disease or condition of interest. Generally, the pharmaceutical composition is sterile and does not contain toxic, carcinogenic or mutagenic compounds that can cause adverse reactions when administered. A kit is further provided, which includes the compound of the present invention and optionally a second therapeutic agent encapsulated separately or together, and instructions with instructions for using these active agents.
在一個實施例中，本發明之化合物與適用於治療其中抑制menin提供益處之疾病或病狀的第二治療劑結合投與。第二治療劑不同於本發明之化合物。本發明之化合物與第二治療劑可同時或依序投與以達成所需效果。此外，本發明之化合物及第二治療劑可自單一組合物或兩種單獨組合物投與。In one embodiment, the compound of the present invention is administered in combination with a second therapeutic agent suitable for the treatment of diseases or conditions in which the inhibition of menin provides benefits. The second therapeutic agent is different from the compound of the present invention. The compound of the present invention and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect. In addition, the compound of the present invention and the second therapeutic agent can be administered from a single composition or two separate compositions.
以提供其所要療效之量投與第二治療劑。各第二治療劑之有效劑量範圍為此項技術中已知的，且在此類已確立範圍內向有需要之個體投與第二治療劑。The second therapeutic agent is administered in an amount that provides the desired therapeutic effect. The effective dose range of each second therapeutic agent is known in the art, and the second therapeutic agent is administered to an individual in need within such an established range.
本發明之化合物與第二治療劑可以單一單位劑量或單獨以多單位劑量一起投與，其中本發明之化合物在第二治療劑之前投與或反之亦然。可投與一或多個劑量之本發明化合物及/或一或多個劑量之第二治療劑。因此，本發明之化合物可與例如但不限於抗癌劑之一或多種第二治療劑結合使用。The compound of the present invention and the second therapeutic agent may be administered together in a single unit dose or separately in multiple unit doses, wherein the compound of the present invention is administered before the second therapeutic agent or vice versa. One or more doses of the compound of the invention and/or one or more doses of the second therapeutic agent can be administered. Therefore, the compounds of the present invention can be used in combination with, for example, but not limited to, one or more second therapeutic agents of anticancer agents.
可藉由本發明之方法治療的疾病及病狀包括但不限於癌症及其他增生性病症、炎性疾病、敗血症、自體免疫疾病及病毒感染。在一個實施例中，用本發明化合物或包含本發明化合物之醫藥組合物來治療人類患者，其中在患者體內以足以抑制menin活性之量投與化合物。在另一實施例中，人類患者為需要治療疾病之18歲以上的人類成人。在另一實施例中，人類患者為需要治療疾病之不超過18歲的人類兒童。The diseases and conditions that can be treated by the method of the present invention include, but are not limited to, cancer and other proliferative disorders, inflammatory diseases, sepsis, autoimmune diseases, and viral infections. In one embodiment, the compound of the present invention or a pharmaceutical composition comprising the compound of the present invention is used to treat a human patient, wherein the compound is administered in the patient in an amount sufficient to inhibit the activity of menin. In another embodiment, the human patient is a human adult over 18 years of age in need of treatment for the disease. In another embodiment, the human patient is a human child under 18 years of age in need of treatment for a disease.
在另一態樣中，本發明提供一種治療個體之癌症之方法，其包含投與治療有效量之本發明之化合物。儘管不限於特定機制，但在一些實施例中，本發明之化合物藉由抑制menin來治療癌症。可治療癌症之實例包括但不限於表2之癌症中之任何一或多者。In another aspect, the present invention provides a method of treating cancer in an individual, which comprises administering a therapeutically effective amount of a compound of the present invention. Although not limited to a specific mechanism, in some embodiments, the compounds of the present invention treat cancer by inhibiting menin. Examples of treatable cancers include, but are not limited to, any one or more of the cancers in Table 2.
表2
在另一實施例中，該癌症為實體腫瘤。在另一實施例中，癌症為血液癌。例示性血液癌包括但不限於表3中列舉之癌症。在另一實施例中，血液癌為急性淋巴球性白血病、慢性淋巴球性白血病(包括B細胞慢性淋巴球性白血病)或急性骨髓性白血病。在另一實施例中，血液癌為骨髓發育不良症候群。In another embodiment, the cancer is a solid tumor. In another embodiment, the cancer is blood cancer. Exemplary blood cancers include, but are not limited to, the cancers listed in Table 3. In another embodiment, the blood cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myelogenous leukemia. In another embodiment, the blood cancer is myelodysplastic syndrome.
表3
在另一實施例中，癌症為白血病，例如選自以下之白血病：急性單核球性白血病、急性淋巴球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病(MLL)。在另一實施例中，白血病為NPM1c突變型急性骨髓性白血病。在另一實施例中，白血病為MLL-r急性骨髓性白血病。在另一實施例中，白血病為MLL-r急性淋巴球性白血病。在另一實施例中，癌症為NUT-中線癌。在另一實施例中，癌症為多發性骨髓瘤。在另一實施例中，癌症為肺癌，諸如小細胞肺癌(SCLC)。在另一實施例中，癌症為神經母細胞瘤。在另一實施例中，癌症為伯基特氏淋巴瘤。在另一實施例中，癌症為宮頸癌。在另一實施例中，癌症為食道癌。在另一實施例中，癌症為卵巢癌。在另一實施例中，癌症為大腸直腸癌。在另一實施例中，癌症為前列腺癌。在另一實施例中，癌症為乳癌。在另一個實施例中，癌症為尤文氏肉瘤(Ewing's sarcoma)。In another embodiment, the cancer is leukemia, such as a leukemia selected from the group consisting of acute monocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed-line leukemia (MLL). In another embodiment, the leukemia is NPM1c mutant acute myeloid leukemia. In another embodiment, the leukemia is MLL-r acute myeloid leukemia. In another embodiment, the leukemia is MLL-r acute lymphocytic leukemia. In another embodiment, the cancer is NUT-midline cancer. In another embodiment, the cancer is multiple myeloma. In another embodiment, the cancer is lung cancer, such as small cell lung cancer (SCLC). In another embodiment, the cancer is neuroblastoma. In another embodiment, the cancer is Burkitt's lymphoma. In another embodiment, the cancer is cervical cancer. In another embodiment, the cancer is esophageal cancer. In another embodiment, the cancer is ovarian cancer. In another embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is prostate cancer. In another embodiment, the cancer is breast cancer. In another embodiment, the cancer is Ewing's sarcoma (Ewing's sarcoma).
在另一實施例中，本發明提供一種治療良性增生性病症之方法，該良性增生性病症諸如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、肉芽腫瘤、脂肪瘤、腦膜瘤、多發性內分泌瘤、鼻息肉、垂體腫瘤、促乳素瘤、假腦瘤、皮脂溢性角化症、胃息肉、甲狀腺結節、胰臟囊性贅瘤、血管瘤、聲帶結節、息肉及囊腫、卡斯特萊曼病(Castleman disease)、慢性潛毛疾病、皮膚纖維瘤、毛髮囊腫、化膿性肉芽腫及青少年多發性息肉症候群。In another embodiment, the present invention provides a method for treating benign proliferative disorders such as but not limited to benign soft tissue tumors, bone tumors, brain and spinal cord tumors, eyelid and orbital tumors, granulation tumors, lipomas , Meningioma, multiple endocrine tumors, nasal polyps, pituitary tumors, prolactinomas, pseudo-brain tumors, seborrheic keratosis, gastric polyps, thyroid nodules, pancreatic cystic neoplasms, hemangioma, vocal cord nodules, Polyps and cysts, Castleman disease (Castleman disease), chronic latent hair disease, dermatofibroma, hair cyst, purulent granuloma and juvenile polyp syndrome.
本發明之化合物亦可藉由向需要此類治療之哺乳動物，尤其人類投與有效量之本發明化合物來治療感染性及非感染性炎症事件以及自體免疫及其他炎性疾病。使用本文所述之化合物及方法治療之自體免疫及炎性疾病、病症及症候群之實例包括炎性骨盆疾病、尿道炎、皮膚曬傷、鼻竇炎、肺炎、腦炎、腦膜炎、心肌炎、腎炎、骨髓炎、肌炎、肝炎、胃炎、腸炎、皮膚炎、齒齦炎、闌尾炎、胰臟炎、膽囊炎、無γ球蛋白血症、牛皮癬、過敏、克羅恩氏病(Crohn's disease)、腸激躁症候群、潰瘍性結腸炎、休格連氏病(Sjogren's disease)、組織移植排斥反應、移植器官之超急性排斥、哮喘、過敏性鼻炎、慢性阻塞性肺病(COPD)、自體免疫多腺疾病(亦稱為自體免疫多腺症候群)、自體免疫禿髮、惡性貧血、絲球體腎炎、皮肌炎、多發性硬化症、硬皮病、脈管炎、自體免疫溶血性及血小板減少性病況、古巴斯德氏症候群(Goodpasture's syndrome)、動脈粥樣硬化、艾迪森氏病(Addison's disease)、帕金森氏病(Parkinson's disease)、阿茲海默氏病(Alzheimer's disease)、I型糖尿病、敗血性休克、全身性紅斑性狼瘡症(SLE)、類風濕性關節炎、牛皮癬性關節炎、青少年關節炎、骨關節炎、慢性特發性血小板減少性紫癜、瓦爾登斯特倫巨球蛋白血症、重症肌無力、橋本氏甲狀腺炎(Hashimoto's thyroiditis)、異位性皮膚炎、退化性關節病、白斑病、自體免疫垂體機能減退、格-巴二氏症候群(Guillain-Barre syndrome)、白塞氏病(Behcet's disease)、硬腫症、蕈樣黴菌病、急性炎性反應(諸如急性呼吸窘迫症候群及局部缺血/再灌注損傷)及格雷夫氏病(Graves' disease)。The compound of the present invention can also be used to treat infectious and non-infectious inflammatory events as well as autoimmune and other inflammatory diseases by administering an effective amount of the compound of the present invention to mammals in need of such treatment, especially humans. Examples of autoimmune and inflammatory diseases, disorders and syndromes treated using the compounds and methods described herein include inflammatory pelvic disease, urethritis, skin sunburn, sinusitis, pneumonia, encephalitis, meningitis, myocarditis, and nephritis , Osteomyelitis, myositis, hepatitis, gastritis, enteritis, dermatitis, gingivitis, appendicitis, pancreatitis, cholecystitis, non-gamma globulinemia, psoriasis, allergy, Crohn's disease, intestinal Irritable syndrome, ulcerative colitis, Sjogren's disease, tissue transplant rejection, hyperacute rejection of transplanted organs, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), autoimmune polyglandria Diseases (also known as autoimmune polyglandular syndrome), autoimmune alopecia, pernicious anemia, glomerulonephritis, dermatomyositis, multiple sclerosis, scleroderma, vasculitis, autoimmune hemolysis, and platelets Reduce sexual conditions, Goodpasture's syndrome, atherosclerosis, Addison's disease, Parkinson's disease, Alzheimer's disease, I Type diabetes, septic shock, systemic lupus erythematosus (SLE), rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, osteoarthritis, chronic idiopathic thrombocytopenic purpura, Waldenstrom Macroglobulinemia, myasthenia gravis, Hashimoto's thyroiditis, atopic dermatitis, degenerative joint disease, leukoplakia, autoimmune hypopituitarism, Guillain-Barre syndrome syndrome), Behcet's disease, scleroderma, mycosis fungoides, acute inflammatory reactions (such as acute respiratory distress syndrome and ischemia/reperfusion injury) and Graves' disease .
在另一實施例中，本發明提供一種藉由向需要此種治療之哺乳動物，特定而言人類投與有效量之本發明化合物，來治療諸如LPS誘導之內毒素休克及/或細菌誘導之敗血症的全身性炎性反應症候群之方法。In another embodiment, the present invention provides a method for treating such as LPS-induced endotoxin shock and/or bacteria-induced disease by administering an effective amount of the compound of the present invention to a mammal in need of such treatment, particularly a human. The method of systemic inflammatory response syndrome of sepsis.
在另一實施例中，本發明提供一種用於治療病毒感染及疾病之方法。使用本文中所描述之化合物及方法來治療之病毒感染及疾病的實例包括基於游離基因之DNA病毒，包括但不限於人類乳頭狀瘤病毒、疱疹病毒、艾司坦-巴爾(Epstein-Barr)病毒、人類免疫不全病毒、B型肝炎病毒及C型肝炎病毒。In another embodiment, the present invention provides a method for treating viral infections and diseases. Examples of viral infections and diseases treated using the compounds and methods described herein include episomal DNA viruses, including but not limited to human papilloma virus, herpes virus, Epstein-Barr virus , Human immunodeficiency virus, hepatitis B virus and hepatitis C virus.
在另一個實施例中，本發明提供在上述疾病，尤其癌症、炎性疾病及/或病毒性疾病中，藉由向需要此類療法之個體投與治療有效量之本發明化合物來調節活體內蛋白質甲基化、基因表現、細胞增殖、細胞分化及/或凋亡的治療方法。In another embodiment, the present invention provides in the above-mentioned diseases, especially cancer, inflammatory diseases and/or viral diseases, by administering a therapeutically effective amount of the compound of the present invention to an individual in need of such therapy to regulate in vivo Therapies for protein methylation, gene expression, cell proliferation, cell differentiation and/or apoptosis.
在另一實施例中，本發明提供一種藉由使細胞與本發明化合物接觸來調節內源或異源啟動子活性的方法。In another embodiment, the invention provides a method for modulating the activity of an endogenous or heterologous promoter by contacting a cell with a compound of the invention.
在本發明之方法中，向有需要之人類投與通常根據醫藥學實踐所調配之治療有效量之本發明的化合物。是否指示此種治療視個體情況而定且經受醫療評估(診斷)，該醫療評估考慮存在產生特定體徵、症狀及/或功能障礙之風險的體徵、症狀及/或功能障礙及其他因素。In the method of the present invention, a therapeutically effective amount of the compound of the present invention, which is usually formulated according to medical practice, is administered to a human in need. Whether such treatment is indicated depends on the individual's condition and undergoes a medical evaluation (diagnosis) that considers signs, symptoms and/or dysfunction and other factors that are at risk of producing specific signs, symptoms, and/or dysfunctions.
本發明之化合物可藉由任何適合途徑投與，例如藉由以下投與：經口、頰內、吸入、舌下、經直腸、經陰道、經由腰椎穿刺之腦池內或鞘內、經尿道、經鼻、經皮(亦即透皮)或非經腸(包括靜脈內、肌肉內、皮下、冠狀動脈內、皮內、乳房內、腹膜內、關節內、鞘內、眼球後、肺內注射及/或手術植入於特定部位處)。非經腸投與可使用穿刺及注射器或使用高壓技術來實現。The compound of the present invention can be administered by any suitable route, for example, by the following administration: oral, buccal, inhalation, sublingual, transrectal, transvaginal, intracisternal or intrathecal via lumbar puncture, transurethral , Nasal, transdermal (i.e. transdermal) or parenteral (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, posterior, intrapulmonary) Injection and/or surgical implantation at a specific site). Parenteral administration can be achieved using punctures and syringes or using high-pressure techniques.
醫藥組合物包括其中以有效量投與本發明化合物以達成其預期目的之彼等組合物。精確調配物、投與途徑及劑量藉由個別醫師鑒於所診斷病狀或疾病來判定。劑量及間隔可經單獨調整以提供足以維持治療效果之水準之本發明的化合物。Pharmaceutical compositions include those compositions in which the compound of the present invention is administered in an effective amount to achieve its intended purpose. The precise formulation, route of administration and dosage are determined by individual physicians in view of the condition or disease diagnosed. The dosage and interval can be individually adjusted to provide the compound of the present invention at a level sufficient to maintain the therapeutic effect.
本發明化合物之毒性及治療功效可藉由標準醫藥學程序在細胞培養基中或實驗動物體內測定，例如以用於確定化合物之最大耐受劑量(MTD)，該最大耐受劑量定義為在動物體內不產生毒性之最高劑量。最大耐受劑量與治療效果(例如對腫瘤生長之抑制)之間的劑量比率為治療指數。劑量可視所採用劑型及所使用投與途徑而定在此範圍內變化。尤其鑒於本文中所提供之詳細揭示內容，對治療有效量之確定完全在熟習此項技術者之能力範圍內。The toxicity and therapeutic efficacy of the compounds of the present invention can be measured in cell culture media or in experimental animals by standard medical procedures, for example, to determine the maximum tolerated dose (MTD) of the compound, which is defined as in vivo The highest dose that does not produce toxicity. The dose ratio between the maximum tolerated dose and the therapeutic effect (for example, inhibition of tumor growth) is the therapeutic index. The dosage may vary within this range depending on the dosage form used and the route of administration used. Especially in view of the detailed disclosure provided in this article, the determination of the therapeutically effective amount is completely within the capabilities of those familiar with the art.
用於治療所需之治療有效量的本發明化合物隨所治療病狀之性質、所要活性之時間長度及患者之年齡及病狀而變化，且最終藉由主治醫師來確定。劑量及間隔時間可經單獨調節以提供足以維持所要治療效果之血漿水準的menin抑制劑。所需劑量可宜以單一劑量投與，或以適當間隔作為多個劑量投與，例如以每天一次、兩次、三次、四次或更多次子劑量。在一個實施例中，每天一次(QD)投與本發明化合物。在另一實施例中，每天兩次(BID)投與本發明化合物。多個劑量通常為所需或需要的。舉例而言，本發明化合物可以以下頻率投與：以四天間隔作為一個劑量/天遞送之四個劑量(q4d×4)；以三天間隔作為一個劑量/天遞送之四個劑量(q3d×4)；以五天間隔每天遞送一個劑量(qd×5)；每週一個劑量持續三週(qwk3)；五次每日劑量，休息兩天，且進行另一個五次每日劑量(5/2/5)；或測定適合於情況之任何給藥方案。The therapeutically effective amount of the compound of the present invention required for treatment varies with the nature of the condition to be treated, the length of time required for activity, and the age and condition of the patient, and is ultimately determined by the attending physician. The dose and interval can be adjusted individually to provide a menin inhibitor sufficient to maintain the desired therapeutic effect in plasma levels. The required dose may be administered as a single dose, or as multiple doses at appropriate intervals, for example, once, twice, three times, four times or more sub-doses per day. In one embodiment, the compound of the invention is administered once a day (QD). In another embodiment, the compound of the invention is administered twice a day (BID). Multiple doses are usually required or required. For example, the compounds of the present invention can be administered at the following frequency: four doses delivered at four-day intervals as one dose/day (q4d×4); four doses delivered at three-day intervals as one dose/day (q3d× 4); deliver one dose per day at five-day intervals (qd×5); one dose per week for three weeks (qwk3); five daily doses, two days off, and another five daily doses (5/ 2/5); or determine any dosage regimen suitable for the situation.
在本發明之方法中使用的本發明之化合物可以每劑量約0.005至約500毫克、每劑量約0.05至約250毫克或每劑量約0.5至約100毫克之量投與。舉例而言，本發明之化合物可以每劑量約0.005、約0.05、約0.5、約5、約10、約20、約30、約40、約50、約100、約150、約200、約250、約300、約350、約400、約450或約500毫克之量投與，包括0.005與500毫克之間的所有劑量。The compound of the present invention used in the method of the present invention can be administered in an amount of about 0.005 to about 500 mg per dose, about 0.05 to about 250 mg per dose, or about 0.5 to about 100 mg per dose. For example, the compound of the present invention can be about 0.005, about 0.05, about 0.5, about 5, about 10, about 20, about 30, about 40, about 50, about 100, about 150, about 200, about 250, It is administered in an amount of about 300, about 350, about 400, about 450, or about 500 mg, including all doses between 0.005 and 500 mg.
含有本發明之化合物的組合物或含有該化合物之組合物的劑量可為約1 ng/kg至約200 mg/kg，約1 μg/kg至約100 mg/kg，或約1 mg/kg至約50 mg/kg。組合物之劑量可為任何劑量，包括但不限於約1 μg/kg。組合物之劑量可為任何劑量，包括但不限於約1 μg/kg、約10 μg/kg、約25 μg/kg、約50 μg/kg、約75 μg/kg、約100 μg/kg、約125 μg/kg、約150 μg/kg、約175 μg/kg、約200 μg/kg、約225 μg/kg、約250 μg/kg、約275 μg/kg、約300 μg/kg、約325 μg/kg、約350 μg/kg、約375 μg/kg、約400 μg/kg、約425 μg/kg、約450 μg/kg、約475 μg/kg、約500 μg/kg、約525 μg/kg、約550 μg/kg、約575 μg/kg、約600 μg/kg、約625 μg/kg、約650 μg/kg、約675 μg/kg、約700 μg/kg、約725 μg/kg、約750 μg/kg、約775 μg/kg、約800 μg/kg、約825 μg/kg、約850 μg/kg、約875 μg/kg、約900 μg/kg、約925 μg/kg、約950 μg/kg、約975 μg/kg、約1 mg/kg、約5 mg/kg、約10 mg/kg、約15 mg/kg、約20 mg/kg、約25 mg/kg、約30 mg/kg、約35 mg/kg、約40 mg/kg、約45 mg/kg、約50 mg/kg、約60 mg/kg、約70 mg/kg、約80 mg/kg、約90 mg/kg、約100 mg/kg、約125 mg/kg、約150 mg/kg、約175 mg/kg、約200 mg/kg或更大。上述劑量為平均情況之示例，但可存在值得更高或更低劑量之個別情況，且此類均在本發明之範疇內。實際上，醫師判定最適合於個別患者之實際給藥方案，該給藥方案可隨特定患者之年齡、體重及反應而變化。The dose of the composition containing the compound of the present invention or the composition containing the compound may be about 1 ng/kg to about 200 mg/kg, about 1 μg/kg to about 100 mg/kg, or about 1 mg/kg to About 50 mg/kg. The dosage of the composition can be any dosage, including but not limited to about 1 μg/kg. The dose of the composition can be any dose, including but not limited to about 1 μg/kg, about 10 μg/kg, about 25 μg/kg, about 50 μg/kg, about 75 μg/kg, about 100 μg/kg, about 125 μg/kg, about 150 μg/kg, about 175 μg/kg, about 200 μg/kg, about 225 μg/kg, about 250 μg/kg, about 275 μg/kg, about 300 μg/kg, about 325 μg /kg, about 350 μg/kg, about 375 μg/kg, about 400 μg/kg, about 425 μg/kg, about 450 μg/kg, about 475 μg/kg, about 500 μg/kg, about 525 μg/kg , About 550 μg/kg, about 575 μg/kg, about 600 μg/kg, about 625 μg/kg, about 650 μg/kg, about 675 μg/kg, about 700 μg/kg, about 725 μg/kg, about 750 μg/kg, about 775 μg/kg, about 800 μg/kg, about 825 μg/kg, about 850 μg/kg, about 875 μg/kg, about 900 μg/kg, about 925 μg/kg, about 950 μg /kg, about 975 μg/kg, about 1 mg/kg, about 5 mg/kg, about 10 mg/kg, about 15 mg/kg, about 20 mg/kg, about 25 mg/kg, about 30 mg/kg , About 35 mg/kg, about 40 mg/kg, about 45 mg/kg, about 50 mg/kg, about 60 mg/kg, about 70 mg/kg, about 80 mg/kg, about 90 mg/kg, about 100 mg/kg, about 125 mg/kg, about 150 mg/kg, about 175 mg/kg, about 200 mg/kg or more. The above-mentioned dosages are examples of average cases, but there may be individual cases worth higher or lower dosages, and these are all within the scope of the present invention. In fact, the physician decides the actual dosage regimen that is most suitable for an individual patient, and the dosage regimen can vary with the age, weight, and response of the particular patient.
如上所陳述，本發明之化合物可與第二治療活性劑組合投與。在一些實施例中，第二治療劑為後生藥物。如本文所用，術語「表觀遺傳藥物」係指靶向表觀遺傳調節子之治療劑。表觀遺傳調控因子之實例包括組織蛋白離胺酸甲基轉移酶、組織蛋白精胺酸甲基轉移酶、組織蛋白去甲基酶、組蛋白去乙醯基酶、組織蛋白乙醯基轉移酶及DNA甲基轉移酶。組蛋白去乙醯酶抑制劑包括但不限於伏立諾他(vorinostat)。As stated above, the compounds of the present invention can be administered in combination with a second therapeutically active agent. In some embodiments, the second therapeutic agent is an epigenetic drug. As used herein, the term "epigenetic drugs" refers to therapeutic agents that target epigenetic regulators. Examples of epigenetic regulatory factors include histone lysine methyltransferase, histone arginine methyltransferase, histone demethylase, histone deacetylase, histone acetyltransferase And DNA methyltransferase. Histone deacetylase inhibitors include but are not limited to vorinostat.
在另一實施例中，化學治療劑或其他抗增殖劑可與本發明化合物組合以治療增殖性疾病及癌症。可與本發明之化合物組合使用之療法及抗癌劑之實例包括手術、放射線療法(例如γ輻射、中子束放射線療法、電子放射線療法、質子療法、近接療法及全身性放射性同位素)、內分泌療法、生物反應調節劑(例如干擾素、介白素、腫瘤壞死因子(TNF)、高溫及超低溫療法、用以減弱任何不良影響之藥劑(例如抗嘔劑)及任何其他經批准的化學治療藥物。In another embodiment, chemotherapeutic agents or other anti-proliferative agents can be combined with the compounds of the present invention to treat proliferative diseases and cancer. Examples of therapies and anticancer agents that can be used in combination with the compounds of the present invention include surgery, radiation therapy (e.g., gamma radiation, neutron beam radiation therapy, electron radiation therapy, proton therapy, brachytherapy, and systemic radioisotopes), endocrine therapy , Biological response modifiers (such as interferon, interleukin, tumor necrosis factor (TNF), hyperthermia and ultra-low temperature therapy, drugs to reduce any adverse effects (such as anti-emetics) and any other approved chemotherapeutic drugs.
在另一實施例中，本文所述之本發明化合物及醫藥組合物可與一或多種選自以下之物質組合使用：抗血管生成劑、信號轉導抑制劑、抗增生劑、糖酵解抑制劑、自體吞噬抑制劑、去甲基化劑、DOT1L抑制劑、IDH1抑制劑、IDH2抑制劑、IDH1/IDH2雙重抑制劑、LSD1抑制劑、XPO1抑制劑或達沙替尼(dastinib)。在另一實施例中，本發明化合物可與選自以下之第二治療劑組合使用：去甲基化劑、DOT1L抑制劑、IDH1抑制劑、IDH2抑制劑、IDH1/IDH2雙重抑制劑、LSD1抑制劑、XPO1抑制劑及達沙替尼。In another embodiment, the compounds and pharmaceutical compositions of the present invention described herein can be used in combination with one or more substances selected from the group consisting of anti-angiogenesis agents, signal transduction inhibitors, anti-proliferative agents, glycolysis inhibitors Agents, autophagy inhibitors, demethylating agents, DOT1L inhibitors, IDH1 inhibitors, IDH2 inhibitors, IDH1/IDH2 dual inhibitors, LSD1 inhibitors, XPO1 inhibitors or dastinib. In another embodiment, the compound of the present invention can be used in combination with a second therapeutic agent selected from the group consisting of demethylating agent, DOT1L inhibitor, IDH1 inhibitor, IDH2 inhibitor, IDH1/IDH2 dual inhibitor, LSD1 inhibitor Agents, XPO1 inhibitors and dasatinib.
去甲基化劑包括抑制或干擾DNA甲基化之物質。在一些實例中，去甲基化劑為DNA甲基轉移酶抑制劑。例示性非限制性去甲基化劑包括5-氮雜胞苷、地西他濱(decitabine)、甲胺喋呤、依達曲沙(edatrexate)、2'-去氧-5-氮雜胞苷、6-硫代鳥嘌呤、5-氟-2'-去氧胞苷、假異胞苷、5,6-二氫-5-氮雜胞苷、法紮拉濱(fazarabine)、澤布拉林(zebularine)、2'-去氧-5,6-二氫-5-氮雜胞苷、4'-硫代-2'-去氧胞苷、5-氮雜-4'-硫代-2'-去氧胞苷、RX-3117、SGI-110、NPEOC-DAC、CP-4200及2'3'5'三乙醯基-5-氮雜胞苷。Demethylating agents include substances that inhibit or interfere with DNA methylation. In some examples, the demethylating agent is a DNA methyltransferase inhibitor. Exemplary non-limiting demethylating agents include 5-azacytidine, decitabine (decitabine), methotrexate, edatrexate, 2'-deoxy-5-aza cell Glycoside, 6-thioguanine, 5-fluoro-2'-deoxycytidine, pseudoisocytidine, 5,6-dihydro-5-azacytidine, fazarabine, Zebu Lalin (zebularine), 2'-deoxy-5,6-dihydro-5-azacytidine, 4'-thio-2'-deoxycytidine, 5-aza-4'-thio -2'-Deoxycytidine, RX-3117, SGI-110, NPEOC-DAC, CP-4200 and 2'3'5' triacetyl-5-azacytidine.
組蛋白甲基轉移酶DOTlL之抑制劑之例示性非限制性實例包括EPZ-5676、SGC-0946及EPZ004777。Illustrative non-limiting examples of inhibitors of histone methyltransferase DOTlL include EPZ-5676, SGC-0946, and EPZ004777.
例示性非限制性IDH1抑制劑包括替布索沃(ivosidnib)、AG-881、AG-120、FT-2102 (olutasidenib)、BAY1436032、IDH-305及ZX-06。IDH2抑制劑之例示性非限制性實例包括恩西地平(idhifa)(艾那尼布(enasidenib)；AG-221)、AG-881、AGl-6780、SH1573及TQ05310。例示性非限制性IDH1/IDH2雙重抑制劑包括HMPL-306。Exemplary non-limiting IDH1 inhibitors include ivosidnib, AG-881, AG-120, FT-2102 (olutasidenib), BAY1436032, IDH-305, and ZX-06. Illustrative non-limiting examples of IDH2 inhibitors include ensidipine (idhifa) (enasidenib; AG-221), AG-881, AG1-6780, SH1573, and TQ05310. Exemplary non-limiting dual IDH1/IDH2 inhibitors include HMPL-306.
LSD1抑制劑之例示性非限制性實例包括ORY-1001、OG-L002、SP2509、4SC-202、GSK2879552、T-3775440及RN-1。Illustrative non-limiting examples of LSD1 inhibitors include ORY-1001, OG-L002, SP2509, 4SC-202, GSK2879552, T-3775440, and RN-1.
XPO1抑制劑之例示性非限制性實例包括塞利尼索(selinexor)(KPT-330)、KPT-8602、KPT25 l及SL-801。Illustrative non-limiting examples of XPO1 inhibitors include selinexor (KPT-330), KPT-8602, KPT251, and SL-801.
抗血管生成劑，諸如MMP-2(基質金屬蛋白酶2)抑制劑、MMP-9(基質金屬蛋白酶9)抑制劑及COX-II(環加氧酶II)抑制劑可與本文所述之本發明化合物及醫藥組合物結合使用。例示性非限制性抗血管生成劑包括雷帕黴素(rapamycin)、坦羅莫司(temsirolimus)(CCI-779)、依維莫司(everolimus)(RAD001)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)及貝伐單抗(bevacizumab)。例示性非限制性COX-II抑制劑包括CELEBREXTM (阿萊昔布(alecoxib))、伐地昔布(valdecoxib)及羅非昔布(rofecoxib)。例示性非限制性基質金屬蛋白酶抑制劑包括WO 96/33172(1996年10月24日公開)、WO 96/27583(1996年3月7日公開)、歐洲專利申請案第97304971.1號(1997年7月8日申請)、歐洲專利申請案第99308617.2號(1999年10月29日申請)、WO 98/07697(1998年2月26日公開)、WO 98/03516(1998年1月29日公開)、WO 98/34918 (1998年8月13日公開)、WO 98/34915 (1998年8月13日公開)、WO 98/33768 (1998年8月6日公開)、WO 98/30566 (1998年7月16日公開)、 歐洲專利公開案606,046(1994年7月13日公開)、歐洲專利公開案931,788(1999年7月28日公開)，WO 90/05719(1990年5月31日公開)、WO 99/52910(1999年10月21日公開)、WO 99/52889(1999年10月21日公開)、WO 99/29667(1999年6月17日公開)、PCT國際申請案第PCT/IB98/01113號(1998年7月21日申請)、歐洲專利申請案第99302232.1號(1999年3月25日申請)、大不列顛專利申請案第9912961.1號(1999年6月3日申請)、 美國臨時申請案第60/148,464號(1999年8月12日申請)、美國專利5,863,949(1999年1月26日授權)，美國專利5,861,510(1999年1月19日授權)及歐洲專利公開案780,386(1997年6月25日公開)，其皆以全文引用之方式併入本文中。在某些實施例中，MMP-2及MMP-9抑制劑具有極少或無抑制MMP-1之活性。在某些實施例中，相對於其他基質金屬蛋白酶(例如MAP-1、MMP-3、MMP-4、MMP-5、MMP-6、MMP-7、MMP-8、MMP-10、MMP-11、MMP-12及MMP-13)，MMP-2及MMP-9抑制劑選擇性抑制MMP-2及/或AMP-9。例示性非限制性MMP抑制劑包括AG-3340、RO 32-3555及RS 13-0830。Anti-angiogenesis agents, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase II) inhibitors can be combined with the present invention described herein The compound and the pharmaceutical composition are used in combination. Exemplary non-limiting anti-angiogenesis agents include rapamycin, temsirolimus (CCI-779), everolimus (RAD001), sorafenib, Sunitinib and bevacizumab. Exemplary non-limiting COX-II inhibitors include CELEBREXTM (alecoxib), valdecoxib and rofecoxib. Exemplary non-limiting matrix metalloproteinase inhibitors include WO 96/33172 (published on October 24, 1996), WO 96/27583 (published on March 7, 1996), European Patent Application No. 97304971.1 (1997 July Filed on October 8), European Patent Application No. 99308617.2 (filed on October 29, 1999), WO 98/07697 (published on February 26, 1998), WO 98/03516 (published on January 29, 1998) , WO 98/34918 (published on August 13, 1998), WO 98/34915 (published on August 13, 1998), WO 98/33768 (published on August 6, 1998), WO 98/30566 (published on August 13, 1998) Published on July 16), European Patent Publication 606,046 (published on July 13, 1994), European Patent Publication 931,788 (published on July 28, 1999), WO 90/05719 (published on May 31, 1990) , WO 99/52910 (published on October 21, 1999), WO 99/52889 (published on October 21, 1999), WO 99/29667 (published on June 17, 1999), PCT International Application No. PCT/ IB98/01113 (filed on July 21, 1998), European Patent Application No. 99302232.1 (filed on March 25, 1999), Great Britain Patent Application No. 9912961.1 (filed on June 3, 1999), U.S. Provisional Application No. 60/148,464 (filed on August 12, 1999), U.S. Patent 5,863,949 (issued on January 26, 1999), U.S. Patent 5,861,510 (issued on January 19, 1999), and European Patent Publication 780,386 (1997) Published on June 25, 2010), all of which are incorporated herein by reference in their entirety. In certain embodiments, MMP-2 and MMP-9 inhibitors have little or no activity to inhibit MMP-1. In certain embodiments, relative to other matrix metalloproteinases (e.g., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11 , MMP-12 and MMP-13), MMP-2 and MMP-9 inhibitors selectively inhibit MMP-2 and/or AMP-9. Exemplary non-limiting MMP inhibitors include AG-3340, RO 32-3555, and RS 13-0830.
例示性非限制性自體吞噬抑制劑包括氯喹(chloroquine)、3-甲基腺嘌呤、羥氯喹(hydroxychloroquine)(Plaquenil™)、巴弗洛黴素A1 (bafilomycin A1)、5-胺基-4-咪唑甲醯胺核苷(AICAR)、岡田井酸(okadaic acid)、抑制2A型或1型蛋白質磷酸酶之自體吞噬抑制性藻類毒素、cAMP類似物，及提高cAMP含量的藥物，諸如腺苷、LY204002、N6-巰基嘌呤核苷及長春鹼。另外，亦可使用抑制蛋白質表現的反義或siRNA，包括但不限於ATG5 (其涉及自體吞噬)。Exemplary non-limiting autophagy inhibitors include chloroquine (chloroquine), 3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1 (bafilomycin A1), 5-amino-4 -Imidazole carbamide nucleoside (AICAR), okadaic acid, autophagy-inhibiting algal toxins that inhibit type 2A or type 1 protein phosphatase, cAMP analogs, and drugs that increase cAMP content, such as glands Glycoside, LY204002, N6-mercaptopurine nucleoside and vinblastine. In addition, antisense or siRNA that inhibit protein expression can also be used, including but not limited to ATG5 (which involves autophagy).
抗增殖化合物之實例包括但不限於芳香酶抑制劑；抗雌性激素；抗雄性激素；性腺釋素促效劑；拓樸異構酶I抑制劑；拓樸異構酶II抑制劑；微管活性劑；烷化劑；類視黃素、類胡蘿蔔素或生育酚；環加氧酶抑制劑；MMP抑制劑；mTOR抑制劑；抗代謝產物；鉑化合物；甲硫胺酸胺基肽酶抑制劑；雙膦酸鹽；抗增殖抗體；肝素酶抑制劑；Ras致癌同功異構物之抑制劑；端粒酶抑制劑；蛋白酶體抑制劑；用於治療惡性血液病之化合物；Flt-3抑制劑；Hsp90抑制劑；運動素紡錘蛋白質抑制劑；MEK抑制劑；抗腫瘤抗生素；亞硝基脲；有絲分裂抑制劑，靶向/降低蛋白質或脂質激酶活性之化合物、靶向/降低蛋白質或脂質磷酸酶活性之化合物或任何其他抗血管生成之化合物。Examples of anti-proliferative compounds include, but are not limited to, aromatase inhibitors; anti-estrogens; anti-androgens; gonadal agonists; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule activity Agents; Alkylating agents; Retinoids, carotenoids or tocopherols; Cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; Antimetabolites; Platinum compounds; Methionine aminopeptidase inhibitors ; Bisphosphonates; Anti-proliferative antibodies; Heparinase inhibitors; Ras carcinogenic isomers inhibitors; Telomerase inhibitors; Proteasome inhibitors; Compounds for the treatment of hematological malignancies; Flt-3 Inhibitors; Hsp90 inhibitors; kinesin spindle protein inhibitors; MEK inhibitors; antitumor antibiotics; nitrosoureas; Phosphatase active compound or any other anti-angiogenic compound.
非限制性例示性芳香酶抑制劑包括但不限於類固醇，諸如阿他美坦(atamestane)、依西美坦(exemestane)及福美司坦(formestane)；及非類固醇，諸如胺格魯米特(aminoglutethimide)、羅谷亞胺(roglethimide)、吡魯米特(pyridoglutethimide)、曲洛司坦(trilostane)、睪內酯(testolactone)、酮康唑(ketokonazole)、伏羅唑(vorozole)、法屈唑(fadrozole)、阿那曲唑(anastrozole)及來曲唑(letrozole)。Non-limiting exemplary aromatase inhibitors include, but are not limited to, steroids, such as atamestane, exemestane, and formestane; and non-steroids, such as amine glumid ( aminoglutethimide, roglethimide, pyridoglutethimide, trilostane, testolactone, ketokonazole, vorozole, fatra Fadrozole, anastrozole and letrozole.
非限制性抗雌性激素包括但不限於他莫昔芬(tamoxifen)、氟維司群(fulvestrant)、雷諾昔酚(raloxifene)及雷諾昔酚氫氯酸鹽。抗雄性激素包括但不限於比卡魯胺(bicalutamide)。性腺釋素促效劑包括但不限於阿巴瑞克(abarelix)、戈舍瑞林(goserelin)及乙酸戈舍瑞林(goserelin acetate)。Non-limiting anti-estrogens include, but are not limited to, tamoxifen, fulvestrant, raloxifene, and raloxifene hydrochloride. Anti-androgens include, but are not limited to, bicalutamide. Gonadal release agonists include, but are not limited to, abarelix, goserelin, and goserelin acetate.
例示性拓樸異構酶I抑制劑包括但不限於拓朴替康(topotecan)、吉馬替康(gimatecan)、伊立替康(irinotecan)、喜樹鹼及其類似物、9-硝基喜樹鹼及巨分子喜樹鹼結合物PNU-166148。拓樸異構酶II抑制劑包括但不限於蒽環黴素(anthracycline)，諸如阿黴素(doxorubicin)、道諾黴素(daunorubicin)、表柔比星(epirubicin)、艾達黴素(idarubicin)及奈莫柔比星(nemorubicin)；蒽醌，諸如米托蒽醌(mitoxantrone)及洛索蒽醌(losoxantrone)；及鬼臼毒素(podophillotoxine)，諸如依託泊苷(etoposide)及替尼泊苷(teniposide)。Exemplary topoisomerase I inhibitors include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecin and its analogs, 9-nitro camptotheca Alkali and giant camptothecin conjugate PNU-166148. Topoisomerase II inhibitors include, but are not limited to, anthracycline, such as doxorubicin, daunorubicin, epirubicin, and idarubicin ) And nemorubicin; anthraquinones, such as mitoxantrone and losoxantrone; and podophillotoxine, such as etoposide and tenipo Glycoside (teniposide).
微管活性劑包括微管穩定、微管不穩定化合物，且微管蛋白聚合抑制劑包括但不限於紫杉烷，諸如太平洋紫杉醇及多烯紫杉醇；長春花生物鹼，諸如長春鹼、硫酸長春花鹼、長春新鹼及長春新鹼硫酸鹽及長春瑞賓(vinorelbine)；迪斯德莫來(discodermolide)；秋水仙鹼及埃博黴素(epothilone)及其衍生物。Microtubule active agents include microtubule stable and microtubule unstable compounds, and tubulin polymerization inhibitors include but are not limited to taxanes, such as paclitaxel and docetaxel; vinca alkaloids, such as vinblastine, vinca sulfate Alkali, vincristine and vincristine sulfate and vinorelbine; discodermolide; colchicine and epothilone and their derivatives.
例示性非限制性烷基化劑包括環磷醯胺、異環磷醯胺、美法侖(melphalan)及亞硝基脲，諸如卡莫司汀(carmustine)及洛莫司汀(lomustine)。Exemplary non-limiting alkylating agents include cyclophosphamide, ifosfamide, melphalan, and nitrosoureas, such as carmustine and lomustine.
例示性非限制性環加氧酶抑制劑包括Cox-2抑制劑、經5-烷基取代之2-芳胺基苯乙酸及衍生物，諸如塞內昔布(celecoxib)、羅非昔布(rofecoxib)、依他昔布(etoricoxib)、伐地昔布(valdecoxib)，或5-烷基-2-芳胺基苯乙酸，諸如魯米昔布(lumiracoxib)。Exemplary non-limiting cyclooxygenase inhibitors include Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, such as celecoxib (celecoxib), rofecoxib ( rofecoxib), etoricoxib, valdecoxib, or 5-alkyl-2-arylaminophenylacetic acid, such as lumiracoxib.
例示性基非限制性質金屬蛋白酶抑制劑(「MMP抑制劑」)包括膠原蛋白肽模擬物及非肽模擬物抑制劑、四環素衍生物、巴馬司他(batimastat)、馬立馬司他(marimastat)、普啉司他(prinomastat)、美他司他(metastat)、BMS-279251、BAY 12-9566、TAA211、MMI270B及AAJ996。Exemplary non-limiting properties of metalloproteinase inhibitors ("MMP inhibitors") include collagen peptide mimetics and non-peptide mimetics inhibitors, tetracycline derivatives, batimastat, marimastat , Prinomastat, metastat, BMS-279251, BAY 12-9566, TAA211, MMI270B and AAJ996.
例示性非限制性mTOR抑制劑包括抑制哺乳動物雷帕黴素目標(mTOR)且擁有抗增殖活性之化合物，諸如西羅莫司(sirolimus)、依維莫司(everolimus)、CCI-779及ABT578。Exemplary non-limiting mTOR inhibitors include compounds that inhibit the mammalian target of rapamycin (mTOR) and possess antiproliferative activity, such as sirolimus, everolimus, CCI-779 and ABT578 .
例示性非限制性抗代謝物包括5-氟尿嘧啶(5-FU)；卡培他濱(capecitabine)；吉西他濱(gemcitabine)；DNA去甲基化合物，諸如5-氮胞苷及地西他濱(decitabine)；甲胺喋呤及依達曲沙(edatrexate)；及葉酸拮抗劑，諸如培美曲塞(pemetrexed)。Exemplary non-limiting antimetabolites include 5-fluorouracil (5-FU); capecitabine; gemcitabine; DNA demethylation compounds such as 5-azacytidine and decitabine ); methotrexate and edatrexate; and folate antagonists such as pemetrexed.
例示性非限制性鉑化合物包括卡鉑、順-鉑(cis-platin)、順鉑(cisplatinum)及奧沙利鉑(oxaliplatin)。Exemplary non-limiting platinum compounds include carboplatin, cis-platin, cisplatinum, and oxaliplatin.
例示性非限制性甲硫胺酸胺基肽酶抑制劑包括苯胍麥或其衍生物及PPI-2458。Exemplary non-limiting methionine amino peptidase inhibitors include benzoguanaline or its derivatives and PPI-2458.
例示性非限制性雙膦酸鹽包括依替酮酸(etridonic acid)、氯膦酸、替魯羅酸(tiludronic acid)、帕米膦酸(pamidronic acid)、阿侖膦酸(alendronic acid)、伊班膦酸(ibandronic acid)、利塞膦酸(risedronic acid)及唑來膦酸(zoledronic acid)。Exemplary non-limiting bisphosphonates include etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, Ibandronic acid, risedronic acid and zoledronic acid.
例示性非限制性抗增殖抗體包括曲妥珠單抗(trastuzumab)、曲妥珠單抗-DMl、西妥昔單抗(cetuximab)、貝伐單抗(bevacizumab)、利妥昔單抗(rituximab)、PR064553及2C4。術語「抗體」意謂包括完整單株抗體、多株抗體、由至少兩種完整抗體形成之多特異性抗體以及抗體片段，只要其呈現所需生物活性即可。Exemplary non-limiting anti-proliferative antibodies include trastuzumab, trastuzumab-DM1, cetuximab, bevacizumab, rituximab ), PR064553 and 2C4. The term "antibody" is meant to include intact monoclonal antibodies, multi-strain antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, as long as they exhibit the desired biological activity.
例示性非限制性肝素酶抑制劑包括靶向、降低或抑制硫酸肝素分解之化合物，諸如PI-88及OGT2115。Exemplary non-limiting heparinase inhibitors include compounds that target, reduce or inhibit the breakdown of heparin sulfate, such as PI-88 and OGT2115.
如本文中所使用，術語「Ras致癌同功異構物之抑制劑」，諸如H-Ras、K-Ras或N-Ras係指靶向、降低或抑制Ras之致癌活性的化合物，例如法呢基(farnesyl)轉移酶抑制劑，諸如L-744832、DK8G557、替吡法尼(tipifarnib)及洛那法尼(lonafarnib)。As used herein, the term "inhibitors of the carcinogenic isomers of Ras", such as H-Ras, K-Ras, or N-Ras, refers to compounds that target, reduce or inhibit the carcinogenic activity of Ras, such as farnes Farnesyl transferase inhibitors, such as L-744832, DK8G557, tipifarnib and lonafarnib.
例示性非限制性端粒酶抑制劑包括靶向、降低或抑制端粒酶之活性的化合物，諸如抑制端粒酶受體之化合物，諸如特羅他汀(telomestatin)。Exemplary non-limiting telomerase inhibitors include compounds that target, decrease or inhibit the activity of telomerase, such as compounds that inhibit the telomerase receptor, such as telomestatin.
例示性非限制性蛋白酶體抑制劑包括靶向、降低或抑制蛋白酶體之活性的化合物，包括但不限於硼替佐米(bortezomid)。Exemplary non-limiting proteasome inhibitors include compounds that target, decrease or inhibit the activity of the proteasome, including but not limited to bortezomid.
如本文所用，片語「用於治療血液科惡性疾病中之化合物」包括FMS樣酪胺酸激酶抑制劑，其為靶向、降低或抑制FMS樣酪胺酸激酶受體(Flt-3R)之活性的化合物；干擾素、I-β-D阿糖呋喃胞嘧啶(ara-c)及白消安(bisulfan)；ALK抑制劑，其為靶向、降低或抑制退行性淋巴瘤激酶的化合物；及BH3模擬物，其為靶向、降低或抑制來自BCL-2家族之抗凋亡蛋白的化合物。As used herein, the phrase "compounds for the treatment of hematological malignancies" includes FMS-like tyrosine kinase inhibitors, which are those that target, decrease or inhibit the FMS-like tyrosine kinase receptor (Flt-3R) Active compounds; interferon, I-β-D arabinofuranocytosine (ara-c) and busulfan (bisulfan); ALK inhibitors, which are compounds that target, reduce or inhibit degenerative lymphoma kinase; And BH3 mimetics, which are compounds that target, reduce or inhibit anti-apoptotic proteins from the BCL-2 family.
例示性非限制性Flt-3抑制劑包括吉列替尼(gilteritinib)、PKC412、米哚妥林(midostaurin)、星形孢菌素衍生物、SU11248及MLN518。Exemplary non-limiting Flt-3 inhibitors include gilteritinib, PKC412, midostaurin, staurosporine derivatives, SU11248, and MLN518.
例示性非限制性Hsp90抑制劑包括靶向、降低或抑制HSP90之固有ATP酶活性；或經由泛素蛋白酶體路徑降解、靶向、降低或抑制HSP90客戶蛋白的化合物。靶向、降低或抑制HSP90之內在ATP酶活性的化合物尤其為抑制HSP90之ATP酶活性的化合物、蛋白質或抗體，諸如17-烯丙基胺基、17-去甲氧基格爾德黴素(17AAG)，一種格爾德黴素衍生物；其他格爾德黴素相關化合物；根赤殼菌素(radicicol)及HDAC抑制劑。Exemplary non-limiting Hsp90 inhibitors include compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90; or compounds that degrade, target, reduce or inhibit HSP90 client proteins via the ubiquitin proteasome pathway. Compounds that target, decrease or inhibit the intrinsic ATPase activity of HSP90 are especially compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin ( 17AAG), a geldanamycin derivative; other geldanamycin related compounds; radicicol and HDAC inhibitors.
例示性非限制性BH3模擬物包括維納妥拉(venetoclax)。Exemplary non-limiting BH3 mimics include venetoclax.
如本文所用，片語「靶向蛋白質或脂質激酶/降低其活性的化合物；或靶向蛋白質或脂質磷酸酶/降低其活性的化合物；或任何其他抗血管生成化合物」包括蛋白酪胺酸激酶及/或絲胺酸及/或蘇胺酸激酶抑制劑或脂質激酶抑制劑，諸如a)靶向血小板衍生之生長因子受體(PDGFR)、降低或抑制其活性的化合物，諸如靶向PDGFR、降低或抑制其活性的化合物，諸如N-苯基-2-嘧啶-胺衍生物，諸如伊馬替尼(imatinib)、SUlOl、SU6668及GFB-111； b)靶向纖維母細胞生長因子受體(FGFR)、降低或抑制其活性的化合物；c)靶向似胰島素生長因子受體I (IGF-IR)、降低或抑制其活性的化合物，諸如靶向IGF-IR、降低或抑制其活性的化合物；d)靶向Trk受體酪胺酸激酶家族、降低或抑制其活性的化合物，或艾普瑞林(ephrin) B4抑制劑； e)靶向Axl受體酪胺酸激酶家族、降低或抑制其活性的化合物；f)靶向Ret受體酪胺酸激酶、降低或抑制其活性的化合物；g)靶向Kit/SCFR受體酪胺酸激酶、降低或抑制其活性的化合物，諸如伊馬替尼；h)靶向c-Kit受體酪胺酸激酶、降低或抑制其活性的化合物，諸如伊馬替尼； i)靶向c-Abl家族之成員、其基因融合產物(例如Bcr-Abl激酶)及突變體、降低或抑制其活性的化合物，諸如N-苯基-2-嘧啶-胺衍生物，諸如伊馬替尼或尼羅替尼(nilotinib)；PD180970；AG957；NSC 680410；PD173955；或達沙替尼(dasatinib)； j)靶向絲胺酸/蘇胺酸激酶之蛋白激酶C (PKC)及Raf家族之成員、MEK之成員、SRC、JAK、FAK、PDK1、PKB/Akt及Ras/MAPK家庭成員及/或週期素依賴性激酶家族(CDK)之成員、降低或抑制其活性的化合物，諸如美國專利第5,093,330號中所揭示的星形孢菌素衍生物，諸如米哚妥林；其他化合物的實例包括UCN-01、沙芬戈(safingol)、BAY 43-9006、苔蘚蟲素(bryostatin) 1、哌立福新(perifosine)；伊莫福新(ilmofosine)；RO 318220及RO 320432；GO 6976；Isis 3521；LY333531/LY379196；異喹啉化合物；法呢基轉移酶抑制劑；PD184352或QAN697或AT7519； k)靶向蛋白質-酪胺酸激酶、降低或抑制其活性的化合物，諸如甲磺酸伊馬替尼或泰福斯汀(tyrphostin)，諸如泰福斯汀A23/RG-50810；AG 99；泰福斯汀AG 213；泰福斯汀AG 1748；泰福斯汀AG 490；泰福斯汀B44；泰福斯汀B44 (+)對映異構體；泰福斯汀AG 555；AG 494；泰福斯汀AG 556、AG957及阿達斯汀(adaphostin) (4-{[(2,5-二羥基苯基)甲基]胺基}-苯甲酸金剛烷基酯；NSC 680410、阿達斯汀)； 1)靶向、降低或抑制受體酪胺酸激酶之表皮生長因子家族(作為均二聚體或雜二聚體之EGFR、ErbB2、ErbB3、ErbB4)及其突變體之活性的化合物，諸如CP 358774、ZD 1839、ZM 105180；曲妥珠單抗、西妥昔單抗、吉非替尼(gefitinib)、埃羅替尼(erlotinib)、OSI-774、Cl-1033、EKB-569、GW-2016、抗體E1.l、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3及E7.6.3以及7H-吡咯并-[2,3-d]嘧啶衍生物；及靶向、降低或抑制c-Met受體之活性的化合物。As used herein, the phrase "target protein or lipid kinase/compound that reduces its activity; or target protein or lipid phosphatase/compound its activity; or any other anti-angiogenic compound" includes protein tyrosine kinase and / Or serine and/or threonine kinase inhibitors or lipid kinase inhibitors, such as a) targeting platelet-derived growth factor receptor (PDGFR), reducing or inhibiting its activity, such as targeting PDGFR, reducing Or compounds that inhibit its activity, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668, and GFB-111; b) targeting fibroblast growth factor receptor (FGFR) ), compounds that reduce or inhibit its activity; c) compounds that target insulin-like growth factor receptor I (IGF-IR), reduce or inhibit its activity, such as compounds that target IGF-IR, reduce or inhibit its activity; d) A compound that targets the Trk receptor tyrosine kinase family, reduces or inhibits its activity, or an ephrin B4 inhibitor; e) Targets the Axl receptor tyrosine kinase family, reduces or inhibits it Active compounds; f) compounds that target Ret receptor tyrosine kinase and reduce or inhibit its activity; g) compounds that target Kit/SCFR receptor tyrosine kinase and reduce or inhibit its activity, such as imatinib H) Compounds that target c-Kit receptor tyrosine kinase and reduce or inhibit its activity, such as imatinib; i) target members of the c-Abl family and their gene fusion products (for example, Bcr-Abl kinase) And mutants, compounds that reduce or inhibit its activity, such as N-phenyl-2-pyrimidin-amine derivatives, such as imatinib or nilotinib; PD180970; AG957; NSC 680410; PD173955; or Satinib (dasatinib); j) Protein kinase C (PKC) targeting serine/threonine kinase and members of the Raf family, members of MEK, SRC, JAK, FAK, PDK1, PKB/Akt and Ras/ MAPK family members and/or members of the cyclin-dependent kinase family (CDK), compounds that reduce or inhibit their activity, such as staurosporine derivatives disclosed in U.S. Patent No. 5,093,330, such as midostauline; Examples of other compounds include UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; ilmofosine; RO 318220 and RO 320432 ; GO 6976; Isis 3521; LY333531/LY379196; isoquinoline compounds; farnesyl transferase inhibitors; PD184352 or QAN697 or AT7519; k) targeting egg White matter-tyrosine kinase, a compound that reduces or inhibits its activity, such as imatinib mesylate or tyrphostin, such as Tyfostin A23/RG-50810; AG 99; Tyfostin AG 213; Tyfostin AG 1748; Tyfostin AG 490; Tyfostin B44; Tyfostin B44 (+) enantiomer; Tyfostin AG 555; AG 494; Tyfostin AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-adamantyl benzoate; NSC 680410, adaphostin); 1) Compounds that target, reduce or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homodimers or heterodimers) and their mutants, such as CP 358774, ZD 1839, ZM 105180; trastuzumab, cetuximab, gefitinib, erlotinib, OSI-774, Cl-1033, EKB-569, GW-2016, Antibodies E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 and E7.6.3 and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; and Compounds that target, decrease or inhibit the activity of c-Met receptors.
靶向蛋白質或脂質磷酸酶、降低或抑制其活性之例示性化合物包括磷酸酶1抑制劑、磷酸酶2A抑制劑或CDC25抑制劑，諸如岡田井酸(okadaic acid)或其衍生物。Exemplary compounds that target protein or lipid phosphatase to reduce or inhibit its activity include phosphatase 1 inhibitors, phosphatase 2A inhibitors, or CDC25 inhibitors, such as okadaic acid or derivatives thereof.
其他抗血管生成化合物包括具有另一種與蛋白質或脂質激酶抑制不相關的針對其活性之機制的化合物，例如沙立度胺(thalidomide)及TNP-470。Other anti-angiogenic compounds include compounds that have another mechanism for their activity that is not related to protein or lipid kinase inhibition, such as thalidomide and TNP-470.
額外非限制性例示性化學治療性化合物包括：道諾黴素(daunorubicin)、阿德力黴素(adriamycin)、Ara-C、VP-16、替尼泊苷、米托蒽醌、艾達黴素(idarubicin)、卡鉑(carboplatinum)、PKC412、6-巰基嘌呤(6-MP)、磷酸氟達拉濱(fludarabine phosphate)、奧曲肽(octreotide)、SOM230、FTY720、6-硫鳥嘌呤、克拉屈濱(cladribine)、6-巰基嘌呤、噴司他丁(pentostatin)、羥基脲、2-羥基-lH-異吲哚-l,3-二酮衍生物、1-(4-氯苯胺基)-4-(4-吡啶基甲基)酞𠯤或其醫藥學上可接受之鹽、1-(4-氯苯胺基)-4-(4-吡啶基甲基)酞𠯤丁二酸鹽、血管生長抑素、內皮生長抑素、鄰胺基苯甲酸醯胺、ZD4190、ZD6474、SU5416、SU6668、貝伐單抗(bevacizumab)、rhuMAb、rhuFab、macugon；FLT-4抑制劑、FLT-3抑制劑、VEGFR-2 IgGI抗體、RPI 4610、貝伐單抗、卟吩姆鈉(porfimer sodium)、阿奈可他(anecortave)、曲安西龍(triamcinolone)、氫皮質酮、11-a-表氫化皮質醇、皮質酮、17a-羥基孕酮、皮質固酮、去氧皮質固酮、睪固酮、雌酮、地塞米松(dexamethasone)、膚輕鬆(fluocinolone)、植物生物鹼、激素化合物及/或拮抗劑、生物反應調節劑(諸如淋巴介質或干擾素)、反義寡核苷酸或寡核苷酸衍生物、shRNA及siRNA，該等化學治療性化合物中之一或多者可與本發明之化合物組合使用。Additional non-limiting exemplary chemotherapeutic compounds include: daunorubicin, adriamycin, Ara-C, VP-16, teniposide, mitoxantrone, adriamycin Idarubicin, carboplatinum, PKC412, 6-mercaptopurine (6-MP), fludarabine phosphate, octreotide, SOM230, FTY720, 6-thioguanine, cladra Cladribine, 6-mercaptopurine, pentostatin, hydroxyurea, 2-hydroxy-lH-isoindole-l,3-dione derivative, 1-(4-chloroanilino)- 4-(4-pyridylmethyl)phthalein or its pharmaceutically acceptable salt, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalein succinate, vascular Somatostatin, endostatin, anthranilamide, ZD4190, ZD6474, SU5416, SU6668, bevacizumab, rhuMAb, rhuFab, macugon; FLT-4 inhibitor, FLT-3 inhibitor , VEGFR-2 IgGI antibody, RPI 4610, bevacizumab, porfimer sodium, anecortave, triamcinolone, hydrocorticosterone, 11-a-epihydrocortex Alcohol, corticosterone, 17a-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, dexamethasone, fluocinolone, plant alkaloids, hormonal compounds and/or antagonists , Biological response modifiers (such as lymphatic mediators or interferons), antisense oligonucleotides or oligonucleotide derivatives, shRNA and siRNA, one or more of these chemotherapeutic compounds can be combined with the compound of the present invention Used in combination.
第二治療劑之其他實例包括但不限於：用於阿茲海默症之治療劑，諸如多奈哌齊(donepezil)及雷斯替明(rivastigmine)；用於帕金森氏病之治療劑，諸如L-DOPA/卡比多巴(carbidopa)、恩他卡朋(entacapone)、羅匹尼羅(ropinrole)、普拉克索(pramipexole)、溴麥角環肽(bromocriptine)、培高利特(pergolide)、三己芬迪(trihexephendyl)及金剛胺(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(mitoxantrone)；用於哮喘之治療劑，諸如沙丁胺醇(albuterol)及孟魯司特(montelukast)；用於治療精神分裂症之藥劑，諸如金普薩(zyprexa)、理斯必妥(risperdal)、思樂康(seroquel)及氟六氫吡啶醇；抗炎劑，諸如皮質類固醇、TNF阻斷劑、IL-1 RA、硫唑嘌呤、環磷醯胺及柳氮磺胺吡啶；免疫調節劑，包括免疫抑制劑，諸如環孢素、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、硫唑嘌呤及柳氮磺胺吡啶；神經營養因子，諸如乙醯膽鹼酯酶抑制劑、MAO抑制劑、干擾素、抗痙攣劑、離子通道阻斷劑、利魯唑(riluzole)或抗帕金森藥劑；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、鈣通道阻斷劑或士他汀(statin)；用於治療肝病之藥劑，諸如皮質類固醇、消膽胺、干擾素及抗病毒藥劑；用於治療血液病症之藥劑，諸如皮質類固醇、抗白血病藥劑或生長因子；或用於治療免疫缺乏病症之藥劑，諸如γ球蛋白，本發明化合物亦可組合該等第二治療劑中之一或多者。Other examples of the second therapeutic agent include, but are not limited to: therapeutic agents for Alzheimer's disease, such as donepezil and rivastigmine; therapeutic agents for Parkinson's disease, such as L- DOPA/carbidopa, entacapone, ropinrole, pramipexole, bromocriptine, pergolide, three Trihexephendyl and amantadine; agents for the treatment of multiple sclerosis (MS), such as beta interferon (e.g. AVONEX® and REBIF®), glatiramer acetate and mitoxant Quinone (mitoxantrone); therapeutic agents for asthma, such as albuterol and montelukast; agents for treating schizophrenia, such as zyprexa, risperdal , Seroquel and fluorohexahydropyridinol; anti-inflammatory agents, such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazine; immunomodulators, Including immunosuppressants such as cyclosporine, tacrolimus, rapamycin, mycophenolate mofetil, interferon, corticosteroids, cyclophosphamide, azathioprine and sulfasalazine Pyridine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, ion channel blockers, riluzole or antiparkinsonian agents; used in the treatment of cardiovascular Drugs for diseases, such as beta blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers or statins; drugs for the treatment of liver diseases, such as corticosteroids, cholestyramine, interferon and Antiviral agents; agents for the treatment of blood disorders, such as corticosteroids, anti-leukemia agents or growth factors; or agents for the treatment of immune deficiency disorders, such as gamma globulin, the compound of the present invention can also be combined with these second therapeutic agents One or more of them.
上述第二治療活性劑如此項技術中所描述來製備及投與，該等第二治療活性劑中之一或多者可與本發明之化合物組合使用。The above-mentioned second therapeutically active agent is prepared and administered as described in this technique, and one or more of the second therapeutically active agents can be used in combination with the compound of the present invention.
本發明化合物通常與針對既定投與途徑及標準醫藥學慣例選擇之醫藥學載劑混合投與。根據本發明供使用之醫藥組合物以習知方式使用一或多種生理學上可接受之載劑進行調配，該等生理學上可接受之載劑包含有助於本發明化合物之加工的賦形劑及/或助劑。The compound of the present invention is usually mixed and administered with a pharmaceutical carrier selected for the established route of administration and standard pharmaceutical practice. The pharmaceutical composition for use according to the present invention is formulated in a conventional manner using one or more physiologically acceptable carriers, which include excipients that facilitate the processing of the compounds of the present invention Agent and/or adjuvant.
此等醫藥組合物可例如藉由習知混合、溶解、成粒、糖衣錠形成、乳化、囊封、包覆或凍乾過程來製造。適當之調配物視所選擇之投與途徑而定。當經口投與治療有效量之本發明之化合物時，組合物通常呈錠劑、膠囊、散劑、溶液或酏劑之形式。當以錠劑形式投與時，組合物另外可含有固體載劑，諸如明膠或佐劑。錠劑、膠囊及粉劑含有約0.01%至約95%，且較佳地約1%至約50%之本發明化合物。當以液體形式投與時，可添加液體載劑，諸如水、石油或動植物來源的油。液體形式之組合物可進一步含有生理鹽水溶液、右旋糖或其他醣溶液或二醇。當以液體形式投與時，組合物含有約0.1重量%至約90重量%，且較佳約1重量%至約50重量%之本發明之化合物。These pharmaceutical compositions can be manufactured, for example, by conventional mixing, dissolution, granulation, dragee formation, emulsification, encapsulation, coating, or freeze-drying processes. The appropriate formulation depends on the chosen route of administration. When a therapeutically effective amount of the compound of the present invention is administered orally, the composition is usually in the form of a lozenge, capsule, powder, solution or elixir. When administered in the form of a lozenge, the composition may additionally contain a solid carrier such as gelatin or an adjuvant. Tablets, capsules and powders contain about 0.01% to about 95%, and preferably about 1% to about 50% of the compound of the present invention. When administered in liquid form, a liquid carrier may be added, such as water, petroleum, or oil of animal and vegetable origin. The composition in liquid form may further contain physiological saline solution, dextrose or other sugar solutions or glycols. When administered in liquid form, the composition contains about 0.1% to about 90% by weight, and preferably about 1% to about 50% by weight of the compound of the present invention.
當藉由靜脈內、皮膚或皮下注射投與治療有效量之本發明之化合物時，組合物呈無熱原質、非經腸可接受之水溶液形式。適當考慮pH、等張性、穩定性及其類似者製備此類非經腸可接受溶液在此項技術之技能範圍內。用於靜脈內、皮膚或皮下注射之較佳組合物通常含有等張媒劑。When a therapeutically effective amount of the compound of the present invention is administered by intravenous, skin or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. Properly considering pH, isotonicity, stability and the like to prepare such parenterally acceptable solutions is within the skill range of this technology. Preferred compositions for intravenous, dermal or subcutaneous injection usually contain isotonic vehicles.
本發明之化合物可易於與此項技術中熟知的醫藥學上可接受之載劑組合。標準醫藥學載劑描述於Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 第19版.1995中。此類載劑實現將本發明化合物調配為用於待治療患者口服攝取之錠劑、丸劑、糖衣藥丸、膠囊、液體、凝膠、糖漿、漿料、懸浮液及其類似者。經口使用之醫藥製劑可藉由以下操作而獲得：將本發明化合物添加至賦形劑，視情況研磨所得混合物，且必要時在添加合適助劑之後加工顆粒之混合物以獲得錠劑或糖衣藥丸芯。適合的賦形劑包括例如填充劑及纖維素製劑。視需要，可添加崩解劑。The compounds of the present invention can be easily combined with pharmaceutically acceptable carriers well known in the art. Standard pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th edition. 1995. Such carriers enable the compound of the present invention to be formulated into tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like for oral ingestion by patients to be treated. Pharmaceutical preparations for oral use can be obtained by adding the compound of the present invention to excipients, grinding the resulting mixture as appropriate, and processing the mixture of granules after adding suitable auxiliaries, if necessary, to obtain lozenges or dragees core. Suitable excipients include, for example, fillers and cellulose preparations. If necessary, disintegrating agents can be added.
本發明化合物可經調配以藉由注射(例如藉由快速注射或連續輸注)而非經腸投與。注射用調配物可呈單位劑型，例如以安瓿或多劑量容器形式，其中添加有防腐劑。組合物可採取諸如於油性或水性媒劑中之懸浮液、溶液或乳液之形式，且可含有諸如懸浮劑、穩定劑及/或分散劑之調配劑。The compounds of the present invention may be formulated for administration by injection (e.g., by bolus injection or continuous infusion) rather than enteral administration. The formulations for injection may be in unit dosage form, for example in the form of ampoules or multi-dose containers, to which a preservative is added. The composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle, and may contain formulation agents such as suspending agents, stabilizers and/or dispersants.
用於非經腸投與之醫藥組合物包括水溶性形式之活性劑的水溶液。另外，可按適當油性注射懸浮液形式來製備本發明之化合物之懸浮液。適合之親脂性溶劑或媒劑包括脂肪油或合成脂肪酸酯。水性注射懸浮液可含有增加懸浮液之黏度的物質。視情況，懸浮液亦可含有適合的穩定劑或增加化合物溶解性且允許製備高度濃縮溶液之藥劑。或者，本發明之組合物可呈粉末形式，以便在使用前用適合之媒劑(例如無菌無熱原質水)復原。The pharmaceutical composition for parenteral administration includes an aqueous solution of the active agent in water-soluble form. In addition, suspensions of the compounds of the present invention can be prepared in the form of appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound and allow the preparation of highly concentrated solutions. Alternatively, the composition of the present invention may be in powder form for reconstitution with a suitable vehicle (for example, sterile pyrogen-free water) before use.
本發明之化合物亦可調配於直腸組合物中，諸如例如含有習知栓劑基質之栓劑或保留灌腸劑。除先前所描述調配物以外，本發明化合物亦可經調配為貯存製劑。此類長效調配物可藉由植入(例如皮下或肌肉內)或藉由肌肉內注射來投與。因此，舉例而言，本發明化合物可經調配有合適之聚合物或疏水性材料(例如作為呈可接受油狀之乳液)或離子交換樹脂。The compounds of the present invention may also be formulated in rectal compositions, such as, for example, suppositories or retention enemas containing conventional suppository bases. In addition to the formulations described previously, the compounds of the present invention can also be formulated as depot preparations. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present invention can be formulated with suitable polymers or hydrophobic materials (for example as an emulsion in the form of an acceptable oil) or ion exchange resins.
特定言之，本發明之化合物可以含有賦形劑(諸如澱粉或乳糖)之錠劑的形式、或以膠囊或卵形栓劑形式(單獨或與賦形劑摻合)或呈含有調味劑或著色劑之酏劑或懸浮液形式經口、頰內或舌下投與。此類液體製劑可用醫藥學上可接受之添加劑，諸如懸浮劑製備。本發明之化合物亦可非經腸注射，例如靜脈內、肌肉內、皮下或冠狀動脈內注射。對於非經腸投與，本發明之化合物通常以可含有其他物質之無菌水溶液的形式使用以製得與血液等張之溶液，該等其他物質例如鹽或單醣，諸如甘露醇或葡萄糖。In particular, the compounds of the present invention may be in the form of tablets containing excipients (such as starch or lactose), or in the form of capsules or oval suppositories (alone or in admixture with excipients), or in the form of flavoring or coloring agents. The drug is administered in the form of an elixir or suspension orally, intrabuccally or sublingually. Such liquid preparations can be prepared with pharmaceutically acceptable additives, such as suspending agents. The compounds of the present invention can also be injected parenterally, such as intravenous, intramuscular, subcutaneous or intracoronary injection. For parenteral administration, the compounds of the present invention are usually used in the form of a sterile aqueous solution that may contain other substances, such as salts or monosaccharides, such as mannitol or glucose, to prepare solutions that are isotonic with blood.
本發明提供與治療個體之疾病有關之以下特定實施例。The present invention provides the following specific examples related to the treatment of individual diseases.
實施例1.一種治療有需要之個體的方法，該方法包含向該個體投與治療有效量之本發明化合物，其中該個體患有癌症。Example 1. A method of treating an individual in need, the method comprising administering to the individual a therapeutically effective amount of a compound of the invention, wherein the individual has cancer.
實施例2.如實施例1之方法，其中該癌症為表2之癌症中之任何一或多者。Embodiment 2. The method of embodiment 1, wherein the cancer is any one or more of the cancers in Table 2.
實施例3.如實施例2之方法，其中該癌症為血液癌。Embodiment 3. The method of embodiment 2, wherein the cancer is blood cancer.
實施例4.如實施例3之方法，其中該血液癌為表3之癌症中之任何一或多者。Embodiment 4. The method of embodiment 3, wherein the blood cancer is any one or more of the cancers in Table 3.
實施例5.如實施例1至4中任一項之方法，其進一步包含投與適用於治療癌症之治療有效量之第二治療劑。Embodiment 5. The method of any one of embodiments 1 to 4, further comprising administering a therapeutically effective amount of a second therapeutic agent suitable for treating cancer.
實施例6.一種醫藥組合物，其包含本發明化合物及醫藥學上可接受之載劑，其用於治療癌症。Example 6. A pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier, which is used for the treatment of cancer.
實施例7.如實施例6之醫藥組合物，其中該癌症為表2之癌症中之任何一或多者。Embodiment 7. The pharmaceutical composition of embodiment 6, wherein the cancer is any one or more of the cancers in Table 2.
實施例8.如實施例7之醫藥組合物，其中該癌症為血液癌。Embodiment 8. The pharmaceutical composition of embodiment 7, wherein the cancer is blood cancer.
實施例9.如實施例8之醫藥組合物，其中該血液癌為表3之癌症中之任何一或多者。Embodiment 9. The pharmaceutical composition of embodiment 8, wherein the blood cancer is any one or more of the cancers in Table 3.
實施例10.一種本發明之化合物，其用於治療癌症。Example 10. A compound of the invention for use in the treatment of cancer.
實施例11.如實施例10之化合物，其中該癌症為表2之癌症中之任何一或多者。Embodiment 11. The compound of embodiment 10, wherein the cancer is any one or more of the cancers in Table 2.
實施例12.如實施例11之化合物，其中該癌症為血液癌。Embodiment 12. The compound of embodiment 11, wherein the cancer is blood cancer.
實施例13.如實施例12之化合物，其中該血液癌為表3之癌症中之任何一或多者。Embodiment 13. The compound of embodiment 12, wherein the blood cancer is any one or more of the cancers in Table 3.
實施例14.一種本發明之化合物之用途，其用於製造用於治療癌症之藥劑。Example 14. The use of a compound of the present invention for the manufacture of a medicament for the treatment of cancer.
實施例15.如實施例14之化合物，其中該癌症為表2之癌症中之任何一或多者。Embodiment 15. The compound of embodiment 14, wherein the cancer is any one or more of the cancers in Table 2.
實施例16.如實施例15之用途，其中該癌症為血液癌。Embodiment 16. The use as in embodiment 15, wherein the cancer is blood cancer.
實施例17.如實施例16之用途，其中該血液癌為表3之癌症中之任何一或多者。Embodiment 17. The use as in embodiment 16, wherein the blood cancer is any one or more of the cancers in Table 3.
在另一實施例中，本發明提供包含本發明化合物(或包含本發明化合物之組合物)之套組，該等套組以有助於其用以實踐本發明之方法的方式進行封裝。在一個實施例中，套組包括封裝於諸如密封瓶或器皿之容器中之本發明化合物(或包含本發明化合物之組合物)，其中描述化合物或組合物實踐本發明之方法之用途的標籤貼附於容器或包括於套組中。在一個實施例中，該化合物或組合物以單位劑型封裝。套組進一步可包括適用於根據預期投與途徑投與組合物之裝置。In another embodiment, the invention provides kits comprising the compounds of the invention (or compositions comprising the compounds of the invention), which are packaged in a way that facilitates their use in practicing the methods of the invention. In one embodiment, the kit includes a compound of the present invention (or a composition containing the compound of the present invention) packaged in a container such as a sealed bottle or vessel, wherein a label describing the use of the compound or composition to practice the method of the present invention Attached to the container or included in the set. In one embodiment, the compound or composition is packaged in unit dosage form. The kit may further include devices suitable for administering the composition according to the intended route of administration.
為了促進對本發明的理解，在下文中定義多個術語及片語。In order to promote the understanding of the present invention, a number of terms and phrases are defined below.
在本發明中，如單獨或作為另一基團之部分使用，術語「鹵基」係指-Cl、-F、-Br或-I。In the present invention, when used alone or as part of another group, the term "halo" refers to -Cl, -F, -Br, or -I.
在本發明中，如單獨或作為另一基團之部分使用，術語「硝基」係指-NO2 。In the present invention, when used alone or as part of another group, the term "nitro" refers to -NO 2 .
在本發明中，如單獨或作為另一基團之部分使用，術語「氰基」係指-CN。In the present invention, when used alone or as part of another group, the term "cyano" refers to -CN.
在本發明中，如單獨或作為另一基團之部分使用，術語「羥基」係指-OH。In the present invention, the term "hydroxyl" refers to -OH when used alone or as part of another group.
在本發明中，如單獨或作為另一基團之部分使用，術語「烷基」係指含有以下各者之未經取代的直鏈或支鏈脂族烴：一個至十二個碳原子，亦即C1 - 12 烷基或C1 -C12 烷基；或指定碳原子數目，例如諸如甲基之C1 烷基、諸如乙基之C2 烷基、諸如丙基或異丙基之C3 烷基、諸如甲基、乙基、丙基或異丙基之C1 - 3 烷基等。在一個實施例中，烷基為C1 - 10 烷基。在另一實施例中，烷基為C1 - 6 烷基。在另一實施例中，烷基為C1 - 4 烷基。在另一實施例中，烷基為直鏈C1-10 烷基。在另一實施例中，烷基為支鏈C3 - 10 烷基。在另一實施例中，烷基為直鏈C1 - 6 烷基。在另一實施例中，烷基為支鏈C3 - 6 烷基。在另一實施例中，烷基為直鏈C1 - 4 烷基。在另一實施例中，烷基為直鏈C3-4 烷基。在另一實施例中，烷基為直鏈或支鏈C3 - 4 烷基。非限制性例示性C1 - 10 烷基包括：甲基、乙基、丙基、異丙基、丁基、第二丁基、第三丁基、異丁基、3-戊基、己基、庚基、辛基、壬基及癸基。非限制性例示性C1 - 4 烷基包括甲基、乙基、丙基、異丙基、丁基、第二丁基、第三丁基及異丁基。In the present invention, when used alone or as part of another group, the term "alkyl" refers to an unsubstituted linear or branched aliphatic hydrocarbon containing one to twelve carbon atoms, i.e., C 1 - 12 alkyl or C 1 -C 12 alkyl group; or a specified number of carbon atoms, e.g. methyl groups such as C 1 alkyl group, the C 2 alkyl group such as ethyl, propyl or isopropyl, such as the C 3 alkyl, such as methyl, ethyl, propyl or isopropyl group of C 1 - 3 alkyl group and the like. In one embodiment, the alkyl group is C 1 - 10 alkyl. In another embodiment embodiment, alkyl is C 1 - 6 alkyl. In another embodiment embodiment, alkyl is C 1 - 4 alkyl. In another embodiment, the alkyl group is a straight chain C 1-10 alkyl group. In another embodiment, the alkyl is a branched C 3 - 10 alkyl. In another embodiment embodiment, alkyl is a straight-chain C 1 - 6 alkyl. In another embodiment, the alkyl is a branched C 3 - 6 alkyl. In another embodiment embodiment, alkyl is a straight-chain C 1 - 4 alkyl. In another embodiment, the alkyl group is a linear C3-4 alkyl group. In another embodiment embodiment, alkyl is a straight-chain or branched C 3 - 4 alkyl. Non-limiting examples of exemplary C 1 - 10 alkyl groups include: methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, 3-pentyl, hexyl, Heptyl, octyl, nonyl and decyl. Non-limiting examples of exemplary C 1 - 4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and isobutyl.
在本發明中，如單獨或作為另一基團之部分使用，術語「視情況經取代之烷基」係指未經取代或經獨立地選自由以下組成之群中之一個、兩個或三個取代基取代的烷基：硝基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、磺醯胺基、烷羰基、芳基羰基、烷基磺醯基、芳基磺醯基、羧基、羧基烷基及烷基羰氧基。在一個實施例中，視情況經取代之烷基經兩個取代基取代。在另一實施例中，視情況經取代之烷基經一個取代基取代。在另一實施例中，視情況經取代之烷基未經取代。非限制性例示性經取代之烷基包括-CH2 CH2 NO2 、-CH2 SO2 CH3 、CH2 CH2 SO2 CH3 ,-CH2 CH2 CO2 H、-CH2 SCH3 、-CH2 CH2 SO2 CH3 、-CH2 CH2 COPh及-CH2 OC(=O)CH3 。In the present invention, when used alone or as part of another group, the term "optionally substituted alkyl" means unsubstituted or independently selected from one, two or three of the following groups: Alkyl groups substituted by one substituent: nitro, haloalkoxy, aryloxy, aralkoxy, alkylthio, sulfonamide, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl An acyl group, a carboxy group, a carboxyalkyl group and an alkylcarbonyloxy group. In one embodiment, the optionally substituted alkyl group is substituted with two substituents. In another embodiment, the optionally substituted alkyl group is substituted with a substituent. In another embodiment, optionally substituted alkyl is unsubstituted. Non-limiting exemplary substituted alkyl groups include -CH 2 CH 2 NO 2 , -CH 2 SO 2 CH 3 , CH 2 CH 2 SO 2 CH 3 , -CH 2 CH 2 CO 2 H, -CH 2 SCH 3 , -CH 2 CH 2 SO 2 CH 3 , -CH 2 CH 2 COPh and -CH 2 OC(=O)CH 3 .
在本發明中，如單獨或作為另一基團之部分使用，術語「環烷基」係指含有一個至三個具有三個至十二個碳原子(亦即C3 - 12 環烷基)或指定碳數目之環的未經取代之飽和或部分不飽和(例如含有一個或兩個雙鍵)環脂族烴。在一個實施例中，環烷基具有兩個環。在另一實施例中，環烷基具有一個環。在另一實施例中，環烷基為飽和的。在另一實施例中，環烷基為不飽和的。在另一實施例中，環烷基為C3 - 8 環烷基。在另一實施例中，環烷基為C3 - 6 環烷基。術語「環烷基」意欲包括其中環-CH2 -經-C(=O)-置換之基團。非限制性例示性環烷基包括環丙基、環丁基、環戊基、環己基、環庚基、環辛基、降冰片烷基、十氫萘、金剛烷基、環己烯基、環戊烯基及環戊酮。In the present invention, as used alone or as part of another group, the term "cycloalkyl" means containing one to three having three to twelve carbon atoms (i.e., C 3 - 12 cycloalkyl) Or an unsubstituted saturated or partially unsaturated (for example, containing one or two double bonds) cycloaliphatic hydrocarbon of a ring with a specified number of carbons. In one embodiment, the cycloalkyl group has two rings. In another embodiment, the cycloalkyl has one ring. In another embodiment, the cycloalkyl group is saturated. In another embodiment, the cycloalkyl group is unsaturated. In another embodiment, the cycloalkyl is a C 3 - 8 cycloalkyl. In another embodiment, the cycloalkyl is C 3 - 6 cycloalkyl group. The term "cycloalkyl" is intended to include those in which a ring -CH 2 - by -C (= O) - group Swap. Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, Cyclopentenyl and cyclopentanone.
在本發明中，如單獨或作為另一基團之部分使用，術語「視情況經取代之環烷基」係指未經取代或經一個、兩個或三個獨立地選自由以下組成之群的取代基取代之環烷基：鹵基、硝基、氰基、羥基、烷基羰氧基、環烷基羰氧基、胺基、鹵烷基、羥基烷基、烷氧基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷基羰基、芳基羰基、烷基磺醯基、芳基磺醯基、羧基、羧基烷基、視情況經取代之烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基、視情況經取代之雜環基、烷氧基烷基、(胺基)烷基、(甲醯胺基)烷基、(雜環)烷基、-OC(=O)-胺基、-N(R19a )C(=O)-R19b 及-N(R20a )SO2 -R20b ， 其中R19a 係選自由氫及烷基組成之群，R19b 係選自由胺基、烷氧基、烷基及視情況經取代之芳基組成之群，R20a 係選自由氫及烷基組成之群，且R20b 係選自由胺基、烷基及視情況經取代之芳基組成之群。術語視情況經取代之環烷基包括具有稠合視情況經取代之芳基，例如苯基或融合視情況經取代之雜芳基，例如吡啶基的環烷基。具有稠合視情況經取代之芳基或稠合視情況經取代之雜芳基的視情況經取代之環烷基可連接至分子之其餘部分，在環烷基環上之任何可用碳原子處。在一個實施例中，視情況經取代之環烷基經兩個取代基取代。在另一實施例中，視情況經取代之環烷基經一個取代基取代。在另一實施例中，視情況經取代之環烷基未經取代。In the present invention, when used alone or as part of another group, the term "optionally substituted cycloalkyl" refers to unsubstituted or one, two or three independently selected from the group consisting of Cycloalkyl substituted by the substituent: halo, nitro, cyano, hydroxy, alkylcarbonyloxy, cycloalkylcarbonyloxy, amine, haloalkyl, hydroxyalkyl, alkoxy, haloalkane Oxy, aryloxy, aralkoxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxyl, carboxyalkane Group, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic group , Alkoxyalkyl, (amino)alkyl, (formamido)alkyl, (heterocyclic)alkyl, -OC(=O)-amino, -N(R 19a )C(=O )-R 19b and -N(R 20a )SO 2 -R 20b , where R 19a is selected from the group consisting of hydrogen and alkyl, and R 19b is selected from the group consisting of amino, alkoxy, alkyl and optionally substituted R 20a is selected from the group consisting of hydrogen and alkyl groups, and R 20b is selected from the group consisting of amino groups, alkyl groups and optionally substituted aryl groups. The term optionally substituted cycloalkyl includes cycloalkyl groups having fused optionally substituted aryl groups, such as phenyl or fused optionally substituted heteroaryl groups, such as pyridyl. An optionally substituted cycloalkyl group with a fused optionally substituted aryl group or a fused optionally substituted heteroaryl group can be attached to the rest of the molecule at any available carbon atom on the cycloalkyl ring . In one embodiment, the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with a substituent. In another embodiment, optionally substituted cycloalkyl is unsubstituted.
在本發明中，如單獨或作為另一基團之部分使用，術語「芳基」係指具有六個至十四個碳原子之未經取代的單環或雙環芳環系統，亦即C6 - 14 芳基。非限制性的例示性芳基包括苯基(縮寫為「Ph」)、萘基、菲基、蒽基、茚基、薁基、聯苯基、伸聯苯基及茀基。在一個實施例中，芳基為苯基或萘基。In the present invention, when used alone or as part of another group, the term "aryl" refers to an unsubstituted monocyclic or bicyclic aromatic ring system with six to fourteen carbon atoms, that is, C 6 --14 aryl group. Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracenyl, indenyl, azulenyl, biphenyl, biphenyl, and stilbyl. In one embodiment, the aryl group is phenyl or naphthyl.
在本發明中，本身或作為另一基團之一部分的如本文所用之術語「視情況經取代之芳基」係指未經取代或經一至五個獨立地選自由以下組成之群的取代基取代之芳基：鹵基、硝基、氰基、羥基、胺基、烷胺基、二烷胺基、視情況經取代之烷基、鹵烷基、羥烷基、烷氧基、鹵烷氧基、芳基氧基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷基羰基、芳基羰基、烷基磺醯基、鹵烷基磺醯基、環烷基磺醯基、(環烷基)烷基磺醯基、芳磺醯基、雜芳基磺醯基、雜環磺醯基、羧基、羧基烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基、視情況經取代之雜環、烷氧基羰基、烷氧基烷基、(胺基)烷基、(甲醯胺基)烷基及(雜環)烷基。In the present invention, the term "optionally substituted aryl" as used herein by itself or as part of another group refers to unsubstituted or one to five substituents independently selected from the group consisting of Substituted aryl groups: halo, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, optionally substituted alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkane Oxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkane Sulfonyl, (cycloalkyl) alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, heterocyclic sulfonyl, carboxyl, carboxyalkyl, optionally substituted cycloalkyl, alkene Group, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxycarbonyl, alkoxyalkyl, (amino)alkyl, (methyl) Amino) alkyl and (heterocyclic) alkyl.
在一個實施例中，視情況經取代之芳基為視情況經取代之苯基。在另一實施例中，視情況經取代之苯基具有四個取代基。在另一實施例中，視情況經取代之苯基具有三個取代基。在另一實施例中，視情況經取代之苯基具有兩個取代基。在另一實施例中，視情況經取代之苯基具有一個取代基。在另一實施例中，視情況經取代之苯基為未經取代的。非限制性例示性經取代之芳基包括：2-甲基苯基、2-甲氧基苯基、2-氟苯基、2-氯苯基、2-溴苯基、3-甲基苯基、3-甲氧基苯基、3-氟苯基、3-氯苯基、4-甲基苯基、4-乙基苯基、4-甲氧基苯基、4-氟苯基、4-氯苯基、2,6-二氟苯基、2,6-二氯苯基、2-甲基,3-甲氧基苯基、2-乙基,3-甲氧基苯基、3,4-二甲氧基苯基、3,5-二氟苯基、3,5-二甲基苯基、3,5-二甲氧基、4-甲基苯基、2-氟-3-氯苯基、3-氯-4-氟苯基、4-(吡啶-4-基磺醯基)苯基。術語視情況經取代之芳基包括具有稠合視情況經取代之環烷基或稠合視情況經取代之雜環基之苯基。具有稠合視情況經取代之環烷基或稠合視情況經取代之雜環基的視情況經取代之苯基可連接至分子之其餘部分，在苯環上之任何可用碳原子處。非限制性實例包括：
在本發明中，如單獨或作為另一基團之部分使用，術語「烯基」係指含有一個、兩個或三個碳-碳雙鍵之烷基。在一個實施例中，烯基具有一個碳-碳雙鍵。在另一實施例中，烯基為C2 - 6 烯基。在另一實施例中，烯基為C2 - 4 烯基。非限制性例示性烯基包括乙烯基、丙烯基、異丙烯基、丁烯基、第二丁烯基、戊烯基及己烯基。In the present invention, when used alone or as part of another group, the term "alkenyl" refers to an alkyl group containing one, two or three carbon-carbon double bonds. In one embodiment, the alkenyl group has a carbon-carbon double bond. In another embodiment, the alkenyl is C 2 - 6 alkenyl group. In another embodiment, the alkenyl is C 2 - 4 alkenyl group. Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, second butenyl, pentenyl, and hexenyl.
在本發明中，如在本文中由其本身或作為另一基團之部分使用，術語「視情況經取代之烯基」係指未經取代或經獨立地選自由以下組成之群之一個、兩個或三個取代基取代的烯基：鹵基、硝基、氰基、羥基、胺基、烷基胺基、二烷基胺基、鹵烷基、羥烷基、烷氧基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷羰基、芳基羰基、烷基磺醯基、芳基磺醯基、羧基、羧基烷基、視情況經取代之烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、雜芳基及視情況經取代之雜環。In the present invention, as used herein by itself or as part of another group, the term "optionally substituted alkenyl" means unsubstituted or independently selected from one of the group consisting of, Alkenyl substituted with two or three substituents: halo, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, halo Alkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxyl, carboxyalkane Group, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, heteroaryl and optionally substituted heterocycle.
在本發明中，如單獨或作為另一基團之部分使用，術語「炔基」係指含有一個至三個碳-碳參鍵之烷基。在一個實施例中，炔基具有一個碳-碳參鍵。在另一實施例中，炔基為C2 - 6 炔基。在另一實施例中，炔基為C2 - 4 炔基。非限制性例示性炔基包括乙炔基、丙炔基、丁炔基、2-丁炔基、戊炔基及己炔基。In the present invention, when used alone or as part of another group, the term "alkynyl" refers to an alkyl group containing one to three carbon-carbon bonds. In one embodiment, the alkynyl group has a carbon-carbon reference bond. In another embodiment, an alkynyl group is a C 2 - 6 alkynyl group. In another embodiment, an alkynyl group is a C 2 - 4 alkynyl group. Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl.
在本發明中，如在本文中單獨或作為部分使用，術語「視情況經取代之炔基」係指未經取代或經獨立地選自由以下各者組成之群中之一個、兩個或三個取代基取代的炔基：鹵基、硝基、氰基、羥基、胺基、烷胺基、二烷胺基、鹵烷基、羥基烷基、烷氧基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷基羰基、芳基羰基、烷磺醯基、芳磺醯基、羧基、羧基烷基、視情況經取代之烷基、環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基及雜環。In the present invention, the term "optionally substituted alkynyl" as used herein alone or as part means unsubstituted or independently selected from one, two or three of the following groups: Alkynyl substituted by a substituent: halo, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy Group, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkanesulfonyl, arylsulfonyl, carboxy, carboxyalkyl, optionally substituted Alkyl, cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl and heterocycle.
在本發明中，如單獨或作為另一基團之部分使用，術語「鹵烷基」係指經一或多個氟、氯、溴及/或碘原子取代之烷基。在一個實施例中，烷基經一個、兩個或三個氟及/或氯原子取代。在另一實施例中，鹵基烷基為C1 - 4 鹵烷基。非限制性例示性鹵烷基包括氟甲基、2-氟乙基、二氟甲基、三氟甲基、五氟乙基、1,1-二氟乙基、2,2-二氟乙基、2,2,2-三氟乙基、3,3,3-三氟丙基、4,4,4-三氟丁基及三氯甲基。In the present invention, when used alone or as part of another group, the term "haloalkyl" refers to an alkyl group substituted with one or more fluorine, chlorine, bromine and/or iodine atoms. In one embodiment, the alkyl group is substituted with one, two or three fluorine and/or chlorine atoms. In another embodiment, the haloalkyl is C 1 - 4 haloalkyl. Non-limiting exemplary haloalkyl groups include fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl Group, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and trichloromethyl.
在本發明中，如單獨或作為另一基團之部分使用，術語「羥烷基」係指經一個、兩個或三個羥基取代之烷基。在一個實施例中，羥烷基為單羥烷基，亦即經一個羥基取代之羥烷基。在另一實施例中，羥烷基為二羥烷基，亦即經兩個羥基取代之羥烷基。非限制性例示性羥烷基包括羥甲基、羥乙基、羥丙基及羥丁基，諸如1-羥乙基、2-羥乙基、1,2-二羥乙基、2-羥丙基、3-羥丙基、3-羥丁基、4-羥丁基、2-羥基-1-甲基丙基及1,3-二羥丙-2-基。In the present invention, when used alone or as part of another group, the term "hydroxyalkyl" refers to an alkyl group substituted with one, two or three hydroxy groups. In one embodiment, the hydroxyalkyl group is a monohydroxyalkyl group, that is, a hydroxyalkyl group substituted with one hydroxy group. In another embodiment, the hydroxyalkyl group is a dihydroxyalkyl group, that is, a hydroxyalkyl group substituted with two hydroxy groups. Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, and hydroxybutyl, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxy Propyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl and 1,3-dihydroxyprop-2-yl.
在本發明中，如單獨或作為另一基團之部分使用，術語「(環烷基)烷基」係指經情況經取代之環烷基取代之烷基。在一個實施例中，(環烷基)烷基為「(C3 - 6
環烷基)C1 - 4
烷基」，亦即經視情況經取代之C3 - 6
環烷基取代之C1 - 4
烷基。非限制性例示性(環烷基)烷基包括：
在本發明中，如單獨或作為另一基團之部分使用，術語「烷磺醯基」係指磺醯基，亦即經視情況經取代之烷基取代之-SO2 -。在一個實施例中，烷基為C1 - 6 烷基。在另一實施例中，烷基為C1 - 4 烷基。非限制性例示性烷基磺醯基為-SO2 CH3 。In the present invention, when used alone or as part of another group, the term "alkylsulfonyl" refers to a sulfonyl, that is, -SO 2 -substituted with optionally substituted alkyl. In one embodiment, the alkyl group is C 1 - 6 alkyl. In another embodiment embodiment, alkyl is C 1 - 4 alkyl. A non-limiting exemplary alkylsulfonyl group is -SO 2 CH 3 .
在本發明中，如單獨或作為另一基團之部分使用，術語「鹵烷磺醯基」係指磺醯基，亦即經鹵烷基取代之-SO2 -。非限制性例示性烷基磺醯基為-SO2 CF3 。In the present invention, when used alone or as part of another group, the term "haloalkanesulfonyl" refers to a sulfonyl group, that is, -SO 2 -substituted by a haloalkyl group. A non-limiting exemplary alkylsulfonyl group is -SO 2 CF 3 .
在本發明中，如單獨或作為另一基團之部分使用，術語「環烷基磺醯基」係指經視情況經取代之環烷基取代之磺醯基，亦即-SO2 -。非限制性例示性烷基磺醯基包括-SO2 -環丙基及-SO2 -環戊基。In the present invention, when used alone or as part of another group, the term "cycloalkylsulfonyl" refers to a sulfonyl group substituted with optionally substituted cycloalkyl, that is, -SO 2 -. Non-limiting exemplary alkylsulfonyl groups include -SO 2 -cyclopropyl and -SO 2 -cyclopentyl.
在本發明中，如單獨或作為另一基團之部分使用，術語「(環烷基)烷基磺醯基」係指經(環烷基)烷基取代之磺醯基，亦即-SO2
-。非限制性例示性(環烷基)烷基磺醯基包括：
在本發明中，如單獨或作為另一基團之部分使用，術語「芳基磺醯基」係指經視情況經取代之芳基取代之磺醯基，亦即-SO2 -。非限制性例示性芳基磺醯基為−SO2 Ph。In the present invention, as used alone or as part of another group, the term "arylsulfonyl" refers to a sulfonyl group substituted with an optionally substituted aryl group, that is, -SO 2 -. A non-limiting exemplary arylsulfonyl group is −SO 2 Ph.
在本發明中，如單獨或作為另一基團之部分使用，術語「雜芳基磺醯基」係指經視情況經取代之雜芳基取代之磺醯基，亦即-SO2
-。非限制性例示性雜芳基磺醯基包括：
在本發明中，如單獨或作為另一基團之部分使用，術語「雜環磺醯基」係指經情況經取代之雜環基取代之磺醯基，亦即-SO2
-。非限制性例示性雜環磺醯基為：
在本發明中，如單獨或作為另一基團之部分使用，術語「磺醯胺基」係指式-SO2 NR21a R21b 之基團，其中R21a 及R21b 各自獨立地選自由以下組成之群：氫、視情況經取代之烷基及視情況經取代之芳基，或R21a 及R21b 與其所連接之氮一起來自3員至8員雜環基。非限制性例示性磺醯胺基包括-SO2 NH2 、-SO2 N(H)CH3 、-SO2 N(CH3 )2 及-SO2 N(H)Ph。In the present invention, when used alone or as part of another group, the term "sulfonamido" refers to a group of formula -SO 2 NR 21a R 21b , wherein R 21a and R 21b are each independently selected from the following Group of composition: hydrogen, optionally substituted alkyl and optionally substituted aryl, or R 21a and R 21b together with the nitrogen to which they are attached are from a 3- to 8-membered heterocyclic group. Non-limiting exemplary sulfonamide groups include -SO 2 NH 2 , -SO 2 N(H)CH 3 , -SO 2 N(CH 3 ) 2 and -SO 2 N(H)Ph.
在本發明中，如單獨或作為另一基團之部分使用，術語「烷氧基」係指與末端氧原子連接的視情況經取代之烷基、視情況經取代之環烷基、視情況經取代之烯基或視情況經取代之炔基。在一個實施例中，烷氧基為連接至末端氧原子之視情況經取代之烷基。在一個實施例中，烷氧基為連接至末端氧原子之C1 - 6 烷基。在另一實施例中，烷氧基為與末端氧原子連接之C1-4 烷基。非限制性例示性烷氧基包括甲氧基、乙氧基、第三丁氧基及-OCH2 SO2 CH3 。In the present invention, when used alone or as part of another group, the term "alkoxy" refers to optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted with a terminal oxygen atom Substituted alkenyl or optionally substituted alkynyl. In one embodiment, the alkoxy group is an optionally substituted alkyl group attached to a terminal oxygen atom. In one embodiment, the alkoxy is the oxygen atom is connected to the terminal C 1--6 alkyl. In another embodiment, the alkoxy group is a C 1-4 alkyl group attached to a terminal oxygen atom. Non-limiting exemplary alkoxy groups include methoxy, ethoxy, tert-butoxy, and -OCH 2 SO 2 CH 3 .
在本發明中，如單獨或作為另一基團之部分使用，術語「烷硫基」係指與末端硫原子連接之視情況經取代之烷基。在一個實施例中，烷硫基為C1-4 烷硫基。非限制性例示性烷硫基包括-SCH3 及-SCH2 CH3 。In the present invention, as used alone or as part of another group, the term "alkylthio" refers to an optionally substituted alkyl group attached to a terminal sulfur atom. In one embodiment, the alkylthio group is a C 1-4 alkylthio group. Non-limiting exemplary alkylthio groups include -SCH 3 and -SCH 2 CH 3 .
在本發明中，如單獨或作為另一基團之部分使用，術語「烷氧基烷基」係指經烷氧基取代之視情況選用的烷基。非限制性例示性烷氧烷基包括甲氧基甲基、甲氧基乙基、甲氧基丙基、甲氧基丁基、乙氧基甲基、乙氧基乙基、乙氧基丙基、乙氧基丁基、丙氧基甲基、異丙氧基甲基、丙氧基乙基、丙氧基丙基、丁氧基甲基、第三丁氧基甲基、異丁氧基甲基、第二丁氧基甲基及戊氧基甲基。In the present invention, when used alone or as part of another group, the term "alkoxyalkyl" refers to an optionally selected alkyl group substituted with an alkoxy group. Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl Group, ethoxybutyl, propoxymethyl, isopropoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tertiary butoxymethyl, isobutoxy Group methyl, second butoxymethyl and pentoxymethyl.
在本發明中，如單獨或作為另一基團之部分使用，術語「鹵烷氧基」係指與末端氧原子連接之鹵烷基。非限制性例示性鹵烷氧基包括：氟甲氧基、二氟甲氧基、三氟甲氧基以及2,2,2-三氟乙氧基。In the present invention, when used alone or as part of another group, the term "haloalkoxy" refers to a haloalkyl group attached to a terminal oxygen atom. Non-limiting exemplary haloalkoxy groups include: fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.
在本發明中，如單獨或作為另一基團之部分使用，術語「芳氧基」係指與末端氧原子連接之視情況經取代之芳基。非限制性例示性芳氧基為PhO-。In the present invention, as used alone or as part of another group, the term "aryloxy" refers to an optionally substituted aryl group attached to a terminal oxygen atom. A non-limiting exemplary aryloxy group is PhO-.
在本發明中，如單獨或作為另一基團之部分使用，術語「芳烷氧基」係指與末端氧原子連接之芳烷基。非限制性例示性芳烷氧基包括PhCH2 O-及PhCH2 CH2 O-。In the present invention, as used alone or as part of another group, the term "aralkyloxy" refers to an aralkyl group attached to a terminal oxygen atom. Non-limiting exemplary aralkoxy groups include PhCH 2 O- and PhCH 2 CH 2 O-.
在本發明中，術語「雜芳基」係指具有5至14個環原子之未經取代之單環及雙環芳族環系統，亦即5員至14員雜芳基，其中環中之一者之至少一個碳原子獨立地經選自由氧、氮及硫組成之群的雜原子置換。在一個實施例中，雜芳基含有獨立地選自由以下組成之群中之1個、2個、3個或4個雜原子：氧、氮及硫。在一個實施例中，雜芳基具有三個雜原子。在另一實施例中，雜芳基具有兩個雜原子。在另一實施例中，雜芳基具有一個雜原子。在另一實施例中，雜芳基為5員至10員雜芳基。在另一實施例中，雜芳基為5員或6員雜芳基。在另一實施例中，雜芳基具有5個環原子，例如噻吩基，一種具有四個碳原子及一個硫原子之5員雜芳基。在另一實施例中，雜芳基具有6個環原子，例如吡啶基，一種具有五個碳原子及一個氮原子之6員雜芳基。非限制性例示性雜芳基包括噻吩基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻嗯基、呋喃基、苯并呋喃基、吡喃基、異苯并呋喃基、苯并㗁酮基、𠳭烯基、𠮿基、2H -吡咯基、吡咯基、咪唑基、吡唑基、吡啶基、吡𠯤基、嘧啶基、噠𠯤基、異吲哚基、3H -吲哚基、吲哚基、吲唑基、嘌呤基、異喹啉基、喹啉基、酞𠯤基、㖠啶基、㖕啉基、喹唑啉基、喋啶基、4aH -咔唑基、咔唑基、β-咔啉基、啡啶基、吖啶基、嘧啶基、啡啉基、啡𠯤基、噻唑基、異噻唑基、苯并噻唑基、異㗁唑基、呋呫基及啡㗁𠯤基。在一個實施例中，雜芳基係選自由以下組成之群：噻吩基(例如，噻吩-2-基及噻吩-3-基)、呋喃基(例如，2-呋喃基及3-呋喃基)、吡咯基(例如，1H-吡咯-2-基及1H-吡咯-3-基)、咪唑基(例如，2H-咪唑-2-基及2H-咪唑-4-基)、吡唑基(例如，1H-吡唑-3-基、1H-吡唑-4-基及1H-吡唑-5-基)、吡啶基(例如，吡啶-2-基、吡啶-3-基及吡啶-4-基)、嘧啶基(例如，嘧啶-2-基、嘧啶-4-基及嘧啶-5-基)、噻唑基(例如，噻唑-2-基、噻唑-4-基及噻唑-5-基)、異噻唑基(例如，異噻唑-3-基、異噻唑-4-基及異噻唑-5-基)、㗁唑基(例如，㗁唑-2-基、㗁唑-4-基及㗁唑-5-基)及異㗁唑基(例如，異㗁唑-3-基、異㗁唑-4-基及異㗁唑-5-基)及吲唑基(例如1H-吲唑-3-基)。術語「雜芳基」亦意欲包括可能的N-氧化物。非限制性的例示性N-氧化物為吡啶基N-氧化物。In the present invention, the term "heteroaryl" refers to an unsubstituted monocyclic and bicyclic aromatic ring system with 5 to 14 ring atoms, that is, a 5-membered to 14-membered heteroaryl group, one of which is At least one of the carbon atoms is independently replaced by a heteroatom selected from the group consisting of oxygen, nitrogen and sulfur. In one embodiment, the heteroaryl group contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen, and sulfur. In one embodiment, the heteroaryl group has three heteroatoms. In another embodiment, the heteroaryl group has two heteroatoms. In another embodiment, the heteroaryl group has one heteroatom. In another embodiment, the heteroaryl group is a 5- to 10-membered heteroaryl group. In another embodiment, the heteroaryl group is a 5-membered or 6-membered heteroaryl group. In another embodiment, the heteroaryl group has 5 ring atoms, such as thienyl, a 5-membered heteroaryl group with four carbon atoms and one sulfur atom. In another embodiment, the heteroaryl group has 6 ring atoms, such as pyridyl, a 6-membered heteroaryl group with five carbon atoms and one nitrogen atom. Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thienyl, furyl, benzofuranyl, pyranyl, isophenyl Furanyl, benzoketone, alkenyl, pyrrolyl, 2 H -pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl, pyrimidinyl, pyridyl, isoindole Group, 3 H -indolyl, indolyl, indazolyl, purinyl, isoquinolinyl, quinolinyl, phthaloline, quinolinyl, quinolinyl, quinazolinyl, pteridine, 4a H -carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrinyl, phenanthrenyl, thiazolyl, isothiazolyl, benzothiazolyl, iso-a Azolyl, furanyl and phenacyl. In one embodiment, the heteroaryl group is selected from the group consisting of: thienyl (for example, thiophen-2-yl and thiophen-3-yl), furanyl (for example, 2-furyl and 3-furyl) , Pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g. , 1H-pyrazol-3-yl, 1H-pyrazol-4-yl and 1H-pyrazol-5-yl), pyridyl (for example, pyridin-2-yl, pyridin-3-yl and pyridine-4- Yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl and thiazol-5-yl) , Isothiazolyl (for example, isothiazol-3-yl, isothiazol-4-yl and isothiazol-5-yl), azolyl (for example, azol-2-yl, azol-4-yl and 㗁Azol-5-yl) and isoazolyl (e.g., isoazol-3-yl, isoazol-4-yl and isoazol-5-yl) and indazolyl (e.g. 1H-indazole-3 -base). The term "heteroaryl" is also intended to include possible N-oxides. A non-limiting exemplary N-oxide is pyridyl N-oxide.
在一個實施例中，雜芳基為5員或6員雜芳基。在一個實施例中，雜芳基為5員雜芳基，亦即雜芳基為具有5個環原子之單環芳環系統，其中環之至少一個碳原子經獨立地選自氮、氧及硫之雜原子置換。非限制性例示性5員雜芳基包括噻吩基、呋喃基、吡咯基、㗁唑基、吡唑基、咪唑基、噻唑基、異噻唑基及異㗁唑基。在另一實施例中，雜芳基為6員雜芳基，例如雜芳基為具有6個環原子之單環芳環系統，其中環之至少一個碳原子經氮原子替換。非限制性例示性6員雜芳基包括吡啶基、吡𠯤基、嘧啶基及噠𠯤基。In one embodiment, the heteroaryl group is a 5-membered or 6-membered heteroaryl group. In one embodiment, the heteroaryl group is a 5-membered heteroaryl group, that is, the heteroaryl group is a monocyclic aromatic ring system with 5 ring atoms, wherein at least one carbon atom of the ring is independently selected from nitrogen, oxygen, and Sulfur heteroatom replacement. Non-limiting exemplary 5-membered heteroaryl groups include thienyl, furyl, pyrrolyl, azazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and iso-azolyl. In another embodiment, the heteroaryl group is a 6-membered heteroaryl group, for example, a heteroaryl group is a monocyclic aromatic ring system with 6 ring atoms, in which at least one carbon atom of the ring is replaced by a nitrogen atom. Non-limiting exemplary 6-membered heteroaryl groups include pyridyl, pyrimidinyl, pyrimidinyl, and pyridyl.
在本發明中，如單獨或作為另一基團之部分使用，術語「視情況經取代之雜芳基」係指未經取代或經一個、三個或四個獨立地選自由以下組成之群的取代基取代之雜芳基：鹵基、硝基、氰基、羥基、胺基、烷胺基、二烷胺基、鹵烷基、羥基烷基、烷氧基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷基羰基、芳基羰基、烷基磺醯基、鹵烷基磺醯基、環烷基磺醯基、(環烷基)烷基磺醯基、芳磺醯基、雜芳基磺醯基、羧基、羧基烷基、視情況經取代之烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基、視情況經取代之雜環、烷氧基烷基、(胺基)烷基、(甲醯胺基)烷基及(雜環)烷基。在一個實施例中，視情況經取代之雜芳基具有一個取代基。在另一實施例中，視情況經取代之雜芳基未經取代。任何可用的碳或氮原子可經取代。術語視情況經取代之雜芳基包括具有稠合視情況經取代之環烷基或稠合視情況經取代之雜環基的雜芳基。具有稠合視情況經取代之環烷基或稠合視情況經取代之雜環基的視情況經取代之雜芳基可連接至分子之其餘部分，在雜芳環上之任何可用碳原子處。In the present invention, when used alone or as part of another group, the term "optionally substituted heteroaryl" refers to unsubstituted or one, three or four independently selected from the group consisting of Substituents substituted heteroaryl: halo, nitro, cyano, hydroxyl, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryl Oxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, haloalkylsulfonyl, cycloalkylsulfonyl, (Cycloalkyl) alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, carboxyl, carboxyalkyl, optionally substituted alkyl, optionally substituted cycloalkyl, alkenyl, alkyne Group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, alkoxyalkyl, (amino)alkyl, (methamido)alkyl and ( Heterocycle) alkyl. In one embodiment, the optionally substituted heteroaryl has one substituent. In another embodiment, optionally substituted heteroaryl groups are unsubstituted. Any available carbon or nitrogen atom can be substituted. The term optionally substituted heteroaryl includes heteroaryl groups having a fused optionally substituted cycloalkyl or a fused optionally substituted heterocyclic group. An optionally substituted heteroaryl with a fused optionally substituted cycloalkyl or a fused optionally substituted heterocyclic group can be attached to the rest of the molecule at any available carbon atom on the heteroaromatic ring .
在本發明中，如單獨或作為另一基團之部分使用，術語「雜環」係指含有一個、兩個或三個具有三個至十四個環成員之環的未經取代之飽和及部分不飽和(例如含有一個或兩個雙鍵)環狀基團，亦即3至14員雜環，其中環中之一者之至少一個碳原子經雜原子置換。各雜原子獨立地選自由以下組成之群：氧、硫(包括亞碸及碸)及/或氮原子(其可經氧化或四級銨化)。術語「雜環」包括其中環-CH2 -經-C(=O)-置換之基團，例如環狀脲基，諸如2-咪唑啶酮，及環醯胺基，諸如β-內醯胺、γ-內醯胺、δ-內醯胺、ε-內醯胺及六哌𠯤-2-酮。術語「雜環」亦包括具有稠合的視情況經取代之芳基的基團，例如吲哚啉基或𠳭烷-4-基。在一個實施例中，雜環基為C4 - 6 雜環，亦即含有一個環及一或兩個氧原子及/或氮原子之4、5或6員環狀基團。在一個實施例中，雜環基為含有一個環及一個氮原子之C4 - 6 雜環。雜環可視情況經由任何可用碳原子或氮原子連接至分子之其餘部分。非限制性例示性雜環基包括氮雜環丁基、二氧雜環己烷基、四氫哌喃基、2-側氧基吡咯啶-3-基、哌𠯤-2-酮、哌𠯤-2,6-二酮、2-咪唑啶酮、六氫吡啶基、嗎啉基、哌𠯤基、吡咯啶基及吲哚啉基。In the present invention, when used alone or as part of another group, the term "heterocyclic ring" refers to an unsubstituted saturated and unsubstituted ring containing one, two, or three rings with three to fourteen ring members. Partially unsaturated (for example, containing one or two double bonds) cyclic group, that is, a 3- to 14-membered heterocyclic ring, in which at least one carbon atom of one of the rings is replaced by a heteroatom. Each heteroatom is independently selected from the group consisting of oxygen, sulfur (including sulfite and sulfite) and/or nitrogen atom (which can be oxidized or quaternary ammonium). The term "heterocyclic ring" includes groups in which the ring -CH 2 -is replaced by -C(=0)-, such as cyclic ureido groups, such as 2-imidazolidinone, and cyclic amide groups, such as β-lactam , Γ-lactam, δ-lactam, ε-lactam and hexapiper-2-one. The term "heterocycle" also includes groups with fused optionally substituted aryl groups, such as indolinyl or 𠳭alkyl-4-yl. In one embodiment, the heterocyclic group is a C 4 - 6 heterocyclic, i.e., containing one ring and one or two oxygen atoms and / or a 5 or 6-membered cyclic group containing a nitrogen atoms. In one embodiment, the heterocyclic group containing one ring nitrogen atom and a C of 4--6 heterocycle. The heterocyclic ring may optionally be connected to the rest of the molecule via any available carbon atom or nitrogen atom. Non-limiting exemplary heterocyclic groups include azetidinyl, dioxanyl, tetrahydropiperanyl, 2-oxopyrrolidin-3-yl, piper-2-one, piperidine -2,6-dione, 2-imidazolidinone, hexahydropyridinyl, morpholinyl, piperidine, pyrrolidinyl and indolinyl.
在本發明中，如單獨或作為另一基團之部分使用，術語「視情況經取代之雜環基」係指未經取代或經一個、兩個、三個或四個獨立地選自由以下組成之群的取代基取代的雜環基：鹵基、硝基、氰基、羥基、胺基、烷胺基、二烷胺基、鹵烷基、羥基烷基、烷氧基、鹵烷氧基、芳氧基、芳烷氧基、烷硫基、甲醯胺基、磺醯胺基、烷基羰基、環烷基羰基、烷氧基羰基、CF3
C(=O)-、芳基羰基、烷基磺醯基、芳磺醯基、羧基、羧基烷基、烷基、視情況經取代之環烷基、烯基、炔基、視情況經取代之芳基、視情況經取代之雜芳基、視情況經取代之雜環基、烷氧基烷基、(胺基)烷基、(甲醯胺基)烷基或(雜環基)烷基。取代可在任何可用碳原子或氮原子或兩者上發生。非限制性例示性經取代之雜環基包括：
在本發明中，如單獨或作為另一基團之部分使用，術語「胺基」係指式-NR22a
R22b
之基團，其中R22a
及R22b
獨立地選自由以下組成之群：氫、烷基、芳烷基、羥烷基、視情況經取代之環烷基、視情況經取代之芳基、視情況經取代之雜環及視情況經取代之雜芳基，或R22a
及R22b
一起形成3員至8員視情況經取代之雜環。非限制性例示性胺基包括-NH2
、-N(H)(CH3
)、
在本發明中，如單獨或作為另一基團之部分使用，術語「(胺基)烷基」係指經胺基取代之C1 - 6
烷基。在一個實施例中，(胺基)烷基為-CH2
NR22a
R22b
，其中R22a
及R22b
獨立地選自由以下組成之群：氫、烷基、芳烷基、羥烷基、視情況經取代之環烷基、視情況經取代之芳基、視情況經取代之雜環及視情況經取代之雜芳基，或R22a
及R22b
一起形成3員至8員視情況經取代之雜環。在另一實施例中，R22a
及R22b
獨立地為氫或C1 - 4
烷基。非限制性例示性(胺基)烷基包括-CH2
NH2
、-CH2
N(H)CH3
、-CH2
N(CH3
)2
、-CH2
CH2
N(CH3
)2
、
在本發明中，如單獨或作為另一基團之部分使用，術語「二烷胺基烷基」係指連接至經二(C1 - 6 烷基)取代之胺基的C1 - 4 烷基。非限制性例示性二烷胺基烷基包括-CH2 N(CH3 )2 、-CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 N(CH3 )2 、-CH2 CH2 CH2 CH2 N(CH3 )2 及-CH2 N(CH2 CH3 )2 。In the present invention, as alone or as part of another group, the term "dialkylamino group" means ligated to two (C 1 - 6 alkyl) amine substituted with the C 1 - 4 alkoxy base. Non-limiting exemplary dialkylaminoalkyl groups include -CH 2 N(CH 3 ) 2 , -CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 N(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 2 N(CH 3 ) 2 and -CH 2 N(CH 2 CH 3 ) 2 .
在本發明中，如單獨或作為另一基團之部分使用，術語「甲醯胺基」係指式-C(=O)NR23a
R23b
之基團，其中R23a
及R23b
各自獨立地選自由以下各者組成之群：氫、視情況經取代之烷基、羥烷基、視情況經取代之環烷基、視情況經取代之芳基、視情況經取代之雜環及視情況經取代之雜芳基，或R23a
及R23b
與其所連接之氮一起形成3員至8員視情況經取代之雜環基。在一個實施例中，R23a
及R23b
各自獨立地為氫或視情況經取代之烷基。在一個實施例中，R23a
及R23b
結合在一起從而與其所連接之氮一起形成3員至8員視情況經取代之雜環基。非限制性例示性甲醯胺基包括-CONH2
、-CON(H)CH3
、-CON(CH3
)2
、-CON(H)Ph、
在本發明中，如單獨或作為另一基團之部分使用，術語「烷基醯胺」係指式-C(=O)NR24a R24b 之基團，其中R24a 係選自由氫及烷基組成之群，且R24b 為烷基。在一個實施例中，R24a 為氫且R24b 為C1 - 6 烷基。在另一實施例中，R24a 為氫且R24b 為C1 - 4 烷基。在另一實施例中，R24a 及R24b 各自獨立地為C1 - 6 烷基。在另一實施例中，R24a 及R24b 各自獨立地為C1 - 4 烷基。非限制性例示性烷基醯胺基包括-CON(H)CH3 、-CON(CH3 )2 、-CON(H)CH2 CH3 及-CON(CH2 CH3 )2 。In the present invention, when used alone or as part of another group, the term "alkyl amide" refers to a group of formula -C(=O)NR 24a R 24b , where R 24a is selected from hydrogen and alkane R 24b is an alkyl group. In one embodiment, R 24a is hydrogen and R 24b is C 1 - 6 alkyl. In another embodiment, R 24a is hydrogen and R 24b is C 1 - 4 alkyl. In another embodiment, R 24a and R 24b are each independently C 1 - 6 alkyl. In another embodiment, R 24a and R 24b are each independently C 1 - 4 alkyl. Non-limiting exemplary alkyl amide groups include -CON(H)CH 3 , -CON(CH 3 ) 2 , -CON(H)CH 2 CH 3 and -CON(CH 2 CH 3 ) 2 .
在本發明中，如單獨或作為另一基團之部分使用，術語「烷羰基」係指經烷基取代之羰基，亦即-C(=O)-。非限制性例示性烷基羰基包括-C(=O)CH3 及-C(=O)CH2 CH2 CH2 CH3 。In the present invention, when used alone or as part of another group, the term "alkylcarbonyl" refers to a carbonyl group substituted with an alkyl group, that is, -C(=O)-. Non-limiting exemplary alkylcarbonyl groups include -C(=0)CH 3 and -C(=0)CH 2 CH 2 CH 2 CH 3 .
在本發明中，如單獨或作為另一基團之部分使用，術語「環烷基羰基」係指羰基，亦即經環烷基取代之-C(=O)-。非限制性例示性環烷基羰基為-C(=O)-環丙基。In the present invention, when used alone or as part of another group, the term "cycloalkylcarbonyl" refers to a carbonyl group, that is, -C(=O)- substituted with a cycloalkyl group. A non-limiting exemplary cycloalkylcarbonyl group is -C(=0)-cyclopropyl.
在本發明中，如單獨或作為另一基團之部分使用，術語「芳基羰基」係指經視情況經取代之芳基取代之羰基，亦即-C(=O)-。非限制性的例示性芳基羰基為-COPh。In the present invention, when used alone or as part of another group, the term "arylcarbonyl" refers to a carbonyl group substituted with an optionally substituted aryl group, that is, -C(=O)-. A non-limiting exemplary arylcarbonyl group is -COPh.
在本發明中，如單獨或作為另一基團之部分使用，術語「烷氧羰基」係指羰基，亦即經烷氧基取代之-C(=O)-。在一個實施例中，烷氧基為C1 - 4 烷氧基。在另一實施例中，烷氧基為C1 - 6 烷氧基。非限制性例示性烷氧羰基包括-C(=O)OMe、-C(=O)OEt及-C(=O)OtBu。In the present invention, when used alone or as part of another group, the term "alkoxycarbonyl" refers to a carbonyl group, that is, -C(=O)- substituted with an alkoxy group. In one embodiment, the alkoxy is C 1 - 4 alkoxy. In another embodiment, the alkoxy is C 1 - 6 alkoxy. Non-limiting exemplary alkoxycarbonyl groups include -C(=0)OMe, -C(=0)OEt, and -C(=0)OtBu.
在本發明中，如單獨或作為另一基團之部分使用，術語「(烷氧羰基)烷基」係指經烷氧羰基取代之烷基。非限制性例示性(烷氧基羰基)烷基包括CH2 C(=O)OMe、-CH2 C(=O)OEt及-CH2 C(=O)OtBu。In the present invention, when used alone or as part of another group, the term "(alkoxycarbonyl)alkyl" refers to an alkyl group substituted with an alkoxycarbonyl group. Non-limiting exemplary (alkoxycarbonyl) alkyl groups include CH 2 C (= O) OMe , -CH 2 C (= O) OEt , and -CH 2 C (= O) OtBu .
在本發明中，如單獨或作為另一基團之部分使用，術語「羧基」係指式-CO2 H之基團In the present invention, when used alone or as part of another group, the term "carboxy" refers to a group of formula -CO 2 H
在本發明中，如單獨或作為另一基團之部分使用，術語「羧基烷基」係指經-CO2 H取代之烷基。非限制性例示性羧基烷基為-CH2 CO2 H。In the present invention, when used alone or as part of another group, the term "carboxyalkyl" refers to an alkyl group substituted with -CO 2 H. Non-limiting exemplary carboxyalkyl is -CH 2 CO 2 H.
在本發明中，如單獨或作為另一基團之部分使用，術語「芳烷基」係指經一個、兩個或三個視情況經取代之芳基取代之烷基。在一個實施例中，芳烷基為經一個視情況經取代之C5 或C6 芳基取代之C1 - 4 烷基。在另一實施例中，芳烷基為經一個視情況經取代之芳基取代之C1 烷基。在另一實施例中，芳烷基為經一個視情況經取代之芳基取代之C2 烷基。在另一實施例中，芳烷基為經一個視情況經取代之芳基取代之C3 烷基。在一個實施例中，芳烷基為經一個視情況經取代之苯基取代之C1 或C2 烷基。非限制性例示性芳烷基包括苯甲基、苯乙基、-CHPh2 、-CH(CH3 )Ph、-CH2 (4-F-Ph)、-CH2 (4-Me-Ph)、-CH2 (4-CF3 -Ph及-CH(4-F-Ph)2 。In the present invention, when used alone or as part of another group, the term "aralkyl" refers to an alkyl group substituted with one, two or three optionally substituted aryl groups. In one embodiment, the aryl group is optionally substituted with one of the substituted C 5 or C 6 aryl-C 1 - 4 alkyl. In another embodiment, the substituted aralkyl group is optionally substituted with one of the aryl C 1 alkyl group. In another embodiment, the aralkyl group is a C 2 alkyl group substituted with an optionally substituted aryl group. In another embodiment, the substituted aralkyl group is optionally substituted with one aryl group of C 3 alkyl. In one embodiment, the aralkyl group is a C 1 or C 2 alkyl group substituted with an optionally substituted phenyl group. Non-limiting exemplary aralkyl groups include benzyl, phenethyl, -CHPh 2 , -CH(CH 3 )Ph, -CH 2 (4-F-Ph), -CH 2 (4-Me-Ph) , -CH 2 (4-CF 3 -Ph and -CH(4-F-Ph) 2 .
在本發明中，如單獨或由另一基團之部分使用，術語「(雜環基)烷基」係指經視情況經取代之雜環基取代之烷基。在一個實施例中，(雜環基)烷基為經一個視情況經取代之雜環基取代的C1 - 4
烷基。非限制性例示性(雜環)烷基包括：
在本發明中，如單獨或由另一基團之部分使用，術語「(雜芳基)烷基」係指經視情況經取代之雜芳基取代之烷基。在一個實施例中，(雜芳基)烷基為經一個視情況經取代之雜芳基取代之C1 - 4
烷基。在另一實施例中，(雜芳基)烷基為經一個視情況經取代之雜芳基取代之C1
烷基。非限制性例示性(雜芳基)烷基包括：
在本發明中，如單獨或由另一基團之部分使用，術語「(甲醯胺基)烷基」係指經一或兩個甲醯胺基取代之烷基。在一個實施例中，(甲醯胺基)烷基為經一個甲醯胺基取代之C1 - 4 烷基，亦即(甲醯胺基)C1 - 4 烷基。在另一實施例中，(甲醯胺基)烷基為經兩個甲醯胺基取代之C1 - 4 烷基。非限制性例示性(甲醯胺基)烷基包括-CH2 CONH2 、-C(H)CH3 -CONH2 及-CH2 CON(H)CH3 。In the present invention, as used alone or as part of another group, the term "(formamido)alkyl" refers to an alkyl group substituted with one or two formamido groups. In one embodiment, (A acyl group) substituted alkyl is a carboxylic acyl group of C 1 - 4 alkyl, i.e. (A acyl group) C 1 - 4 alkyl. In another embodiment, (A amino acyl) group is substituted by the two carboxylic acyl group of C 1 - 4 alkyl. Non-limiting exemplary (formamido) alkyl groups include -CH 2 CONH 2 , -C(H)CH 3 -CONH 2 and -CH 2 CON(H)CH 3 .
在本發明中，如單獨或作為另一基團之部分使用，術語「(芳氧基)烷基」係指經芳氧基取代之烷基。在一個實施例中，「(芳氧基)烷基」為經芳氧基取代之C1 - 4 烷基。在一個實施例中，「(芳氧基)烷基」為經芳氧基取代之C2 - 4 烷基。非限制性例示性(芳氧基)烷基包括-CH2 CH2 OPh及-CH2 CH2 CH2 OPh。In the present invention, when used alone or as part of another group, the term "(aryloxy)alkyl" refers to an alkyl group substituted with an aryloxy group. In one embodiment, "(aryloxy) alkyl" substituted with an aryloxy group of C 1 - 4 alkyl. In one embodiment, "(aryloxy) alkyl" substituted with an aryloxy group of C 2 - 4 alkyl. Non-limiting exemplary (aryloxy)alkyl groups include -CH 2 CH 2 OPh and -CH 2 CH 2 CH 2 OPh.
在本發明中，如單獨或作為另一基團之部分使用，術語「烷基羰氧基」係指伸氧基，例如經烷基羰基取代之-O-。非限制性例示性「烷基羰氧基」包括-OC(=O)CH2 CH3 、-OC(=O)CH3 ，亦即乙醯氧基-OC(=O)CH2 CH2 CH3 及-OC(=O)CH(CH3 )2 。In the present invention, as used alone or as part of another group, the term "alkylcarbonyloxy" refers to an oxyethylene group, such as -O- substituted with an alkylcarbonyl group. Non-limiting exemplary "alkylcarbonyloxy" includes -OC(=O)CH 2 CH 3 , -OC(=O)CH 3 , that is, acetyloxy-OC(=O)CH 2 CH 2 CH 3 and -OC(=O)CH(CH 3 ) 2 .
在本發明中，如單獨或作為另一基團之部分使用，術語「環烷基羰基氧基」係指經環烷基羰基取代之氧基，例如-O-。非限制性例示性「環烷基羰基氧基」包括-OC(=O)-環丙基、-OC(=O)-環丁基及-OC(=O)-環戊基。In the present invention, as used alone or as part of another group, the term "cycloalkylcarbonyloxy" refers to an oxy group substituted with a cycloalkylcarbonyl group, such as -O-. Non-limiting exemplary "cycloalkylcarbonyloxy" includes -OC(=0)-cyclopropyl, -OC(=0)-cyclobutyl, and -OC(=0)-cyclopentyl.
在本發明中，如單獨或作為另一基團之部分使用，術語「雜環基羰基」係指經視情況經取代之雜環基取代之羰基，亦即，-C(=O)-。非限制性例示性雜環基羰基包括：
在本發明中，如單獨或作為另一基團之部分使用，術語「經鹵基取代之雜環基羰基」係指連接至經至少一個鹵基取代之雜環基的羰基，亦即-(C=O)-。在一個實施例中，雜環基經一個鹵基取代。在另一實施例中，雜環基經兩個鹵基取代。非限制性例示性經鹵基取代之雜環基羰基包括：
如本文中所使用，術語「menin抑制劑」或「menin之抑制劑」係指干擾(例如抑制)menin-MLL融合蛋白質相互作用之化合物。As used herein, the term "menin inhibitor" or "menin inhibitor" refers to a compound that interferes with (eg inhibits) the interaction of the menin-MLL fusion protein.
術語「其中抑制menin提供益處之疾病或病狀」係關於其中menin及/或menin與menin相互作用蛋白質之相互作用對於例如彼疾病或病狀之發作、進展或表現為重要或必要之疾病或病狀，或已知藉由menin抑制劑治療之疾病或病狀。此類病狀之實例包括但不限於癌症、慢性自體免疫疾病、炎性疾病、增殖性疾病、敗血症及病毒性感染。一般熟習此項技術者易於能夠例如藉由可適宜地用以評估特定化合物之活性的檢定，來判定化合物是否治療由任何特定細胞類型之menin介導之疾病或病狀。The term "disease or condition in which the inhibition of menin provides benefits" refers to a disease or condition in which the interaction of menin and/or menin and menin interacting proteins is important or necessary for, for example, the onset, progression or manifestation of that disease or condition. Symptoms, or diseases or conditions known to be treated by menin inhibitors. Examples of such conditions include, but are not limited to, cancer, chronic autoimmune diseases, inflammatory diseases, proliferative diseases, sepsis, and viral infections. Those skilled in the art can easily determine whether the compound treats a disease or condition mediated by menin of any specific cell type, for example, by an assay that can be suitably used to assess the activity of a specific compound.
術語「第二治療劑」係指不同於本發明之化合物且已知治療所關注疾病或病狀之治療劑。舉例而言，當癌症為所關注疾病或病狀時，第二治療劑可為如紫杉醇之已知化學治療藥物或例如輻射。The term "second therapeutic agent" refers to a therapeutic agent that is different from the compound of the present invention and is known to treat the disease or condition of interest. For example, when cancer is the disease or condition of interest, the second therapeutic agent may be a known chemotherapeutic drug such as paclitaxel or, for example, radiation.
術語「疾病」或「病狀」表示障礙及/或異常，其一般而言被視為病理學病狀或功能，且自身可以特定體徵、症狀及/或故障之形式顯現。如下文所證實，本發明之化合物為menin抑制劑且可用於治療其中menin抑制提供益處之疾病及病狀。The term "disease" or "symptom" means a disorder and/or abnormality, which is generally regarded as a pathological condition or function, and can manifest itself in the form of specific signs, symptoms, and/or malfunctions. As demonstrated below, the compounds of the present invention are menin inhibitors and can be used to treat diseases and conditions in which menin inhibition provides benefits.
如本文所用，術語「治療(treat/treating/treatment)」及其類似者係指消除、減輕或改善疾病或病狀及/或與其相關之症狀。儘管不排除，但治療疾病或病狀無需將疾病、病狀或與其相關之症狀完全消除。如本文所用，術語「治療(treat/treating/treatment)」及其類似者可包括「預防性治療」，其係指降低個體之疾病或病狀復發之機率或先前所控制疾病或病狀之復發機率，該個體未患但處於疾病或病狀復發或疾病或病狀之再發之風險下或易復發疾病或病狀或易受疾病或病狀之復發影響。術語「治療」及同義詞涵蓋向需要此類治療之個體投與治療有效量之本發明之化合物。As used herein, the term "treat/treating/treatment" and the like refer to the elimination, reduction or amelioration of a disease or condition and/or symptoms related thereto. Although it is not excluded, the treatment of the disease or condition does not require the complete elimination of the disease, condition or symptoms related to it. As used herein, the term "treat/treating/treatment" and the like can include "prophylactic treatment", which refers to reducing the chance of an individual's disease or condition recurring or the recurrence of a previously controlled disease or condition Probability that the individual does not suffer from the disease or condition but is at risk of recurrence of the disease or condition or is prone to recurrence of the disease or condition or is susceptible to the recurrence of the disease or condition. The term "treatment" and synonyms encompass the administration of a therapeutically effective amount of a compound of the invention to an individual in need of such treatment.
在本發明之含義內，「治療」亦包括復發預防或階段預防以及治療急性或慢性體徵、症狀及/或功能障礙。治療可根據症狀定向，例如以抑制症狀。其可在較短時段內實現、在中等時期內定向或可為長期治療，例如在維持療法之上下文內。Within the meaning of the present invention, "treatment" also includes recurrence prevention or stage prevention and treatment of acute or chronic signs, symptoms and/or dysfunctions. Treatment can be symptomatically directed, for example to suppress symptoms. It can be achieved in a short period of time, targeted in a medium period or can be a long-term treatment, for example in the context of maintenance therapy.
如本文中所使用，術語「治療有效量」或「有效劑量」係指在藉由本發明之方法投與時足以向有需要之個體有效遞送用於治療所關注病狀或疾病之活性成份之活性成份的量。在癌症或其他增殖病症之情況下，治療有效量之藥劑可減少(亦即在一定程度上延緩且較佳地終止)非所需細胞增殖；減少癌細胞之數目；減小腫瘤大小；抑制(亦即在一定程度上延緩且較佳地終止)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地終止)腫瘤轉移；在一定程度上抑制腫瘤生長；降低靶細胞中之menin相互作用；及/或在一定程度上緩解與癌症相關聯之症狀中之一或多者。在所投與之化合物或組合物阻止生長及/或殺死現有癌細胞之情況下，其可為細胞抑制性的及/或細胞毒性的。As used herein, the term "therapeutically effective amount" or "effective dose" refers to an activity sufficient to effectively deliver an active ingredient for the treatment of the condition or disease of interest to an individual in need when administered by the method of the present invention The amount of ingredients. In the case of cancer or other proliferative disorders, a therapeutically effective amount of an agent can reduce (that is, to a certain extent, delay and preferably stop) undesired cell proliferation; reduce the number of cancer cells; reduce tumor size; inhibit ( That is, to a certain extent, delay and preferably stop) the infiltration of cancer cells into the surrounding organs; to inhibit (that is, to delay and preferably to terminate) tumor metastasis; to inhibit tumor growth to a certain extent; to reduce target cells Menin interaction; and/or to a certain extent alleviate one or more of the symptoms associated with cancer. Where the administered compound or composition prevents growth and/or kills existing cancer cells, it can be cytostatic and/or cytotoxic.
術語「容器」意謂因而適用於儲存、運送、分配及/或操縱醫藥產品之任何盛器及密封件。The term "container" means any container and seal that is therefore suitable for storing, transporting, dispensing and/or handling pharmaceutical products.
術語「說明書」意謂隨附醫藥產品之資訊，該資訊提供對如何投與產品以及允許醫師、藥劑師及患者考慮產品之用途而做出知情決策所需的安全性及功效資料之描述。包裝說明書大體上視為醫藥產品之「標籤」。The term "instructions" means the information accompanying the medicinal product, which provides a description of how to administer the product and the safety and efficacy data required to allow physicians, pharmacists, and patients to make informed decisions regarding the use of the product. The package insert is generally regarded as the "label" of the pharmaceutical product.
「並行(Concurrent)投與」、「組合投與」、「同時(simultaneous)投與」及類似片語意謂向正在治療之個體同時投與兩種或更多種試劑。「並行」意謂以任何次序在不同時間點同時或依序投與各藥劑。然而，若不同時投與，則意謂以使得提供所要療效且可協同作用之次序及在時間上充分接近地向個體投與該等藥劑。舉例而言，本發明之化合物可作為第二治療劑同時或以任何次序在不同時間點依序投與。本發明化合物及第二治療劑可以任何適當形式且藉由任何合適之途徑單獨投與。當不同時投與本發明化合物及第二治療劑時，應理解，其可以任何次序向有需要之個體投與。舉例而言，本發明化合物可在向有需要之個體投與第二治療劑治療模式之前(例如5分鐘、15分鐘、30分鐘、45分鐘、1小時、2小時、4小時、6小時、12小時、24小時、48小時、72小時、96小時、1週、2週、3週、4週、5週、6週、8週或12週之前)、與其同時或在其之後(例如5分鐘、15分鐘、30分鐘、45分鐘、1小時、2小時、4小時、6小時、12小時、24小時、48小時、72小時、96小時、1週、2週、3週、4週、5週、6週、8週或12週之後)進行投與。在各種實施例中，本發明化合物與第二治療劑相隔1分鐘、相隔10分鐘、相隔30分鐘、相隔少於1小時、相隔1小時、相隔1小時至2小時、相隔2小時至3小時、相隔3小時至4小時、相隔4小時至5小時、相隔5小時至6小時、相隔6小時至7小時、相隔7小時至8小時、相隔8小時至9小時、相隔9小時至10小時、相隔10小時至11小時、相隔11小時至12小時、相隔不超過24小時或相隔不超過48小時進行投與。在一個實施例中，組合療法之組分相隔約1分鐘至約24小時投與。"Concurrent administration", "combined administration", "simultaneous administration" and similar phrases mean the simultaneous administration of two or more agents to the individual being treated. "Parallel" means that each agent is administered simultaneously or sequentially in any order at different points in time. However, if they are not administered at the same time, it means to administer the agents to the individual in a sequence that provides the desired therapeutic effect and can be synergistic and sufficiently close in time. For example, the compound of the present invention can be administered as a second therapeutic agent simultaneously or in any order at different time points. The compound of the present invention and the second therapeutic agent can be administered separately in any suitable form and by any suitable route. When the compound of the present invention and the second therapeutic agent are not administered at the same time, it should be understood that they can be administered to individuals in need in any order. For example, the compound of the present invention can be administered to an individual in need before the second therapeutic agent treatment mode (e.g. 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 Hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks or 12 weeks before), at the same time as it or after it (e.g. 5 minutes , 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 Weeks, 6 weeks, 8 weeks or 12 weeks later). In various embodiments, the compound of the present invention and the second therapeutic agent are separated by 1 minute, 10 minutes, 30 minutes, less than 1 hour, 1 hour, 1 hour to 2 hours, 2 hours to 3 hours apart, 3 hours to 4 hours apart, 4 hours to 5 hours apart, 5 hours to 6 hours apart, 6 hours to 7 hours apart, 7 hours to 8 hours apart, 8 hours to 9 hours apart, 9 hours to 10 hours apart, apart The administration should be carried out from 10 hours to 11 hours, 11 hours to 12 hours apart, no more than 24 hours apart, or no more than 48 hours apart. In one embodiment, the components of the combination therapy are administered about 1 minute to about 24 hours apart.
如本文所用，術語「立體異構體」對於個別分子的所有異構體為通用術語，該個別分子僅在空間中其原子取向上不同。其包括具有一個以上對掌性中心之化合物的對映異構體及不為彼此鏡像之異構體(非對映異構體)。As used herein, the term "stereoisomer" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers of compounds with more than one pair of centers and isomers that are not mirror images of each other (diastereomers).
術語「對掌性中心」或「非對稱碳原子」係指與四個不同基團連接之碳原子。The term "opposite center" or "asymmetric carbon atom" refers to a carbon atom connected to four different groups.
術語「對映異構體」及「對映異構」係指不能疊加於其鏡像上且因此具有光學活性的分子，其中對映異構體沿一個方向旋轉偏光平面，其鏡像化合物則沿相反方向旋轉偏光平面。The terms "enantiomers" and "enantiomers" refer to molecules that cannot be superimposed on their mirror images and are therefore optically active. The enantiomers rotate the polarization plane in one direction, while the mirror image compounds move in the opposite direction. Rotate the polarization plane in the direction.
術語「外消旋」係指等份之對映異構體之混合物且該混合物為光學無活性的。在一個實施例中，本發明之化合物為外消旋的。The term "racemic" refers to a mixture of equal parts of enantiomers and the mixture is optically inactive. In one embodiment, the compound of the invention is racemic.
術語「絕對組態」係指對掌性分子實體(或基團)之原子的空間排列及其立體化學描述，例如R或S。The term "absolute configuration" refers to the spatial arrangement and stereochemical description of the atoms of the opposite molecular entity (or group), such as R or S.
除非另有指示，否則本說明書中所使用之立體化學術語及定則意謂與Pure & Appl . Chem 68 :2193 (1996)中所描述之彼等一致。Unless otherwise indicated, the stereochemical terms and rules used in this specification mean the same as those described in Pure & Appl . Chem 68 :2193 (1996).
術語「對映異構體過量」或「ee」係指一種對映異構體與另一種對映異構體相比存在多少之量度。對於R 及S 對映異構體之混合物，對映異構過量百分比經限定為│R - S │*100，其中R 及S 為對映異構體於混合物中之各別莫耳或重量分數以使得R +S =1。藉由對掌性物質之旋光度的瞭解，對映異構體過量百分比定義為([α]obs /[α]max ) *100，其中[α]obs 為對映異構體之混合物的旋光度且[α]max 為純對映異構體之旋光度。使用包括NMR光譜分析、對掌性管柱層析或光學旋光測定法之多種分析技術來測定對映異構過量為可能的。The term "enantiomeric excess" or "ee" refers to a measure of how much one enantiomer is present compared to another. For a mixture of R and S enantiomers, the enantiomeric excess percentage is limited to │ R - S │*100, where R and S are the respective moles or weight fractions of the enantiomers in the mixture So that R + S =1. Based on the understanding of the optical rotation of palm substances, the enantiomeric excess percentage is defined as ([α] obs /[α] max ) *100, where [α] obs is the optical rotation of the mixture of enantiomers Degree and [α] max is the optical rotation of the pure enantiomer. It is possible to determine the enantiomeric excess using a variety of analytical techniques including NMR spectroscopy, parallel column chromatography, or optical polarimetry.
除非另有指示，否則術語「一(a/an)」、「該」及類似參考物在本發明之上下文中(尤其在申請專利範圍之上下文中)解釋為涵蓋單數及複數兩者。除非本文中另有指示，否則本文中對值的範圍之敍述意欲充當各自參考屬於所述範圍內之各單獨值的速記方法，且各單獨值併入至本說明書中，如同其在本文中各自敍述一般。除非另外主張，否則本文提供之任何及所有實例或例示性語言(例如，「諸如」)之使用旨在更好地說明本發明，而非對本發明之範疇的限制。本說明書之語言均不應解釋為指示任何非主張之要素對於本發明之實踐為必不可少的。Unless otherwise indicated, the terms "a/an", "the" and similar references are interpreted in the context of the present invention (especially in the context of the scope of patent application) to cover both the singular and the plural. Unless otherwise indicated herein, the description of the ranges of values herein is intended to serve as a shorthand method for each reference to each individual value falling within the stated range, and each individual value is incorporated into this specification as if it were each in this document The narrative is general. Unless otherwise claimed, the use of any and all examples or illustrative language (eg, "such as") provided herein is intended to better illustrate the present invention, rather than to limit the scope of the present invention. The language of this specification should not be construed as indicating that any non-claimed element is indispensable for the practice of the present invention.
如本文所用之術語「約」在與數值或值範圍組合使用時意謂值或值之範圍可偏離至對於一般熟習此項技術者而言認為合理的程度。As used herein, the term "about" when used in combination with a value or a range of values means that the value or range of values can deviate to an extent deemed reasonable for those skilled in the art.
態樣IAspect I
態樣1. 一種化合物，其具有式I
：
及其醫藥學上可接受之鹽，其中：And its pharmaceutically acceptable salts, of which:
R1a 、R1b 及R1c 各自獨立地選自由氫及鹵基組成之群；R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen and halogen;
G為-SO2 -X-Z2 ；G is -SO 2 -XZ 2 ;
R2
係選自由以下組成之群：
R3
係選自由以下組成之群：
L為
R10a 係選自由以下組成之群：氫、鹵基、氰基、C1 - 4 烷基、C1 - 4 烷氧基及羥基；R 10a selected from the group consisting of the group consisting of: hydrogen, halo, cyano, C 1 - 4 alkyl, C 1 - 4 alkoxy and hydroxy;
X係選自由以下組成之群：
其中Y連接至Z2 ；Where Y is connected to Z 2 ;
Y為-C(=O)-；Y is -C(=O)-;
o及p各自獨立地為0、1、2或3；o and p are each independently 0, 1, 2 or 3;
Z2 係選自由以下組成之群：-C(R13a )=C(R13b )(R13c )、-C≡CR13d 及Ra4 ，其中當X為X-10時，Z2 不存在；Z 2 selected from the group consisting of the group consisting of: -C (R 13a) = C (R 13b) (R 13c), - when C≡CR 13d and R a4, wherein when X is X-10, Z 2 is absent;
R8a 及R8b 獨立地選自由以下組成之群：氫及鹵基；R 8a and R 8b are independently selected from the group consisting of hydrogen and halo;
R13a 、R13b 、R13c 及R13d 各自獨立地選自由以下組成之群：氫、甲基及二甲基胺基甲基；R 13a , R 13b , R 13c and R 13d are each independently selected from the group consisting of hydrogen, methyl, and dimethylaminomethyl;
Ra3 係選自由以下組成之群：烷氧基羰基及烷基磺醯基；R a3 is selected from the group consisting of alkoxycarbonyl and alkylsulfonyl;
Ra4 為-N(H)CH2 CH=CH-Ra5 ；且R a4 is -N(H)CH 2 CH=CH-R a5 ; and
Ra5 係選自由以下組成之群：烷氧基羰基及烷基磺醯基；R a5 is selected from the group consisting of: alkoxycarbonyl and alkylsulfonyl;
其限制條件為：The restrictions are:
當X為X-1，o及p各自為0，且Z2 為C(R13a )=C(R13b )(R13c )時，則R13a 、R13b 及R13c 中無一者為二甲基胺基甲基；When X is X-1, o and p are each 0, and Z 2 is C(R 13a )=C(R 13b )(R 13c ), then none of R 13a , R 13b and R 13c is two Methylaminomethyl;
當X為X-1，R10a
為氫、F、OH、甲基或甲氧基，Z2
為-C≡CR13d
，且R2
為
當X為X-1，Z2
為CH=CH2
，且R2
為
當X為X-9且Z2 為CH=CH2 時，則R10a 不為氫、F或甲基；且When X is X-9 and Z 2 is CH=CH 2 , then R 10a is not hydrogen, F or methyl; and
式(I)化合物不為
態樣2. 如態樣1之化合物，其具有式II
：
或其醫藥學上可接受之鹽。Or its pharmaceutically acceptable salt.
態樣3. 如態樣1之化合物，其具有式XI 
或其醫藥學上可接受之鹽。Or its pharmaceutically acceptable salt.
態樣4. 如態樣1至3中任一項之化合物，其中：Aspect 4. The compound of any one of aspects 1 to 3, wherein:
R2
係選自由以下組成之群：
R10a 係選自由以下組成之群：氫、氟、氰基、甲基、甲氧基、乙氧基及羥基；R 10a is selected from the group consisting of hydrogen, fluorine, cyano, methyl, methoxy, ethoxy and hydroxyl;
Z2 係選自由以下組成之群：-C(R13a )=C(R13b )(R13c )及-C≡CR13d ；Z 2 is selected from the group consisting of: -C(R 13a )=C(R 13b )(R 13c ) and -C≡CR 13d ;
R8a 及R8b 獨立地選自由以下組成之群：氫及氟；且R 8a and R 8b are independently selected from the group consisting of hydrogen and fluorine; and
R13a 、R13b 、R13c 及R13d 各自獨立地選自由以下組成之群：氫、甲基及二甲基胺基甲基。R 13a , R 13b , R 13c and R 13d are each independently selected from the group consisting of hydrogen, methyl, and dimethylaminomethyl.
態樣5. 如態樣1至4中任一項之化合物，其中R2
為
或其醫藥學上可接受之鹽。Or its pharmaceutically acceptable salt.
態樣6. 如態樣1至4之化合物或其醫藥學上可接受之鹽，其中R2 為Aspect 6. The compound of aspects 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 is
或其醫藥學上可接受之鹽。Or its pharmaceutically acceptable salt.
態樣7. 如態樣4之化合物或其醫藥學上可接受之鹽，其中R2
為
態樣8. 如態樣1至7中任一項之化合物，其中R8a 及R8b 為氫，或其醫藥學上可接受之鹽。Aspect 8. The compound of any one of aspects 1 to 7, wherein R 8a and R 8b are hydrogen, or a pharmaceutically acceptable salt thereof.
態樣9. 如態樣1至7中任一項之化合物，其中R8a 為氟，或其醫藥學上可接受之鹽。Aspect 9. The compound of any one of aspects 1 to 7, wherein R 8a is fluorine, or a pharmaceutically acceptable salt thereof.
態樣10. 如態樣1至9中任一項之化合物，其中R1a 、R1b 及R1c 中之至少一者為氟或其醫藥學上可接受之鹽。Aspect 10. The compound of any one of aspects 1 to 9, wherein at least one of R 1a , R 1b and R 1c is fluorine or a pharmaceutically acceptable salt thereof.
態樣11. 如態樣1至10中任一項之化合物，其中R10a 為氫或其醫藥學上可接受之鹽。Aspect 11. The compound of any one of aspects 1 to 10, wherein R 10a is hydrogen or a pharmaceutically acceptable salt thereof.
態樣12. 如態樣1至10中任一項之化合物，其中R10a 為氟，或其醫藥學上可接受之鹽。Aspect 12. The compound of any one of aspects 1 to 10, wherein R 10a is fluorine, or a pharmaceutically acceptable salt thereof.
態樣13. 如態樣1至12中任一項之化合物，其中X為X-1、X-9或X-12，或其醫藥學上可接受之鹽。Aspect 13. The compound of any one of aspects 1 to 12, wherein X is X-1, X-9 or X-12, or a pharmaceutically acceptable salt thereof.
態樣14. 如態樣1至13中任一項之化合物，其中X為X-1，或其醫藥學上可接受之鹽。Aspect 14. The compound of any one of aspects 1 to 13, wherein X is X-1, or a pharmaceutically acceptable salt thereof.
態樣15. 如態樣1至13中任一項之化合物，其中X為X-9，或其醫藥學上可接受之鹽。Aspect 15. The compound of any one of aspects 1 to 13, wherein X is X-9, or a pharmaceutically acceptable salt thereof.
態樣16. 如態樣1至12中任一項之化合物，其中X為X-10，或其醫藥學上可接受之鹽。Aspect 16. The compound of any one of aspects 1 to 12, wherein X is X-10, or a pharmaceutically acceptable salt thereof.
態樣17. 如態樣1至13中任一項之化合物，其中X為X-12，或其醫藥學上可接受之鹽。Aspect 17. The compound of any one of aspects 1 to 13, wherein X is X-12, or a pharmaceutically acceptable salt thereof.
態樣18. 如態樣1至17中任一項之化合物，其中R3
為
或其醫藥學上可接受之鹽。Or its pharmaceutically acceptable salt.
態樣19. 如態樣1至18中任一項之化合物，其中R3
為
或其醫藥學上可接受之鹽。Or its pharmaceutically acceptable salt.
態樣20. 如態樣1至19中任一項之化合物，其中Z2 為-C(R13a )=C(R13b )(R13c )，或其醫藥學上可接受之鹽。Aspect 20. The compound of any one of aspects 1 to 19, wherein Z 2 is -C(R 13a )=C(R 13b )(R 13c ), or a pharmaceutically acceptable salt thereof.
態樣21. 如態樣20之化合物，其中R13a 及R13b 為氫，且R13c 為二甲基胺基甲基，或其醫藥學上可接受之鹽。Aspect 21. The compound of aspect 20, wherein R 13a and R 13b are hydrogen, and R 13c is dimethylaminomethyl, or a pharmaceutically acceptable salt thereof.
態樣22. 如態樣20之化合物，其中R13c 為甲基，且R13a 及R13b 為氫，或其醫藥學上可接受之鹽。Aspect 22. The compound of aspect 20, wherein R 13c is methyl, and R 13a and R 13b are hydrogen, or a pharmaceutically acceptable salt thereof.
態樣23. 如態樣20之化合物，其中R13a 、R13b 及R13c 中之每一者為氫，或其醫藥學上可接受之鹽。Aspect 23. The compound of aspect 20, wherein each of R 13a , R 13b and R 13c is hydrogen, or a pharmaceutically acceptable salt thereof.
態樣25. 如態樣1至12及18至24中任一項之化合物，其中X係選自由以下組成之群：
其中羰基連接至Z2 ，或其醫藥學上可接受之鹽。Wherein the carbonyl group is connected to Z 2 , or a pharmaceutically acceptable salt thereof.
態樣26. 如態樣1至19中任一項之化合物，其中Z2
係選自由以下組成之群：
或其醫藥學上可接受之鹽。Or its pharmaceutically acceptable salt.
態樣27. 如態樣1之化合物，其中該化合物為表1之化合物中之任何一或多者，或其醫藥學上可接受之鹽。Aspect 27. The compound of aspect 1, wherein the compound is any one or more of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
態樣28. 一種醫藥組合物，其包含如態樣1至27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載劑。Aspect 28. A pharmaceutical composition comprising the compound of any one of aspects 1 to 27 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
態樣29. 一種治療患者之方法，該方法包含向該患者投與治療有效量之態樣1至27中任一項之化合物或其醫藥學上可接受之鹽，其中該患者患有癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。Aspect 29. A method of treating a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of aspects 1 to 27 or a pharmaceutically acceptable salt thereof, wherein the patient suffers from cancer, Chronic autoimmune conditions, inflammatory conditions, proliferative conditions, sepsis, or viral infections.
態樣30. 如態樣29之方法，其中該患者患有癌症。Aspect 30. The method as in aspect 29, wherein the patient has cancer.
態樣31. 如態樣30之方法，其中該癌症為表2之癌症中之任何一或多者。Aspect 31. The method of aspect 30, wherein the cancer is any one or more of the cancers in Table 2.
態樣32. 如態樣31之方法，其中該癌症係選自由以下組成之群：急性單核球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病、混合系白血病、NUT-中線癌、多發性骨髓瘤、小細胞肺癌、神經母細胞瘤、伯基特氏淋巴瘤、宮頸癌、食道癌、卵巢癌、大腸直腸癌、前列腺癌及乳癌。Aspect 32. The method of aspect 31, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mixed-line leukemia, NUT -Midline cancer, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitt’s lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer and breast cancer.
態樣33. 如態樣29至32中任一項之方法，其進一步包含投與適用於治療疾病或病狀之治療有效量之第二治療劑。Aspect 33. The method of any one of aspects 29 to 32, further comprising administering a therapeutically effective amount of a second therapeutic agent suitable for treating the disease or condition.
態樣34. 如態樣28之醫藥組合物，其用於治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。Aspect 34. The pharmaceutical composition of aspect 28, which is used to treat cancer, chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis, or viral infections.
態樣35. 如態樣34之醫藥組合物，其用於治療癌症。Aspect 35. A pharmaceutical composition such as aspect 34, which is used to treat cancer.
態樣36. 如態樣35之醫藥組合物，其中該癌症為表2之癌症中之任何一或多者。Aspect 36. The pharmaceutical composition of aspect 35, wherein the cancer is any one or more of the cancers in Table 2.
態樣37. 如態樣36之醫藥組合物，其中該癌症係選自由以下組成之群：急性單核球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病、混合系白血病、NUT-中線癌、多發性骨髓瘤、小細胞肺癌、神經母細胞瘤、伯基特氏淋巴瘤、宮頸癌、食道癌、卵巢癌、大腸直腸癌、前列腺癌及乳癌。Aspect 37. The pharmaceutical composition of aspect 36, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, and mixed-line leukemia , NUT-midline cancer, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitt’s lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer and breast cancer.
態樣38. 如態樣1至27中任一項之化合物或其醫藥學上可接受之鹽，其用於治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。Aspect 38. The compound of any one of aspects 1 to 27 or a pharmaceutically acceptable salt thereof, which is used for the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis or viral infections .
態樣39. 如態樣38之化合物，其用於治療癌症。Aspect 39. A compound such as aspect 38, which is used to treat cancer.
態樣40. 如態樣39之化合物，其中該癌症為表2之癌症中之任何一或多者。Aspect 40. A compound such as aspect 39, wherein the cancer is any one or more of the cancers in Table 2.
態樣41. 如態樣40之化合物，其中該癌症係選自由以下組成之群：急性單核球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病、混合系白血病、NUT-中線癌、多發性骨髓瘤、小細胞肺癌、神經母細胞瘤、伯基特氏淋巴瘤、宮頸癌、食道癌、卵巢癌、大腸直腸癌、前列腺癌及乳癌。Aspect 41. The compound of aspect 40, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mixed-line leukemia, NUT -Midline cancer, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitt’s lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer and breast cancer.
態樣42. 一種如態樣1至27中任一項之化合物或其醫藥學上可接受之鹽之用途，其係用於製造用以治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染之藥劑。Aspect 42. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of aspects 1 to 27, which is used in the manufacture for the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, and hyperplasia Drugs for sexual diseases, sepsis, or viral infections.
態樣43. 如態樣42之用途，其用於治療癌症。Aspect 43. Like the purpose of aspect 42, it is used to treat cancer.
態樣44. 如態樣43之用途，其中該癌症為表2之癌症中之任何一或多者。Aspect 44. For the purpose of aspect 43, the cancer is any one or more of the cancers in Table 2.
態樣45. 如態樣44之用途，其中該癌症係選自由以下組成之群：急性單核球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病、混合系白血病、NUT-中線癌、多發性骨髓瘤、小細胞肺癌、神經母細胞瘤、伯基特氏淋巴瘤、宮頸癌、食道癌、卵巢癌、大腸直腸癌、前列腺癌及乳癌。Aspect 45. Such as the use of aspect 44, where the cancer is selected from the group consisting of acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, mixed-line leukemia, NUT -Midline cancer, multiple myeloma, small cell lung cancer, neuroblastoma, Burkitt’s lymphoma, cervical cancer, esophageal cancer, ovarian cancer, colorectal cancer, prostate cancer and breast cancer.
態樣IIAspect II
態樣1. 一種具有式Ia
之化合物，
或其醫藥學上可接受之鹽，其中Or a pharmaceutically acceptable salt thereof, in which
L-M-G為
R1a 、R1b 及R1c 各自獨立地選自由氫及鹵基組成之群；R 1a , R 1b and R 1c are each independently selected from the group consisting of hydrogen and halogen;
G為-SO2 -X-Z2 或-CH2 -X-Z2 ；G is -SO 2 -XZ 2 or -CH 2 -XZ 2 ;
R2
係選自由以下組成之群：
R3 係選自由以下組成之群：The R 3 series is selected from the group consisting of:
L為
各R10a 獨立地選自由以下組成之群：氫、鹵基、氰基、C1 - 4 烷基、C1 - 4 烷氧基及羥基；Each R 10a is independently selected from the group consisting of: hydrogen, halo, cyano, C 1 - 4 alkyl, C 1 - 4 alkoxy and hydroxy;
X係選自由以下組成之群：
其中Y連接至Z2 ；Where Y is connected to Z 2 ;
Y為-C(=O)-；Y is -C(=O)-;
o及p各自獨立地為0、1、2或3；o and p are each independently 0, 1, 2 or 3;
Z2 係選自由以下組成之群：-C(R13a )=C(R13b )(R13c )、-C≡CR13d 及Ra4 ，Z 2 selected from the group consisting of the group consisting of: -C (R 13a) = C (R 13b) (R 13c), - C≡CR 13d and R a4,
當X為X-10時或當X為X-45時，Z2 不存在；When X is X-10 or when X is X-45, Z 2 does not exist;
R8a 及R8b 獨立地選自由以下組成之群：氫、-SO2 -C1 -C6 烷基及鹵基；R 8a and R 8b are independently selected from the group consisting of hydrogen, -SO 2 -C 1 -C 6 alkyl and halo;
R13a 、R13b 、R13c 及R13d 各自獨立地選自由以下組成之群：氫、C1 -C6 烷基及二-C1 -C6 烷基胺基C1 -C4 烷基。R 13a , R 13b , R 13c and R 13d are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and di-C 1 -C 6 alkylamino C 1 -C 4 alkyl.
Ra3 係選自由以下組成之群：C1 -C6 烷氧基羰基-、雜環基-羰基-、經鹵基取代之雜環基-羰基-、C1 -C6 烷基醯胺及C1 -C6 烷基磺醯基；R a3 is selected from the group consisting of: C 1 -C 6 alkoxycarbonyl-, heterocyclyl-carbonyl-, heterocyclyl substituted by halo-carbonyl-, C 1 -C 6 alkyl amide and C 1 -C 6 alkylsulfonyl;
Ra4 為-N(H)CH2 CH=CH-Ra5 ；且R a4 is -N(H)CH 2 CH=CH-R a5 ; and
Ra5 係選自由以下組成之群：C1 -C6 烷氧基羰基-、雜環基-羰基-、經鹵基取代之雜環基-羰基-、C1 -C6 烷基醯胺及C1 -C6 烷基磺醯基；R a5 is selected from the group consisting of: C 1 -C 6 alkoxycarbonyl-, heterocyclic group-carbonyl-, heterocyclic group substituted by halo-carbonyl-, C 1 -C 6 alkyl amide and C 1 -C 6 alkylsulfonyl;
其限制條件為：The restrictions are:
當X為X-1，o及p各自為0，且Z2 為C(R13a )=C(R13b )(R13c )時，則R13a 、R13b 及R13c 中無一者為二甲基胺基甲基；When X is X-1, o and p are each 0, and Z 2 is C(R 13a )=C(R 13b )(R 13c ), then none of R 13a , R 13b and R 13c is two Methylaminomethyl;
當X為X-1，R10a
為氫、F、OH、甲基或甲氧基，Z2
為-C≡CR13d
，且R2
為
當X為X-1，Z2
為CH=CH2
，且R2
為
當X為X-9且Z2 為CH=CH2 時，則R10a 不為氫、F或甲基；When X is X-9 and Z 2 is CH=CH 2 , then R 10a is not hydrogen, F or methyl;
僅當X為X-12時，R2 為-CN；且Only when X is X-12, R 2 is -CN; and
式(I)化合物不為
態樣2. 如態樣1之化合物，其具有式II
：
或其醫藥學上可接受之鹽。Or its pharmaceutically acceptable salt.
態樣3. 如態樣1之化合物，其具有式XI 
或其醫藥學上可接受之鹽。Or its pharmaceutically acceptable salt.
態樣4. 如態樣1至3中任一項之化合物，其中：Aspect 4. The compound of any one of aspects 1 to 3, wherein:
R2
係選自由以下組成之群：
R10a 係選自由以下組成之群：氫、氟、氰基、甲基、甲氧基、乙氧基及羥基；R 10a is selected from the group consisting of hydrogen, fluorine, cyano, methyl, methoxy, ethoxy and hydroxyl;
Z2 係選自由以下組成之群：-C(R13a )=C(R13b )(R13c )及-C≡CR13d ；Z 2 is selected from the group consisting of: -C(R 13a )=C(R 13b )(R 13c ) and -C≡CR 13d ;
R8a 及R8b 獨立地選自由以下組成之群：氫及氟；且R 8a and R 8b are independently selected from the group consisting of hydrogen and fluorine; and
R13a 、R13b 、R13c 及R13d 各自獨立地選自由以下組成之群：氫、甲基及二甲基胺基甲基。R 13a , R 13b , R 13c and R 13d are each independently selected from the group consisting of hydrogen, methyl, and dimethylaminomethyl.
態樣5. 如態樣1至4中任一項之化合物，其中R2
為
或其醫藥學上可接受之鹽。Or its pharmaceutically acceptable salt.
態樣6. 如態樣1至4之化合物或其醫藥學上可接受之鹽，其中R2 為Aspect 6. The compound of aspects 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R 2 is
或其醫藥學上可接受之鹽。Or its pharmaceutically acceptable salt.
態樣7. 如態樣4之化合物或其醫藥學上可接受之鹽，其中R2
為
態樣8. 如態樣1至7中任一項之化合物，其中R8a 及R8b 為氫，或其醫藥學上可接受之鹽。Aspect 8. The compound of any one of aspects 1 to 7, wherein R 8a and R 8b are hydrogen, or a pharmaceutically acceptable salt thereof.
態樣9. 如態樣1至7中任一項之化合物，其中R8a 為氟，或其醫藥學上可接受之鹽。Aspect 9. The compound of any one of aspects 1 to 7, wherein R 8a is fluorine, or a pharmaceutically acceptable salt thereof.
態樣10. 如態樣1至9中任一項之化合物，其中R1a 、R1b 及R1c 中之至少一者為氟，或其醫藥學上可接受之鹽。Aspect 10. The compound of any one of aspects 1 to 9, wherein at least one of R 1a , R 1b and R 1c is fluorine, or a pharmaceutically acceptable salt thereof.
態樣11. 如態樣1至10中任一項之化合物，其中R10a 為氫，或其醫藥學上可接受之鹽。Aspect 11. The compound of any one of aspects 1 to 10, wherein R 10a is hydrogen, or a pharmaceutically acceptable salt thereof.
態樣12. 如態樣1至10中任一項之化合物，其中R10a 為氟，或其醫藥學上可接受之鹽。Aspect 12. The compound of any one of aspects 1 to 10, wherein R 10a is fluorine, or a pharmaceutically acceptable salt thereof.
態樣13. 如態樣1至12中任一項之化合物，其中X為X-1、X-9或X-12，或其醫藥學上可接受之鹽。Aspect 13. The compound of any one of aspects 1 to 12, wherein X is X-1, X-9 or X-12, or a pharmaceutically acceptable salt thereof.
態樣14. 如態樣1至13中任一項之化合物，其中X為X-1，或其醫藥學上可接受之鹽。Aspect 14. The compound of any one of aspects 1 to 13, wherein X is X-1, or a pharmaceutically acceptable salt thereof.
態樣15. 如態樣1至13中任一項之化合物，其中X為X-9，或其醫藥學上可接受之鹽。Aspect 15. The compound of any one of aspects 1 to 13, wherein X is X-9, or a pharmaceutically acceptable salt thereof.
態樣16. 如態樣1至12中任一項之化合物，其中X為X-10，或其醫藥學上可接受之鹽。Aspect 16. The compound of any one of aspects 1 to 12, wherein X is X-10, or a pharmaceutically acceptable salt thereof.
態樣17. 如態樣1至13中任一項之化合物，其中X為X-12，或其醫藥學上可接受之鹽。Aspect 17. The compound of any one of aspects 1 to 13, wherein X is X-12, or a pharmaceutically acceptable salt thereof.
態樣18. 如態樣1至17中任一項之化合物，其中R3
為
或其醫藥學上可接受之鹽。Or its pharmaceutically acceptable salt.
態樣19. 如態樣1至18中任一項之化合物，其中R3
為
或其醫藥學上可接受之鹽。Or its pharmaceutically acceptable salt.
態樣20. 如態樣1至19中任一項之化合物，其中Z2 為-C(R13a )=C(R13b )(R13c )，或其醫藥學上可接受之鹽。Aspect 20. The compound of any one of aspects 1 to 19, wherein Z 2 is -C(R 13a )=C(R 13b )(R 13c ), or a pharmaceutically acceptable salt thereof.
態樣21. 如態樣20之化合物，其中R13a 及R13b 為氫，且R13c 為二甲基胺基甲基，或其醫藥學上可接受之鹽。Aspect 21. The compound of aspect 20, wherein R 13a and R 13b are hydrogen, and R 13c is dimethylaminomethyl, or a pharmaceutically acceptable salt thereof.
態樣22. 如態樣20之化合物，其中R13c 為甲基，且R13a 及R13b 為氫，或其醫藥學上可接受之鹽。Aspect 22. The compound of aspect 20, wherein R 13c is methyl, and R 13a and R 13b are hydrogen, or a pharmaceutically acceptable salt thereof.
態樣23. 如態樣20之化合物，其中R13a 、R13b 及R13c 中之每一者為氫，或其醫藥學上可接受之鹽。Aspect 23. The compound of aspect 20, wherein each of R 13a , R 13b and R 13c is hydrogen, or a pharmaceutically acceptable salt thereof.
態樣24. 如態樣1至12及18至23中任一項之化合物，其中X係選自由以下組成之群：
其中羰基連接至Z2 ，或其醫藥學上可接受之鹽。Wherein the carbonyl group is connected to Z 2 , or a pharmaceutically acceptable salt thereof.
態樣25. 如態樣1至19中任一項之化合物，其中Z2
係選自由以下組成之群：
或其醫藥學上可接受之鹽。Or its pharmaceutically acceptable salt.
態樣26. 如態樣1之化合物，其中該化合物為表1之化合物中之任何一或多者，或其醫藥學上可接受之鹽。Aspect 26. The compound of aspect 1, wherein the compound is any one or more of the compounds in Table 1, or a pharmaceutically acceptable salt thereof.
態樣27. 一種醫藥組合物，其包含如態樣1至26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載劑。Aspect 27. A pharmaceutical composition comprising the compound of any one of aspects 1 to 26 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
態樣28. 一種治療患者之方法，該方法包含向該患者投與治療有效量之態樣1至26中任一項之化合物或其醫藥學上可接受之鹽，其中該患者患有癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。Aspect 28. A method of treating a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of any one of aspects 1 to 26 or a pharmaceutically acceptable salt thereof, wherein the patient suffers from cancer, Chronic autoimmune conditions, inflammatory conditions, proliferative conditions, sepsis, or viral infections.
態樣29. 如態樣28之方法，其中該患者患有癌症。Aspect 29. The method as in aspect 28, wherein the patient has cancer.
態樣30. 如態樣29之方法，其中該癌症為表2之癌症中之任何一或多者。Aspect 30. The method of aspect 29, wherein the cancer is any one or more of the cancers in Table 2.
態樣31. 如態樣30之方法，其中該癌症係選自由以下組成之群：急性單核細胞性白血病、急性淋巴球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病。Aspect 31. The method of aspect 30, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia And mixed lineage leukemia.
態樣32. 如態樣28至31中任一項之方法，其進一步包含投與適用於治療疾病或病狀之治療有效量之第二治療劑。Aspect 32. The method of any one of aspects 28 to 31, further comprising administering a therapeutically effective amount of a second therapeutic agent suitable for treating the disease or condition.
態樣33. 如態樣27之醫藥組合物，其用於治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。Aspect 33. The pharmaceutical composition of aspect 27, which is used to treat cancer, chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis, or viral infections.
態樣34. 如態樣33之醫藥組合物，其用於治療癌症。Aspect 34. A pharmaceutical composition such as aspect 33, which is used to treat cancer.
態樣35. 如態樣34之醫藥組合物，其中該癌症為表2之癌症中之任何一或多者。Aspect 35. The pharmaceutical composition of aspect 34, wherein the cancer is any one or more of the cancers in Table 2.
態樣36. 如態樣34之醫藥組合物，其中該癌症係選自由以下組成之群：急性單核細胞性白血病、急性淋巴球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病。Aspect 36. The pharmaceutical composition of aspect 34, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytes Sexual leukemia and mixed lineage leukemia.
態樣37. 如態樣1至26中任一項之化合物或其醫藥學上可接受之鹽，其用於治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染。Aspect 37. The compound of any one of aspects 1 to 26 or a pharmaceutically acceptable salt thereof, which is used for the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, proliferative disorders, sepsis or viral infections .
態樣38. 如態樣37之化合物，其用於治療癌症。Aspect 38. A compound such as aspect 37, which is used to treat cancer.
態樣39. 如態樣38之化合物，其中該癌症為表2之癌症中之任何一或多者。Aspect 39. A compound such as aspect 38, wherein the cancer is any one or more of the cancers in Table 2.
態樣40. 如態樣38之化合物，其中該癌症係選自由以下組成之群：急性單核細胞性白血病、急性淋巴球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病。Aspect 40. A compound such as aspect 38, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia And mixed lineage leukemia.
態樣41. 一種如態樣1至26中任一項之化合物或其醫藥學上可接受之鹽之用途，其係用於製造用以治療癌症、慢性自體免疫病症、炎性病狀、增生性病症、敗血症或病毒感染之藥劑。Aspect 41. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of Aspects 1 to 26, which is used in the manufacture for the treatment of cancer, chronic autoimmune disorders, inflammatory conditions, and hyperplasia Drugs for sexual diseases, sepsis, or viral infections.
態樣42. 如態樣41之用途，其用於治療癌症。Aspect 42. Like the purpose of aspect 41, it is used to treat cancer.
態樣43. 如態樣42之用途，其中該癌症為表2之癌症中之任何一或多者。Aspect 43. As the use of aspect 42, where the cancer is any one or more of the cancers in Table 2.
態樣44. 如態樣42之用途，其中該癌症係選自由以下組成之群：急性單核細胞性白血病、急性淋巴球性白血病、急性骨髓性白血病、慢性骨髓性白血病、慢性淋巴球性白血病及混合系白血病。Aspect 44. Such as the use of aspect 42, wherein the cancer is selected from the group consisting of acute monocytic leukemia, acute lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia And mixed lineage leukemia.
實例Instance
實例1Example 1
S7 之合成 
S1S1 之合成Synthesis
在0℃下，向(1R,2S)-2-胺基環丁烷鹽酸鹽S0 (11 g，79.9 mmol)及Boc2 O (20.9 g，95.9 mmol)於二氯甲烷(200 mL)中之溶液中，逐滴添加Et3 N (20.9 mL，119.9 mmol)。使反應混合物升溫至室溫。在攪拌隔夜之後，用飽和鹽水洗滌反應混合物，且用二氯甲烷萃取水相兩次。經合併之有機溶劑經Na2 SO4 脫水，過濾且真空濃縮。藉由急驟管柱層析來純化殘餘物，得到呈油狀之中間物S1 (15.5 g，96%)。1 H NMR (400 MHz, CDCl3 ) δ 4.85 (s, 1H), 4.16 (s, 1H), 3.80 (s, 1H), 2.02-1.95 (m, 1H), 1.93-1.87 (m, 1H), 1.86-1.77 (m, 2H), 1.70-1.65 (m, 1H), 1.59-1.51 (m, 2H), 1.45 (s, 9H)。To (1R, 2S)-2-aminocyclobutane hydrochloride S0 (11 g, 79.9 mmol) and Boc 2 O (20.9 g, 95.9 mmol) in dichloromethane (200 mL) at 0°C To the solution, add Et 3 N (20.9 mL, 119.9 mmol) dropwise. The reaction mixture was allowed to warm to room temperature. After stirring overnight, the reaction mixture was washed with saturated brine, and the aqueous phase was extracted twice with dichloromethane. The combined the organic solvent was Na 2 SO 4 dried, filtered and concentrated in vacuo. The residue was purified by flash column chromatography to obtain intermediate S1 (15.5 g, 96%) as an oil. 1 H NMR (400 MHz, CDCl 3 ) δ 4.85 (s, 1H), 4.16 (s, 1H), 3.80 (s, 1H), 2.02-1.95 (m, 1H), 1.93-1.87 (m, 1H), 1.86-1.77 (m, 2H), 1.70-1.65 (m, 1H), 1.59-1.51 (m, 2H), 1.45 (s, 9H).
S2S2 之合成Synthesis
在-35℃下，向亞硫醯二氯(7 mL，96.3 mmol)於無水乙腈(150 mL)中之溶液中，添加中間物S1 (15.5 g，77.0 mmol)於乙腈(150 mL)中之溶液。接著，逐滴添加吡啶(18.7 mL，231 mmol)，且使反應混合物緩慢升溫至室溫。在攪拌隔夜之後，濃縮反應混合物，且添加水及乙酸乙酯。分離有機層且用乙酸乙酯萃取水層三次。經合併之有機溶劑經Na2 SO4 脫水，過濾且濃縮。藉由管柱層析來純化殘餘物，得到呈油狀之中間物S2 (18.8 g，98%)。1H NMR (400 MHz, CDCl3) δ 5.74 (t, J = 4.6 Hz, 1H), 4.46 (s, 1H), 2.14-2.09 (m, 1H), 1.90-1.68 (m, 5H), 1.52 (s, 9H)。At -35℃, to a solution of thiol dichloride (7 mL, 96.3 mmol) in anhydrous acetonitrile (150 mL), add intermediate S1 (15.5 g, 77.0 mmol) in acetonitrile (150 mL) Solution. Next, pyridine (18.7 mL, 231 mmol) was added dropwise, and the reaction mixture was slowly warmed to room temperature. After stirring overnight, the reaction mixture was concentrated, and water and ethyl acetate were added. The organic layer was separated and the aqueous layer was extracted three times with ethyl acetate. The combined the organic solvent was Na 2 SO 4 dried, filtered, and concentrated. The residue was purified by column chromatography to obtain intermediate S2 (18.8 g, 98%) as an oil. 1H NMR (400 MHz, CDCl3) δ 5.74 (t, J = 4.6 Hz, 1H), 4.46 (s, 1H), 2.14-2.09 (m, 1H), 1.90-1.68 (m, 5H), 1.52 (s, 9H).
S3S3 之合成Synthesis
在0℃下，向中間物S2 (18.8 g，76 mmol)於乙腈(100 mL)及H2 O (100 mL)中之溶液中，逐份添加NaIO4 (24.4 g，114 mmol)，隨後添加RuCl3 .3H2 O (315 mg，1.5 mmol)。反應物在室溫下攪拌2小時。接著，用二乙醚萃取水層三次。經合併之有機溶劑經Na2 SO4 脫水，過濾且濃縮。藉由管柱層析來純化殘餘物，得到呈白色固體狀之標題化合物S3 (19 g，95%)。1 H NMR (400 MHz, CDCl3 ) δ 5.18-5.15 (m, 1H), 4.56-4.53 (m, 1H), 2.23-2.18 (m, 1H), 2.06-1.95 (m, 3H), 1.87-1.77 (m, 2H), 1.55 (s, 9H)。針對C10 H17 NO5 S [M+Na]+ 之ESI-MS計算值=286.07，實驗值：286.10。At 0°C, to a solution of intermediate S2 (18.8 g, 76 mmol) in acetonitrile (100 mL) and H 2 O (100 mL), NaIO 4 (24.4 g, 114 mmol) was added portionwise, followed by RuCl 3 .3H 2 O (315 mg, 1.5 mmol). The reaction was stirred at room temperature for 2 hours. Next, the aqueous layer was extracted three times with diethyl ether. The combined the organic solvent was Na 2 SO 4 dried, filtered, and concentrated. The residue was purified by column chromatography to obtain the title compound S3 (19 g, 95%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 5.18-5.15 (m, 1H), 4.56-4.53 (m, 1H), 2.23-2.18 (m, 1H), 2.06-1.95 (m, 3H), 1.87-1.77 (m, 2H), 1.55 (s, 9H). ESI-MS calculated value for C 10 H 17 NO 5 S [M+Na] + =286.07, experimental value: 286.10.
S5S5 之合成Synthesis
向2-(3-氟苯基)乙腈(5 g，37.01 mmol)於MeOH (50 mL)中之溶液中，添加甲醇鈉(12 mL，55.52 mmol，25 wt%於甲醇中)，且短暫攪拌。向此溶液中添加1-苯甲基六氫吡啶-4-酮(7.01 g，37.01 mmol)，且使反應物回流。在隔夜之後，移除溶劑，添加水及EtOAc且進行分離。水層另外用EtOAc萃取兩次，經Na2 SO4 脫水，過濾且濃縮，得到S4 ，其不經進一步純化即使用。To a solution of 2-(3-fluorophenyl)acetonitrile (5 g, 37.01 mmol) in MeOH (50 mL), add sodium methoxide (12 mL, 55.52 mmol, 25 wt% in methanol), and stir briefly . To this solution was added 1-benzylhexahydropyridin-4-one (7.01 g, 37.01 mmol), and the reaction was refluxed. After overnight, the solvent was removed, water and EtOAc were added and separation was performed. Further aqueous layer was extracted twice with EtOAc, and Na 2 SO 4 dried, filtered and concentrated to give S4, which was used without further purification.
將粗產物S4 (37.01 mmol)再溶解於MeOH (50 mL)中，且緩慢添加NaBH4 (4.2 g，111.03 mmol)。在隔夜之後，藉由TLC檢查反應(若反應不完全，則添加更多NaBH4 )。在完成S4 轉化為S5 之後，添加8 mL水，且濃縮反應物，接著添加更多H2 O及EtOAc且進行分離。水層用EtOAc萃取三次，經Na2 SO4 脫水，過濾，濃縮且藉由管柱層析(DCM/EtOAc梯度)來純化，得到呈油狀之S5 。1 H NMR (400 MHz, MeOD) δ 7.44-7.38 (m, 1H), 7.32-7.28 (m, 4H), 7.27-7.22 (m, 1H), 7.18-7.16 (m, 1H), 7.13-7.05 (m, 2H), 3.98 (d,J = 7.1 Hz, 1H), 3.48 (s, 2H), 2.96-2.87 (m, 2H), 2.00-1.92 (m, 2H), 1.87-1.80 (m, 1H), 1.79-1.72 (m, 1H), 1.59-1.52 (m, 1H), 1.50-1.39 (m, 2H)；針對C20 H21 FN2 [M+H]+ 之ESI-MS計算值= 309.17，實驗值：309.16。The crude product S4 (37.01 mmol) was redissolved in MeOH (50 mL), and NaBH 4 (4.2 g, 111.03 mmol) was added slowly. After overnight, check the reaction by TLC (if the reaction is not complete, add more NaBH 4 ). After completion of the conversion into S5 S4, 8 mL of water was added, and the reaction was concentrated, followed by addition of additional H 2 O and EtOAc and separated. The aqueous layer was extracted three times with EtOAc, and Na 2 SO 4 dried, filtered, concentrated and purified by column chromatography (DCM / EtOAc gradient) to afford an oil of S5. 1 H NMR (400 MHz, MeOD) δ 7.44-7.38 (m, 1H), 7.32-7.28 (m, 4H), 7.27-7.22 (m, 1H), 7.18-7.16 (m, 1H), 7.13-7.05 ( m, 2H), 3.98 (d, J = 7.1 Hz, 1H), 3.48 (s, 2H), 2.96-2.87 (m, 2H), 2.00-1.92 (m, 2H), 1.87-1.80 (m, 1H) , 1.79-1.72 (m, 1H), 1.59-1.52 (m, 1H), 1.50-1.39 (m, 2H); calculated for C 20 H 21 FN 2 [M+H] + ESI-MS = 309.17, Experimental value: 309.16.
S7 及 S8 之合成 
向乾燥圓底燒瓶中，添加化合物S5 (2.18 g，7.07 mmol)、18-冠-6 (5.61 g，21.21 mmol)及化合物S3 (5.58 g，21.21 mmol)。接著，燒瓶用擦拭紙覆蓋且在真空乾燥器中乾燥1-2天。在乾燥步驟之後，自乾燥器移出燒瓶且迅速用隔膜封蓋。對系統抽真空且保護在氮氣氛圍下。接著，將燒瓶中之內含物用60 mL新鮮蒸餾THF徹底溶解。接著，對溶液短暫抽真空，接著置於氮氣氛圍下(另外重複此吹掃兩次)。將反應物冷卻至0℃，逐滴添加KHMDS (0.5 M於甲苯中，42.4 mL，21.21 mmol)，且接著使反應物升溫至室溫且攪拌隔夜。在隔在隔夜之後，添加濃H2 SO4 (0.6 mL，11.31 mmol)於H2 O (10 mL)中之溶液(注意：溶液之pH應＜7)，且劇烈攪拌溶液隔夜。接著，反應混合物經緩慢淬滅且用飽和NaHCO3 鹼化，用乙酸乙酯萃取三次。經合併之有機溶劑經Na2 SO4 脫水，過濾且濃縮。藉由管柱層析來純化殘餘物，得到呈黃色固體狀之比率為3:2的非對映異構體混合物(2.5 g，73%)。接著，藉由逆相製備型HPLC來分離非對映異構體，分別得到呈三氟乙酸之鹽之對映體純標題化合物S7 (1.2 g，36%)及S8 (0.8 g，24%)。To a dry round bottom flask, compound S5 (2.18 g, 7.07 mmol), 18-crown-6 (5.61 g, 21.21 mmol) and compound S3 (5.58 g, 21.21 mmol) were added. Next, the flask was covered with wipes and dried in a vacuum dryer for 1-2 days. After the drying step, the flask was removed from the desiccator and quickly capped with a septum. Evacuate the system and protect it under a nitrogen atmosphere. Next, completely dissolve the contents of the flask with 60 mL of freshly distilled THF. Then, the solution was evacuated briefly, and then placed under a nitrogen atmosphere (repeating the purging twice additionally). The reaction was cooled to 0°C, KHMDS (0.5 M in toluene, 42.4 mL, 21.21 mmol) was added dropwise, and then the reaction was warmed to room temperature and stirred overnight. After overnight, add a solution of concentrated H 2 SO 4 (0.6 mL, 11.31 mmol) in H 2 O (10 mL) (note: the pH of the solution should be less than 7), and stir the solution vigorously overnight. Then, the reaction mixture was slowly quenched and basified with saturated NaHCO 3 and extracted three times with ethyl acetate. The combined the organic solvent was Na 2 SO 4 dried, filtered, and concentrated. The residue was purified by column chromatography to obtain a mixture of diastereomers (2.5 g, 73%) in a ratio of 3:2 as a yellow solid. Next, the diastereomers were separated by reverse phase preparative HPLC to obtain the enantiomerically pure title compounds S7 (1.2 g, 36%) and S8 (0.8 g, 24%) as the salt of trifluoroacetic acid, respectively. .
藉由在比率為4:1之己烷與二氯甲烷溶液中再結晶來分離對映純化合物S7 。S7 之數據 ： 1 H NMR (400 MHz, MeOD) δ 7.44-7.39 (m, 1H), 7.35 (d,J = 7.9 Hz, 1H), 7.31-7.22 (m, 6H), 7.11-7.06 (m, 1H), 3.82-3.77 (m, 1H), 3.46 (s, 2H), 2.91 (t,J = 12.5 Hz, 2H), 2.81-2.76 (m, 1H), 2.07-1.93 (m, 5H), 1.80-1.72 (m, 1H), 1.62-1.46 (m, 5H), 1.33 (s, 9H), 1.27-1.17 (m, 2H)；C30 H38 FN3 O2 [M+H]+ 之ESI-MS計算值=492.29，實驗值：492.36。[α]D 20 = + 23.1, (c 1.17×10-3 g/mL, MeOH);t R (UPLC) =4.46 min。S8 之數據 ： 1 H NMR (400 MHz, MeOD) δ 7.50-7.43 (m, 6H), 7.27 (d,J = 7.3 Hz, 1H), 7.20 (d,J = 9.9 Hz, 1H), 7.14 (t,J = 8.3 Hz, 1H), 4.24 (s, 2H), 4.02-3.98 (m, 1H), 3.54-3.45 (m, 2H), 3.08 (t,J = 11.4 Hz, 2H), 2.88-2.83 (m, 2H), 2.59 (t,J = 11.8 Hz, 1H), 2.25 (d,J = 14.0 Hz, 1H), 1.99-1.87 (m, 2H), 1.79-1.74 (m, 1H), 1.67-1.57 (m, 3H), 1.46 (s, 9H), 1.43-1.37 (m, 2H), 1.33-1.18 (m, 1H)；C30 H38 FN3 O2 [M+H]+ 之ESI-MS計算值=492.29，實驗值：492.36。[α]D 20 = + 9.4, (c 1.07 ×10-3 g/mL, MeOH);t R (UPLC) = 4.63 min。 The enantiomerically pure compound S7 was separated by recrystallization in a 4:1 ratio of hexane and dichloromethane solution. S7 data : 1 H NMR (400 MHz, MeOD) δ 7.44-7.39 (m, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.31-7.22 (m, 6H), 7.11-7.06 (m, 1H), 3.82-3.77 (m, 1H), 3.46 (s, 2H), 2.91 (t, J = 12.5 Hz, 2H), 2.81-2.76 (m, 1H), 2.07-1.93 (m, 5H), 1.80 -1.72 (m, 1H), 1.62-1.46 (m, 5H), 1.33 (s, 9H), 1.27-1.17 (m, 2H); C 30 H 38 FN 3 O 2 [M+H] + ESI- MS calculated value=492.29, experimental value: 492.36. [α] D 20 = + 23.1, (c 1.17×10 -3 g/mL, MeOH); t R (UPLC) = 4.46 min. S8 data : 1 H NMR (400 MHz, MeOD) δ 7.50-7.43 (m, 6H), 7.27 (d, J = 7.3 Hz, 1H), 7.20 (d, J = 9.9 Hz, 1H), 7.14 (t , J = 8.3 Hz, 1H), 4.24 (s, 2H), 4.02-3.98 (m, 1H), 3.54-3.45 (m, 2H), 3.08 (t, J = 11.4 Hz, 2H), 2.88-2.83 ( m, 2H), 2.59 (t, J = 11.8 Hz, 1H), 2.25 (d, J = 14.0 Hz, 1H), 1.99-1.87 (m, 2H), 1.79-1.74 (m, 1H), 1.67-1.57 (m, 3H), 1.46 (s, 9H), 1.43-1.37 (m, 2H), 1.33-1.18 (m, 1H); C 30 H 38 FN 3 O 2 [M+H] + ESI-MS calculation Value=492.29, experimental value: 492.36. [α] D 20 = + 9.4, (c 1.07 ×10 -3 g/mL, MeOH); t R (UPLC) = 4.63 min.
S13
及S16
之合成
S9S9 之合成Synthesis
向乾燥RB燒瓶中添加S7 (3 g，6.1 mmol)，用擦拭紙覆蓋且置於已置於真空1-2天之乾燥器中。在真空抽吸步驟之後，自乾燥器移出燒瓶，且迅速用隔膜封蓋，且在N2 氛圍下對系統進行抽真空。向燒瓶中添加無水甲苯(30 ml，Sigma，目錄號244511)，接著在冰浴中冷卻至0℃。在0℃下，在攪拌下，用注射器緩慢將二異丁基氫化鋁(25%於甲苯中，16.4 mL，24.4 mmol，4當量)注射至反應混合物中。接著，移出冰浴，使用UPLC-質譜監測反應(約4 h)。在S7 之質譜(492)之後，在0℃下，將20 ml NaOH (1 M)溶液緩慢添加至反應混合物中，以淬滅反應物。在攪拌5 min之後，移出冰浴且添加額外20 ml飽和鹽水。接著，添加約50 mL EA，形成凝膠。凝膠用矽藻土過濾，且用EA洗滌，合併溶劑。溶液分別用EA、二氯甲烷(DCM)萃取兩次。有機溶劑經Na2 SO4 脫水，過濾且在旋轉真空下濃縮。接著添加DCM (50 ml)，且再次濃縮(重複兩次以完全移除EA)。 S7 (3 g, 6.1 mmol) was added to the dry RB flask, covered with wipe paper and placed in a desiccator that had been placed in a vacuum for 1-2 days. After the vacuum suction step, the flask was removed from the desiccator, and quickly covered with a septum, and the system was evacuated under N 2 atmosphere. Anhydrous toluene (30 ml, Sigma, catalog number 244511) was added to the flask, followed by cooling to 0°C in an ice bath. At 0°C, under stirring, diisobutylaluminum hydride (25% in toluene, 16.4 mL, 24.4 mmol, 4 equivalents) was slowly injected into the reaction mixture with a syringe. Then, the ice bath was removed, and the reaction was monitored using UPLC-mass spectrometry (approximately 4 h). After the mass spectrum of S7 (492), 20 ml of NaOH (1 M) solution was slowly added to the reaction mixture at 0°C to quench the reaction. After stirring for 5 min, the ice bath was removed and an additional 20 ml saturated brine was added. Next, add about 50 mL of EA to form a gel. The gel was filtered through celite and washed with EA, and the solvents were combined. The solution was extracted twice with EA and dichloromethane (DCM) respectively. The organic solvent was Na 2 SO 4 dried, filtered and concentrated under rotary vacuum. Then DCM (50 ml) was added, and concentrated again (repeat twice to completely remove EA).
接著，將殘餘物再溶解於MeOH (100 mL)中，在0℃下緩慢添加NaBH4 (461 mg，12.2 mmol，4當量)。在添加NaBH4 完成後，在室溫下攪拌反應混合物，同時使用UPLC-Mass(超效能液相層析質法)監測其(約2天)。若仍存在亞胺中間物(質量：495)，則每12小時添加NaBH4 (1當量)。在亞胺中間物消失之後，濃縮反應混合物，且用水稀釋。分別用EA、DCM萃取溶液兩次。有機溶劑經Na2 SO4 脫水，過濾且旋轉真空濃縮，得到無需進一步純化之粗產物S9 (質量：496)。1H NMR (400 MHz, MeOD) δ 7.41-7.35 (m, 1H), 7.33-7.23 (m, 6H), 7.18 (d, J = 11.6 Hz, 1H), 6.99-6.95 (m, 1H), 4.07-4.02 (m, 1H), 3.52-3.44 (m, 2H), 3.24 (d, J = 14.4 Hz, 1H), 3.09 (d, J = 14.4 Hz, 1H), 2.98 (d, J = 11.2 Hz, 1H), 2.91 (d, J = 10.8 Hz, 1H), 2.35-2.29 (m, 1H), 2.12-2.04 (m, 2H), 2.01-1.94 (m, 2H), 1.77-1.69 (m, 1H), 1.61-1.58 (m, 1H), 1.54-1.47 (m, 2H), 1.44 (s, 9H), 1.41-1.29 (m, 3H), 1.22-1.14 (m, 2H)；C30 H42 FN3 O2 [M+H]+ 之ESI-MS計算值=496.33，實驗值：496.48。Next, the residue was redissolved in MeOH (100 mL), and NaBH 4 (461 mg, 12.2 mmol, 4 equivalents) was slowly added at 0°C. After the addition of NaBH 4 was completed, the reaction mixture was stirred at room temperature while monitoring it using UPLC-Mass (Ultra Performance Liquid Chromatography) (about 2 days). If there is still an imine intermediate (mass: 495), NaBH 4 (1 equivalent) is added every 12 hours. After the imine intermediate disappeared, the reaction mixture was concentrated and diluted with water. The solution was extracted twice with EA and DCM respectively. The organic solvent was dehydrated by Na 2 SO 4 , filtered and concentrated in a rotary vacuum to obtain the crude product S9 (quality: 496) without further purification. 1H NMR (400 MHz, MeOD) δ 7.41-7.35 (m, 1H), 7.33-7.23 (m, 6H), 7.18 (d, J = 11.6 Hz, 1H), 6.99-6.95 (m, 1H), 4.07- 4.02 (m, 1H), 3.52-3.44 (m, 2H), 3.24 (d, J = 14.4 Hz, 1H), 3.09 (d, J = 14.4 Hz, 1H), 2.98 (d, J = 11.2 Hz, 1H ), 2.91 (d, J = 10.8 Hz, 1H), 2.35-2.29 (m, 1H), 2.12-2.04 (m, 2H), 2.01-1.94 (m, 2H), 1.77-1.69 (m, 1H), 1.61-1.58 (m, 1H), 1.54-1.47 (m, 2H), 1.44 (s, 9H), 1.41-1.29 (m, 3H), 1.22-1.14 (m, 2H); C 30 H 42 FN 3 O 2 ESI-MS calculated value of [M+H] + =496.33, experimental value: 496.48.
S10S10 之合成Synthesis
向中間物S9 (3 g，6.05 mmol)於乙腈(150 mL)中之溶液中，添加1,3-二溴丙烷(1.47 g，0.74 ml，7.26 mmol，1.2當量)、K2 CO3 (2.51 g，18 mmol，3當量)及KI (100 mg，0.6 mmol，0.1當量)。在80℃下攪拌混合物1到2天。接著，用矽藻土過濾混合物，以移除大部分K2 CO3 固體。濃縮混合物，且將其溶解於水中，分別用乙酸乙酯及DCM萃取兩次，經Na2 SO4 脫水，且真空蒸發溶劑，得到無需進一步純化之粗產物S10 。1H NMR (400 MHz, MeOD) δ 7.47-7.40 (m, 6H), 7.16-7.03 (m, 3H), 4.52-4.46 (m, 2H), 4.38-4.31 (m, 1H), 4.19-4.10 (m, 2H), 4.19 (s, 2H), 3.70-3.66 (m, 1H), 3.44-3.40 (m, 3H), 3.01-2.90 (m, 2H), 2.79-2.73 (m, 1H), 2.56-2.46 (m, 1H), 2.42-2.36 (m, 1H), 2.05-1.93 (m, 4H), 1.82-1.73 (m, 2H), 1.68-1.57 (m, 3H), 1.37-1.29 (m, 1H), 1.22 (s, 9H), 1.06-0.98 (m, 1H)。C33 H46 FN3 O2 [M+H]+ 之ESI-MS計算值=536.36，實驗值：536.44。To a solution of intermediate S9 (3 g, 6.05 mmol) in acetonitrile (150 mL), add 1,3-dibromopropane (1.47 g, 0.74 ml, 7.26 mmol, 1.2 equivalents), K 2 CO 3 (2.51 g, 18 mmol, 3 equivalents) and KI (100 mg, 0.6 mmol, 0.1 equivalents). The mixture was stirred at 80°C for 1 to 2 days. Next, the mixture was filtered through diatomaceous earth to remove most of the K 2 CO 3 solids. The mixture was concentrated, and dissolved in water and DCM were extracted twice with ethyl acetate, dehydrated over Na 2 SO 4, and the solvent was evaporated in vacuo to give the crude product was used without further purification S10. 1H NMR (400 MHz, MeOD) δ 7.47-7.40 (m, 6H), 7.16-7.03 (m, 3H), 4.52-4.46 (m, 2H), 4.38-4.31 (m, 1H), 4.19-4.10 (m , 2H), 4.19 (s, 2H), 3.70-3.66 (m, 1H), 3.44-3.40 (m, 3H), 3.01-2.90 (m, 2H), 2.79-2.73 (m, 1H), 2.56-2.46 (m, 1H), 2.42-2.36 (m, 1H), 2.05-1.93 (m, 4H), 1.82-1.73 (m, 2H), 1.68-1.57 (m, 3H), 1.37-1.29 (m, 1H) , 1.22 (s, 9H), 1.06-0.98 (m, 1H). ESI-MS calculated value for C 33 H 46 FN 3 O 2 [M+H] + =536.36, experimental value: 536.44.
S11S11 之合成Synthesis
將化合物S10 (2.55 g，4.76 mmol)溶解於二氯甲烷(5 mL)中，且在0℃下緩慢添加三氟乙酸(10 mL)。在室溫下攪拌2 h之後，真空濃縮反應混合物，且將其再溶解於100 mL DCM中。添加Amberlyst® A21 (3 g)(樹脂，Sigma，目錄號216410)，且攪拌30 min，以中和TFA。接著，過濾樹脂，且濃縮有機溶劑，得到無需進一步純化之粗產物S11 。針對C28 H38 FN3 [M+H]+ 之ESI-MS計算值=436.30，實驗值：436.32。Compound S10 (2.55 g, 4.76 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (10 mL) was slowly added at 0°C. After stirring for 2 h at room temperature, the reaction mixture was concentrated in vacuo and redissolved in 100 mL DCM. Add Amberlyst® A21 (3 g) (resin, Sigma, catalog number 216410) and stir for 30 min to neutralize TFA. Then, the resin was filtered, and the organic solvent was concentrated to obtain the crude product S11 without further purification. ESI-MS calculated value for C 28 H 38 FN 3 [M+H] + =436.30, experimental value: 436.32.
S12S12 之合成Synthesis
將S11 (2.07 g，4.75 mmol)溶解於無水二氯甲烷(50 mL)中。接著，在0℃下添加N,N-二異丙基乙胺 (3.31 mL，19 mmol)及二碳酸二甲酯(764 mg，5.7 mmol，1.2當量)。在室溫下攪拌2 h之後，在真空下濃縮反應混合物。藉由逆相製備型HPLC純化殘餘物，得到呈三氟乙酸鹽形式之標題化合物S12 。1H NMR (400 MHz, MeOD) δ 7.48-7.40 (m, 6H), 7.14-7.10 (m, 2H), 7.02 (d, J = 7.6 Hz, 1H), 4.52-4.47 (m, 2H), 4.38-4.31 (m, 2H), 4.21 (s, 2H), 4.11 (d, J = 15. 6 Hz, 1H), 3.76 (d, J = 15.6 Hz, 1H), 3.46-3.41 (m, 3H), 3.29 (s, 3H), 3.02-2.90 (m, 2H), 2.77-2.71 (m, 1H), 2.55-2.48 (m, 1H), 2.46-2.40 (m, 1H), 2.05-2.02 (m, 2H), 1.99-1.95 (m, 2H), 1.88-1.82 (m, 1H), 1.77-1.73 (m, 1H), 1.69-1.61 (m, 3H), 1.43-1.34 (m, 1H), 1.07-0.97 (m, 1H)；C30 H40 FN3 O2 [M+H]+ 之ESI-MS計算值=494.31，實驗值：494.45。 Dissolve S11 (2.07 g, 4.75 mmol) in dry dichloromethane (50 mL). Next, N,N-diisopropylethylamine (3.31 mL, 19 mmol) and dimethyl dicarbonate (764 mg, 5.7 mmol, 1.2 equivalents) were added at 0°C. After stirring for 2 h at room temperature, the reaction mixture was concentrated under vacuum. The residue was purified by reverse phase preparative HPLC to obtain the title compound S12 in the form of the trifluoroacetate salt. 1H NMR (400 MHz, MeOD) δ 7.48-7.40 (m, 6H), 7.14-7.10 (m, 2H), 7.02 (d, J = 7.6 Hz, 1H), 4.52-4.47 (m, 2H), 4.38- 4.31 (m, 2H), 4.21 (s, 2H), 4.11 (d, J = 15.6 Hz, 1H), 3.76 (d, J = 15.6 Hz, 1H), 3.46-3.41 (m, 3H), 3.29 (s, 3H), 3.02-2.90 (m, 2H), 2.77-2.71 (m, 1H), 2.55-2.48 (m, 1H), 2.46-2.40 (m, 1H), 2.05-2.02 (m, 2H) , 1.99-1.95 (m, 2H), 1.88-1.82 (m, 1H), 1.77-1.73 (m, 1H), 1.69-1.61 (m, 3H), 1.43-1.34 (m, 1H), 1.07-0.97 ( m, 1H); ESI-MS calculated value for C 30 H 40 FN 3 O 2 [M+H] + =494.31, experimental value: 494.45.
S13S13 之合成Synthesis
在N2氛圍下，向三氟乙酸鹽S12 (1.6 g，3.24 mmol)於甲醇(50 mL)中之溶液中添加10% Pd/C(344 mg，0.1 eq，Sigma目錄號205699)。隨後，在攪拌下將燒瓶脫氣三次。接著，在室溫下，於氫氣氛圍(正常壓力)下，攪拌混合物2 h。在過濾出Pd/C催化劑之後，藉由旋轉蒸發移除溶劑，得到標題化合物S13 。1H NMR (400 MHz, MeOD) δ 7.48-7.43 (m, 1H), 7.16-7.06 (m, 3H), 4.51-4.45 (m, 2H), 4.38-4.27 (m, 2H), 4.10 (d, J = 15.6 Hz, 1H), 3.77 (d, J = 15.2 Hz, 1H), 3.55-3.52 (m, 1H), 3.40-3.33 (m, 2H), 3.31 (s, 3H), 3.01-2.89 (m, 2H), 2.78-2.72 (m, 1H), 2.58-2.48 (m, 1H), 2.46-2.39 (m, 1H), 2.05-1.93 (m, 5H), 1.78-1.70 (m, 1H), 1.68-1.54 (m, 3H), 1.39-1.30 (m, 1H), 1.08-1.02 (m, 1H)；C23 H34 FN3 O2 [M+H]+ 之ESI-MS計算值=404.26，實驗值：404.42。Under N2 atmosphere, to a solution of trifluoroacetate S12 (1.6 g, 3.24 mmol) in methanol (50 mL) was added 10% Pd/C (344 mg, 0.1 eq, Sigma catalog number 205699). Subsequently, the flask was degassed three times with stirring. Next, at room temperature, under a hydrogen atmosphere (normal pressure), the mixture was stirred for 2 h. After filtering out the Pd/C catalyst, the solvent was removed by rotary evaporation to obtain the title compound S13 . 1H NMR (400 MHz, MeOD) δ 7.48-7.43 (m, 1H), 7.16-7.06 (m, 3H), 4.51-4.45 (m, 2H), 4.38-4.27 (m, 2H), 4.10 (d, J = 15.6 Hz, 1H), 3.77 (d, J = 15.2 Hz, 1H), 3.55-3.52 (m, 1H), 3.40-3.33 (m, 2H), 3.31 (s, 3H), 3.01-2.89 (m, 2H), 2.78-2.72 (m, 1H), 2.58-2.48 (m, 1H), 2.46-2.39 (m, 1H), 2.05-1.93 (m, 5H), 1.78-1.70 (m, 1H), 1.68- 1.54 (m, 3H), 1.39-1.30 (m, 1H), 1.08-1.02 (m, 1H); C 23 H 34 FN 3 O 2 [M+H] + ESI-MS calculated value = 404.26, experimental value : 404.42.
S13 可轉化成適用於製備一些所主張之化合物(例如化合物27-29及35)的各種中間化合物。對應於S13 之其他化合物中之基團可類似地藉由選擇適當S7 起始物質來製備。遵循下文所描述之用於將S13 轉化為S15 之程序之變化形式，可製備S15 之類似物。舉例而言，使用適當S14 a類似物(其中對應於R10a 之基團為例如H、甲基、F、CN等)，可製備S15 之類似物。 S13 can be transformed into various intermediate compounds suitable for preparing some of the claimed compounds (such as compounds 27-29 and 35). The groups in other compounds corresponding to S13 can be prepared similarly by selecting appropriate S7 starting materials. Follow hereinafter described for the conversion of S13 to S15 in the form of program changes, the analogs can be prepared by the S15. For example, using appropriate S14a analogs (wherein the group corresponding to R 10a is, for example, H, methyl, F, CN, etc.), analogs of S15 can be prepared.
S14aS14a 之合成Synthesis
在-78℃下在氬氣氛圍下向DMSO(0.78 mL，11.0 mmol)於DCM(30 mL)中之溶液中添加(COCl)2 (2.8 mL，2M於DCM中)。在0.5 h之後，添加S14 (800 mg，3.68 mmol)，且在-78℃下攪拌混合物2 h。接著，添加Et3 N (3.1 mL，22.0 mmol)，且在用飽和NH4 Cl (aq)將其淬滅之前再攪拌混合物0.5 h。用DCM萃取溶液3次。經合併之有機溶劑用鹽水洗滌且經Na2 SO4 脫水，過濾且旋轉真空濃縮，得到無需進一步純化之粗產物S14 a。To a solution of DMSO (0.78 mL, 11.0 mmol) in DCM (30 mL) was added (COCl) 2 (2.8 mL, 2M in DCM) under argon atmosphere at -78°C. After 0.5 h, S14 (800 mg, 3.68 mmol) was added, and the mixture was stirred at -78°C for 2 h. Then, Et 3 N (3.1 mL, 22.0 mmol) was added, and the mixture was stirred for another 0.5 h before quenching it with saturated NH 4 Cl (aq). The solution was extracted 3 times with DCM. The combined organic solvents were washed with brine and dehydrated with Na 2 SO 4 , filtered and concentrated in a rotary vacuum to obtain the crude product S14 a without further purification.
S15S15 之合成Synthesis
向S13 (1.40 g，3.48 mmol)於DCE (30 mL)中之溶液中，添加Et3 N (1.2 mL，8.70 mmol)，隨後添加AcOH (0.8 mL，13.9 mmol)及S14 a (748 mg，3.48 mmol)。在3 h之後，添加NaBH(OAc)3 (2.21 g，10.4 mmol)。攪拌混合物隔夜，用水淬滅且真空濃縮。藉由逆相製備型HPLC純化殘餘物，得到呈三氟乙酸鹽形式之標題化合物S15 。1H NMR (400 MHz, 甲醇-d4) δ 7.37 (td, J = 8.4, 6.2 Hz, 1H), 7.10 - 7.01 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 4.40 (m, 1H), 4.32 - 4.15 (m, 1H), 4.14 - 3.93 (m, 4H), 3.86 - 3.68 (m, 4H), 3.64 (d, J = 8.0 Hz, 2H), 3.38 (m, 4H), 3.28 - 3.14 (m, 6H), 2.99 (tp, J = 23.5, 11.8, 11.2 Hz, 2H), 2.70 (q, J = 9.1 Hz, 1H), 2.46 (dq, J = 11.5, 9.2 Hz, 1H), 2.34 (m, 1H), 2.00 - 1.83 (m, 4H), 1.78 (d, J = 5.8 Hz, 1H), 1.70 (dt, J = 8.8, 4.4 Hz, 1H), 1.64 - 1.47 (m, 3H), 1.36 (m, 11H)。C33 H52 FN4 O5 [M+H]+ 之ESI-MS計算值=603.39，實驗值：603.13。To a solution of S13 (1.40 g, 3.48 mmol) in DCE (30 mL), Et 3 N (1.2 mL, 8.70 mmol) was added, followed by AcOH (0.8 mL, 13.9 mmol) and S14 a (748 mg, 3.48) mmol). After 3 h, NaBH(OAc) 3 (2.21 g, 10.4 mmol) was added. The mixture was stirred overnight, quenched with water and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC to obtain the title compound S15 in the form of the trifluoroacetate salt. 1H NMR (400 MHz, methanol-d4) δ 7.37 (td, J = 8.4, 6.2 Hz, 1H), 7.10-7.01 (m, 2H), 6.97 (d, J = 8.0 Hz, 1H), 4.40 (m, 1H), 4.32-4.15 (m, 1H), 4.14-3.93 (m, 4H), 3.86-3.68 (m, 4H), 3.64 (d, J = 8.0 Hz, 2H), 3.38 (m, 4H), 3.28 -3.14 (m, 6H), 2.99 (tp, J = 23.5, 11.8, 11.2 Hz, 2H), 2.70 (q, J = 9.1 Hz, 1H), 2.46 (dq, J = 11.5, 9.2 Hz, 1H), 2.34 (m, 1H), 2.00-1.83 (m, 4H), 1.78 (d, J = 5.8 Hz, 1H), 1.70 (dt, J = 8.8, 4.4 Hz, 1H), 1.64-1.47 (m, 3H) , 1.36 (m, 11H). ESI-MS calculated value for C 33 H 52 FN 4 O 5 [M+H] + =603.39, experimental value: 603.13.
S16S16 之合成Synthesis
將化合物S15 (2.20 g，3.48 mmol)溶解於DCM (50 mL)中，接著添加三氟乙酸(5.0 mL，73.1 mmol)。在室溫下攪拌2 h之後，蒸發反應混合物，得到無需進一步純化之粗標題產物S16 。Compound S15 (2.20 g, 3.48 mmol) was dissolved in DCM (50 mL), and then trifluoroacetic acid (5.0 mL, 73.1 mmol) was added. After stirring for 2 h at room temperature, the reaction mixture was evaporated to give the crude title product S16 without further purification.
實例2Example 2
或者，S13
或其類似物可根據以下流程轉化成S18
或其類似物：
S18S18 之合成Synthesis
向中間物S13 (400 mg，0.991 mmol)於乙腈(5 mL)中之溶液添加化合物S17 (548 mg，1.19 mmol)、K2 CO3 (274 mg，0.198 mmol)及KI (16 mg，0.099 mmol)。將混合物在80℃下攪拌隔夜。隨後，用二氯甲烷萃取混合物，用鹽水洗滌，經Na2 SO4 乾燥，且在真空下蒸發溶劑。藉由逆相製備型HPLC純化殘餘物，得到S18 之 三氟乙酸鹽。S18 可用於製備化合物35。To a solution of intermediate S13 (400 mg, 0.991 mmol) in acetonitrile (5 mL) was added compound S17 (548 mg, 1.19 mmol), K 2 CO 3 (274 mg, 0.198 mmol) and KI (16 mg, 0.099 mmol) ). The mixture was stirred at 80°C overnight. Subsequently, the mixture was extracted with dichloromethane, washed with brine, dried over Na 2 SO 4, and the solvent evaporated under vacuum. The residue was purified by reverse phase preparative HPLC to obtain the trifluoroacetate salt of S18. S18 can be used to prepare compound 35.
實例3Example 3
S16
或其類似物(其中，例如，對應於R10a
之基團為H、F、氰基等)可藉由使其與結構上可概述為以下之各種化合物反應而轉化成最終產物：
S19 化合物之各種類似物可根據熟習此項技術者已知之各種方法製備。 Various analogs of the S19 compound can be prepared according to various methods known to those skilled in the art.
S19-1 之合成 
將A1 (3.63 g，13.00 mmol)及A2 (1.58 g，10.84 mmol)溶解於50 mL之乙腈中，隨後添加K2 CO3 (2.39g，17.34 mmol)，且使反應物回流。在隔夜之後，將反應物冷卻，添加水，且用乙酸乙酯萃取溶液三次。在管柱純化之後，得到3.26 g之A3 。 A1 (3.63 g, 13.00 mmol) and A2 (1.58 g, 10.84 mmol) were dissolved in 50 mL of acetonitrile, then K 2 CO 3 (2.39 g, 17.34 mmol) was added, and the reaction was refluxed. After overnight, the reaction was cooled, water was added, and the solution was extracted three times with ethyl acetate. After column purification, 3.26 g of A3 was obtained.
將mCPBA (77% w/w，1.40g，6.25 mmol)添加至冷卻溶液，將0℃之A3
(3.27g，2.50 mmol)溶解於10 mL之DCM中。使溶液升溫至室溫，隨後在4小時之後，用飽和NaHCO3
溶液將其淬滅且用乙酸乙酯萃取三次。在管柱純化之後，得到3.1 g之S19 - 1
。
根據用以製得S19 - 1 之程序來合成中間物S19 - 2 至S19 - 4 。 S19 prepared according to - the procedure to synthesize Intermediate 1 S19 - 2 to S19 - 4.
根據用以製得S19 - 1
之程序來合成中間物S20 - 1
至S20 - 2
。
S19-5 之合成 
將甲磺醯氯(213 µL，2.76 mmol)添加至冷溶液，將0℃之A4 (500 mg，2.30 mmol)及三甲胺(960 µL，6.90 mmol)溶解於4 mL之DCM中。在1h之後，添加水且用DCM萃取反應物三次，濃縮並藉由柱純化，得到714 mg之A5 。Add mesyl chloride (213 µL, 2.76 mmol) to the cold solution, and dissolve A4 (500 mg, 2.30 mmol) and trimethylamine (960 µL, 6.90 mmol) at 0°C in 4 mL of DCM. After 1 h, water was added and the reaction was extracted three times with DCM, concentrated and purified by column to obtain 714 mg of A5 .
將碳酸鉀(432 mg，3.129 mmol)添加至A5 (308 mg，1.18 mmol)及A6 (267 mg，2.08 mmol)於3 mL之乙腈中之溶液且回流。在隔夜之後，將反應物冷卻，添加水，且用乙酸乙酯萃取溶液三次。在管柱純化之後，得到307 mg之A7 。Potassium carbonate (432 mg, 3.129 mmol) was added to a solution of A5 (308 mg, 1.18 mmol) and A6 (267 mg, 2.08 mmol) in 3 mL of acetonitrile and refluxed. After overnight, the reaction was cooled, water was added, and the solution was extracted three times with ethyl acetate. After column purification, 307 mg of A7 was obtained.
將mCPBA (77%w/w，526 mg，2.35 mmol)添加至冷卻溶液，將0℃之A7
(307 mg，0.939 mmol)溶解於5 mL之DCM中。使溶液升溫至室溫，隨後在4小時之後，用飽和NaHCO3
溶液將其淬滅且用乙酸乙酯萃取三次。在管柱純化之後，得到305 mg之S19 - 5
。
根據用以製得S19 - 5 之程序來合成中間物S19 -6 至S19 - 11 。According to prepare S19 - the procedure to synthesize intermediate 5 S19 - 6 to S19 - 11.
S19-12 之合成 
將三苯基膦(1.83g，6.967 mmol)及CBr4 (2.31g，6.967 mmol)添加至A8 (1.0g，4.645 mmol)於16 mL之THF中之溶液。在攪拌隔夜之後，用水稀釋反應物，用二乙醚萃取，濃縮且藉由管柱層析純化，產生588 mg之A9 。Triphenylphosphine (1.83 g, 6.967 mmol) and CBr 4 (2.31 g, 6.967 mmol) were added to a solution of A8 (1.0 g, 4.645 mmol) in 16 mL of THF. After stirring overnight, the reaction was diluted with water, extracted with diethyl ether, concentrated and purified by column chromatography to yield 588 mg of A9 .
將碳酸鉀(436 mg，3.162 mmol)添加至A9 (293 mg，1.054 mmol)及A10 (270 mg，2.108 mmol)於3 mL之乙腈中之溶液且回流。在隔夜之後，將反應物冷卻，添加水，且用乙酸乙酯萃取溶液三次。在管柱純化之後，得到325 mg之A11 。Potassium carbonate (436 mg, 3.162 mmol) was added to a solution of A9 (293 mg, 1.054 mmol) and A10 (270 mg, 2.108 mmol) in 3 mL of acetonitrile and refluxed. After overnight, the reaction was cooled, water was added, and the solution was extracted three times with ethyl acetate. After column purification, 325 mg of A11 was obtained.
將mCPBA (77% w/w，559 mg，2.497 mmol)添加至冷卻溶液，將0℃之A11
(325mg，0.999 mmol)溶解於5 mL之DCM中。使溶液升溫至室溫，隨後在4小時之後，用飽和NaHCO3
溶液將其淬滅且用乙酸乙酯萃取三次。在管柱純化之後，得到303 mg之S19 - 12
。
根據用以製得S19 - 12 之程序來合成中間物S19 - 13 。According to prepare S19 - program 12 of the intermediate synthesized S19 - 13.
S19-14 之合成 
將(1S,4S)-2-Boc-2,5-二氮雜雙環[2.2.1]庚烷A12 (1.0 g，5.05 mmol)添加至溶解於40 mL之DCM中的A13 (1.08 g，5.55 mmol)及三甲胺(2.1 mL，15.2 mmol)之0℃冷溶液。在5h之後，添加水且用DCM萃取反應物三次，濃縮並藉由管柱純化以得到1.61 g之S19-14 。(1S,4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane A12 (1.0 g, 5.05 mmol) was added to A13 (1.08 g, 5.55 mmol) and trimethylamine (2.1 mL, 15.2 mmol) at 0°C cold solution. After 5h, water was added and the reaction was extracted three times with DCM, concentrated and purified by column to obtain 1.61 g of S19-14 .
實例4Example 4
製備((1S,2R)-2-((S)-2-(2-乙基-1H-咪唑-1-基)-1-(1-((1-(3-氟-5-(((R)-1-(((E)-3-(甲磺醯基)烯丙基)胺甲醯基)六氫吡啶-3-基)磺醯基)吡啶-2-基)氮雜環丁-3-基)甲基)六氫吡啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯(化合物 70
)
步驟step AA ：: 33 -((-(( 66 -- 氯chlorine -- 55 -- 氟吡啶Flupyridine -- 33 -- 基base )) 硫基Sulfur )) 丙酸甲酯Methyl propionate
在100℃下在N2 氛圍下製備5-溴-2-氯-3-氟吡啶(5.0 g，23.761 mmol，1.0當量)、3-巰基丙酸甲酯(2.86 g，23.761 mmol，1.0當量)、Pd2 (dba)3 (1.09 g，1.188 mmol，0.05當量)、XantPhos (0.69 g，1.19 mmol，0.05 當量)及DIPEA (9.20 g，71.283 mmol，3.0當量)於甲苯(25 mL)中之混合物持續16h。隨後在減壓下濃縮反應溶液且藉由矽膠急驟管柱層析純化殘餘物，得到呈黃色油狀之3-((6-氯-5-氟吡啶-3-烯基)硫基)丙酸甲酯(2.3 g，產率39%)。LC-MS: 250 (M+H)+ 。 Prepare 5-bromo-2-chloro-3-fluoropyridine (5.0 g, 23.761 mmol, 1.0 equivalent) and methyl 3-mercaptopropionate (2.86 g, 23.761 mmol, 1.0 equivalent) under N 2 atmosphere at 100°C , Pd 2 (dba) 3 (1.09 g, 1.188 mmol, 0.05 equivalent), XantPhos (0.69 g, 1.19 mmol, 0.05 equivalent) and DIPEA (9.20 g, 71.283 mmol, 3.0 equivalent) in toluene (25 mL) Lasts 16h. The reaction solution was then concentrated under reduced pressure and the residue was purified by silica gel flash column chromatography to obtain 3-((6-chloro-5-fluoropyridin-3-enyl)thio)propionic acid as a yellow oil Methyl ester (2.3 g, yield 39%). LC-MS: 250 (M+H) + .
步驟step BB 及and CC ：: (( RR )-)- 33 -((-(( 66 -- 氯chlorine -- 55 -- 氟吡啶Flupyridine -- 33 -- 基base )) 硫基Sulfur )) 六氫吡啶Hexahydropyridine -- 11 -- 甲酸Formic acid 第三丁Third D 酯ester
在-65℃下在N2 氛圍下向3-((6-氯-5-氟吡啶-3-基)硫基)丙酸甲酯(1.6 g，6.408 mmol，1.0當量)於THF(20 mL)中之溶液中添加t-BuOK (1.08 g，9.612 mmol，1.5當量，於5 mL THF中)。隨後將反應混合物在此溫度下攪拌30分鐘。隨後反應混合物未經任何進一步純化即直接用於下一步驟中。LC-MS: 164 (M+H)+ 。At -65 ℃ to 3 in N 2 atmosphere - ((6-chloro-5-fluoro-3-yl) thio) propanoate (1.6 g, 6.408 mmol, 1.0 eq.) In THF (20 mL Add t-BuOK (1.08 g, 9.612 mmol, 1.5 equivalents in 5 mL THF) to the solution in ). The reaction mixture was then stirred at this temperature for 30 minutes. The reaction mixture was then used directly in the next step without any further purification. LC-MS: 164 (M+H) + .
向以上混合物中添加(S)-3-((甲磺醯基)氧基)六氫吡啶-1-甲酸第三丁酯(2.15 g，7.690 mmol，1.2當量)及K2 CO3 (1.77 g，12.816 mmol，2.0當量)。隨後在N2 氛圍下將混合物加熱至80℃持續16小時。反應混合物用H2 O (20 mL)稀釋且用EtOAc (20 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體狀之(R)-3-((6-氯-5-氟吡啶-3-基)硫基)六氫吡啶-1-甲酸第三丁酯(1.0 g，產率45%)。LC-MS: 347 (M+H)+ 。 Add (S)-3-((methylsulfonyl)oxy)hexahydropyridine-1-carboxylate (2.15 g, 7.690 mmol, 1.2 equivalents) and K 2 CO 3 (1.77 g) to the above mixture , 12.816 mmol, 2.0 equivalents). The mixture was then heated to 80°C for 16 hours under an N 2 atmosphere. The reaction mixture was diluted with H 2 O (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to obtain (R)-3-((6-chloro-5-fluoropyridin-3-yl)thio)hexahydropyridine-1-carboxylic acid as a white solid Tributyl ester (1.0 g, 45% yield). LC-MS: 347 (M+H) + .
步驟step DD ：: (( RR )-)- 33 -((-(( 66 -- 氯chlorine -- 55 -- 氟吡啶Flupyridine -- 33 -- 基base )) 磺醯基Sulfonyl )) 六氫吡啶Hexahydropyridine -- 11 -- 甲酸第三丁酯Tert-butyl formate
向(R)-3-((6-氯-5-氟吡啶-3-基)硫基)六氫吡啶-1-甲酸第三丁酯(620 mg，1.787 mmol，1.0當量)於丙酮(15 mL)及水(5 mL)中之混合物中逐份添加過硫酸氫鉀(2.74 g，4.469 mmol，2.5當量)。在25℃下攪拌混合物16 h。反應混合物用H2 O (10 mL)稀釋且用EtOAc (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體狀之(R)-3-((6-氯-5-氟吡啶-3-基)磺醯基)六氫吡啶-1-甲酸第三丁酯(370 mg，產率55%)。LC-MS: 379 (M+H)+ 。 To (R)-3-((6-chloro-5-fluoropyridin-3-yl)thio)hexahydropyridine-1-carboxylic acid tert-butyl ester (620 mg, 1.787 mmol, 1.0 equivalent) in acetone (15 mL) and water (5 mL) was added potassium hydrogen persulfate (2.74 g, 4.469 mmol, 2.5 equivalents) in portions. The mixture was stirred at 25°C for 16 h. The reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to obtain (R)-3-((6-chloro-5-fluoropyridin-3-yl)sulfonyl)hexahydropyridine-1-carboxylic acid as a white solid Tertiary butyl ester (370 mg, 55% yield). LC-MS: 379 (M+H) + .
步驟step EE ：: (( RR )-)- 33 -((-(( 66 -(-( 33 -((-(( 44 -((-(( SS )-)- 22 -(-( 22 -- 乙基Ethyl -- 1H1H -- 咪唑Imidazole -- 11 -- 基base )-)- 11 -(-( 33 -- 氟苯基Fluorophenyl )-1-(()-1-(( 1R1R ,, 2S2S )-)- 22 -((-(( 甲氧羰基Methoxycarbonyl )) 胺基Amino )) 環戊基Cyclopentyl )) 乙基Ethyl )) 六氫吡啶Hexahydropyridine -- 11 -- 基base )) 甲基methyl )) 氮雜環丁Azetidine -- 11 -- 基base )-)- 55 -- 氟吡啶Flupyridine -- 33 -- 基base )) 磺醯基Sulfonyl )) 六氫吡啶Hexahydropyridine -- 11 -- 甲酸Formic acid 第三丁Third D 酯ester
在100℃下在N2 氛圍下攪拌((1S,2R)-2-((S)-1-(1-(氮雜環丁-3-基甲基)六氫吡啶-4-基)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯(284 mg，0.55 mmol，1.0當量)、(R)-3-((6-氯-5-氟吡啶-3-基)磺醯基)六氫吡啶-1-甲酸第三丁酯(270 mg，0.72 mmol，1.3當量)、Pd2 (dba)3 (10 mg，0.011 mmol，0.02當量)、Xant-Phos (10 mg，0.021 mmol，0.04當量)及Cs2 CO3 (538 mg，1.65 mmol，3.0當量)於甲苯(10 mL)中之混合物持續16h。反應混合物用H2 O (10 mL)稀釋且用EtOAc (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈黃色固體狀之(R)-3-((6-(3-((4-((S)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧羰基)胺基)環戊基)乙基)六氫吡啶-1-基)甲基)氮雜環丁-1-基)-5-氟吡啶-3-基)磺醯基)六氫吡啶-1-甲酸第三丁酯(150 mg，產率28%)。LC-MS: 854 (M+H)+ 。 Stir at 100°C under N 2 atmosphere ((1S,2R)-2-((S)-1-(1-(azetidin-3-ylmethyl)hexahydropyridin-4-yl)- Methyl 2-(2-ethyl-1H-imidazol-1-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate (284 mg, 0.55 mmol, 1.0 equivalent), ( R)-3-((6-chloro-5-fluoropyridin-3-yl)sulfonyl)hexahydropyridine-1-carboxylic acid tert-butyl ester (270 mg, 0.72 mmol, 1.3 equivalents), Pd 2 (dba ) 3 (10 mg, 0.011 mmol, 0.02 equivalent), Xant-Phos (10 mg, 0.021 mmol, 0.04 equivalent) and Cs 2 CO 3 (538 mg, 1.65 mmol, 3.0 equivalent) in toluene (10 mL) Lasts 16h. The reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to obtain (R)-3-((6-(3-((4-((S)-2-(2-ethyl-1H- Imidazol-1-yl)-1-(3-fluorophenyl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)hexahydropyridine-1- (Yl)methyl)azetidin-1-yl)-5-fluoropyridin-3-yl)sulfonyl)tert-butyl hexahydropyridine-1-carboxylate (150 mg, 28% yield). LC-MS: 854 (M+H) + .
步驟step FF ：: (((( 1S1S ,, 2R2R )-)- 22 -((-(( SS )-)- 22 -(-( 22 -- 乙基Ethyl -- 1H1H -- 咪唑Imidazole -- 11 -- 基base )-)- 11 -(-( 11 -((-(( 11 -(-( 33 -- 氟fluorine -- 55 -((-(( RR )-)- 六氫吡啶Hexahydropyridine -- 33 -- 基base )) 磺醯基Sulfonyl )) 吡啶Pyridine -- 22 -- 基base )) 氮雜環丁Azetidine -- 33 -- 基base )) 甲基methyl )) 六氫吡啶Hexahydropyridine -- 44 -- 基base )-)- 11 -(-( 33 -- 氟苯基Fluorophenyl )) 乙基Ethyl )) 環戊基Cyclopentyl )) 胺amine 基甲酸甲酯Methyl carboxylate
在室溫下攪拌(R)-3-((6-(3-((4-((S)-2-(2-乙基-1H-咪唑-1-基)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)六氫吡啶-1-基)甲基)氮雜環丁-1-基)-5-氟吡啶-3-基)磺醯基)六氫吡啶-1-甲酸第三丁酯(150 mg，0.176 mmol)及TFA (2 ml)於DCM (6 mL)中之溶液1 h。隨後在減壓下濃縮反應混合物，得到呈黃色油狀之((1S,2R)-2-((S)-2-(2-乙基-1H-咪唑-1-基)-1-(1-((1-(3-氟-5-((R)-六氫吡啶-3-基)磺醯基)吡啶-2-基)氮雜環丁-3-基)甲基)六氫吡啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯(130 mg，TFA鹽)。LC-MS: 754 (M+H)+ 。 Stir (R)-3-((6-(3-((4-((S)-2-(2-ethyl-1H-imidazol-1-yl)-1-(3-fluoro Phenyl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)hexahydropyridin-1-yl)methyl)azetidin-1- A solution of -5-fluoropyridin-3-yl)sulfonyl)hexahydropyridine-1-carboxylate (150 mg, 0.176 mmol) and TFA (2 ml) in DCM (6 mL) 1 h. The reaction mixture was then concentrated under reduced pressure to obtain ((1S,2R)-2-((S)-2-(2-ethyl-1H-imidazol-1-yl)-1-(1 -((1-(3-Fluoro-5-((R)-hexahydropyridin-3-yl)sulfonyl)pyridin-2-yl)azetidin-3-yl)methyl)hexahydropyridine Methyl -4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate (130 mg, TFA salt). LC-MS: 754 (M+H) + .
步驟step GG ：: (((( 1S1S ,, 2R2R )-)- 22 -((-(( SS )-)- 22 -(-( 22 -- 乙基Ethyl -- 1H1H -- 咪唑Imidazole -- 11 -- 基base )-)- 11 -(-( 11 -((-(( 11 -(-( 33 -- 氟fluorine -- 55 -(((-((( RR )-)- 11 -(((-((( EE )-)- 33 -(-( 甲磺醯基Methylsulfonyl )) 烯丙基Allyl )) 胺甲醯基Carbamate )) 六氫吡啶Hexahydropyridine -- 33 -- 基base )) 磺醯基Sulfonyl )) 吡啶Pyridine -- 22 -- 基base )) 氮雜環丁Azetidine -- 33 -- 基base )) 甲基methyl )) 六氫吡啶Hexahydropyridine -- 44 -- 基base )-)- 11 -(-( 33 -- 氟苯基Fluorophenyl )) 乙基Ethyl )) 環戊基Cyclopentyl )) 胺amine 基甲酸甲酯Methyl carboxylate (( 化合物Compound 7070 ))
向3-(甲磺醯基)丙-2-烯-1-胺(47 mg，0.345 mmol，2.0當量)於THF(15 mL)中之溶液(E)中添加TEA(0.12 mL，0.862 mmol，5.0當量)及CDI(67 mg，0.414 mmol，2.4當量)。在室溫下攪拌1 h之後，將((1S,2R)-2-((S)-2-(2-乙基-1H-咪唑-1-基)-1-(1-((1-(3-氟-5-(((R)六氫吡啶-3-基)磺醯基)吡啶-2-基)氮雜環丁-3-基)甲基)六氫吡啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯(130 mg，0.172 mmol)添加至以上混合物中。隨後在此溫度下攪拌混合物16小時。反應混合物用H2 O (10 mL)稀釋且用EtOAc (10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析及RP-製備型HPLC純化殘餘物，得到呈白色半固體狀之化合物 70 (33 mg，產率21%)。LC-MS: 915 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 8.28 (d, 1H), 7.67 (dd, 1H), 7.56 - 7.52 (m, 1H), 7.49 - 7.44 (m, 2H), 7.36 (d, 1H), 7.23 - 7.19 (m, 1H), 6.99 (s, 1H), 6.85 (dt, 1H), 6.61 (d, 1H), 4.62 (d, 1H), 4.50 - 4.45 (m, 2H), 4.15 - 4.05 (m, 3H), 4.01 - 3.94 (m, 2H), 3.74 - 3.65 (m, 2H), 3.64 (s, 3H), 3.50 - 3.45 (m, 3H), 3.20 - 3.05 (m, 6H), 2.95 (s, 3H), 2.90 - 2.83 (m, 1H), 2.70 - 2.63 (m, 2H), 2.32 - 2.27 (m, 1H), 2.17 - 2.11 (m, 1H), 2.06 - 2.04 (m, 1H), 1.98 - 1.78 (m, 4H), 1.59 - 1.53 (m, 4H), 1.45 - 1.41 (m, 3H), 1.40 - 1.37 (m, 2H), 1.29 - 1.12 (m, 3H), 1.06 - 0.94 (m, 1H)。To a solution (E) of 3-(methylsulfonyl)prop-2-en-1-amine (47 mg, 0.345 mmol, 2.0 equivalents) in THF (15 mL) was added TEA (0.12 mL, 0.862 mmol, 5.0 equivalents) and CDI (67 mg, 0.414 mmol, 2.4 equivalents). After stirring for 1 h at room temperature, ((1S,2R)-2-((S)-2-(2-ethyl-1H-imidazol-1-yl)-1-(1-((1- (3-Fluoro-5-(((R)hexahydropyridin-3-yl)sulfonyl)pyridin-2-yl)azetidin-3-yl)methyl)hexahydropyridin-4-yl) Methyl-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate (130 mg, 0.172 mmol) was added to the above mixture. The mixture was then stirred at this temperature for 16 hours. The reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography and RP-preparative HPLC to obtain compound 70 (33 mg, yield 21%) as a white semi-solid. LC-MS: 915 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 8.28 (d, 1H), 7.67 (dd, 1H), 7.56-7.52 (m, 1H), 7.49-7.44 (m, 2H), 7.36 (d, 1H) ), 7.23-7.19 (m, 1H), 6.99 (s, 1H), 6.85 (dt, 1H), 6.61 (d, 1H), 4.62 (d, 1H), 4.50-4.45 (m, 2H), 4.15- 4.05 (m, 3H), 4.01-3.94 (m, 2H), 3.74-3.65 (m, 2H), 3.64 (s, 3H), 3.50-3.45 (m, 3H), 3.20-3.05 (m, 6H), 2.95 (s, 3H), 2.90-2.83 (m, 1H), 2.70-2.63 (m, 2H), 2.32-2.27 (m, 1H), 2.17-2.11 (m, 1H), 2.06-2.04 (m, 1H) ), 1.98-1.78 (m, 4H), 1.59-1.53 (m, 4H), 1.45-1.41 (m, 3H), 1.40-1.37 (m, 2H), 1.29-1.12 (m, 3H), 1.06-0.94 (m, 1H).
實例5Example 5
製備 (( 1S , 2R )- 2 -(( S )- 2 -( 氮雜環丁 - 1 - 基 )- 1 -( 1 -(( 1 -( 4 -(( 1 -((( E )- 4 -( 二甲基胺基 )- 4 - 側氧基丁 - 2 - 烯 - 1 - 基 ) 胺 基甲醯基 ) 氮雜環丁 - 3 - 基 ) 甲基 ) 苯基 ) 氮雜環丁 - 3 - 基 ) 甲基 ) 六氫吡啶 - 4 - 基 )- 1 -( 3 - 氟苯基 ) 乙基 ) 環戊基 ) 胺基甲酸甲酯 ( 化合物 122 ) 
步驟step AA ：: 33 -(-( 44 -- 溴苯甲基Bromobenzyl )) 氮雜環丁烷Azetidine -- 11 -- 甲酸第三丁酯Tert-butyl formate
在H2 氛圍(1 atm)下攪拌3-(4-溴苯甲基茚)氮雜環丁烷-1-甲酸第三丁酯(F1) (600 mg，1.851 mmol，1.0當量；參考：WO2016/30310，2016，A1第43頁)及10% Pd/C(60 mg)於EtOAc(15 mL)中之混合物2小時。過濾反應混合物，且減壓濃縮。藉由矽膠急驟管柱層析純化殘餘物，得到呈白色固體狀之3-(4-溴苯甲基)氮雜環丁烷-1-甲酸第三丁酯(F2)(500 mg，產率83%)。LC-MS: 326, 328 (M+H)+ 。 Stirring 3-(4-bromobenzyl indene) azetidine-1-carboxylic acid tert-butyl ester (F1) (600 mg, 1.851 mmol, 1.0 equivalent) under H 2 atmosphere (1 atm); reference: WO2016 /30310, 2016, A1 page 43) and a mixture of 10% Pd/C (60 mg) in EtOAc (15 mL) for 2 hours. The reaction mixture was filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to obtain 3-(4-bromobenzyl)azetidine-1-carboxylic acid tert-butyl ester (F2) (500 mg, yield) as a white solid 83%). LC-MS: 326, 328 (M+H) + .
步驟step BB ：: 33 -(-( 44 -(-( 33 -((-(( 44 -((-(( SS )-)- 22 -(-( 氮雜環丁Azetidine -- 11 -- 基base )-)- 11 -(-( 33 -- 氟苯基Fluorophenyl )-)- 11 -((-(( 1R1R ,, 2S2S )-)- 22 -((-(( 甲氧基羰基Methoxycarbonyl )) 胺基Amino )) 環戊基Cyclopentyl )) 乙基Ethyl )) 六氫吡啶Hexahydropyridine -- 11 -- 基base )) 甲基methyl )) 氮雜環丁Azetidine -- 11 -- 基base )) 苯甲基Benzyl )) 氮雜環丁烷Azetidine -- 11 -- 甲酸第三丁酯Tert-butyl formate
在100℃下在N2 氛圍下攪拌((1S,2R)-2-((S)-2-(氮雜環丁-1-基)-1-(1-(氮雜環丁-3-甲基)六氫吡啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯(300 mg，0.635 mmol，1.0當量)、3-(4-溴苯甲基)氮雜環丁烷-1-甲酸第三丁酯(412 mg，1.269 mmol，2.0當量)、Pd2 (dba)3 (116 mg，0.127 mmol，0.2當量)、X-Phos (60.54 mg，0.127 mmol，0.2當量)及Cs2 CO3 (621 mg，1.905 mmol，3.0當量)於甲苯(15 mL)中之混合物16小時。隨後反應混合物用H2 O (10 mL)稀釋且用EtOAc (10 mL×3)萃取。將經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。所得殘餘物藉由矽膠急驟管柱層析純化，得到呈白色油狀之3-(4-(3-((4-((S)-2-(氮雜環丁-1-基)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)六氫吡啶-1-基)甲基)氮雜環丁-1-基)苯甲基)氮雜環丁烷-1-甲酸第三丁酯(255 mg，產率56%)。LC-MS: 718 (M+H)+ 。 Stirring ((1S,2R)-2-((S)-2-(azetidin-1-yl)-1-(1-(azetidin-3-yl) under N 2 atmosphere at 100°C Methyl)hexahydropyridin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate (300 mg, 0.635 mmol, 1.0 equivalent), 3-(4-bromo Benzyl) azetidine-1-carboxylic acid tert-butyl ester (412 mg, 1.269 mmol, 2.0 equivalents), Pd 2 (dba) 3 (116 mg, 0.127 mmol, 0.2 equivalents), X-Phos (60.54 A mixture of mg, 0.127 mmol, 0.2 equivalent) and Cs 2 CO 3 (621 mg, 1.905 mmol, 3.0 equivalent) in toluene (15 mL) for 16 hours. Then the reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography to obtain 3-(4-(3-((4-((S)-2-(azetidin-1-yl)-1) as a white oil -(3-Fluorophenyl)-1-((1R,2S)-2-((methoxycarbonyl)amino)cyclopentyl)ethyl)hexahydropyridin-1-yl)methyl)aza (Cyclobut-1-yl)benzyl)azetidine-1-carboxylate (255 mg, yield 56%). LC-MS: 718 (M+H) + .
步驟step CC ：: (((( 1S1S ,, 2R2R )-)- 22 -((-(( SS )-)- 22 -(-( 氮雜環丁Azetidine -- 11 -- 基base )-)- 11 -(-( 11 -((-(( 11 -(-( 44 -(-( 氮雜環丁Azetidine -- 33 -- 基甲基Base methyl )) 苯基Phenyl )) 氮雜環丁Azetidine -- 33 -- 基base )) 甲基methyl )) 六氫吡啶Hexahydropyridine -- 44 -- 基base )-)- 11 -(-( 33 -- 氟苯基Fluorophenyl )) 乙基Ethyl )))) 環戊基Cyclopentyl )) 胺基甲酸甲酯Methyl carbamate
向3-(4-(3-((4-((S)-2-(氮雜環丁-1-基)-1-(3-氟苯基)-1-((1R,2S)-2-((甲氧基羰基)胺基)環戊基)乙基)六氫吡啶-1-基)甲基)氮雜環丁-1-基)苯甲基)氮雜環丁烷-1-甲酸第三丁酯(255 mg，0.355 mmol)於DCM(10 mL)中之攪拌溶液中添加TFA (1 mL)。隨後在室溫下攪拌反應溶液16小時。隨後用飽和NaHCO3 溶液(30 mL)稀釋反應混合物且用DCM(20 mL×3)萃取。用鹽水(30 mL)洗滌合併之有機層，經Na2 SO乾燥且在減壓下濃縮，得到呈黃色油狀之((1S,2R)-2-((S)-2-(氮雜環丁-1-基)-1-(1-((1-(4-(氮雜環丁-3-基甲基)苯基)氮雜環丁-3-基)甲基)六氫吡啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯(210 mg，產率96%)。LC-MS: 618 (M+H)+ 。 To 3-(4-(3-((4-((S)-2-(azetidin-1-yl)-1-(3-fluorophenyl)-1-((1R,2S)- 2-((Methoxycarbonyl)amino)cyclopentyl)ethyl)hexahydropyridin-1-yl)methyl)azetidin-1-yl)benzyl)azetidine-1 -TFA (1 mL) was added to a stirred solution of tert-butyl formate (255 mg, 0.355 mmol) in DCM (10 mL). The reaction solution was then stirred at room temperature for 16 hours. The reaction mixture was then diluted with saturated NaHCO 3 solution (30 mL) and extracted with DCM (20 mL×3). The combined organic layer was washed with brine (30 mL), dried over Na 2 SO and concentrated under reduced pressure to give ((1S,2R)-2-((S)-2-(nitrogen heterocycle) as a yellow oil But-1-yl)-1-(1-((1-(4-(azetidin-3-ylmethyl)phenyl)azetidin-3-yl)methyl)hexahydropyridine- Methyl 4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)carbamate (210 mg, yield 96%). LC-MS: 618 (M+H) + .
步驟step DD ：: (( EE )-()-( 44 -(-( 二甲胺基Dimethylamino )) -- 44 -- 側氧基丁Pendant -- 22 -- 烯Ene -- 11 -- 基base )) 胺基甲酸第三丁酯Tert-butyl carbamate
向(E)-4-((第三丁氧基羰基)胺基)丁-2-烯酸(350 mg，1.739 mmol，1.0當量；參考：Angewandte Chemie-International Edition；第57卷；nb.35; (2018);第11193-11197頁)、HATU(992 mg，2.6 mmol，1.5當量)、二甲胺(2.0 M於THF中，1.1 mL，2.2 mmol，1.27當量)於DCM(15 mL)中之混合物中添加TEA(0.5 mL，3.479 mmol，2.0當量)。在25℃下攪拌混合物16 h。隨後反應混合物用H2 O(10 mL)稀釋且用EtOAc(10 mL×3)萃取。合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮，殘餘物藉由矽膠急驟管柱層析純化，得到(E)-(4-(二甲胺基)-4-側氧基丁-2-烯-1-基)胺基甲酸第三丁酯(100 mg，產率25%)。LC-MS: 229 (M+H)+ 。 To (E)-4-((tertiary butoxycarbonyl)amino)but-2-enoic acid (350 mg, 1.739 mmol, 1.0 equivalent; reference: Angewandte Chemie-International Edition; Volume 57; nb.35 ; (2018); pages 11193-11197), HATU (992 mg, 2.6 mmol, 1.5 equivalents), dimethylamine (2.0 M in THF, 1.1 mL, 2.2 mmol, 1.27 equivalents) in DCM (15 mL) TEA (0.5 mL, 3.479 mmol, 2.0 equivalents) was added to the mixture. The mixture was stirred at 25°C for 16 h. Then the reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to obtain (E)-(4-(dimethylamino) ) Tertiary butyl-4-oxobut-2-en-1-yl)carbamate (100 mg, yield 25%). LC-MS: 229 (M+H) + .
步驟step EE ：: (( EE )-)- 44 -- 胺基Amino -- NN ,, NN -- 二甲基丁Dimethyl butyl -- 22 -- 烯醯胺Enixamide
在室溫下攪拌(E)-(4-(二甲胺基)-4-側氧基丁-2-烯-1-基)胺基甲酸第三丁酯(100 mg，0.44 mmol)及TFA(0.2 mL)於DCM(5 mL)中之混合物2小時。隨後在減壓下濃縮反應混合物，得到呈黃色油狀之(E)-4-胺基-N,N-二甲基丁-2-烯醯胺(130 mg，TFA鹽)。LC-MS: 129 (M+H)+ 。 Stir (E)-(4-(dimethylamino)-4-oxobut-2-en-1-yl) tertiary butyl ester (100 mg, 0.44 mmol) and TFA at room temperature (0.2 mL) in DCM (5 mL) for 2 hours. The reaction mixture was then concentrated under reduced pressure to obtain (E)-4-amino-N,N-dimethylbut-2-enamide (130 mg, TFA salt) as a yellow oil. LC-MS: 129 (M+H) + .
步驟step FF ：: (((( 1S1S ,, 2R2R )-)- 22 -((-(( SS )-)- 22 -(-( 氮雜環丁Azetidine -- 11 -- 基base )) 11 -(-( 11 -((-(( 11 -(-( 44 -((-(( 11 -(((-((( EE )-)- 44 -(-( 二甲胺基Dimethylamino )-)- 44 -- 側氧基丁Pendant -- 22 -- 烯Ene -- 11 -- 基base )) 胺甲醯基Carbamate )) 氮雜環丁Azetidine -- 33 -- 基base )) 甲基methyl )) 苯基Phenyl )) 氮雜環丁Azetidine -- 33 -- 基base )) 甲基methyl )) 六氫吡啶Hexahydropyridine -- 44 -- 基base )-)- 11 -(-( 33 -- 氟苯基Fluorophenyl )) 乙基Ethyl )) 環戊基Cyclopentyl )) 胺基甲酸甲酯Methyl carbamate (( 化合物Compound 122122 ))
在室溫下攪拌(E)-4-胺基-N,N-二甲基丁-2-烯醯胺(50 mg，0.388 mmol，2.4當量)、TEA(0.09 mL，0.648 mmol，4.0當量)及CDI(63 mg，0.388 mmol，2.4當量)於THF(15 mL)中之溶液1小時。隨後向反應物中添加((1S,2R)-2-((S)-2-(氮雜環丁-1-基)-1-(1-((1-(4-(氮雜環丁-3-基甲基)苯基)氮雜環丁-3-基)甲基)六氫吡啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯(100 mg，0.162 mmol，1.0當量)。在16小時之後，反應混合物用H2 O(10 mL)稀釋且用EtOAc(10 mL×3)萃取。經合併之有機層用鹽水(10 mL)洗滌，經Na2 SO4 乾燥且在減壓下濃縮。藉由矽膠急驟管柱層析及RP-製備型HPLC純化殘餘物，得到呈白色半固體狀之化合物122(3 mg，產率2%)。LC-MS: 772 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.31 - 7.26 (m, 1H), 7.26 - 7.22 (m, 1H), 7.16 (d, 1H), 7.01 (d, 2H), 6.91 (td, 1H), 6.67 (dt, 1H), 6.45 (dt, 1H), 6.41 (d, 2H), 3.98 - 3.92 (m, 5H), 3.88 (dd, 2H), 3.62 (dd, 2H), 3.47 (s, 3H), 3.41 (dd, 2H), 3.38 - 3.36 (m, 1H), 3.11 (s, 3H), 3.08 - 3.06 (m, 1H), 3.02 - 2.99 (m, 1H), 2.98 (s, 3H), 2.97 - 2.87 (m, 3H), 2.85 - 2.75 (m, 3H), 2.67 - 2.60 (m, 2H), 2.52 (dd, 1H), 2.18 (t, 1H), 2.06 - 1.89 (m, 8H), 1.84 - 1.78 (m, 1H), 1.67 - 1.51 (m, 6H), 0.93 -0.87 (m, 2H)。Stir (E)-4-amino-N,N-dimethylbut-2-enamide (50 mg, 0.388 mmol, 2.4 equivalents), TEA (0.09 mL, 0.648 mmol, 4.0 equivalents) at room temperature And CDI (63 mg, 0.388 mmol, 2.4 equivalents) in THF (15 mL) for 1 hour. ((1S,2R)-2-((S)-2-(azetidin-1-yl)-1-(1-((1-(4-(azetidin -3-ylmethyl)phenyl)azetidin-3-yl)methyl)hexahydropyridin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl)aminocarboxylic acid Methyl ester (100 mg, 0.162 mmol, 1.0 equivalent). After 16 hours, the reaction mixture was diluted with H 2 O (10 mL) and extracted with EtOAc (10 mL×3). The combined organic layer was washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography and RP-preparative HPLC to obtain compound 122 (3 mg, yield 2%) as a white semi-solid. LC-MS: 772 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.31-7.26 (m, 1H), 7.26-7.22 (m, 1H), 7.16 (d, 1H), 7.01 (d, 2H), 6.91 (td, 1H) ), 6.67 (dt, 1H), 6.45 (dt, 1H), 6.41 (d, 2H), 3.98-3.92 (m, 5H), 3.88 (dd, 2H), 3.62 (dd, 2H), 3.47 (s, 3H), 3.41 (dd, 2H), 3.38-3.36 (m, 1H), 3.11 (s, 3H), 3.08-3.06 (m, 1H), 3.02-2.99 (m, 1H), 2.98 (s, 3H) , 2.97-2.87 (m, 3H), 2.85-2.75 (m, 3H), 2.67-2.60 (m, 2H), 2.52 (dd, 1H), 2.18 (t, 1H), 2.06-1.89 (m, 8H) , 1.84-1.78 (m, 1H), 1.67-1.51 (m, 6H), 0.93 -0.87 (m, 2H).
實例6Example 6
製備 (( 1S , 2R )- 2 -(( S )- 2 -( 氮雜環丁 - 1 - 基 )- 1 -( 3 - 氟苯基 )- 1 -( 1 -(( 1 -( 4 -(( 1 -((( E )- 3 -( 甲基磺醯基 ) 烯丙基 ) 胺甲醯基 ) 氮雜環丁 - 3 - 基 ) 甲基 ) 苯基 ) 氮雜環丁 - 3 - 基 ) 甲基 ) 六氫吡啶 - 4 - 基 ) 乙基 ) 環戊基 ) 胺基甲酸甲酯 ( 化合物 123 ) 
在0℃下向(E)-3-(甲磺醯基)丙-2-烯-1-胺(44 mg，0.324 mmol，0.2當量)於THF(5 mL)中之溶液中添加TEA(0.1 mL，0.81 mmol，5.0當量)及CDI(52 mg，0.32 mmol，0.2當量)。在N2 氛圍下，在室溫下攪拌混合物1小時。隨後將於THF(5 mL)中之((1S,2R)-2-((S)-2-(氮雜環丁-1-基)-1-(1-((1-(4-(氮雜環丁-3-基甲基)苯基)氮雜環丁-3-基)甲基)六氫吡啶-4-基)-1-(3-氟苯基)乙基)環戊基)胺基甲酸甲酯(F5) (100 mg，0.16 mmol，1.0當量)逐滴添加至以上混合物中。在室溫下攪拌混合物3小時。在減壓下濃縮反應混合物且藉由製備型TLC及RP-製備型HPLC純化殘餘物，得到呈白色固體狀之化合物123(2 mg，產率2%)。LC-MS: 779 (M+H)+ 。1 H NMR (400 MHz, MeOD-d4 ) δ 7.50 - 7.44 (m, 1H), 7.18 - 7.12 (m, 2H), 7.07 - 7.03 (m, 3H), 6.84 (dt, 1H), 6.58 (dt, 1H), 6.43 (d, 2H), 4.59 - 4.29 (m, 5H), 4.15 (d, 1H), 4.03 - 3.92 (m, 6H), 3.83 - 3.71 (m, 2H), 3.63 (dd, 2H), 3.56 - 3.47 (m, 5H), 3.36 (d, 2H), 3.15 - 3.03 (m, 2H), 3.02 - 2.90 (m, 4H), 2.88 - 2.72 (m, 3H), 2.64 - 2.37 (m, 3H), 2.13 - 1.96 (m, 5H), 1.83 - 1.53 (m, 6H), 1.50 - 1.42 (m, 1H)。Add TEA (0.1 mL, 0.81 mmol, 5.0 equivalents) and CDI (52 mg, 0.32 mmol, 0.2 equivalents). Under an N 2 atmosphere, the mixture was stirred at room temperature for 1 hour. Then add ((1S,2R)-2-((S)-2-(azetidin-1-yl)-1-(1-((1-(4-( Azetidin-3-ylmethyl)phenyl)azetidin-3-yl)methyl)hexahydropyridin-4-yl)-1-(3-fluorophenyl)ethyl)cyclopentyl ) Methyl carbamate (F5) (100 mg, 0.16 mmol, 1.0 equivalent) was added dropwise to the above mixture. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative TLC and RP-preparative HPLC to obtain compound 123 (2 mg, yield 2%) as a white solid. LC-MS: 779 (M+H) + . 1 H NMR (400 MHz, MeOD- d 4 ) δ 7.50-7.44 (m, 1H), 7.18-7.12 (m, 2H), 7.07-7.03 (m, 3H), 6.84 (dt, 1H), 6.58 (dt , 1H), 6.43 (d, 2H), 4.59-4.29 (m, 5H), 4.15 (d, 1H), 4.03-3.92 (m, 6H), 3.83-3.71 (m, 2H), 3.63 (dd, 2H) ), 3.56-3.47 (m, 5H), 3.36 (d, 2H), 3.15-3.03 (m, 2H), 3.02-2.90 (m, 4H), 2.88-2.72 (m, 3H), 2.64-2.37 (m , 3H), 2.13-1.96 (m, 5H), 1.83-1.53 (m, 6H), 1.50-1.42 (m, 1H).
實例7Example 7
本發明化合物之合成及表徵Synthesis and characterization of the compounds of the present invention
本發明之其他化合物可使用前述流程及前述實例中所述之方法以及相關方法來製備，參見例如WO 2017/192543、WO 2018/183857、WO 2019/191526、WO 2020/072391。藉由此等方法來製備之代表性本發明化合物之LCMS(ESI)資料提供於表1及1A中。Other compounds of the present invention can be prepared using the methods described in the foregoing procedures and the foregoing examples and related methods, see, for example, WO 2017/192543, WO 2018/183857, WO 2019/191526, WO 2020/072391. The LCMS (ESI) data of representative compounds of the present invention prepared by this method are provided in Tables 1 and 1A.
本發明其他化合物之1 H NMR提供於表4中。 1 H NMR of other compounds of the present invention are provided in Table 4.
表4
實例8Example 8
MeninMenin 結合親和力Binding affinity
結合檢定Combination test 11
使用螢光偏振(FP)競爭性結合檢定來測定代表性menin抑制劑之結合親和力。標記為螢光探針之FAM基於MLL1胜肽(FAM-MM2)來進行設計及合成。由蛋白質飽和實驗藉由監測由處於固定濃度下之螢光探針及具有直至完全飽和之增加濃度的蛋白質組成之混合物的總螢光偏振，來測定menin蛋白質之FAM-MM2的平衡解離常數(K d )值。在檢定緩衝液中將蛋白質之連續稀釋液與FAM-MM2混合至200 μl之最終體積(在檢定之前添加具有0.02%牛γ-球蛋白及4% DMSO、0.01%特立通X-100之PBS)。最終FAM-MM2濃度為2 nM。在室溫下將培養盤培育30分鐘，伴以平緩振盪以確保均衡。使用Infinite M-1000板讀取器(TecanU.S., Research Triangle Park, NC)在Microfluor 196孔黑色v形底板(Thermo Scientific, Waltham, MA)中於485 nm之激發波長及530 nm之發射波長下量測微偏振單元(mP)中之FP值。FAM-MM2之K d 值經測定為1.4 nM，該值藉由使用Graphpad Prism 6.0軟體(Graphpad Software, San Diego, CA)將S形劑量依賴型FP增加擬合為蛋白質濃度之函數來進行計算。Fluorescence polarization (FP) competitive binding assay was used to determine the binding affinity of representative menin inhibitors. The FAM labeled as a fluorescent probe is designed and synthesized based on the MLL1 peptide (FAM-MM2). From the protein saturation experiment, the equilibrium dissociation constant (K d ) value. Mix the serial dilutions of the protein and FAM-MM2 in the assay buffer to a final volume of 200 μl (add PBS with 0.02% bovine gamma-globulin, 4% DMSO, and 0.01% Teriton X-100 before the assay ). The final FAM-MM2 concentration is 2 nM. Incubate the plate for 30 minutes at room temperature with gentle shaking to ensure equilibrium. Use the Infinite M-1000 plate reader (TecanU.S., Research Triangle Park, NC) in a Microfluor 196-well black v-shaped bottom plate (Thermo Scientific, Waltham, MA) at an excitation wavelength of 485 nm and an emission wavelength of 530 nm Measure the FP value in the micro-polarization unit (mP). The K d value of FAM-MM2 was determined to be 1.4 nM, which was calculated by fitting the sigmoidal dose-dependent FP increase as a function of protein concentration using Graphpad Prism 6.0 software (Graphpad Software, San Diego, CA).
在競爭性結合實驗中測定代表性本發明化合物之IC50 。將5 μl含所測試化合物之DMSO與195 μl含預培育蛋白質/探針複合物溶液之檢定緩衝液的混合物，添加至在室溫下伴以平緩振盪培育30分鐘之檢定盤中。menin蛋白之最終濃度為4 nM，且最終探針濃度為2 nM。各檢定培養盤中包括僅含有蛋白質/探針複合物之陰性對照(等效於0%抑制)及僅不含探針之陽性對照(等效於100%抑制)。如上文所描述來量測FP值。藉由競爭曲線之非線性回歸擬合來測定IC50 值。Determination of IC 50 Representative compounds of the present invention in a competitive binding experiments. A mixture of 5 μl of DMSO containing the test compound and 195 μl of assay buffer containing the pre-incubated protein/probe complex solution was added to the assay plate incubated at room temperature with gentle shaking for 30 minutes. The final concentration of menin protein was 4 nM, and the final probe concentration was 2 nM. Each test culture plate includes a negative control containing only the protein/probe complex (equivalent to 0% inhibition) and a positive control containing only the probe (equivalent to 100% inhibition). Measure the FP value as described above. IC 50 values were determined by nonlinear regression of the competition curves fitting.
結合檢定Combination test 22
化合物結合效能亦藉由使用一種探針36之基於螢光之極化配位體移位檢定針對重組menin蛋白量測，如Zhou(2013)中所描述，具有以下修改。參見Zhou等人, Structure-Based Design of High-Affinity Macrocyclic Peptidomimetics to Block the Menin-Mixed Lineage Leukemia 1 (MLL1) Protein-Protein Interaction. J. Med. Chem., 2013; 56(3):1113-23。所有化合物製備為DMSO中之10 mM儲備溶液。The compound binding efficiency was also measured for recombinant menin protein by using a fluorescence-based polarization ligand shift assay using a probe 36, as described in Zhou (2013), with the following modifications. See Zhou et al., Structure-Based Design of High-Affinity Macrocyclic Peptidomimetics to Block the Menin-Mixed Lineage Leukemia 1 (MLL1) Protein-Protein Interaction. J. Med. Chem., 2013; 56(3):1113-23. All compounds were prepared as 10 mM stock solutions in DMSO.
對於使用探針36之化合物之檢定，在含有100 mM磷酸鉀，pH 7.5、100 μg/ml牛γ球蛋白、0.02%疊氮化鈉、0.005%特立通X-100及2% DMSO之緩衝液中進行結合研究。首先將化合物之10點劑量反應曲線添加至孔中，隨後添加含有90 nM重組menin蛋白及6 nM探針36之緩衝溶液。使系統在室溫下在暗處平衡60分鐘，且接著在Ex480/Em530下讀取FP信號。將FP信號資料與四參數劑量方程式擬合以允許IC50資料之提取。For the assay of compounds using probe 36, in a buffer containing 100 mM potassium phosphate, pH 7.5, 100 μg/ml bovine gamma globulin, 0.02% sodium azide, 0.005% Triton X-100 and 2% DMSO Conjugation studies are carried out in liquid. The 10-point dose response curve of the compound was first added to the well, and then a buffer solution containing 90 nM recombinant menin protein and 6 nM probe 36 was added. The system was allowed to equilibrate in the dark at room temperature for 60 minutes, and then the FP signal was read under Ex480/Em530. Fit the FP signal data to a four-parameter dose equation to allow the extraction of IC50 data.
在前述檢定分析中測試本文所揭示之特定化合物，且測定其具有如表5中所闡述之IC50。縮寫(NT)表示未測試。The specific compounds disclosed herein were tested in the aforementioned assays and determined to have IC50 as set forth in Table 5. The abbreviation (NT) means not tested.
表5
實例9Example 9
細胞生長抑制Cell growth inhibition
程序program 11
在4天或7天增殖檢定中測定代表性本發明化合物對於細胞生存力之影響。在37℃及5% CO2 之氛圍下，將細胞維持於具有10% FBS之適當培養基中。The effect of representative compounds of the invention on cell viability was determined in a 4-day or 7-day proliferation assay. Maintain the cells in an appropriate medium with 10% FBS at 37°C and 5% CO 2.
在100 μl之培養基中，以2,000至3,000個細胞/孔之密度，將細胞接種於96孔平坦底部(Corning COSTAR, Corning, NY, 目錄號3595)中。將化合物連續稀釋於適當培養基中，且將100 μl之稀釋化合物添加至細胞培養盤之適當孔中。在添加化合物之後，在37℃下於5% CO2 之氛圍中培育細胞4或7天。在7天檢定中，根據製造商之說明書使用WST (2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺基苯基)-2H-四唑鎓，單鈉鹽)細胞計數-8套組(Dojindo Molecular Technologies, Inc., Rockville, MD)來測定細胞生存力。在4天檢定中，細胞生存力係根據製造商之說明書使用CellTiter-Glo®發光細胞生存力試劑來測定。In 100 μl of medium, cells were seeded in 96-well flat bottom (Corning COSTAR, Corning, NY, catalog number 3595) at a density of 2,000 to 3,000 cells/well. The compound was serially diluted in the appropriate medium, and 100 μl of the diluted compound was added to the appropriate wells of the cell culture plate. After the compound was added, the cells were incubated for 4 or 7 days in an atmosphere of 5% CO 2 at 37°C. In the 7-day test, use WST (2-(2-methoxy-4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-bis Sulfophenyl)-2H-tetrazolium, monosodium salt) cell count-8 set (Dojindo Molecular Technologies, Inc., Rockville, MD) to determine cell viability. In the 4-day test, cell viability was measured using CellTiter-Glo® Luminescent Cell Viability Reagent according to the manufacturer's instructions.
將細胞生存力試劑以10% (v/v)之最終濃度添加至各孔中，且隨後在37℃下培育培養盤1-2小時用於顯色。使用SPECTRAmax PLUS板讀取器(Molecular Devices, Sunnyvale, CA)來量測450 nm下之吸光度。讀數經標準化為經DMSO處理之細胞數，且使用GraphPad Prism 5軟體(GraphPad Software, La Jolla, CA)，藉由非線性回歸(與可變斜率擬合、最小平方擬合且無約束條件之四參數S型)分析來計算半數最大抑制濃度(IC50 )。The cell viability reagent was added to each well at a final concentration of 10% (v/v), and then the culture plate was incubated at 37°C for 1-2 hours for color development. A SPECTRAmax PLUS plate reader (Molecular Devices, Sunnyvale, CA) was used to measure the absorbance at 450 nm. The readings were normalized to the number of cells processed by DMSO, and GraphPad Prism 5 software (GraphPad Software, La Jolla, CA) was used by non-linear regression (fourth with variable slope fitting, least square fitting and unconstrained conditions) Parametric S-type) analysis to calculate the half maximum inhibitory concentration (IC 50 ).
程序program 22
在4天或7天增殖檢定中測定代表性本發明化合物對於細胞生存力之影響。在37℃及5% CO2 之氛圍下，將細胞維持於具有10% FBS之適當培養基中。The effect of representative compounds of the invention on cell viability was determined in a 4-day or 7-day proliferation assay. Maintain the cells in an appropriate medium with 10% FBS at 37°C and 5% CO 2.
在50 μl之培養基中，以4,000-7,500個細胞/孔之密度，將細胞接種於96孔平坦底部(Corning COSTAR, Corning, NY,目錄號3903)中。將化合物連續稀釋於適當培養基中，且將50 μl之稀釋化合物添加至細胞培養盤之適當孔中。在添加化合物之後，在37℃下於5% CO2 之氛圍中培育細胞4或7天。根據製造商之說明書使用CellTiter-Glo®發光細胞生存力試劑測定細胞生存力。In 50 μl of medium, cells were seeded in 96-well flat bottom (Corning COSTAR, Corning, NY, catalog number 3903) at a density of 4,000-7,500 cells/well. The compound was serially diluted in the appropriate medium, and 50 μl of the diluted compound was added to the appropriate wells of the cell culture plate. After the compound was added, the cells were incubated for 4 or 7 days in an atmosphere of 5% CO 2 at 37°C. Use CellTiter-Glo® Luminescent Cell Viability Reagent to determine cell viability according to the manufacturer's instructions.
將CellTiter-Glo®發光細胞生存力試劑添加至各孔中且在室溫下在定軌振盪器上培育10分鐘。使用EnSpire®盤讀取器(PerkinElmer，Waltham, MA)量測發光信號。讀數經標準化為經DMSO處理之細胞數，且使用GraphPad Prism 5軟體(GraphPad Software, La Jolla, CA)，藉由非線性回歸(與可變斜率擬合、最小平方擬合且無約束條件之四參數S型)分析來計算半數最大抑制濃度(IC50 )。Add CellTiter-Glo® Luminescent Cell Viability Reagent to each well and incubate on an orbital shaker for 10 minutes at room temperature. An EnSpire® disc reader (PerkinElmer, Waltham, MA) was used to measure the luminescence signal. The readings were normalized to the number of cells processed by DMSO, and GraphPad Prism 5 software (GraphPad Software, La Jolla, CA) was used by non-linear regression (fourth with variable slope fitting, least square fitting and unconstrained conditions) Parametric S-type) analysis to calculate the half maximum inhibitory concentration (IC 50 ).
在前述檢定中測試本文所揭示之特定化合物，且用如表6中所闡述之IC50測定以抑制細胞增殖。縮寫(NT)表示未測試。The specific compounds disclosed herein were tested in the aforementioned assays, and determined with IC50 as set forth in Table 6 to inhibit cell proliferation. The abbreviation (NT) means not tested.
表6
現已完整描述本文中提供之方法、化合物及物質組成，熟習此項技術者將理解，在不影響本文中或其任一實施例所提供之方法、化合物及組合物之範疇的情況下，該等方法、化合物及物質組成可在病狀、調配物及其他參數之廣泛且等效範圍內執行。Now that the methods, compounds, and material compositions provided in this article have been fully described, those familiar with the art will understand that, without affecting the scope of the methods, compounds, and compositions provided in this article or any of its embodiments, the Such methods, compounds and composition of substances can be performed within a wide and equivalent range of disease conditions, formulations and other parameters.
本文中引用之所有專利、專利申請案及公開案全部均以其全文引用之方式併入本文中。All patents, patent applications and publications cited in this article are incorporated into this article in their entirety by citation.
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| US5455258A (en) | 1993-01-06 | 1995-10-03 | Ciba-Geigy Corporation | Arylsulfonamido-substituted hydroxamic acids |
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| US9212180B2 (en) | 2013-06-12 | 2015-12-15 | The Regents Of The University Of Michigan | Menin-MLL inhibitors and methods of use thereof |
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| CA3112340A1 (en) | 2018-10-03 | 2020-04-09 | The Regents Of The University Of Michigan | Small molecule menin inhibitors |
-
2020
- 2020-09-29 TW TW109133968A patent/TW202126636A/en unknown
- 2020-09-29 WO PCT/US2020/053186 patent/WO2021067215A1/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| WO2021067215A1 (en) | 2021-04-08 |
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