TW200916458A - Heterocyclic compounds and methods of use thereof - Google Patents

Heterocyclic compounds and methods of use thereof Download PDF

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TW200916458A
TW200916458A TW097133986A TW97133986A TW200916458A TW 200916458 A TW200916458 A TW 200916458A TW 097133986 A TW097133986 A TW 097133986A TW 97133986 A TW97133986 A TW 97133986A TW 200916458 A TW200916458 A TW 200916458A
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Benjamin Fauber
Alexander Hird
James Janetka
Daniel John Russell
Bin Yang
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Astrazeneca Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The present disclosure relates to heterocyclic amide compounds, which are useful for inhibiting the Hedgehog pathway, and their use in treating a disease or medical condition mediated alone or in part by Hedgehog pathway inhibition. Also disclosed are methods for manufacture of these compounds, pharmaceutical compositions including these compounds, and use of these compounds in the manufacture of medicaments for treating such diseases and medical conditions in a subject.

Description

200916458 九、發明說明： 本申請案主張2007年9月5曰申請之美國臨時申請案第 6〇/97〇，1〇7 號及 2008 年 3 月 Η 曰申請之 61/036,661 在35 U.S.C. § 119(e)下之優先權；哕辇 。亥專申睛案之各者之全部内 容在此以引用之方式全部明確併入。 【先前技術】200916458 IX. INSTRUCTIONS: This application claims US Provisional Application Nos. 6〇/97〇, 1〇7 and March 2008 曰 曰 application for 61/036,661 at 35 USC § 119 (e) Priority under; The entire contents of each of the Hai Hai Shen Shen Cases are hereby incorporated by reference in their entirety. [Prior Art]

Hedgehog路徑（HH路徑）為影響大量生物進程（諸如胚胎 發生，其中該路徑經活化且介導胚胎成型、細胞分化及增 殖）之經充分研究之路徑。該路徑存在於整個進化期間， 且已在許多物種（包括海膽、螺蟲 '蒼蠅及哺乳動物）中鑑 別出該路徑之組份。大部分關於HH路徑之當前認識來自 果蠅（Drosophila)之研究。人類基因組含有三種hedgeh〇g基 因：Sonic (SHH)、Indian (IHH)及 Desert (DHH)。The Hedgehog pathway (HH pathway) is a well-studied pathway that affects a large number of biological processes, such as embryogenesis, where the pathway is activated and mediates embryo formation, cell differentiation, and proliferation. This pathway exists throughout evolution and has been identified in many species, including sea urchins, spirochetes, flies and mammals. Most of the current understanding of the HH pathway comes from the study of Drosophila. The human genome contains three hedgeh〇g genes: Sonic (SHH), Indian (IHH), and Desert (DHH).

Hedgehog為三種基因中之最廣泛表現者，且研究展示該基 因在胚胎發生之許多態樣中發揮作用。Hedgehog is the most widely expressed of the three genes, and studies have shown that this gene plays a role in many aspects of embryogenesis.

Sonic基因編碼SHH蛋白配體。所有hedgeh〇g蛋白由細胞 分泌且與其通用12次跨膜蛋白ptch 1結合，PTCH1之功能 在於抑制稱為Smoothened (SMO)之7次GPCR樣膜蛋白。 SHH與PTCH1之結合減輕對於sm〇之抑制，使得可將SMO 轉運至膜繼而隨後引發信號轉導路徑（Varj〇sal〇等人，jThe Sonic gene encodes a SHH protein ligand. All hedgeh〇g proteins are secreted by cells and bind to their universal 12-transmembrane protein ptch 1 , which functions to inhibit 7 GPCR-like membrane proteins called Smoothened (SMO). The combination of SHH and PTCH1 mitigates the inhibition of sm〇, allowing SMO to be transported to the membrane followed by signal transduction pathways (Varj〇sal〇 et al., j

Cell Sci. 120:3-6 (2007))。近年來，已展示sm〇定位於膜 尤其存在於哺乳動物細胞之纖毛中（CaSpary等人，〇6乂· Cell 12:767-778 (2007))。此外，鞭毛内轉運蛋白之突變導 致異常SHH信號傳輸且導致發育畸形，類似於SHH突變情 I34079.doc 200916458 況下所觀察到之彼等者。HH路徑活化之後，SMO下游複 雜的相互作用系列最終引起GLI轉錄因子之加工及轉運至 核中，其中GLI轉錄因子充當轉錄調節者。在脊椎動物 中，存在三種GLI基因（GLn、GLI2及GLI3)，其為鋅指轉 錄因子家族之成員。GLI1及GLI2主要充當轉錄活化因子， 而GLI3充當轉錄抑制因子。GLI2基因經組成性表現且咸 信其為SMO活化之主要目標。在SHH配體及SMO活化存在 下，GLI2蛋白變得穩定且發揮調升大量確定為HH路徑標 靶之基因（包括GLI1、PTCH、BCL2、c-myc及IGF2)的作 用。在該等基因中’研究表明GLI 1似乎為量測HH路徑活 化之最可靠生物學終點。 靶向HH路徑之一困難為對信號轉導路徑之不完全認識 及對正路徑調郎者缺乏鑑別方法。西洛帕明（Cyclopamine) 為明確建立之HH路徑之天然產物拮抗劑，已證明其為調 節HH路徑之有效手段。西洛帕明已展示直接與sm〇結合 且抑制其活化’使得可在活體外與活體内調降該路徑 (Chen 等人，Cancer Sci. 98:68-76 (2007) ; Mukherjee 等 人，Cancer Bio & Therapy 5:674-683 (2006)) ° 近年來’已建立Hedgehog路徑與疾病（諸如癌症）之聯 繫。PTCH或SMO之活化突變均已與基底細胞癌、成神經 管細胞瘤及橫紋肌肉瘤關聯。此外，如由SHH過度表現所 量測之該路徑之上調或GLI 1表現之上調已與實體腫瘤，包 括***、胰腺、上消化道腫瘤，及小細胞肺癌關聯（Bak 等人，Pharmacogenomica 4:411-429 (2003))。此外，已藉 134079.doc 200916458 由在特定組織中過度表現路徑組份或組織特異性基因剔除 在小鼠中引起腫瘤形成之組份開發出若干轉殖基因或基因 剔除/敲入模型。舉例而言，組成性活性SM〇在乳腺中之 過度表現引起增殖增加，分化改變及乳腺管發育異常 (Moraes等人，Development 134:1231-1242 (2007))。雜合 PTCH之小鼠當曝露於UV光時形成基底細胞癌（Aszterbaum 等人 Nat. Med. 5:1285-1291 (1999))，且 SHH 在胰腺中之組 織特異性過度表現產生類似於人類胰腺癌之異常小管結構 (Thayer等人，Nature 425:851-850 (2003))。此外，若干研 九報導HH信號組份在包括（但不限於）以下人類腫瘤組織之 組織中之表現：***、胰腺、卵巢、黑色素瘤、***、 結腸、肺、食道、胃、膽、肝細胞及多發性骨髓瘤。 腫瘤微環境為腫瘤發生之極重要之態樣，但尚未瞭解生 長因子信號傳輸路徑如何影響腫瘤微環境。該等路徑可以 自體分泌方式發揮作用’其中配體由腫瘤細胞產生且因此 活化腫瘤細胞内之信號傳輸路徑。然而，認為在正常發育 期間’ HH路徑以旁分泌方式發揮作用，其中反應性基質 細胞產生生長因子且將信號發送回產生腫瘤中（Fan等人，Cell Sci. 120:3-6 (2007)). In recent years, it has been shown that sm〇 localizes to membranes, especially in the cilia of mammalian cells (CaSpary et al., 〇6乂· Cell 12:767-778 (2007)). In addition, mutations in the flagellar transporter cause abnormal SHH signaling and lead to developmental malformations, similar to those observed in the SHH Mutant I34079.doc 200916458. Following activation of the HH pathway, a complex series of interactions downstream of the SMO ultimately causes processing and transport of GLI transcription factors into the nucleus, with the GLI transcription factor acting as a transcriptional regulator. In vertebrates, there are three GLI genes (GLn, GLI2 and GLI3) which are members of the zinc finger transcription factor family. GLI1 and GLI2 primarily act as transcriptional activators, while GLI3 acts as a transcriptional repressor. The GLI2 gene is constitutively expressed and is believed to be the primary target of SMO activation. In the presence of SHH ligand and SMO activation, the GLI2 protein becomes stable and functions to upregulate a large number of genes (including GLI1, PTCH, BCL2, c-myc, and IGF2) identified as HH pathway targets. Studies in these genes have shown that GLI 1 appears to be the most reliable biological endpoint for measuring HH pathway activation. One of the difficulties in targeting HH pathways is the incomplete recognition of signal transduction pathways and the lack of identification methods for positive pathway strategists. Cyclopamine has been shown to be an effective means of modulating HH pathways as a natural product antagonist of the established HH pathway. Cilopamine has been shown to bind directly to sm〇 and inhibit its activation' so that this pathway can be downregulated in vitro and in vivo (Chen et al, Cancer Sci. 98:68-76 (2007); Mukherjee et al., Cancer Bio & Therapy 5:674-683 (2006)) ° In recent years, the link between the Hedgehog pathway and disease (such as cancer) has been established. Activating mutations in PTCH or SMO have been associated with basal cell carcinoma, medulloblastoma, and rhabdomyosarcoma. In addition, up-regulation of this pathway as measured by SHH overexpression or GLI 1 upregulation has been associated with solid tumors, including prostate, pancreas, upper gastrointestinal tumors, and small cell lung cancer (Bak et al., Pharmacogenomica 4:411 -429 (2003)). In addition, several transgenic genes or gene knockout/knock-in models have been developed from the components that cause tumor formation in mice by overexpressing path components or tissue-specific gene knockouts in specific tissues by 134079.doc 200916458. For example, overexpression of constitutively active SM(R) in the mammary gland results in increased proliferation, differentiation, and mammary gland dysplasia (Moraes et al., Development 134: 1231-1242 (2007)). Mice heterozygous for PTCH form basal cell carcinoma when exposed to UV light (Aszterbaum et al. Nat. Med. 5: 1285-1291 (1999)), and tissue specificity of SHH in the pancreas produces a human pancreas similar to human Abnormal tubule structure of cancer (Thayer et al, Nature 425:851-850 (2003)). In addition, several studies report the performance of HH signaling components in tissues including, but not limited to, human tumor tissue: prostate, pancreas, ovary, melanoma, breast, colon, lung, esophagus, stomach, gallbladder, hepatocytes And multiple myeloma. The tumor microenvironment is a very important aspect of tumorigenesis, but it is not known how the growth factor signaling pathway affects the tumor microenvironment. These pathways can function in an autocrine manner where the ligand is produced by tumor cells and thus activates signaling pathways within the tumor cells. However, it is believed that the HH pathway functions in a paracrine manner during normal development, where reactive stromal cells produce growth factors and send signals back to the tumor (Fan et al.

Endocrinology 145:3961-3970 (2004))。 除對增殖及分化之效應之外’ HH路徑亦與血管生成過 程有關’其使得自現有血管結構生長新血管且將較小血管 重塑為較大血管。所有該等效應均有助於促進腫瘤生長及 存活（Klagsbrun and D' Amore，Annu. Rev. Physiol. 53:217-239 (1991) ; Cherington等人，Adv. Cancer Res. 79:1-38 134079.doc 200916458 (2000)) 〇 此外’ ΗΗ路徑可在癌症幹細胞之產生領域中發揮作 用。幹細胞為具有自發產生確切複製之能力的緩慢複製細 胞以及後代細胞之異質群體。在癌症之幹細胞模型中，一 種罕見細胞亞群具有自我更新之能力，產生另一惡性幹細 胞以及非致瘤癌細胞，由此增加腫瘤之異質細胞群體。新 近研究展示在白血病及若干實體腫瘤（包括腦、***、 騰腺、結腸及***）中少數癌細胞具有活體内廣泛增殖且 形成新異質腫瘤之能力（Clarke等人Cancer Res. 66:9339-9344 (2006))。舉例而言，在胰腺中，亦已報導該等癌症 幹細胞具有高含量之GLI表現（Li等人，Cancer Res. 67.1030-1037 (2007))。因此有效抑制Hedgehog路徑之化合 物可適用於降低癌症幹細胞增殖或分化活性。 【發明内容】 因此，提供新穎化合物，其為Hedgehog路徑之有效抑制 劑及效應物且因此擁有防止藉由GLI蛋白質實現基因轉錄 之能力。該抑制能力產生防止或減少細胞分化、增殖及/ 或影響基質微環境調節。所揭示化合物適用於治療單獨戋 部分地藉由Hedgehog路徑抑制介導之疾病及醫學病狀，且 因此擁有抗增生性（諸如抗癌）活性。該活性適用於治療具 有PTCH功能損失表型、SM0功能獲得表型或取牝化吆功 能獲得表型之個體。 本發明之一態樣提供式I化合物 134079.doc 200916458Endocrinology 145: 3961-3970 (2004)). In addition to the effects on proliferation and differentiation, the 'HH pathway is also associated with the process of angiogenesis', which causes new blood vessels to grow from existing vascular structures and remodel small blood vessels into larger blood vessels. All of these effects contribute to tumor growth and survival (Klagsbrun and D' Amore, Annu. Rev. Physiol. 53:217-239 (1991); Cherington et al., Adv. Cancer Res. 79:1-38 134079 .doc 200916458 (2000)) In addition, the 'ΗΗ path can play a role in the field of cancer stem cell production. Stem cells are heterogeneous populations of slow-replicating cells that have the ability to spontaneously produce exact replication, as well as progeny cells. In the cancer stem cell model, a rare subset of cells has the ability to self-renew, producing another malignant stem cell as well as non-tumorigenic cancer cells, thereby increasing the heterogeneous cell population of the tumor. Recent studies have shown that a small number of cancer cells in leukemia and several solid tumors (including brain, prostate, gonad, colon and breast) have the ability to proliferate in vivo and form new heterogeneous tumors (Clarke et al. Cancer Res. 66:9339-9344) (2006)). For example, in the pancreas, these cancer stem cells have also been reported to have high levels of GLI expression (Li et al, Cancer Res. 67.1030-1037 (2007)). Therefore, a compound which effectively inhibits the Hedgehog pathway can be applied to reduce cancer stem cell proliferation or differentiation activity. SUMMARY OF THE INVENTION Accordingly, novel compounds are provided which are potent inhibitors and effectors of the Hedgehog pathway and thus possess the ability to prevent transcription of genes by GLI proteins. This inhibitory ability produces the prevention or reduction of cell differentiation, proliferation and/or effects on matrix microenvironment regulation. The disclosed compounds are useful for the treatment of diseases and medical conditions mediated, in part, by Hedgehog pathway inhibition, and thus possess antiproliferative (e.g., anti-cancer) activity. This activity is useful for treating individuals with a PTCH loss profile, a SM0 function to obtain a phenotype, or a sputum sputum function to obtain a phenotype. One aspect of the invention provides a compound of formula I 134079.doc 200916458

其中 R丨、各獨立地選自由以下基團組成之群：1、 C!_6烷基及鹵素； 選自由以下基團、组成之群：Ci6貌基、画基C』基 及鹵素； 各W獨立地選自由以下基團組成之群：CR5、NR5、N、 〇及s，其中R5選自由以下基團組成之群：氫、6烷氧基 (例如-OCH3)、Ci.6烷氧基C,.6院基、C,·6院氧基羰基、匚16 烷基（例如-CH3)、甲脒基、醯胺基、胺基（例如胺基Ci6烷 基）Ci·6燒基幾基、方基、缓酿胺基、c3_8環烧基、氰 基、鹵基C]-6烷基、鹵素、雜環基、雜環基c16烧基、經 基、經基Cl·6院基、硝基、硫化物、亞續酿基、續醢胺基 及磺醯基，或 2個相鄰w原子可連同其R5取代基一起形成稍合第二 環’其中第二環視需要經一或多個Rs取代基取代且係選自 由以下環組成之群：芳基、C3-8環烷基、5或6員雜芳基， 及5或6員雜環基； 至少一個W為N ; 134079.doc 10 200916458 q為〇或1，其中 若q為0且2個相鄰W原子連同其取代基—起形成稠合 第一％，則相鄰W原子之一為N且第二環為6員雜環基，且 若q為0，且由W原子構成之環為2_咪唑基，則化不為未 經取代苯基環； A選自由以下基團組成之群：Cr6、NR6、n、〇及s ; 尸R6選自由以下基團組成之群：氫、€16烷氧基、Cw烷 氧基Cy烷基、Cl_0烷氧基羰基、e烷基、Ci 6烷基（例如 -CH3)、甲肺基、醯胺基、胺基（例如胺基烷基）、a』 烧基幾基、芳基、幾醯胺基、C38環烧基、氛基、齒基“ 烧基（例如三敗甲基）、鹵素（例如α)、雜環基、雜環基Cm 烷基、雜環基(^_6烷氧基（例如2_吡啶基甲氧基）、羥基、羥 基（^.6烧基、硝基、亞磺酿基、硫化物、續醯胺基及績酿 基，或 2個相鄰A原子可連同其〜取代基一起形成稍合第二環， 其中第二環為5或6員雜環基，例如形成稠合乙3-二氫_丨，4_ 本并'一氧雜環己稀； 至少-個A選自由以下基團組成之群：肌、n、。及 P為0或1，其中 若p為0且Ri、R2及R4各為曱基，則A不為s ; 其中式i化合物不為 134079.doc -11 - 200916458Wherein R丨, each independently selected from the group consisting of: 1, C!_6 alkyl and halogen; selected from the group consisting of Ci6, base C, and halogen; each W Independently selected from the group consisting of CR5, NR5, N, hydrazine and s, wherein R5 is selected from the group consisting of hydrogen, 6 alkoxy (eg -OCH3), Ci.6 alkoxy C,.6 院, C,·6 oxycarbonyl, 匚16 alkyl (such as -CH3), methionyl, decylamino, amine (such as amine Ci6 alkyl) Ci·6 alkyl Base, aryl group, slow-lating amine group, c3_8 cycloalkyl group, cyano group, halo C]-6 alkyl group, halogen, heterocyclic group, heterocyclic group c16 alkyl group, transbasic group, transbasic group , a nitro group, a sulfide, a sulfonyl group, a hydrazine group, and a sulfonyl group, or two adjacent w atoms may form a second ring together with the R 5 substituents, wherein the second ring a plurality of Rs substituents substituted and selected from the group consisting of aryl, C3-8 cycloalkyl, 5 or 6 membered heteroaryl, and 5 or 6 membered heterocyclic; at least one W is N; 134079 .doc 10 200916458 q is 〇 or 1, where q is 0 and 2 An adjacent W atom together with its substituent forms a first % fused, then one of the adjacent W atoms is N and the second ring is a 6-membered heterocyclic group, and if q is 0, and is composed of W atoms The ring is a 2-imidazolyl group which is not an unsubstituted phenyl ring; A is selected from the group consisting of Cr6, NR6, n, hydrazine and s; cadaver R6 is selected from the group consisting of hydrogen: , €16 alkoxy, Cw alkoxy Cyalkyl, Cl_0 alkoxycarbonyl, ealkyl, Ci 6 alkyl (eg -CH3), alpha lung, guanamine, amine (eg amin a), a aryl group, aryl, amidino, C38 cycloalkyl, aryl, dentate "alkyl (eg, tri-methyl), halogen (eg alpha), heterocyclic, hetero Cycloalkyl Cm alkyl, heterocyclic (^-6 alkoxy (eg 2-pyridylmethoxy), hydroxy, hydroxy (^.6 alkyl, nitro, sulfinyl, sulfide, decylamine) The base and the base, or two adjacent A atoms, together with the substituent thereof, form a slightly second ring, wherein the second ring is a 5 or 6 membered heterocyclic group, for example, forming a fused B 3-dihydro group.丨, 4 _ _ _ oxirane; at least - A selected from The group consisting of: muscle, n, and P is 0 or 1, wherein if p is 0 and Ri, R2 and R4 are each sulfhydryl, then A is not s; wherein the compound of formula i is not 134079. Doc -11 - 200916458

其中L選自由NH及CH組成之 群’且若L為NH，則Μ為CH2，且若L為CH，則Μ為CH ; 及其醫藥學上可接受之鹽。 本發明之另一態樣提供式Π化合物：Wherein L is selected from the group consisting of NH and CH' and if L is NH, then Μ is CH2, and if L is CH, Μ is CH; and a pharmaceutically acceptable salt thereof. Another aspect of the invention provides a hydrazine compound:

其中， A選自由N及CR10組成之群； X選自由以下基團組成之群：鹵素及Cl.6烷基； Y選自由以下基團組成之群：NR5、〇及S ; 各Rs獨立地選自由以下基團組成之群：氫、Ci 6烷基及 羥基Cw烷基； 134079.doc -12· 200916458 R7選自由以下基團組成之群：氫、鹵素、氰基、Cl.6烷 基、C,_6鹵烷基、胺基（例如Cl.6烷基胺基）、Cn6烷氧基、 芳氧基、羥基、磺醯基、磺醯胺及雜環基，其中R7可視需 要經一或多個Rn取代；Wherein A is selected from the group consisting of N and CR10; X is selected from the group consisting of halogen and Cl. 6 alkyl; Y is selected from the group consisting of NR5, hydrazine and S; each Rs independently Selected from the group consisting of hydrogen, Ci 6 alkyl and hydroxy Cw alkyl; 134079.doc -12· 200916458 R7 is selected from the group consisting of hydrogen, halogen, cyano, Cl.6 alkyl , C, _6 haloalkyl, amine (for example, Cl. 6 alkylamino), Cn6 alkoxy, aryloxy, hydroxy, sulfonyl, sulfonamide and heterocyclic group, wherein R7 may be subjected to a Or multiple Rn substitutions;

Rs、R·9及Ri〇各獨立地選自由以下基團組成之群：氫、 Cm烷基（例如-CH3)、鹵素（例如C1或F)、Cu烷氧基（例如 -OCH3)、胺基、羥基、鹵烷基、氰基、績酿基及績酿胺； R"可選自由以下基團組成之群：齒素、經基、胺基、 烧基、c】·6院氧基、芳基及雜環基，其中R"可視需要 經一或多個R】2取代；且 R〗2可選自由以下基團組成之群：胺基、氰基、羥基、 Cl-6烧基、環烧基及芳基， 或其醫藥學上可接受之鹽。 在另一態樣中，本發明提供式III化合物Rs, R·9 and Ri〇 are each independently selected from the group consisting of hydrogen, Cm alkyl (eg -CH3), halogen (eg C1 or F), Cu alkoxy (eg -OCH3), amine Base, hydroxy, haloalkyl, cyano, broth, and aryl amine; R" can be selected from the group consisting of dentate, thiol, amine, alkyl, c. , aryl and heterocyclic groups, wherein R" may optionally be substituted by one or more R]2; and R"2 may be selected from the group consisting of: an amine group, a cyano group, a hydroxyl group, a Cl-6 alkyl group. , a cycloalkyl group and an aryl group, or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides a compound of formula III

其中 η為0、1、2或 3 ; Ζ為直接鍵、NRa、S及Ο，其中Ra選自由以下基團組成 之群：H、烷基及環烷基， R_3選自由以下基團組成之群：氫、鹵素及烷基； 134079.doc -13- 200916458 各〜選自由以下基團組成之群··氫、幽素、經基、硫 化物幾酿胺、c】_6貌基艘基、胺基、烧基、烧氧基、院 氧基幾基、亞續醯基、確酿基、氰基、環燒基、芳基或雜 環基，其中各r14視需要經以下基團取A : Ci6烧基叛基、 經基、絲Cl-6烧基、齒素、胺基、硝基、Ci6炫基、確酿 氰基 '院氧基或雜環基，以便t 所連接之味嗤基 環為2-咪唑基時，Ru不為未經取代苯基；Wherein η is 0, 1, 2 or 3; Ζ is a direct bond, NRa, S and Ο, wherein Ra is selected from the group consisting of H, alkyl and cycloalkyl, and R_3 is selected from the group consisting of Group: hydrogen, halogen and alkyl; 134079.doc -13- 200916458 each ~ selected from the group consisting of: hydrogen, glutamate, meridine, sulfide chitosan, c] _6 appearance base, An amine group, an alkyl group, an alkoxy group, an alkoxy group, a sulfhydryl group, a decyl group, a cyano group, a cycloalkyl group, an aryl group or a heterocyclic group, wherein each r14 is taken as the following group : Ci6 alkyl radical, thiol, silk Cl-6 alkyl, dentate, amine, nitro, Ci6 succinyl, indeed cyano-steryloxy or heterocyclic group, so that t is connected to the miso When the base ring is 2-imidazolyl, Ru is not an unsubstituted phenyl group;

Rl5選自由以下基團組成之群：-(CHW雜環、_(CH)0-5· NRbRb -(CH)。-故基、_(CH)()_5_Cr6院氧基、芳基及雜環 基（例如派嗓），其中Rls視需要經心6取代，且各&選自由 Η、烷基及環烷基組成之群；且 心選自由以下基團組成之群：齒基、烧基、烧氧基、 &基硫基’其中Rl6視需要經芳基或雜芳基取代， 或其醫藥學上可接受之鹽。 在本發明之另-態樣中，提供—種醫藥組合物，其包含 與一或多種f藥學上可接受之制__起調配之—或多種本 文所述之化合物。 本發月之另一態樣係關於一種抑制Hedgeh〇g路徑之方 法’其包含向個體（例如有需要之個體）投與治療有效量之 或夕種本文所述之化合物，或本文所述之醫藥組合物， 以使Hedgehog路徑受抑制。 在另一態樣中，本發明提供一種減少細胞增殖、分化及/ 或影響基質微環境調節之方法，包含向個體（例如有需要 之個體）投與治療有效量之—或多種本文所述之化合物或 I34079.doc •14- 200916458 本文所述之醫藥組合物，由此減少個體中細胞增殖、分化 及/或影響基質微環境調節。 【實施方式】 本揭示案係關於適用於抑制Hedgehog路徑之雜環醯胺化 合物及其在治療僅或部分由Hedgehog路徑抑制介導之疾病 或醫學病狀中之用途。亦揭示製備該等化合物、包括該= 化合物之醫藥組合物之方法，及該等化合物在製備用於治 療個體中該等疾病及醫學病狀之藥劑中之用途。 應瞭解上述概述及以下實施方式僅為例示性及說明性 的，而並非限制如所主張之本發明。此外，包括化合物、 方法及醫藥組合物之本發明將參考以下為方便起見如下闡 述之定義描述： 除非另外規定，否則化學基團係指其未經取代及經取代 之形式。 如本文中所使用之術語，,搭"或"甲醯基"係指基團-C Η 0。 如本文中所使用之術語”稀基，，係指具有至少一個碳-碳雙 鍵之不飽和直鏈或支鏈烴，諸如具有2_12、2_1〇或2_6個碳 原子之本文中分別稱為C2_Ci2烯基、C2_Cw烯基及C^C6烯 基之直鏈或支鏈基團。例示性烯基包括（但不限於）乙烯 基、烯丙基、丁烯基、戊烯基、己烯基、丁二烯基、戊二 稀基、己二稀基、2-乙基己稀基、2_丙基_2_丁稀基、4_(2_ 甲基-3-丁稀）-戊稀基等。 如本文中所使用之術語”烷氧基”係指與氧連接之烷基 (-〇-烷基-)。例示性烷氧基包括（但不限於）具有丨_丨2、i _8 134079.doc 200916458 或1-6個碳原子之烷基、烯基或炔基之本文中分別稱為 C!2烧氧基、CrC：8烧氧基、及C〗-C6烷氧基之基團。例示性 烷氧基包括（但不限於）甲氧基、乙氧基等。類似地，例示 性"烯氧基"包括（但不限於）乙烯基氧基、烯丙基氧基、丁 烯氧基等。 如本文中所使用之術語”烷基”係指飽和直鏈或支鏈烴， 諸如具有1-12、1-1〇或1-6個碳原子之本文中分別稱為 C〗2烧基、CrCw炫基及C^-Ce燒基的直鏈或支鏈基團。例 示性烷基包括（但不限於）甲基、乙基、丙基、異丙基、2_ 甲基-1-丙基、2-曱基-2-丙基、2-曱基-1-丁基、3_〒基-卜 丁基、2-甲基-3-丁基、2,2-二曱基-1-丙基、2-曱基_丨_戊 基、3-甲基-1·戊基、4_甲基戊基、2_曱基_2_戊基、夂甲 基-2-戊基、4-曱基-2-戊基、2,2-二甲基-1-丁基、3,3-二甲 基-1-丁基、2-乙基-i_ 丁基、丁基、異丁基、第三丁基、 戊基、異戊基、新戊基、己基、庚基、辛基等。 院基可視情況經選自由以下基團組成之群之至少一基團 取代或中斷：烷氧基、烷基、烯基、炔基、醯胺、胺基、 芳基、芳基烷基、胺基曱酸酯、羧基、氰基、環烷基、 酯、醚、曱醯基、齒素、函基烷基、雜芳基、雜環基 '羥 基、酮、硝基、硫基、磺醯胺及磺醯基。 如本文中所使用之術語"炔基"係指具有至少一個碳_碳參 鍵之不飽和直鏈或支鏈烴，諸如具有2_12、2_8或2_6個碳 原子之本文中分別稱為C2_Cn炔基、era炔基及（^-匕炔 基之直鍵或支鏈基團。例示性炔基包括（但不限於）乙块 134079.doc -16_ 200916458 基、丙炔基、丁炔基、戊炔基、己炔基、甲基丙快基、4-甲基-1-丁块基、4 -丙基-2-戊快基及4 -丁基-2-己炔基等。 如本文中所使用之術語”醯胺”或"醯胺基"係指形式 -RaC(0)N(Rb)-、-RaC(0)N(Rb)Rc-或-C(0)NRbRc 之基團， 其中Rb及1^各自獨立地選自由以下基團組成之群：烷氧 基、炫i基、稀基、块基、酿胺、胺基、芳基、芳基烧基、 胺基曱酸酯、叛基、氰基、環院基、酯、縫、甲醢基、鹵 素、卣基院基、雜芳基、雜環基、氫、經基、酮及硝基。 醯胺可與另一基團經由碳、氮、Rb、Rc*Ra連接。醯胺亦 可為環狀，例如Rb及Re、Ra&Rb或1及！^可經接合以形成 3至1 2員環，諸如3至1 0員環或5至6員環。術語"甲醯胺基" 係指結構-C(0)NRbRc。 如本文中所使用之術語”甲脒基”係指形式_c(=nr)nrir” 之基團，其中R、R，及R"可各自獨立地選自由以下組成之 群：烧基、㈣、块基、醯胺、芳基、芳基烧基、氛基、 環烷基、ώ基烷基、雜芳基、雜環基、羥基、酮及硝基。 如本文中所使用之術語"胺"或"胺基"係指形式·Ν^、 -N(Rd)Re-或-ReN(Rd)Rr之基團，其中Rd、mj獨立地 選自以下基團組成之群：院氧基、烧基、稀基、块基、醯 胺、胺基、芳&、芳基烷基、胺基甲酸酯、環烷基、酯、 醚、甲醯基、齒素、鹵基烷基、雜芳基、雜環基、氫、羥 基、闕及硝基。胺基可與母體分子基團經由氮、HA Rf連接。胺基亦可為環狀，例如任何兩個&、匕或心均可 接合在-起或與N接合在—起以形成3至12貝環，例如嗎琳 134079.doc 200916458 或哌啶基。術語胺基亦包括任何胺基之相應第四銨鹽，例 如-[N(Rd)(Re)(Rf)r。例示性胺基包括胺基烷基，其中Rl5 is selected from the group consisting of: -(CHW heterocycle, _(CH)0-5.NRbRb-(CH).--, _(CH)()_5_Cr6, aryl, heterocyclic a group (for example, a group), wherein Rls is optionally substituted with a centrosome 6, and each & is selected from the group consisting of an anthracene, an alkyl group, and a cycloalkyl group; and the core is selected from the group consisting of a dentate group, a decyl group , alkoxy group, &thio group, wherein R16 is optionally substituted with an aryl or heteroaryl group, or a pharmaceutically acceptable salt thereof. In another aspect of the invention, a pharmaceutical composition is provided , which comprises a compound formulated with one or more pharmaceutically acceptable compounds - or a plurality of compounds described herein. Another aspect of this month relates to a method of inhibiting the Hedgeh〇g pathway. An individual (e.g., an individual in need thereof) is administered a therapeutically effective amount of a compound described herein, or a pharmaceutical composition described herein, to inhibit the Hedgehog pathway. In another aspect, the invention provides a A method of reducing cell proliferation, differentiation, and/or affecting the regulation of the microenvironment of the matrix, including to individuals (eg, in need thereof) Administration of a therapeutically effective amount - or a plurality of the compounds described herein or I34079.doc • 14- 200916458 The pharmaceutical compositions described herein, thereby reducing cell proliferation, differentiation and/or affecting matrix microenvironment regulation in an individual. Embodiments The present disclosure relates to heterocyclic guanamine compounds useful for inhibiting the Hedgehog pathway and their use in the treatment of diseases or medical conditions mediated only or partially by Hedgehog pathway inhibition. Also disclosed are the preparation of such compounds, including The method of the pharmaceutical composition of the compound, and the use of the compound in the preparation of a medicament for treating such diseases and medical conditions in an individual. It is to be understood that the above summary and the following embodiments are merely illustrative and illustrative. The present invention, including the claimed compounds, methods and pharmaceutical compositions, will be described with reference to the following definitions for convenience: Unless otherwise specified, chemical groups refer to Substituted and substituted form. As used herein, the term "," or "“基基基" refers to a group -C Η 0 As used herein, the term "dilute group" refers to an unsaturated straight or branched chain hydrocarbon having at least one carbon-carbon double bond, such as having 2 to 12, 2 to 1 or 2 to 6 carbon atoms, respectively referred to herein as Linear or branched groups of C2_Ci2 alkenyl, C2_Cw alkenyl and C^C6 alkenyl. Exemplary alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, pentenyl, hexenyl Butadienyl, pentylene, hexamethylene, 2-ethylhexyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butyl)-pentyl The term "alkoxy" as used herein refers to an alkyl group (-indole-alkyl-) attached to an oxygen. Exemplary alkoxy groups include, but are not limited to, alkyl, alkenyl or alkynyl groups having 丨_丨2, i _8 134079.doc 200916458 or 1-6 carbon atoms, respectively referred to herein as C! 2 oxygenated a group having a base, CrC: 8 alkoxy group, and a C-C6 alkoxy group. Exemplary alkoxy groups include, but are not limited to, methoxy, ethoxy, and the like. Similarly, exemplary "alkenyloxy" includes, but is not limited to, vinyloxy, allyloxy, butenyloxy, and the like. The term "alkyl" as used herein refers to a saturated straight or branched chain hydrocarbon, such as having 1-12, 1-1, or 1-6 carbon atoms, referred to herein as C 2 alkyl, respectively. a linear or branched group of a CrCw leucoyl group and a C^-Ce alkyl group. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-1-propyl, 2-mercapto-2-propyl, 2-mercapto-1-butene , 3_mercapto-bubutyl, 2-methyl-3-butyl, 2,2-dimercapto-1-propyl, 2-indolyl-indole-pentyl, 3-methyl-1·pentyl , 4-methylpentyl, 2-fluorenyl-2-pentyl, fluorenylmethyl-2-pentyl, 4-mercapto-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-Dimethyl-1-butyl, 2-ethyl-i-butyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, Xinji et al. The base may optionally be substituted or interrupted by at least one group selected from the group consisting of alkoxy, alkyl, alkenyl, alkynyl, decylamine, amine, aryl, arylalkyl, amine Phthalate, carboxyl, cyano, cycloalkyl, ester, ether, sulfhydryl, dentate, functional alkyl, heteroaryl, heterocyclyl 'hydroxy, ketone, nitro, thio, sulfonium Amines and sulfonyl groups. The term "alkynyl" as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon bond, such as having 2 to 12, 2 to 8 or 2 to 6 carbon atoms, referred to herein as C2_Cn, respectively. Alkynyl, erynyl and (^-decynyl) straight or branched groups. Exemplary alkynyl groups include, but are not limited to, b 134079.doc -16_200916458, propynyl, butynyl, Pentynyl, hexynyl, methylpropanyl, 4-methyl-1-butenyl, 4-propyl-2-pentyl and 4-butyl-2-hexynyl, etc. The term "nonylamine" or "nonylamine" as used herein refers to the form -RaC(0)N(Rb)-, -RaC(0)N(Rb)Rc- or -C(0)NRbRc a group, wherein Rb and 1 are each independently selected from the group consisting of an alkoxy group, a thiol group, a dilute group, a block group, a brewing amine, an amine group, an aryl group, an aryl group, an amine group. Phthalate, thiol, cyano, ring, ester, sulphide, mercapto, halogen, fluorenyl, heteroaryl, heterocyclic, hydrogen, thiol, ketone and nitro. It is linked to another group via carbon, nitrogen, Rb, Rc*Ra. The guanamine may also be cyclic, for example Rb and Re, Ra&Rb or 1 and ! can be joined to form a 3 to 12 membered ring, such as a 3 to 10 membered ring or a 5 to 6 membered ring. The term "mercaptoamine" -C(0)NRbRc. The term "mercapto" as used herein refers to a group of the form _c(=nr)nrir", wherein R, R, and R" can each independently be selected from the group consisting of Group: alkyl, (d), block, decylamine, aryl, arylalkyl, aryl, cycloalkyl, decylalkyl, heteroaryl, heterocyclic, hydroxy, ketone and nitro. The term "amine" or "amine" as used herein refers to a group of the formula Ν^, -N(Rd)Re- or -ReN(Rd)Rr, wherein Rd, mj are independently selected a group consisting of: an alkoxy group, an alkyl group, a dilute group, a block group, a decylamine, an amine group, an aromatic & an arylalkyl group, a urethane, a cycloalkyl group, an ester, an ether, Mercapto, dentate, haloalkyl, heteroaryl, heterocyclic, hydrogen, hydroxy, hydrazine and nitro. The amine group can be bonded to the parent molecular group via nitrogen, HA Rf. The amine group can also be a ring Shape, for example, any two &, 匕 or heart can be joined at or from To form a 3 to 12-shell ring, such as morphine 134079.doc 200916458 or piperidinyl. The term amine also includes the corresponding fourth ammonium salt of any amine group, such as -[N(Rd)(Re) ( Rf)r. Exemplary amine groups include aminoalkyl groups, of which

Re或之至卜者為m特定實_中，胺基為^ 烷基胺基。 如本文中所使用之術語，，芳基”係指單_、雙_或其他多碳 環芳族環系統。芳基可視情況稠合至一或多個選自由芳 基、環⑥基及雜環基組成之群之環。纟發明《芳基可經選 自由以下基團組成之群之基團取代：烷氧基、烷基、烯 基、块基、醯胺、胺基、芳基、芳基貌基、胺基甲酸酿、 羧基、氰基、環烷基、酯、醚、甲醯基、齒素、鹵基烷 基、雜芳基、雜環基、經基、酮、硝基、硫基、續酿胺及 磺醯基。例示性芳基包括（但不限於）苯基、甲苯基、蒽 基、第基、茚基、钟奥基及萘基，以及苯稠合之碳環部 分’諸如5,6,7,8-四氫萘基。 如本文中所使用之術語，，芳基烷基”係指具有至少一個烷 基取代基之芳基，例如·芳基烧基_。例示性芳基烧基包括 (但不限於）具有單環芳族環系統之芳基烧基，其中該環包 含6個碳原子。舉例而言，”苯基燒基”包括苯基C4烧基、 苯甲基、1-苯基乙基、2_苯基乙基等。 如本文中所使用之術語"胺基甲酸酯”係指形式 -Rg0C(0)N(Rh)- . -Rg〇C(0)N(Rh)Ri-^.〇C(〇)NRhRi^^ 團其中Rg、Rh及心各自獨立地選自由以下基團組成之 群：烧氧基、芳基氧基、院基、稀基、炔基、酿胺、胺 基、方基、芳基燒基、胺基甲酸醋、缓基、氛基、環烷 134079.doc •18· 200916458 基、酯、醚、曱醯基、齒素、齒基烷基、雜芳基、雜環 基、經基、酮、硝基、硫基、㈣基、及伽胺。例示性 胺基曱酸醋包括（但不限於）（例如）芳基胺基甲酸醋或雜芳 基胺基甲酸自旨，其中Rg、RjRif之至少—者係獨立地選 自以下基團組成之群：芳基或雜芳基，諸如苯基及吼咬 基。 如本文中所使用之術語”M基”係指基團_c(〇)_。 如本文中所使用之術語”甲醯胺基"係指基團_ c(〇)nrr,， 其中R及R’可相同或不同。R&R，可選自由以下基團組成之 群：例如’烷基、芳基、芳基烷基、環烷基、甲醯基、鹵 基烷基、雜芳基及雜環基。 如本文中所使用之術語"羧基”係指基團_c〇〇H或其相應 鹽，例如-COONa等。 如本文中所使用之術語”氰基”係指基團_ c N。 如本文中所使用之術語”環烷氧基”係指與氧連接之環烷 基。 如本文中所使用之術語"環烷基”係指具有3_12、3_8、4_ 8或4-6個碳的本文中稱為（例如ycq環烷基"之來源於環烷 烴的一價飽和或不飽和環狀、雙環或橋接雙環烴基。例示 性％烷基包括（但不限於）環己烷、環己烯、環戊烷、環戊 烯、環丁烷及環丙烷。環烷基可經以下基團取代：烷氧 基、烷基、烯基、炔基、醯胺、胺基、芳基、芳基烷基、 胺基甲酸酯、羧基、氰基、環烷基、酯、醚、曱醯基、鹵 素、鹵基烧基、雜芳基、雜環基、經基、酮、硝基、硫 134079.doc 19 200916458 基、磺醯胺及磺醯基。環烷基可稠合至其他環烧基、芳式 或雜環基。 術語"醚"係指具有結構-RP-Rc之基團，其中心及^可 獨立地為烷基、芳基、環烷基、雜環基或醚。醚可與母體 分子基團經由ISRm連接。例示性醚包括（但不限於）烧氧 基烷基及烷氧基芳基。醚亦包括聚醚，例如其中^及^中 之一者或兩者為鱗。 如本文中所使用之術語”鹵基"或"鹵素"或"Hai"係指ρ、 Cl、Br 或 I。 如本文中所使用之術語"鹵基烷基"係指經一或多個齒素 原子取代之烷基。 如本文中所使用之術語"雜芳基，，係指含有一或多個雜原 子，例如1至4個雜原子（諸如氮、氧及硫）之單_、雙或其他 多環芳族環系統。雜芳基可經一或多個以下取代基取代： 包括烧氧基、烧基、稀基、快基、醯胺、胺基、芳基、芳 基烷基、胺基曱酸酯、羧基、氰基、環烷基、酯、醚、甲 醯基、函素、鹵基烷基、雜芳基、雜環基、羥基、酮、硝 基、硫基、磺醯胺及磺醯基。雜芳基亦可輞合至非芳族 ί哀。雜芳基之說明性實例包括（但不限於）吡啶基、噠嗪 基、嘴σ定基、吼唾基（pyrazyl)、三嗓基、„比略基、η比嗤基 (pyrazolyl)、味。坐基、（1，2 3 )-及（1，2,4)_ ***基、吡嗓 基、°比嗪基、嘧咬基、四嗤基、呋喃基、噻吩基、異噁唑 基、嗟°坐基、呋喃基、苯基、異噁唑基及噁唑基。例示性 雜芳基包括（但不限於）環包含2至5個碳原子及丨至3個雜原 134079.doc -20· 200916458 子之單環芳族環。 々本文中所使用之術語"雜環””雜環基”係指飽和 刀不飽牙$不飽和4· 12員含有至少—個獨立地選自由氮、 氧及硫組成之群之㈣子的I除㈣外規定，否則雜肩 子可經碳或氮鍵聯，指2•基團可視叫置換，且 環硫原子可視情驗氧化以形成亞伽基或俩基。雜環 可為芳族(雜芳基)或非芳族。雜環可經一或多個以下取代 基取代··包括貌氧基、烷基、稀基、炔基、醯胺、胺基、 芳基、芳基烷基、胺基子酸酯、羧基、氰基、環烷基、 醋、趟、甲醯基、豳素、南基炫基、雜芳基、雜環基、羥 基、羥基烷基、酮、硝基、硫基、磺醯胺及磺醯基。在某 些實施例中，雜環經甲基或羥基乙基取代。 雜環亦包括雙環、三環及四環基團，其中以上雜環中之 任一者稠合至一或兩個獨立地選自由芳基、環烷基及雜環 組成之群之環。例示性雜環包括吖啶基、苯并咪唑基、苯 并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、生物 素基、口辛喏啉基、二氫呋喃基、二氫吲哚基、二氫哌喃 基、一風β塞吩基、二°塞°坐基、°夫β南基、高派β定基、味唾Π定 基、咪唑啉基、咪唑基、吲哚基、異喹啉基、異噻唑咬 基、異噻唑基、異噁唑啶基、異噁唑基、嗎啉基、噁二唑 基、11惡°坐咬基、嗯峻基、派°桊基、派咬基、η辰喃基、β比嗤 σ定基、°比嗓基、吼嗤基、吼咕琳基、嚷嗓基、吼咬基、喷 咬基（pyrimidinyl)、嘴咬基（pyrimidyl)、π比σ各咬基、β比口各 咬-2 -酮基、吼略琳基、吼洛基、啥琳基、唾嗔琳基、四氫 134079.doc -21 · 200916458 咳喃基、四氫異㈣基、四氫㈣基、四氫㈣基、四嗤 基、=—嗤基、°塞㈣基、嗟唾基、嗔吩基、硫代嗎琳 基、奴代哌喃基及***基。在某些實施例中，雜環為芳 知在某些其他實施财，料經部》或完全飽和。在特 定實施例中，雜環為咪唑基。 如本文中所使用之術語，，雜s基烧氧基”係指與院氧基連 接之雜環基。 術語，，雜環基氧基烷基"係指與氧（_〇_)連接之雜環基’直 中該雜環基與烷基連接。 如本文中所使用之術語”羥基"係指基團_OH。 本文中所使用之術語"羥基烷基"係指與烷基連接之羥 基。 如本文中所使用之術語"味0坐基”得到技術公認且包括所 有異構形式之經取代或未經取代之味峻基。舉例而言術 浯”啼唑基”包括丨_咪唑基、2_咪唑基、3_咪唑基、4_咪唑 基及5·味嗤基，其每一者可經⑴個取代基取代。該等取 代基可包括函素（例如F)、羥基、烷基（例如甲基）、烷氧 基、烷氧基Μ基、亞確酿基、績酿基、氣基、環貌基 '芳 基或雜環。 如本文中所使用之術語"硝基"係指基團-Ν02。 如本文中所使用之術語”苯基"係指6員碳環芳族環。苯 基亦可祠合至環己院或環戊院環。苯基可經一或多個以下 =代基取代：⑥氧基1基、縣、炔基、㈣、胺基、 芳基、芳基烧基、胺基甲酸醋、缓基、氰基、環院基、 134079.doc -22- 200916458 酯、醚、甲醯基、函素、齒基烷基、雜芳基、雜環基、羥 基、酮、硝基、硫基、績醯胺及績醯基。 如本文所使用之術語”磺醯胺"係指具有結構 S(0)2-Rs-或-S(0)2-N(Rr)Rs之基團，其中RjRs可為（例如） 氫、烷基、芳基、環烷基及雜環基。例示性磺醯胺包括烷 基磺醯胺（例如，其中Rs為烷基）、芳基磺醯胺（例如，其中Re or the above is m-specific, the amine group is an alkylamino group. As used herein, the term "aryl" refers to a mono-, bis- or other polycarbocyclic aromatic ring system. The aryl group may optionally be fused to one or more selected from the group consisting of aryl, cyclo 6 and hetero a ring of a group consisting of a cyclic group. The invention "aryl" may be substituted with a group selected from the group consisting of alkoxy, alkyl, alkenyl, block, decyl, amine, aryl, Aryl base, aminocarboxylic acid, carboxyl, cyano, cycloalkyl, ester, ether, formamidine, dentate, haloalkyl, heteroaryl, heterocyclic, ketone, ketone, nitro , thiol, extender amine and sulfonyl. Exemplary aryl groups include, but are not limited to, phenyl, tolyl, fluorenyl, decyl, fluorenyl, quinolyl and naphthyl, and benzene fused carbon Ring moiety 'such as 5,6,7,8-tetrahydronaphthyl. As used herein, the term arylalkyl" refers to an aryl group having at least one alkyl substituent, for example, an arylalkyl group. _. Exemplary aryl alkyl groups include, but are not limited to, aryl alkyl groups having a single ring aromatic ring system wherein the ring contains 6 carbon atoms. For example, "phenylalkyl" includes phenyl C4 alkyl, benzyl, 1-phenylethyl, 2-phenylethyl and the like. The term "urethane" as used herein refers to the form -Rg0C(0)N(Rh)-. -Rg〇C(0)N(Rh)Ri-^.〇C(〇)NRhRi Wherein Rg, Rh and the heart are each independently selected from the group consisting of an alkoxy group, an aryloxy group, a decyl group, a dilute group, an alkynyl group, a stilbene amine, an amine group, a aryl group, an aryl group. Burning base, urethane acetal, buffer base, aryl group, naphthenic 134079.doc •18· 200916458 base, ester, ether, sulfhydryl, dentate, dentylalkyl, heteroaryl, heterocyclic, Bases, ketones, nitro groups, thio groups, (tetra) groups, and glycerides. Exemplary amino phthalic acid vinegars include, but are not limited to, for example, arylamino carboxylic acid vinegar or heteroaryl carboxylic acid carboxylic acid, wherein At least one of Rg, RjRif is independently selected from the group consisting of aryl or heteroaryl, such as phenyl and anthracenyl. The term "M-based" as used herein refers to a group _ c(〇)_. The term "mercaptoamine" as used herein refers to the group _c(〇)nrr, where R and R' may be the same or different. R&R, optionally selected from the group consisting of: 'alkyl, aryl, arylalkyl, cycloalkyl, indolyl, haloalkyl, heteroaryl and heterocyclic. The term "carboxy" as used herein refers to the group _c〇〇H or its corresponding salt, such as -COONa, etc. As used herein, the term "cyano" refers to the group _cN. The term "cycloalkoxy" as used herein, refers to a cycloalkyl group attached to an oxygen. The term "cycloalkyl" as used herein means having 3 to 12, 3 to 8, 4 to 8 or 4 to 6 carbons. A monovalent saturated or unsaturated cyclic, bicyclic or bridged bicyclic hydrocarbon group derived from a cycloalkane (for example, ycq cycloalkyl) is referred to herein. Exemplary % alkyl groups include, but are not limited to, cyclohexane, rings Hexene, cyclopentane, cyclopentene, cyclobutane and cyclopropane. The cycloalkyl group may be substituted by an alkoxy group, an alkyl group, an alkenyl group, an alkynyl group, a decylamine group, an amine group, an aryl group, Arylalkyl, urethane, carboxyl, cyano, cycloalkyl, ester, ether, decyl, halogen, haloalkyl, heteroaryl, heterocyclyl, ketone, ketone, nitro Sulfur 134079.doc 19 200916458, sulfonamide and sulfonyl. The cycloalkyl group can be fused to other cycloalkyl, aral or heterocyclic groups. The term "ether" A group having the structure -RP-Rc, the center of which may independently be an alkyl group, an aryl group, a cycloalkyl group, a heterocyclic group or an ether. The ether may be bonded to the parent molecular group via an ISRm. Exemplary ethers include But not limited to) alkoxyalkyl and alkoxyaryl. Ethers also include polyethers, such as one or both of them. The term "halo" or as used herein. "Halogen" or "Hai" means ρ, Cl, Br or I. The term "haloalkyl" as used herein refers to an alkyl group substituted with one or more dentate atoms. The term "heteroaryl" as used herein, refers to a mono-, di- or other polycyclic aromatic group containing one or more heteroatoms, for example 1 to 4 heteroatoms such as nitrogen, oxygen and sulfur. Ring system. Heteroaryl groups may be substituted by one or more of the following substituents: including alkoxy, alkyl, dilute, fast radical, decylamine, amine, aryl, arylalkyl, amino phthalate ,carboxy, cyano, cycloalkyl, ester, ether, formamidine, hydroxyl, haloalkyl, heteroaryl, heterocyclyl, hydroxy, ketone, nitro, thio, sulfonate Amines and sulfonyl groups. Heteroaryl groups can also be conjugated to non-aromatic groups. Illustrative examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, sigma, pyrazyl , triterpene, „bilobyl, ηpyrazolyl, taste. sitin, (1,2 3 )- and (1,2,4)_triazolyl, pyridyl, pyridazine Base, pyrimidine, tetradecyl, furyl, thienyl, isoxazolyl, oxime, furyl, phenyl, isoxazolyl and oxazolyl. Exemplary heteroaryls include (but not It is limited to a single-ring aromatic ring containing 2 to 5 carbon atoms and 丨 to 3 heterogenes 134079.doc -20·200916458. The term "heterocyclic" "heterocyclyl" as used herein refers to a saturated knife that is not saturated with a non-saturated 4.12 member containing at least one (four) member independently selected from the group consisting of nitrogen, oxygen, and sulfur. I, except for (4), otherwise the hetero-shoulders may be bonded via carbon or nitrogen, meaning that the 2• group can be called a substitution, and the ring sulfur atom can be oxidized to form a sub-gal group or two groups. Family (heteroaryl) or non-aromatic. Heterocycles may be substituted by one or more of the following substituents: including morphoxy, alkyl, dilute, alkynyl, decylamine, amine, aryl, aryl Alkyl, amino acid ester, carboxyl, cyano, cycloalkyl, vinegar, hydrazine, methylidene, halogen, sulfhydryl, heteroaryl, heterocyclic, hydroxy, hydroxyalkyl, ketone, nitrate a thiol group, a sulfonamide, and a sulfonyl group. In certain embodiments, the heterocyclic ring is substituted with a methyl group or a hydroxyethyl group. The heterocyclic ring also includes a bicyclic, tricyclic, and tetracyclic group, wherein the above heterocyclic ring Either fused to one or two rings independently selected from the group consisting of aryl, cycloalkyl and heterocycle. Exemplary heterocycles include acridinyl, benzimidazolyl, benzene And furyl, benzothiazolyl, benzothienyl, benzoxazolyl, biotinyl, octyl porphyrin, dihydrofuranyl, indanyl, dihydropyranyl, one wind β Steenyl, s-sodium, sylvestre, sulphate, sulphate, sulphate, imidazolyl, imidazolyl, sulfhydryl, isoquinolyl, isothiazole, isothiazole Base, isoxazolidinyl, isoxazolyl, morpholinyl, oxadiazolyl, 11 oxa stagnation, 峻 基 、, 派 桊 、, 派 基, 辰 喃 、, 嗤 嗤σ定基,° 嗓 嗓, 吼嗤, 吼咕 基, 嚷嗓, 吼 base, pyrimidinyl, pyrimidyl, π ratio σ each bite, β ratio Bite-2 -keto, valeryl, fluorenyl, sulfonyl, sulphonyl, tetrahydro 134079.doc -21 · 200916458 coughyl, tetrahydroiso(tetra)yl, tetrahydro(tetra)yl, tetra Hydrogen (tetra), tetradecyl, = fluorenyl, thiopyranyl, decyl, decyl, thiomorphinyl, natepipenyl and triazolyl. In certain embodiments, The ring is known to be in some other implementations, the Ministry of Economic Affairs or Fully saturated. In a specific embodiment, the heterocycle is imidazolyl. As used herein, the term ,, heteroaryl group burn s group "means a group connected with the hospital heterocyclyl group. The term "heterocyclyloxyalkyl" refers to a heterocyclyl group attached to an oxygen (_〇-) which is bonded to an alkyl group. The term "hydroxy" as used herein refers to the group _OH. The term "hydroxyalkyl" as used herein refers to a hydroxy group attached to an alkyl group. The term "flavor as used herein The 0-based group is technically recognized and includes all substituted or unsubstituted taste groups in isomeric forms. For example, 浯"carbazolyl" includes hydrazine-imidazolyl, 2-imidazolyl, 3-imidazolyl, 4-imidazolyl, and 5-terridyl, each of which may be substituted with (1) substituent. The substituents may include a hydroxyl group (e.g., F), a hydroxyl group, an alkyl group (e.g., a methyl group), an alkoxy group, an alkoxy fluorenyl group, an anthracene group, a mercapto group, a gas group, and a ring group. Base or heterocycle. The term "nitro" as used herein refers to the group -Ν02. The term "phenyl" as used herein refers to a 6-membered carbocyclic aromatic ring. The phenyl group may also be attached to a cyclohexyl or cyclopentane ring. The phenyl group may be substituted by one or more of the following = Substituted: 6 oxy 1 yl, county, alkynyl, (tetra), amine, aryl, arylalkyl, amino carboxylic acid vinegar, buffer, cyano, ring-based, 134079.doc -22- 200916458 ester, Ether, methionyl, cyclin, dentylalkyl, heteroaryl, heterocyclyl, hydroxy, ketone, nitro, thio, decylamine and fluorenyl. The term "sulfonamide" as used herein. " refers to a group having the structure S(0)2-Rs- or -S(0)2-N(Rr)Rs, wherein RjRs can be, for example, hydrogen, alkyl, aryl, cycloalkyl, and Heterocyclic group. Exemplary sulfonamides include alkylsulfonamides (e.g., wherein Rs is an alkyl group), arylsulfonamides (e.g., wherein

Rs為芳基）、環烷基磺醯胺（例如，其中心為環烷基）及雜環 基磺醯胺（例如，其中Rs為雜環基）等。Rs is an aryl group, a cycloalkyl sulfonamide (for example, a cycloalkyl group in the center thereof), and a heterocyclic sulfonamide (for example, wherein Rs is a heterocyclic group) and the like.

如本文中所使用之術語”磺醯基，，係指具有結構RuS〇2•之 基團’其中Ru可為烷基、芳基、環烷基及雜環基，例如烷 基續酿基。如本文中所使用之術語％㈣醯基"係指與= 醯基連接之烷基。 S 如本文中所使用之術語”硫基”係指具有結構RzS-之基 團，其中Rz可為院氧基、院基、稀基、快基、酿胺、胺 基、芳基、芳基烷基、胺基甲酸酯、羧基、環烷基、酯、 醚、甲醯基、函基院基、雜芳基、雜環基及綱。如本文中 所使用之術語1基硫基”係指與硫料連接^基。例干 性硫基包括"硫代基"，如本文中所使用其係指-SH基團Γ 如本文中所使用之術語"鑿薤 醫樂學上可接受之載劑"係指盥 所投與之樂物相容之任何及所有溶劑、分散介質、塗層、 等渗及吸收延遲劑及其_你札 , 類㈣°此項技術中所熟知該等介 貝及樂劑用於醫藥學活性物質之用途。組合物亦可含有提 供補充、其他或增強治療功能之其他活性化合物。 如本文中所使用之術語”醫藥組合物”係指包含盘—或多 134079.doc •23· 200916458 種醫藥學上可接受之載劑一起調配之至少_ 示之化合物的組合物。 中所揭 如本文中所使用之術語，，醫藥學上可接受之 在於本發明之組合物中 现係私可存 ^ ^ 中所用之化合物中的酸性或鹼性Λϋ 之孤本發明之組合物中所包括之性質為驗性之化1物 能夠與各種無機及有機酸形成多種鹽。可用於製㈣ 上可接受之該等驗性化合物之酸加成鹽之酸為彼等形二 毒性酸加成鹽之酸，亦即含有藥理學上可接受之= 鹽，包括(但不限於)頻果酸鹽、乙二酸鹽、氣化物、淳化 物、埃化物、硝酸鹽、硫酸鹽、硫酸氫鹽、鱗酸鹽、酸式 填酸鹽、異柊驗酸鹽、乙酸鹽、乳酸鹽、水揚酸鹽、檸檬 酸鹽、酒石酸鹽1酸鹽、丹寧酸鹽、泛酸鹽、酒石酸氣 鹽、抗壞血酸鹽、琥㈣鹽、順丁烯二酸鹽、龍膽酸鹽、 反丁稀二酸鹽、葡糖酸鹽、葡糖碳酸鹽（gl職議ate)、酶 酸鹽、甲酸鹽、苯甲酸鹽、麩胺酸鹽、甲石黃酸酿、乙續酸 鹽、苯績酸鹽1甲苯續酸鹽及雙料酸鹽（亦即m 曱基-雙_(2_經基-3_萘甲酸鹽））。除上述酸之外，本發明之 組合物中所包括之包括胺基部分之化合物可與各種胺基酸 形成醫藥學上可接受之鹽。本發明之組合物中所包括之性 質為酸性之化合物能夠與各種藥理學上可接受之陽離子形 成鹼式鹽。该等鹽之實例包括鹼金屬或鹼土金屬鹽且尤其 包括約、鎮、鈉、經、辞、钟及鐵鹽。 術語"個體"意欲包括生物體，例如原核生物及真核生 物，其能夠患增殖病症，例如癌症，且該等增殖病症僅或 134079.doc -24· 200916458 部分由Hedgehog路徑介導。個體之實例包括哺乳動物，例 如人類、犬、牛、馬、豬、綿羊、山羊、貓、小鼠、兔、 大鼠及轉殖基因非人類動物。在某些實施例中，個體為人 類，例如患有癌症、具有患癌症之危險或潛在地能夠患癌 症之人類。在某些實施例中，個體具有具有pTCH功能喪 失表型、SMO功能獲得表型或Hedgeh〇g功能獲得表型。 本揭示案之化合物可含有一或多個對掌性中心（例如其 中一些可明確地如此藉由包括鍵取向/標示來表示）及/或雙 鍵，且因此以立體異構物形式存在，諸如幾何異構物 '對 映異構物或非對映異構物。當用於本文中時，術語"立體 異構物，，包含所有幾何異構物、對映異構物或非對映異構 物。視立體生成碳原子周圍之取代基構型而定，該等化人 物可由符號T或T表示。本發明包涵該等化合物之㈣ 立體異構物及其混合物。立體異構物包括對 :映異構物：對映異構物或非對映異構物之混合物可在： 法中表π為⑴"，但熟習此項技術者將認 可無疑地表示對掌性中心。 早、，、口構 本發明之化合物的個別立體異構 體生成中心夕食仕m d另个對稱或立 生成中。之市售原料合成製備， 物繼而進行—护1 泉侑外肩奴混合 熟習此項技術者所熟知之拆分方法… 拆分方法藉由以下t i Υ- 云該等 棺田以下方法例不：⑴將對 對掌性助劑連拯，盆丄 ，、稱物之混合物與 藉由再結晶或層析分雜 物之混合物，及白4刀離所付非對映異構 ,助劑釋放光學純產物，(2)使用m 拆分劑形成鹽或（3)直接 （）使用先活性 子掌彳層析管柱上分離光學對映 134079.doc -25- 200916458 混合物。立體異構混合物亦可藉由熟知方法拆分 為其，，且伤立體異構物，該等熟知方法 ^ ^ ^ ^ U 4 - 堵如對掌性相氣相層 二對掌性㈣效液相層析法、將化合物結晶為對掌性 可由iL轳+ 、，，°日日。立體異構物亦 =體異構純中間物、試劑及催化劑藉由不對稱合成方 本發明之化合物巾亦可存在幾何異構物 自碳-碳雙鍵周圍之取代基排列或碳環周圍之取代= ^各種幾何異構物及其混合物。碳.碳雙鍵周圍之 旱使用。除非另外規定，否則，描述雙鍵之 與"Ζ”異構物。 再匕成t 或者，碳-碳雙鍵周圍之取代基可稱為”順"或”反”， 順”表示在雙鍵同一側之取代基， 八 且夂表不在雙鍵對側 之取代基。取代碳環周圍取代基之排列表示為言或"反"。 術語”順”表示環平面同一側之取代&，且術語"反"表亍環 平面對側之取代基。取代基位於環平面同一側與對側之化 合物之混合物表示為"順/反"。 本發明之化合物可以溶劑化以及非溶劑化形式（諸如水 合形式）存在。在-實施例中，化合物為非晶型。在一實 施例中，化合物為多晶型。在另一實施例中，化 體形式。 1 ·本發明之化合物 本文中揭示式I化合物 134079.doc -26 - 200916458The term "sulfonyl," as used herein, refers to a group having the structure RuS 2 ' wherein Ru can be an alkyl group, an aryl group, a cycloalkyl group, and a heterocyclic group, such as a alkyl aryl group. The term %(tetra)indolyl, as used herein, refers to an alkyl group attached to a thiol group. S. The term "thio" as used herein refers to a radical having the structure RzS-, wherein Rz can be Oxyl, hospital, dilute, fast-radical, amine, amine, aryl, arylalkyl, urethane, carboxyl, cycloalkyl, ester, ether, formazan, functional base The term "heteroaryl", "heteroaryl" and "heteroaryl" as used herein refers to a thiol group. A dry thio group includes "thio group", as used herein, refers to a -SH group, as used herein, as the term "healing medically acceptable carrier" Any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents which are compatible with the pleasures to which they are administered and their _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ For the use of pharmaceutically active substances. The compositions may also contain other active compounds which provide supplementation, other or enhanced therapeutic functions. The term "pharmaceutical composition" as used herein refers to a composition comprising at least one of the compounds shown in the tray-or multi-134079.doc • 23·200916458 pharmaceutically acceptable carriers. The term as used herein, pharmaceutically acceptable in the composition of the invention is in the composition of the invention of the acidic or basic oxime in the compound used in the privately available compound. Included in the nature of the assay is the ability to form a variety of salts with various inorganic and organic acids. The acid which can be used in the preparation of the acid addition salt of the above-mentioned acceptable test compound is an acid of the same toxic acid addition salt, that is, it contains a pharmacologically acceptable salt, including but not limited to Frectoate, oxalate, sulphate, sulphate, sulphate, nitrate, sulphate, hydrogen sulphate, sulphate, acid sulphate, isophthalic acid salt, acetate, lactic acid Salt, salicylate, citrate, tartrate 1, acid salt, tannin, pantothenate, tartaric acid salt, ascorbate, amber salt, maleate, gentisate, anti Butarate, gluconate, glucose carbonate (gl), acid salt, formate, benzoate, glutamate, formazonic acid, ethyl acetate Benzene acid salt 1 toluene acid salt and double acid salt (that is, m decyl-bis-(2_carbyl-3_naphthoate)). In addition to the above acids, the compound including the amine moiety included in the composition of the present invention can form a pharmaceutically acceptable salt with various amino acids. The compound which is acidic in the composition of the present invention is capable of forming a basic salt with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and include, in particular, about, town, sodium, meridian, rhodium, bell and iron salts. The term "individual" is intended to include organisms such as prokaryotes and eukaryotic organisms that are capable of developing proliferative disorders, such as cancer, and that are only mediated by the Hedgehog pathway in part or by the 134079.doc-24. Examples of individuals include mammals such as humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic non-human animals. In certain embodiments, the individual is a human, such as a human having cancer, having a risk of developing cancer, or potentially being able to develop cancer. In certain embodiments, the individual has a pTCH functional loss phenotype, an SMO functional acquired phenotype, or a Hedgeh〇g functionalized phenotype. The compounds of the present disclosure may contain one or more pairs of palmar centers (eg, some of which may be explicitly represented by inclusion of a key orientation/indicator) and/or double bonds, and thus exist in stereoisomeric forms, such as Geometric isomers 'enantiomers or diastereomers. As used herein, the term "stereoisomer", encompasses all geometric isomers, enantiomers or diastereomers. Depending on the configuration of the substituent around the sterically generated carbon atom, the equivalent human can be represented by the symbol T or T. The present invention encompasses (iv) stereoisomers of such compounds and mixtures thereof. Stereoisomers include p-anomers: enantiomers or mixtures of diastereomers may be found in the formula: π is (1)", but those skilled in the art will recognize the palm of their hand Sex center. Early,, and Oral Structures The individual stereoisomers of the compounds of the present invention are formed in another symmetry or formation. The commercially available raw materials are synthesized and prepared, and the materials are then carried out. - 1 侑 侑 侑 侑 奴 混合 混合 混合 混合 混合 混合 混合 混合 混合 混合 混合 ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... ... (1) A mixture of a mixture of a palmitic auxiliary, a pot, a pot, and a mixture, and a mixture of recrystallized or chromatographic impurities, and a diastereomer of the white Pure product, (2) using m resolving agent to form a salt or (3) direct () using an active proton sluridine column to separate the optically complexed 134079.doc -25- 200916458 mixture. Stereoisomeric mixtures can also be resolved by well-known methods, and the stereoisomers are damaged, and the well-known methods ^ ^ ^ ^ U 4 - block such as the palm phase phase gas phase two pairs of palm (four) effect liquid Phase chromatography, crystallization of the compound to the palm of the hand can be iL 轳 +,,, ° day. Stereoisomers also = isomerically pure intermediates, reagents and catalysts. By asymmetric synthesis, the compound towels of the present invention may also have geometric isomers arranged from substituents around the carbon-carbon double bond or around the carbon ring. Substitution = ^ various geometric isomers and mixtures thereof. Carbon. Carbon use around the double bond. Unless otherwise specified, the double bond is described with the "Ζ" isomer. Further, t or the substituent around the carbon-carbon double bond may be referred to as "shun" or "reverse", and Substituents on the same side of the double bond, and the substituents are not on the opposite side of the double bond. The arrangement of the substituents around the substituted carbocyclic ring is expressed as or "anti". The term "shun" means the substitution on the same side of the ring plane. &, and the term "anti" refers to the substituent on the opposite side of the plane of the ring. The mixture of the substituents on the same side of the ring plane and the compound on the opposite side is expressed as "cis/trans". The compound of the present invention can be a solvent And non-solvated forms such as hydrated forms are present. In the examples, the compound is amorphous. In one embodiment, the compound is polymorphic. In another embodiment, the form of the compound. Compounds of the Invention Disclosed herein are compounds of formula I 134079.doc -26 - 200916458

其中 h及I各獨立地選自由以下基團組成之群：氫、 C 1 -6院基及鹵素； 心選自由以下基團組成之群：cl-6烧基、函基C1•及基 及鹵素； 各貿獨立地選自由以下基團組成之群：CR5、NR5、n、 0及S，其中Rs選自由以下基團組成之群：氫、Cw烷氧基 (例如-OCH3)、Cl·6烷氧基Cl.6烷基、Ci.6烷氧基羰基、 烷基（例如-CH3)、曱胨基、醯胺基、胺基（例如胺基Gy烷 基）、Cw烷基羰基、芳基、羧醯胺基、Cs·8環烷基、氰 基、鹵基Cw烷基、鹵素、雜環基、雜環基6烷基、羥 基、羥基Cw烷基、硝基、硫化物、亞磺醯基、磺醯胺基 及磺醢基，或 2個相鄰W原子可連同其Rs取代基一起形成稠合第二 裱，其中第二環視需要經一或多個Rs取代基取代且係選自 由以下環組成之群··芳基、CM環烷基、5或6員雜芳基， 及5或6員雜環基； 至少一個W為N ; 134079.doc 27· 200916458 q為〇或〗，其尹 若q為0且2個相鄰W原子連同其&取代基—起形成稠合 第二環，則相鄰W原子之一為N且第二環為6員雜環基，且 A選自由以下基團組成之群：Cr6、NR6、N、〇及s ,· _ R0選自由以下基團組成之群··氫、烷氧基、〔μ烷 氧基C,·6烷基、C|·6烷氧基羰基、Ci ό烷基、Cw烷基（例如 CH3)甲脒基、醯胺基、胺基（例如胺基cN6烷基）、q 6 烷基羰基、芳基、羧醯胺基、c3 8環烷基、氰基、-基C" 烷基（例如三氟甲基）、鹵素（例如C1)、雜環基、雜環基Cu 烷基雜丨衣基C丨_6烷氧基（例如2-吡啶基甲氧基）、羥基、羥 基C!—烷基、硝基、亞磺醯基、硫化物、磺醯胺基及磺醯 基，或 2個相鄰A原子可連同其&取代基一起形成稠合第二環， 其中第一 ί衣為5或6員雜環基，例如形成稠合2,3_二氫_丨，4_ 苯并二氧雜環己烯； 至）一個Α選自由以下基團組成之群：Nr6、Ν、〇及s ; p為0或1，其中 若P為0且R]、R2及R4各為甲基，則A不為s ; 其中式I化合物不為Wherein h and I are each independently selected from the group consisting of hydrogen, C 1 -6, and halogen; the core is selected from the group consisting of cl-6 alkyl, functional C1• and Halogen; each trade is independently selected from the group consisting of CR5, NR5, n, 0 and S, wherein Rs is selected from the group consisting of hydrogen, Cw alkoxy (eg -OCH3), Cl· 6 alkoxy Cl. 6 alkyl, Ci. 6 alkoxycarbonyl, alkyl (eg -CH3), fluorenyl, decylamino, amine (eg amino Gy alkyl), Cw alkylcarbonyl, Aryl, carboxylamido, Cs.8 cycloalkyl, cyano, halo Cw alkyl, halogen, heterocyclyl, heterocyclyl 6 alkyl, hydroxy, hydroxy Cw alkyl, nitro, sulfide, A sulfinyl group, a sulfonylamino group, and a sulfonyl group, or two adjacent W atoms, together with its Rs substituent, form a fused second oxime, wherein the second ring is optionally substituted with one or more Rs substituents and Is selected from the group consisting of the following rings: aryl, CM cycloalkyl, 5 or 6 membered heteroaryl, and 5 or 6 membered heterocyclic; at least one W is N; 134079.doc 27· 200916458 q is 〇 Or 〗, its Yin Ruo q is 0 and 2 An adjacent W atom together with its & substituent forms a fused second ring, wherein one of the adjacent W atoms is N and the second ring is a 6 membered heterocyclic group, and A is selected from the group consisting of: Cr6, NR6, N, 〇 and s , · _ R0 is selected from the group consisting of hydrogen, alkoxy, [μ alkoxy C, · 6 alkyl, C | 6 alkoxycarbonyl, Ci decyl, Cw alkyl (eg CH3)carboxamidine, decylamino, amine (eg amine cN6 alkyl), q 6 alkylcarbonyl, aryl, carboxamide, c3 8 cycloalkyl , cyano, -yl C" alkyl (e.g., trifluoromethyl), halogen (e.g., C1), heterocyclyl, heterocyclyl Cu alkyl fluorenyl C丨_6 alkoxy (e.g., 2-pyridine) Methoxy), hydroxy, hydroxy C!-alkyl, nitro, sulfinyl, sulfide, sulfonylamino and sulfonyl, or two adjacent A atoms together with their & substituent Forming a fused second ring, wherein the first oxime is a 5- or 6-membered heterocyclic group, for example, forming a fused 2,3-dihydro-indole, 4-benzodioxine; a group consisting of: Nr6, Ν, 〇, and s; p is 0 or 1, where P is 0 and R], R2 and R4 are each a methyl group, then A is not s; wherein the compound of formula I is not

134079.doc -28- 200916458134079.doc -28- 200916458

其中L選自由NH及CH組成之 群’且若L為NH ’則Μ為CH2，且若L為CH，則Μ為CH ; 及其醫藥學上可接受之鹽。在某些實施例中，若q為〇且 由W原子構成之環為2-咪唑基，則R5不為未經取代苯基 環。在某些實施例中，5個A基團之一為N。在某些實施例 中，I為H、在某些實施例中，2個相鄰冒原 子不連同其Rs取代基一起形成稠合第二環。在特定實施例 中，若q為0，貝,丨4個W原子不為N。在另一特定實施例中， 由W原子構成之環為„米唾。在另一特定實施例中，由八原 子構成之環為3 -吡啶基。 本發明之另一實施例提供式π化合物：Wherein L is selected from the group consisting of NH and CH', and if L is NH', then Μ is CH2, and if L is CH, Μ is CH; and a pharmaceutically acceptable salt thereof. In certain embodiments, if q is oxime and the ring composed of W atoms is 2-imidazolyl, then R5 is not an unsubstituted phenyl ring. In certain embodiments, one of the five A groups is N. In certain embodiments, I is H. In certain embodiments, two adjacent moths do not together with their Rs substituent form a fused second ring. In a particular embodiment, if q is 0, B, 丨 4 W atoms are not N. In another particular embodiment, the ring composed of W atoms is s. In another particular embodiment, the ring composed of eight atoms is a 3-pyridyl group. Another embodiment of the present invention provides a compound of formula π :

〇 II 其中， :鹵素及Cw烷基； Α選自由Ν及CR10組成之群； X選自由以下基團組成之群： 134079.doc -29· 200916458 Y選自由以下基團組成之群：NRs、〇及s，例如，NR5 及S ; 各Rs獨立地選自由以下基團組成之群：氫、烷基（例 如甲基）及羥基Cw烷基（例如羥甲基），例如氫及烷 基； I選自由以下基團組成之群··氫、齒素、氣基4•次 基:C,-6鹵録、胺基（例如Ci 6烧基胺基）、。院氧基、 芳氧基、經基、續醯基、續醯胺及雜環基，其中^可視需 要經一或多個R ] i取代； 心…丨。各獨立地選自由以下基團組成之群：氫、 c】-6院基（例如-ch3)、鹵素（例如cut F)、Ci 6院氧基（例如 -〇ch3)、胺基、經基、_貌基、氰基、續醯基及續酿胺； R"可選自由以下基團組成之群：齒素、經基、胺基、〇II wherein: halogen and Cw alkyl; oxime selected from the group consisting of ruthenium and CR10; X is selected from the group consisting of: 134079.doc -29· 200916458 Y is selected from the group consisting of: NRs, And s, for example, NR5 and S; each Rs is independently selected from the group consisting of hydrogen, alkyl (such as methyl) and hydroxy Cw alkyl (such as hydroxymethyl), such as hydrogen and alkyl; I is selected from the group consisting of hydrogen, dentate, and gas groups. 4: Subunit: C, -6 halo, amine (for example, Ci 6 alkylamino). Oxyl, aryloxy, thiol, decyl, decylamine and heterocyclic, wherein ^ may be substituted by one or more R] i; Each is independently selected from the group consisting of hydrogen, c]-6-yard (eg, -ch3), halogen (eg, cut F), Ci 6-oxime (eg, -〇ch3), amine, thiol , _ morphine, cyano, ruthenium and extender amine; R " optional group of the following groups: dentate, meridine, amine,

Cw院基、Cl·6院氧基、芳基及雜環基，其中可視需 經一或多個R12取代；且 R,2可選自由以下基團組成之群：胺基、氰基、經基、 C〗-6烷基、環烷基及芳基， 或其醫藥學上可接受之鹽。在竿 、 牡呆些實施例中，R7選自由 以下土團組成之群：2_吡啶基甲氧基、0·甲 甲氧基、π氰基苯基）甲氧基、[(2S)小二…底咬基） _ 一 J T基吡咯啶-2-其1 甲氧基、[(2RH-f基料❹基氧基、2 土 乙氧基+塞吩基、3_二乙基胺基丙氧 二甲二 基乙基）㈣小基、4令經基 （-一^基胺 Λ田a、β丸 土 ^取奈-1·基、4-(2-吡啶 基甲基）终^基、4_(環丙基甲基㈣Ml基、^ 134079.doc •30· 200916458 基、氟基、氫、異丁氧基、嗎啉基、苯氧基、三氟甲基、 4-甲基哌嗪-1-基、[2_(二甲基胺基）乙基]甲基胺基、（2_嗎 啉-4-基乙基）胺基、2-羥基乙基胺基、哌嗪_丨基、2_(二甲 基胺基）乙基胺基、[(2S)-1-乙基吼咯啶_2_基]甲基胺基， (1_甲基吡咯啶_3_基）甲氧基、甲基哌啶_2•基）曱氧基、 2-嗎啉基-4-基乙氧基、2_D比咯啶基乙氧基、（1_甲基哌 咬-3-基）甲氧基、⑽小甲基„底咬_2_基]甲氧基、（2^· 曱基哌啶基]曱氧基、（3S)-1-曱基哌啶_3·基]甲氧基、 (叫1_甲基哌啶_3-基]甲氧基、甲基及其任何組合。舉例 而言，在特定實施例中，&選自由以下基團組成之群：（1_ 甲基-4·哌啶基）甲氧基、[(2^甲基吡咯啶_2_基]甲氧 基、三氟甲基、⑴曱基旅咬_2_基）曱氧基、〇_甲基派咬_ 3_基)甲氧基、甲基及其任何組合。 在弋I之特疋實施例中，化合物具有式：Cw, K.6, ethoxy, aryl and heterocyclic, wherein one or more R12 may be substituted; and R, 2 may be selected from the group consisting of: an amine group, a cyano group, a A C,-6 alkyl, cycloalkyl or aryl group, or a pharmaceutically acceptable salt thereof. In some examples of hydrazine and glutinous, R7 is selected from the group consisting of: 2-pyridylmethoxy, 0.methyloxy, π-cyanophenyl)methoxy, [(2S) small ... 底 底 底 _ 一 一 一 J 一 一 一 一 一 一 一 一 一 一 一 J J 一 J J J J 其 其 J 其 其 其 其 其 其 其 其 其 其 其 其 其 其 其 其 其 其 J 其Propyl dimethyldiethyl) (4) small group, 4 ruthenyl group (--l-amine amine Λ田 a, β 丸土 ^奈-1·yl, 4-(2-pyridylmethyl) terminal ^ Base, 4_(cyclopropylmethyl(tetra)yl), 134079.doc •30·200916458, fluoro, hydrogen, isobutoxy, morpholinyl, phenoxy, trifluoromethyl, 4-methylper Pyrazin-1-yl, [2-(dimethylamino)ethyl]methylamino, (2-morpholin-4-ylethyl)amine, 2-hydroxyethylamino, piperazine_丨, 2_(dimethylamino)ethylamino, [(2S)-1-ethyl-pyridin-2-yl]methylamino, (1-methylpyrrolidine-3-yl) Oxyl, methyl piperidine 2 yl) decyloxy, 2-morpholinyl-4-ylethoxy, 2_D-pyridyl ethoxy, (1-methylpiperidin-3-yl) Methoxy, (10) small methyl „ bottom bite 2 — yl] methoxy, (2^ Mercaptopiperidinyl]nonyloxy, (3S)-1-indolylpiperidine-3-yl]methoxy, (1-methylpiperidin-3-yl)methoxy, methyl and Any combination. For example, in a particular embodiment, & is selected from the group consisting of: (1_methyl-4·piperidinyl)methoxy, [(2^methylpyrrolidine_2_) A methoxy group, a trifluoromethyl group, a (1) fluorenyl group, a methoxy group, a methoxy group, a methyl group, and any combination thereof. In a particular embodiment, the compound has the formula:

在另f施例中，本發明提供式III化合物In another embodiment, the invention provides a compound of formula III

134079.doc -31 - 200916458 其中 η為0、1、2或3(例如，η為2或3); Ζ為直接鍵、NRa、S及〇，其中心選自由以下基團組成 之群：H、烷基及環烷基。 R3選自由以下基團組成之群：氫、_素及烧基；134079.doc -31 - 200916458 wherein η is 0, 1, 2 or 3 (for example, η is 2 or 3); Ζ is a direct bond, NRa, S and 〇, the center of which is selected from the group consisting of: H , alkyl and cycloalkyl. R3 is selected from the group consisting of hydrogen, _ and calcination;

各Rm選自由以下基團組成之群：氫、鹵素、羥基、硫 化物、叛醯胺、Cl-6院基幾基、胺基、貌基、院氧基、^ 氧基羰基、亞磺醯基、磺醯基、氰基、環烷基、芳基或^ 環基，其中各R丨4視需要經以下基團取代：c] 6烷基羰基、 羥基、羥基Cw烷基（例如羥曱基）、齒素、胺基、硝基、 烷基（例如曱基）、磺醯基、氰基、烷氧基或雜環基， 以便當Rm所連接之咪唑基環為2_w米唑基時，Rm不為未經 取代苯基； R"選自由以下基團組成之群：_(CH)〇-5_雜環（例如 •(CH)〇.2-雜環）、_(CH)〇.5-NRbRb(例如 2_NRbRb)、 -(ch)0.5·經基（例如 _(ch)().2-經基）、_(CHV5_Ci 6烷氧基（例 如-(CHh—z-C!·6烷氧基）、芳基及雜環基（例如哌嗪），其中 R】5視需要經R〗6取代，且各Rb選自由以下基團組成之群： Η、烷基及環烷基；且Each Rm is selected from the group consisting of hydrogen, halogen, hydroxy, sulfide, smectin, Cl-6, amide, amine, methoxy, oxycarbonyl, sulfin a sulfonyl group, a cyano group, a cycloalkyl group, an aryl group or a cyclyl group, wherein each R 丨 4 is optionally substituted with a group: c] 6 alkylcarbonyl, hydroxy, hydroxy Cw alkyl (eg oxindole) a dentate, an amine group, a nitro group, an alkyl group (for example, a fluorenyl group), a sulfonyl group, a cyano group, an alkoxy group or a heterocyclic group, such that when the imidazolyl ring to which Rm is attached is a 2-w-mazozolyl group Rm is not an unsubstituted phenyl group; R" is selected from the group consisting of _(CH)〇-5_heterocyclic ring (e.g., (CH)〇.2-heterocyclic ring), _(CH)〇 .5-NRbRb (eg 2_NRbRb), -(ch)0.5. thiol (eg _(ch)().2-trans), _(CHV5_Ci 6 alkoxy (eg -(CHh-zC!·6) Oxy), aryl and heterocyclic (eg piperazine), wherein R] 5 is optionally substituted by R 6 and each R b is selected from the group consisting of hydrazine, alkyl and cycloalkyl;

Rw選自由以下基團組成之群：鹵基、烷基、烷氧基、 烧基硫基’其tR!6視需要經芳基或雜芳基取代， 或其醫藥學上可接受之鹽。在某些實施例中，尺14為H、 羥基C!-6烷基（例如羥基曱基）或Ci6烷基（例如甲基）。 本發明之化合物及組合物亦適用於製造用於抑制需要其 134079.doc •32· 200916458 之個體中之Hedge—路徑㈣劑。—實施例提供所揭示化 合物及組合物在製造用於在需要其之個體中減少細胞分 化、增殖及/或影響基質微環境調節之藥劑中的用途。另 -實施例提供所揭示化合物及組合物在製造用於在需要其 之個體中’α療單獨或部分藉由Hedgeh〇g路徑抑制介導之疾 病或醫學病狀的藥劑中之用途。 A.本發明之其他化合物 本文揭示式IV化合物Rw is selected from the group consisting of halo, alkyl, alkoxy, alkylthio wherein 'tR! 6 is optionally substituted with an aryl or heteroaryl group, or a pharmaceutically acceptable salt thereof. In certain embodiments, the ruler 14 is H, hydroxy C!-6 alkyl (eg, hydroxyindenyl) or Ci6 alkyl (eg, methyl). The compounds and compositions of the present invention are also suitable for use in the manufacture of Hedge-path (IV) agents for use in individuals requiring their 134079.doc • 32· 200916458. - The examples provide for the use of the disclosed compounds and compositions in the manufacture of a medicament for reducing cell differentiation, proliferation and/or affecting the regulation of the matrix microenvironment in an individual in need thereof. Further - the examples provide the use of the disclosed compounds and compositions in the manufacture of a medicament for the treatment of a disease or medical condition mediated by Hedgeh〇g pathway inhibition alone or in part in an individual in need thereof. A. Other Compounds of the Invention Compounds of Formula IV are disclosed herein.

其中 、Rr及各獨立地選自氫、C丨.6烷基及鹵素；Wherein Rr and each are independently selected from the group consisting of hydrogen, C.6 alkyl and halogen;

Rr係選自Cw烷基、鹵基Cl_6烷基及鹵素； 各W1獨立地選自CR5,、NR5.、N、Ο及S，其中R5,係選自 氫、Cw烧氧基、Cw烷氧基CN6烷基、CN6烷氧基羰基、 Ct·6烧基、脒基、醯胺基、胺基、芳基、羧醯胺基、 烧基、氰基、鹵基Ck烷基、鹵素、雜環基匚“烷基、羥 基、羥基Ci·6烷基、硝基、硫化物、磺醯胺基及磺醯基，或 2個相鄰W'原子可一起形成稠合之第二環，其中第二環 視需要經一或多個r5取代基取代且係選自芳基、（：3-8環烷 134079.doc -33- 200916458 基、5或6員雜芳基，及5或6員雜環基； 至少一個W，為N ; q1為〇或1，其中 若q’為0且2個相鄰w，原子-起形成稍合之第二環，則相 4W原子之且第二環為6員雜芳基或6員雜環基及 若q'為0，則4個W，原子不; A'係選自 CR6、NR6、N、〇及 s ; 尺6’係選自氫、C, P备《·Rr is selected from the group consisting of Cw alkyl, haloCl-6 alkyl and halogen; each W1 is independently selected from CR5, NR5., N, hydrazine and S, wherein R5 is selected from hydrogen, Cw alkoxy, Cw alkoxy CN6 alkyl, CN6 alkoxycarbonyl, Ct.6 alkyl, fluorenyl, decylamine, amine, aryl, carboxy oxime, alkyl, cyano, halo Ck alkyl, halogen, hetero The cyclic group 匚 "alkyl, hydroxy, hydroxy Ci. 6 alkyl, nitro, sulfide, sulfonylamino and sulfonyl, or two adjacent W' atoms may together form a fused second ring, wherein The second ring is optionally substituted with one or more r5 substituents and is selected from the group consisting of aryl, (: 3-8 cycloalkane 134079.doc -33- 200916458 base, 5 or 6 membered heteroaryl, and 5 or 6 membered hetero a ring group; at least one W, is N; q1 is 〇 or 1, wherein if q' is 0 and two adjacent w, the atom - forms a slightly second ring, then the phase 4W atom and the second ring is 6-membered heteroaryl or 6-membered heterocyclic group and if q' is 0, then 4 W, atom is not; A' is selected from CR6, NR6, N, 〇 and s; Ruler 6' is selected from hydrogen, C , P prepared "·

I-6坑氧基、Cl_6烷氧基Cl0烷基、C烧 氧基羰基、C〗6烷美、胖且 •基脒基、醯胺基、胺基、芳基、羧醯 胺基、（1：3-8環燒基、氰《、 _基c,·6烷基、函素、雜環基 I 1 ·6况I、經基、夠其Γ ^ ^ , 及續醯基，或 ]·〜m化物、伽胺基 其令第二環選 2個相鄰A，原子可一起形成稠合第二環 自5或6員雜芳基及5或6員雜環基； 至少一個A，係選自NR6,、N、〇及s; p1為0或1，其中 =:合、:Γ:.各”基，'不為s;I-6 pitoxy, Cl_6 alkoxy C0 alkyl, C alkoxycarbonyl, C 6 alkyl, fat and fluorenyl, amide, amine, aryl, carboxy guanamine, 1:3-8 cycloalkyl, cyanyl, _yl c, ·6 alkyl, a functional group, a heterocyclic group I 1 ·6 condition I, a thiol group, a sufficient Γ ^ ^ , and a hydrazine group, or] • a m compound, a gamma group such that the second ring selects two adjacent A, and the atoms may together form a fused second ring from a 5 or 6 membered heteroaryl group and a 5 or 6 membered heterocyclic group; at least one A, Is selected from NR6, N, 〇 and s; p1 is 0 or 1, wherein =: combined,: Γ:. each "base, 'not s;

134079.doc •34 200916458134079.doc •34 200916458

3 ’其中L'選自NH及CH，且若L， 為NH，則Μ'為CH2，且若L，為CH，則Μ'為CH ; 及其醫藥學上可接受之鹽。 在一實施例中，R,.、Rr及Rr各為氫。在另一實施例 中，R4,為氯基。在另一實施例中，Rs,選自氫、C] 6烷氧基 羰基、CK6烷基及胺基。 在一實施例中，2個相鄰W，原子一起形成具有至少一個 N雜原子之6,6_稠合雙環雜芳基。在另一實施例中，2個相 鄰W原子一起形成具有至少一個n雜原子之5,6_稠合雙環 雜芳基。 在另一實施例中’ 2個W，為N且q'為1，諸如吡嗪基。在 實施例中’式⑴化合物為N-[3-(5-胺基。比嗪_2·基）-4-氣· 苯基]-2-甲基·6-(三氟甲基）吡啶_3_甲醯胺。在另一實施例 中’至少一個W為Ν且q為0。在另一實施例中，式I化合物 包含咪唑基或噻唑基，諸如選自Ν-[4-氯-3·(1，5-二甲基咪 。坐-2-基）笨基]_2_甲基_6-(三氟曱基）吡啶-3-曱醯胺、Ν-[4-氯-3-(1-曱基咪唑·2·基）苯基]_2•甲基_6_(三氟曱基）d比啶_3_ 曱酿胺及2-[2-氯-5-[[2-曱基-6-(三氟曱基比啶-3-羰基]胺 基]表基]1，3-。塞吐-5-甲酸甲i旨之化合物。 134079.doc -35- 200916458 在一實施例中，一個A，為N且p|為1。在另—實施例中， 一個R6’為c丨.6烷基且一個R6,為南基Cl 6炫基。 在一些實施例中，本發明係關於式V化合物：3' wherein L' is selected from NH and CH, and if L is NH, then Μ' is CH2, and if L is CH, Μ' is CH; and a pharmaceutically acceptable salt thereof. In one embodiment, R, . . . , Rr and Rr are each hydrogen. In another embodiment, R4 is a chloro group. In another embodiment, Rs is selected from the group consisting of hydrogen, C] 6 alkoxycarbonyl, CK6 alkyl, and amine. In one embodiment, two adjacent W, atoms together form a 6,6-fused bicyclic heteroaryl having at least one N heteroatom. In another embodiment, two adjacent W atoms together form a 5,6-fused bicyclic heteroaryl having at least one n heteroatom. In another embodiment, '2 W' is N and q' is 1, such as pyrazinyl. In the examples, the compound of the formula (1) is N-[3-(5-amino.pyrazine-2.yl)-4-a-phenyl]-2-methyl-6-(trifluoromethyl)pyridine _3_carbamamine. In another embodiment 'at least one W is Ν and q is zero. In another embodiment, the compound of Formula I comprises an imidazolyl or thiazolyl group, such as selected from the group consisting of Ν-[4-chloro-3.(1,5-dimethylmiso.yt-2-yl)phenyl]_2_ Methyl-6-(trifluoromethyl)pyridin-3-indoleamine, fluorene-[4-chloro-3-(1-indolizyl-2-yl)phenyl]_2•methyl_6_(three Fluorinyl)d-pyridyl_3_ an amine and 2-[2-chloro-5-[[2-mercapto-6-(trifluoromethylidene-3-carbonyl)amino]amino]] , 3-. Cet-5-carboxylic acid, a compound of the formula. 134079.doc -35- 200916458 In one embodiment, one A, N and p| is 1. In another embodiment, one R6' Is a c丨.6 alkyl group and one R6 is a south group Cl 6 炫. In some embodiments, the invention relates to a compound of formula V:

PP

VV

或其醫藥學上可接受之鹽，其中， A'係選自N及CRn.; X'係選自鹵素及CN6烷基； Y'係選自NR5.及S ;Or a pharmaceutically acceptable salt thereof, wherein A' is selected from N and CRn.; X' is selected from halogen and CN6 alkyl; Y' is selected from NR5. and S;

Rs'係選自氫及Cw烷基；Rs' is selected from the group consisting of hydrogen and Cw alkyl;

Re，及Rr各獨立地選自氫及C丨·6炫基；Re, and Rr are each independently selected from hydrogen and C丨·6 dad;

R9.選自氫、鹵素、cN6烷基、Ci6烷氧基、芳氧基及雜 基，其中R_9_可視需要經一或多個Ri2，取代R9. is selected from the group consisting of hydrogen, halogen, cN6 alkyl, Ci6 alkoxy, aryloxy and hetero, wherein R_9_ may be substituted by one or more Ri2

Rs，、R丨〇’及Rn’各獨立地選自氫、鹵素及€丨·6烷氧基 ’其中Rs, R丨〇' and Rn' are each independently selected from the group consisting of hydrogen, halogen and 丨·6 alkoxy ’

Ri2.可選自函素、胺基、C“烷基、芳基及雜環： R〗2可視需要經一或多個R丨3取代；且 土 R1 31可選自氰基、C!.6烷基、環烷基及芳基。 (1.甲基- 在其他實施例中，RS,及Re,均為曱基且&為氫。 在其他實施例中，R9,係選自2_吡啶基曱氧基、 I34079.doc • 36 - 200916458 4-派咬基）甲氧基、（3_氰基苯基）曱氧基、[(以分卜曱基n比咯 咬-2-基]曱氧基、2_二曱基胺基乙氧基、2_噻吩基、3_二乙 基胺基丙氧基、4-(2·二曱基胺基乙基）哌嗪-1-基、4-(2-羥 基乙基）派嗪-1-基、4-(2-吡啶基甲基）哌嗪-1-基、4-(環丙 基甲基）哌嗪-1-基、氣基、氰基、氟基、氫、異丁氧基、 甲基、曱基、嗎啉基、苯氧基、三氟甲基及甲基。 B ·合成流程 式I化合物可自下文流程1_3中所述之通用合成方法合 成。應瞭解’式I化合物’諸如根據下文通用方法合成之 彼等化合物’可自身另外衍生以形成其他式〗化合物。以 下流程僅意謂示範性的’且一般技術者將識別其可行組 合0 在流程1中所示’硝基蝴酸芳酯1可使用各種條件，諸如 氯化鐵及肼或催化氫化還原成苯胺2。產生化合物4之醯胺 鍵形成可藉由與酸氯化物3及諸如吡啶之鹼之反應來實 現。或者，苯胺2與羧酸3利用標準醯胺形成條件，諸如利 用HATU或EDCI及諸如漢格氏鹼（Hunig，s Base)或N-甲基嗎 啉之鹼之反應。所得蝴酸酯4與芳基或雜環親電子試劑5經 由過渡金屬介導偶合，諸如Suzuki條件（pd(ph3)4，Cs2C〇3) 之反應產生式I化合物。 134079.doc •37· 200916458 流程1Ri2. may be selected from the group consisting of a hydroxyl group, an amine group, a C "alkyl group, an aryl group and a heterocyclic ring: R" 2 may optionally be substituted by one or more R丨3; and the earth R1 31 may be selected from a cyano group, C!. 6 alkyl, cycloalkyl and aryl. (1. Methyl - In other embodiments, RS, and Re are both fluorenyl and & is hydrogen. In other embodiments, R9 is selected from 2 _Pyridinyl methoxy, I34079.doc • 36 - 200916458 4- ketone) methoxy, (3-cyanophenyl) decyloxy, [( 以 曱 n n n -2- -2- -2-) Alkoxy, 2-didecylaminoethoxy, 2-thienyl, 3-diethylaminopropoxy, 4-(2·didecylaminoethyl)piperazin-1-yl 4-(2-hydroxyethyl)pyrazine-1-yl, 4-(2-pyridylmethyl)piperazin-1-yl, 4-(cyclopropylmethyl)piperazin-1-yl, Gas radical, cyano, fluoro, hydrogen, isobutoxy, methyl, decyl, morpholinyl, phenoxy, trifluoromethyl and methyl. B · Synthesis of the compound of formula I can be carried out from Scheme 1_3 below Synthetic methods described in the synthesis. It is understood that 'compounds of formula I' such as those synthesized according to the general methods below can be additionally derivatized by themselves to form Compounds. The following schemes are meant to be exemplary only' and the average skilled person will identify their feasible combinations. 0 The nitrofolate aryl ester 1 shown in Scheme 1 can be used in various conditions, such as ferric chloride and ruthenium or catalysis. Hydrogenation to aniline 2. The formation of the indole bond of compound 4 can be achieved by reaction with acid chloride 3 and a base such as pyridine. Alternatively, aniline 2 and carboxylic acid 3 can be formed using standard guanamine conditions, such as with HATU. Or the reaction of EDCI with a base such as Hungg, s Base or N-methylmorpholine. The resulting folate 4 is coupled to an aryl or heterocyclic electrophile 5 via a transition metal, such as Suzuki. The reaction of the conditions (pd(ph3)4, Cs2C〇3) yields a compound of formula I. 134079.doc •37· 200916458 Scheme 1

式I化合物之另一路線概述於流程2中，其按照與流程1 相同之轉變系列，除外的是起始硝基衍生物6為芳基或雜 環鹵化物或三氟曱磺酸酯而非_酸酯1。最終轉變涉及在 諸如Pd(0)之過渡金屬介導條件下，諸如在Suzuki偶合中之 酉朋酸酯9之偶合或Negishi交叉偶合中之芳基/雜芳基鋅9之 條件下，使親電子試劑8及_酸酯9反應。 流程2Another route of the compound of formula I is outlined in Scheme 2, following the same series of transitions as in Scheme 1, except that the starting nitro derivative 6 is an aryl or heterocyclic halide or a trifluorosulfonate rather than _ester 1. The final transformation involves the formation of an aryl/heteroaryl zinc 9 in a coupling metal-mediated condition such as Pd(0), such as a coupling of a phthalate 9 in a Suzuki coupling or an aryl/heteroaryl zinc 9 in a Negishi cross coupling. Electron reagent 8 and _ester 9 react. Process 2

LG=Br, I, OTfLG=Br, I, OTf

或 X=0H 偶合劑，驗Or X=0H coupling agent, test

134079.doc -38- 200916458 另外，式i化合物可利用芳基快u、猜12或酸，/酸】3作 為式I之Z環之起動點，自各種其他方法（流程3)合成。舉例 而言’藉由分別與疊氮基及重氮基試狀反應，块為諸如 二唑（Bock 等人 Eur. J. 〇rg. Chem 5丨_68 (2〇〇6))及吡唑 (Fulton等人Eur. J. 〇rg· Chem 1479_1492 (2〇〇5》之環的適 用前驅物。腈適用作噻唑及其他雜環之起始物質（C〇llier， S. J.; Langer，P.，〇/办㈣⑺·& 19:411 (2〇〇4》。醛 及酮可用作包括（但不限於）咪唑、苯并咪唑及喹喏啉之各 種雜環（Nakamura 等人，j. Med. chem, 46:5416-5427 (2003))之前驅物。羧酸及其衍生物可轉化成各種雜環，諸 如苯并咪唑或苯并噻唑。 流程3Further, the compound of formula i can be synthesized from various other methods (Scheme 3) using aryl fast u, guess 12 or acid, / acid 3 as the starting point of the Z ring of formula I. For example, by reacting with an azide group and a diazo group, respectively, the block is such as a diazole (Bock et al. Eur. J. 〇rg. Chem 5丨_68 (2〇〇6)) and pyrazole. (Fulton et al. Eur. J. 〇rg. Chem 1479_1492 (2〇〇5) Applicable precursors. Nitriles are suitable as starting materials for thiazoles and other heterocycles (C〇llier, SJ; Langer, P., 〇/办(4)(7)·& 19:411 (2〇〇4). Aldehydes and ketones can be used as various heterocycles including, but not limited to, imidazole, benzimidazole and quinoxaline (Nakamura et al., j. Med Chem, 46:5416-5427 (2003)) Precursors. Carboxylic acids and their derivatives can be converted into various heterocyclic rings, such as benzimidazole or benzothiazole.

134079.doc -39· 200916458 Η·醫藥組合物 本揭不案亦提供包含本文中所揭示之與一或多種醫藥學 上可接受之載劑一起調配之化合物的醫藥組合物。該等調 配物包括適合於經口、經直腸、局部、頰内及非經腸（例 如皮下、肌肉内、皮内或靜脈内）投與之調配物，儘管在 任何所給情況了 ’最合適投藥形式取決於欲治療病狀之程 度及嚴重性且取決於所用特定化合物之性質。134079.doc -39· 200916458 医药·Pharmaceutical Compositions The present invention also provides pharmaceutical compositions comprising a compound as disclosed herein in combination with one or more pharmaceutically acceptable carriers. Such formulations include those suitable for oral, rectal, topical, buccal and parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) administration, although in any given case, 'the most suitable The form of administration will depend on the extent and severity of the condition being treated and will depend on the nature of the particular compound employed.

在一實施例中，將化合物或醫藥組合物向個體（諸如溫 血動物)投與。在另—實施例中，溫血動物為哺乳動物， 諸如人類。 週令於經π投與之調配物可以離散單位形式存在，諸如 膠囊广，囊劑、***劑或錠劑’ I自含有預定量之粉末或 顆粒形式，於水洛液或非水性液體中之溶液或懸浮液形 式；或水中油或油中水乳化液形式之化合物。如所表明， 該等調配物可藉由任何合適藥劑學方法來製備，該方法包 括使活性化合物與載劑或賦形劑（其可構成—或多種輔助 成伤）結合之步驟。載劑必一〜立 員在疋忍義上（與調配物之其 他成伤相容與不可對受體 俨或㈣m 又體有。)為可接受的。载劑可為固 m 合物—起調配成單位劑量調配 物，例如錠劑，其可含有約〇 仆八胳甘里里/0至約95重量〇/〇的活性 化合物。其他樂理學上活性物 子在，包括其他化合 之調配物可藉由藥劑學熟知枯化士 ^ (包括將組份混合）來製備。 、、 nJ之任一者 對於固體組合物而言， I知無母性固包括（例如） 134079.doc 200916458 醫藥級甘露糖醇、乳糖、澱 石、纖維素、葡萄糖、斧糖μ月曰酸鎂、糖精鈉、滑 理學上可投與之組合物可(例如)藉由將：：似物。液體樂 化合物及可選醫藥佐劑溶 八…文所述之活性 水、右旋糖水溶液、甘油、乙醇於（諸如）水、鹽 以由此形成溶液或懸浮液來製備。二“场之賦形劑中’ 可藉由將活性化合物與液 又:’合適調配物 且緊密.、曰入，曰L 飞，、田叔狀固體載劑或兩者均勻 二 要)使產物成型來製備。舉例而 。’錠劑可藉由壓製或模製化合物之粉 以及-或多種輔助成份來製 2、、立視、況) "T藉由在合適機器中愿製 由流動形式（諸如粉末或顆粒）之化合物（ 劑、潤滑劑、惰性稀釋劑、表面活性劑/分散劑混合、 備壓製錠劑。可藉由在合適機器中模製經惰性液體稀釋劑 濕潤之粉末狀化合物來製備模製錠劑。 適合於頰内(舌下)投與之調配物包括：***劑，其在調 味基質(通常為蔗糖與***膠或黃蓍膠)中包含化合物； 及片9劑’其在惰性基質（諸如明穋與丙三醇或薦糖與阿拉 伯膠）中包含該化合物。 適口於非經腸投與之本發明之調配物包含該等化合物之 無菌製劑水溶液’其與所欲受體之血液大致等滲。儘管該 等製劑亦可藉助於皮下、肌肉内或皮内注射實現投藥，但 較佳以靜脈内方式投藥。該等製劑可便利地藉由將化合物 與水扣合且使传所得溶液無菌a與金液等渗來製備。本發 明之可注射組合物可含有約0· i至約5% w/w活性化合物。 134079.doc -41 - 200916458 適合於經直腸投與之調配物以單位劑量栓劑形式存在。 =可藉由將該化合物與一或多種習知固體載劑（例如可可 月旨）混合且隨後使所得混合物成型來製備。 適合於局部施用於皮膚之調配物可採用軟膏劑、乳膏 劑、洗劑、糊劑、凝膠劑、喷霧劑、霧劑或油劑之形式。 可使用之载劑及賦形劑包括凡士林、羊毛脂、聚乙二醇、 乙醇及其兩者或兩者以上之組合。活性化合物通常以組合 广 物之約〇.1%至約15% W/W，例如約0.5。/。至約2% w/w濃产存 丨 在。 ’ 活性化合物投與之量可取決於欲治療之個體、個體之體 重、投藥方式及開藥醫師之判斷。舉例而言，給藥方案可 包括以約10 至約100 mg之感知劑量（perceived d〇sage)每 日或半日投與膠囊化化合物。在另一實施例中，可採用間 歇式投與一定劑量之膠囊化化合物，諸如以月或年計。膠 囊化有利於接近作用位點且使得可同時投與活性成份，理 U 論上產生協同效應。根據標準給藥方案，醫師將易於確定 最佳劑篁且應能夠易於對投藥進行改變以達成該等劑量。 治療有效量之本文中所揭示之化合物或組合物可由化合 物之療效量測。本發明之化合物可以每日約1 gg/kg至約 200 mg/kg ’ 諸如約 1 pg/kg至約 150 mg/kg ’ 約 1 mg/kg至約 200 mg/kg，約 1 gg/kg至約 1〇〇 mg/kg，約 1 pg/kg至約 1 mg/kg ’ 約 50 pg/kg 至約 200 mg/kg，約 1〇 pg/kg 至約 1 mg/kg ’ 約 10 pg/kg 至約 1〇〇 pg/kg，約 100 pg/kg 至約 10 mg/kg，及約500 pg/kg至約50 mg/kg之劑量投與。然而， 134079.doc -42- 200916458 呑亥等劑s可視患者需要、欲治療病狀之嚴重性及所用化合 物而變化。在-實施例中，所揭示化合物之治療有效量足 以建立介於約0.001 μΜ至約1〇〇 μΜ，例如Μ _至約2〇 μΜ之最大血漿濃度。（例如)根據動物試驗及用於人類投藥 之劑量換算所確定之初步給藥係根據技術上可接受之實踐 執行。 可藉由在細胞培養物或實驗動物中之標準醫藥程序（例 r 如，用於測定群體1〇5()值（50%致死之劑量））及ED5G值（在群 I 體之50。/。中治療有效之劑量））來確定毒性及治療功效。毒 性效應與治療效應之間的劑量比率為治療指數且其可表示 為比率LDm/EDsq。展現較大治療指數之組合物較佳。 治療有效劑量可最初自細胞培養物檢定估算。可在動物 模型中調配劑量以達成包括如在細胞培養物檢定或動物模 型中所測定之1(：5〇值（亦即，達成一半_最大之症狀抑制的 測試治療濃度）之循環血漿濃度。可（例如）藉由高效液相層 (_； 析法來量測在血漿中之含量。任何特定劑量之效應可藉由合 適生物檢定監視。劑量之實例為：約01xIC5g值、約〇 5xICm 值、約 1xIC5〇值、約 5xIC50值、i〇xic5()值、約 50xIC5g值及 約 100xIC5o 值。 自細胞培養物檢定及動物研究獲得之資料可用於調配用 於人類之劑量範圍。可使用此項技術中已知之轉化因子 (參見（例如）Freireich等人，Cancer Chemother. Rep〇rts 5〇 (4):219-244 (1966)及表1等表面積劑量因子）將一動物模型中 所達成之治療有效劑量轉化以用於另一動物，包括人類。 134079.doc -43- 200916458 表1In one embodiment, the compound or pharmaceutical composition is administered to an individual, such as a warm-blooded animal. In another embodiment, the warm-blooded animal is a mammal, such as a human. The formulation may be in discrete units, such as a capsule, a sachet, a buccal or a lozenge, containing a predetermined amount of powder or granules, in a water solution or a non-aqueous liquid. In the form of a solution or suspension; or a compound in the form of an emulsion of water or oil in water. As indicated, the formulations may be prepared by any suitable method of pharmacy which includes the step of bringing into association the active compound with carriers or excipients which may comprise one or a plurality of auxiliary agents. The carrier must be one of the members on the 疋 义 ( (compatible with the other damages of the formulation and not with the receptor 俨 or (4) m.) is acceptable. The carrier can be formulated as a unit dosage formulation, such as a lozenge, which may contain the active compound in an amount of from about 8 to about 95 weights per guanidine. Other physiochemically active species, including other compounds, can be prepared by pharmacy well known to be a compound (including mixing the components). Any of nJ for solid compositions, I know that there is no maternal solid, including, for example, 134079.doc 200916458 pharmaceutical grade mannitol, lactose, hydrate, cellulose, glucose, axe, magnesium citrate The sodium saccharin, slippery composition can be administered, for example, by: The liquid music compound and the optional pharmaceutical adjuvant dissolve the active water, aqueous dextrose solution, glycerol, ethanol, such as water, salt to form a solution or suspension therefrom. The second "excipient in the field" can be formed by molding the active compound with a liquid: 'suitable formulation and tight, intrusion, 曰L fly, sturdy solid carrier or both) Preparation. For example, a tablet can be made by compressing or molding a powder of a compound and/or a plurality of auxiliary components, and can be made into a flow form (such as by a suitable machine). a powder or granule compound (agent, lubricant, inert diluent, surfactant/dispersant mixed, compressed tablet). It can be prepared by molding a powdered compound moistened with an inert liquid diluent in a suitable machine. Molded tablets. Formulations suitable for buccal (sublingual) administration include: a buccal containing a compound in a flavoring base (usually sucrose and gum arabic or tragacanth); and a tablet 9 The compound is included in an inert matrix such as alum and glycerol or sucrose and gum arabic. The formulation of the present invention which is suitable for parenteral administration comprises an aqueous solution of a sterile preparation of such a compound which is intended to be The blood of the body is roughly isotonic Although the preparations can also be administered by subcutaneous, intramuscular or intradermal injection, it is preferably administered intravenously. The preparations can be conveniently sterilized by binding the compound to water and allowing the resulting solution to be sterile. Prepared by isotonicity with gold liquid. The injectable compositions of the present invention may contain from about 0.1% to about 5% w/w of active compound. 134079.doc -41 - 200916458 Suitable for rectal administration of formulations in unit doses In the form of a suppository. = can be prepared by mixing the compound with one or more conventional solid carriers (e.g., cocoa) and then shaping the resulting mixture. Formulations suitable for topical application to the skin can be formulated with ointments, In the form of a cream, lotion, paste, gel, spray, aerosol or oil. Carriers and excipients which may be used include petrolatum, lanolin, polyethylene glycol, ethanol and both Or a combination of the two or more. The active compound is usually present in an amount of from about 1% to about 15% W/W of the broad composition, for example from about 0.5% to about 2% w/w. The amount of administration may depend on the individual to be treated, The weight, the mode of administration, and the judgment of the prescribing physician. For example, the dosing regimen can include administering the encapsulated compound daily or half a day at a perceived dose of from about 10 to about 100 mg. In embodiments, it is possible to intermittently administer a dose of an encapsulated compound, such as in months or years. Encapsulation facilitates access to the site of action and allows simultaneous administration of the active ingredient, resulting in a synergistic effect. In a standard dosing regimen, the physician will readily be able to determine the optimal dosage and should be able to readily modify the dosage to achieve such dosage. The therapeutically effective amount of a compound or composition disclosed herein can be measured by the therapeutic effect of the compound. The compound may be from about 1 gg/kg to about 200 mg/kg per day, such as from about 1 pg/kg to about 150 mg/kg' from about 1 mg/kg to about 200 mg/kg, from about 1 gg/kg to about 1 Torr. 〇mg/kg, from about 1 pg/kg to about 1 mg/kg' from about 50 pg/kg to about 200 mg/kg, from about 1 pg/kg to about 1 mg/kg' from about 10 pg/kg to about 1 〇〇pg/kg, dose from about 100 pg/kg to about 10 mg/kg, and from about 500 pg/kg to about 50 mg/kg . However, 134079.doc -42- 200916458 呑hai et al. may vary depending on the needs of the patient, the severity of the condition to be treated, and the compound used. In an embodiment, the therapeutically effective amount of the disclosed compound is sufficient to establish a maximum plasma concentration of from about 0.001 μΜ to about 1 μ μΜ, such as Μ _ to about 2 μ μ〇. The initial administration, e.g., based on animal testing and dose conversion for human administration, is performed according to technically acceptable practices. This can be done by standard medical procedures in cell cultures or experimental animals (eg, for the determination of population 1〇5() values (50% lethal dose)) and ED5G values (50 in group I). The therapeutically effective dose)) is used to determine toxicity and therapeutic efficacy. The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index and it can be expressed as the ratio LDm/EDsq. Compositions exhibiting a larger therapeutic index are preferred. The therapeutically effective dose can be estimated initially from cell culture assays. Dosages can be formulated in animal models to achieve circulating plasma concentrations including 1 (: 5 〇 value (i.e., test therapeutic concentration to achieve half-maximal symptom suppression) as determined in cell culture assays or animal models. The amount in plasma can be measured, for example, by a high performance liquid phase layer. The effect of any particular dose can be monitored by a suitable bioassay. An example of a dose is: about 01 x IC 5 g value, about x 5 x ICm value , about 1xIC5 〇 value, about 5xIC50 value, i〇xic5() value, about 50xIC5g value, and about 100xIC5o value. Data obtained from cell culture assays and animal studies can be used to formulate dose ranges for humans. Transformation factors known in the art (see, for example, Freireich et al, Cancer Chemother. Rep〇rts 5(4): 219-244 (1966) and Table 1 surface area dose factors) will be treated in an animal model Effective doses are converted for use in another animal, including humans. 134079.doc -43- 200916458 Table 1

"亥等化合物之劑量較佳處於包括且"Hai and other compounds are preferably included in the dose

C, 之叫。之循環濃度的範圍内1量；視:二、或…毒性 藥途徑而在此範圍内變化。 麵用劑型及所用投 般而《，治療有效量可隨個體之I^ 及之年齡、減及性別以 、心 醫予病狀之嚴重性而變化。劑量可由醫師確定且 視需要調節以適合所觀察之治療效應。 -實施例提供向個體與輻射治療一起投與式[化合物。 在另實施例中’將本文中所揭示之化合物或其醫藥學上 可接欠之鹽或水合物與-或多種治療劑組合投與。該治療 劑可與本文中所揭示之化合物獨立、依次或同時投與。組 合治療之劑量範圍可與單一治療相當。 相對於僅投與化合物，治療劑可提供附加或協同價值。 治療劑可（例如）選自由以下各物組成之群： (i) 如用於腫瘤内科中之抗增殖/抗贅生性藥物及其組 合’諸如烧化劑（例如順|自（cis-platin)、卡波始 (carboplatin)、環填醯胺、I 芥（nitrogen mustard)、美法命 (melphalan)、苯丁 酸氮芥（chlorambucil)、白消安（busulphan) 及亞硝基脲（nitrosourea));抗代謝物（例如抗葉酸物，諸如 134079.doc -44- 200916458 氟°密°定（如5-氟尿嘴咬及喃氟咬（tegafur))、雷替曲賽 (raltitrexed)、曱胺喋呤（methotrexate)、阿糖胞苷（Cyt〇sine arabinoside)及經基脲（hydroxyurea));抗腫瘤抗生素（例如 蒽環黴素（anthracycline)，例如阿德力黴素（adriamycin)、 博萊黴素（bleomycin)、阿黴素（doxorubicin)、道諾黴素 (daunomydn)、表柔比星（epirubicin)、黃膽素（idarubicin)、 絲裂黴素C (mitomycin-C)、更生黴素（dactinomycin)及米 拉黴素（mithramycin));抗有絲***劑（例如長春花生物鹼 (如長春新鹼（vincristine)、長春鹼（vinblastine)、長春地辛 (vindesine)及長春瑞賓（vinorelbine))及紫杉醇（如紫杉酚 (taxol)及克癌易（taxotere)));及拓撲異構酶抑制劑（例如表 鬼臼素（epipodophyllotoxin)(例如依託泊苷（etoposide)及替 尼、泊苦（teniposide))、安 口丫咬（amsacrine)、拓撲替康 (amsacrine)及喜樹鹼（carnptothecin)); (ii)細胞生長抑制劑，諸如抗***（例如三苯氧胺 (tamoxifen)、托瑞米芬（toremifene)、雷洛昔芬（rai〇xifene)、 屈洛昔务（droloxifene)及艾多昔芬（i〇d〇xyfene))、雄激素受 體下調劑（例如氟維司群（fulvestrant))、抗雄激素（例如比 卡魯胺（bicalutamide)、氟他胺（flutamide)、尼魯胺（nilutamide) 及乙酸環佐酮（cyproterone aeetate))、lhrh拮抗劑或 LHRH促效劑（例如戈舍瑞林（g〇serelin)、亮丙瑞林（ieupr〇reHn) 及布舍瑞林（buserelin))、孕激素（例如甲地孕酮（megestr〇1 acetate)) ^•香_抑制劑（例如安美達鍵（anastr〇z〇ie)、來 曲0坐（letr〇Z〇le)、沃拉唑（vorazole)及依西美坦（exemestane)) 134079.doc -45· 200916458 及5α_還原酶抑制劑（諸如非那雄安（finasteride》； (in)抑制癌細胞侵襲之藥劑（例如金屬蛋白酶抑制劑， 如馬立馬司他（marimastat),及尿激酶血聚素原活化劑受 體功能抑制劑）； (iv)生長因子功能抑制劑：例如該等抑制劑包括：生 長因子抗體’生長因子受體抗體（例如，抗6灿2抗體曲妥 珠單抗[Herceptin M]及抗erbbi抗體西妥昔單抗[C225]);法 呢基轉移酶抑制劑；MEK抑制劑；酿胺酸激酶抑制劑及絲 胺酸/蘇胺酸激酶抑制劑；表皮生長因子家族抑制劑（例如 EGFR家族赂胺酸激酶抑制劑，諸如叫3_氯_4_氣苯基 甲氧基-6-(3-嗎啉基丙氧基）喹唑啉_4_胺（吉非替尼 (gefnnub) ’ AZD1839)、N-(3-乙炔基苯基）_6,7_雙（2·曱氧 基乙氧基）喧唾琳-4-胺（埃羅替尼，〇51_774)及6.丙稀酿胺 基-N-(3-氣-4-氟苯基）_7_(3_嗎啉基丙氧基）喹唑啉_4_胺（ci 103 3))，血小板衍生生長因子家族抑制劑及肝細胞生長因 子家族抑制劑； (v) 抗血管生成劑，諸如彼等抑制血管内皮生長因子 之效應者，（例如抗血管内皮細胞生長因子抗體貝伐單抗 (bevacizumab)[Avastin，，諸如在國際專利申請案w〇 97/22596、WO 97/30035、WO 97/32856及 WO 98/13354 中 揭示之彼等化合物）及藉由其它機制發揮作用之化合物（例 如雷諾麥德（linomide)、整合素ανρ3功能及血管抑制素之 抑制劑）； (vi) 血管破壞劑，諸如康柏斯達汀（c〇mbretastatin) 134079.doc -46- 200916458 及國際專利申請案w〇 99/()2166、加_彻Μ、觸 00/41669 ^ WO 01/92224 > WO 02/04434^ WO 02/08213 t 所揭示之化合物； 、（νΠ)反向療法，例如針對上文所列之標乾之彼等療 法，諸如ISIS 2 5 03，一種抗_ras反向療法； (wn)基因療法，包括（例如）替代諸如異f p53或異常 或BRCA2之異常基因之方法；GDEPT(基因定向酶 前藥療法）；諸如彼等使用胞㉝錢胺酶、胸#激酶或細 菌硝基還原酶之方法；及增加患者對化學療法或放射療法 之耐受性之方法（諸如多藥物抗性基因療法）； (ix)免疫療法，包括（例如）增加患者腫瘤細胞免疫原性 (諸如以諸如介白素2、介白素4或顆粒球巨噬細胞群落刺 激因子之細胞激素轉染）之離體及活體内方法；降低τ細胞 無能之方法；使用諸如經細胞激素轉染之樹突狀細胞之經 轉染免疫細胞的方法；使用經細胞激素轉染之腫瘤細胞株 之方法；及使用抗遺傳型抗體之方法； (X) 細胞週期抑制劑，包括（例如）CDK抑制劑（例如黃 皮利多（flavopiridol))及其他細胞週期檢查點抑制劑（例如 檢查點激酶）；與有絲***及細胞質***調節有關之極光 激酶（aurora kinase)及其他激酶之抑制劑（例如有絲***驅 動蛋白）；及組蛋白脫乙醯基酶抑制劑；C, called. The amount of circulating concentration is within 1 range; depending on the second or the toxic drug route, it varies within this range. In terms of the dosage form and the dosage used, the therapeutically effective amount may vary depending on the age of the individual, the age, the sex, and the severity of the condition. The dosage can be determined by the physician and adjusted as needed to suit the therapeutic effect being observed. - Examples provide administration of a compound [compound to an individual with radiation therapy. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt or hydrate thereof, is administered in combination with - or a plurality of therapeutic agents. The therapeutic agent can be administered separately, sequentially or simultaneously with the compounds disclosed herein. The range of doses for combination therapy can be comparable to a single treatment. The therapeutic agent can provide additional or synergistic value relative to the administration of only the compound. The therapeutic agent can, for example, be selected from the group consisting of: (i) anti-proliferative/anti-neoplastic drugs as used in oncology and combinations thereof, such as a burn-in agent (eg, cis-platin, Carboplatin, cyclopamine, nitrogen mustard, melphalan, chlorambucil, busulphan, and nitrosourea Antimetabolites (eg, antifolates, such as 134079.doc -44- 200916458 Fluorine (such as 5-fluoro urinary bite and tegafur), raltitrexed, guanamine Meth (methotrexate), Cyt〇sine arabinoside and hydroxyurea; anti-tumor antibiotics (such as anthracycline, such as adriamycin, Bole Blomycin, doxorubicin, dauniumdn, epirubicin, idarubicin, mitomycin-C, dactinomycin (dactinomycin) and mirabia (mithramycin); anti-mitotic agents (such as vinca alkaloids ( Vincristine, vinblastine, vindesine, and vinorelbine, and paclitaxel (such as taxol and taxotere); and topological differences Enzyme inhibitors (eg epipodophyllotoxin (eg etoposide and teini, teniposide), amsacrine, amsacrine and camptothecin (carnptothecin)); (ii) cytostatic agents such as antiestrogens (eg, tamoxifen, toremifene, raloxifene, droloxifene, and Iddoxifen (i〇d〇xyfene), androgen receptor downregulator (such as fulvestrant), antiandrogen (such as bicalutamide, flutamide, Nilutamide and cyproterone aeetate, lhrh antagonists or LHRH agonists (eg gserelin, eilupril (ieupr〇reHn) and buseri (bererelin), progesterone (eg megestrol 〇 1 acetat e)) ^•香_inhibitors (eg, anastrom® (anastr. z), let 〇 let (letr〇Z〇le), vorazole and exemestane) 134079 .doc -45· 200916458 and 5α_reductase inhibitors (such as finasteride; (in) agents that inhibit cancer cell invasion (eg metalloproteinase inhibitors such as marimastat, and urine) a kinase plasminogen activator receptor functional inhibitor); (iv) a growth factor function inhibitor: for example, the inhibitor includes: a growth factor antibody 'growth factor receptor antibody (eg, an anti-6can 2 antibody trastuzel) Monoclonal antibody [Herceptin M] and anti-erbbi antibody cetuximab [C225]); farnesyl transferase inhibitor; MEK inhibitor; tyrosine kinase inhibitor and serine/threonine kinase inhibitor; Epidermal growth factor family inhibitors (eg, the EGFR family of histidine kinase inhibitors, such as, for example, 3-chloro-4-indolyl-6-(3-morpholinylpropoxy)quinazoline_4_ Amine (gefnnub 'AZD1839), N-(3-ethynylphenyl)_6,7-bis(2·decyloxyethoxy)喧 salin-4-amine ( Rotinib, 〇51_774) and 6. acrylamide-N-(3-vapor-4-fluorophenyl)-7-(3-morpholinylpropoxy)quinazoline-4-amine (ci 103 3)), platelet-derived growth factor family inhibitors and hepatocyte growth factor family inhibitors; (v) anti-angiogenic agents, such as those that inhibit vascular endothelial growth factor (eg, anti-vascular endothelial growth factor antibody shellfish) Bevacizumab [Avastin, such as those disclosed in International Patent Application No. WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and by other mechanisms Compounds (such as linomide, integrin ανρ3 function and inhibitors of angiostatin); (vi) vascular disrupting agents, such as compostatin (c〇mbretastatin) 134079.doc -46- 200916458 and International Patent Application No. WO 〇 99/() 2166, _ _ Μ Μ, 00/41669 ^ WO 01/92224 > WO 02/04434 ^ WO 02/08213 t disclosed compounds; , (νΠ) reverse therapy For example, for the treatments listed above, such as ISIS 2 5 03, an anti-ras reverse therapy; Wn) gene therapy, including, for example, methods for replacing aberrant genes such as iso-f p53 or aberrant or BRCA2; GDEPT (gene-directed enzyme prodrug therapy); such as the use of cytosolic 33-kinase, chest # kinase or bacterial nitrate a method of reductive enzymes; and a method of increasing tolerance of a patient to chemotherapy or radiation therapy (such as multidrug resistance gene therapy); (ix) immunotherapy, including, for example, increasing tumor cell immunogenicity of a patient (such as In vitro and in vivo methods of transfection with cytokines such as interleukin 2, interleukin 4 or granule macrophage colony stimulating factor; methods for reducing the inability of tau cells; using trees transfected with cytokines Method for transfecting immune cells into a cell; method for using a cell line transfected with a cytokine; and method for using an anti-genetic antibody; (X) a cell cycle inhibitor, including, for example, a CDK inhibitor ( For example, flavopiridol and other cell cycle checkpoint inhibitors (such as checkpoint kinases); aurora kinases associated with mitosis and regulation of cytokinesis (aurora) Inhibitors of kinases and other kinases (eg, mitotic-driven proteins); and histone deacetylase inhibitors;

(XI) 内皮素拮抗劑，包括内皮素A拮抗劑、内皮素8拮 抗贫彳及内皮素A與B拮抗劑；例如ZD4054及ZD 1611 (WO 96/40681)、阿曲生坦（atrasentan)及 YM598。 134079.doc •47· 200916458 式i化合物可適用作用於評估實驗動物(諸如貓、犬、 兔、猴、大鼠及小鼠)中軸—§路徑抑制效應之 標準化活體外及活體内測試系統中之醫藥手段，作為搜索 新穎治療劑之一部分。 、 III.使用方法(XI) Endothelin antagonists, including endothelin A antagonists, endothelin 8 antagonists of barrenness and endothelin A and B antagonists; for example ZD4054 and ZD 1611 (WO 96/40681), atrasentan (atrasentan) and YM598. 134079.doc •47· 200916458 Compounds of formula i are suitable for use in standardized in vitro and in vivo test systems for assessing axis-§ pathway inhibition effects in experimental animals such as cats, dogs, rabbits, monkeys, rats and mice. Medical means as part of the search for novel therapeutic agents. , III. How to use

在某些實施例中，本發明之化合物及組合物可適用於抑 制Hedgehog路徑之方法。本文中揭示減少細胞分化、增殖 及/或影響基質微環境調節之方法，#包含向有需要之個 體投與治療有效量之本發明之化合物。抑制Hedgehog路徑 提供治療僅或部分由該路徑介導之疾病或醫學病狀之有效 方法。該等疾病包括癌症及其他增瘦疾病。 雖…':主要焦點為癌症，但亦已展示取如⑽拮抗劑減少 牛皮癬之症狀（丁as 等人，Dermat〇l〇gy 2〇9:126_131 (2004))。牛皮癖為—種由皮膚病變及斑塊表徵之慢性皮膚 病且目則為其為自體免疫疾病，儘管其病源學並未明 確疋義。因此，預期本發明之化合物對患有牛皮癬之個體 具有有利作用。 因此’實施例提供一種抑制Hedgehog路徑之方法，其 包s向有需要之個體投與治療有效量之所揭示之化合物或 醫藥組合物。另一實施例提供一種減少細胞增殖、分化及/ 或衫響基質微環境調節之方法，《包含向有需要之個體投 與~療有效罝之所揭示之化合物或醫藥組合物。在一實施 例中’細胞為基質細胞。纟另一實施例中，細胞為癌細 胞在另一實施例中，細胞為幹細胞，諸如癌症幹細胞。 134079.doc ，48 · 200916458 在一實施例中，基質微環境調節包含血管調節。在另一 實施例中，基質微環境調節包含調降基質細胞中之In certain embodiments, the compounds and compositions of the invention are applicable to methods of inhibiting the Hedgehog pathway. Methods for reducing cell differentiation, proliferation, and/or affecting the regulation of the microenvironment of the substrate are disclosed herein, and comprise administering to a subject in need thereof a therapeutically effective amount of a compound of the invention. Inhibition of the Hedgehog Pathway provides an effective means of treating a disease or medical condition mediated only by this pathway. These diseases include cancer and other thinning diseases. Although...': The main focus is cancer, but it has also been shown that (10) antagonists reduce the symptoms of psoriasis (Dings et al., Dermat〇l〇gy 2〇9:126_131 (2004)). Psoriasis is a chronic skin disease characterized by skin lesions and plaques and is intended to be an autoimmune disease, although its etiology is not clearly defined. Thus, the compounds of the invention are expected to have a beneficial effect on individuals suffering from psoriasis. Thus, the present invention provides a method of inhibiting the Hedgehog pathway, which comprises administering a therapeutically effective amount of the disclosed compound or pharmaceutical composition to an individual in need thereof. Another embodiment provides a method of reducing cell proliferation, differentiation, and/or matrix microenvironment regulation, comprising a compound or pharmaceutical composition disclosed for administration to a subject in need thereof. In one embodiment the 'cell is a stromal cell. In another embodiment, the cell is a cancer cell. In another embodiment, the cell is a stem cell, such as a cancer stem cell. 134079.doc, 48 · 200916458 In one embodiment, the matrix microenvironment regulation comprises vascular regulation. In another embodiment, the matrix microenvironment regulation comprises in a downregulated stromal cell

Hedgehog路徑。在另一實施例中，基質細胞為纖維母細 胞。 在一實施例中，藉由向有需要之個體投與治療有效量之 斤揭示之化5物或醫樂組合物阻礙細胞增殖、分化及/或 基質微環境調節。如本文中所使用之"阻礙”係指降低獲得 給定疾病或病症之風險。 亦揭不治療僅或部分由Hedgehog路徑抑制介導之疾病或 醫學病狀之方法，其包含向有需要之個體投與治療有效量 之本文中所揭示之化合物或組合物。 在一實施例中，"治療"係指改善疾病或病症或至少其一 可辨別之症狀。在另一實施例中，”治療"係指改善至少一 可量測、患者未必可辨別之物理參數。在另一實施例中， "治療"係指實體上（例如，穩定可辨別之症狀）、生理上（例 如，穩定物理參數）或實體上與生理上抑制疾病或病症之 進程。在實施例巾，"治療"係指延緩疾病或病症之發 作。 在一實施例中，僅或部分由Hedgeh〇g路徑抑制介導之疾 病或醫學病狀與癌症相關。例示性疾病及病狀包括（但不 限於）基底細胞癌、成神經管細胞瘤、橫紋肌肉瘤、肉 瘤、淋巴瘤、白血病、膠質母細胞瘤、***癌、胰腺 癌、卵巢癌、黑色素瘤、乳癌、結腸癌、肺癌、食道癌、 胃癌、膽癌、肝細胞癌及多發性骨髓瘤。因此，本發明之 134079.doc -49· 200916458 化合物及組合物具有抗增殖活性，諸如抗癌活性。 在另-實施例中，疾病或醫學病狀為牛皮癖。在另一實 施例中’牛皮癖可藉由與—或多種抗牛皮癬藥劑組合投與 本發明之化合物治療。 在-實施例巾’個體表徵為具有選自由以下表型組成之 群之表型· PTCH功能喪失表型、SM〇功能獲得表型及 Hedgehog功能獲得表型。 例示 V. 實驗、程序、實例及中間物之下列描述意欲為本發明之 實施例之例不’且並非意欲以任何方式限制本發明。本發 明之化合物可以熟習有機合成技術者熟知之許多方式來製 備。更特定而言，本發明之化合物可使用本文中所述之反 應及技術來製備。在下文所述之合成方法之描述中，應瞭 解，除非另外指示，否則所有所建議之反應條件，包括溶 劑、反應大氣塵、反應溫度、實驗持續時間及處理程序之 選擇可選為用於彼反應之標準條件。_機合成技術者 應瞭解〃子之各種部分上存在之官能度應可與所建議之 試劑及反應相容。不可與反應條件相容之取代基對熟習此 項技術者而言為明顯的，且因此指示替代方法。 用於實例之起始物質為市售的或易藉由標準方法 材料製備。在以下實例中，除非另外 ° T除非另夕卜陳迷，否則條件& 下· ⑴溫度以攝氏溫度(。〇給出；除非另外陳述，否則 操作在室溫下(RT)或環境溫度下進行，諸如在約 134079.doc •50- 200916458 1 8-25°C之範圍進行； ⑻經（例如）無水硫酸鈉或硫酸鎂乾燥溶液；有機溶 劑之有機物蒸發係使用旋轉蒸發器減壓進行(例 如’約 4.5-30 rnniHg、，f/fei l、 8)(例如）至多約6(TC之浴溫 度； (iii)層析係指矽膠急驟層蚯.佳a 〜那增斫，溥層層析（TLC)在矽膠 板上進行； ㈣—般而言’反應過程接著TLC或液相層析/質譜分 析（LC/MS) ’ 給出反應時間僅用於說明； ⑺已使用質子核磁共振（NMR)光譜及/或質譜資料分 析最終產物； (vi)、給出產量僅用於說明且不—定為可藉由不斷努力 之方法開發所獲得之彼等產量；若需要更多物 質’則可重複製備； (Vii)當給出時，核磁共振（NMR)資料呈主診斷質子之δ 值形式，以相對於作為内標準之四甲基矽烷 (TMS)之百萬分率（ppm)給出，其在3〇〇或4〇〇ΜΗζ 下，在d6-DMSO中測定； (vni)化學符號具有其在此項技術中常用之含義； (ix)溶劑比率以體積：體積（v/v)術語給出； (X) 化合物之純化可使用以下方法之一或多者進行： a) 正相矽膠急驟層析； b) 使用1sc〇 Combiflash®分離系統之矽膠急驟層析：流速 (諸如）20-80 mL/min (ISCO MPLC)之 RediSep正相急驟管 134079.doc 51 200916458 柱； C)使用Biotage®分離系統之矽膠急驟層析； d) Gilson半製備HPLC分離系統：（例如）YMC裝填〇DS_ AQ官柱，100x20 mm，S 5 μηι 12 nm，水（0.1〇/〇三氟乙酸） 及乙腈（0.1 %二氟乙酸）作為溶劑或水（含有5%乙腈之i 〇 mM乙酸銨）及乙腈，10-20 min運作；及 e) 使用標準技術之結晶或再結晶。 本文中所用之縮寫表示以下化合物、試劑及取代基：乙 酸錢（NH4〇Ac)、乙腈（MeCN)、0-(7-氮雜苯并***-1-基）_ ；V，四甲基錁六氟磷酸酯（HATU)、二異丙基乙 胺或漢格氏驗（DIPEA)、三乙胺（TEA)、二甲基乙醯胺 (DMA)、乙二醇二曱醚（DME)、***（Et20)、二曱基曱醯 胺（DMF)、二甲亞砜（DMS0)、乙醇（EtOH)、甲醇 (MeOH)、四氫呋喃（THF)、7H3-二曱基胺基丙基）-iV_乙基 碳化二醯亞胺（EDCI)、胎牛血清（FBS)、1-羥基-7-氮雜苯 并***（HOAt)、Sonic Hedgehog (shh配位體）、對硝基齡 (pNp)、磷酸鹽緩衝鹽水（pbs)、二氯甲烷或CH2C12 (DCM)、乙酸乙酯（EtOAc)、硫酸鈉（Na2S04)、硫酸鎂 (MgS04)、氫氧化鈉（NaOH)、氫氧化鋰（LiOH)、鹽酸 (HC1)、氫（h2)、碳酸鉋（Cs2C03)、碳酸鉀（K2C03)、碳酸 鈉（Na2C03)、碳酸氫鈉（NaHC03)、碳酸氫鉀（KHC03)、肆 (三苯基膦）鈀（0)lPd(PPh3)4j、氯化銨（NH4C1)、硼氫化鈉 (NaBH4)、N，N-二甲基吡啶-4-胺（DMAP)、氫氧化銨 (NH4OH)、1，2-二氯乙烧（DCE)、乙酸鉀（KOAc)、N-曱基 134079.doc •52- 200916458 吼咯啶酮（NMP)、乙酸（AcOH)、曱基-第三丁基醚 (MTBE)、偶氮二甲酸二異丙酯（DIAD)、2,2·-雙（二苯基膦 基）-1，1'-聯萘（BINAP)、參（二亞苄基丙酮）二鈀（Pd2dba3)、 [1,1，_雙（二苯基膦基）二茂鐵]二氣鈀（II)[PdCl2 (dppf)]、氫 化納（NaH)及埃化納（Nal)。 實例1 N_[4-氣-3-(l，5-二甲基-1H-咪唑-2-基）苯基]-2-曱基-6-(三氟 曱基）吡啶-3-甲醯胺 ηHedgehog path. In another embodiment, the stromal cells are fibroblasts. In one embodiment, cell proliferation, differentiation, and/or matrix microenvironment regulation are inhibited by administering a therapeutically effective amount of the drug to a subject in need thereof. "obstruction" as used herein refers to a reduction in the risk of obtaining a given disease or condition. Also disclosed is a method of treating a disease or medical condition mediated solely or partially by Hedgehog pathway inhibition, including The individual is administered a therapeutically effective amount of a compound or composition disclosed herein. In one embodiment, "treatment" refers to amelioration of a disease or condition or at least one of its discernible symptoms. In another embodiment, "Treatment" means improving at least one measurable physical parameter that the patient may not be able to discern. In another embodiment, "treatment" refers to a process that is physically (e.g., stabilizes a discernible symptom), physiologically (e.g., stabilizes a physical parameter), or physically and physiologically inhibits a disease or condition. In the example towel, "treatment" refers to delaying the onset of a disease or condition. In one embodiment, the disease or medical condition mediated solely or partially by Hedgeh〇g pathway inhibition is associated with cancer. Exemplary diseases and conditions include, but are not limited to, basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, sarcoma, lymphoma, leukemia, glioblastoma, prostate cancer, pancreatic cancer, ovarian cancer, melanoma, breast cancer Colon cancer, lung cancer, esophageal cancer, gastric cancer, biliary cancer, hepatocellular carcinoma and multiple myeloma. Accordingly, the compounds and compositions of the present invention 134079.doc -49.200916458 have antiproliferative activity, such as anticancer activity. In another embodiment, the disease or medical condition is psoriasis. In another embodiment, psoriasis can be treated by administering a compound of the invention in combination with - or a plurality of anti-psoriatic agents. In the -Example towel, the individual is characterized by having a phenotype selected from the group consisting of the following phenotypes, a PTCH function loss phenotype, a SM 〇 function obtaining phenotype, and a Hedgehog function obtaining phenotype. The following description of the examples, the procedures, the examples, and the intermediates are intended to be illustrative of the embodiments of the invention and are not intended to limit the invention in any way. The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. More specifically, the compounds of the invention can be prepared using the reactions and techniques described herein. In the description of the synthetic methods described below, it is to be understood that, unless otherwise indicated, all suggested reaction conditions, including solvent, reactive atmospheric dust, reaction temperature, duration of the experiment, and treatment options may be selected for Standard conditions for the reaction. It should be understood that the functionality present on various parts of the scorpion should be compatible with the reagents and reactions suggested. Substituents which are not compatible with the reaction conditions are apparent to those skilled in the art and thus indicate alternative methods. Starting materials for the examples are either commercially available or readily prepared by standard process materials. In the following examples, unless otherwise in addition to the conditions, the conditions & (1) temperature is given in degrees Celsius (. ;; unless otherwise stated, the operation is at room temperature (RT) or ambient temperature Carrying out, for example, in the range of about 134079.doc • 50-200916458 1 8-25 ° C; (8) drying the solution by, for example, anhydrous sodium sulfate or magnesium sulfate; organic solvent evaporation of the organic solvent is carried out under reduced pressure using a rotary evaporator ( For example, 'about 4.5-30 rnniHg,, f/fei l, 8) (for example) up to about 6 (the bath temperature of TC; (iii) chromatography refers to the catalyzed layer of ruthenium 佳. good a ~ that 斫, 溥 layer Analysis (TLC) is carried out on a silicone board; (iv) Generalally, 'reaction process followed by TLC or liquid chromatography/mass spectrometry (LC/MS)' gives the reaction time for illustration only; (7) Proton nuclear magnetic resonance has been used ( NMR) Spectroscopy and/or mass spectrometry data analysis of the final product; (vi), giving yields for illustration only and not for the production that can be obtained by continuous efforts; if more substances are needed' Repeatable preparation; (Vii) when given, nuclear magnetic resonance (NMR) data Diagnosing the δ value form of protons, given in parts per million (ppm) relative to tetramethyl decane (TMS) as an internal standard, measured at 3〇〇 or 4〇〇ΜΗζ in d6-DMSO (vni) chemical symbols have their usual meanings in the art; (ix) solvent ratios are given in terms of volume: volume (v/v); (X) purification of compounds may use one or more of the following methods Perform: a) normal phase gel chromatography; b) silica gel flash chromatography using 1 sc〇Combiflash® separation system: flow rate (such as) 20-80 mL/min (ISCO MPLC) RediSep positive phase flash tube 134079.doc 51 200916458 Column; C) Silicone flash chromatography using Biotage® separation system; d) Gilson semi-preparative HPLC separation system: (for example) YMC filled 〇DS_ AQ column, 100x20 mm, S 5 μηι 12 nm, water (0.1〇/ 〇Trifluoroacetic acid) and acetonitrile (0.1% difluoroacetic acid) as solvent or water (containing 5% acetonitrile in mM mM ammonium acetate) and acetonitrile for 10-20 min; and e) crystallization or recrystallization using standard techniques . The abbreviations used herein denote the following compounds, reagents and substituents: acetic acid (NH4〇Ac), acetonitrile (MeCN), 0-(7-azabenzotriazol-1-yl)_; V, tetramethyl Hexafluorophosphate (HATU), diisopropylethylamine or Hanges' test (DIPEA), triethylamine (TEA), dimethylacetamide (DMA), ethylene glycol dioxime (DME) , diethyl ether (Et20), dimethyl decylamine (DMF), dimethyl sulfoxide (DMS0), ethanol (EtOH), methanol (MeOH), tetrahydrofuran (THF), 7H3-didecylaminopropyl)- iV_ethylcarbodiimide (EDCI), fetal bovine serum (FBS), 1-hydroxy-7-azabenzotriazole (HOAt), Sonic Hedgehog (shh ligand), p-nitroso pNp), phosphate buffered saline (pbs), dichloromethane or CH2C12 (DCM), ethyl acetate (EtOAc), sodium sulfate (Na2S04), magnesium sulfate (MgS04), sodium hydroxide (NaOH), lithium hydroxide ( LiOH), hydrochloric acid (HC1), hydrogen (h2), carbonic acid planer (Cs2C03), potassium carbonate (K2C03), sodium carbonate (Na2C03), sodium hydrogencarbonate (NaHC03), potassium hydrogencarbonate (KHC03), hydrazine (triphenyl) Phosphine) palladium (0) lPd (PPh3) 4j, ammonium chloride (NH4C1), Sodium hydride (NaBH4), N,N-dimethylpyridin-4-amine (DMAP), ammonium hydroxide (NH4OH), 1,2-dichloroethene (DCE), potassium acetate (KOAc), N-曱Base 134079.doc •52- 200916458 Acrolidone (NMP), Acetic Acid (AcOH), Mercapto-Tertiary Butyl Ether (MTBE), Diisopropylazodicarboxylate (DIAD), 2,2·- Bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), ginseng (dibenzylideneacetone) dipalladium (Pd2dba3), [1,1,_bis(diphenylphosphino) ferrocene Iron] digas palladium (II) [PdCl2 (dppf)], sodium hydride (NaH) and enamel (Nal). Example 1 N_[4-Ga-3-(l,5-dimethyl-1H-imidazol-2-yl)phenyl]-2-indolyl-6-(trifluoromethyl)pyridine-3-carboxamidine Amine η

5-胺基-2-氯苯基_酸 在25 0 mL圓底燒瓶中添加2-氣-5-硝基苯基g朋酸（5,〇 g， 24.83 mmol)、氣化鐵（111)(8.04 g，2_48 mmol，5%於石夕膠 中）、活性碳（2.086 g，173.81 mmol)及 MeOH (124 mL)以 得到懸浮液。將反應加熱至75°C歷時20 min，之後添加耕 一水合物（9.55 g ’ 297.96 mmol)。在70°C下將反應授拌3 h。將反應混合物過濾且真空濃縮以得到粗產物，藉由 134079.doc • 53- 200916458 ISCO MPLC (10% MeOH/DCM)將其純化以得到標題化合 物（3·8 g，產率 90%)。 或者，5·胺基-2-氣苯基蝴酸可使用以下程序合成： 在500 mL圓底燒瓶中，將2-氣-5-硝基苯基_酸（1〇 〇 g， 49.66 mmol)、鐵（2.7 g，496.6 mmol)及 NH4C1 (26.6 g， 496.6 mmol)組合於EtOH (100 mL)中以得到黑色懸浮液。 用水（100 mL)稀釋反應混合物且加熱至55°C歷時〇·5 h。經 由矽膠墊過濾後，將濾液減壓濃縮以移除EtOH。將剩餘 ‘ 水性懸浮液過濾以得到呈固體之標題化合物（5·4 g，產率 640/〇)。1h NMR (DMSO-d6) δ 5.06 (s，2 H)，6.51 (dd，1 H)， 6.94 (d, 1 Η), 7.01 (d，1 H)。MS (M+H+)=172。 YB. [2-氯-5-({[2-甲基-6-(三氟甲基）吡啶-3_基]羰基》胺基) 苯基]酉明酸 在100 mL圓底燒瓶中，將5_胺基_2_氣笨基賴酸（25〇〇 g，14.59 mmol)置放於吡啶（25 mL)中以得到溶液。向溶液 添加2_甲基-6-(三氟曱基）菸鹼醯基氯（3.26 g，η.% mmol)。在RT下將反應授拌丨h。真空濃縮後，藉由ISC〇 MPLC (10% MeOH/DCM)純化粗產物以得到標題化合物 (4.5 g ’ 86%)。MS (M+H+)=359。 \C. N-[4-氯-3-(1,5-二甲基咪唑-2-基）苯基]-2-甲基·6·(三 氟甲基）吡啶-3-甲醯胺 在 20 mL 管中，將麵酸（〇. g，0.33 μιηοΐ)、Cs2C〇3 (0.22 g，0.67 μπιοί)、2_溴-is·二曱基 _1H_咪唑（〇12 g， 0·67 μιηοΐ)添加於二噁烷（8 mL)及水（2 mL)中以得到懸浮 134079.doc -54- 200916458 液。將氮鼓泡於管中歷時約15 min，之後添加Pd(PPh3)4 (0.039 g，〇,〇3 μηιοί)。在1〇〇。〇下，在微波爐中將反應混 合物加熱20 min。真空濃縮反應且隨後添加1 mL之DMSO 以溶解殘餘物。過濾後，藉由Gilson HPLC純化粗樣本以 得到標題化合物（24.7mg，18%)。1HNMR(DMSO-d6)δ 2.24 (s, 3 Η), 2.64 (s, 3 Η), 3.38 (s, 3 Η), 6.84 (s, 1 Η), 7.63 (s, 1 Η), 7.82 (s, 1 Η), 7.90 (s, 2 Η), 8.21 (s, 1 Η), 10.89 (s，1 Η)。MS (Μ+Η+)=409 〇 以下實例2-6以與實例1相似之方式，利用市售起始物質 來製備： 實例 名稱 結構 MW MS (M+H^) *HNMR (δ ppm) 2 Ν-[4-氣-3-(1-甲 基-1H-咪唑-2-基） 苯基]-2-曱基-6-(三氟甲基）°比咬-3_甲醯胺 N% 394.78 395 2.65 (m, 3 H), 3.52 (m, 3 H), 7.03 (m, 1 H), 7.33 (m, 1 H), 7.60 (m, 1 H), 7.87 (m, 3 H), 8.23 (d, 1 H), 10.88 (m, 1 H) 3 N-[3-(5-胺基11比唤-2·基)-4-亂苯基]-2-曱基_6_(三氟曱基） 比咬-3-甲醯胺 C' n^nh2 407.78 408 2.64 (m, 3 H), 6.74 (m，2 H), 7.59 (m，1 H), 7.74 (m, 1 H), 7.90 (d, 1 H), 8.01 (m, 2 H), 8.24 (m, 2 H), 10.83 (m, 1 H) 4 2-[2-氣-5-({[2-甲 基-6-(三氟甲基)〇比 咬-3-基]徵基}胺 基)苯基]-1,3-噻唾-5-曱酸甲酯 )r-〇 ° CHa 455.84 456 2.65 (s, 3 H), 3.90 (s，3 H)，7.72 (s，1 H)，7.89 (s，2 H)， 8.24 (s, 1 H), 8.67 (s，1 H)，8.86 (s，1 H), 10.97 (s, 1 H) 134079.doc -55· 200916458 實例 名稱 結構 MW MS (M+H4) ^NMR (δ ppm) 5 N-[4-氣-3-(4-甲 基-1H-咪唑-2-基） 苯基]-2-甲基-6-(三氟甲基）吡啶-3-曱醯胺 CH, Ο N^C^NH 394.78 395 2.37 (s, 3 H), 2.65 (s, 3 H)，7.62 (s，1 H), 7.78 (m, 1 H), 7.87 (m, 1 H), 7.92 (d, 1 H), 8.22 (d, 1 H)， 8.30 (d， H)， 11.19 (s, 1 H), 14.69 (s, 1 H) 6 N-[4-氣-3·(1，4-二 甲基-1Η-咪唑-2-基)苯基]-2-甲基-6-(三氟甲基)。比啶-3-甲醯胺 CH- O N^C^NH ch3 408.81 409 2.34 (s, 3 H), 2.65 (s, 3 H), 3.67 (s, 3 H), 7.62 (s, 1 H), 7.81 (m, 1 H), 7.90 (m，2 H)，8.22 (d，1 H), 8.27 (s, 1 H), 11.16 (s, 1H) 實例7 N-[4-曱基- 3-(4-甲基-1H-咪吐-2-基）苯基]_4-(2-吼咬基甲氧 基）苯曱醯胺5-Amino-2-chlorophenyl-acid Add 2-gas-5-nitrophenyl g-phenic acid (5, 〇g, 24.83 mmol), gasified iron (111) in a 25 0 mL round bottom flask (8.04 g, 2_48 mmol, 5% in Shiqi gum), activated carbon (2.086 g, 173.81 mmol) and MeOH (124 mL) to give a suspension. The reaction was heated to 75 °C for 20 min before cultivating monohydrate (9.55 g '297.96 mmol). The reaction was stirred at 70 ° C for 3 h. The reaction mixture was filtered and evaporated to dryness crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal crystal Alternatively, 5-amino-2-phenylphenyl-carboxylic acid can be synthesized using the following procedure: 2-Ga-5-nitrophenyl-acid (1 〇〇g, 49.66 mmol) in a 500 mL round bottom flask Iron (2.7 g, 496.6 mmol) and NH4C1 (26.6 g, 496.6 mmol) were combined in EtOH (100 mL) to give a black suspension. The reaction mixture was diluted with water (100 mL) and heated to 55 ° C for EtOAc. After filtration through a pad of ruthenium, the filtrate was concentrated under reduced pressure to remove EtOH. The remaining 'aqueous suspension was filtered to give the title compound as a solid (5·4 g, yield 640 / 〇). 1h NMR (DMSO-d6) δ 5.06 (s, 2 H), 6.51 (dd, 1 H), 6.94 (d, 1 Η), 7.01 (d, 1 H). MS (M+H+) = 172. Y-[2-chloro-5-({[2-methyl-6-(trifluoromethyl)pyridine-3-yl]carbonyl)amino)phenyl]decanoic acid in a 100 mL round bottom flask, 5-Amino-2-oxoic acid (25 〇〇g, 14.59 mmol) was placed in pyridine (25 mL) to give a solution. To the solution was added 2-methyl-6-(trifluoromethyl)nicotinyl chloride (3.26 g, η.% mmol). The reaction was stirred at RT. After concentrating in vacuo, EtOAc (EtOAc:EtOAc) MS (M+H+) = 359. \C. N-[4-Chloro-3-(1,5-dimethylimidazol-2-yl)phenyl]-2-methyl·6·(trifluoromethyl)pyridine-3-carboxamide In a 20 mL tube, face acid (〇.g, 0.33 μιηοΐ), Cs2C〇3 (0.22 g, 0.67 μπιοί), 2_bromo-is·dimercapto_1H_imidazole (〇12 g, 0·67) (μιηοΐ) was added to dioxane (8 mL) and water (2 mL) to give suspension 134079.doc -54 - 200916458. Nitrogen was bubbled through the tube for about 15 minutes, after which Pd(PPh3)4 (0.039 g, 〇, 〇3 μηιοί) was added. At 1〇〇. The reaction mixture was heated in a microwave oven for 20 min. The reaction was concentrated in vacuo and then 1 mL DMSO was added to dissolve residue. After filtration, the crude title was purified mjjjjjjjj 1HNMR(DMSO-d6)δ 2.24 (s, 3 Η), 2.64 (s, 3 Η), 3.38 (s, 3 Η), 6.84 (s, 1 Η), 7.63 (s, 1 Η), 7.82 (s , 1 Η), 7.90 (s, 2 Η), 8.21 (s, 1 Η), 10.89 (s, 1 Η). MS (Μ+Η+) = 409 〇 Example 2-6 below was prepared in a similar manner to Example 1 using commercially available starting materials: Example name structure MW MS (M+H^) *HNMR (δ ppm) 2 Ν-[4-Ga-3-(1-methyl-1H-imidazol-2-yl)phenyl]-2-mercapto-6-(trifluoromethyl) ° ratio bite-3_carbamamine N % 394.78 395 2.65 (m, 3 H), 3.52 (m, 3 H), 7.03 (m, 1 H), 7.33 (m, 1 H), 7.60 (m, 1 H), 7.87 (m, 3 H) , 8.23 (d, 1 H), 10.88 (m, 1 H) 3 N-[3-(5-Amino 11 ～-2·yl)-4- phenyl)-2-indenyl _6_( Trifluoromethyl) butyl 3-carbamide C' n^nh2 407.78 408 2.64 (m, 3 H), 6.74 (m, 2 H), 7.59 (m, 1 H), 7.74 (m, 1 H ), 7.90 (d, 1 H), 8.01 (m, 2 H), 8.24 (m, 2 H), 10.83 (m, 1 H) 4 2-[2-gas-5-({[2-methyl) -6-(trifluoromethyl)indole butyl-3-yl] levy}amino)phenyl]-1,3-thiasin-5-nonanoate methyl ester)r-〇°CHa 455.84 456 2.65 ( s, 3 H), 3.90 (s, 3 H), 7.72 (s, 1 H), 7.89 (s, 2 H), 8.24 (s, 1 H), 8.67 (s, 1 H), 8.86 (s, 1 H), 10.97 (s, 1 H) 134079.doc -55· 200916458 Example name structure MW MS (M+H4) ^NMR (δ ppm) 5 N-[4-Ga-3-(4-methyl- 1H-imidazole-2- Phenyl]-2-methyl-6-(trifluoromethyl)pyridine-3-decylamine CH, Ο N^C^NH 394.78 395 2.37 (s, 3 H), 2.65 (s, 3 H ), 7.62 (s, 1 H), 7.78 (m, 1 H), 7.87 (m, 1 H), 7.92 (d, 1 H), 8.22 (d, 1 H), 8.30 (d, H), 11.19 (s, 1 H), 14.69 (s, 1 H) 6 N-[4-Gas-3·(1,4-Dimethyl-1Η-imidazol-2-yl)phenyl]-2-methyl- 6-(trifluoromethyl).比 -3- 醯 醯 醯 醯 - - - - - - - - - - - 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 2. 7.81 (m, 1 H), 7.90 (m, 2 H), 8.22 (d, 1 H), 8.27 (s, 1 H), 11.16 (s, 1H) Example 7 N-[4-曱- 3- (4-methyl-1H-mito-2-yl)phenyl]_4-(2-indole methoxy)benzamide

ΊΑ. N-(4-甲基-3-(4,4,5,5-四甲基-1，3,2-二氧硼咮-2-基）苯 基）-4-(吼啶-2-基甲氧基）苯甲醯胺 在500 mL圓底燒瓶中，將4-(吡啶_2·基曱氧基）苯曱酸 (1.50 g，6.54 mmol)、4-曱基-3-(4,4,5,5-四甲基_1，3,2-二 氧删咪-2-基）苯胺（1.525 g ’ 6.54 mmol)及 DIPEA (2.286 mL，13.09 mmol)溶解於DMF (10.0 mL)中以得到棕色溶 液。將溶液冷卻至〇°C且緩慢添加HATU (2.61 g，6.87 mmol)。將反應混合物溫至尺丁後，將其再授摔i 5 h。用水 134079.doc -56- 200916458 (200 mL)稀釋反應混合物且再授拌0.5 h。藉由過渡收集固 體且用EtOAc (50 mL)洗務以得到呈白色固體之標題化合 物（2.0 g，產率 69%)。A NMR (DMS0-d6) δ 1.31 (s，12 H)， 2.43 (s, 3 Η), 5.28 (s, 2 Η), 7.14 (d, 3 Η), 7.37 (dd, 1 Η), 7.54 (d, 1 Η), 7.86 (m, 2 Η), 7.97 (m, 3 Η), 8.60 (d, 1 Η), 10.04 (s，1 H)。MS (M+H+)=445。 ΊΒ，N-[4-甲基-3-(4-甲基-1H-咪唑-2-基）苯基]-4_(2-。比咬 基甲氧基）苯曱醯胺 使用製備N-[3-(l，5-二曱基咪唑_2_基）_4_甲基-苯基]_2_曱 基-6-(二氟曱基）吡啶曱醯胺（實例57)之相似程序製備標 題化合物（產率 33%)。iH NMR (DMS〇_d6) δ 2 35 (s, 3 h)， 2.36 (s, 3 Η), 5.34 (s, 2 Η), 7.20 (m, 2 Η), 7.46 (m, 2 Η), 7.56 (s，1 H)，7.63 (d，1 H)，7.82 (dd，1 H)，7.99 (m，2 H)， 8.18 (d，1 H)，8.66 (s，1 H)，10.40 (s，！ H)，14 34 (m, i H)， 14.48 (s，1 H)。MS (M+H+)=399。 以下實例8-9以與實例7相似之方式，利用市售起始物質 來製備： 實例 名稱 結構 MW MS (Μ+ΐΓ) !h nmr ίδ DDm) 8 N-[4-甲基-3-(1-甲基-1H-咪 唑-2-基)苯基]-4-(吡啶-2-基甲 氧基)苯曱醯胺 —-— 398.46 399 2.12 (s, 3 H), 3.49 (s, 3 H), 5.28 (s, 2 H), 7.00 (s, 1 H), 7.16 (d, 2 H), 7.26 (s，1 H)，7.30 (d，1 H)， 7.37 (m, 1 H), 7.54 (d, 1 H), 7.74 (m, 2 H), 7.84 (m, 1 H), 7.95 (d, 2 H), 8.60 (d, 1 H), 10.14 (s, 1 H) 134079.doc 57- 200916458 實例 名稱 結構 MW MS (M+H4) !h nmr (δ ppm) 9 N-[3-(l，5-二甲 基-1H-味唾_2_ 基)_4-曱基苯 基]-4-(〇 比》定·2_ 基甲氧基)苯甲 醯胺 412.49 413 2.16 (s, 3 H), 2.38 (s, 3 H), 3.56 (s, 3 H), 5.34 (s, 2 H), 7.19 (d, 2 H), 7.48 (d, 2 H), 7.64 (m, 2 H), 7.85 (m, 1 H), 7.99 (d, 3 H)，8.07 (s，1 H)，8.66 (d， 1 H), 10.43 (s, 1 H), 14.51 (s, 1 H) 實例ίο N-[4-氯-3-(1 η-咪唑_2_基）苯基]-2-甲基-6-(三氟曱基）吡啶- 3-曱醯胺ΊΑ. N-(4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborin-2-yl)phenyl)-4-(acridine- 2-(Methoxymethoxy)benzamide Benzyl 4-(pyridin-2-yloxy)benzoic acid (1.50 g, 6.54 mmol), 4-mercapto-3- in a 500 mL round bottom flask (4,4,5,5-tetramethyl-1,3,2-dioxapyridin-2-yl)aniline (1.525 g ' 6.54 mmol) and DIPEA (2.286 mL, 13.09 mmol) dissolved in DMF (10.0 In mL) to give a brown solution. The solution was cooled to 〇 ° C and HATU (2.61 g, 6.87 mmol) was slowly added. After the reaction mixture was warmed to the scale, it was again given for 5 h. The reaction mixture was diluted with water 134079.doc -56- 200916458 (200 mL) and mixed for 0.5 h. The title compound (2.0 g, yield 69%) was obtained as a white solid. A NMR (DMS0-d6) δ 1.31 (s, 12 H), 2.43 (s, 3 Η), 5.28 (s, 2 Η), 7.14 (d, 3 Η), 7.37 (dd, 1 Η), 7.54 ( d, 1 Η), 7.86 (m, 2 Η), 7.97 (m, 3 Η), 8.60 (d, 1 Η), 10.04 (s, 1 H). MS (M+H+) = 445. ΊΒ, N-[4-methyl-3-(4-methyl-1H-imidazol-2-yl)phenyl]-4_(2-. butyl methoxy) benzoguanamine is used to prepare N- Preparation of a similar procedure for [3-(l,5-diamidazolyl-2-yl)_4-methyl-phenyl]_2-fluorenyl-6-(difluoroindolyl)pyridiniumamine (Example 57) The title compound (yield 33%). iH NMR (DMS〇_d6) δ 2 35 (s, 3 h), 2.36 (s, 3 Η), 5.34 (s, 2 Η), 7.20 (m, 2 Η), 7.46 (m, 2 Η), 7.56 (s,1 H), 7.63 (d,1 H), 7.82 (dd,1 H), 7.99 (m,2 H), 8.18 (d,1 H), 8.66 (s,1 H),10.40 ( s,! H), 14 34 (m, i H), 14.48 (s, 1 H). MS (M+H+) = 399. The following Examples 8-9 were prepared in a similar manner to Example 7 using commercially available starting materials: Example name structure MW MS (Μ+ΐΓ) !h nmr ίδ DDm) 8 N-[4-methyl-3-( 1-Methyl-1H-imidazol-2-yl)phenyl]-4-(pyridin-2-ylmethoxy)phenylamine--- 398.46 399 2.12 (s, 3 H), 3.49 (s, 3 H), 5.28 (s, 2 H), 7.00 (s, 1 H), 7.16 (d, 2 H), 7.26 (s, 1 H), 7.30 (d, 1 H), 7.37 (m, 1 H) ), 7.54 (d, 1 H), 7.74 (m, 2 H), 7.84 (m, 1 H), 7.95 (d, 2 H), 8.60 (d, 1 H), 10.14 (s, 1 H) 134079 .doc 57- 200916458 Example name structure MW MS (M+H4) !h nmr (δ ppm) 9 N-[3-(l,5-Dimethyl-1H-flavor salin-2-yl)_4-mercaptobenzene Base]-4-(〇比的定定·2_ methoxy)benzamide 412.49 413 2.16 (s, 3 H), 2.38 (s, 3 H), 3.56 (s, 3 H), 5.34 (s , 2 H), 7.19 (d, 2 H), 7.48 (d, 2 H), 7.64 (m, 2 H), 7.85 (m, 1 H), 7.99 (d, 3 H), 8.07 (s, 1 H), 8.66 (d, 1 H), 10.43 (s, 1 H), 14.51 (s, 1 H) Instance ίο N-[4-chloro-3-(1 η-imidazolium-2-yl)phenyl] -2-methyl-6-(trifluoromethyl)pyridine-3-decylamine

UiA. 2-(2-氣_5-硝基苯基）-1Η-咪。坐 在200 mL圓底燒瓶中添加NH4OH (12 mL，308.17 mmol) 及 氣-5-硝基苯甲醛（2·0 g，10.8 mmol)於 EtOH (12 mL)中 以得到無色懸浮液。冷卻至〇°c後，逐滴添加草醛（丨_854 mL ’ 16·17 mmol)，混合物在9〇°C在微波下加熱1 h。在用 水（40 mL)稀釋後，混合物用DCM (2x30 mL)萃取。真空濃 縮合併之有機相’且藉由ISCO MPLC (EtOAc/己烷）純化以 得到標題化合物（〇,4 g ’產率16%)。iH nmr (DMSO-d6) δ 7.17 (s，1 Η), 7·39 (s，1 Η)，7,87 (d，1 Η)，8.21 (dd，1 Η), 8.64 (d，1 Η)，12.61 (s，1 Η)。LCMS (Μ+Η+)=224。 \0它，Ν-[4-氣-3-(1 H-咪唑-2-基）苯基]-2-甲基-6-(三氟甲基) 134079.doc •58· 200916458 °比啶-3-甲醯胺 在75 mL圓底燒瓶中2-(2-氣-5-硝基苯基）-ΐη·咪唑（0.30 g，1.34 mmol)及 FeCl3 於矽膠中（0_869 g，〇_27 mm〇l)於UiA. 2-(2-Ga-5-nitrophenyl)-1Η-mi. A 200 mL round bottom flask was charged with NH.sub.4OH (12 mL, 308.17 mmol) and m.sup.5-nitrobenzaldehyde (2.0 g, 10.8 mmol) in EtOH (12 mL). After cooling to 〇 °c, oxalic acid (丨_854 mL '16·17 mmol) was added dropwise, and the mixture was heated at 9 ° C for 1 h under microwave. After diluting with water (40 mL), the mixture was extracted with DCM (2×30 mL). Concentrate in vacuo and EtOAc (EtOAc) elute iH nmr (DMSO-d6) δ 7.17 (s,1 Η), 7·39 (s,1 Η), 7,87 (d,1 Η), 8.21 (dd,1 Η), 8.64 (d,1 Η) ), 12.61 (s, 1 Η). LCMS (Μ+Η+) = 224. \0 It, Ν-[4-gas-3-(1 H-imidazol-2-yl)phenyl]-2-methyl-6-(trifluoromethyl) 134079.doc •58· 200916458 ° 3-Procarbazine in a 75 mL round bottom flask with 2-(2-Ga-5-nitrophenyl)-ΐη·imidazole (0.30 g, 1.34 mmol) and FeCl3 in silica gel (0_869 g, 〇_27) Mm〇l)

MeOH (6,71 mL)中合併，得到無色懸浮液。混合物在75。〇 加熱20 min，之後添加肼（0.972 mL，2〇 12 mm〇1)。反應 混合物再攪拌3 h。冷卻至RT後，過濾反應混合物，且真 空濃縮以得到4-氯-3-(1Η-咪唑-2-基）苯胺》該粗產物稀釋 ， 於DCM (1 mL)中以得到無色溶液。向溶液添加吡啶〇 mL)，接著添加2-甲基-6-(三氟曱基）菸鹼醯基氯〇4〇 g， 0.18 mmol)，反應混合物在RT下攪拌隔夜。真空濃縮反應 混合物’且藉由Gilson HPLC (MeCN/於水中之10 mM NH4〇Ac)純化以得到標題化合物（〇 〇25 g，產率36%)。]H NMR (DMSO-d6) δ 2.65 (s, 3 Η), 7.08 (s, 1 Η), 7.29 (s, 1 Η), 7.56 (d5 1 Η), 7.75 (dd, 1 Η), 7.90 (d, 1 H), 8.21 (m, 2 H)，10.83 (s，1 H)，12.30 (d，1 H)。LCMS (M+H+)=381。 實例11 N-[4-氣-3-(8-甲基-1，7_二氮雜雙環[4.3.0]壬 _2,4,6,8_四烯_ 9-基）笨基]-2-曱基-6-(三氟甲基）吼咬_3·曱醯胺Combined in MeOH (6,71 mL) gave a colourless suspension. The mixture is at 75.加热 Heat for 20 min, then add hydrazine (0.972 mL, 2 〇 12 mm 〇 1). The reaction mixture was stirred for a further 3 h. After cooling to RT, the reaction mixture was crystallised eluted elution elution elution elution elution To the solution was added pyridinium chloride), followed by 2-methyl-6-(trifluoromethyl)nicotinium sulfonium chloride 4, g (0.18 mmol), and the mixture was stirred at RT overnight. The reaction mixture was concentrated in vacuo <RTI ID=0.0>: </RTI> </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; ]H NMR (DMSO-d6) δ 2.65 (s, 3 Η), 7.08 (s, 1 Η), 7.29 (s, 1 Η), 7.56 (d5 1 Η), 7.75 (dd, 1 Η), 7.90 ( d, 1 H), 8.21 (m, 2 H), 10.83 (s, 1 H), 12.30 (d, 1 H). LCMS (M+H+) = 381. Example 11 N-[4-Ga-3-(8-methyl-1,7-diazabicyclo[4.3.0]壬_2,4,6,8-tetraene-9-yl) stupyl] -2-mercapto-6-(trifluoromethyl) bite _3·guanamine

\\Α· 4-氣-3-(2-曱基咪嗤并[1，2-(^]。比咬-3-基）苯胺 134079.doc -59· 200916458 在50 mL小瓶中，將5-胺基-2-氣苯基綳酸（0.15 g，0,88 mmol)、3 -溴-2-曱基咪唑并[l，2-a]吡啶（0.240 g，1.14 mmol)及 Cs2C〇3 (0.713 g，2.19 mmol)添加於二 °惡烧（4 mL) 中以得到黃色懸浮液。用水（0.80 mL)稀釋反應混合物且在 氮中鼓泡 10 min後，添加Pd(PPh3)4 (0.303 g，0.26 mmol)。 在100°C下，使用微波加熱反應20 min。減壓移除溶劑且藉 由ISCO MPLC (EtOAc/己烷）純化殘餘物以得到標題化合物 (0.11 g，產率 49%)。4 NMR (DMSO-d6) δ 2.27 (s，3 H)， 5.47 (s, 2 Η), 6.64 (d, 1 Η), 6.72 (dd, 1 Η), 6.86 (t, 1 Η), 7.24 (m，2 Η), 7.52 (m, 1 Η), 7.78 (d, 1 Η)。MS (M+H+) = 258。 \\B. N-[4-氯-3-(8-甲基-1,7-二氮雜雙環[4.3.0]壬-2,4,6,8-四烯-9-基）苯基]-2-曱基-6-(三氟甲基）吼啶-3-曱醯胺 在50 mL圓底燒瓶中，將4·氣-3-(2-曱基咪唑并[l，2-a]吡 。定-3-基）苯胺（0.104 g，0.40 mmol)溶解於吼。定（1.342 mL) 中以得到無色溶液。將溶液冷卻至〇。(：，且添加2-曱基-6-(三氟曱基）終驗醢基氯（0.09 g，0.40 mmol)。在〇°C下授拌 5 min後，減壓濃縮反應，藉由ISCO MPLC (EtOAc/DCM) 純化以得到標題化合物（0.10 g，產率60%)。NMR (DMSO-d6) δ 2.30 (s, 3 Η), 2.65 (s, 3 Η), 6.90 (t, 1 Η), 7.29 (m, 1 Η), 7.57 (d, 1 Η), 7.73 (d, 1 Η), 7.90 (m, 4 Η), 8.22 (d，1 H)，10_90 (s，1 H)。MS (M+H十) = 445。 實例12 N-[4-氣-3-(l，5-二曱基咪唑-2-基）苯基]-2-曱氧基-吡啶·3·曱醯胺 134079.doc •60- 200916458\\Α· 4-gas-3-(2-indolyl oxime [1,2-(^]. than -3-yl) aniline 134079.doc -59· 200916458 In a 50 mL vial, 5 -Amino-2-phenylphenyl decanoic acid (0.15 g, 0,88 mmol), 3-bromo-2-indolimido[l,2-a]pyridine (0.240 g, 1.14 mmol) and Cs2C〇3 (0.713 g, 2.19 mmol) was added to EtOAc (4 mL) to give a yellow suspension. The mixture was diluted with water (0.80 mL) and sifted in nitrogen for 10 min, then Pd(PPh3)4 (0.303) g, 0.26 mmol). The reaction was heated with EtOAc (EtOAc)EtOAc. 4 NMR (DMSO-d6) δ 2.27 (s, 3 H), 5.47 (s, 2 Η), 6.64 (d, 1 Η), 6.72 (dd, 1 Η), 6.86 (t, 1 Η), 7.24 (m,2 Η), 7.52 (m, 1 Η), 7.78 (d, 1 Η). MS (M+H+) = 258. \\B. N-[4-chloro-3-(8-A) 1,-diazabicyclo[4.3.0]non-2,4,6,8-tetraen-9-yl)phenyl]-2-mercapto-6-(trifluoromethyl)anthracene Pyridin-3-amine in a 50 mL round bottom flask with 4·gas-3-(2-mercaptoimidazo[l,2-a]pyridin-3-yl)aniline (0 .104 g, 0.40 mmol) was dissolved in hydrazine (1.342 mL) to give a colorless solution. The solution was cooled to hydrazine. (:, and 2-mercapto-6-(trifluoromethyl) thiol was added. Chlorine (0.09 g, 0.40 mmol), EtOAc (EtOAc) (EtOAc). (DMSO-d6) δ 2.30 (s, 3 Η), 2.65 (s, 3 Η), 6.90 (t, 1 Η), 7.29 (m, 1 Η), 7.57 (d, 1 Η), 7.73 (d, 1 Η), 7.90 (m, 4 Η), 8.22 (d, 1 H), 10_90 (s, 1 H). MS (M+H tens) = 445. Example 12 N-[4-gas-3-( l,5-Dimercaptoimidazole-2-yl)phenyl]-2-indolyloxy-pyridine·3·decylamine 134079.doc •60- 200916458

\2A. 4-氯-3-(1,5-二甲基咪唑-2-基）苯胺 在35 mL小瓶中，將5-胺基-2-氣苯基蝴酸（0.7 g，4.08 mmol)、2 -漠-1，5-二曱基-1 Η-p米 0坐（1.072 g，6.13 mmol)及 KOAc (1.203 g，12.25 mmol)置放於二 °惡烧（8 mL)以得到 黃色懸浮液。用水（2.0 mL)稀釋反應混合物且在氮中鼓泡 10 min後，添加 Pd(PPh3)4 (0.472 g，0.41 mmol) ° 在 1〇〇。。 下，使用微波加熱反應85 min。真空濃縮後，藉由ISCO MPLC (10% MeOH於DCM中）純化殘餘物以得到產物（〇.45 g，產率 50%)。NMR (DMSO-d6) δ 2.19 (s，3 H)，3.30 (s， 3 Η), 5.41 (s, 2 Η), 6.56 (d, 1 Η), 6.66 (m, 2 Η), 7.16 (d, 1 Η)。MS (Μ+Η+)=222。 Ν-[4-氯-3-(1,5-二甲基咪唑-2-基）苯基]-2-甲氧基-吼 咬-3-甲醯胺 在10 mL小瓶中，將4-氣-3-(1,5-二曱基-1H-咪唑-2-基） 笨胺（0.06 g ’ 0.27 mmol)、2-曱氧基菸鹼酸（0.27 mmol)及 HATU (0.103 g，0.27 mmol)溶解於 DMF (1.0 mL)中以得到 棕色溶液。添加HATU (0.103 g，0,27 mmol)。在RT下將反 應攪拌72 h且隨後真空濃縮。藉由Gilson HPLC (MeCN/於 水中之10 mM NH4〇Ac)純化殘餘物。濃縮所收集之溶離份 134079.doc -61- 200916458 以得到產物（0.033 g，產率 34%)。iH NMR (DMSO-d6) δ 2·23 (s，3 H)，3.35 (s，3 H)，3.97 (s，3 H)，6.77 (s，1 Η), 7.15 (dd, 1 H), 7.58 (d, 1 H), 7.87 (m, 2 H), 8.04 (dd, 1 H), 8.34 (dd，1 H)，10.43 (s，i h)。MS (M+H+) = 357。 以下實例13-22以與實例12相似之方式，利用市售起始 物質來製備： 實例 名稱 結構 MW MS (M+H+) 'hnmr (δ ppm) 13 N-[4-氣-3-(1，5_ 二甲基-1H-咪 唑-2-基)苯基]-6-曱基吡啶-3-甲醯胺 〇 n&quot;V^NH Λ ^ 341 340.81 2.23 (s, 3 H), 2.56 (s, 3 H)，3.36 (s，3 H)， 6.77 (s, 1 H), 7.43 (d，1 H)，7.59 (d，1 H), 7.91 (m, 2 H), 8.19 (dd, 1 H), 8.99 (d，1 H)，10.56 (s，1 H) 14 N-[4-氣-3-(l，5-二甲基-lH-咪 。坐-2-基)苯基]· 2-甲基吡啶-3· 曱醯胺 NH I 341 340.81 2.23 (s, 3 H), 2.56 (s, 3 H), 3.35 (s, 3 H), 6.77 (s, 1 H), 7.36 (dd, 1 H), 7.59 (d, 1 H), 7.86 (m, 3 H), 8.57 (dd, 1 H), 10.69 (s，1 H) 15 2- 氯-N-[4-氣- 3- (1，5-二甲基-1H-咪唑-2-基） 苯基]-6-曱基 吡啶-3-甲醯胺 O^NH 375 375.26 2.22 (s, 3 H), 2.50 (s, 3 H), 3.35 (s, 3 H), 6.77 (s, 1 H), 7.42 (d, 1 H), 7.59 (d, 1 H), 7.79 (m, 2 H), 7.98 (d, 1 H), 10.82 (s,lH) 16 N-[4-氣-3-(l，5-二甲基-lH-咪 峻-2-基)苯基]-6-氰基°比°定-3-甲醯胺 0 (bl -Hs Ti&gt;ch3 352 351.8 2.23 (s, 3 H), 3.36 (s, 3 H)，6.78 (s，1 H)， 7.62 (m, 1 H), 7.89 (dd, 2 H), 8.25 (d, 1 H), 8.52 (dd, 1 H), 9.22 (d，1 H)，10.87 (s, 1 H) 134079.doc • 62 - 200916458 實例 名稱 結構 MW MS (M+H， !hismr (δ ppm) 17 N-[4-氣-3-(l，5-二曱基-1H-咪 唑-2-基)苯基]-6-氟吡啶-3-曱 酿胺 N 345 344.78 2.23 (s, 3 H), 3.36 (s, 3 H), 6.78 (s, 1 H), 7,39 (dd，1 H)，7.61 (m, 1 H), 7.90 (m, 2 H)，8.50 (td，1 H)， 8.81 (s, 1 H), 10.66 (s, 1 H) 18 6-氣-N-[4-氣-3-(1，5-二甲基-1Η-»米唑-2-基) 苯基]。比啶-3-曱醯胺 ,,:0¾ (X， 361 361.23 2.23 (s, 3 H), 3.36 (s, 3 H), 6.78 (s, 1 H), 7.61 (m, 1 H), 7.73 (d, 1 H), 7.90 (m, 2 H), 8.35 (dd, 1 H), 8.95 (d, 1 H), 10.70 (s，1 H) 19 2- 氣-N-[4-氣- 3- (1,5-二曱基· 1H-咪嗤-2-基） 苯基]-6-噻吩-2-基吡啶-3-曱 醯胺 £ ycl 0人NH 443 443.36 2.23 (s, 3 H), 3.36 (s, 3 H), 6.77 (s，1 H)， 7.23 (dd, 1 H), 7.61 (d, 1 H), 7.81 (m, 3 H), 7.98 (d, 1 H), 8.08 (m，1 H), 8.15 (m, 1 H), 10.89 (s, 1 H) 20 N-[4-氯-3-(l，5-二甲基·lH-咪 唑-2-基)苯基]-4-(吡啶-2-基曱 氧基)苯甲醯胺 433 432.91 2.23 (s, 3 H), 3.36 (s, 3 H)，5.29 (s，2 H)， 6.78 (s，1 H)，7.17 (d, 2 H), 7.37 (m, 1 H), 7.55 (m, 2 H), 7.90 (m, 5 H), 8.60 (d, 1 H), 10.33 (s, 1 H) 21 N-[4-氣-3-(l，5-二曱基-lH-咪 唑-2-基)苯基]-6-嗎啉基-4-基 吡咬-3-曱醯胺 ％ 412 411.89 2.23 (s, 3 H), 3.35 (s, 3 H), 3.60 (m, 4 H), 3.70 (m, 4 H), 6.77 (s，1 H)，6,93 (d，1 H), 7.56 (d, H), 7.90 (m, 2 H), 8.10 (dd, 1 H), 8.75 (d, 1 H), 10.23 (s，1 H) 22 N-[4-氣-3-(1Η· 咪唑-2-基）苯 基]-4-( °比β定-2-基甲氧基)苯曱 醯胺 405 404.86 5.29 (s, 2 H), 7.08 (s, 1 H)，7.17 (m, 2 H)， 7.28 (s, 1 H), 7.35 (br s. 1 H)，7.53 (t，2 H)，7.85 (s，2 H)， 7.98 (m, 2 H), 8.25 (s, 1 H), 8.60 (br s, 1 H), 10.31 (s, 1 H), 12.27 (br s，1 H) 134079.doc •63- 200916458 實例23 N [4_氣·3-(ΐ，5_二曱基咪嗤_2_基）苯基]_3_甲氧基-苯曱醯胺\2A. 4-Chloro-3-(1,5-dimethylimidazol-2-yl)aniline 5-Amino-2-phenylphenyl-carboxylic acid (0.7 g, 4.08 mmol) in a 35 mL vial , 2 -Molys-1,5-dimercapto-1 Η-p m 0 sitting (1.072 g, 6.13 mmol) and KOAc (1.203 g, 12.25 mmol) were placed in 2° smoldering (8 mL) to give yellow suspension. After diluting the reaction mixture with water (2.0 mL) and bubbling in nitrogen for 10 min, Pd(PPh3)4 (0.472 g, 0.41 mmol). . Next, the reaction was heated using microwave for 85 min. After concentrating in vacuo, EtOAc EtOAc m. NMR (DMSO-d6) δ 2.19 (s, 3 H), 3.30 (s, 3 Η), 5.41 (s, 2 Η), 6.56 (d, 1 Η), 6.66 (m, 2 Η), 7.16 (d , 1 Η). MS (Μ+Η+)=222. Ν-[4-Chloro-3-(1,5-dimethylimidazol-2-yl)phenyl]-2-methoxy-bite-3-carboxamide in a 10 mL vial, 4- Gas-3-(1,5-dimercapto-1H-imidazol-2-yl) stilbene (0.06 g '0.27 mmol), 2-decyloxynicotinic acid (0.27 mmol) and HATU (0.103 g, 0.27) Methyl) was dissolved in DMF (1.0 mL) to give a brown solution. Add HATU (0.103 g, 0,27 mmol). The reaction was stirred at RT for 72 h and then concentrated in vacuo. The residue was purified by Gilson HPLC (MeCN / 10 mM NH4 EtOAc in water). The collected fractions 134079.doc -61- 200916458 were concentrated to give the product (0.033 g, yield 34%). iH NMR (DMSO-d6) δ 2·23 (s, 3 H), 3.35 (s, 3 H), 3.97 (s, 3 H), 6.77 (s, 1 Η), 7.15 (dd, 1 H), 7.58 (d, 1 H), 7.87 (m, 2 H), 8.04 (dd, 1 H), 8.34 (dd, 1 H), 10.43 (s, ih). MS (M+H+) = 357. The following Examples 13-22 were prepared in a similar manner to Example 12 using commercially available starting materials: Example name structure MW MS (M+H+) 'hnmr (δ ppm) 13 N-[4-gas-3-(1) ,5_Dimethyl-1H-imidazol-2-yl)phenyl]-6-decylpyridin-3-carboxamide 〇n&quot;V^NH Λ ^ 341 340.81 2.23 (s, 3 H), 2.56 (s , 3 H), 3.36 (s, 3 H), 6.77 (s, 1 H), 7.43 (d, 1 H), 7.59 (d, 1 H), 7.91 (m, 2 H), 8.19 (dd, 1 H), 8.99 (d, 1 H), 10.56 (s, 1 H) 14 N-[4- gas-3-(l,5-dimethyl-lH-m..sup.2-yl)phenyl] · 2-Methylpyridine-3·decalamine NH I 341 340.81 2.23 (s, 3 H), 2.56 (s, 3 H), 3.35 (s, 3 H), 6.77 (s, 1 H), 7.36 ( Dd, 1 H), 7.59 (d, 1 H), 7.86 (m, 3 H), 8.57 (dd, 1 H), 10.69 (s,1 H) 15 2-chloro-N-[4- gas-3 - (1,5-Dimethyl-1H-imidazol-2-yl)phenyl]-6-mercaptopyridine-3-carboxamide O^NH 375 375.26 2.22 (s, 3 H), 2.50 (s, 3 H), 3.35 (s, 3 H), 6.77 (s, 1 H), 7.42 (d, 1 H), 7.59 (d, 1 H), 7.79 (m, 2 H), 7.98 (d, 1 H ), 10.82 (s,lH) 16 N-[4-Ga-3-(l,5-dimethyl-lH-mio-2-yl)phenyl]-6-cyano)°° -carbamamine 0 (bl -H s Ti&gt;ch3 352 351.8 2.23 (s, 3 H), 3.36 (s, 3 H), 6.78 (s, 1 H), 7.62 (m, 1 H), 7.89 (dd, 2 H), 8.25 (d, 1 H), 8.52 (dd, 1 H), 9.22 (d,1 H), 10.87 (s, 1 H) 134079.doc • 62 - 200916458 Instance Name Structure MW MS (M+H, !hismr (δ ppm) 17 N-[4-Ga-3-(l,5-dimercapto-1H-imidazol-2-yl)phenyl]-6-fluoropyridine-3-indoleamine N 345 344.78 2.23 (s, 3 H ), 3.36 (s, 3 H), 6.78 (s, 1 H), 7,39 (dd, 1 H), 7.61 (m, 1 H), 7.90 (m, 2 H), 8.50 (td, 1 H ), 8.81 (s, 1 H), 10.66 (s, 1 H) 18 6-gas-N-[4- gas-3-(1,5-dimethyl-1Η-»misazol-2-yl) Phenyl].比 曱醯 曱醯 曱醯 ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, (d, 1 H), 7.90 (m, 2 H), 8.35 (dd, 1 H), 8.95 (d, 1 H), 10.70 (s, 1 H) 19 2- gas-N-[4- gas- 3-(1,5-dimercapto-1H-amido-2-yl)phenyl]-6-thiophen-2-ylpyridin-3-ylamine £ ycl 0 human NH 443 443.36 2.23 (s, 3 H), 3.36 (s, 3 H), 6.77 (s, 1 H), 7.23 (dd, 1 H), 7.61 (d, 1 H), 7.81 (m, 3 H), 7.98 (d, 1 H) , 8.08 (m,1 H), 8.15 (m, 1 H), 10.89 (s, 1 H) 20 N-[4-chloro-3-(l,5-dimethyl·lH-imidazol-2-yl) Phenyl]-4-(pyridin-2-yloxy)benzamide 433 432.91 2.23 (s, 3 H), 3.36 (s, 3 H), 5.29 (s, 2 H), 6.78 (s , 1 H), 7.17 (d, 2 H), 7.37 (m, 1 H), 7.55 (m, 2 H), 7.90 (m, 5 H), 8.60 (d, 1 H), 10.33 (s, 1 H) 21 N-[4-Ga-3-(l,5-dimercapto-lH-imidazol-2-yl)phenyl]-6-morpholinyl-4-ylpyridin-3-amine % 412 411.89 2.23 (s, 3 H), 3.35 (s, 3 H), 3.60 (m, 4 H), 3.70 (m, 4 H), 6.77 (s,1 H),6,93 (d,1 H), 7.56 (d, H), 7.90 (m, 2 H), 8.10 (dd, 1 H), 8.75 (d, 1 H), 10.23 (s, 1 H) 22 N-[4-Ga-3-(1Η·imidazol-2-yl)phenyl]-4-( ° ratio β-but-2-ylmethoxy)phenyl hydrazine 405 404.86 5.29 (s, 2 H), 7.08 (s, 1 H), 7.17 (m, 2 H), 7.28 (s, 1 H), 7.35 (br s. 1 H), 7.53 (t, 2 H), 7.85 (s, 2 H), 7.98 (m, 2 H), 8.25 (s, 1 H), 8.60 (br s, 1 H), 10.31 (s, 1 H), 12.27 (br s,1 H) 134079.doc •63- 200916458 Example 23 N [4_Gas-3-(ΐ,5_二曱基米嗤_2_yl)phenyl]_3_methoxy-benzoguanamine

I /10 mL小瓶中，將4_氣_3-〇心二甲基基） 本胺（0.04 mg ’ 〇，18叫〇1)溶解於MM (〇 5响中以得到 ，色溶液。將溶液冷卻至代，之後添加3_甲氧基节醯基 二（3 g ’ 018 μπι〇1)且隨後用吡咬（〇_5 稀釋反應混合 攪拌隔夜且減壓?農縮後’將殘餘物溶於DMS〇 〇机） 中且藉由Gilson HPLC (MeCN/於水中之】〇 mM NH4〇Ac)純 化以得到軚題化合物（〇.〇17 g)。(DMs〇_d6) δ 2 23 (s’ 3 Η), 3.36 (s，3 Η)，3.84 (s，3 Η)，6.77 (s，1 Η), 7.17 (dt， 1 Η), 7.46 (m, 2 Η), 7.56 (m, 2 Η), 7.92 (m, 2 Η), 10.44 (s,In a /10 mL vial, 4_gas_3-heart dimethyl group) amine (0.04 mg '〇, 18 〇1) was dissolved in MM (〇5 ring to obtain a color solution. After cooling to the next generation, add 3_methoxyoxypurinyl di(3 g ' 018 μπι〇1) and then dissolve the residue with a bite (〇_5 dilution reaction, stir and overnight, decompression, and atrophy) Purified by Gilson HPLC (MeCN/water 〇 mM NH4 〇Ac) to give the title compound (〇.〇17 g). (DMs〇_d6) δ 2 23 (s) ' 3 Η), 3.36 (s, 3 Η), 3.84 (s, 3 Η), 6.77 (s, 1 Η), 7.17 (dt, 1 Η), 7.46 (m, 2 Η), 7.56 (m, 2 Η), 7.92 (m, 2 Η), 10.44 (s,

1 H)。MS (M+H+)=356。 以下實例24-；33以與實例22相似之方式，利用市售起始 物質來製備： 實例 名稱 結構 MW MS (M+H+) *H NMR (δ ppm) 24 N-[4-氣-3-(l，5-二甲基-1H-咪 。坐-2-基）苯基]-2-氟-4-(三氟甲 基)苯甲醯胺 O^NH 411.79 412 2.23 (s, 3 Η), 3.35 (s, 3 Η), 6.77 (s，1 H)，7.61 (d, 1 H), 7.80 (m, 3 H), 7.92 (m, 2 H), 10.88 (s, 1H) 134079.doc -64- 200916458 實例 名稱 結構 MW MS (M+H, *HNMR (δ ppm) 25 N-[4-氣-3-(l，5-二甲基-lH-咪 唑-2-基）苯基]-2,3_ 二氫-1，4-苯 并二氧雜環己 烯-6-甲醯胺 TXi-CHs 383.83 384 2.23 (s, 3 H), 3.33 (s, 3 H)，4.31 (s，4 H)，6.77 (s, 1 H), 7.00 (d, 1 H), 7.53 (m，3 H)，7.91 (m， 2 H), 10.27 (s, 1 H) 26 N-[4-氯-3-(l,5-二曱基-lH-咪 唑-2-基）苯基]-6-苯氧基°比咬-3-曱醯胺 I1&gt;CH= 418.88 419 2.23 (s, 3 H), 3.35 (s, 3 H), 6.77 (s, 1 H), 7.18 (m, 3 H), 7.27 (m, 1 H), 7.46 (t, 2 H), 7.59 (m, 1 H), 7.89 (m, 2 H), 8.36 (dd，1 H), 8.71 (d，1 H)， 10.53 (s, 1 H) 27 2-氣-Ν-[4-氣-3-(1，5-二曱基-1Η-咪唑-2-基)苯基] 吡啶-3-曱醯胺 α, O^NH 361.23 361 2.22 (s, 3 H), 3.35 (s, 3 H), 6.77 (s, 1 H), 7.60 (s, 2 H), 7.80 (s, 2 H), 8.11 (s，1 H)，8.55 (s，1 H), 10.91 (s, 1 H) 28 Ν-[4-氣-3-(1，5-二甲基-1Η-咪 4-2-基）苯基] 吡啶-3-甲醯胺 0 N^^Y^NH 326.79 327 2.23 (s, 3 H), 3.36 (s, 3 H), 6.78 (s, 1 H), 7.59 (m，2 H)，7.91 (m，2 H)， 8.29 (m, 1 H), 8.78 (dd, 1 H), 9.11 (d, 1 H), 10.67 (s, 1 H) 29 Ν-[4-氣-3-(l，5-二甲基-lH-咪 。坐-2-基）苯基]-2-甲氧基苯曱 醯胺 H^-0 0 355.82 356 2.23 (s, 3 H), 3.35 (s, 3 H)，3.88 (s，3 H)，6,76 (s, 1 H), 7.06 (t, 1 H), 7.18 (d, 1 H), 7.56 (m, 3 H), 7.88 (m, 2 H), 10.35 (s, 1 H) 30 Ν-[4-氣-3-(1，5-二曱基-1Η-咪 唑-2·基）苯基]-6-(三氟甲基)口比 啶-3-曱醯胺 ；^s,. 394.78 395 2.23 (s，3 H)，3.36 (s，3 H), 6.78 (s, 1 H), 7.63 (m, 1 H), 7.91 (m, 2 H), 8.13(d，lH)，8.56(m，l H), 9.25 (s, 1 H), 10.86 (s，1 H) 31 2,6·二氣-Ν-[4-氣-3-(1，5-二曱 基-1Η-咪》坐-2-基）苯基]-5-氟 吡啶-3-曱醯胺 Cl 夺， O^NH 413.67 414 2.23 (s, 3 H), 3.35 (s, 3 H), 6.77 (s, 1 H), 7.62 (m, 1 H), 7.75 (m, 1 H), 7.82 (d, 1 H), 8.51 (d, 1 H), 11.00(s, 1H) 134079.doc •65- 200916458 實例 名稱 結構 MW MS (m+hT) !hnmr (δ ppm) 32 Ν-[4-氣-3-(l，5-二甲基-lH-咪 唑-2-基）笨基]-2,3-二甲氧基笨 甲醯胺 CC：- 。人 NhfH3 ά,Γ3 ΤΧ/Ά 385.85 386 2.23 (s, 3 H), 3.35 (s, 3 H), 3.79 (s, 3 H), 3.85 (s, 3 H), 6.77 (s, 1 H), 7.09 (m, 1 H), 7.19 (m, 2 H), 7.56 (d, 1 H), 7.84 (m, 2 H), 10.50 (s, 1 H) 33 Ν-[4-氣-3-(l，5-二甲基-lH-咪 °坐-2-基）苯基]-3,5-二甲氧基苯 曱醯胺 ο Η^ΟγΎ^ΝΗ Cl 385.85 386 2.23 (s, 3 H), 3.36 (s, 3 H), 3.82 (s, 6 H), 6.74 (m, 2 H), 7.10 (d, 2 H), 7.58 (d, 1 H), 7.91 (m, 2 H), 10.39 (s, 1H) 實例34 N-[4-氣-3-(l，5-二曱基咪唑_2-基）苯基]-6-[4-(2-羥基乙基） 哌嗪-1-基]吡啶-3-甲醯胺1 H). MS (M+H+) = 356. The following Examples 24-33 were prepared in a similar manner to Example 22 using commercially available starting materials: </ RTI> </ RTI> </ RTI> MW MS (M+H+) *H NMR (δ ppm) 24 N-[4-gas-3- (l,5-Dimethyl-1H-methanol. sit-2-yl)phenyl]-2-fluoro-4-(trifluoromethyl)benzamide M^ 411.79 412 2.23 (s, 3 Η ), 3.35 (s, 3 Η), 6.77 (s, 1 H), 7.61 (d, 1 H), 7.80 (m, 3 H), 7.92 (m, 2 H), 10.88 (s, 1H) 134079. Doc -64- 200916458 Example name structure MW MS (M+H, *HNMR (δ ppm) 25 N-[4- gas-3-(l,5-dimethyl-lH-imidazol-2-yl)phenyl ]-2,3_ Dihydro-1,4-benzodioxan-6-carboxamide TXi-CHs 383.83 384 2.23 (s, 3 H), 3.33 (s, 3 H), 4.31 (s , 4 H), 6.77 (s, 1 H), 7.00 (d, 1 H), 7.53 (m, 3 H), 7.91 (m, 2 H), 10.27 (s, 1 H) 26 N-[4- Chloro-3-(l,5-dimercapto-lH-imidazol-2-yl)phenyl]-6-phenoxy ° ratio 曱醯-3-decylamine I1&gt;CH=418.88 419 2.23 (s, 3 H), 3.35 (s, 3 H), 6.77 (s, 1 H), 7.18 (m, 3 H), 7.27 (m, 1 H), 7.46 (t, 2 H), 7.59 (m, 1 H) , 7.89 (m, 2 H), 8.36 (dd,1 H), 8.71 (d,1 H), 10.53 (s, 1 H) 27 2-Qi-Ν-[4-气-3- (1,5-dimercapto-1Η-imidazol-2-yl)phenyl]pyridin-3-decylamine α, O^NH 361.23 361 2.22 (s, 3 H), 3.35 (s, 3 H), 6.77 (s, 1 H), 7.60 (s, 2 H), 7.80 (s, 2 H), 8.11 (s, 1 H), 8.55 (s, 1 H), 10.91 (s, 1 H) 28 Ν- [4-Gas-3-(1,5-dimethyl-1Η-amido-4-enyl)phenyl]pyridin-3-carboxamide 0 N^^Y^NH 326.79 327 2.23 (s, 3 H ), 3.36 (s, 3 H), 6.78 (s, 1 H), 7.59 (m, 2 H), 7.91 (m, 2 H), 8.29 (m, 1 H), 8.78 (dd, 1 H), 9.11 (d, 1 H), 10.67 (s, 1 H) 29 Ν-[4- gas-3-(l,5-dimethyl-lH-mi. Sodium-2-yl)phenyl]-2-methoxybenzamine H^-0 0 355.82 356 2.23 (s, 3 H), 3.35 (s, 3 H), 3.88 (s, 3 H), 6,76 (s, 1 H), 7.06 (t, 1 H), 7.18 (d, 1 H), 7.56 (m, 3 H), 7.88 (m, 2 H), 10.35 (s, 1 H) 30 Ν-[4-Ga-3-(1,5-dimercapto-1Η-imidazole-2.yl)phenyl]-6-(trifluoromethyl)-p-pyridin-3-ylamine; , 394.78 395 2.23 (s,3 H), 3.36 (s,3 H), 6.78 (s, 1 H), 7.63 (m, 1 H), 7.91 (m, 2 H), 8.13 (d, lH) , 8.56 (m, l H), 9.25 (s, 1 H), 10.86 (s, 1 H) 31 2,6·digas-Ν-[4-gas-3-(1,5-dimercapto- 1Η-咪》坐-2-yl)phenyl]-5-fluoropyridin-3-indoleamine Cl, O^NH 413.67 414 2.23 (s, 3 H), 3.35 (s, 3 H), 6.77 ( s, 1 H), 7.62 (m, 1 H), 7.75 (m, 1 H), 7.82 (d, 1 H), 8.51 (d, 1 H), 11.00(s, 1H) 134079.doc •65- 200916458 Instance name structure MW MS (m+hT) !hnmr (δ ppm) 32 Ν-[4-gas-3-(l,5-dimethyl-lH-imidazol-2-yl)phenyl]-2, 3-Dimethoxybenzamide A: CC:-. Human NhfH3 ά, Γ3 ΤΧ/Ά 385.85 386 2.23 (s, 3 H), 3.35 (s, 3 H), 3.79 (s, 3 H), 3.85 (s, 3 H), 6.77 (s, 1 H), 7.09 (m, 1 H), 7.19 (m, 2 H), 7.56 (d, 1 H), 7.84 (m, 2 H), 10.50 (s, 1 H) 33 Ν-[4-gas-3-( l,5-Dimethyl-lH-miso-2-yl)phenyl]-3,5-dimethoxybenzamine ο Η^ΟγΎ^ΝΗ Cl 385.85 386 2.23 (s, 3 H) , 3.36 (s, 3 H), 3.82 (s, 6 H), 6.74 (m, 2 H), 7.10 (d, 2 H), 7.58 (d, 1 H), 7.91 (m, 2 H), 10.39 (s, 1H) Example 34 N-[4-Ga-3-(l,5-diamidazolyl-2-yl)phenyl]-6-[4-(2-hydroxyethyl)piperazine-1 -yl]pyridine-3-carboxamide

在10 mL小瓶中，將6-氣-N-(4-氯-3-(1,5-二曱基-1H-味 嗤-2-基）苯基）終鹼醯胺（0.15 g，0,42 mmol)及2-(派嗪_ι_ 基）乙醇（0.271 g，2.08 mmol)組合於DME (2.0 mL)以得到 白色懸浮液。在9〇它下將反應攪拌隔夜。真空濃縮後，藉 由Gilson HPLC (MeCN/於水中之1〇 mM NH4OAc)純化殘餘 物以得到標題化合物（0.062 g，33%)。4 NMR CDMS〇_d6；) δ 2.23 (s, 3 Η), 2.43 (t, 2 Η), 2.52 (s, 4 Η), 3.35 (s, 3 Η), 3.54 (t，2 Η)，3.62 (m，4 Η)，4.46 (s，1 Η)，6.77 (s，1 Η)， 6.91 (d，1 Η)，7.55 (d，1 Η)，7.89 (m，2 Η)，8.06 (dd，1 η)， 134079.doc -66 - 200916458 8.72 (d，1 H)，10.20 (S，1 H)。MS (M+H+)=455。 以下實例35-44以與實例34相似之方式，利用市售起始 物質來製備： 實例 名稱In a 10 mL vial, 6-gas-N-(4-chloro-3-(1,5-dimercapto-1H-miso-2-yl)phenyl) decylamine (0.15 g, 0) , 42 mmol) and 2-(Pyridazinium iodo)ethanol (0.271 g, 2.08 mmol) were combined in DME (2.0 mL) to give a white suspension. The reaction was stirred overnight at 9 Torr. After concentrating in vacuo, EtOAc EtOAc m. 4 NMR CDMS〇_d6;) δ 2.23 (s, 3 Η), 2.43 (t, 2 Η), 2.52 (s, 4 Η), 3.35 (s, 3 Η), 3.54 (t, 2 Η), 3.62 (m,4 Η), 4.46 (s,1 Η), 6.77 (s,1 Η), 6.91 (d,1 Η), 7.55 (d,1 Η), 7.89 (m,2 Η), 8.06 (dd , 1 η), 134079.doc -66 - 200916458 8.72 (d, 1 H), 10.20 (S, 1 H). MS (M+H+) = 455. The following Examples 35-44 were prepared in a similar manner to Example 34 using commercially available starting materials: Example Name

MW MS (M+H+) Ή NMR (θ ppm) N-[4-氣-3-(l，5-二 甲基-1H-咪唑-2-基）苯基]-6-[4-(環 丙基曱基)哌嗪-1-基]吡啶-3-曱醯胺 35 yj.w (m, z Η), 〇.48 (m，2 H)，0.85 (m，1 H), 2.23 (m, 5 H), 2.53 (m, 4H), 3.35 (s, 465 465 1 H)，3·63 (m，4 H)， 6.77 (s，1 H)，6.92 (d， 1 H), 7.55 (d, 1 H), 7.89 (m, 2 H), 8.06 (m, 1 H), 8.72 (m, 1 H), 10.20 (s, 1 H) 36 N-[4-氣-3-(l，5-二 甲基-1H-咪唑-2-基）苯基]-6-[4-(&quot;比 啶-2-基曱基）哌 嗪-1-基]吡啶-3-甲 醯胺 02 02· aH)GH).52tl.l，H)(dH) ο 7 7 m 1 ·53·7， ，ί251 2· ? 6* Μ' 8 8·， H),5(sH)5fH7.7㈣H),3(s印 3.366.，«)91.71， s，3 s，，(dH.8d，8 G (x(^ 2 7 (xo 3 H 5 H 9 15 7 H 2 2 16 2 w X o LI λ 2 4 3 17 H 8 37 Ν-[4·氣-3-(1,5-二 甲基-1Η-°米》坐-2-基）苯基]-6-{4-[2-(二曱基胺基）乙 基]°底。秦-1-基} °比 啶-3-曱醯胺 482.03 482 0H3 2.15 (s，6 H)，2.23 (s， 3 H), 2.41 (m, 4 H), 2.48 (m, 4 H), 3.35 (s, 3 H)，3.61 (m，4 H)， 6.77 (s，1 H)，6.91 (d， 1 H), 7.55 (d, 1 H), 7.90 (m, 2 H)，8.06 (d, 1H), 8.72(8,1¾ 10.21 (s, 1 H) 38 Ν-[4-氣-3-(1,5-二 甲基-1Η-咪唑-2-基）苯基]-6-(4-甲 基派嗓-1-基）0比 啶-3-曱醯胺MW MS (M+H+) Ή NMR (θ ppm) N-[4- gas-3-(l,5-dimethyl-1H-imidazol-2-yl)phenyl]-6-[4-(cyclo Propyl hydrazino) piperazin-1-yl]pyridine-3-decylamine 35 yj.w (m, z Η), 〇.48 (m, 2 H), 0.85 (m, 1 H), 2.23 ( m, 5 H), 2.53 (m, 4H), 3.35 (s, 465 465 1 H), 3·63 (m, 4 H), 6.77 (s, 1 H), 6.92 (d, 1 H), 7.55 (d, 1 H), 7.89 (m, 2 H), 8.06 (m, 1 H), 8.72 (m, 1 H), 10.20 (s, 1 H) 36 N-[4-gas-3-(l ,5-Dimethyl-1H-imidazol-2-yl)phenyl]-6-[4-(&quot;bipyridin-2-ylindenyl)piperazin-1-yl]pyridine-3-carboxamide 02 02· aH)GH).52tl.l,H)(dH) ο 7 7 m 1 ·53·7, ,ί251 2· ? 6* Μ' 8 8·, H),5(sH)5fH7.7(4)H ), 3 (sprint 3.366., «) 91.71, s, 3 s,, (dH.8d, 8 G (x(^ 2 7 (xo 3 H 5 H 9 15 7 H 2 2 16 2 w X o LI λ 2 4 3 17 H 8 37 Ν-[4·gas-3-(1,5-dimethyl-1Η-°米) sit-2-yl)phenyl]-6-{4-[2-( Dimethylamino)ethyl]° bottom. Qin-1-yl} ° pyridine-3-meramine 482.03 482 0H3 2.15 (s,6 H), 2.23 (s, 3 H), 2.41 (m, 4 H), 2.48 (m, 4 H), 3.35 (s, 3 H), 3.61 (m, 4 H), 6.77 (s, 1 H), 6.91 (d 1 H), 7.55 (d, 1 H), 7.90 (m, 2 H), 8.06 (d, 1H), 8.72 (8,13⁄4 10.21 (s, 1 H) 38 Ν-[4-gas-3-( 1,5-Dimethyl-1Η-imidazol-2-yl)phenyl]-6-(4-methylpyridin-1-yl)0-pyridin-3-indoleamine

424.93 425 2.37 (s，3 H), 2.84 (s， H), 3.0-3.15 (m, 2 Η), 3.15-3.35 (m, 2 Η), 3.48 (m, 4 Η), 3.57 (s, 3 Η), 4.60 (m, Η), 7.06 (d, 1 Η), 7.65 (s，1 Η), 7.76 (d， 1 Η)，7.97 (dd，1 Η)， 8.15 (dd, 1 Η), 8.24 (d, 1 Η), 8.77 (d, 1 Η) 134079.doc -61· 200916458 實例 名稱 結構 MW MS (M+H+) *HNMR (δ ppm) 39 N-[4-氣-3-(1,5-二 曱基-1H-咪唑-2-基）笨基]-6-{[2-(二甲基胺基）乙 基](甲基)胺基}&quot;比 啶-3-甲醯胺 426.95 427 2.38 (s, 3 H), 2.85 (s, 6 H), 3.07 (s, 3 H), 3.32 (dd，2 H)，3.59 (s，3 H)，3.98 (dd, 2 H), 6.78 (d, 1 H), 7.65 (s, 1 H), 7.74 (d, 1 H), 7.97 (dd, 1 H), 8.12 (dd, 1 H), 8.23 (d, 1 H), 8.74 (d, 1 H), 10.5 (s, 1 H) 40 N-[4-氣-3-(1,5-二 甲基-1H-&quot;米峻-2-基）笨基]-6-[(2-嗎 琳-4-基乙基）胺 基]吡啶-3-曱醯胺 Cl M 454.96 455 2.35 (s，3 H)，3.31 (m， 6 H), 3.57 (s, 3 H), 3.71 (m, 2 H), 3.84 (m, 4 H), 6.62 (d, 1 H), 7.63 (s, 1 H), 7.74 (d, 1 H), 7.97 (m, 2 H), 8.23 (s, 1 H), 8.74 (s, 1 H), 10.5 (s, 1 H) 41 N-[4-氣-3-(1,5-二 甲基-1H-咪唑-2-基）苯基]-6-[(2-羥 基乙基）胺基]D比 啶-3-曱醯胺 Cl 385.85 386 2.36 (s, 3 H), 2.83 (br s, 1 H), 3.32-3.56 (m, 5 H), 3.57 (s, 3 H), 6.78 (d, 1 H), 7.64 (s, 1 H), 7.75 (d, 1 H), 7.94 (dd, 1 H), 8.02 (dd, 1 H), 8.21 (s, 1 H), 8.58 (s, 1 H), 10.5 (s, 1 H) 42 N-[4-氣-3-(1,5-二曱基-1H-咪唑-2-基）苯基]-6-»底 嗪-1-基吡啶-3-曱醯胺 ο ΗνΟ ^ ci N-y 410.91 411 2.01 (s, 3 H)，3.14 (m， 4 H), 3.58 (s, 3 H), 3.91 (m，4 H)，7.06 (d, 1 H), 7.67 (s, 1 H), 7.15 (d, 1 H), 8.11 (dd, 1 H), 8.30 (m, 2 H), 8.84 (d, 1 H) 43 N-[4-氣-3-(l，5-二 曱基-1H-咪唑-2-基）苯基]-6-{[2-(二甲基胺基）乙 基]胺基}D比啶-3-甲醯胺 0 ch3 n^V^nh 412.92 413 2.37 (s, 3 H), 2.82 (s, 6 H), 3.26 (m, 2 H), 3.57 (s, 3 H), 3.65 (m, 2 H), 6.62 (d, 1 H), 7.58 (m, 1 H), 7.65 (s, 1 H), 7.75 (d, 1 H), 7.97 (m, 2 H), 8.22 (d, 1 H), 8.68 (d, 1 H), 10.48 (s, 1 H) 134079.doc -68- 200916458 實例 名稱 結構 MW MS (M+H+) 1hnS (δ ppm、 44 N-[4-氯·3-(l，5-二甲基-lH-咪唑-2-基）苯基]-6-({[(2S)-1-乙基&quot;比 咯啶-2-基]甲基} 胺基）吡啶-3-甲 醞胺 2 對掌性 452.99 453424.93 425 2.37 (s,3 H), 2.84 (s, H), 3.0-3.15 (m, 2 Η), 3.15-3.35 (m, 2 Η), 3.48 (m, 4 Η), 3.57 (s, 3 Η), 4.60 (m, Η), 7.06 (d, 1 Η), 7.65 (s, 1 Η), 7.76 (d, 1 Η), 7.97 (dd, 1 Η), 8.15 (dd, 1 Η), 8.24 (d, 1 Η), 8.77 (d, 1 Η) 134079.doc -61· 200916458 Example name structure MW MS (M+H+) *HNMR (δ ppm) 39 N-[4-gas-3-(1 ,5-dimercapto-1H-imidazol-2-yl)phenyl]-6-{[2-(dimethylamino)ethyl](methyl)amino}&quot;醯amine 426.95 427 2.38 (s, 3 H), 2.85 (s, 6 H), 3.07 (s, 3 H), 3.32 (dd, 2 H), 3.59 (s, 3 H), 3.98 (dd, 2 H ), 6.78 (d, 1 H), 7.65 (s, 1 H), 7.74 (d, 1 H), 7.97 (dd, 1 H), 8.12 (dd, 1 H), 8.23 (d, 1 H), 8.74 (d, 1 H), 10.5 (s, 1 H) 40 N-[4-Ga-3-(1,5-Dimethyl-1H-&quot;米峻-2-yl) Stupid]-6 -[(2-Methyl-4-ylethyl)amino]pyridin-3-ylamine Cl M 454.96 455 2.35 (s,3 H), 3.31 (m, 6 H), 3.57 (s, 3 H ), 3.71 (m, 2 H), 3.84 (m, 4 H), 6.62 (d, 1 H), 7.63 (s, 1 H), 7.74 (d, 1 H), 7.97 (m, 2 H), 8.23 (s, 1 H), 8.74 (s, 1 H), 10.5 (s, 1 H 41 N-[4-Ga-3-(1,5-dimethyl-1H-imidazol-2-yl)phenyl]-6-[(2-hydroxyethyl)amino]D-pyridin-3 - guanamine Cl 385.85 386 2.36 (s, 3 H), 2.83 (br s, 1 H), 3.32-3.56 (m, 5 H), 3.57 (s, 3 H), 6.78 (d, 1 H), 7.64 (s, 1 H), 7.75 (d, 1 H), 7.94 (dd, 1 H), 8.02 (dd, 1 H), 8.21 (s, 1 H), 8.58 (s, 1 H), 10.5 ( s, 1 H) 42 N-[4-Ga-3-(1,5-dimercapto-1H-imidazol-2-yl)phenyl]-6-»-endazin-1-ylpyridine-3-indole醯 ο ο ΟνΟ ^ ci Ny 410.91 411 2.01 (s, 3 H), 3.14 (m, 4 H), 3.58 (s, 3 H), 3.91 (m, 4 H), 7.06 (d, 1 H), 7.67 (s, 1 H), 7.15 (d, 1 H), 8.11 (dd, 1 H), 8.30 (m, 2 H), 8.84 (d, 1 H) 43 N-[4- gas-3-(l ,5-dimercapto-1H-imidazol-2-yl)phenyl]-6-{[2-(dimethylamino)ethyl]amino}D-pyridyl-3-carboxamide 0 ch3 n ^V^nh 412.92 413 2.37 (s, 3 H), 2.82 (s, 6 H), 3.26 (m, 2 H), 3.57 (s, 3 H), 3.65 (m, 2 H), 6.62 (d, 1 H), 7.58 (m, 1 H), 7.65 (s, 1 H), 7.75 (d, 1 H), 7.97 (m, 2 H), 8.22 (d, 1 H), 8.68 (d, 1 H ), 10.48 (s, 1 H) 134079.doc -68- 200916458 Example name structure MW MS (M+H+) 1hnS (δ ppm 44 N-[4-Chloro-3-(l,5-dimethyl-lH-imidazol-2-yl)phenyl]-6-({[(2S)-1-ethyl&quot;biridine- 2-yl]methyl}amino)pyridine-3-carboxamide 2 to palmity 452.99 453

'—J 實例45 N-[4_氣- 3_(1，5_二曱基-111-咪°坐-2-基）苯基]-6-(2_甲基丙氧 基）吡啶-3-甲醯胺'—J Example 45 N-[4_Gas- 3_(1,5-dimercapto-111-m-yt-2-yl)phenyl]-6-(2-methylpropoxy)pyridine-3 -Procarbamide

在10 mL小瓶中，將6·氣-N-(4-氣-3-(1，5·二曱基-1H-味 唑-2-基）苯基）菸鹼醯胺（〇·ΐ2 mg，〇·33 μιηοΐ)、2-曱基丙_ 1-醇（0.148 g，1.99 μηιοί)及第三丁 氧化鈉（〇 383 mg，3 % μπιοί)添加於t-BuOH (3 mL)中以得到白色懸浮液。在95乞 下將反應攪拌隔夜。冷卻至RT後，用水（15 mL)&amp;DCM (15 mL)稀釋混合物。ffiDCM (2χ1〇 mL)萃取水層，且真空 濃縮所組合之有機層。藉由Gils〇n HpLC (MeCN/於水中之 10 mM 化粗產物以得到標題化合物（〇〇43 g， ^ ^ 32〇/〇) 〇 Ή NMR (DMSO-d6) δ 0.98 (d, 6 Η), 2.06 (m, 1 H),2.23 ^3Η),3.35(853Η),4.12(ά,2Η),6.77(δ51Η), 6.96 (d, 1 H), 7.59 (m, 1 H), 7.90 (m, 2 H), 8.22 (dd, 1 H)! 134079.doc -69- 200916458 8.76 (d，1 Η), 10.45 (s，1 Η)。MS (M+H+)=399。 以下實例46-56以與實例45相似之方式，利用市售起始 物質來製備： 實例 名稱 結構 MW MS (M+H^ 'hnmr (δ ppm) 46 N-[4-氣-3-(l，5-二甲基-lH-咪 唑-2-基）苯基]-6-[2-(二甲基胺 基）乙氧基]»比 啶-3-甲醯胺 ?H3 〇 Η3&quot;^〇〇λ TX/-CH^ 413.91 414 2.20 (s, 6 H), 2.23 (s, 3 H), 2.63 (t, 2 H), 3.35 (s, 3 H), 4.42 (t, 2 H), 6.77 (s, 1 H), 6.95 (d, 1 H), 7.59 (m, 1 H), 7.90 (m, 2 H), 8.22 (dd, 1 H), 8.77 (d, 1 H), 10.45 (s，1 H) 47 N-[4-氣-3-(l，5-二曱基-lH-咪 嗤-2-基）笨基]-6-[(1-甲基哌啶-4-基）甲氧基]&quot;比 啶-3-甲醯胺 rf°^^{rCH3 H〆 453.97 454 1.31 (s, 2 H), 1.71 (m, 3 H), 1.85 (m, 2 H), 2.14 (s, 3 H), 2.23 (s, 3 H), 2.77 (d, 2 H), 3.35 (s, 3 H), 4.19 (d, 2 H), 6.77 (s, 1 H), 6.95 (d，1 H)，7.58 (d，1 H)，7.89 (m，2 H)， 8.22 (dd, 1 H), 8.76 (d, 1 H), 10.45 (s, 1 H) 48 N-[4-氣-3-(1,5-二曱基-1H-咪 唑-2-基）苯基]-6-[3-(二己基胺 基）丙氧基]0比 啶-3-曱醯胺 455.99 456 0.94 (m, 6 H), 1.87 (m, 2 H), 2.23 (s, 3 H), 2.44 (m, 6 H), 3.36 (s, 3 H), 4.36 (t, 2 H)，6.77 (s，1 H)， 6.94 (d, 1 H), 7.58 (d, 1 H), 7.90 (m, 2 H), 8.22 (d, 1 H), 8.76 (s, 1 H), 10.46 (br s, 1 H) 134079.doc 70· 200916458 實例 ___名稱 結構 MW MS (M+H+) ^NMR (δ ppm) 49 N'[4-^-3-(1,5-二甲基-1H-咪 基)苯基]· 6-{[(2S)-l-甲 基· °比咯啶-2-基]甲氧基}。比 甲醞胺 Cl ^ 439.94 440 1.66 (m, 3 H), 1.93 (m, 1 H), 2.17 (m, 1 H), 2.23 (s, 3 H), 2.35 (s, 3 H), 2.54 (m, 1 H), 2.95 (ddd, 1 H), 3.35 (s, 3 H), 4.22 (m, 1 H), 4.34 (m, 1 H), 6.77 (s, 1 H)，6.95 (d，1 H), 7.58 (m, 1 H), 7.91 (m, 2 H), 8.22 (dd, 1 H), 8.77 (d, 1 H), 10.46 (s, 1 H) 50 Ν·[4-氣-3-(1，5-—甲基-1Η_咪 唑-2-基）笨基]_ 6_[(^氣基苄 基）氧基]吼。定-3-甲酿胺 Cl N 457.92 458 2.23 (s, 3 H), 3.36 (s, 3 H)，5.50 (s，2 H)， 6.78 (s, 1 H), 7.08 (d, 1 H), 7.61 (m, 2 H), 7.82 (d, 2 H), 7.90 (m, 2 H), 7.95 (s, 1 H), 8.27 (dd, 1 H), 8.78 (d, 1 H), 10.48 (s, 1 H) 51 Ν-[4·氣·3-(l，5· 二甲基-lH-咪 °坐-2-基)笨基]_6_ [(1-甲基哌啶-2-基)甲氧基]°比啶-3-甲醯胺 〇 453.97 454 1.31 (m, 1 H) 1.37 (dd, 1 H) 1.42-1.55 (m，2 H) 1.62-1,78 (m, 2 H) 2.02 (td, 1 H) 2.19 (m, 1 H) 2.24 (s, 6 H) 2.67-2.84 (m，1 H) 3.36 (s, 3 H) 4.28-4.47 (m, 2 H) 6.78 (s，1 H) 6.96 (d，1 H) 7.58 (d, 1 H) 7.88 (s, 1 H) 7.91 (m, 1 H) 8.22 (dd, 1 H) 8.77 (d, 1 H) 10.45 (s, 1 H) 52 Ν-[4-氣-3-(l，5-二甲基-lH-咪 唑-2-基)苯基]-6-(2-嗎啉-4-基乙 氧基）吡啶-3-曱 醯胺 ο ν^ι^νη ο〜。/紅 455.94 456 2.21 (s, 3 H), 2.45 (m, 4 H), 2.69 (t, 2 H), 3.43 (s, 3 H), 3.55 (m, 4 H), 4.45 (t, 2 H), 6.76 (d, 1 H), 6.94 (d, 1 H), 7.56 (dd, 1 H), 7.87 (m, 2 H), 8.21 (dd, 1 H)，8.75 (d, 1 H)， 10.45 (s, 1 H) 134079.doc -71 · 200916458 實例 名稱 結構 MW MS (M+H^ !hnmr (δ ppm) 53 Ν-[4-氯-3-(l，5-二甲基-lH-咪 唑-2-基）苯基]- 6-(2-11 比 口各0定-1 - 基乙乳基)°比0定-3-甲醯胺 0 N^V^NH 〇〜。^私3 439.94 440 1.88 (m, 2 H), 1.99 (m, 2 H), 2.36 (s, 3 H), 3.10 (m, 4 H)， 3.56 (s，3 H)，3.60 (m, 2 H), 4.63 (m, 2 H), 6.99 (d, 1 H), 7.61 (s, 1 H), 7.76 (m, 1 H), 7.97 (m, 1 H), 8.22 (m, 1 H), 8.29 (dd, 1 H), 8.80 (d, 1 H) 10.8 (s, 1 H) 54 N-[4-氯-3_(1，5-二曱基-1H-咪 唑-2-基）苯基]-6-[(1-曱基哌啶-3-基）甲氧基]吼 啶-3-甲醯胺 ch3 453.97 454 1.27 (m, 1 H), 1.70 (m, 1 H), 1.85 (m, 2 H), 2.31 (s, 3 H), 2.78 (s, 3 H), 2.84 (m, 2 H), 3.43 (m, 3 H), 3.57 (s, 3 H), 4.26 (m, 2 H), 6.97 (d, 1 H), 7.66 (m, 1 H), 7.77 (d, 1 H), 7.98 (d, 1 H), 8.26 (d，2 H)，8.78 (s，1 H), 10.78 (s, 1 H) 55 N-[4-氣-3-(l，5-二曱基-m-咪 嗤-2-基）苯基]-6-{[(2R)-l-曱 基0比洛β定-2-基]曱氧基}°比 啶-3-曱醯胺 0 對掌性 439.95 440 - 56 Ν-(4-氯-3-(l，5-二甲基-lH-咪 。坐-2-基）苯基)-6-((1-甲基吼咯 啶-3-基）甲氧 基)菸鹼醯胺 〇 XT)^CH3 439.95 440 14.92 (br s，1 H)， 11.04 (d, 1 H), 8.84 (dd, 1 H), 8.22-8.38 (m, 2 H), 8.01-8.15 (m，1 H), 7.72 (d，1 H), 7.62 (s, 1 H)， 6.83-7.07 (m, 1 H), 4.23-4.47 (m, 2 H), 3.49-3.69 (m, 5 H), 3.28-3.49 (m, 2 H), 3.06=3.22 (m, 1 H), 2.96 (d, 1 H), 2.82 (d, 1 H), 2.73 (dd, 3 H)，2.33 (s, 3 H)， 2.13-2.28 (m，1 H), 1.51-1.79 (m, 1 H) 134079.doc -72· 200916458 實例57 N-[3-(l，5-二曱基_唾·2·基）_4_甲基_苯基]2_甲基_6《三氟 甲基）吡啶-3-曱醯胺In a 10 mL vial, 6·gas-N-(4-gas-3-(1,5·didecyl-1H-isoazol-2-yl)phenyl)nicotinamide (〇·ΐ2 mg) , 〇·33 μιηοΐ), 2-mercaptopropen-1-ol (0.148 g, 1.99 μηιοί) and sodium tributoxide (〇383 mg, 3 % μπιοί) were added to t-BuOH (3 mL) to obtain White suspension. The reaction was stirred overnight at 95 Torr. After cooling to RT, the mixture was diluted with water (15 mL) &amp;DCM (15 mL). The aqueous layer was extracted with ffiDCM (2 χ 1 〇 mL), and the combined organic layers were concentrated in vacuo. The title compound (〇〇43 g, ^^32〇/〇) 〇Ή NMR (DMSO-d6) δ 0.98 (d, 6 Η) was obtained by Gils 〇n HpLC (MeCN/10 mM crude product in water). , 2.06 (m, 1 H), 2.23 ^3Η), 3.35 (853Η), 4.12 (ά, 2Η), 6.77 (δ51Η), 6.96 (d, 1 H), 7.59 (m, 1 H), 7.90 (m , 2 H), 8.22 (dd, 1 H)! 134079.doc -69- 200916458 8.76 (d,1 Η), 10.45 (s,1 Η). MS (M+H+) = 399. The following Examples 46-56 were prepared in a similar manner to Example 45 using commercially available starting materials: Example Name Structure MW MS (M+H^ 'hnmr (δ ppm) 46 N-[4-Ga-3-(l ,5-dimethyl-lH-imidazol-2-yl)phenyl]-6-[2-(dimethylamino)ethoxy]»pyridin-3-carboxamide?H3 〇Η3&quot;^ 〇〇λ TX/-CH^ 413.91 414 2.20 (s, 6 H), 2.23 (s, 3 H), 2.63 (t, 2 H), 3.35 (s, 3 H), 4.42 (t, 2 H), 6.77 (s, 1 H), 6.95 (d, 1 H), 7.59 (m, 1 H), 7.90 (m, 2 H), 8.22 (dd, 1 H), 8.77 (d, 1 H), 10.45 ( s,1 H) 47 N-[4-Ga-3-(l,5-dimercapto-lH-amido-2-yl)phenyl]-6-[(1-methylpiperidin-4- Methoxy]&quot;bipyridine-3-carbamide rf°^^{rCH3 H〆453.97 454 1.31 (s, 2 H), 1.71 (m, 3 H), 1.85 (m, 2 H), 2.14 (s, 3 H), 2.23 (s, 3 H), 2.77 (d, 2 H), 3.35 (s, 3 H), 4.19 (d, 2 H), 6.77 (s, 1 H), 6.95 ( d,1 H), 7.58 (d,1 H), 7.89 (m,2 H), 8.22 (dd, 1 H), 8.76 (d, 1 H), 10.45 (s, 1 H) 48 N-[4 -gas-3-(1,5-dimercapto-1H-imidazol-2-yl)phenyl]-6-[3-(dihexylamino)propoxy]0-pyridin-3-indoleamine 455.99 456 0.94 (m, 6 H) , 1.87 (m, 2 H), 2.23 (s, 3 H), 2.44 (m, 6 H), 3.36 (s, 3 H), 4.36 (t, 2 H), 6.77 (s, 1 H), 6.94 (d, 1 H), 7.58 (d, 1 H), 7.90 (m, 2 H), 8.22 (d, 1 H), 8.76 (s, 1 H), 10.46 (br s, 1 H) 134079.doc 70· 200916458 Example ___Name Structure MW MS (M+H+) ^NMR (δ ppm) 49 N'[4-^-3-(1,5-Dimethyl-1H-mimi)phenyl]· 6-{[(2S)-l-methyl·°pyrrolidin-2-yl]methoxy}. Ratio of procarbamide Cl ^ 439.94 440 1.66 (m, 3 H), 1.93 (m, 1 H), 2.17 (m, 1 H), 2.23 (s, 3 H), 2.35 (s, 3 H), 2.54 ( m, 1 H), 2.95 (ddd, 1 H), 3.35 (s, 3 H), 4.22 (m, 1 H), 4.34 (m, 1 H), 6.77 (s, 1 H), 6.95 (d, 1 H), 7.58 (m, 1 H), 7.91 (m, 2 H), 8.22 (dd, 1 H), 8.77 (d, 1 H), 10.46 (s, 1 H) 50 Ν·[4-gas -3-(1,5--Methyl-1Η-imidazol-2-yl)phenyl]_ 6_[(^-ylbenzyl)oxy]anthracene. D-Benzylamine Cl N 457.92 458 2.23 (s, 3 H), 3.36 (s, 3 H), 5.50 (s, 2 H), 6.78 (s, 1 H), 7.08 (d, 1 H) , 7.61 (m, 2 H), 7.82 (d, 2 H), 7.90 (m, 2 H), 7.95 (s, 1 H), 8.27 (dd, 1 H), 8.78 (d, 1 H), 10.48 (s, 1 H) 51 Ν-[4·Ga·3-(l,5· dimethyl-lH-m-??-yl-2-yl) phenyl]_6_ [(1-methylpiperidin-2- Methoxy]° pyridine-3-carbamide 453.97 454 1.31 (m, 1 H) 1.37 (dd, 1 H) 1.42-1.55 (m, 2 H) 1.62-1,78 (m, 2 H) 2.02 (td, 1 H) 2.19 (m, 1 H) 2.24 (s, 6 H) 2.67-2.84 (m,1 H) 3.36 (s, 3 H) 4.28-4.47 (m, 2 H) 6.78 ( s,1 H) 6.96 (d,1 H) 7.58 (d, 1 H) 7.88 (s, 1 H) 7.91 (m, 1 H) 8.22 (dd, 1 H) 8.77 (d, 1 H) 10.45 (s , 1 H) 52 Ν-[4-Ga-3-(l,5-dimethyl-lH-imidazol-2-yl)phenyl]-6-(2-morpholin-4-ylethoxy) Pyridine-3-indenyl ο ν^ι^νη ο~. /Red 455.94 456 2.21 (s, 3 H), 2.45 (m, 4 H), 2.69 (t, 2 H), 3.43 (s, 3 H), 3.55 (m, 4 H), 4.45 (t, 2 H ), 6.76 (d, 1 H), 6.94 (d, 1 H), 7.56 (dd, 1 H), 7.87 (m, 2 H), 8.21 (dd, 1 H), 8.75 (d, 1 H), 10.45 (s, 1 H) 134079.doc -71 · 200916458 Example name structure MW MS (M+H^ !hnmr (δ ppm) 53 Ν-[4-chloro-3-(l,5-dimethyl-lH -imidazol-2-yl)phenyl]- 6-(2-11 than the corresponding 0-decyl-1 -ylethyl lactyl) ° ratio 0--3-carbamide 0 N^V^NH 〇~.^ Private 3 439.94 440 1.88 (m, 2 H), 1.99 (m, 2 H), 2.36 (s, 3 H), 3.10 (m, 4 H), 3.56 (s, 3 H), 3.60 (m, 2 H) ), 4.63 (m, 2 H), 6.99 (d, 1 H), 7.61 (s, 1 H), 7.76 (m, 1 H), 7.97 (m, 1 H), 8.22 (m, 1 H), 8.29 (dd, 1 H), 8.80 (d, 1 H) 10.8 (s, 1 H) 54 N-[4-chloro-3_(1,5-dimercapto-1H-imidazol-2-yl)phenyl ]-6-[(1-mercaptopiperidin-3-yl)methoxy]acridin-3-carboxamide ch3 453.97 454 1.27 (m, 1 H), 1.70 (m, 1 H), 1.85 ( m, 2 H), 2.31 (s, 3 H), 2.78 (s, 3 H), 2.84 (m, 2 H), 3.43 (m, 3 H), 3.57 (s, 3 H), 4.26 (m, 2 H), 6.97 (d, 1 H), 7.66 (m, 1 H), 7.77 (d, 1 H), 7.98 (d, 1 H), 8.26 (d, 2 H), 8.78 (s, 1 H), 10.78 (s, 1 H) 55 N-[4- gas-3-(l,5-dimercapto-m-imiline- 2-yl)phenyl]-6-{[(2R)-l-fluorenyl 0 piroxicam-2-yl] decyloxy}° pyridine-3-decylamine 0 to palmity 439.95 440 - 56 Ν-(4-chloro-3-(l,5-dimethyl-lH-mi. Sodium-2-yl)phenyl)-6-((1-methylpyridin-3-yl)methoxy)nicotinium oxime XT)^CH3 439.95 440 14.92 (br s,1 H), 11.04 (d, 1 H), 8.84 (dd, 1 H), 8.22-8.38 (m, 2 H), 8.01-8.15 (m,1 H), 7.72 (d,1 H), 7.62 (s, 1 H ), 6.83-7.07 (m, 1 H), 4.23-4.47 (m, 2 H), 3.49-3.69 (m, 5 H), 3.28-3.49 (m, 2 H), 3.06=3.22 (m, 1 H ), 2.96 (d, 1 H), 2.82 (d, 1 H), 2.73 (dd, 3 H), 2.33 (s, 3 H), 2.13-2.28 (m, 1 H), 1.51-1.79 (m, 1 H) 134079.doc -72· 200916458 Example 57 N-[3-(l,5-Dimercapto-salt-2-yl)_4_methyl-phenyl]2_methyl_6 "Trifluoromethyl Pyridin-3-indenylamine

敗2-甲基春(4-甲基_3-(4 4 5 5_四甲基·132_二氧硼咪_ 2-基）苯基）-6-(三氟甲基）珞鹼醯胺 在100 mL圓底燒瓶中，將4_曱基_3_(4,4,5,5·四曱基_ (15.0 mL)以得到無色溶液且用吼咬（丨5 mL)稀釋溶液。將 溶液冷卻至〇t，之後添加2-曱基_6·(三氟曱基）菸鹼醯基氣 0·918 g，8.58 mmol)。在〇°C下攪拌2 h後，減壓移除溶劑 且用EhO (1〇 mL)稀釋殘餘物。將懸浮液攪拌1〇 min，過 /慮且乾燥以得到呈固體之標題化合物（2· 1 g，產率5 8。/〇)。 ]H NMR (DMSO-d6) δ 1.31 (s, 12 Η), 2.44 (s, 3 Η), 2.63 (s, 3 Η), 7.19 (d, 1 Η), 7.75 (dd, 1 Η), 7.94 (m, 2 Η), 8.16 (d, 1 H)，10.53 (s，1 H)。MS (M+H+)=421。 5ΊΒ. N-[3-(l，5-二甲基咪唑-2-基）-4-甲基-苯基]·2-甲基-6· (三氟甲基）吡啶-3-甲醯胺 在10 mL小瓶中，將2-甲基-N-(4-甲基-3-(4,4,5,5 -四甲 基-1，3,2-一氣删咪-2-基）本基）-6-(三氟甲基）終驗醢胺（〇.1 134079.doc -73- 200916458 g ’ 0·24 mmol)、Cs2C03 (0.194 g ’ 0.59 mmol)及 2-溴-1，5-一甲基-1 H-咪。坐（0.062 g，0.36 mmol)置放於二&quot;惡烧（4 mL) 中以得到無色懸浮液。用水（1 mL)稀釋反應混合物。將氮 鼓泡穿過混合物歷時20 min，之後添加Pd(PPh3)4 (0.041 g ’ 0.04 mmol)且使用微波將反應加熱至i〇〇°c歷時40 min。真空濃縮後，用EtOAc (10 mL)及水（1〇 mL)稀釋殘 餘物。用EtOAc (2x10 mL)萃取水層。乾燥（Na2S04)所組合 之有機層且真空濃縮以得到粗產物，藉由ISCO MPLC (於 DCM中之10% MeOH)將其純化以得到標題化合物（〇 〇35 g ’ 產率 38%)。】H NMR (DMSO-d6) δ 2.13 (s，3 H)，2.23 (s， 3 Η), 2.64 (s, 3 Η), 3.34 (s, 3 Η), 6.76 (s, 1 Η), 7.33 (s, 1 Η), 7.65 (s, 2 Η), 7.89 (s, 1Η), 8.18 (s, 1 H), 10.63 (s, 1 H)。MS (M+H+) = 389。 實例58 N-[4-氯-3-(1，2-二甲基-11^口米唑-5-基）苯基]_6-{[(28)-1-甲2-methylchun (4-methyl_3-(4 4 5 5 -tetramethyl·132_dioxaboron-2-yl)phenyl)-6-(trifluoromethyl)decanoate Amine In a 100 mL round bottom flask, 4_mercapto_3_(4,4,5,5·tetradecyl-(15.0 mL) was obtained as a colorless solution and the solution was diluted with a bite (丨5 mL). The solution was cooled to 〇t, then 2-mercapto-6(trifluoromethyl)nicotinium sulfhydryl gas 0.918 g, 8.58 mmol) was added. After stirring at 〇 ° C for 2 h, the solvent was removed under reduced pressure and the residue was diluted with EtOAc (1 EtOAc). The suspension was stirred for 1 〇 min, then dried and evaporated to give titled compound (2·1 g, yield s. ]H NMR (DMSO-d6) δ 1.31 (s, 12 Η), 2.44 (s, 3 Η), 2.63 (s, 3 Η), 7.19 (d, 1 Η), 7.75 (dd, 1 Η), 7.94 (m, 2 Η), 8.16 (d, 1 H), 10.53 (s, 1 H). MS (M+H+) = 421. 5ΊΒ. N-[3-(l,5-Dimethylimidazol-2-yl)-4-methyl-phenyl]·2-methyl-6·(trifluoromethyl)pyridine-3-carboxamidine Amine in a 10 mL vial, 2-methyl-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-a-methylene-2-yl) Benzo)-6-(trifluoromethyl)-final amine (〇.1 134079.doc -73- 200916458 g '0·24 mmol), Cs2C03 (0.194 g '0.59 mmol) and 2-bromo-1, 5-monomethyl-1 H-mi. Sitting (0.062 g, 0.36 mmol) was placed in a two &quot;haste (4 mL) to give a colourless suspension. The reaction mixture was diluted with water (1 mL). Nitrogen was bubbled through the mixture for 20 min before Pd(PPh3)4 (0.041 g&apos; 0.04 mmol) was added and the reaction was heated to i 〇〇 °c for 40 min using microwave. After concentration in vacuo, the residue was diluted with EtOAc (10 mL) The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layers were dried (EtOAc EtOAc m. H NMR (DMSO-d6) δ 2.13 (s, 3 H), 2.23 (s, 3 Η), 2.64 (s, 3 Η), 3.34 (s, 3 Η), 6.76 (s, 1 Η), 7.33 (s, 1 Η), 7.65 (s, 2 Η), 7.89 (s, 1 Η), 8.18 (s, 1 H), 10.63 (s, 1 H). MS (M+H+) = 389. Example 58 N-[4-Chloro-3-(1,2-dimethyl-11^-triazol-5-yl)phenyl]_6-{[(28)-1-A

基吡咯啶-2-基]曱氧基}吡啶_3_甲醯胺Pyrrrolidin-2-yl]nonyloxy}pyridine_3_formamide

WA. (S)-6-((l-甲基吼咯啶-2-基）甲氧基）菸酸 向（S)-(l-甲基吡咯啶·2-基）曱醇（4.39 g, 38.〇8 mm〇1)及 6-氣菸鹼酸（1.0 g ’ 6·35 mm〇i)之溶液緩慢添加固體第三丁 134079.doc • 74· 200916458 氧化納（7.32 g，76.16 _〇1)。在95。〇下將反應擾拌8 h，隨 後冷部至灯，用水稀釋且用HC1調整PH至5-6,用EtOAc萃 取’辰縮水層至乾燥以得到標題化合物。ms (M+H+)=237。 WB’（S)-2-氣-5-(6-((1.甲基σ比洛咬_2_基）甲氧基）於驗酿胺 基）苯基蝴酸 將（S)-6-((l-曱基。比咯啶_2_基）甲氧基）终酸（〗.〇 g，4 mmol)♦於SOCh (50 mL)中，接著添加幾滴dmf且隨後在 RT下攪拌隔夜。真空濃縮後，將殘餘物再溶解於dcm 中，濃縮且隨後置放於高真空下以得到6_{[(2S)_卜甲基吡 各定2-基]甲氧基}吡啶_3_碳醯氯。向該粗酸氯化物於二 氣甲烷（20 mL)及吡啶（20 ml)中之溶液添加5_胺基_2_氣苯 基蝴酸（0.66 g，3.85 mmol)。在RT下將溶液攪拌隔夜且隨 後真工，辰縮至乾燥且隨後藉由ISCO MPLC (10-20% MeOH/ 具有3% NhOH之DCM)純化以得到呈白色固體之標題化合 物（1.20 g，80 %)。MS (M+H+) 390。 # (S)-N-(4-氯-3-(1-甲基-1H-咪唑-4-基）苯基）_6_((1_ 甲 基吼咯啶-2-基）甲氡基）珞鹼醯胺 向 4-溴-1-甲基-1H-咪唑（165 mg，1.03 mmol)、⑻-之-氣- 5-(6-((1-甲基吼咯啶-2-基）甲氧基）菸驗醯胺基）苯基_酸 (200 mg，0.51 mmol)及 KOAc (151 mg，1.54 mmol)於二噁 烷（3 mL)及水（1 mL)中之溶液添加固體Pd(pph3)4 (59 3 mg，0.05 mmol)。將氮氣鼓泡穿過溶液歷時1〇 min且隨後 在130°C下，置放於微波中歷時4 h。移除水層，接著濃縮 °惡 。精由 Gilson HPLC (5-75% CN/於水中之 〇 1 % 134079.doc •75- 200916458 TFA)純化粗殘餘物。將含有產物之所組合之溶離份濃縮且 使用 GUson (5-95% MeCN/於水中之 1〇 mM NH4〇Ac)再純WA. (S)-6-((l-Methyloxaridin-2-yl)methoxy)nicotinic acid to (S)-(l-methylpyrrolidin-2-yl)nonanol (4.39 g , 38. 〇 8 mm 〇 1) and 6-gas nicotinic acid (1.0 g '6·35 mm〇i) solution slowly added solid third 134079.doc • 74· 200916458 oxidized sodium (7.32 g, 76.16 _ 〇 1). At 95. The reaction was stirred for 8 h, then cooled to mp EtOAc (EtOAc)EtOAc. Ms (M+H+) = 237. WB'(S)-2-Gas-5-(6-((1.methyl σ 洛 咬 _2 _ _)) methoxy) in the amylamine phenyl carboxylic acid (S)-6 -((l-fluorenyl.byridine-2-yl)methoxy)finic acid (〗 〖g, 4 mmol) ♦ in SOCh (50 mL), followed by a few drops of dmf and then at RT Stir overnight. After concentration in vacuo, the residue was redissolved in dcm, concentrated and then placed under high vacuum to afford 6-{[(2S)- </RTI> </ RTI> </ RTI> </ RTI> <RTIgt; . To a solution of the crude acid chloride in di-methane (20 mL) and pyridine (20 ml) was added 5-amino-2-phenophthalic acid (0.66 g, 3.85 mmol). The solution was stirred at rt EtOAc (m.) %). MS (M+H+) 390. #(S)-N-(4-Chloro-3-(1-methyl-1H-imidazol-4-yl)phenyl)_6_((1-methyloxaridin-2-yl)methylhydrazinyl) Alkaline decylamine to 4-bromo-1-methyl-1H-imidazole (165 mg, 1.03 mmol), (8)---- 5-(6-((1-methylpyridin-2-yl)) Add a solid Pd to a solution of oxy) acetamino)phenyl-acid (200 mg, 0.51 mmol) and KOAc (151 mg, 1.54 mmol) in dioxane (3 mL) and water (1 mL) Pph3)4 (59 3 mg, 0.05 mmol). Nitrogen gas was bubbled through the solution for 1 min and then placed in the microwave for 4 h at 130 °C. Remove the water layer and then concentrate the evil. The crude residue was purified by Gilson HPLC (5-75% CN / EtOAc 1% 134079. The combined fractions containing the product are concentrated and re-purified using GUson (5-95% MeCN/1 mM MH4 in Ac)

mg，4.69 %)。】H NMR 化以得到標題化合物（12.40 (DMSO-d6)51.87(m，1H),2.〇2(m，2H)，2 28 (m，iH) 2.92(d，3H)，3.11(m，1H)，3.62(mlH) 3 83 (miH) 3.94 (s，3 H)，4.71 (m，2 H)，7 〇8 (d，丨 h)，7 67 ⑷】h)， 7-92 (dd, 1H), 8.10(s, 1H), 8.30 (djlH)5 8.40 (dd, 1 H),Mg, 4.69 %). H NMR gave the title compound (12.40 (DMSO-d6) 51.87 (m, 1H), 2. 〇2 (m, 2H), 2 28 (m, iH) 2.92 (d, 3H), 3.11 (m, 1H), 3.62 (mlH) 3 83 (miH) 3.94 (s, 3 H), 4.71 (m, 2 H), 7 〇 8 (d, 丨h), 7 67 (4)] h), 7-92 (dd , 1H), 8.10(s, 1H), 8.30 (djlH)5 8.40 (dd, 1 H),

8.91 (d,lH), 9.24 (s51H)51〇.92 (s? ! H), 11.15 ( br s, 1 H)。MS (M+H+)=426。8.91 (d,lH), 9.24 (s51H)51〇.92 (s? ! H), 11.15 ( br s, 1 H). MS (M+H+) = 426.

實例59-61以與實例58相似之 來製備： 方式，利用市售起始物 質 實例 名稱 - 〜__ 結構 MW MS (M+H+) !hnmr (δ ppm) 59 N-[4-氣-Βοή- 味 η 坐 _4_ 基）笨基]-6-{[(2S；M-甲基 °比咯啶-2-基] 甲氧基}吡 °定·3-曱酿胺 $ν/? rr^NH對掌性 。心 TXnh 411.89 412 1.80 (m, 1 H), 2.04 (m, 2 H), 2.27 (m, 1 H), 2.93 (d, 3 H), 3.11 (m, 1 H), 3.61 (m, 1 H), 3.91 (m, 1 H), 4.70 (dd, 2 H)，7.08 (d，1 H)，7.68 (d, 1 H), 7.92 (dd, 1 H), 8.03 (s, 1 H), 8.26 (s, 1 H), 8.39 (dd, 1 H), 8.90 (s, 1 H), 9.31 (s, 1 H), 10.88 (s，1 H)，11.04 (br s, 1 H), 14.95 (br s, 1 H) 134079.doc -76- 200916458 實例 名稱 結構 MW MS (M+H+) ^NMR (δ ppm) 60 N-[4-氣-3-(2_ 甲基-1H-咪 唑-5-基）笨 基]-6-{[(2S)-1-曱基°比略 啶-2-基]甲氧 基}吡啶-3-甲 醯胺 〇 1 對掌性 ci &lt; 425.92 426 1.96 (m, 2 H), 2.04 (m, 1 H)，2.27 (m, 1 H)， 2.64 (s，3 H), 2.95 (d，3 H)，3.16 (m，1 H), 3.59 (m, 1 H), 3.84 (m, 1 H), 4.67 (dd, 2 H), 7.11 (d, 1 H), 7.68 (d, 1 H), 7.82 (dd, 1 H), 7.91 (s，1 H)， 8.25 (d, 1 H), 8.38 (dd, 1 H), 8.86 (d, 1 H), 10.54 (br s, 1 H), 10.74 (s, 1 H), 14.4 (brs, 1 H) 61 N-[4-氣-3-(1，2-二甲基-1H-咪唑-5- 基）笨基]-6- r\ 1 對掌性 {[(2S)-1-曱基 吡咯啶-2-基] 甲氧基} °比 咬-3-甲酿胺 叫飞Η3 439.94 440 使用 4 性HPLC 分離（Chiralpak AD/20 μ管柱，50x500 _ ’ 1〇〇% 乙醇：曱醇（1:1)，0.1%二乙胺，120 mL/min)， 藉由純化實例51獲得實例62-63 : 實例 名稱 ___ 結構 MW MS *HNMR (δ ppm) 62 Ν·[4-氣·3__ d，5-二曱基-1H-味峻.2、 基）笨基]-6、 {[(2S)-1- ψ 基哌啶-2-基] 甲氧基}&quot;比 咬-3-甲酿胺 〇 ν&quot;^Υ^νη CC： ^ ci wJ! — 453.97 454 (d3-MeOD) 1.32-1.46 (m, 1 H) 1.53-1.69 (m, 3H) 1.82(m,2H)2.22 (td, 1 H) 2.30 (s, 3 H) 2.35 (m, 1 H)2.38 (s, 3 H) 2.92 (m, 1 H) 3.45 (s, 3 H) 4.47 (dd, 2 H) 6.83 (s, 1 H) 6.93 (d, 1 H) 7.54 (d, 1 H) 7.81 (d, 1 H) 7.89 (dd, 1 H) 8.20 (dd, 1 H) 8.75 (d, 1H) 1 134079.doc -77- 200916458 (d3-MeOD) 1.32-1.46 N-[4-氱-3- (m, 1 Η) 1.53-1.69 (m, (1，5-二甲基- 3 Η) 1.82 (m, 2 Η) 2.22 1H-咪唑-2- 〇 (td, 1 Η) 2.30 (s, 3 Η) 63 基）笨基]-6-U(2R)-1-曱 基旅咬-2- N^V^NH CQ仏 453.97 454 2.35 (m, 1 Η) 2.38 (s, 3 Η) 2.92 (m, 1 Η) 3.45 (s, 3 Η) 4.47 (dd, 2 Η) 6.83 (s, 1 Η) 6.93 (d, 1 基]甲氧基} Η) 7.54 (d, 1 Η) 7.81 吡啶-3-曱 (d, 1 Η) 7.89 (dd, 1 Η) 醯胺 8.20 (dd, 1 Η) 8.75 (d, 1H) 使用掌性HPLC分離（Chiralpak AD/20 μ管柱，50x500 mm ; 100% 乙醇：曱醇（1:1)，0.1% 二乙胺，120 mL/min)，藉由 純化實例54獲得實例64-65 : 實例 名稱 結構 MW MS (M+H^ !hnmr (δ ppm) 64 N-[4-氣-3-(l，5-二甲基-lH-咪 唑_2_基）苯基]-6-{[(3R)-l-曱基 哌啶-3-基]甲氧 基}吡啶-3-甲 醒胺 453.97 454 (drMeOD) 8.73 (d，1 H)， 8.19 (dd, 1 H), 7.88 (dd，1 H), 7.80 (d, 1 H), 7.54 (d, 1 H), 6.89 (d, 1 H), 6.83 (s. 1 H), 4.25 (m, 2 H), 3.44 (s, 3 H), 3.03 (d, 1 H), 2.85 (d, 1 H), 2.30 (s, 6 H)，2.08-2.23 (m，1 H)， 1.94-2.08 (m, 1 H), 1.72-1.94 (m, 3 H), 1.65-1.72 (m，1 H), 1.12 (dd，1 H) 65 N-[4-氣-3-(l，5-二甲基-lH-咪 0坐-2-基)苯基]-6-{[(3S)-1-曱基n辰 啶基]曱氧基} 吡啶-3-曱醯胺 CHj 453.97 454 (d3-MeOD) 8.73 (d, 1 H), 8.19 (dd, 1 H), 7.88 (dd, 1 H), 7.80 (d, 1 H), 7.54 (d, 1 H), 6.89 (d, 1 H), 6.83 (s, 1 H), 4.25 (m, 2 H), 3.44 (s, 3 H), 3.03 (d, 1 H), 2.85 (d, 1 H), 2.30 (s, 6 H), 2.08-2.23 (m, 1 H), 1.94-2.08 (m, 1 H), 1.72-1.94 (m, 3 H), 1.65-1.72 (m, 1 H), 1.12 (dd, 1 H) 實例66以與實例1相似之方式，利用市售起始物質來製 備： 134079.doc -78- 200916458 實例 名稱 結構 MW MS (M+H+) 'HNMRia ppm) 66 N-[4-|L-3-(l,2-二曱基-1H-咪 唑-4-基)苯基]- 2- 甲基-6-(三 氟曱基）°比咬- 3- 曱醯胺 Cl N^/ ch3 408.81 409 2.61 (s, 3 H), 2.65 (s, 3 H), 3.80 (s, 3 H), 7.67 (m, 2 H), 7.91 (d, 1 H), 8.00 (s, 1 H), 8.21 (m, 2 H), 10.99 (s, 1 H) 實例67Examples 59-61 were prepared in analogy to Example 58: Method using commercially available starting material example name - ___ Structure MW MS (M+H+) !hnmr (δ ppm) 59 N-[4-气-Βοή- Taste η sit _4_ base) stupid base]-6-{[(2S; M-methyl-pyrrolidin-2-yl) methoxy}pyridine·3-anthracene amine $ν/? rr^ NH to palm. Heart TXnh 411.89 412 1.80 (m, 1 H), 2.04 (m, 2 H), 2.27 (m, 1 H), 2.93 (d, 3 H), 3.11 (m, 1 H), 3.61 (m, 1 H), 3.91 (m, 1 H), 4.70 (dd, 2 H), 7.08 (d, 1 H), 7.68 (d, 1 H), 7.92 (dd, 1 H), 8.03 (s , 1 H), 8.26 (s, 1 H), 8.39 (dd, 1 H), 8.90 (s, 1 H), 9.31 (s, 1 H), 10.88 (s, 1 H), 11.04 (br s, 1 H), 14.95 (br s, 1 H) 134079.doc -76- 200916458 Example name structure MW MS (M+H+) ^NMR (δ ppm) 60 N-[4- gas-3-(2_methyl- 1H-imidazole-5-yl)phenyl]-6-{[(2S)-1-fluorenylpyrrolidin-2-yl]methoxy}pyridine-3-carbamimidoxime 1 pair of palm ci &lt; 425.92 426 1.96 (m, 2 H), 2.04 (m, 1 H), 2.27 (m, 1 H), 2.64 (s, 3 H), 2.95 (d, 3 H), 3.16 (m, 1 H) ), 3.59 (m, 1 H), 3.84 (m, 1 H), 4.67 (dd, 2 H), 7.11 (d, 1 H), 7.6 8 (d, 1 H), 7.82 (dd, 1 H), 7.91 (s, 1 H), 8.25 (d, 1 H), 8.38 (dd, 1 H), 8.86 (d, 1 H), 10.54 ( Br s, 1 H), 10.74 (s, 1 H), 14.4 (brs, 1 H) 61 N-[4- gas-3-(1,2-dimethyl-1H-imidazol-5-yl) stupid Base]-6-r\ 1 pair of palmity {[(2S)-1-indolylpyrrolidin-2-yl]methoxy} ° than biting 3-cartoamine called locust 3 439.94 440 using 4-HPLC Separation (Chiralpak AD/20 μ column, 50×500 _ '1 〇〇 % ethanol: decyl alcohol (1:1), 0.1% diethylamine, 120 mL/min), Examples 62-63 were obtained by purification example 51: Example name ___ Structure MW MS * HNMR (δ ppm) 62 Ν · [4-gas · 3__ d, 5-dimercapto-1H-weijun. 2, base) Stupid base]-6, {[(2S) -1- ψ 哌piperidin-2-yl] methoxy}&quot;比比甲甲甲胺胺〇ν&quot;^Υ^νη CC: ^ ci wJ! — 453.97 454 (d3-MeOD) 1.32-1.46 (m, 1 H) 1.53-1.69 (m, 3H) 1.82 (m, 2H) 2.22 (td, 1 H) 2.30 (s, 3 H) 2.35 (m, 1 H) 2.38 (s, 3 H) 2.92 ( m, 1 H) 3.45 (s, 3 H) 4.47 (dd, 2 H) 6.83 (s, 1 H) 6.93 (d, 1 H) 7.54 (d, 1 H) 7.81 (d, 1 H) 7.89 (dd , 1 H) 8.20 (dd, 1 H) 8.75 (d, 1H) 1 134079.doc -77- 200916458 (d3-MeOD) 1.32-1.46 N-[4-氱-3- (m, 1 Η) 1.53-1.69 (m, (1,5-dimethyl- 3 Η) 1.82 (m, 2 Η) 2.22 1H -imidazol-2-indole (td, 1 Η) 2.30 (s, 3 Η) 63 base) stupid base]-6-U(2R)-1-indenyl travel bite-2- N^V^NH CQ仏453.97 454 2.35 (m, 1 Η) 2.38 (s, 3 Η) 2.92 (m, 1 Η) 3.45 (s, 3 Η) 4.47 (dd, 2 Η) 6.83 (s, 1 Η) 6.93 (d, 1 base) Methoxy} Η) 7.54 (d, 1 Η) 7.81 Pyridine-3-indole (d, 1 Η) 7.89 (dd, 1 Η) decyl 8.20 (dd, 1 Η) 8.75 (d, 1H) HPLC separation (Chiralpak AD/20 μ column, 50×500 mm; 100% ethanol: decyl alcohol (1:1), 0.1% diethylamine, 120 mL/min). Example 64-65 was obtained by purification example 54: Example Name structure MW MS (M+H^ !hnmr (δ ppm) 64 N-[4-gas-3-(l,5-dimethyl-lH-imidazolium-2-yl)phenyl]-6-{[ (3R)-l-nonylpiperidin-3-yl]methoxy}pyridin-3-methylamine 453.97 454 (drMeOD) 8.73 (d,1 H), 8.19 (dd, 1 H), 7.88 (dd , 1 H), 7.80 (d, 1 H), 7.54 (d, 1 H), 6.89 (d, 1 H), 6.83 (s. 1 H), 4.25 (m, 2 H), 3.44 (s, 3 H), 3.03 (d, 1 H), 2.85 (d, 1 H), 2.30 (s, 6 H), 2.08-2.23 (m, 1 H), 1.94-2.08 (m, 1 H), 1.72-1.94 (m, 3 H), 1.65-1.72 (m, 1 H), 1.12 (dd, 1 H) 65 N-[4-Ga-3-(l,5-dimethyl-lH-miso-2-yl-2-phenyl)phenyl]-6-{[(3S)-1-indenyl n-n-yl]曱oxy} pyridine-3-decylamine CHj 453.97 454 (d3-MeOD) 8.73 (d, 1 H), 8.19 (dd, 1 H), 7.88 (dd, 1 H), 7.80 (d, 1 H) , 7.54 (d, 1 H), 6.89 (d, 1 H), 6.83 (s, 1 H), 4.25 (m, 2 H), 3.44 (s, 3 H), 3.03 (d, 1 H), 2.85 (d, 1 H), 2.30 (s, 6 H), 2.08-2.23 (m, 1 H), 1.94-2.08 (m, 1 H), 1.72-1.94 (m, 3 H), 1.65-1.72 (m , 1 H), 1.12 (dd, 1 H) Example 66 was prepared in a similar manner as in Example 1 using commercially available starting materials: 134079.doc -78- 200916458 Example name structure MW MS (M+H+) 'HNMRia Phenyl) 66 N-[4-|L-3-(l,2-dimercapto-1H-imidazol-4-yl)phenyl]-2-methyl-6-(trifluoromethyl)° - 3- guanamine Cl N^/ ch3 408.81 409 2.61 (s, 3 H), 2.65 (s, 3 H), 3.80 (s, 3 H), 7.67 (m, 2 H), 7.91 (d, 1 H), 8.00 (s, 1 H), 8.21 (m, 2 H), 10.99 (s, 1 H) Example 67

Hedgehog路徑細胞分化檢定 本發明之化合物抑制Hedgehog路徑之能力可藉由以下細 胞分化檢定來測定。 以5000個細胞/孔之濃度將於dmEM/1〇〇/0 FBS中之 C3H10T1/2細胞塗於384孔板中。第二天，將培養基改變成 20%改良性培養基（低血清培養基dmEM/20/〇 FBS + Shh配位 體）。將化合物溶解於100% DMS0中達到1〇 mM之濃度且 隨後在100% DMSO中連續稀釋3倍。細胞塗佈中之最高濃 度為30 μΜ且最低濃度為3 nM〇隨後將化合物添加至細胞 中。用化合物將細胞塗佈物培養72小時且隨後使用pNp作 為文質檢定鹼性峨酸酶產生。簡言之’培養72小時後，自 細胞吸出培養基且用3〇 μ 1之PBS洗務細胞。將pbS自細胞 吸出且將15 μΐ之1XRIPA細胞溶解緩衝液添加於細胞上。 後在-8 0 C下將細胞塗佈物培養3 0分鐘以確保適當之細 胞溶解。隨後將塗佈物解凍回室溫。隨後將含有於pH 9.8 之二乙醇胺緩衝液中之丨mg/mL pNp的受質溶液添加於溶 解細胞上。在30°C下培養塗佈物用於顯色且在4〇5 nm之吸 134079.doc •79· 200916458 光率下讀取。隨後自吸光率 百刀比及ic50值。 資料，使用 標準程序計算抑制 虽隹上述檢定 饮不小於約30 f ’示範性化甘物展示小紙 μΜ之IC50。舉例而言，如 ' 划表2中所示’獲得以下結果 表2Hedgehog Pathway Cell Differentiation Assay The ability of the compounds of the invention to inhibit the Hedgehog pathway can be determined by the following cell differentiation assay. C3H10T1/2 cells in dmEM/1〇〇/0 FBS were plated in 384-well plates at a concentration of 5000 cells/well. The next day, the medium was changed to 20% modified medium (low serum medium dmEM/20/〇 FBS + Shh ligand). The compound was dissolved in 100% DMS0 to a concentration of 1 mM and then serially diluted 3 fold in 100% DMSO. The highest concentration in the cell coating was 30 μΜ and the lowest concentration was 3 nM, and the compound was then added to the cells. The cell coating was incubated with the compound for 72 hours and then assayed for alkaline tannase using pNp as a characterization. Briefly, after 72 hours of culture, the medium was aspirated from the cells and the cells were washed with 3 μl of PBS. The pbS was aspirated from the cells and 15 μL of 1XRIPA cell lysis buffer was added to the cells. The cell coating was then incubated at -8 0 C for 30 minutes to ensure proper cell lysis. The coating was then thawed back to room temperature. A substrate solution containing 丨mg/mL pNp in diethanolamine buffer at pH 9.8 was then added to the dissolved cells. The coating was incubated at 30 ° C for color development and read at 4 〇 5 nm absorbance 134079.doc • 79· 200916458 light. The self-absorption rate is then 100% and ic50. Data, using standard procedures to calculate inhibition, although the above assay is not less than about 30 f ′ of the exemplary glycan display small paper μΜ IC50. For example, as shown in 'Description 2', the following results are obtained. Table 2

根據上文所述之檢定’本文中揭示之所有實例在3 下 之抑制百分比展示於表3中。 表3 實例 在3 μΜ下之抑制百分比 1 71.7 2 71.4 3 80.7 4 76.4 5 80.0 6 80.0 7 81.1 8 81.5 9 54.1 10 77.4 11 69.0 12~~~~ 54.7 13 60.5 14 54.9 15 55.9 16 60.1 17 50.8 18 60.6 19~~~~ 64.1 20 69.4 21 59.4 22 86.8 23 74.9 24 76.2 25 74.7 26 74.7 27 72.0 28 65.3 29 62.9 30 77.8 31 72.1 32 37.0 33 75.1 34 71.6 35 75.5 36 76.5 37 69.9 38 76.8 39 75.8 40 77.8 41 76.6 42 85.8 43 84.5 44 86.2 45 72.3 46 76.9 47 76.8 48 77.1 49 76.1 134079.doc -80- 200916458 58 59 ~~6ί7 -~~~ 60 ~66Λ '-- 61 .~3Ζ6~~~-- 62 ~~~~ 63 -- 64 81.5 ' 65 UA--According to the assay described above, the percent inhibition at 3 in all of the examples disclosed herein is shown in Table 3. Table 3 Percent inhibition of the example at 3 μΜ 1 71.7 2 71.4 3 80.7 4 76.4 5 80.0 6 80.0 7 81.1 8 81.5 9 54.1 10 77.4 11 69.0 12~~~~ 54.7 13 60.5 14 54.9 15 55.9 16 60.1 17 50.8 18 60.6 19~~~~ 64.1 20 69.4 21 59.4 22 86.8 23 74.9 24 76.2 25 74.7 26 74.7 27 72.0 28 65.3 29 62.9 30 77.8 31 72.1 32 37.0 33 75.1 34 71.6 35 75.5 36 76.5 37 69.9 38 76.8 39 75.8 40 77.8 41 76.6 42 85.8 43 84.5 44 86.2 45 72.3 46 76.9 47 76.8 48 77.1 49 76.1 134079.doc -80- 200916458 58 59 ~~6ί7 -~~~ 60 ~66Λ '-- 61 .~3Ζ6~~~-- 62 ~~ ~~ 63 -- 64 81.5 ' 65 UA--

以引用的方式併入 、公開之專利申請案及其 之方式明確併入本文中。 因此，本文所引用之所有專利 他文獻的全部内容係以全文引用 等效物 〜、λ項技術者將認識到或能夠僅僅使用常規實驗來確 疋文所述之特定程序的諸多等效物。認為該等等效物係 在本發明之範嘴内且由以下中請專利範圍所覆蓋。在整個 申叫案中所引用之所有參考文獻、頒予之專利及公開之 專利申π案的内容係以引入的方式併入本文中。 134079.doc -81 -The patent application, which is hereby incorporated by reference, is hereby incorporated by reference in its entirety in its entirety herein in Therefore, all patents cited herein are hereby incorporated by reference in their entirety in their entirety in the the the the the the Such equivalents are considered to be within the scope of the invention and are covered by the scope of the following patents. The contents of all of the references, issued patents, and published patent applications are hereby incorporated by reference in their entirety. 134079.doc -81 -

Claims (1)

200916458 十、申請專利範圍： 1. 一種式I化合物200916458 X. Patent application scope: 1. A compound of formula I 其中 以下組成之群：氫、c丨 Ri、R2及&amp;各獨立地選自由 烧基及函素； R4選自由以下組成之群：冀 本. K6烷基、鹵基c,_6烷基及鹵 素， 各W獨立地選自由以下組成之群：cR5m〇 及S’其中r5選自由以下組成之群：氫、C4氧基、一 烧乳基基、C1.6絲基幾基、基、脉基、酿 胺基H Cl·6院基録1基、㈣胺基、〜環院 基、氰基、齒基cN6院基、㈣、雜環基、雜環基院 基、經基、羥基Cl4基、確基、硫化物、亞項酿基、 續醯胺基及續醯基，或 2個相鄰W原子可與其Rs取代基一起形成稠合之第二 環，其中該第二環視需要經一或多個&amp;取代基取代且係 選自由以下組成之群：芳基、CM環烷基、5或6員雜芳 基，及5或6員雜環基； 至少一個W為N ; 134079.doc 200916458 q為0或1，其中 —相鄰W原子與其⑽代基一 第二環，則該等相鄰工 山 又裯合之 環基，及專相❹原子之-為N且該第二環為6員雜 若#0且該等W原子構成之該環為2_味唾基，則 為未經取代之苯環； 5 a選自由以下組成之群，、NR6、N、aaS; R6選自由以下組成之群：氫、Ci-6烷氧基、c〗_6烷氧基 16烧基Ci _6院氧基緩基、Cu烧基、脉基、醯胺基、 胺基、Cl_6烷基羰I、芳&amp;、羧醯胺·&amp;、c3_8環烷基、氰 基、鹵基C〗—6烷基、_素、雜環基、雜環基ci 6烷基、雜 %基(^_6烷氧基、羥基、羥基C1_6烷基、硝基、亞磺醯 基、硫化物、磺醯胺基及磺醯基，或 2個相鄰A原子可與其R6取代基一起形成稠合之第二 環，其中該第二環為5或6員雜環基； 至少一個A選自由以下組成之群：Nr6、n、Ο及S ; P為0或1，其中 若p為0且R,、R2及只4各為曱基，則A不為S ; 其中該式Η匕合物不為The group consisting of: hydrogen, c丨Ri, R2, and &amp; each independently selected from the group consisting of an alkyl group and a aryl group; and R4 is selected from the group consisting of 冀本. K6 alkyl, halo c, _6 alkyl and Halogen, each W is independently selected from the group consisting of cR5m〇 and S', wherein r5 is selected from the group consisting of hydrogen, C4 oxy, a calcined base, C1.6 selyl, yl, mai. Base, enriched amine H Cl · 6 base record 1 base, (tetra) amine group, ~ ring hospital base, cyano group, dentate cN6 yard base, (d), heterocyclic group, heterocyclic group, base group, hydroxyl group Cl4 a base, a sulphide, a sulfide, a sub-further, a hydrazine, and a hydrazine, or two adjacent W atoms, together with its Rs substituent, form a fused second ring, wherein the second ring One or more &amp; substituents are substituted and selected from the group consisting of aryl, CM cycloalkyl, 5 or 6 membered heteroaryl, and 5 or 6 membered heterocyclic; at least one W is N; 134079 .doc 200916458 q is 0 or 1, where - adjacent W atoms and their (10) bases and a second ring, then the adjacent ring of the adjacent mountain, and the exclusive phase of the atom - N and The second ring is 6 members heterozygous #0 and the W atoms constitute the ring 2 is a non-substituted benzene ring; 5 a is selected from the group consisting of NR6, N, aAS R6 is selected from the group consisting of hydrogen, Ci-6 alkoxy, c _6 alkoxy 16 alkyl Ci_6 alkoxy slow-base, Cu alkyl, sulfhydryl, amidino, amine, Cl_6 Alkylcarbonyl I, aryl &amp;, carboxamide, &amp; c3_8 cycloalkyl, cyano, halo C-6 alkyl, _ s, heterocyclyl, heterocyclyl ci 6 alkyl, heteropoly (^_6 alkoxy, hydroxy, hydroxy C1_6 alkyl, nitro, sulfinyl, sulfide, sulfonylamino and sulfonyl, or two adjacent A atoms may form a thick base with their R6 substituent And a second ring, wherein the second ring is a 5- or 6-membered heterocyclic group; at least one A is selected from the group consisting of Nr6, n, Ο, and S; P is 0 or 1, wherein if p is 0 and R, R2 and only 4 are each a fluorenyl group, then A is not S; wherein the compound is not 134079.doc 200916458134079.doc 200916458 群’且若L為NH CH ； ’其中L選自由NH及CH組成之 則Μ為CH2 ’且若l為CH，則Μ為 及其醫藥學上可接受之鹽 2. —種式II化合物： RGroup ' and if L is NH CH ; ' wherein L is selected from the group consisting of NH and CH, then Μ is CH 2 ' and if l is CH, then Μ is a pharmaceutically acceptable salt thereof. - a compound of formula II: R 其中，among them, Α選自由Ν及CR10組成之群； X選自由以下組成之群：函素及Ci 6烷基； γ選自由以下組成之群：NRs、0及3，例如NRs&amp;s; 各Rs獨立地選自由以下組成之群：氫、Ci6烷基及羥 基C 1 · 6烧基； I選自由以下組成之群：氫、鹵素、氰基、c丨-6烷 基、C,·6鹵烷基、胺基（例如Ci 6烷基胺基）、6烷氧 基、芳氧基、羥基、磺醯基、磺醯胺及雜環基，其中R7 可視需要經一或多個Rh取代； 134079.doc 200916458 R8、R9及R丨〇各獨立地選自由以下組成之群：氫、C :基、齒素、c】-6烷氧基、胺基、羥基、自烷基、氰 基、磺醯基及磺醯胺； R&quot;可選自由以下組成之群：鹵素、羥基、胺基、 烧基、c〗_6烧氧基、芳基及雜環基，笪中R 濉衣丞兵丨可視需要經 一或多個R!2取代；及 Ru可選自由以下組成之群：胺基、氰基、羥基、Ci 6 烷基、環烷基及芳基， 土 1-6 或其醫藥學上可接受之鹽。 3.如味求項2之化合物，其中該化合物具有下式：The oxime is selected from the group consisting of ruthenium and CR10; X is selected from the group consisting of: a phytosine and a Ci 6 alkyl group; γ is selected from the group consisting of NRs, 0 and 3, such as NRs &amp;s; each Rs is independently selected Free group consisting of hydrogen, Ci6 alkyl and hydroxy C 1-6 alkyl; I is selected from the group consisting of hydrogen, halogen, cyano, c丨-6 alkyl, C, ·6 haloalkyl, Amino (eg, Ci 6 alkylamino), 6 alkoxy, aryloxy, hydroxy, sulfonyl, sulfonamide, and heterocyclic, wherein R 7 may be substituted with one or more Rh as desired; 200916458 R8, R9 and R are each independently selected from the group consisting of hydrogen, C: group, dentate, c]-6 alkoxy, amine, hydroxy, self-alkyl, cyano, sulfonyl And sulfonamide; R&quot; can be selected from the following groups: halogen, hydroxyl, amine, alkyl, c _6 alkoxy, aryl and heterocyclic, 笪 R R 濉 丞 丨 丨 丨 丨Or a plurality of R!2 substitutions; and Ru may be selected from the group consisting of amine, cyano, hydroxy, Ci 6 alkyl, cycloalkyl and aryl, 1-6 or pharmaceutically acceptable Of salt. 3. The compound of claim 2, wherein the compound has the formula: 4.如晴求項2之化合物，其中R?選自由以下組成之群：2_吡 啶基甲氧基、（1-曱基-4-哌啶基）甲氧基、（3_氰基苯基）曱 氧基、[(2S)-1-曱基吡咯啶_2_基]甲氧基、[(之尺)-^甲基〇比 咯啶-2-基]曱氧基、2_二甲基胺基乙氧基、2_噻吩基、3_ 二乙基胺基丙氧基、4-(2-二曱基胺基乙基）哌嗪-丨_基、 4-(2-羥基乙基）哌嗪基、4_(2_吡啶基甲基）哌嗪_丨·基、 4-(環丙基甲基）哌嗪_丨_基、氯基、氰基、氟基、氫、異 丁氧基、嗎啉基、苯氧基、三氟甲基、4_曱基哌嗪 基、[2_(—曱基胺基）乙基]曱基胺基、（2-嗎琳-4-基乙基） 胺基、2-羥基乙基胺基、哌嗪_丨基、2_(二甲基胺基）乙基 134079.doc 200916458 胺基、[(2S)-1-乙基吡咯啶-2-基]甲基胺基、（1-曱基吡咯 °定-3-基）曱氧基、（1-曱基略咬-2-基）甲氧基）、2-嗎琳-4-基乙氧基、2-°比咯啶-1-基乙氧基、（1-甲基哌啶-3-基）甲 氧基）、（2S)-1-甲基哌啶-2-基]曱氧基、（2R)-1-甲基哌啶-2-基]曱氧基、（3S)-1-曱基哌啶-3-基]甲氧基、（3R)-1-曱 基°底咬-3-基]甲氧基、曱基及其任何組合。 5. —種式III化合物4. A compound according to claim 2, wherein R? is selected from the group consisting of: 2-pyridylmethoxy, (1-indolyl-4-piperidyl)methoxy, (3-cyanobenzene) Alkyloxy, [(2S)-1-decylpyrrolidin-2-yl]methoxy, [(尺)-^methylpyridin-2-yl]methoxy, 2_ Dimethylaminoethoxy, 2-thienyl, 3-diethylaminopropoxy, 4-(2-didecylaminoethyl)piperazine-indoleyl, 4-(2-hydroxyl Ethyl) piperazinyl, 4-(2-pyridylmethyl)piperazine-indenyl, 4-(cyclopropylmethyl)piperazine-indoleyl, chloro, cyano, fluoro, hydrogen, Isobutoxy, morpholinyl, phenoxy, trifluoromethyl, 4-mercaptopiperazinyl, [2_(-decylamino)ethyl]decylamino, (2-Merlin-4 -ylethyl)amino, 2-hydroxyethylamino, piperazine-fluorenyl, 2-(dimethylamino)ethyl 134079.doc 200916458 Amino, [(2S)-1-ethylpyrrolidine -2-yl]methylamino, (1-indolylpyrrole-3-yl)nonyloxy, (1-indolyl-2-yl)methoxy), 2-line-4 -ylethoxy, 2-pyrrolidin-1-ylethoxy, (1-methylpiperidin-3-yl)methoxy (2S)-1-methylpiperidin-2-yl]decyloxy, (2R)-1-methylpiperidin-2-yl]decyloxy, (3S)-1-indolylpiperidine- 3-yl]methoxy, (3R)-1-indenyl-3-methoxy]methoxy, thiol and any combination thereof. 5. - Compound of formula III η為 0、1、2或 3 ; Ζ為一直接鍵、NRa、S及〇，其中匕選自由以下組成 之群：H、烷基及環烷基η is 0, 1, 2 or 3; Ζ is a direct bond, NRa, S and 〇, wherein 匕 is selected from the group consisting of H, alkyl and cycloalkyl I選自由以下組成之群：氫、函素及烷基； 各R&quot;選自由以下組成之群：氫、鹵素、羥基、硫化 物、羧醯胺、C〗·6烷基羰基 氧基羰基、亞磺醯基、續酿 雜環基 、胺基、烷基、烷氧基、烷 基、氰基、環烷基、芳基或 其中各Rm視需要 經以下取代：CN6烷基羰基 赵基、經基C,·6烧基、_素、胺基、石肖基、成基、確 醯基、氰基m或雜環基，當〜所連接之^坐基環 為2-㈣基時，‘不為未經取代之苯基； 134079.doc 200916458 選自由以下組成之群. 人、砰._(ch)0-5-雜環、_fC NRbRb、-(CH)〇 5·經基、 „ ^ ^ (CH)〇-5· , (CHV5-Ci·6烷氧基、芳基及雜 環基（例如哌嗪），其中R 以Μ 规*要’H6取代’各Rb選自由 以下、、且成之群：H、院基及環院基；及 選自由以下組成之群：卤 护其^ β 基 '炫基 ;,L&quot;，、中尺丨6視需要經芳基或雜芳基取代， 或其醫藥學上可接受之鹽。 6.如請求項5之化合物，其中r . 丹TH丨4為Η、羥基C烷基或 烷基。 土叫-6 7. -種醫藥組合物’其包含一或多種如請求項…或5之 化合物與一或多種醫藥學上可接受之载劑一起調配。 8. -種^制Hedgehog路徑之方法，其包含向個體投與治療 有效量之一或多種如請求項1、2或5之化合物或如請求 項7之醫藥組合物以抑制該Hedgehog路徑。 9. 一種減少細胞增殖、分化及/或影響基質微環境調節之方 法，其包含向個體投與治療有效量之一或多種如請求項 1、2或5之化合物或如請求項7之醫藥組合物，進而在該 個體中減少細胞增殖、分化及/或影響基質微環境調節。 I 〇·如請求項9之方法，其中該細胞為基質細胞。 II ·如請求項9之方法’其中該細胞為癌細胞。 12. 如請求項9之方法，其中該細胞為幹細胞。 13. 如請求項丨2之方法，其中該幹細胞為癌幹細胞。 134079.doc 200916458 七、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式:I is selected from the group consisting of hydrogen, a hydroxyl, and an alkyl group; each R&quot; is selected from the group consisting of hydrogen, halogen, hydroxyl, sulfide, carboxamide, C -6 alkylcarbonyloxycarbonyl, Sulfosyl, styrene, amino, alkyl, alkoxy, alkyl, cyano, cycloalkyl, aryl or each of the Rm thereof may be substituted as follows: CN6 alkylcarbonyl Zhaoji, By a group C, ·6 alkyl, _, an amine, a succinyl group, a thiol group, a decyl group, a cyano group or a heterocyclic group, when the attached ring is a 2-(tetra) group, 'no Is an unsubstituted phenyl group; 134079.doc 200916458 is selected from the group consisting of: human, 砰._(ch)0-5-heterocycle, _fC NRbRb, -(CH)〇5·ion group, „ ^ ^ (CH)〇-5· , (CHV5-Ci.6 alkoxy, aryl and heterocyclic (e.g. piperazine), wherein R is substituted by 'H6'. Each Rb is selected from the following, and Group: H, yard base and ring yard base; and selected from the group consisting of: halogen protecting its ^ β-based 'Hyun base;, L&quot;,, medium-sized crucible 6 as needed to be replaced by aryl or heteroaryl, Or a pharmaceutically acceptable salt thereof 6. The compound of claim 5, wherein r. Dan TH丨4 is hydrazine, hydroxy C alkyl or alkyl. Soil is -6 7. A pharmaceutical composition 'which contains one or more of the claims... or Compound of 5 is formulated with one or more pharmaceutically acceptable carriers. 8. A method of producing a Hedgehog pathway comprising administering to a subject one or more therapeutically effective amounts as claimed in claim 1, 2 or 5 a compound or a pharmaceutical composition according to claim 7 for inhibiting the Hedgehog pathway. 9. A method of reducing cell proliferation, differentiation and/or affecting regulation of a matrix microenvironment comprising administering to a subject one or more of a therapeutically effective amount A compound of claim 1, 2 or 5, or a pharmaceutical composition according to claim 7, which in turn reduces cell proliferation, differentiation and/or affects matrix microenvironment regulation in the individual. I. The method of claim 9, wherein The cell is a stromal cell. II. The method of claim 9, wherein the cell is a cancer cell. 12. The method of claim 9, wherein the cell is a stem cell. 13. The method of claim 2, wherein the stem cell is Cancer stem cells. 134079.doc 2 00916458 VII. Designation of representative drawings: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 134079.doc134079.doc
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